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WO2025133252A1 - Immunoglobulin single variable domains targeting ceacam5 - Google Patents

Immunoglobulin single variable domains targeting ceacam5 Download PDF

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Publication number
WO2025133252A1
WO2025133252A1 PCT/EP2024/088111 EP2024088111W WO2025133252A1 WO 2025133252 A1 WO2025133252 A1 WO 2025133252A1 EP 2024088111 W EP2024088111 W EP 2024088111W WO 2025133252 A1 WO2025133252 A1 WO 2025133252A1
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WO
WIPO (PCT)
Prior art keywords
amino acid
seq
acid sequence
isvd
ceacam5
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2024/088111
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French (fr)
Inventor
Björn NIEBEL
Evelyn De Tavernier
Emmanuelle Vigne
Anand Kumar
Alexey RAK
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Ablynx NV
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Ablynx NV
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Publication of WO2025133252A1 publication Critical patent/WO2025133252A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3007—Carcino-embryonic Antigens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/22—Immunoglobulins specific features characterized by taxonomic origin from camelids, e.g. camel, llama or dromedary
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/35—Valency
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Definitions

  • Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5, also known as CEA) has an N-terminal IgV-like domain followed by six IgC-like domains and normally functions as an adhesion molecule but it also has roles in regulating differentiation, immune modulation, and inhibiting anoikis (Thomas J. et al., “CEACAMS 1, 5, and 6 in disease and cancer: interactions with pathogens”, Genes Cancer, 2023, 14:12-29).
  • antibodies targeting the A1B1 domains shared by CEACAM5 and CEACAM6 were shown to affect cell migration, cell invasion, and cell adhesion and affect metastasis and host survival (Blumenthal R.D., Hansen H. J, Goldenberg D.M., “Inhibition of adhesion, invasion, and metastasis by antibodies targeting CEACAM6 (NCA-90) and CEACAM5 (Carcinoembryonic Antigen)”, Cancer Res 1 October 2005; 65 (19): 8809–8817).
  • the immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein ⁇ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 9; ⁇ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 10; and ⁇ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 11; or ⁇ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 234; ⁇ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 235; and ⁇ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 236.
  • the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NOs: 115-117, 160-170.
  • the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NOs: 115-117, 160-170.
  • the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of GLTFSTYTXG (SEQ ID NO: 333), wherein the amino acid residue X is selected from V or M; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GLTFSTYTXG (SEQ ID NO: 333), wherein the amino acid residue X is selected from V or M; c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences GLTFSTYTXG (SEQ ID NO: 333), wherein the amino acid residue X is selected from V or M; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SX1IX2SGS
  • the immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein ⁇ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ⁇ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 336; and ⁇ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 339; or ⁇ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 334; ⁇ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 337; and ⁇ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 340.
  • the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NOs: 118-119, 171-174.
  • the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NOs: 118-119, 171-174.
  • the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTFSDXAMG (SEQ ID NO: 356), wherein the amino acid residue X is selected from F or Y; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTFSDXAMG (SEQ ID NO: 356), wherein the amino acid residue X is selected from F or Y; c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTFSDXAMG (SEQ ID NO: 356), wherein the amino acid residue X is selected from F or Y; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AINWSGGWTY (SEQ ID NO:
  • the immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein ⁇ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 359; ⁇ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 357; and ⁇ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 360; or ⁇ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 234; ⁇ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 357; and ⁇ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 361.
  • the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NOs: 122 or 123.
  • the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NOs: 122 or 123.
  • the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTFNINEYHLA (SEQ ID NO: 363); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTFNINEYHLA (SEQ ID NO: 363); c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTFNINEYHLA (SEQ ID NO: 363); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AIWWSTGNKI (SEQ ID NO: 364); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AIWWSTGNKI (SEQ ID NO: 364); c ) amino acid
  • the immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein ⁇ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 363; ⁇ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 364; and ⁇ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 365.
  • the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NO: 124.
  • the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NO: 124.
  • the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AIWWSTGNRI (SEQ ID NO: 369); b) amino acid sequences that have at least 80%
  • the immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein ⁇ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 368; ⁇ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 369; and ⁇ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 370.
  • the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NO: 125.
  • the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NO: 125.
  • the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of GDXLNSYHMA (SEQ ID NO: 373), wherein the amino acid residue X is selected from T or N; b ) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GDXLNSYHMA (SEQ ID NO: 373), wherein the amino acid residue X is selected from T or N; c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of GDXLNSYHMA (SEQ ID NO: 373), wherein the amino acid residue X is selected from T or N; and -
  • the immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein ⁇ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 376; ⁇ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 377; and ⁇ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 365; or ⁇ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 378; ⁇ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 379; and ⁇ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 380.
  • the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NOs: 126 or 127.
  • the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NOs: 126 or 127.
  • the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GX1TFSX2YAMG (SEQ ID NO: 386), wherein the amino acid residue X1 is selected from G or R, and wherein the amino acid residue X2 is selected from S or N; b ) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GX 1 TFSX 2 YAMG (SEQ ID NO: 386), wherein the amino acid residue X 1 is selected from G or R, and wherein the amino acid residue X2 is selected from S or N; c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences GX1TFSX2YAMG (SEQ ID NO: 386), wherein the amino acid residue X1 is selected
  • the immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein ⁇ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 389; ⁇ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 387; and ⁇ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 390; or ⁇ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 391; ⁇ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 387; and ⁇ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 392.
  • the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NOs: 128, 129, or 134.
  • the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NOs: 128, 129, or 134.
  • the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GGTVSTYTMG (SEQ ID NO: 397); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GGTVSTYTMG (SEQ ID NO: 397); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GGTVSTYTMG (SEQ ID NO: 397); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence SIIWSGSTTV (SEQ ID NO: 398); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence SIIWSGSTTV (SEQ ID NO: 398); c ) amino acid sequences that have
  • the immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein ⁇ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 397; ⁇ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 398; and ⁇ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 399.
  • the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NOs: 130.
  • the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NOs: 130.
  • the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AIWWSTGNTI (SEQ ID NO: 379); b) amino acid sequences that have at least 80%
  • the immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein ⁇ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 368; ⁇ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 379; and ⁇ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 365.
  • the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NO: 131.
  • the immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: ⁇ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ⁇ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 336; and ⁇ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 339, or ⁇ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 334; ⁇ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 337; and ⁇ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 340; or ⁇ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ⁇ CDR2 (AbM numbering) consists of
  • the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NOs: 8, 31, 32, 118-119, 130, 150-159, 171- 174.
  • the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NOs: 8, 31, 32, 118-119, 130, 150-159, 171-174.
  • the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from a) the amino acid sequence GRTFDNX1AMG (SEQ ID NO: 593); wherein the amino acid residue X1 is selected from H, L or E; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTFDNX1AMG (SEQ ID NO: 593); wherein the amino acid residue X1 is selected from H, L or E; c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTFDNX1AMG (SEQ ID NO: 593); wherein the amino acid residue X1 is selected from H, L or E; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTFDN
  • the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 610; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 610; c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 610.
  • the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from a) the amino acid sequence GFTFSSYDMS (SEQ ID NO: 611); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GFTFSSYDMS (SEQ ID NO: 611); c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GFTFSSYDMS (SEQ ID NO: 611); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence TINRGGSSTS (SEQ ID NO: 612); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GTINRGGSSTS (SEQ ID NO: 612); c ) amino
  • the immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: ⁇ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 611; ⁇ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 612; and ⁇ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 610.
  • the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NOs: 547, 549-563.
  • the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NOs: 547, 549-563.
  • the immunoglobulin single variable domain of the present technology may essentially consist of a VHH, such as a humanized VHH, or a VH, such as a camelized VH, a human VH, a camelized human VH, a domain antibody, a single domain antibody, and/or a dAb.
  • the present technology also relates to polypeptides and constructs comprising such immunoglobulin single variable domain, and optionally further comprising one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers.
  • the immunoglobulin single variable domains of the present technology and polypeptides and constructs comprising said immunoglobulin single variable domains showed a high binding affinity in FACS binding assay on and a high internalization efficacy in FACS internalization assay of BxPC-3 cell line expressing CEACAM5, and could be efficiently produced (e.g., in microbial hosts such as Pichia, e.g., P. pastoris, or in E. coli).
  • the immunoglobulin single variable domain, polypeptide or construct of the present technology may further comprise one or more other groups, residues, moieties or binding units, optionally linked via one or more peptidic linkers, in which said one or more other groups, residues, moieties or binding units provide the ISVD, polypeptide or construct with increased half- life, compared to the corresponding ISVD, polypeptide or construct without said one or more other groups, residues, moieties or binding units.
  • Said one or more other groups, residues, moieties or binding units that provide the ISVD, polypeptide or construct with increased half-life may be chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that can bind to serum proteins, an Fc portion, and small proteins or peptides that can bind to serum proteins.
  • the binding units that provide the ISVD, polypeptide or construct with increased half-life may be chosen from the group consisting of binding units that can bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG), e.g., human serum albumin.
  • the binding unit that can bind to serum albumin is an ISVD.
  • the ISVD binding to human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which CDR1 is SEQ ID NO: 80, CDR2 is SEQ ID NO: 81, CDR3 is SEQ ID NO: 82.
  • the ISVD binding to human serum albumin comprises a sequence identity of more than 90% (such as 95%) with SEQ ID NO: 62.
  • the ISVD binding to human serum albumin comprises or consists of the amino acid sequence of SEQ ID NO: 62.
  • the ISVD binding to human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 47), ALB23 (SEQ ID NO: 48), ALBX00001 (SEQ ID NO: 61) and ALB23002 (SEQ ID NO: 62).
  • the ISVD binding to human serum albumin is ALB23002 (SEQ ID NO: 62).
  • a nucleic acid molecule capable of expressing the immunoglobulin single variable domain or polypeptide of the present technology a vector comprising the nucleic acid, and a composition comprising the polypeptide, nucleic acid or vector.
  • a (non-human) host or host cell comprising such a nucleic acid.
  • the composition can be a pharmaceutical composition which further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and optionally comprises one or more further pharmaceutically active polypeptides and/or compounds.
  • the immunoglobulin single variable domain, polypeptide or construct of the present technology, a composition comprising the immunoglobulin single variable domain, polypeptide or construct, and a composition comprising a nucleic acid comprising a nucleotide sequence that encodes the immunoglobulin single variable domain or polypeptide can be used as a medicament.
  • the immunoglobulin single variable domain, polypeptide, construct or composition of the present technology can be used in the treatment.
  • the immunoglobulin single variable, polypeptide, construct or composition can be used in the treatment of cancer. Accordingly, the present technology also encompasses a method of treating cancer. In some embodiments, the present technology encompasses a method of treating cancer, wherein said method comprises administering, to a subject in need thereof, a pharmaceutically active amount of an immunoglobulin single variable domain, polypeptide or construct of the present technology, a nucleic acid encoding an ISVD or polypeptide of the present technology or a composition comprising the same. Accordingly, the present technology also encompasses the use of an immunoglobulin single domain, polypeptide or construct of the present technology in the preparation of a pharmaceutical composition for treating cancer.
  • Figure 2 Quality check of unpurified VHH-HA-His produced in FreeStyle 293-F cells with SDS-PAGE. Following clones are shown: line 1: 14R04-02 ; line 2 : 14R04-03 ; line 3 : 14R04-04; line 4: 14R04- 05; line 5: 14R04-06; line 6: 14R04-07; line 7: 14R04-08; line 8: 14R04-09; line 9: 14R04-10; line 10: 14R04-11; line 11: 14R04-12; line 12: 14R04-13; line 13: 14R04-14; line 14: 14R04-15; line 15: 14R04-16; line 16: 14R04-17; line 17: 14R04-18; line 18: 14R04-19; line 19: 14R04-20; line 20: 14R04-21; line 21: 14R04-22.
  • Figure 3A and 3B EC50 determination of anti-CEACAM5 VHHs by ELISA on hCEACAM5 and cCEACAM5.
  • the ELISA assay was conducted with serial dilutions of non-purified VHHs produced in FreeStyle 293-F cells.
  • Figure 4A and 4B Evaluation of the affinity constant (KD) and maximum binding capacity (Bmax) to MKN45 cell line by flow cytometry.
  • the FACS assay was conducted with serial dilutions of non- purified VHHs produced in FreeStyle 293-F cells.
  • Figure 5 EC50 determination of anti-CEACAM5 VHHs by ELISA on (A) hCEACAM5 and (B) hCEACAM6.
  • Figure 6 Characterization by flow cytometry of the binding of anti-CEACAM5 VHHs on LS174T cells.
  • Figure 7a and 7b Evaluation of the internalization of VHHs on LS174T cell line. The ISVD applied to the cell line are indicated in the legend. pHrhodo: only the pHrhodo anti-Flag antibody was applied; IRR: an ISVD not binding to CEACAM5 was applied to the cell line.
  • Figure 8 Detailed views of interactions between the A2-B2 domains of hCEACAM5 and ISVD T232000134.
  • Figure 9 Detailed views of interactions between the A2-B2 domains of hCEACAM5 and ISVD 2G08.
  • A Epitope-paratope key interacting residues between the A2-B2 domains of hCEACAM5 and 2G08, dotted line represents H-bond interactions (dark gray). The residues from ISVD 2G08 are indicated with “VHH”.
  • B Key interacting residues of paratope located at ⁇ 3.8 ⁇ distance from the hCEACAM5, backbone is in brown, and residues are shown with side chains in Yellow.
  • C Key interacting residues of epitope located at ⁇ 3.8 ⁇ distance from IVSD 2G08, interacting residues are shown in colored in light see brown. 5 Detailed description of the present technology 5.1 Definitions Unless indicated or defined otherwise, all terms used have their usual meaning in the art, which will be clear to the skilled person.
  • sequence as used herein (for example in terms like “immunoglobulin sequence”, “antibody sequence”, “variable domain sequence”, “VHH sequence” or “protein sequence”), should generally be understood to include both the relevant amino acid sequence as well as nucleic acids or nucleotide sequences encoding the same, unless the context requires a more limited interpretation. Amino acid residues will be indicated according to the standard three-letter or one-letter amino acid code. Reference is made to Table A-2 on page 48 of WO 08/020079.
  • a nucleic acid or amino acid is considered to be “(in) (essentially) isolated (form)” - for example, compared to the reaction medium or cultivation medium from which it has been obtained - when it has been separated from at least one other component with which it is usually associated in said source or medium, such as another nucleic acid, another protein/polypeptide, another biological component or macromolecule or at least one contaminant, impurity or minor component.
  • a nucleic acid or amino acid is considered “(essentially) isolated” when it has been purified at least 2-fold, in particular at least 10-fold, more in particular at least 100-fold, and up to 1000-fold or more.
  • a nucleic acid or amino acid that is “in (essentially) isolated form” is preferably essentially homogeneous, as determined using a suitable technique, such as a suitable chromatographical technique, such as polyacrylamide-gel electrophoresis.
  • a suitable technique such as a suitable chromatographical technique, such as polyacrylamide-gel electrophoresis.
  • this may mean that the latter nucleotide sequence or amino acid sequence has been incorporated into the first mentioned nucleotide sequence or amino acid sequence, respectively, but more usually this generally means that the first mentioned nucleotide sequence or amino acid sequence comprises within its sequence a stretch of nucleotides or amino acid residues, respectively, that has the same nucleotide sequence or amino acid sequence, respectively, as the latter sequence, irrespective of how the first mentioned sequence has actually been generated or obtained (which may for example be by any suitable method described herein).
  • a polypeptide when said polypeptide is said to comprise an immunoglobulin single variable domain, this may mean that said immunoglobulin single variable domain sequence has been incorporated into the sequence of the polypeptide, but more usually this generally means that the polypeptide contains within its sequence the sequence of the immunoglobulin single variable domains irrespective of how said polypeptide has been generated or obtained.
  • the first mentioned nucleic acid or nucleotide sequence is preferably such that, when it is expressed into an expression product (e.g., a polypeptide), the amino acid sequence encoded by the latter nucleotide sequence forms part of said expression product (in other words, that the latter nucleotide sequence is in the same reading frame as the first mentioned, larger nucleic acid or nucleotide sequence).
  • an expression product e.g., a polypeptide
  • the later nucleic acid sequence or amino acid sequence either is exactly the same as the polypeptide (e.g., the CDR region; the ISVD) or corresponds to the polypeptide (e.g., the CDR region; the ISVD) which has a limited number of amino acid residues, such as 1-20 amino acid residues, for example 1-10 amino acid residues and preferably 1-6 amino acid residues, such as 1, 2, 3, 4, 5 or 6 amino acid residues, added at the amino terminal end, at the carboxy terminal end, or at both the amino terminal end and the carboxy terminal end of the immunoglobulin single variable domain.
  • the percentage of “sequence identity” between a first amino acid sequence and a second amino acid sequence may be calculated by dividing [the number of amino acid residues in the first amino acid sequence that are identical to the amino acid residues at the corresponding positions in the second amino acid sequence] by [the total number of amino acid residues in the first amino acid sequence] and multiplying by [100%], in which each deletion, insertion, substitution or addition of an amino acid residue in the second amino acid sequence - compared to the first amino acid sequence - is considered as a difference at a single amino acid residue (i.e., at a single position).
  • amino acid sequence identity a sequence identity between two amino acid sequences in accordance with the calculation method outlined hereinabove
  • amino acid sequence with the greatest number of amino acid residues will be taken as the “first” amino acid sequence
  • amino acid sequence with the greatest number of amino acid residues will be taken as the “second” amino acid sequence.
  • amino acid difference refers to a deletion, insertion or substitution of a single amino acid residue vis-à-vis a reference sequence.
  • an “amino acid difference” is a substitution.
  • amino acid substitutions are conservative substitutions.
  • Such conservative substitutions are substitutions in which one amino acid within the following groups (a) – (e) is substituted by another amino acid residue within the same group: (a) small aliphatic, nonpolar or slightly polar residues: Ala, Ser, Thr, Pro and Gly; (b) polar, negatively charged residues and their (uncharged) amides: Asp, Asn, Glu and Gln; (c) polar, positively charged residues: His, Arg and Lys; (d) large aliphatic, nonpolar residues: Met, Leu, Ile, Val and Cys; and (e) aromatic residues: Phe, Tyr and Trp.
  • conservative substitutions are as follows: Ala into Gly or into Ser; Arg into Lys; Asn into Gln or into His; Asp into Glu; Cys into Ser; Gln into Asn; Glu into Asp; Gly into Ala or into Pro; His into Asn or into Gln; Ile into Leu or into Val; Leu into Ile or into Val; Lys into Arg, into Gln or into Glu; Met into Leu, into Tyr or into Ile; Phe into Met, into Leu or into Tyr; Ser into Thr; Thr into Ser; Trp into Tyr; Tyr into Trp; and/or Phe into Val, into Ile or into Leu.
  • aliphatic index refers to the relative volume occupied by aliphatic side chains (alanine, valine, isoleucine, and leucine)-
  • the “GRAVY value” (grand average of hydropathicity value), as used herein, is calculated as the sum of hydropathy value of all the amino acids, divided by the number of residues in the sequence (Kyte, J. "A simple method for displaying the hydropathic character of a protein.” J. Mol. Biol.268 (1993): 10558-10563).
  • VHH family refers to a group of VHH sequences that have identical lengths (i.e., they have the same number of amino acids within their sequence) and of which the amino acid sequence between position 8 and position 106 (according to Kabat numbering) has an amino acid sequence identity of 89% or more.
  • epitopope and antigenic determinant refer to the part of a macromolecule, such as a polypeptide or protein that is recognized by antigen-binding molecules, such as immunoglobulins, conventional antibodies, or immunoglobulin single variable domains, and more particularly by the antigen-binding site of said molecules.
  • Epitopes define the minimum binding site for an immunoglobulin, and thus represent the target of specificity of an immunoglobulin.
  • the part of an antigen-binding molecule (such as an immunoglobulin, a conventional antibody, an immunoglobulin single variable domain) that recognizes the epitope is called a “paratope”.
  • a polypeptide such as an immunoglobulin, an antibody, an immunoglobulin single variable domain, or generally an antigen binding molecule or a fragment thereof
  • a polypeptide that can “bind to” or “specifically bind to”, that “has affinity for” and/or that “has specificity for” a certain epitope, antigen or protein (or for at least one part, fragment or epitope thereof) is said to be "against” or “directed against” said epitope, antigen or protein or is a “binding” molecule with respect to such epitope, antigen or protein, or is said to be “anti”-epitope, “anti”-antigen or “anti”-protein (e.g., “anti”- CEACAM5).
  • binding specifically refers to the number of different target molecules, such as antigens, from the same organism to which a particular binding unit, such as an ISVD, can bind with sufficiently high affinity (see below). “Specificity”, “binding specifically” or “specific binding” are used interchangeably herein with “selectivity”, “binding selectively” or “selective binding”. Binding units, such as ISVDs, specifically bind to their designated targets. The specificity/selectivity of a binding unit can be determined based on affinity. The affinity denotes the strength or stability of a molecular interaction. The affinity is commonly given by the KD, or dissociation constant, which has units of mol/liter (or M).
  • the affinity can also be expressed as an association constant, KA, which equals 1/KD and has units of (mol/liter) -1 (or M -1 ).
  • the affinity is a measure for the binding strength between a moiety and a binding site on the target molecule: the lower the value of the KD, the stronger the binding strength between a target molecule and a targeting moiety.
  • binding units used in the present technology will bind to their targets with a dissociation constant (KD) of 10 -5 to 10 -12 moles/liter or less, 10 -7 to 10 -12 moles/liter or less, or 10 -8 to 10 -12 moles/liter (i.e., with an association constant (KA) of 10 5 to 10 12 liter/moles or more, 10 7 to 10 12 liter/moles or more, or 10 8 to 10 12 liter/moles).
  • KD dissociation constant
  • KA association constant
  • Any KD value greater than 10 -4 mol/liter (or any KA value lower than 10 4 liters/mol) is generally considered to indicate non-specific binding.
  • the KD for biological interactions such as the binding of immunoglobulin sequences to an antigen, which are considered specific are typically in the range of 10 -5 moles/liter (10000 nM or 10 ⁇ M) to 10 -12 moles/liter (0.001 nM or 1 pM) or less. Accordingly, specific/selective binding may mean that -using the same measurement method, e.g., SPR- a binding unit (or polypeptide comprising the same) binds to CEACAM5 with a KD value of 10- 5 to 10 -12 moles/liter or less and binds to related CEACAMs members with a KD value greater than 10 -4 moles/liter.
  • CEACAM1 An example of a related CEACAMs member is CEACAM1, CEACAM6, CEACAM7 and CEACAM8.
  • the ISVD binds to (human) CEACAM5 with a KD value of 10 -5 to 10 -12 moles/liter or less and binds to CEACAM1, CEACAM6, CEACAM7 or CEACAM8 of the same species with a KD value greater than 10 -4 moles/liter.
  • Specific binding to a certain target from a certain species does not exclude that the binding unit can also specifically bind to the analogous target from a different species.
  • binding unit or a polypeptide comprising the same can also specifically bind to CEACAM5 from cynomolgus monkeys (“cyno”).
  • Specific binding of a binding unit to its designated target can be determined in any suitable manner known per se, including, for example, Scatchard analysis and/or competitive binding assays, such as radioimmunoassays (RIA), enzyme immunoassays (EIA) and sandwich competition assays, and the different variants thereof known per se in the art; as well as the other techniques mentioned further herein.
  • the dissociation constant may be the actual or apparent dissociation constant, as will be clear to the skilled person.
  • An amino acid sequence is said to be “cross-reactive” for two different antigens or antigenic determinants (such as e.g., serum albumin from two different species of mammal, such as e.g., human serum albumin and cyno serum albumin, such as e.g., CEACAM5 from different species of mammal, such as e.g., human CEACAM5, cyno CEACAM5 and mouse CEACAM5) if it is specific for (as defined herein) these different antigens or antigenic determinants.
  • serum albumin from two different species of mammal
  • cyno serum albumin such as e.g., CEACAM5 from different species of mammal, such as e.g., human CEACAM5, cyno CEACAM5 and mouse CEACAM5
  • block is used interchangeably herein to mean the ability of an immunoglobulin, antibody, immunoglobulin single variable domain, polypeptide or other binding agent to interfere with the binding of another protein, polypeptides, ligand or binding agent to a given target.
  • the extent to which an immunoglobulin, antibody, immunoglobulin single variable domain, polypeptide or other binding agent is able to interfere with the binding of another ligand to the target, and therefore whether it can be said to “block”, can be determined using competition binding assays.
  • FACS fluorescence-activated cell sorting
  • a FACS competition experiment can be performed using cells (such as, e.g., Flp-InTM-293 cells) overexpressing human CEACAM5 and the parental cells as background cell line.
  • Different detection reagents can be used including, e.g., monoclonal ANTI-FLAG® M2 antibody (Sigma- Aldrich, cat# F1804), monoclonal anti-C-myc antibody (Sigma-Aldrich, cat# WH0004609M2), monoclonal ANTI-HIS TAG antibody (Sigma-Aldrich, cat# SAB1305538), each labeled differently.
  • fluorophores can be used as labels in flow cytometry (such as, e.g., PE (R- Phycoerythrin), 7-aminoactinomycin D (7-AAD), Acridine Orange, various forms of Alexa Fluor, Allophycocyanin (APC), AmCyan, Aminocoumarin, APC Cy5, APC Cy7, APC-H7, APC/Alexa Fluor 750, AsRed2, Azami-Green, Azurite, B ODIPY FL C5-ceramide, BCECF-AM, Bis-oxonol DiBAC2(3), BODIPY- FL, Calcein, Calcein AM, Caroxy-H2DCFDA, Cascade Blue, Cascade Yellow, Cell Tracker Green, Cerulean, CFSE, Chromomycin A3, CM-H2DCFDA, Cy2, Cy3, Cy3.5, Cy3B, Cy5, Cy5.5, Cy7, CyPet, DAF-FM DAF-FM dia
  • Fluorophores are typically attached to the antibody (e.g., the immunoglobulin single variable domain) that recognizes CEACAM5 or to the antibody that is used as detection reagent.
  • Various conjugated antibodies are available, such as (without being limiting) for example antibodies conjugated to Alexa Fluor®, DyLight®, Rhodamine, PE, FITC, and Cy3.
  • Alexa Fluor® conjugated to Alexa Fluor®
  • DyLight® Rhodamine
  • PE FITC
  • Cy3 Cy3
  • Each fluorophore has a characteristic peak excitation and emission wavelength.
  • the combination of labels which can be used will depend on the wavelength of the lamp(s) or laser(s) used to excite the fluorophore and on the detectors available.
  • binding agent B* a dilution series of cold (without any label) binding agent A is added to (e.g., 200000) cells together with the labeled binding agent B*.
  • concentration of binding agent B* in the test mix should be high enough to readily saturate the binding sites on CEACAM5 expressed on the cells.
  • concentration of binding agent B* that saturates the binding sites for that binding agent on CEACAM5 expressed on the cells can be determined with a titration series of binding agent B* on the CEACAM5 cells and determination of the EC50 value for binding.
  • binding agent B* can be used at 100x the EC50 concentration.
  • a reduction of fluorescence for the cells incubated with the mixture of binding agent A and B* compared to the fluorescence for the cells incubated with the separate solution of binding agent B* indicates that binding agent A blocks binding by binding agent B* to CEACAM5 expressed on the cells.
  • a cross-blocking immunoglobulin, antibody, immunoglobulin single variable domain, polypeptide or other binding agent is one which will bind to the CEACAM5 in the above competition FACS such that during the assay and in the presence of the second binding agent the recorded fluorescence is between 80% and 0.1% (e.g., 80% to 4%) of the maximum fluorescence (measured for the separate labelled immunoglobulin, antibody, immunoglobulin single variable domain, polypeptide or other binding agent), specifically between 75% and 0.1% (e.g., 75% to 4%) of the maximum fluorescence, and more specifically between 70% and 0.1% (e.g., 70% to 4%) of maximum fluorescence (as just defined above).
  • the competition between two test binding agents (termed A* and B*) for binding to CEACAM5 can also be evaluated by adding both binding agents, each labeled with a different fluorophore, to the CEACAM5 expressing cells. After incubation and cells wash, read out can be performed on a FACS. A gate is set for each fluorophore and the total amount of channel fluorescence is recorded. Reduction and/or absence of fluorescence of one of the fluorophores indicates blocking by the binding agents for binding to CEACAM5 expressed on the cells.
  • Cell culture-based potency assays are often the preferred format for determining biological activity since they measure the physiological response elicited by the agent and can generate results within a relatively short period of time.
  • Various types of cell-based assays based on the mechanism of action of the product, can be used, such as e.g., in a FACS assay analysing the binding of the immunoglobulin single variable domains of the present technology to human CEACAM5 expressed on BxPC-3 cells, which is a human pancreatic adenocarcinoma cell line (as further described in the Example section).
  • the “efficacy” of an agent such as an ISVD or polypeptide, measures the maximum strength of the effect itself, at saturating agent concentrations.
  • Efficacy indicates the maximum response achievable from the agent. It refers to the ability of the agent to produce the desired (therapeutic) effect.
  • the efficacy of an agent can be evaluated using in vitro functional assays or in vivo models.
  • 5.2 Immunoglobulin single variable domains The present technology aims at providing a novel type of drug for treating diseases associated with CEACAM5.
  • an immunoglobulin single variable domain comprising a CDR1 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO:1 ; a CDR2 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 2 (AbM); and a CDR3 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 230, or an immunoglobulin single variable domain comprising a CDR1 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 231; a CDR2 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 232; and a CDR3 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 233; or an immunoglobulin single variable domain comprising a CDR1 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 242; a CDR2 (AbM numbering) consisting of the amino acid sequence of SEQ
  • immunoglobulin single variable domains are highly specific for CEACAM5 and do not bind related CEACAM family members. They are thus a highly specific tool that can be used in the detection, targeting and/or treatment of diseases associated with CEACAM5.
  • immunoglobulin single variable domain (ISVD), interchangeably used with “single variable domain”, defines immunoglobulin molecules wherein the antigen binding site is present on, and formed by, a single immunoglobulin domain.
  • immunoglobulin single variable domains apart from “conventional” immunoglobulins (e.g., monoclonal antibodies) or their fragments (such as Fab, Fab’, F(ab’)2, scFv, di-scFv), wherein two immunoglobulin domains, in particular two variable domains, interact to form an antigen binding site.
  • a heavy chain variable domain (VH) and a light chain variable domain (VL) interact to form an antigen binding site.
  • VH heavy chain variable domain
  • VL light chain variable domain
  • the complementarity determining regions (CDRs) of both VH and VL will contribute to the antigen binding site, i.e., a total of 6 CDRs will be involved in antigen binding site formation.
  • the antigen-binding domain of a conventional 4-chain antibody such as an IgG, IgM, IgA, IgD or IgE molecule; known in the art
  • a conventional 4-chain antibody such as an IgG, IgM, IgA, IgD or IgE molecule; known in the art
  • a Fab fragment, a F(ab')2 fragment, an Fv fragment such as a disulfide linked Fv or a scFv fragment, or a diabody (all known in the art) derived from such conventional 4-chain antibody would normally not be regarded as an immunoglobulin single variable domain, as, in these cases, binding to the respective epitope of an antigen would normally not occur by one (single) immunoglobulin domain but by a pair of (associating) immunoglobulin domains such as light and heavy chain variable domains, i.e., by a VH- VL pair of immunoglobulin domains, which jointly bind to an epitope
  • immunoglobulin single variable domains are capable of specifically binding to an epitope of the antigen without pairing with an additional immunoglobulin variable domain.
  • the binding site of an immunoglobulin single variable domain is formed by a single VH, a single VHH or single VL domain.
  • the single variable domain may be a light chain variable domain sequence (e.g., a VL- sequence) or a suitable fragment thereof; or a heavy chain variable domain sequence (e.g., a VH- sequence or VHH sequence) or a suitable fragment thereof; as long as it is capable of forming a single antigen binding unit (i.e., a functional antigen binding unit that essentially consists of the single variable domain, such that the single antigen binding domain does not need to interact with another variable domain to form a functional antigen binding unit).
  • a light chain variable domain sequence e.g., a VL- sequence
  • a heavy chain variable domain sequence e.g., a VH- sequence or VHH sequence
  • An immunoglobulin single variable domain can for example be a heavy-chain ISVD, such as a VHH, including a humanized VHH, a VH, including a camelized VH and a human VH. In one embodiment, it is a VHH, a camelized VH or humanized VHH.
  • Heavy chain ISVDs can be derived from a conventional four-chain antibody or from a heavy chain antibody.
  • the immunoglobulin single variable domain may be a single domain antibody (or an amino acid sequence that is suitable for use as a single domain antibody), a "dAb” or dAb (or an amino acid sequence that is suitable for use as a dAb) or a NANOBODY® ISVD (as defined herein and including but not limited to a VHH); other single variable domains, or any suitable fragment of any one thereof.
  • the immunoglobulin single variable domain may be a NANOBODY® ISVD (such as a VHH, including a humanized VHH or camelized VH) or a suitable fragment thereof.
  • VHH domains also known as VHHs, VHH antibody fragments, have originally been described as the antigen binding immunoglobulin variable domain of “heavy chain antibodies” (i.e., of “antibodies devoid of light chains”; Hamers-Casterman et al. Nature 363: 446-448, 1993).
  • VHH domain has been chosen in order to distinguish these variable domains from the heavy chain variable domains that are present in conventional 4-chain antibodies (which are referred to herein as “VH domains”) and from the light chain variable domains that are present in conventional 4- chain antibodies (which are referred to herein as “VL domains”).
  • VHH For a further description of VHH’s, reference is made to the review article by Muyldermans (Reviews in Molecular Biotechnology 74: 277-302, 2001).
  • the generation of immunoglobulin sequences, such as VHHs has been described extensively in various publications, among which WO 94/04678, Hamers-Casterman et al.1993 and Muyldermans et al. 2001 (Reviews in Molecular Biotechnology 74: 277-302, 2001).
  • camelids are immunized with the target antigen in order to induce an immune response against said target antigen.
  • the repertoire of VHHs obtained from said immunization is further screened for VHHs that bind the target antigen.
  • Antigens can be purified from natural sources, or in the course of recombinant production. Immunization and/or screening for immunoglobulin sequences can be performed using peptide fragments of such antigens. Immunoglobulin sequences of different origin, comprising mouse, rat, rabbit, donkey, human and camelid immunoglobulin sequences can be used in the present technology. Also, fully human, humanized or chimeric sequences can be used. For example, camelid immunoglobulin sequences and humanized camelid immunoglobulin sequences, or camelized domain antibodies, e.g., camelized dAb as described by Ward et al.
  • the ISVDs can be fused forming a multivalent and/or multispecific construct (for multivalent and multispecific polypeptides containing one or more VHH domains and their preparation, reference is also made to Conrath et al. 2001 (J. Biol. Chem., Vol. 276, 10.
  • the ISVD comprised in the present technology is not limited as to the origin of the ISVD sequence (or of the nucleotide sequence used to express it), nor as to the way that the ISVD sequence or nucleotide sequence is (or has been) generated or obtained.
  • the ISVD sequences may be naturally occurring sequences (from any suitable species) or synthetic or semi-synthetic sequences.
  • the ISVD sequence is a naturally occurring sequence (from any suitable species) or a synthetic or semi-synthetic sequence, including but not limited to “humanized” (as defined herein) immunoglobulin sequences (such as partially or fully humanized camelid, mouse or rabbit immunoglobulin sequences, and in particular partially or fully humanized VHH sequences), “camelized” (as defined herein) immunoglobulin sequences (and in particular camelized VH sequences), as well as ISVDs that have been obtained by techniques such as affinity maturation (for example, starting from synthetic, random or naturally occurring immunoglobulin sequences), CDR grafting, veneering, combining fragments derived from different immunoglobulin sequences, PCR assembly using overlapping primers, and similar techniques for engineering immunoglobulin sequences well known to the skilled person; or any suitable combination of any of the foregoing.
  • “humanized” as defined herein
  • immunoglobulin sequences such as partially or fully humanized camelid, mouse or rabbit immunoglobulin sequences,
  • nucleotide sequences may be naturally occurring nucleotide sequences or synthetic or semi-synthetic sequences, and may for example be sequences that are isolated by PCR from a suitable naturally occurring template (e.g., DNA or RNA isolated from a cell), nucleotide sequences that have been isolated from a library (and in particular, an expression library), nucleotide sequences that have been prepared by introducing mutations into a naturally occurring nucleotide sequence (using any suitable technique known per se, such as mismatch PCR), nucleotide sequence that have been prepared by PCR using overlapping primers, or nucleotide sequences that have been prepared using techniques for DNA synthesis known per se.
  • a suitable naturally occurring template e.g., DNA or RNA isolated from a cell
  • nucleotide sequences that have been isolated from a library and in particular, an expression library
  • nucleotide sequences that have been prepared by introducing mutations into a naturally occurring nucleotide sequence using any suitable technique
  • a “humanized VHH” comprises an amino acid sequence that corresponds to the amino acid sequence of a naturally occurring VHH domain, but that has been “humanized”, i.e., by replacing one or more amino acid residues in the amino acid sequence of said naturally occurring VHH sequence (and in particular in the framework sequences) by one or more of the amino acid residues that occur at the corresponding position(s) in a VH domain from a conventional 4-chain antibody from a human being (e.g., indicated above).
  • This can be performed in a manner known per se, which will be clear to the skilled person, for example on the basis of the prior art (e.g., WO 2008/020079).
  • VHHs can be obtained in any suitable manner known per se and thus are not strictly limited to polypeptides that have been obtained using a polypeptide that comprises a naturally occurring VHH domain as a starting material.
  • a “camelized VH” comprises an amino acid sequence that corresponds to the amino acid sequence of a naturally occurring VH domain, but that has been “camelized”, i.e., by replacing one or more amino acid residues in the amino acid sequence of a naturally occurring VH domain from a conventional 4-chain antibody by one or more of the amino acid residues that occur at the corresponding position(s) in a VHH domain of a (camelid) heavy chain antibody.
  • the VH sequence that is used as a starting material or starting point for generating or designing the camelized VH is a VH sequence from a mammal, such as the VH sequence of a human being, such as a VH3 sequence.
  • a mammal such as the VH sequence of a human being, such as a VH3 sequence.
  • camelized VH can be obtained in any suitable manner known per se and thus are not strictly limited to polypeptides that have been obtained using a polypeptide that comprises a naturally occurring VH domain as a starting material.
  • the structure of an immunoglobulin single variable domain sequence can be considered to be comprised of four framework regions (“FRs”), which are referred to in the art and herein as “Framework region 1” (“FR1”); as “Framework region 2” (“FR2”); as “Framework region 3” (“FR3”); and as “Framework region 4” (“FR4”), respectively; which framework regions are interrupted by three complementary determining regions (“CDRs”), which are referred to in the art and herein as “Complementarity Determining Region 1” (“CDR1”); as “Complementarity Determining Region 2” (“CDR2”); and as “Complementarity Determining Region 3” (“CDR3”), respectively.
  • CDRs complementary determining regions
  • the amino acid residues of an ISVD can be numbered according to the general numbering for VH domains given by Kabat et al. (“Sequence of proteins of immunological interest”, US Public Health Services, NIH Bethesda, MD, Publication No. 91), as applied to VHH domains from Camelids in the article of Riechmann and Muyldermans, 2000 (J. Immunol. Methods 240 (1-2): 185-195; see for example Figure 2 of this publication).
  • the total number of amino acid residues in each of the CDRs may vary and may not correspond to the total number of amino acid residues indicated by the Kabat numbering. That is, one or more positions according to the Kabat numbering may not be occupied in the actual sequence, or the actual sequence may contain more amino acid residues than the number allowed for by the Kabat numbering. This means that, generally, the numbering according to Kabat may or may not correspond to the actual numbering of the amino acid residues in the actual sequence.
  • the total number of amino acid residues in a VH domain and a VHH domain will usually be in the range of from 110 to 120, often between 112 and 115.
  • FR1 of an ISVD comprises the amino acid residues at positions 1-25
  • CDR1 of an ISVD comprises the amino acid residues at positions 26-35
  • FR2 of an ISVD comprises the amino acids at positions 36- 49
  • CDR2 of an ISVD comprises the amino acid residues at positions 50-58
  • FR3 of an ISVD comprises the amino acid residues at positions 59-94
  • CDR3 of an ISVD comprises the amino acid residues at positions 95-102
  • FR1 of an ISVD comprises the amino acid residues at positions 1-30
  • CDR1 of an ISVD comprises the amino acid residues at positions 31-35
  • FR2 of an ISVD comprises the amino acids at positions 36-49
  • CDR2 of an ISVD comprises the amino acid residues at positions 50-65
  • FR3 of an ISVD comprises the amino acid residues at positions 66-94
  • CDR3 of an ISVD comprises the amino acid residues at positions 95-102
  • FR4 of an ISVD comprises the amino acid residues at positions 103-113.
  • the framework sequences are (a suitable combination of) immunoglobulin framework sequences or framework sequences that have been derived from immunoglobulin framework sequences (for example, by humanization or camelization).
  • the framework sequences may be framework sequences derived from a light chain variable domain (e.g., a VL-sequence) and/or from a heavy chain variable domain (e.g., a VH-sequence or VHH sequence).
  • the framework sequences are either framework sequences that have been derived from a VHH- sequence (in which said framework sequences may optionally have been partially or fully humanized) or are conventional VH sequences that have been camelized (as defined herein).
  • the framework sequences present in the ISVD sequence used in the methods described herein may contain one or more of hallmark residues (as defined herein), such that the ISVD sequence is a NANOBODY® ISVD, such as, e.g., a VHH, including a humanized VHH, or camelized VH.
  • a NANOBODY® ISVD such as, e.g., a VHH, including a humanized VHH, or camelized VH.
  • NANOBODY® ISVDs in particular VHH sequences, including (partially) humanized VHH sequences and camelized VH sequences
  • VHH sequences including (partially) humanized VHH sequences and camelized VH sequences
  • Hallmark residues as described herein
  • a NANOBODY® ISVD can be defined as an immunoglobulin sequence with the (general) structure FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4 in which FR1 to FR4 refer to framework regions 1 to 4, respectively, and in which CDR1 to CDR3 refer to the complementarity determining regions 1 to 3, respectively, and in which one or more of the Hallmark residues are as further defined herein.
  • Table 1 Hallmark Residues in NANOBODY® ISVDs P osition Human VH3 Hallmark Residues 11 L, V; predominantly L L, S, V, M, W, F, T, Q, E, A, R, G, K, Y, N, P, I; preferably L 3 7 V, I, F; usually V F(1), Y, V, L, A, H, S, I, W, C, N, G, D, T, P, preferably F(1) or Y 4 4(8) G E(3), Q(3), G(2), D, A, K, R, L, P, S, V, H, T, N, W, M, I; preferably G (2) , E (3) or Q (3) ;most preferably G (2) or Q (3) .
  • sequences such as TERE (for example TEREL), TQRE (for example TQREL), KECE (for example KECEL or KECER), KQCE (for example KQCEL), RERE (for example REREG), RQRE (for example RQREL, RQREF or RQREW), QERE (for example QEREG), QQRE, (for example QQREW, QQREL or QQREF), KGRE (for example KGREG), KDRE (for example KDREV) are possible.
  • Some other possible, but less preferred sequences include for example DECKL and NVCEL. ( 4) With both GLEW at positions 44-47 and KERE or KQRE at positions 43-46.
  • the GLEW group also contains GLEW-like sequences at positions 44-47, such as for example GVEW, EPEW, GLER, DQEW, DLEW, GIEW, ELEW, GPEW, EWLP, GPER, GLER and ELEW.
  • the present technology relates to ISVDs that specifically bind to CEACAM5.
  • the target molecules for the ISVDs is CEACAM5.
  • Examples are mammalian CEACAM5.
  • human CEACAM5 SEQ ID NO: 26
  • the versions from other species are also amenable to the present technology, for example CEACAM5 from mice, rats, rabbits, cats, dogs, goats, sheep, horses, pigs, non-human primates, such as cynomolgus monkeys (also referred to herein as “cyno”), or camelids, such as llama or alpaca.
  • the ISVDs of the present technology bind to human CEACAM5 (hCEACAM5; SEQ ID NO: 26).
  • the ISVDs of the present technology bind to human CEACAM5 and cyno CEACAM5 (cCEACAM5; SEQ ID NO: 27). Sequences of human, and cyno CEACAM5 are depicted in Table A-1 (SEQ ID NOs: 26 and 27).
  • the immunoglobulin single variable domains of the present technology show a highly affinity on CEACAM5 (e.g., as measured by SPR) as a (monovalent) single variable domain.
  • the immunoglobulin single variable domains of the present technology show a high potency for binding CEACAM5 on cells (e.g., as measured in (FACS) binding assay) as a (monovalent) single variable domain.
  • the immunoglobulin single variable domains of the present technology show a high potency for internalization of CEACAM5 expressing cells (e.g., as measured in internalization assay, for example as described herein) as a (monovalent) single variable domain.
  • the immunoglobulin single variable domains of the present technology are efficiently produced (e.g., in microbial hosts, such as Pichia, e.g., P. pastoris), even when encompassed with binders to other targets, and have good stability. Because of their small size, (monovalent) immunoglobulin single variable domains are more efficient for the penetration of epithelial tissues.
  • the immunoglobulin single variable domains of the present technology show a highly affinity on CEACAM5 as a (monovalent) single variable domain.
  • the affinity of a molecular interaction between two molecules can be measured via different techniques known per se, such as the well-known surface plasmon resonance (SPR) biosensor technique (see for example Ober et al. 2001, Intern. Immunology 13: 1551-1559).
  • SPR surface plasmon resonance
  • bio-layer Interferometry refers to a label-free optical technique that analyzes the interference pattern of light reflected from two surfaces: an internal reference layer (reference beam) and a layer of immobilized protein on the biosensor tip (signal beam).
  • reference beam an internal reference layer
  • signal beam a layer of immobilized protein on the biosensor tip
  • a change in the number of molecules bound to the tip of the biosensor causes a shift in the interference pattern, reported as a wavelength shift (nm), the magnitude of which is a direct measure of the number of molecules bound to the biosensor tip surface. Since the interactions can be measured in real-time, association and dissociation rates and affinities can be determined.
  • BLI can for example be performed using the well-known Octet® Systems (ForteBio, a division of Pall Life Sciences, Menlo Park, USA).
  • affinities can be measured in Kinetic Exclusion Assay (KinExA) (see for example Drake et al. 2004, Anal. Biochem., 328: 35-43), using the KinExA® platform (Sapidyne Instruments Inc, Boise, USA).
  • KinExA refers to a solution-based method to measure true equilibrium binding affinity and kinetics of unmodified molecules.
  • ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of GLTFSTYTMG (SEQ ID NO:1); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GLTFSTYTMG (SEQ ID NO: 1); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences GLTFSTYTMG (SEQ ID NO: 1); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AIIWSGSNTY (SEQ ID NO: 2); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AIIWSGSNTY (
  • the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 1, 2, and/or 230.
  • the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 8, 31, 32, 150-159.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 3.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 33.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 249.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 250.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 251.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 252.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 253.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 254.
  • ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315007E07 (SEQ ID NO: 8) and sequence optimized variants thereof in Table A-4 (in addition to the CDRs as defined above).
  • the ISVD comprises or consists of the full amino acid sequence of A0315007E07 (SEQ ID NO: 8); T028501789 (SEQ ID NO: 31), or T028501789 (E1D) (SEQ ID NO: 32), A031500251 (SEQ ID NO: 150), A031500252 (SEQ ID NO: 151), A031500253 (SEQ ID NO: 152), A031500254 (SEQ ID NO: 153), A031500379 (SEQ ID NO: 154), A031500382 (SEQ ID NO: 155), A031500383 (SEQ ID NO: 156), A031500385 (SEQ ID NO: 157), A031500387 (SEQ ID NO: 158), and A031500394 (SEQ ID NO: 159) (see Table A-2, Table A-4).
  • the SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition.
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of TYTMG (SEQ ID NO: 17); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of TYTMG (SEQ ID NO: 17); c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of TYTMG (SEQ ID NO: 17); and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AIIWSGSNTYYADSVKG (SEQ ID NO: 18); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AIIWSGSNTYYADSVKG (SEQ ID NO:
  • the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 17, 18, and/or 230.
  • the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 8, 31, 32, 150-159.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 3.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 33.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 249.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 250.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 251.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 252.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 253.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 254.
  • ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315007E07 (SEQ ID NO: 8) and sequence optimized variants thereof in Table A-4 (in addition to the CDRs as defined above).
  • the ISVD comprises or consists of the full amino acid sequence of A0315007E07 (SEQ ID NO: 8); T028501789 (SEQ ID NO: 31), or T028501789 (E1D) (SEQ ID NO: 32), A031500251 (SEQ ID NO: 150), A031500252 (SEQ ID NO: 151), A031500253 (SEQ ID NO: 152), A031500254 (SEQ ID NO: 153), A031500379 (SEQ ID NO: 154), A031500382 (SEQ ID NO: 155), A031500383 (SEQ ID NO: 156), A031500385 (SEQ ID NO: 157), A031500387 ((SEQ ID NO: 158), and A031500394 (SEQ ID NO: 159) (see Table A-2, Table A-4).
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 8, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 8.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 31, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 31.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 32, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 32.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 150, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 150.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 151, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 151.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 152, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 152.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 153, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 153.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 154, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 154.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 157, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 157.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 158, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 158.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 159, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 159.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 8, 31, 32, 150-159, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to CEACAM5 when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 8, 31, 32, 150-159, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 8, 31, 32, 150-159
  • the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 8, 31, 32, 150-159, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 8, 31, 32, 150-159
  • the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 8, 31, 32, 150-159, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 8, 31, 32, 150-159, the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD).
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 8, 31, 32, 150-159, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 8, 31, 32, 150-159, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8 or other members of the CEACAM family.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a dissociation constant (K D ) of 10 -7 to 10 -11 moles/litre or less, and preferably 10 -8 to 10 -10 moles/litre or less and more preferably 1x10 -8 to 1x10 -9 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 1.34x10 -9 moles/litre or 1.24x10 -9 moles/litre, as determined by SPR.
  • K D dissociation constant
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a k on -rate of between 10 4 M -1 s -1 to about 10 7 M -1 s -1 , preferably between 10 5 M -1 s -1 and 10 7 M -1 s -1 , more preferably between 10 5 M -1 s -1 and 10 6 M -1 s -1 , such as between 1x10 5 M -1 s -1 and 5x10 5 M -1 s -1 , even more preferably of about 3.17x10 5 M -1 s -1 or 7.16x10 5 M -1 s -1 , as determined by SPR.
  • the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (K D ) of 10 -7 to 10 -10 moles/litre or less, and preferably 5x10 -8 to 10 -9 moles/litre or less and more preferably 5x10 -8 to 1x10 -8 moles/litre, even more preferably wherein the ISVD specifically binds to cyno CEACAM5 with a K D of about 1.76x10 -8 moles/litre, as determined by SPR.
  • K D dissociation constant
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 100-fold lower affinity (KD). In preferred embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family.
  • the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno CEACAM1, CEACAM6, CEACAM7 or CEACAM8.
  • a preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay.
  • the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a BxPC-3 cell line, which is a human pancreatic adenocarcinoma cell line.
  • VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5.
  • the immunoglobulin single variable domains of the present technology may have EC50 values of 10 -7 M or lower, more preferably of 10 -8 M or lower, or even of 10 -9 M or lower.
  • the immunoglobulin single variable domains of the present technology may have EC50 values between 10 -11 M and 10 -8 M, such as between 10- 10 M and 10 -8 M, between 5x10 -9 M and 10 -8 M or between 10 -9 M and 10 -8 M.
  • the immunoglobulin single variable domains of the present technology has an CEACAM5-mediated internalization potency (EC50 value) of 10 -7 M or lower, more preferably of 5x10 -8 M or lower, or even of 10 -8 M or lower, such as between 10 -7 M and 10 -10 M, between 10 -7 M and 10 -9 M, between 5x10 -8 M and 10 -9 M or between 5x10 -8 M and 10 -8 M, for example, as measured in a FACS internalization assay on BxPC-3 cells expressing human CEACAM5.
  • EC50 value CEACAM5-mediated internalization potency
  • ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of GX1TFSX2YAX3G (SEQ ID NO: 231), wherein the amino acid residue X1 is selected from R or H, the amino acid residue X2 is selected from E or D and the amino acid residue X3 is selected from L or M; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GX1TFSX2YAX3G (SEQ ID NO: 231), wherein the amino acid residue X1 is selected from R or H, the amino acid residue X2 is selected from E or D and the amino acid residue X3 is selected from L or M; c ) amino acid sequences that
  • the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 231, 232, and/or 233.
  • the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 16, 39, 40, 120, 121, 135-149.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 9, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 10 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 11.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 234, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 235 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 236.
  • the ISVD comprises or consists of the full amino acid sequence of A0315001C02 (SEQ ID NO.: 120) or A0315026D05 (SEQ ID NO.: 121), see Table A-2.
  • the SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition.
  • the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 240, 241, and/or 233.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 145, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 145.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 146, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 146.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 135-149, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 135-149, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 135-149, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD).
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 135-149
  • the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 135-149, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 135-149
  • the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 135- 149, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 135-149, the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD).
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 135-149, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 135-149, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with dissociation constant (KD) of 10 -7 to 10 -10 moles/litre or less, and preferably 5x10 -8 to 10 -9 moles/litre or less and more preferably 5x10 -8 to 5x10 -9 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a K D of about 1.06x10 -8 moles/litre, 4,86x10 -9 moles/litre or 8.9x10 -9 moles/litre, as determined by SPR.
  • KD dissociation constant
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with kon-rate of between 10 4 M -1 s -1 to about 10 7 M -1 s -1 , preferably between 10 5 M -1 s -1 and 10 7 M -1 s -1 , more preferably between 10 5 M -1 s -1 and 10 6 M -1 s -1 , such as between 1x10 5 M -1 s -1 and 5x10 5 M -1 s -1 , even more preferably of about 1.2x10 5 M -1 s -1 , 1.6x10 5 M -1 s -1 , 1.98x10 5 M -1 s, or 2.38x10 5 M -1 s , as determined by SPR.
  • the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (KD) of 10 -7 to 10 -11 moles/litre or less, and preferably 10 -8 to 10 -10 moles/litre or less and more preferably 5x10 -9 to 10 -9 moles/litre, even more preferably wherein the ISVD specifically binds to cyno CEACAM5 with a KD of about 6.94x10 -9 moles/litre, 2.28x10 -9 moles/litre or 4.86x10 -9 moles/litre, as determined by SPR.
  • KD dissociation constant
  • the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a kon-rate of between 10 4 M -1 s -1 to about 10 7 M -1 s -1 , preferably between 10 5 M -1 s -1 and 10 7 M -1 s -1 , more preferably between 10 5 M -1 s -1 and 10 6 M -1 s -1 , such as between 2x10 5 M -1 s -1 and 1x10 6 M -1 s -1 , even more preferably of about 5.9x10 5 M -1 s -1 , 9.94x10 5 M -1 s -1 , or 8.62x10 5 M -1 s -1 , as determined by SPR.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 100-fold lower affinity (KD). In preferred embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family.
  • the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno CEACAM1, CEACAM6, CEACAM7 or CEACAM8.
  • a preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay.
  • the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a BxPC-3 cell line, which is a human pancreatic adenocarcinoma cell line.
  • VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5.
  • the immunoglobulin single variable domains of the present technology may have EC50 values of 10 -7 M or lower, more preferably of 5x10 -8 M or lower, or even of 10 -8 M or lower.
  • the immunoglobulin single variable domains of the present technology may have EC50 values between 10 -11 M and 10 -7 M, such as between 10 -10 M and 10 -7 M, between 10 -9 M and 5x10 -8 M or between 5x10 -9 M and 5x10 -8 M.
  • the immunoglobulin single variable domains of the present technology has an CEACAM5-mediated internalization potency (EC50 value) of 5x10 -7 M or lower, more preferably of 10 -7 M or lower, or even of 5x10 -8 M or lower, such as between 10 -7 M and 10 -10 M, between 10- 7 M and 10 -9 M, between 8x10 -8 M and 10 -9 M or between 8x10 -8 M and 10 -8 M, for example, as measured in a FACS internalization assay on BxPC-3 cells expressing human CEACAM5.
  • EC50 value CEACAM5-mediated internalization potency
  • ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTFXSYDMG (SEQ ID NO: 242), wherein the amino acid residue X is selected from N, E, G, P, S or T; b ) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTFXSYDMG (SEQ ID NO: 242), wherein the amino acid residue X is selected from N, E, G, P, S or T; c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTFXSYDMG (SEQ ID NO: 242), wherein the amino acid residue X is selected from N, E, G, P,
  • the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 242, 256, and/or 257.
  • the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 114, 175-208.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 255, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 256 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 257.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 284, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 256 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 257.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 287, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 256 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 257.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 288, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 256 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 257.
  • the ISVD comprises or consists of the full amino acid sequence of A0315001D07 (SEQ ID NO: 114) (see Table A-2 and Table A-7).
  • SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition.
  • the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 289, 290, and/or 257.
  • ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315001D07 (SEQ ID NO: 114) and sequence optimized variants thereof in Table A-7 (in addition to the CDRs as defined above).
  • the ISVD comprises or consists of the full amino acid sequence of A031500014 (SEQ ID NO: 175), A031500015 (SEQ ID NO: 176), A031500016 (SEQ ID NO: 177), A031500017 (SEQ ID NO: 178), A031500018 (SEQ ID NO: 179), A031500019 (SEQ ID NO: 180), A031500020 (SEQ ID NO: 181), A031500021 (SEQ ID NO: 182), A031500022 (SEQ ID NO: 183), A031500023 (SEQ ID NO: 184), A031500024 (SEQ ID NO: 185), A031500025 (SEQ ID NO: 186), A031500026 (SEQ ID NO: 187), A031500027 (SEQ ID NO: 188), A031500028 (SEQ ID NO: 189), A031500029 (SEQ ID NO: 190), A031500030 (SEQ ID NO: 191)
  • the ISVD comprises or consists of the full amino acid sequence of A0315001D07 (SEQ ID NO: 114) (see Table A-2 and Table A-7).
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 114, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 114.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 175, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 175.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 176, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 176.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 177, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 177.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 178, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 178.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 179, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 179.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 180, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 180.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 181, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 181.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 182, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 182.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 187, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 188, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 189, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 190, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 190.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 191, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 191.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 192, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 192.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 193, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 193.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 194, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 194.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 195, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 195.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 196, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 196.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 197, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 197.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 198, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 198.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 199, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 199.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 200, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 200.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 201, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 201.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 202, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 202.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 203, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 203.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 204, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 204.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 205, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 205.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 206, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 206.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 207, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 207.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 208, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 208.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 114, 175-208, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 114, 175-208, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to CEACAM5 when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 114, 175-208, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 114, 175-208, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD).
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with at least 100-fold lower affinity (KD), such as a at least 400-fold lower affinity (KD). In preferred embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family.
  • VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5.
  • the immunoglobulin single variable domains of the present technology may have EC50 values of 10 -7 M or lower, more preferably of 10 -8 M or lower, or even of 10 -9 M or lower.
  • the immunoglobulin single variable domains of the present technology may have EC50 values between 10 -11 M and 10 -7 M, such as between 10- 10 M and 10 -8 M, between 10 -9 M and 5x10 -8 M or between 10 -9 M and 10 -8 M.
  • the immunoglobulin single variable domains of the present technology has an CEACAM5-mediated internalization potency (EC50 value) of 10 -7 M or lower, more preferably of 5x10 -8 M or lower, or even of 10 -8 M or lower, such as between 10 -7 M and 10 -10 M, between 10 -7 M and 10 -9 M, between 5x10 -8 M and 10 -9 M or between 10 -8 M and 10 -9 M, for example, as measured in a FACS internalization assay on BxPC-3 cells expressing human CEACAM5.
  • EC50 value CEACAM5-mediated internalization potency
  • ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTFSDXAMG (SEQ ID NO: 356), wherein the amino acid residue X is selected from F or Y; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTFSDXAMG (SEQ ID NO: 356), wherein the amino acid residue X is selected from F or Y; c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTFSDXAMG (SEQ ID NO: 356), wherein the amino acid residue X is selected from F or Y; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from:
  • the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 356, 357, and/or 358.
  • the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 122 or 123.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 359, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 357 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 360.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 234, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 357 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 361.
  • ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315001C11 (SEQ ID NO: 122), A0315004G01 (SEQ ID NO: 123), and sequence optimized variants thereof (in addition to the CDRs as defined above).
  • the SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition.
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of DXAMG (SEQ ID NO:237), wherein the amino acid residue X is selected from Y or F; b ) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of DXAMG (SEQ ID NO: 237), wherein the amino acid residue X is selected from Y or F; c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of DXAMG (SEQ ID NO: 237), wherein the amino acid residue X is selected from Y or F; and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AIN
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 122 or 123, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to CEACAM5 when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 100-fold lower affinity (KD).
  • the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above)
  • the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, and CEACAM8.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 122 or 123, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 122 or 123, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 100-fold lower affinity (KD).
  • KD 100-fold lower affinity
  • the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, and CEACAM8.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 122 or 123
  • the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 122 or 123, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 122 or 123
  • the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 122 or 123, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 122 or 123, the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 100-fold lower affinity (KD).
  • the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 122 or 123, the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 100-fold lower affinity (KD).
  • the ISVD specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, and CEACAM8.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a dissociation constant (KD) of 10 -7 to 10 -11 moles/litre or less, and preferably 10 -8 to 10 -10 moles/litre or less and more preferably 1x10 -8 to 1x10 -9 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 5.85x10 -9 moles/litre, or 6.01x10 -9 moles/litre, as determined by SPR.
  • KD dissociation constant
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a k on -rate of 10 4 M -1 s -1 to about 10 7 M -1 s -1 , preferably between 10 4 M -1 s -1 and 10 6 M -1 s -1 , more preferably between 10 4 M -1 s -1 and 10 5 M -1 s -1 , such as between 5x10 4 M -1 s -1 and 1x10 5 M -1 s -1 , even more preferably of about 8.68x10 4 M -1 s -1 , or 8.07x10 4 M -1 s -1 , as determined by SPR.
  • the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a k on -rate of between 10 4 M -1 s -1 to about 10 7 M -1 s -1 , preferably between 10 5 M -1 s -1 and 10 7 M -1 s -1 , more preferably between 10 5 M -1 s -1 and 10 6 M -1 s -1 , such as between 1x10 5 M -1 s -1 and 5x10 5 M -1 s -1 , even more preferably of about 3.04x10 5 M -1 s -1 , or 3.18x10 5 M -1 s -1 , as determined by SPR.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (K D ). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 100-fold lower affinity (KD). In a preferred embodiment, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family.
  • the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno CEACAM1, CEACAM6, or CEACAM8.
  • a preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay.
  • the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a BxPC-3 cell line, which is a human pancreatic adenocarcinoma cell line.
  • VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5.
  • the immunoglobulin single variable domains of the present technology may have EC50 values of 10 -7 M or lower, more preferably of 10 -8 M or lower, or even of 10 -9 M or lower.
  • the immunoglobulin single variable domains of the present technology may have EC50 values between 10 -11 M and 10 -7 M, such as between 10- 10 M and 10 -7 M, between 10 -9 M and 10 -7 M or between 5x10 -9 M and 10 -7 M.
  • the immunoglobulin single variable domains of the present technology has an CEACAM5-mediated internalization potency (EC50 value) of 10 -7 M or lower, more preferably of 5x10 -8 M or lower, or even of 10 -8 M or lower, such as between 10 -7 M and 10 -10 M, between 10 -7 M and 10 -9 M, between 5x10 -8 M and 10 -9 M or between 5x10 -8 M and 10 -8 M, for example, as measured in a FACS internalization assay on BxPC-3 cells expressing human CEACAM5.
  • EC50 value CEACAM5-mediated internalization potency
  • ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTFNINEYHLA (SEQ ID NO: 363); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTFNINEYHLA (SEQ ID NO: 363); c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTFNINEYHLA (SEQ ID NO: 363); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AIWWSTGNKI (SEQ ID NO: 364); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence the amino acid AI
  • the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 363, 364, and/or 365.
  • the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NO: 124.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 363, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 364 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 365.
  • CDR1 AbM numbering
  • CDR2 AbM numbering
  • CDR3 AbM numbering
  • Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315025D01 (SEQ ID NO: 124) and sequence optimized variants thereof (in addition to the CDRs as defined above).
  • the SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8).
  • the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition.
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of INEYHLA (SEQ ID NO: 366); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of INEYHLA (SEQ ID NO: 366); c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of INEYHLA (SEQ ID NO: 366); and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AIWWSTGNKIVADSVKG (SEQ ID NO: 367); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AIWWSTGNKIVADSV
  • the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 366, 367, and/or 365.
  • the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NO: 124.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 366, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 367 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 365.
  • CDR1 Kabat numbering
  • CDR2 Kabat numbering
  • CDR3 Kabat numbering
  • Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315025D01 (SEQ ID NO: 124) and sequence optimized variants thereof (in addition to the CDRs as defined above).
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 124, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 124.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NO: 124, wherein the binding affinity is measured using the same method, such as e.g. SPR.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NO: 124, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to CEACAM5 when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NO: 124, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NO: 124, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD).
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 124, the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NO: 124, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (KD) of 10 -7 to 10 -10 moles/litre or less, and preferably 10 -7 to 10 -9 moles/litre or less and more preferably 5x10 -7 to 1x10 -8 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a K D of about about 3.65x10 -8 moles/litre, as determined by SPR.
  • KD dissociation constant
  • the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno CEACAM1, CEACAM6, CEACAM7 or CEACAM8.
  • a preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay.
  • the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a BxPC-3 cell line, which is a human pancreatic adenocarcinoma cell line.
  • VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5.
  • the immunoglobulin single variable domains of the present technology may have EC50 values of 10 -7 M or lower, more preferably of 10 -8 M or lower, or even of 10 -9 M or lower.
  • the immunoglobulin single variable domains of the present technology may have EC50 values between 10 -11 M and 10 -7 M, such as between 10- 10 M and 10 -7 M, between 5x10 -9 M and 8x10 -8 M or between 10 -9 M and 8x10 -8 M.
  • the immunoglobulin single variable domains of the present technology has an CEACAM5-mediated internalization potency (EC50 value) of 10 -7 M or lower, more preferably of 5x10 -8 M or lower, or even of 10 -8 M or lower, such as between 10 -7 M and 10 -10 M, between 10 -7 M and 10 -9 M, between 5x10 -8 M and 10 -9 M or between 5x10 -8 M and 10 -8 M, for example, as measured in a FACS internalization assay on BxPC-3 cells expressing human CEACAM5.
  • EC50 value CEACAM5-mediated internalization potency
  • ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AIWWSTGNRI (SEQ ID NO: 369); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AIWWSTGN
  • the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 368, 369, and/or 370.
  • the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NO: 125.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 368, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 369 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 370.
  • CDR1 AbM numbering
  • CDR2 AbM numbering
  • CDR3 AbM numbering
  • Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315020C01 (SEQ ID NO: 125) and sequence optimized variants thereof (in addition to the CDRs as defined above).
  • the SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8).
  • the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition.
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of DYHMA (SEQ ID NO: 371); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of DYHMA (SEQ ID NO: 371); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of DYHMA (SEQ ID NO: 371); and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AIWWSTGNRIVADSVKG (SEQ ID NO: 372); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AIWWSTGNRIVADSVKG (SEQ ID NO: 372
  • the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 371, 372, and/or 370.
  • the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NO: 125.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 371, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 372 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 370.
  • CDR1 Kabat numbering
  • CDR2 Kabat numbering
  • CDR3 Kabat numbering
  • Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315020C01 (SEQ ID NO: 125) and sequence optimized variants thereof (in addition to the CDRs as defined above).
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 125, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 125.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NO: 125, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NO: 125, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to CEACAM5 when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NO: 125, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NO: 125, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a k on -rate of between 10 4 M -1 s -1 to about 10 7 M -1 s -1 , preferably between 10 4 M -1 s -1 and 10 6 M -1 s -1 , more preferably between 10 4 M -1 s -1 and 5x10 5 M -1 s -1 , such as between 5x10 4 M -1 s -1 and 1x10 5 M -1 s -1 , even more preferably of about 8.70x10 4 M -1 s -1 , as determined by SPR.
  • the immunoglobulin single variable domains of the present technology may have EC50 values between 10 -11 M and 10 -7 M, such as between 10 -10 M and 10 -7 M, between 5x10 -9 M and 8x10 -8 M or between 10 -9 M and 8x10 -8 M.
  • ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315026B01 (SEQ ID NO: 126) and A0315008B03 (SEQ ID NO: 127), and sequence optimized variants thereof (in addition to the CDRs as defined above).
  • the SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition.
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence SYHMA (SEQ ID NO: 381); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence SYHMA (SEQ ID NO: 381); c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences SYHMA (SEQ ID NO: 381); and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AIWWSTGNXIVADSVKG (SEQ ID NO: 382), wherein the amino acid residue X is selected from A or T; b ) amino acid sequences that have at least 80% amino acid identity with the amino acid
  • the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 381, 382, and/or 375.
  • the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 126 or 127.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 127, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 127.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 126 or 127, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 126 or 127, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to CEACAM5 when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 126 or 127, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 126 or 127, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD).
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 126 or 127
  • the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 126 or 127, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 126 or 127
  • the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 126 or 127, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 126 or 127, the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD).
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 126 or 127, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 126 or 127, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8 or other members of the CEACAM family.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a dissociation constant (KD) of 10 -7 to 10 -11 moles/litre or less, and preferably 10 -7 to 10 -9 moles/litre or less and more preferably 1x10 -7 to 1x10 -8 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 4.11x10 -8 moles/litre, or 2.67x10 -8 moles/litre, as determined by Surface Plasmon Resonance.
  • KD dissociation constant
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a k on rate of between 10 4 M -1 s -1 to about 10 7 M -1 s -1 , preferably between 10 5 M -1 s -1 and 10 7 M -1 s -1 , more preferably between 10 5 M -1 s -1 and 10 6 M -1 s -1 , such as between 1x10 5 M -1 s -1 and 5x10 5 M -1 s -1 , even more preferably of about 1.93x10 5 M -1 s -1 , or 2.18x10 5 M -1 s -1 , as determined by Surface Plasmon Resonance .
  • the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (K D ) of 10 -6 to 10 -10 moles/litre or less, and preferably 5x10 -7 to 10 -9 moles/litre or less and more preferably 5x10 -7 to 1x10 -8 moles/litre, even more preferably wherein the ISVD specifically binds to cyno CEACAM5 with a KD of about 4.71x10 -8 moles/litre, or 2.72x10 -7 moles/litre, as determined by Surface Plasmon Resonance.
  • K D dissociation constant
  • the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a kon rate of between 10 4 M -1 s -1 to about 10 7 M -1 s -1 , preferably between 10 4 M -1 s -1 and 10 6 M -1 s -1 , more preferably between 5x10 4 M -1 s -1 and 10 6 M -1 s -1 , such as between 5x10 4 M -1 s -1 and 5x10 5 M -1 s -1 , even more preferably of about 6.61x10 4 M -1 s -1 , or 1.22x10 5 M -1 s -1 , as determined by Surface Plasmon Resonance.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 100-fold lower affinity (KD). In preferred embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family.
  • the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno CEACAM1, CEACAM6, CEACAM7 or CEACAM8.
  • a preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay.
  • the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a BxPC-3 cell line, which is a human pancreatic adenocarcinoma cell line.
  • VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention.
  • ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GX1TFSX2YAMG (SEQ ID NO: 386), wherein the amino acid residue X 1 is selected from G or R, and wherein the amino acid residue X 2 is selected from S or N; b ) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GX1TFSX2YAMG (SEQ ID NO: 386), wherein the amino acid residue
  • the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 386, 387, and/or 388.
  • the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 128, 129, or 134.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 389, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 387 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 390.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 391, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 387 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 392.
  • ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315003D09 (SEQ ID NO: 128), A0315009B07 (SEQ ID NO: 129), and A031500085 (SEQ ID NO: 134), and sequence optimized variants thereof (in addition to the CDRs as defined above).
  • the SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9).
  • the ISVDs provided by the present technology can be also described using the Kabat definition.
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence XYAMG (SEQ ID NO: 393), wherein the amino acid residue X is selected from S or N; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence XYAMG (SEQ ID NO: 393), wherein the amino acid residue X is selected from S or N; c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences XYAMG (SEQ ID NO: 393), wherein the amino acid residue X is selected from S or N;
  • the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 393, 394, and/or 388.
  • the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 128, 129 or 134.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 395, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 394 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 390.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 396, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 394 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 392.
  • ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315003D09 (SEQ ID NO: 128), A0315009B07 (SEQ ID NO: 129) and A031500085 (SEQ ID NO: 134), and sequence optimized variants thereof (in addition to the CDRs as defined above).
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 128, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 128.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 128, 129, or 134
  • the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 128, 129, or 134, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (K D ). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 10-fold lower affinity (KD). In preferred embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family.
  • the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno, CEACAM6 or CEACAM7.
  • a preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay.
  • the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a BxPC-3 cell line, which is a human pancreatic adenocarcinoma cell line.
  • VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5.
  • the immunoglobulin single variable domains of the present technology may have EC50 values of 10 -7 M or lower, more preferably of 10 -8 M or lower, or even of 10 -9 M or lower.
  • the immunoglobulin single variable domains of the present technology may have EC50 values between 10 -11 M and 10 -8 M, such as between 10- 10 M and 10 -8 M, between 10 -9 M and 10 -8 M or between 5x10 -10 M and 5x10 -9 M.
  • the immunoglobulin single variable domains of the present technology has an CEACAM5-mediated internalization potency (EC50 value) of 10 -7 M or lower, more preferably of 10 -8 M or lower, or even of 5x10 -9 M or lower, such as between 10 -7 M and 10 -10 M, between 10 -8 M and 10 -10 M, between 5x10 -9 M and 10 -10 M or between 5x10 -9 M and 10 -9 M, for example, as measured in a FACS internalization assay on BxPC-3 cells expressing human CEACAM5.
  • EC50 value CEACAM5-mediated internalization potency
  • ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GGTVSTYTMG (SEQ ID NO: 397); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GGTVSTYTMG (SEQ ID NO: 397); c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GGTVSTYTMG (SEQ ID NO: 397); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence SIIWSGSTTV (SEQ ID NO: 398); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence SIIWSGST
  • the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 397, 398, and/or 399.
  • the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NO: 130.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 397, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 398 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 399.
  • CDR1 AbM numbering
  • CDR2 AbM numbering
  • CDR3 AbM numbering
  • Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315003F04 (SEQ ID NO: 130) and sequence optimized variants thereof (in addition to the CDRs as defined above).
  • the SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8).
  • the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition.
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of TYTMG (SEQ ID NO: 17); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence TYTMG (SEQ ID NO: 17); c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences TYTMG (SEQ ID NO: 17); and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence SIIWSGSTTVYADSVKG (SEQ ID NO: 400); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence SIIWSGSTTVYADSVKG (SEQ ID NO: 400);
  • the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 17, 400, and/or 399.
  • the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NO: 130.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 400 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 399.
  • CDR1 Kabat numbering
  • CDR2 Kabat numbering
  • CDR3 Kabat numbering
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 130, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 130.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NO: 130, wherein the binding affinity is measured using the same method, such as e.g.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NO: 130, wherein the binding affinity is measured using the same method, such as e.g. SPR.
  • the ISVD specifically binding to CEACAM5 when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 50-fold lower affinity (KD).
  • the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above)
  • the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM6 and CEACAM7.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NO: 130, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NO: 130, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD).
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 50-fold lower affinity (KD).
  • KD 50-fold lower affinity
  • the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM6 and CEACAM7.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 130, the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NO: 130, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 130, the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NO: 130, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 130, the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD).
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 130, the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 50-fold lower affinity (KD).
  • KD 50-fold lower affinity
  • the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 130, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM6 and CEACAM7.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a dissociation constant (K D ) of 10 -7 to 10 -11 moles/litre or less, and preferably 10 -9 to 10 -11 moles/litre or less and more preferably 1x10 -9 to 1x10 -10 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a K D of about 7.90x10 -10 moles/litre, as determined by SPR.
  • K D dissociation constant
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a kon rate of between 10 4 M -1 s -1 to about 10 7 M -1 s -1 , preferably between 10 5 M -1 s -1 and 10 7 M -1 s -1 , more preferably between 10 6 M -1 s -1 and 10 7 M -1 s -1 , such as between 1x10 6 M -1 s -1 and 5x10 6 M -1 s -1 , even more preferably of about 1.19x10 6 M -1 s -1 , as determined by SPR.
  • the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (K D ) of 10 -7 to 10 -10 moles/litre or less, and preferably 1x10 -8 to 10 -10 moles/litre or less and more preferably 1x10 -8 to 1x10 -9 moles/litre, even more preferably wherein the ISVD specifically binds to cyno CEACAM5 with a KD of about 6.61x10 -9 moles/litre, as determined by SPR.
  • K D dissociation constant
  • the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a k on rate of between 10 4 M -1 s -1 to about 10 7 M -1 s -1 , preferably between 10 5 M -1 s -1 and 10 7 M -1 s -1 , more preferably between 10 5 M -1 s -1 and 10 6 M -1 s -1 , such as between 5x10 5 M -1 s -1 and 1x10 6 M -1 s -1 , even more preferably of about 9.2x10 5 M -1 s -1 , as determined by SPR.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (K D ). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 50-fold lower affinity (KD). In preferred embodiments, the immunoglobulin single variable domains specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family.
  • the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno CEACAM6 or CEACAM7.
  • a preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay.
  • the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a BxPC-3 cell line, which is a human pancreatic adenocarcinoma cell line.
  • VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5.
  • the immunoglobulin single variable domains of the present technology may have EC50 values of 10 -7 M or lower, more preferably of 10 -8 M or lower, or even of 10 -9 M or lower.
  • the immunoglobulin single variable domains of the present technology may have EC50 values between 10 -11 M and 10 -8 M, such as between 10- 10 M and 10 -8 M, between 5x10 -10 M and 10 -8 M or between 10 -9 M and 10 -8 M.
  • the immunoglobulin single variable domains of the present technology has an CEACAM5-mediated internalization potency (EC50 value) of 10 -7 M or lower, more preferably of 10 -8 M or lower, or even of 5x10 -9 M or lower, such as between 10 -7 M and 10 -10 M, between 10 -8 M and 10 -10 M, between 5x10 -9 M and 10 -10 M or between 5x10 -9 M and 10 -9 M, for example, as measured in a FACS internalization assay on BxPC-3 cells expressing human CEACAM5.
  • EC50 value CEACAM5-mediated internalization potency
  • ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AIWWSTGNTI (SEQ ID NO: 379); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AIWW
  • the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 368, 379, and/or 365.
  • the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NO: 131.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 368, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 379 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 365.
  • CDR1 AbM numbering
  • CDR2 AbM numbering
  • CDR3 AbM numbering
  • Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315021A01 (SEQ ID NO: 131) and sequence optimized variants thereof (in addition to the CDRs as defined above).
  • the SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8).
  • the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition.
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of DYHMA (SEQ ID NO: 371); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence DYHMA (SEQ ID NO: 371); c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences DYHMA (SEQ ID NO: 371); and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AIWWSTGNTIVADSVKG (SEQ ID NO: 385); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AIWWSTGNTIVADSVKG (SEQ ID NO:
  • the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 371, 385, and/or 365.
  • the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NO: 131.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 371, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 385 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 365.
  • CDR1 Kabat numbering
  • CDR2 Kabat numbering
  • CDR3 Kabat numbering
  • Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315021A01 (SEQ ID NO: 131) and sequence optimized variants thereof (in addition to the CDRs as defined above).
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 131, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 131.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NO: 131, wherein the binding affinity is measured using the same method, such as e.g. SPR.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NO: 131, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to CEACAM5 when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NO: 131, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NO: 131, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD).
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 131
  • the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NO: 131, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 131
  • the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NO: 131, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 131, the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD).
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 131, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 131, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8 or other members of the CEACAM family.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a dissociation constant (K D ) of 10 -7 to 10 -11 moles/litre or less, and preferably 10 -7 to 10 -9 moles/litre or less and more preferably 1x10 -7 to 1x10 -8 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a K D of about 3.12x10 -8 moles/litre, as determined by SPR.
  • K D dissociation constant
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a kon rate of between 10 4 M -1 s -1 to about 10 7 M -1 s -1 , preferably between 10 5 M -1 s -1 and 10 7 M -1 s -1 , more preferably between 10 5 M -1 s -1 and 10 6 M -1 s -1 , such as between 1x10 5 M -1 s -1 and 5x10 5 M -1 s -1 , even more preferably of about 2.16x10 5 M -1 s -1 ,as determined by SPR.
  • the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (K D ) of 10 -7 to 10 -10 moles/litre or less, and preferably 1x10 -7 to 10 -9 moles/litre or less and more preferably 1x10 -7 to 10 -8 moles/litre, even more preferably wherein the ISVD specifically binds to cyno CEACAM5 with a KD of about 3.45x10 -8 moles/litre, as determined by SPR.
  • K D dissociation constant
  • the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a kon rate of between 10 4 M -1 s -1 to about 10 7 M -1 s -1 , preferably between 10 4 M -1 s -1 and 10 6 M -1 s -1 , more preferably between 10 4 M -1 s -1 and 10 5 M -1 s -1 , such as between 5x10 4 M -1 s -1 and 1x10 5 M -1 s -1 , even more preferably of about 7.16x10 4 M -1 s -1 , as determined by SPR.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 100-fold lower affinity (KD). In preferred embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family.
  • the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno CEACAM1, CEACAM6, CEACAM7 or CEACAM8.
  • a preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay.
  • the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a BxPC-3 cell line, which is a human pancreatic adenocarcinoma cell line.
  • VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5.
  • the immunoglobulin single variable domains of the present technology may have EC50 values of 10 -7 M or lower, more preferably of 10 -8 M or lower, or even of 10 -9 M or lower.
  • the immunoglobulin single variable domains of the present technology may have EC50 values between 10 -11 M and 5x10 -8 M, such as between 10 -10 M and 5x10 -8 M, between 5x10 -9 M and 5x10 -8 M or between 10 -9 M and 5x10 -8 M.
  • the immunoglobulin single variable domains of the present technology has an CEACAM5-mediated internalization potency (EC50 value) of 10 -6 M or lower, more preferably of 5x10 -6 M or lower, or even of 10 -7 M or lower, such as between 10 -6 M and 10 -10 M, between 10 -6 M and 10 -9 M, between 5x10 -6 M and 10 -9 M or between 5x10 -6 M and 10 -8 M, for example, as measured in a FACS internalization assay on BxPC-3 cells expressing human CEACAM5.
  • EC50 value CEACAM5-mediated internalization potency
  • ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GX1TFSX2X3AX4G (SEQ ID NO: 530); wherein the amino acid residue X 1 is selected from R or H; wherein the amino acid residue X 2 is selected from E or D; wherein the amino acid residue X 3 is selected from F or Y; and wherein the amino acid residue X 4 is selected from L or M; b ) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GX1TFSX2X3AX4G (SEQ ID NO: 530); wherein the amino acid residue X1 is selected from R or H; wherein the amino acid residue X
  • the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID Nos: 530, 531, and/or 532.
  • the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 9, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 10 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 11.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 234, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 235 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 236.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 234, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 238 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 239.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 359, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 357 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 360.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 234, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 357 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 361.
  • CDR1 AbM numbering
  • CDR2 AbM numbering
  • CDR3 AbM numbering
  • Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315024B02 (SEQ ID NO: 16) and sequence optimized variants thereof in Table A-3 (in addition to the CDRs as defined above).
  • the ISVD comprises or consists of the full amino acid sequence of A0315024B02 (SEQ ID NO: 16); T028501817 (SEQ ID NO: 39), or T028501817(E1D) (SEQ ID NO: 40), A031500086 (SEQ ID NO: 135), A031500087 (SEQ ID NO: 136), A031500088 (SEQ ID NO: 137), A031500089 (SEQ ID NO: 138), A031500090 (SEQ ID NO: 139), A031500091 (SEQ ID NO: 140), A031500092 (SEQ ID NO: 141), A031500093 (SEQ ID NO: 142), A031500094 (SEQ ID NO: 143), A031500095 (SEQ ID NO: 144), A031500096 (SEQ ID NO: 145, A031500097 (SEQ ID NO: 146), A031500098 (SEQ ID NO: 147), and A031500100 (SEQ ID NO:
  • the ISVD comprises or consists of the full amino acid sequence of A0315001C02 (SEQ ID NO.: 120) or A0315026D05 (SEQ ID NO.: 121), A0315001C11 (SEQ ID NO: 122), or A0315004G01 (SEQ ID NO: 123) see Table A-2.
  • the SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9).
  • the ISVDs provided by the present technology can be also described using the Kabat definition.
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence X1X2AX3G (SEQ ID NO: 533); wherein the amino acid residue X1 is selected from E or D, X2 is selected from Y or F; and the amino acid residue X 3 is selected from L or M; b ) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence X 1 X 2 AX 3 G (SEQ ID NO: 533); wherein the amino acid residue X 1 is selected from E or D, X2 is selected from Y or F;
  • the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 533, 534, and/or 535.
  • the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 21, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 22 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 11.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 21, a CDR2 (Kabat numbering) that is the amino acid sequence of (AINWGGGWTYYADSVKG) SEQ ID NO: 43 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 11.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 243, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 244 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 236.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 243, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 245 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 246.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 229, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 362 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 360.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 243, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 362 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 361.
  • ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315024B02 (SEQ ID NO: 16) and sequence optimized variants thereof in Table A-3 (in addition to the CDRs as defined above).
  • the ISVD comprises or consists of the full amino acid sequence of A0315024B02 (SEQ ID NO: 16); T028501817 (SEQ ID NO: 39), or T028501817(E1D) (SEQ ID NO: 40), A031500086 (SEQ ID NO: 135), A031500087 (SEQ ID NO: 136), A031500088 (SEQ ID NO: 137), A031500089 (SEQ ID NO: 138), A031500090 (SEQ ID NO: 139), A031500091 (SEQ ID NO: 140), A031500092 (SEQ ID NO: 141), A031500093 (SEQ ID NO: 142), A031500094 (SEQ ID NO: 143), A031500095 (SEQ ID NO: 144), A031500096 (SEQ ID NO: 145, A031500097 (SEQ ID NO: 146), A031500098 (SEQ ID NO: 147), and A031500100 (SEQ ID NO:
  • the ISVD comprises or consists of the full amino acid sequence of A0315001C02 (SEQ ID NO.: 120) or A0315026D05 (SEQ ID NO.: 121), A0315001C11 (SEQ ID NO: 122), or A0315004G01 (SEQ ID NO: 123) see Table A-2.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 16, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 16.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 39, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 39.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 40, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 40.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 120, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 120.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 121, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 121.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 135, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 135.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 136, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 136.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 137, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 137.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 138, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 138.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 139, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 139.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 140, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 140.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 141, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 141.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 142, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 142.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 143, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 143.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 144, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 144.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 145, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 145.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 146, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 146.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 147, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 147.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 148, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 148.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 149, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 149.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 122, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 122.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 123, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 123.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149, wherein the binding affinity is measured using the same method, such as, e.g, SPR.
  • the ISVD specifically binding to CEACAM5 when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD).
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149
  • the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149
  • the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149, the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD).
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, and CEACAM8, or other members of the CEACAM family.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with dissociation constant (KD) of 10 -7 to 10 -11 moles/litre or less, and preferably 5x10 -8 to 10 -10 moles/litre or less and more preferably 1x10 -8 to 1x10 -9 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a K D of about 1.06x10 -8 moles/litre, 4.86x10 -9 moles/litre, 8.9x10 -9 moles/litre, 5.85x10 -9 moles/litre, or 6.01x10 -9 moles/litre, as determined by SPR.
  • KD dissociation constant
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with kon-rate of between 10 4 M -1 s -1 to about 10 7 M -1 s -1 , preferably between 10 4 M -1 s -1 and 10 6 M -1 s -1 , more preferably between 10 4 M -1 s -1 and 5x10 5 M -1 s -1 , such as between 5x10 4 M -1 s -1 and 5x10 5 M -1 s -1 , even more preferably of about 1.2x10 5 M -1 s -1 , 1.6x10 5 M -1 s -1 , 1.98x10 5 M -1 s, 2.38x10 5 M -1 s , 8.68x10 4 M -1 s -1 , or 8.07x10 4 M -1 s -1 , as determined by SPR.
  • the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (KD) of 10 -7 to 10 -11 moles/litre or less, and preferably 10 -8 to 10 -10 moles/litre or less and more preferably 10 -8 to 1x10 -9 moles/litre, even more preferably wherein the ISVD specifically binds to cyno CEACAM5 with a K D of about 6.94x10 -9 moles/litre, 2.28x10 -9 moles/litre, 4.86x10 -9 moles/litre, 8.16x10 -9 moles/litre, or 6.47x10- 9 moles/litre, as determined by SPR.
  • KD dissociation constant
  • the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a kon-rate of between 10 4 M -1 s -1 to about 10 7 M -1 s -1 , preferably between 10 5 M -1 s -1 and 10 7 M -1 s -1 , more preferably between 10 5 M -1 s -1 and 10 6 M -1 s -1 , such as between 2x10 5 M -1 s -1 and 1x10 6 M -1 s -1 , even more preferably of about 5.9x10 5 M -1 s -1 , 9.94x10 5 M -1 s -1 , 8.62x10 5 M -1 s -1 , 3.04x10 5 M -1 s -1 , or 3.18x10 5 M -1 s -1 , as determined by SPR.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 100-fold lower affinity (KD). In preferred embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family.
  • the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno CEACAM1, CEACAM6, or CEACAM8.
  • a preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay.
  • the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a BxPC-3 cell line, which is a human pancreatic adenocarcinoma cell line.
  • VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5.
  • the immunoglobulin single variable domains of the present technology may have EC50 values of 10 -7 M or lower, more preferably of 5x10 -8 M or lower, or even of 10 -8 M or lower.
  • the immunoglobulin single variable domains of the present technology may have EC50 values between 10 -11 M and 10 -7 M, such as between 10 -10 M and 10 -7 M, between 10 -9 M and 5x10 -8 M or between 5x10 -9 M and 5x10 -8 M.
  • the immunoglobulin single variable domains of the present technology has an CEACAM5-mediated internalization potency (EC50 value) of 5x10 -7 M or lower, more preferably of 10 -7 M or lower, or even of 5x10 -8 M or lower, such as between 10 -7 M and 10 -10 M, between 10- 7 M and 10 -9 M, between 5x10 -8 M and 10 -9 M or between 10 -7 M and 10 -8 M, for example, as measured in a FACS internalization assay on BxPC-3 cells expressing human CEACAM5.
  • EC50 value CEACAM5-mediated internalization potency
  • ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GX1X2X3X4X5YX6X7X8 (SEQ ID NO: 536); wherein the amino acid residue X1 is selected from R or D, the amino acid residue X2 is selected from N or T; wherein the amino acid residue X3 is selected from F or L; wherein the amino acid residue X 4 is selected from N, E, G, P, S, or T; wherein the amino acid residue X 5 is selected from S, D, or the stretch of the following amino acids: I, N and E; wherein the amino acid residue X 6 is selected from D or H; wherein the amino acid residue X7 is
  • the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 536, 537, and/or 538.
  • the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 114, 124-127, 175-208.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 255, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 256 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 257.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 284, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 256 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 257.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 285, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 256 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 257.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 286, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 256 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 257.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 287, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 256 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 257.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 288, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 256 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 257.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 363, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 364 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 365.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 368, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 369 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 370.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 376, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 377 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 365.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 378, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 379 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 380.
  • ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315001D07 (SEQ ID NO: 114), A0315025D01 (SEQ ID NO: 124), A0315020C01 (SEQ ID NO: 125), A0315026B01 (SEQ ID NO: 126) and A0315008B03 (SEQ ID NO: 127) and sequence optimized variants thereof in Table A-7 (in addition to the CDRs as defined above).
  • the ISVD comprises or consists of the full amino acid sequence of A031500014 (SEQ ID NO: 175), A031500015 (SEQ ID NO: 176), A031500016 (SEQ ID NO: 177), A031500017 (SEQ ID NO: 178), A031500018 (SEQ ID NO: 179), A031500019 (SEQ ID NO: 180), A031500020 (SEQ ID NO: 181), A031500021 (SEQ ID NO: 182), A031500022 (SEQ ID NO: 183), A031500023 (SEQ ID NO: 184), A031500024 (SEQ ID NO: 185), A031500025 (SEQ ID NO: 186), A031500026 (SEQ ID NO: 187), A031500027 (SEQ ID NO: 188), A031500028 (SEQ ID NO: 189), A031500029 (SEQ ID NO: 190), A031500030 (SEQ ID NO: 191)
  • the ISVD comprises or consists of the full amino acid sequence of A0315001D07 (SEQ ID NO: 114), A0315025D01 (SEQ ID NO: 124), A0315020C01 (SEQ ID NO: 125), A0315026B01 (SEQ ID NO: 126) and A0315008B03 (SEQ ID NO: 127) (see Table A-2 and Table A-7).
  • the SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9).
  • the ISVDs provided by the present technology can be also described using the Kabat definition.
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence X1YX2X3X4 (SEQ ID NO: 539); wherein the amino acid residue X1 is selected from D, S or the stretch of the following amino acids: I, N and E; wherein the amino acid residue X2 is selected from H or D; wherein the amino acid residue X3 is selected from L or M; and wherein the amino acid residue X 4 is selected from A or G; b ) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of X 1 YX 2
  • the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 539, 540, and/or 538.
  • the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 114, 124-127, 175-208.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 289, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 291 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 257.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 289, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 292 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 257.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 289, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 293 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 257.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 289, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 294 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 257.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 366, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 367 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 365.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 371, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 372 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 370.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 381, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 384 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 365.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 381, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 385 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 380.
  • ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315001D07 (SEQ ID NO: 114), A0315025D01 (SEQ ID NO: 124), A0315020C01 (SEQ ID NO: 125), A0315026B01 (SEQ ID NO: 126) and A0315008B03 (SEQ ID NO: 127) and sequence optimized variants thereof in Table A-7 (in addition to the CDRs as defined above).
  • the ISVD comprises or consists of the full amino acid sequence of A031500014 (SEQ ID NO: 175), A031500015 (SEQ ID NO: 176), A031500016 (SEQ ID NO: 177), A031500017 (SEQ ID NO: 178), A031500018 (SEQ ID NO: 179), A031500019 (SEQ ID NO: 180), A031500020 (SEQ ID NO: 181), A031500021 (SEQ ID NO: 182), A031500022 (SEQ ID NO: 183), A031500023 (SEQ ID NO: 184), A031500024 (SEQ ID NO: 185), A031500025 (SEQ ID NO: 186), A031500026 (SEQ ID NO: 187), A031500027 (SEQ ID NO: 188), A031500028 (SEQ ID NO: 189), A031500029 (SEQ ID NO: 190), A031500030 (SEQ ID NO: 191)
  • the ISVD comprises or consists of the full amino acid sequence of A0315001D07 (SEQ ID NO: 114), A0315025D01 (SEQ ID NO: 124), A0315020C01 (SEQ ID NO: 125), A0315026B01 (SEQ ID NO: 126) and A0315008B03 (SEQ ID NO: 127) (see Table A-2 and Table A-7).
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 114, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 114.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 175, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 175.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 176, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 176.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 177, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 177.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 178, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 178.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 179, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 179.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 180, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 180.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 181, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 181.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 182, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 182.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 183, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 183.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 184, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 184.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 185, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 185.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 186, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 186.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 187, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 187.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 188, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 188.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 189, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 189.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 190, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 190.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 191, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 191.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 192, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 192.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 193, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 193.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 194, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 194.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 195, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 195.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 196, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 196.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 197, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 197.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 198, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 198.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 199, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 199.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 200, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 200.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 201, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 201.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 202, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 202.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 203, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 203.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 204, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 204.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 205, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 205.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 206, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 206.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 207, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 207.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 208, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 208.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 124, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 124.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 125, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 125.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 126, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 126.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 127, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 127.
  • the ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above)
  • the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 114, 124-127, 175-208, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 114, 124-127, 175-208, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to CEACAM5 when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 114, 124-127, 175-208, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 114, 124-127, 175-208, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD).
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 114, 124-127, 175-208, the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 114, 124-127, 175-208, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 114, 124-127, 175-208, the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 114, 124-127, 175-208, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 114, 124-127, 175-208, the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD).
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 114, 124-127, 175-208, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 114, 124-127, 175-208, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8 or other members of the CEACAM family.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a dissociation constant (KD) of 10 -7 to 10 -11 moles/litre or less, and preferably 10 -7 to 10 -9 moles/litre or less and more preferably 5x10 -8 to 5x10 -9 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a K D of about 1.87x10 -8 moles/litre, 2.49x10 -8 moles/litre, 2.39x10 -8 moles/litre, 4.11x10 -8 moles/litre, or 2.67x10- 8 moles/litre, as determined by SPR.
  • KD dissociation constant
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a k on -rate of between 10 4 M -1 s -1 to about 10 7 M -1 s -1 , preferably between 10 5 M -1 s -1 and 10 7 M -1 s -1 , more preferably between 10 5 M -1 s -1 and 10 6 M -1 s -1 , such as between 1x10 5 M -1 s -1 and 5x10 5 M -1 s -1 , even more preferably of about 3.96x10 5 M -1 s -1 , 2.01x10 5 M -1 s -1 , 2.19x10 5 M -1 s -1 , 1.93x10 5 M -1 s -1 , or 2.18x10 5 M -1 s -1 , as determined by SPR.
  • the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (KD) of 10 -6 to 10 -10 moles/litre or less, and preferably 5x10 -7 to 10 -9 moles/litre or less and more preferably 5x10 -7 to 10 -8 moles/litre, even more preferably wherein the ISVD specifically binds to cyno CEACAM5 with a K D of about 7.92x10 -7 moles/litre, 1.73x10 -7 moles/litre, 3.65x10 -8 moles/litre, 5.81x10 -8 moles/litre, 4.71x10- 8 moles/litre, or 2.72x10 -7 moles/litre, as determined by SPR.
  • KD dissociation constant
  • the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a kon-rate of between 10 4 M -1 s -1 to about 10 7 M -1 s -1 , preferably between 10 4 M -1 s -1 and 10 6 M -1 s -1 , more preferably between 5x10 4 M -1 s -1 and 10 6 M -1 s -1 , such as between 5x10 4 M -1 s -1 and 5x10 5 M -1 s -1 , even more preferably of about 7.98x10 4 M -1 s -1 , 8.70x10 4 M -1 s -1 , 6.61x10 4 M -1 s -1 , or 1.22x10 5 M -1 s -1 , as determined by SPR.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (K D ). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 100-fold lower affinity (KD). In preferred embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family.
  • the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno CEACAM1, CEACAM6, CEACAM7 or CEACAM8.
  • a preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay.
  • the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a BxPC-3 cell line, which is a human pancreatic adenocarcinoma cell line.
  • VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention.
  • ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of GX1TX2STYTX3G (SEQ ID NO: 541); wherein the amino acid residue X 1 is selected from G or L; wherein the amino acid residue X 2 is selected from V or F; and wherein the amino acid residue X 3 is selected from V or M; b ) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of
  • the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 541, 542, and/or 543.
  • the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 8, 31, 32, 118-119, 130, 150-159, 171-174.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 336 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 339.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 334, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 337 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 340.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 3.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 33.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 249.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 250.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 251.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 252.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 253.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 254.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 397, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 398 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 399.
  • ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315002G06 (SEQ ID NO: 118), A0315002C10 (SEQ ID NO: 119), A0315007E07 (SEQ ID NO: 8), A0315003F04 (SEQ ID NO: 130) and sequence optimized variants thereof in Table A-6 (in addition to the CDRs as defined above).
  • the ISVD comprises or consists of the full amino acid sequence of A031500010 (SEQ ID NO: 171), A031500011 (SEQ ID NO: 172), A031500012 (SEQ ID NO: 173), or A031500013 (SEQ ID NO: 174) (see Table A-2, Table A-6).
  • the ISVD comprises or consists of the full amino acid sequence of A0315002G06 (SEQ ID NO: 118) or A0315002C10 (SEQ ID NO: 119) (Table A-2).
  • the ISVD comprises or consists of the full amino acid sequence of T028501789 (SEQ ID NO: 31), or T028501789 (E1D) (SEQ ID NO: 32), A031500251 (SEQ ID NO: 150), A031500252 (SEQ ID NO: 151), A031500253 (SEQ ID NO: 152), A031500254 (SEQ ID NO: 153), A031500379 (SEQ ID NO: 154), A031500382 (SEQ ID NO: 155), A031500383 (SEQ ID NO: 156), A031500385 (SEQ ID NO: 157), A031500387 (SEQ ID NO: 158), and A031500394 (SEQ ID NO: 159) (see Table A-4).
  • the ISVD comprises or consists of the full amino acid sequence of A0315007E07 (SEQ ID NO: 8) (Table A-2). In other embodiments, the ISVD comprises or consists of the full amino acid sequence of A0315003F04 (SEQ ID NO: 130) (Table A-2).
  • the SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition.
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence TYTXG (SEQ ID NO: 341); wherein the amino acid residue X is selected from M or V; b ) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence TYTXG (SEQ ID NO: 341); wherein the amino acid residue X is selected from M or V; c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences TYTXG (SEQ ID NO: 341); wherein the amino acid residue X is selected from M or V; and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence the amino acid sequence of
  • the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 341, 544, and/or 543.
  • the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 8, 31, 32, 118-119, 130, 150-159, 171-174.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 334 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 339.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 342, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 345 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 340.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 3.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 33.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 249.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 250.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 251.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 252.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 253.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 254.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 400 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 399.
  • ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315002G06 (SEQ ID NO: 118), A0315002C10 (SEQ ID NO: 119), A0315007E07 (SEQ ID NO: 8), A0315003F04 (SEQ ID NO: 130) and sequence optimized variants thereof in Table A-6 (in addition to the CDRs as defined above).
  • the ISVD comprises or consists of the full amino acid sequence of A031500010 (SEQ ID NO: 171), A031500011 (SEQ ID NO: 172), A031500012 (SEQ ID NO: 173), or A031500013 (SEQ ID NO: 174) (see Table A-2, Table A-6).
  • the ISVD comprises or consists of the full amino acid sequence of A0315002G06 (SEQ ID NO: 118) or A0315002C10 (SEQ ID NO: 119) (Table A-2).
  • the ISVD comprises or consists of the full amino acid sequence of T028501789 (SEQ ID NO: 31), or T028501789 (E1D) (SEQ ID NO: 32), A031500251 (SEQ ID NO: 150), A031500252 (SEQ ID NO: 151), A031500253 (SEQ ID NO: 152), A031500254 (SEQ ID NO: 153), A031500379 (SEQ ID NO: 154), A031500382 (SEQ ID NO: 155), A031500383 (SEQ ID NO: 156), A031500385 (SEQ ID NO: 157), A031500387 (SEQ ID NO: 158), and A031500394 (SEQ ID NO: 159) (see Table A-4).
  • the ISVD comprises or consists of the full amino acid sequence of A0315007E07 (SEQ ID NO: 8) (Table A-2). In other embodiments, the ISVD comprises or consists of the full amino acid sequence of A0315003F04 (SEQ ID NO: 130) (Table A-2).
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 118, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 118.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 119, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 119.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 171, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 171.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 172, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 172.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 173, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 173.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 174, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 174.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 8, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 8.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 31, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 31.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 32, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 32.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 150, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 150.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 151, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 151.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 152, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 152.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 153, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 153.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 154, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 154.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 155, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 155.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 156, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 156.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 157, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 157.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 158, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 158.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 159, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 159.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 130, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 130.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID Nos: 8, 31, 32, 118-119, 130, 150-159, 171-174, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID Nos: 8, 31, 32, 118-119, 130, 150-159, 171-174, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to CEACAM5 when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with at least 100-fold lower affinity (KD), such as a at least 400-fold lower affinity (KD).
  • KD 100-fold lower affinity
  • KD at least 400-fold lower affinity
  • the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above)
  • the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM6, and CEACAM7.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 8, 31, 32, 118-119, 130, 150-159, 171-174, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD).
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with at least 100-fold lower affinity (KD), such as a at least 400-fold lower affinity (KD).
  • KD 100-fold lower affinity
  • KD at least 400-fold lower affinity
  • the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, and CEACAM7.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 8, 31, 32, 118-119, 130, 150-159, 171-174
  • the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 8, 31, 32, 118- 119, 130, 150-159, 171-174, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 8, 31, 32, 118-119, 130, 150-159, 171-174
  • the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID Nos: 8, 31, 32, 118- 119, 130, 150-159, 171-174, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 8, 31, 32, 118-119, 130, 150-159, 171-174, the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD).
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 8, 31, 32, 118-119, 130, 150-159, 171-174, the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with at least 100-fold lower affinity (KD), such as a at least 400-fold lower affinity (KD).
  • KD 100-fold lower affinity
  • the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 8, 31, 32, 118-119, 130, 150-159, 171-174, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, and CEACAM7.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a dissociation constant (KD) of 10 -7 to 10 -11 moles/litre or less, and preferably 10 -8 to 10 -11 moles/litre or less and more preferably 10 -8 to 10 -10 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a K D of about 8.83x10 -9 moles/litre, 1.44x10 -10 moles/litre, 7.90x10 -10 moles/litre, 1.34x10 -9 moles/litre or 1.24x10 -9 moles/litre, as determined by SPR.
  • KD dissociation constant
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a k on -rate of between 10 4 M -1 s -1 to about 10 7 M -1 s -1 , preferably between 10 5 M -1 s -1 and 10 7 M -1 s -1 , more preferably between 10 5 M -1 s -1 and 5x10 6 M -1 s -1 , even more preferably of about 4.70x10 5 M -1 s -1 , or 1.91x10 6 M -1 s -1 , 1.19x10 6 M -1 s -1 , 3.17x10 5 M -1 s -1 or 7.16x10 5 M -1 s -1 , as determined by SPR.
  • the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (KD) of 10 -7 to 10 -10 moles/litre or less, and preferably 10 -7 to 10 -9 moles/litre or less and more preferably 5x10 -8 to 10 -9 moles/litre, even more preferably wherein the ISVD specifically binds to cyno CEACAM5 with a K D of about 3.92x10 -8 moles/litre, or 1.56x10 -9 moles/litre, 1.76x10 -8 moles/litre, 6.61x10 -9 moles/litre, as determined by SPR.
  • KD dissociation constant
  • the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a k on -rate of between 10 4 M -1 s -1 to about 10 7 M -1 s -1 , preferably between 10 5 M -1 s -1 and 10 7 M -1 s -1 , more preferably between 10 5 M -1 s -1 and 5x10 6 M -1 s -1 , such as between 2x10 5 M -1 s -1 and 2x10 6 M -1 s -1 , even more preferably of about 2.92x10 5 M -1 s -1 , or 1.23x10 6 M -1 s -1 , 2.17x10 5 M -1 s -1 , 9.2x10 5 M -1 s -1 , as determined by SPR.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with at least 100-fold lower affinity (KD), such as a at least 400-fold lower affinity (KD). In preferred embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family.
  • the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno CEACAM1, CEACAM6, or CEACAM7.
  • a preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay.
  • the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a BxPC-3 cell line, which is a human pancreatic adenocarcinoma cell line.
  • VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5.
  • the immunoglobulin single variable domains of the present technology may have EC50 values of 10 -7 M or lower, more preferably of 10 -8 M or lower, or even of 10 -9 M or lower.
  • the immunoglobulin single variable domains of the present technology may have EC50 values between 10 -11 M and 10 -7 M, such as between 10- 10 M and 10 -8 M, between 10 -9 M and 5x10 -8 M or between 10 -9 M and 10 -8 M.
  • the immunoglobulin single variable domains of the present technology has an CEACAM5-mediated internalization potency (EC50 value) of 10 -7 M or lower, more preferably of 5x10 -8 M or lower, or even of 10 -8 M or lower, such as between 10 -7 M and 10 -10 M, between 10 -7 M and 10 -9 M, between 5x10 -8 M and 10 -9 M or between 10 -8 M and 10 -9 M, for example, as measured in a FACS internalization assay on BxPC-3 cells expressing human CEACAM5.
  • EC50 value CEACAM5-mediated internalization potency
  • ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), that interacts with one or more amino acids of the CEACAM5 protein selected from K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, L343, E346, D405, P406, V407, I408, L409, N410, L412, N442, P444, and A483.
  • the ISVD interacts with an epitope on CEACAM5 that comprises at least three amino acids selected K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, L343, E346, D405, P406, V407, I408, L409, N410, L412, N442, P444, and A483.
  • the ISVD interacts with an epitope on CEACAM5 that comprises at least five amino acids selected from K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, L343, E346, D405, P406, V407, I408, L409, N410, L412, N442, P444, and A483.
  • the ISVD interacts with an epitope on CEACAM5 that comprises at least eight amino acids selected from K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, L343, E346, D405, P406, V407, I408, L409, N410, L412, N442, P444, and A483.
  • the ISVD interacts with an epitope on CEACAM5 that comprises at least 10 amino acids selected from K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, L343, E346, D405, P406, V407, I408, L409, N410, L412, N442, P444, and A483.
  • the ISVD interacts with an epitope on CEACAM5 that comprises following amino acids: K324, S329, N330, N331, S332, N333, E346, and D405.
  • the epitope on CEACAM5 that is specifically bound by the ISVDs of the present technology comprises the following amino acids: K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, L343, E346, D405, P406, V407, I408, L409, N410, L412, N442, P444, and A483.
  • the interacting amino acids preferably have a distance of ⁇ 3.8 ⁇ , wherein the distance between the amino acids is measured e.g., in Cryogenic- electron microscopy (cryo-EM).
  • the ISVDs specifically binding to this epitope on CEACAM5 form an interaction site (paratope) on CEACAM5 only with the CDR2 and CDR3.
  • CDR2 and CDR3 of the ISVD participate in the interaction with the CEACAM5 protein.
  • CDR2 and CDR3 of the ISVD form part of the paratope (the site with which the ISVD interacts with the CEACAM5 molecule) of the ISVD.
  • the amino acids that form part of this interaction sites are selected from T52, W52a, R53, G55, S56, T57, and H58 (Kabat numbering) in CDR2.
  • the amino acids that form part of this interaction sites are R53, S56, and H58 (Kabat numbering) in CDR2. In some embodiments, the amino acids that form part of this interaction sites are T52, W52a, R53, G55, S56, T57, and H58 (Kabat numbering) in CDR2. In some embodiments, the amino acids that form part of this interaction sites are D95, I100b, T100d, T100e, Q100f, and N101 (Kabat numbering) in the CDR3.
  • the amino acids that form part of this interaction sites are D95, L96, R97, F99, G100, P100a, I100b, T100c, T100d, T100e, Q100f, I100g, and N101 (Kabat numbering) in the CDR3.
  • the amino acids that form part of this interaction sites are R53, S56, and H58 (Kabat numbering) in CDR2 and D95, I100b, T100d, T100e, Q100f, and N101 (Kabat numbering) in the CDR3.
  • the amino acids that form part of this interaction sites are T52, W52a, R53, G55, S56, T57, and H58 (Kabat numbering) in CDR2 and D95, L96, R97, F99, G100, P100a, I100b, T100c, T100d, T100e, Q100f, I100g, and N101 (Kabat numbering) in the CDR3.
  • the amino acids that form part of this interaction sites are R53, S56, or H58 (Kabat numbering) in CDR2, wherein R53 forms an interaction site ( ⁇ 3.8 ⁇ distance) with D405 in the CEACAM5 epitope, wherein S56 forms an interaction site ( ⁇ 3.8 ⁇ distance) with K324 in the CEACAM5 epitope, and/or wherein H58 forms an interaction site ( ⁇ 3.8 ⁇ distance) with E346 in the CEACAM5 epitope.
  • the amino acids that form part of this interaction sites are R53, S56, and H58 (Kabat numbering) in CDR2, wherein R53 forms an interaction site ( ⁇ 3.8 ⁇ distance) with D405 in the CEACAM5 epitope, wherein S56 forms an interaction site ( ⁇ 3.8 ⁇ distance) with K324 in the CEACAM5 epitope, and/or wherein H58 forms an interaction site ( ⁇ 3.8 ⁇ distance) with E346 in the CEACAM 5 epitope (wherein the distance between the amino acids is measured e.g., in Cryogenic-electron microscopy (cryo-EM).
  • Cryogenic-electron microscopy cryo-EM
  • the amino acids that form part of this interaction sites are D95, I100b, T100d, T100e, Q100f, or N101 (Kabat numbering) in the CDR3, wherein D95 forms an interaction site ( ⁇ 3.8 ⁇ distance) with S332 in the CEACAM5 epitope, wherein I100b forms an interaction site ( ⁇ 3.8 ⁇ distance) with S329 in the CEACAM5 epitope, wherein T100d forms an interaction site ( ⁇ 3.8 ⁇ distance) with S329 in the CEACAM epitope, wherein T100e forms an interaction site ( ⁇ 3.8 ⁇ distance) with N330 in the CEACAM5 epitope, wherein Q100f forms an interaction site ( ⁇ 3.8 ⁇ distance) with N331 in the CEACAM5 epitope, and/or wherein N101 forms an interaction site ( ⁇ 3.8 ⁇ distance) with N333 in the CEACAM 5 epitope.
  • D95 forms an interaction site ( ⁇ 3.8 ⁇ distance) with S332 in the CEACAM5 epitope
  • I100b forms an interaction site (
  • the amino acids that form part of this interaction sites are D95, I100b, T100d, T100e, Q100f, and N101 (Kabat numbering) in the CDR3, wherein D95 forms an interaction site ( ⁇ 3.8 ⁇ distance) with S332 in the CEACAM5 epitope, wherein I100b forms an interaction site ( ⁇ 3.8 ⁇ distance) with S329 in the CEACAM5 epitope, wherein T100d forms an interaction site ( ⁇ 3.8 ⁇ distance) with S329 in the CEACAM epitope, wherein T100e forms an interaction site ( ⁇ 3.8 ⁇ distance) with N330 in the CEACAM5 epitope, wherein Q100f forms an interaction site ( ⁇ 3.8 ⁇ distance) with N331 in the CEACAM5 epitope, and/or wherein N101 forms an interaction site ( ⁇ 3.8 ⁇ distance) with N333 in the CEACAM 5 epitope (wherein the distance between the amino acids is measured e.g., in Cryogenic-electron microscopy (cryo-EM
  • the amino acids that form part of this interaction sites are R53, S56, and H58 (Kabat numbering) in CDR2, and D95, I100b, T100d, T100e, Q100f, and N101 (Kabat numbering) in the CDR3, wherein R53 forms an interaction site ( ⁇ 3.8 ⁇ distance) with D405 in the CEACAM5 epitope, wherein S56 forms an interaction site ( ⁇ 3.8 ⁇ distance) with K324 in the CEACAM5 epitope, wherein H58 forms an interaction site ( ⁇ 3.8 ⁇ distance) with E346 in the CEACAM 5 epitope, wherein D95 forms an interaction site ( ⁇ 3.8 ⁇ distance) with S332 in the CEACAM5 epitope, wherein I100b forms an interaction site ( ⁇ 3.8 ⁇ distance) with S329 in the CEACAM5 epitope, wherein T100d forms an interaction site ( ⁇ 3.8 ⁇ distance) with S329 in the CEACAM5 epitope, wherein T100e forms an interaction site ( ⁇ 3.8 ⁇ distance) with D4
  • the ISVDs specifically binding to this epitope on CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X 1 is any amino acid independently chosen, preferably wherein the amino acid residue X 1 is W, and/or - CDR3 (AbM numbering) consists of an amino acid sequence X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581) wherein X1, X2, X3, X4, X5, and X6 are any amino acid independently chosen, preferably wherein the amino acid residue X1 is D, wherein the amino acid residue X2 is R, wherein the amino acid residue X 3 is G, wherein the amino acid residue X 4 is T, wherein the amino
  • the ISVDs specifically binding to this epitope on CEACAM5 may also be ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N, preferably wherein the amino acid residue X 1 is W; and - CDR3 (AbM numbering) consists of an amino acid sequence X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X 5 is selected from T and E
  • the ISVDs specifically binding to this epitope on CEACAM5 further comprises a CDR1 (AbM Numbering) : a ) having a length of 10 amino acids; b) having an aliphatic index of 49.00 or 10.00, preferably of 10.00; c) having a grand average of hydropathicity (GRAVY) of -0.970, -0.270, -1.000 preferably -0.970; d ) comprising one positively charged and at least one negatively charged residue; e) comprising 30% or 40% hydrophobic, 10% or 20% acid, 20% or 10% basic and 40% neutral amino acids, such as comprising 30% hydrophobic, 10% acid, 20% basic and 40% neutral amino acids; or comprising 40% hydrophobic, 10% acid, 10% basic and 40% neutral amino acids; or comprising 30% hydrophobic, 20% acid, 21% basic and 40% neutral amino acids; f ) consisting of a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, a hydrophobic amino acid, an acid
  • the ISVDs specifically binding to the above specific epitope on CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N, preferably wherein the amino acid residue X 1 is W; and - CDR3 (AbM numbering) consists of an amino acid sequence X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from
  • the ISVDs specifically binding to the above specific epitope on CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTFDNX1AMG (SEQ ID NO: 593); wherein the amino acid residue X1 is selected from H, L or E; b ) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTFDNX 1 AMG (SEQ ID NO: 593); wherein the amino acid residue X 1 is selected from H, L or E; c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTFDNX1AMG (SEQ ID NO: 593); wherein the amino acid residue X1 is selected from H, L or E; and - CDR2 (AbM numbering) consists of an amino acid
  • the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 548, 564-576. It should be noted, however, that the ISVDs specifically binding to CEACAM5 may not necessarily be limited to those binding to the above-specified epitope.
  • ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; b ) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GITX 1 RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X 1 is selected from W and N; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence
  • any of the ISVDs described above i.e., the ISVDs binding specifically binding to CEACAM5 and which are not necessarily limited to binding to the above specific epitope on CEACAM5 and to ISVDs specifically binding to the above-specified epitope on CEACAM5.
  • the ISVDs specifically binding to CEACAM5 further comprises a CDR1 (AbM Numbering): a ) having a length of 10 amino acids; b) having an aliphatic index of 49.00 or 10.00, preferably of 10.00; c) having a grand average of hydropathicity (GRAVY) of -0.970, -0.270, -1.000 preferably -0.970; d ) comprising one positively charged and at least one negatively charged residue; e) comprising 30% or 40% hydrophobic, 10% or 20% acid, 20% or 10% basic and 40% neutral amino acids, such as comprising 30% hydrophobic, 10% acid, 20% basic and 40% neutral amino acids; or comprising 40% hydrophobic, 10% acid, 10% basic and 40% neutral amino acids; or comprising 30% hydrophobic, 20% acid, 21% basic and 40% neutral amino acids; f ) consisting of a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, a hydrophobic amino acid, an acidic amino acid, a
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; b ) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GITX 1 RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X 1 is selected from W and N; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GITX1
  • ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 579 or 580; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 579 or 580; c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 579 or 580; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NOs: 582-589, b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 582-589; c ) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid
  • the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 579; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 579; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 579; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 582; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 582; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 582.
  • - CDR2 AbM numbering
  • - CDR2
  • the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 579; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 579; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 579; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 583; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 583; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 583.
  • - CDR2 AbM numbering
  • - CDR2
  • the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 579; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 579; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 579; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 584; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 584; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 584.
  • - CDR2 AbM numbering
  • - CDR2
  • the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 579; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 579; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 579; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 585; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 585; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 585.
  • - CDR2 AbM numbering
  • - CDR2
  • the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 579; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 579; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 579; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 586; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 586; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 586.
  • - CDR2 AbM numbering
  • - CDR2
  • the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 579; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 579; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 579; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 587; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 587; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 587.
  • - CDR2 AbM numbering
  • - CDR2
  • the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 579; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 579; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 579; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 588; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 588; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 588.
  • - CDR2 AbM numbering
  • the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 579; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 579; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 579; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 589; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 589; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 589.
  • - CDR2 AbM numbering
  • the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 580; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 580; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 580; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 582; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 582; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 582.
  • - CDR2 AbM numbering
  • - CDR2
  • the CDR2 and CDR3 sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR2 sequences of SEQ ID NOs: 579, or 580 and/or the CDR3 sequences of SEQ ID NOs: 582-589.
  • the ISVD comprise a CDR2 and CDR3 (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 548, 564-576.
  • the ISVD comprises a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 582.
  • the ISVD comprises a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 583. In one embodiment, the ISVD comprises a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 584. In one embodiment, the ISVD comprises a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 585.
  • the ISVD comprises a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 586.
  • the ISVD comprises a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 587.
  • the ISVD comprises a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 588.
  • the ISVD comprises a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 589.
  • the ISVD comprises a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 580 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 582.
  • the SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9).
  • the ISVDs provided by the present technology can be also described using the Kabat definition.
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 591 or 592; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 591 or 592; c ) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 591 or 592; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 582-589; e) amino acid sequence
  • the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 591; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 591; c ) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 591; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 582; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 582; f ) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 582.
  • - CDR2 Kabat numbering
  • the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 591; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 591; c ) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 591; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 583; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 583; f ) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 583.
  • - CDR2 Kabat numbering
  • the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 591; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 591; c ) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 591; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 584; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 584; f ) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 584.
  • - CDR2 Kabat numbering
  • the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 591; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 591; c ) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 591; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 585; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 585; f ) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 585.
  • - CDR2 Kabat numbering
  • the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 591; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 591; c ) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 591; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 586; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 586; f ) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 586.
  • - CDR2 Kabat numbering
  • the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 591; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 591; c ) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 591; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 587; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 587; f ) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 587.
  • - CDR2 Kabat numbering
  • the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 591; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 591; c ) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 591; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 588; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 588; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 588.
  • - CDR2 Kabat numbering
  • the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 591; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 591; c ) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 591; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 589; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 589; f ) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 589.
  • - CDR2 Kabat numbering
  • the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 592; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 592; c ) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 592; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 582; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 582; f ) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 582.
  • - CDR2 Kabat numbering
  • the CDR2 and CDR3 sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR2 sequences of SEQ ID NOs: 591 or 592 and/or the CDR3 sequences of SEQ ID NOs: 582-589.
  • the ISVD comprise a CDR2 and CDR3 (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 548, 564-576.
  • the ISVD comprises a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 582.
  • the ISVD comprises a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 583. In one embodiment, the ISVD comprises a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 584. In one embodiment, the ISVD comprises a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 585.
  • the ISVD comprises a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 586.
  • the ISVD comprises a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 587.
  • the ISVD comprises a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 588.
  • the ISVD comprises a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 589. In one embodiment, the ISVD comprises a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 592 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 582.
  • ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTFDNX1AMG (SEQ ID NO: 593); wherein the amino acid residue X 1 is selected from H, L or E; b ) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTFDNX1AMG (SEQ ID NO: 593); wherein the amino acid residue X1 is selected from H, L or E; c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTFDNX 1 AMG (SEQ ID NO: 593); wherein the amino acid residue X 1 is selected from H, L or E; d) and - CDR2 (AbM numbering) consists of an amino acid sequence selected from:
  • the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID Nos: 593, 578, and/or 581.
  • the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 548, 564-576.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 594, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 582.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 594, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 583.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 594, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 584.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 594, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 585.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 594, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 586.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 594, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 587.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 594, CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 588.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 594, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 589.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 594, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 580 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 582.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 595, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 582.
  • the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 596, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 582.
  • CDR1 AbM numbering
  • CDR2 AbM numbering
  • CDR3 AbM numbering
  • Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for T023200134 (SEQ ID NO: 548) and sequence optimized variants thereof in Table A-17 (in addition to the CDRs as defined above).
  • the ISVD comprises or consists of the full amino acid sequence of T028500003 (SEQ ID NO: 564), T028500004 (SEQ ID NO: 565), T028500005 (SEQ ID NO: 566), T028500591 (SEQ ID NO: 567), T0285000588 (SEQ ID NO: 568), T028500582 (SEQ ID NO: 569), T028500593 (SEQ ID NO: 570), T028500592 (SEQ ID NO: 571), T028500587 (SEQ ID NO: 572), T028500581 (SEQ ID NO: 573), T028500590 (SEQ ID NO: 574), T028500594 (SEQ ID NO: 575), or T028500583 (SEQ ID NO: 576) (see Table A-2, Table A-17).
  • the SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition.
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence NX1AMG (SEQ ID NO: 597); wherein the amino acid residue X 1 is selected from H, L or E; b ) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence NX 1 AMG (SEQ ID NO: 597); wherein the amino acid residue X 1 is selected from H, L or E; c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence NX1AMG (SEQ ID NO: 597); wherein the amino acid residue X1 is selected from H, L or E; and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence NX1
  • the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 597, 590, and/or 581.
  • the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 548, 564-576.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 598, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 582.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 598, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 583.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 598, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 584.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 598, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 585.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 598, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 586.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 598, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 587.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 598, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 588.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 598, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 589.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 598, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 592 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 582.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 599, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 582.
  • the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 600, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 582.
  • CDR1 Kabat numbering
  • CDR2 Kabat numbering
  • CDR3 Kabat numbering
  • Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for T023200134 (SEQ ID NO: 548) and sequence optimized variants thereof in Table A-17 (in addition to the CDRs as defined above).
  • the ISVD comprises or consists of the full amino acid sequence of T028500003 (SEQ ID NO: 564), T028500004 (SEQ ID NO: 565), T028500005 (SEQ ID NO: 566), T028500591 (SEQ ID NO: 567), T0285000588 (SEQ ID NO: 568), T028500582 (SEQ ID NO: 569), T028500593 (SEQ ID NO: 570), T028500592 (SEQ ID NO: 571), T028500587 (SEQ ID NO: 572), T028500581 (SEQ ID NO: 573), T028500590 (SEQ ID NO: 574), T028500594 (SEQ ID NO: 575), or T028500583 (SEQ ID NO: 576) (see Table A-2, Table A-17).
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 548, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 548.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 564, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 564.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 565, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 565.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 566, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 556.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 567, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 567.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 568, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 568.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 569, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 569.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 570, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 570.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 571, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 571.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 572, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 572.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 573, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 573.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 574, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 574.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 575, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 575.
  • the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 576, wherein the CDRs are as defined above.
  • the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 576.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 548, 564-576, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 548, 564-576, wherein the binding affinity is measured using the same method, such as, e.g, SPR.
  • the ISVD specifically binding to CEACAM5 when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 548, 564-576, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 548, 564-576, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD).
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 548, 564-576, the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 548, 564-576, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 548, 564-576, the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 548, 564-576, wherein the binding affinity is measured using the same method, such as, e.g., SPR.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 548, 564-576, the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD).
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 548, 564-576, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family.
  • the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 548, 564-576, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM6 or other members of the CEACAM family.
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with dissociation constant (KD) of 10 -7 to 10 -11 moles/litre or less, and preferably 1x10 -7 to 10 -10 moles/litre or less such as more preferably 1x10 -8 to 1x10 -10 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 1.20x10 -9 moles/litre, 2.82x10 -9 moles/litre, 6.51x10 -9 moles/litre, 1.27x10 -8 moles/litre, 2.44x10 -8 moles/litre, 3.07 x10 -8 moles/litre, 3.17 x10 -8 moles/litre, 7.62 x10 -8 moles/litre, 9.28 x10- 8 moles/litre, 1.59 x10 -7 moles/litre, or 1.97 x10 -7 moles/litre, as determined by SPR.
  • KD dissociation constant
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with k on -rate of between 10 4 M -1 s -1 to about 10 7 M -1 s -1 , preferably between 10 4 M -1 s -1 and 10 6 M -1 s -1 , more preferably between 10 5 M -1 s -1 and 10 6 M -1 s -1 , such as between 1x10 5 M -1 s -1 and 5x10 5 M -1 s -1 , even more preferably of about 4.3x10 5 M -1 s -1 , as determined by SPR.
  • the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (K D ) of 10 -7 to 10 -11 moles/litre or less, and preferably 10 -7 to 10 -10 moles/litre or less and more preferably 5x10 -8 to 10 -9 moles/litre, even more preferably wherein the ISVD specifically binds to cyno CEACAM5 with a KD of about 1.90x10 -9 moles/litre, 3.06x10 -9 moles/litre, 6.07x10 -9 moles/litre, 8.06x10 -9 moles/litre, 3.16x10 -8 moles/litre, 3.71x10 -8 moles/litre, 1.65x10 -8 moles/litre, 7.04x10 -8 moles/litre, 1.16x10 -8 moles/litre, 1.55x10 -8 moles/litre, or 9.68x10 -8 moles/litre, as determined by SPR.
  • K D dissociation constant
  • the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a kon-rate of between 10 4 M -1 s -1 to about 10 7 M -1 s -1 , preferably between 10 5 M -1 s -1 and 10 7 M -1 s -1 , more preferably between 10 5 M -1 s -1 and 10 6 M -1 s -1 , as determined by SPR.
  • the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno CEACAM1, CEACAM6, CEACAM7 and CEACAM8.
  • a preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay.
  • the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a LS174T cell line, which is a human colonic carcinoma cell line.
  • VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention.
  • the internalization can be measured using a Live-Cell Analysis Systems capable of recording fluorescence and bright field images, such as the Incucyte instrument (Sartorius).
  • the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5.
  • the immunoglobulin single variable domains of the present technology may have EC50 values of 10 -7 M or lower, more preferably of 5x10 -8 M or lower, or even of 10 -8 M or lower.
  • the immunoglobulin single variable domains of the present technology may have EC50 values between 10 -11 M and 10 -7 M, such as between 10 -10 M and 10 -7 M, between 10 -9 M and 5x10 -8 M or between 10 -9 M and 5x10 -9 M, such as 1.98x10 -9 M,
  • the immunoglobulin single variable domains of the present technology has an CEACAM5-mediated internalization potency (EC50 value) of 5x10 -7 M or lower, more preferably of 10 -7 M or lower, or even of 5x10 -8 M or lower, such as between 10 -7 M and 10 -10 M, between 10- 7 M and 10 -9 M, between 5x10 -8 M and 10 -9 M or between 5x10 -8 M and 10 -8 M, for example, as measured in a fluorescence based internalization assay on LS174T cells expressing human CEACAM5.
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR3 (AbM numbering) consists of the amino acid sequence GDHRGPWYN (SEQ ID NO: 610).
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 610; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 610; c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 610.
  • FR1 to FR4 framework regions
  • CDR1 to CDR3 complementarity determining regions
  • the ISVDs specifically binding to CEACAM5 may further comprise a CDR1 (AbM numbering): a ) having a length of 10 amino acids (AbM numbering); b) having an aliphatic index of 0.00; c) having a grand average of hydropathicity (GRAVY) of -0.080; d) comprising one negatively charged residue; e) comprising 30% hydrophobic, 10% acidic and 60% neutral amino acids; f) consisting of a polar neutral amino acid, a hydrophobic amino acid, a polar neutral amino acid, a hydrophobic amino acid, three polar neutral amino acids, an acidic amino acid, a hydrophobic amino acid, and a polar neutral amino acid; and/or g ) comprising at least one, preferably all of the amino acids G, F, T, S, Y, D, or M.
  • a CDR1 AbM numbering
  • the ISVDs specifically binding to CEACAM5 may further comprise a CDR2 (AbM numbering): a ) having a length of 10 amino acids (AbM numbering); b) having an aliphatic index of 39.00; c) having a grand average of hydropathicity (GRAVY) of -0.810; d) comprising one positively charged residue; e) comprising 10% hydrophobic, 10% basic and 80% neutral amino acids; f) consisting of a polar neutral amino acid, a hydrophobic amino acid, a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, six polar neutral amino acid, preferably in that order; and/or g ) comprising at least one, preferably all of the amino acids T, I, N, R, G, S or T.
  • a CDR2 AbM numbering
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 610; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 610; c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 610; and - CDR1 (AbM numbering): a) has a length of 10 amino acids; b) has an aliphatic index of 0.00; c) has a grand average of hydropathicity (GRAVY) of -0.080; d) comprises one negatively charged residue; e) comprises 30% hydrophobic, 10% acidic and 60% neutral amino acids; f) consisting of a polar neutral
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 610; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 610; c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 610; and - CDR2 (AbM numbering): a) has a length of 10 amino acids (AbM numbering); b) having an aliphatic index of 39.00; c) having a grand average of hydropathicity (GRAVY) of -0.810; d) comprises one positively charged residue; e) comprises 10% hydrophobic, 10% basic and 80% neutral amino acids; f) consists of
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 610; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 610; c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 610; - CDR1 (AbM numbering): a) has a length of 10 amino acids; b) has an aliphatic index of 0.00; c) has a grand average of hydropathicity (GRAVY) of -0.080; d) comprises one negatively charged residue; e) comprises 30% hydrophobic, 10% acidic and 60% neutral amino acids; f) consists of a polar neutral amino acid sequence selected
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR3 (AbM numbering) consists of the amino acid sequence GDHRGPWYN (SEQ ID NO: 610); and - CDR1 (AbM numbering): a) has a length of 10 amino acids; b) has an aliphatic index of 0.00; c) has a grand average of hydropathicity (GRAVY) of -0.080; d) comprises one negatively charged residue; e) comprises 30% hydrophobic, 10% acidic and 60% neutral amino acids; f) consists of a polar neutral amino acid, a hydrophobic amino acid, a polar neutral amino acid, a hydrophobic amino acid, three polar neutral amino acids, an acidic amino acid, a hydrophobic amino acid, and a polar neutral amino acid; and/or g )
  • the ISVDs comprise a CDR3 (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 547, 549-563.
  • CDR3 AbM numbering
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - FR1 (AbM numbering) consists of the amino acid sequence EVQLVESGGGXVQPGGSLRLSCAAS (SEQ ID NO: 647); wherein the amino acid residue X is selected from V and L.
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - FR1 (AbM numbering) consists of the amino acid sequence EVQLVESGGGXVQPGGSLRLSCAAS (SEQ ID NO: 647); wherein the amino acid residue X is V.
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - FR1 (AbM numbering) consists of the amino acid sequence EVQLVESGGGXVQPGGSLRLSCAAS (SEQ ID NO: 647); wherein the amino acid residue X is L.
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - FR2 (AbM numbering) consists of the amino acid sequence WVRQX1PGKGX2EWVS (SEQ ID NO: 641); wherein the amino acid residue X 1 is selected from A and P; and wherein the amino acid residue X 2 is selected from I and L.
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - FR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence WVRQPPGKGIEWVS (SEQ ID NO: 625); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 625; or c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 625.
  • FR2 AbM numbering
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein FR2 (AbM numbering) consists of an amino acid sequence selected from: a ) the amino acid sequence WVRQAPGKGIEWVS (SEQ ID NO: 626); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 626; or c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 626.
  • FR2 AbM numbering
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein FR2 (AbM numbering) consists of an amino acid sequence selected from: a ) the amino acid sequence WVRQPPGKGLEWVS (SEQ ID NO: 627); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 627; or c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 627.
  • FR2 AbM numbering
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - FR3 (AbM numbering) consists of the amino acid sequence YX 1 X 2 X 3 VX 4 GRFTISRDNAX 5 NTLYLQMNSLX 6 X 7 EDTAX 8 YYCTT (SEQ ID NO: 651); wherein the amino acid residue X 1 is selected from R and A, wherein the amino acid residue X 2 is selected from V and D, wherein the amino acid residue X 3 is selected from P and S, wherein the amino acid residue X 4 is selected from E and K, wherein the amino acid residue X 5 is selected from E and K, wherein the amino acid residue X 6 is selected from K and R, wherein the amino acid residue X 7 is selected from T, S and P, and wherein the amino acid residue X 8 is selected from V and
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 610; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 610; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 610; and - FR2 (AbM numbering) consists of an amino acid sequence selected from: I.
  • amino acid sequence WVRQPPGKGIEWVS SEQ ID NO: 625
  • amino acid sequence WVRQAPGKGIEWVS SEQ ID NO: 626
  • the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610 and a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 625. In one embodiment, the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610 and a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 626. In one embodiment, the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610 and a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 627.
  • the ISVDs comprise a FR1, FR2, FR3 and FR4 and a CDR3 (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR3 and FR1, FR2, FR3, and FR4 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 547, 549- 563.
  • the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 4, a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 625, a FR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 628, and a FR4 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 640.
  • CDR3 AbM numbering
  • FR1 AbM numbering
  • FR2 AbM numbering
  • FR3 AbM numbering
  • FR4 AbM numbering
  • the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 34, a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 625, a FR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 629, and a FR4 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 640.
  • CDR3 AbM numbering
  • FR1 AbM numbering
  • FR2 AbM numbering
  • FR3 AbM numbering
  • FR4 AbM numbering
  • the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 34, a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 625, a FR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 630, and a FR4 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 640.
  • CDR3 AbM numbering
  • FR1 AbM numbering
  • FR2 AbM numbering
  • FR3 AbM numbering
  • FR4 AbM numbering
  • the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 34, a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 625, a FR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 629, and a FR4 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 7.
  • the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 34, a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 626, a FR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 631, and a FR4 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 640.
  • CDR3 AbM numbering
  • FR1 AbM numbering
  • FR2 AbM numbering
  • FR3 AbM numbering
  • FR4 AbM numbering
  • the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 34, a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 626, a FR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 632, and a FR4 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 640.
  • CDR3 AbM numbering
  • FR1 AbM numbering
  • FR2 AbM numbering
  • FR3 AbM numbering
  • FR4 AbM numbering
  • the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 34, a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 625, a FR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 633, and a FR4 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 640.
  • CDR3 AbM numbering
  • FR1 AbM numbering
  • FR2 AbM numbering
  • FR3 AbM numbering
  • FR4 AbM numbering
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - FR1 (Kabat numbering) consists of the amino acid sequence EVQLVESGGGXVQPGGSLRLSCAASGFTFS (SEQ ID NO: 650); wherein the amino acid residue X is V.
  • the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein FR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence WVRQPPGKGLEWVS (SEQ ID NO: 627); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 627; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 627.
  • FR2 Kabat numbering
  • the ISVD comprises a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 624, a FR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 625, a FR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 645, and a FR4 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 640.
  • ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GFTFSSYDMS (SEQ ID NO: 611); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GFTFSSYDMS (SEQ ID NO: 611); c ) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GFTFSSYDMS (SEQ ID NO: 611); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence TINRGGSSTS (SEQ ID NO: 612); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence TINRGGSSTS (SEQ ID NO: 612); c

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Abstract

The present technology provides polypeptides that bind to CEACAM5. The present technology also provides nucleic acids, vectors and compositions.

Description

IMMUNOGLOBULIN SINGLE VARIABLE DOMAINS TARGETING CEACAM5 1 Field of the present technology The present technology relates to immunoglobulin single variable domains (ISVDs) targeting Carcino-embryonic antigen Cell Adhesion Molecule 5 (CEACAM5) and more in particular to polypeptides and constructs that comprise or essentially consist of one or more such ISVDs. It also relates to nucleic acid molecules encoding the ISVDs and polypeptides and vectors comprising the nucleic acids, and to compositions comprising the ISVD, polypeptide, nucleic acid or vector. The present technology further relates to these products for use in a method of treating a subject suffering from cancer. The present technology also relates to methods of producing these products. 2 Technological Background CEACAM5, also known as carcinoembryonic antigen-related cell adhesion molecule 5, is a member of the carcinoembryonic antigen (CEA) family of highly glycosylated cell surface glycoproteins involved in cell adhesion and signalling. Members of this family are structurally similar and consist of varying numbers of immunoglobulin variable (IgV-like) and constant (IgC-like) domains in their extracellular regions. Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5, also known as CEA) has an N-terminal IgV-like domain followed by six IgC-like domains and normally functions as an adhesion molecule but it also has roles in regulating differentiation, immune modulation, and inhibiting anoikis (Thomas J. et al., “CEACAMS 1, 5, and 6 in disease and cancer: interactions with pathogens”, Genes Cancer, 2023, 14:12-29). CEACAM5 plays an important role in clinical routine as a tumour marker for several tumour entities, including gastrointestinal and respiratory malignancies because it is weakly expressed in normal epithelial tissues and expression is restricted to the apical/luminal surface of epithelial cell membranes, making it inaccessible to antibodies, but is highly expressed in several epithelial tumour types, such as tumours of the gastrointestinal tract, lung, breast, pancreas, gallbladder, bladder or ovary (see, e.g., Hammarström S., “The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues”, Semin Cancer Biol.1999 Apr;9(2):67-81.; Blumenthal R.D., Hansen H. J, Goldenberg D.M, “Inhibition of adhesion, invasion, and metastasis by antibodies targeting CEACAM6 (NCA-90) and CEACAM5 (Carcinoembryonic Antigen)”, Cancer Res 1 October 2005; 65 (19): 8809–8817; Shirasu, N. & Kuroki, M. CEACAM5 (Carcinoembryonic antigen-related cell adhesion molecule 5 (Carcinoembryonic antigen)), Atlas Genet Cytogenet Oncol Haematol.2018). In cancer cells, CEACAM5 loses its polarized expression and is thought to facilitate tumorigenesis and metastasis by acting as homophilic and heterophilic adhesion molecule which can thus promote cell adhesion and migration and allow for immune evasion of cancer cells. Moreover, CEACAM5 was also found to prevent anoikis (induction of apoptosis in cells upon loss of attachment to the extracellular matrix (ECM) and neighbouring cells), which is thought to promote metastasis (Thomas J. et al., Genes Cancer, 2023, 14:12-29). Due to its distinct expression pattern CEACAM5 in tumor versus normal tissues, CEACAM5 is an attractive therapeutic target, and monoclonal antibodies targeting CEACAM5 have been developed. For instance, antibodies targeting the A1B1 domains shared by CEACAM5 and CEACAM6 were shown to affect cell migration, cell invasion, and cell adhesion and affect metastasis and host survival (Blumenthal R.D., Hansen H. J, Goldenberg D.M., “Inhibition of adhesion, invasion, and metastasis by antibodies targeting CEACAM6 (NCA-90) and CEACAM5 (Carcinoembryonic Antigen)”, Cancer Res 1 October 2005; 65 (19): 8809–8817). In addition, there are ongoing phase 2 and phase 3 clinical trials of the potential first-in-class CEACAM5-targeted agent tusamitamab ravtansine (formerly SAR408701), which is a humanized monoclonal antibody covalently linked to a cytotoxic maytansinoid. In the phase I dose - escalation study, a favorable safety profile signals of antitumor activity were observed (Gazzah A, Bedard PL, Hierro C, Kang YK, Abdul Razak A, Ryu MH, Demers B, Fagniez N, Henry C, Hospitel M, Soria JC, Tabernero J., “Safety, pharmacokinetics, and antitumor activity of the anti-CEACAM5-DM4 antibody-drug conjugate tusamitamab ravtansine (SAR408701) in patients with advanced solid tumors: first-in-human dose-escalation study”, Ann Oncol.2022 Apr;33(4):416-425). However, at least some of the antibodies developed lack specificity for related antigens due to homologies within the CEACAM family, as antibodies that bind to repetitive epitopes of CEACAM5 present in the different immunoglobulin domains show cross-reactivity to other CEACAM members such as CEACAM1, CEACAM6, CEACAM7 or CEACAM8 and lack specificity for CEACAM5. Consequently, for CEA-targeted therapies, the specificity of the anti-CEACAM5 antibody is desired so that it binds to human CEACAM5-expressing tumour cells but not to some normal tissues expressing the other CEACAM members. On the other hand, to facilitate pre-clinical development of potential therapeutic molecules, cross-reactivity of the anti-CEACAM5 antibody to a therapeutic model such as cynomolgus monkey is desired. In addition, another disadvantage of the known anti-CEACAM5-antibodies, include their manufacturing process and storage (e.g., low efficiency of production, low product quality) as well as their therapeutic applications, as antibodies in general, due to their size, there is a chance they may not be able to penetrate diseased tissue effectively. There is still a need for improved small-molecule biologics to CEACAM5. Such small-molecule biologics are also useful for combining with other (cancer)-target binders in a single chain, while maintaining a relatively small size, high affinity, potency and/or efficacy, in addition to good manufacturing yields. Furthermore, the biological drug should show safety, convenience, patient compliance and improve patients’ quality of life. 3 Summary of the present technology In some embodiments, the present technology relates to immunoglobulin single variable domains (ISVDs) specifically targeting CEACAM5. In some embodiments, the present technology relates to high affinity immunoglobulin single variable domains specifically targeting CEACAM5. In some embodiments, the present technology relates to high potency immunoglobulin single variable domains specifically targeting CEACAM5. In some embodiments, the present technology relates to high efficacy immunoglobulin single variable domains specifically targeting CEACAM5. In some embodiments the present technology relates to immunoglobulin single variable domains (ISVDs) specifically targeting different epitopes on CEACAM5 that can be used in different applications, e.g., in the preparation of biparatopic constructs. Targeting CEACAM5 with a biologic that is small (in size), such as a monovalent or bivalent immunoglobulin single variable domain and keeping a high affinity may be advantageous in certain applications where a very small binder is desired. Small binders may be advantageous, e.g., for penetration in the tumor environment, or when additional binders for other (tumor) targets are implicated in the same construct, facilitating manufacturing and further handling of the therapeutic compound. The immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of GLTFSTYTMG (SEQ ID NO: 1); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GLTFSTYTMG (SEQ ID NO: 1); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences GLTFSTYTMG (SEQ ID NO: 1); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AIIWSGSNTY (SEQ ID NO: 2); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AIIWSGSNTY (SEQ ID NO: 2); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AIIWSGSNTY (SEQ ID NO: 2); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of QHFGPIGLTTRGYXY (SEQ ID NO: 230), wherein the amino acid residue X is selected from N, A, F, G, I, L, Y or H; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of QHFGPIGLTTRGYXY (SEQ ID NO: 230), wherein the amino acid residue X is selected from N, A, F, G, I, L, Y or H; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of QHFGPIGLTTRGYXY (SEQ ID NO: 230), wherein the amino acid residue X is selected from N, A, F, G, I, L, Y or H. The immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 3; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO:1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 33; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO:1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYAY (SEQ ID NO: 249); or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO:1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYFY (SEQ ID NO: 250), or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO:1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYGY (SEQ ID NO: 251); or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO:1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYIY (SEQ ID NO: 254); or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO:1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYLY (SEQ ID NO: 252); or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO:1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYYY (SEQ ID NO: 253). In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NOs: 8, 31, 32, or 150-159. In one embodiment, the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NOs: 8, 31, 32, or 150-159. In another embodiment, the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of GX1TFSX2YAX3G (SEQ ID NO: 231), wherein the amino acid residue X1 is selected from R or H, the amino acid residue X2 is selected from E or D and the amino acid residue X3 is selected from L or M; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GX1TFSX2YAX3G (SEQ ID NO: 231), wherein the amino acid residue X1 is selected from R or H, the amino acid residue X2 is selected from E or D and the amino acid residue X3 is selected from L or M; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences GX1TFSX2YAX3G (SEQ ID NO: 231), wherein the amino acid residue X1 is selected from R or H, the amino acid residue X2 is selected from E or D and the amino acid residue X3 is selected from L or M; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AINWGGXWTY (SEQ ID NO: 232), wherein the amino acid residue X is selected from T, G or S; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AINWGGXWTY (SEQ ID NO: 232), wherein the amino acid residue X is selected from T, G or S; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AINWGGXWTY (SEQ ID NO: 232), wherein the amino acid residue X is selected from T, G or S); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SX1DYAGGX2PTGYX3Y (SEQ ID NO: 233), wherein the amino acid residue X1 is selected from S, P or L, the amino acid residue X2 is selected from N or S, the amino acid residue X3 is selected from P or A; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SX1DYAGGX2PTGYX3Y (SEQ ID NO: 233), the amino acid residue X1 is selected from S, P or L, the amino acid residue X2 is selected from N or S, the amino acid residue X3 is selected from P or A; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SX1DYAGGX2PTGYX3Y (SEQ ID NO: 233), wherein the amino acid residue X1 is selected from S, P or L, the amino acid residue X2 is selected from N or S, the amino acid residue X3 is selected from P or A. The immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 9; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 10; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 11; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 234; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 235; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 236. or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 234; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 238; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 239. In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NOs: 16, 39, 40, 120, 121, 135-149. In one embodiment, the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NOs: 16, 39, 40, 120, 121, 135-149. In another embodiment, the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTFXSYDMG (SEQ ID NO: 242), wherein the amino acid residue X is selected from N, E, G, P, S or T; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTFXSYDMG (SEQ ID NO: 242), wherein the amino acid residue X is selected from N, E, G, P, S or T; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTFXSYDMG (SEQ ID NO: 242), wherein the amino acid residue X is selected from N, E, G, P, S or T; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AIRWSAGSTV (SEQ ID NO: 256); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AIRWSAGSTV (SEQ ID NO: 256); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AIRWSAGSTV (SEQ ID NO: 256); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence VRPSFRPLSTYWKDYDN (SEQ ID NO: 257); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence VRPSFRPLSTYWKDYDN (SEQ ID NO: 257); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence VRPSFRPLSTYWKDYDN (SEQ ID NO: 257). The immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 255; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 256; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 257; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 284; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 256; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 257; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 285; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 256; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 257; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 286; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 256; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 257; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 287; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 256; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 257; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 288; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 256; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 257. In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NOs: 114, 175-208. In one embodiment, the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NOs: 114, 175-208. In another embodiment, the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GXAFSTYTMA (SEQ ID NO: 318), wherein the amino acid residue X is selected from R or G; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GXAFSTYTMA (SEQ ID NO: 318), wherein the amino acid residue X is selected from R or G; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GXAFSTYTMA (SEQ ID NO: 318), wherein the amino acid residue X is selected from R or G; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence X1X2SWRSX3X4TV (SEQ ID NO: 319); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E and wherein the amino acid residue X4 is selected from T or I; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence X1X2SWRSX3X4TV (SEQ ID NO: 319); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E and wherein the amino acid residue X4 is selected from T or I; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence the amino acid X1X2SWRSX3X4TV (SEQ ID NO: 319); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E and wherein the amino acid residue X4 is selected from T or I; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y. The immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 321; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 322; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 323; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 324; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 325; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 326; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 324; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 325; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 327. In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NOs: 115-117, 160-170. In one embodiment, the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NOs: 115-117, 160-170. In another embodiment, the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of GLTFSTYTXG (SEQ ID NO: 333), wherein the amino acid residue X is selected from V or M; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GLTFSTYTXG (SEQ ID NO: 333), wherein the amino acid residue X is selected from V or M; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences GLTFSTYTXG (SEQ ID NO: 333), wherein the amino acid residue X is selected from V or M; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SX1IX2SGSNTX3 (SEQ ID NO: 335); wherein the amino acid residue X1 is selected from I or M, wherein the amino acid residue X2 is selected from W or Y, and wherein the amino acid residue X3 is selected from V or L; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence SX1IX2SGSNTX3 (SEQ ID NO: 335); wherein the amino acid residue X1 is selected from I or M, wherein the amino acid residue X2 is selected from W or Y, and wherein the amino acid residue X3 is selected from V or L; c) amino acid sequences that 3, 2, or 1 amino acid difference with the amino acid sequence SX1IX2SGSNTX3 (SEQ ID NO: 335); wherein the amino acid residue X1 is selected from I or M, wherein the amino acid residue X2 is selected from W or Y, and wherein the amino acid residue X3 is selected from V or L; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of QHFGPX1SLTTRGYX2Y (SEQ ID NO: 338); wherein the amino acid residue X1 is selected from V or I, and wherein the amino acid residue X2 is selected from Y or F; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of QHFGPX1SLTTRGYX2Y (SEQ ID NO: 338); wherein the amino acid residue X1 is selected from V or I, and wherein the amino acid residue X2 is selected from Y or F; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of QHFGPX1SLTTRGYX2Y (SEQ ID NO: 338); wherein the amino acid residue X1 is selected from V or I, and wherein the amino acid residue X2 is selected from Y or F. The immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 336; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 339; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 334; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 337; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 340. In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NOs: 118-119, 171-174. In one embodiment, the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NOs: 118-119, 171-174. In another embodiment, the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTFSDXAMG (SEQ ID NO: 356), wherein the amino acid residue X is selected from F or Y; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTFSDXAMG (SEQ ID NO: 356), wherein the amino acid residue X is selected from F or Y; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTFSDXAMG (SEQ ID NO: 356), wherein the amino acid residue X is selected from F or Y; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AINWSGGWTY (SEQ ID NO: 357); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AINWSGGWTY (SEQ ID NO: 357); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AINWSGGWTY (SEQ ID NO: 357); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence SSDYAGGRSTGYXY (SEQ ID NO: 358); wherein the amino acid residue X is selected from A or D; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence SSDYAGGRSTGYXY (SEQ ID NO: 358); wherein the amino acid residue X is selected from A or D; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence SSDYAGGRSTGYXY (SEQ ID NO: 358); wherein the amino acid residue X is selected from A or D. The immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 359; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 357; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 360; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 234; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 357; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 361. In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NOs: 122 or 123. In one embodiment, the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NOs: 122 or 123. In another embodiment, the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTFNINEYHLA (SEQ ID NO: 363); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTFNINEYHLA (SEQ ID NO: 363); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTFNINEYHLA (SEQ ID NO: 363); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AIWWSTGNKI (SEQ ID NO: 364); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AIWWSTGNKI (SEQ ID NO: 364); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AIWWSTGNKI (SEQ ID NO: 364); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence VRFSFRPLSTYWKDYDN (SEQ ID NO: 365); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence VRFSFRPLSTYWKDYDN (SEQ ID NO: 365); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence VRFSFRPLSTYWKDYDN (SEQ ID NO: 365). The immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 363; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 364; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 365. In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NO: 124. In one embodiment, the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NO: 124. In another embodiment, the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AIWWSTGNRI (SEQ ID NO: 369); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AIWWSTGNRI (SEQ ID NO: 369); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AIWWSTGNRI (SEQ ID NO: 369); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence VRFSFRPLSTYWKDYDI (SEQ ID NO: 370); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence VRFSFRPLSTYWKDYDI (SEQ ID NO: 370); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence VRFSFRPLSTYWKDYDI (SEQ ID NO: 370). The immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 368; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 369; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 370. In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NO: 125. In one embodiment, the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NO: 125. In another embodiment, the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of GDXLNSYHMA (SEQ ID NO: 373), wherein the amino acid residue X is selected from T or N; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GDXLNSYHMA (SEQ ID NO: 373), wherein the amino acid residue X is selected from T or N; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of GDXLNSYHMA (SEQ ID NO: 373), wherein the amino acid residue X is selected from T or N; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AIWWSTGNXI (SEQ ID NO: 374), wherein the amino acid residue X is selected from A or T; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AIWWSTGNXI (SEQ ID NO: 374), wherein the amino acid residue X is selected from A or T; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AIWWSTGNXI (SEQ ID NO: 374), wherein the amino acid residue X is selected from A or T); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence VRFXFRPLSTYWKDYDN (SEQ ID NO: 375); wherein the amino acid residue X is selected from S or Q; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence VRFXFRPLSTYWKDYDN (SEQ ID NO: 375); wherein the amino acid residue X is selected from S or Q; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence VRFXFRPLSTYWKDYDN (SEQ ID NO: 375); wherein the amino acid residue X is selected from S or Q. The immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 376; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 377; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 365; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 378; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 379; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 380. In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NOs: 126 or 127. In one embodiment, the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NOs: 126 or 127. In another embodiment, the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GX1TFSX2YAMG (SEQ ID NO: 386), wherein the amino acid residue X1 is selected from G or R, and wherein the amino acid residue X2 is selected from S or N; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GX1TFSX2YAMG (SEQ ID NO: 386), wherein the amino acid residue X1 is selected from G or R, and wherein the amino acid residue X2 is selected from S or N; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences GX1TFSX2YAMG (SEQ ID NO: 386), wherein the amino acid residue X1 is selected from G or R, and wherein the amino acid residue X2 is selected from S or N; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GMSWSGGSTH (SEQ ID NO: 387); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GMSWSGGSTH (SEQ ID NO: 387); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GMSWSGGSTH (SEQ ID NO: 387); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GXNPMGPIATRPSVHDY (SEQ ID NO: 388); wherein the amino acid residue X is selected from Q or R; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GXNPMGPIATRPSVHDY (SEQ ID NO: 388); wherein the amino acid residue X is selected from Q or R; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GXNPMGPIATRPSVHDY (SEQ ID NO: 388); wherein the amino acid residue X is selected from Q or R. The immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 389; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 387; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 390; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 391; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 387; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 392. In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NOs: 128, 129, or 134. In one embodiment, the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NOs: 128, 129, or 134. In another embodiment, the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GGTVSTYTMG (SEQ ID NO: 397); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GGTVSTYTMG (SEQ ID NO: 397); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GGTVSTYTMG (SEQ ID NO: 397); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence SIIWSGSTTV (SEQ ID NO: 398); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence SIIWSGSTTV (SEQ ID NO: 398); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence SIIWSGSTTV (SEQ ID NO: 398); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence QHFGPVSQTTKGYFY (SEQ ID NO: 399); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence QHFGPVSQTTKGYFY (SEQ ID NO: 399); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence QHFGPVSQTTKGYFY (SEQ ID NO: 399). The immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 397; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 398; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 399. In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NOs: 130. In one embodiment, the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NOs: 130. In another embodiment, the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AIWWSTGNTI (SEQ ID NO: 379); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AIWWSTGNTI (SEQ ID NO: 379); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AIWWSTGNTI (SEQ ID NO: 379); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence VRFSFRPLSTYWKDYDN (SEQ ID NO: 365); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence VRFSFRPLSTYWKDYDN (SEQ ID NO: 365); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence VRFSFRPLSTYWKDYDN (SEQ ID NO: 365). The immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 368; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 379; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 365. In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NO: 131. In one embodiment, the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NO: 131. In another embodiment, the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GX1TFSX2X3AX4G (SEQ ID NO: 530); wherein the amino acid residue X1 is selected from R or H; wherein the amino acid residue X2 is selected from E or D; wherein the amino acid residue X3 is selected from F or Y; and wherein the amino acid residue X4 is selected from L or M; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GX1TFSX2X3AX4G (SEQ ID NO: 530); wherein the amino acid residue X1 is selected from R or H; wherein the amino acid residue X2 is selected from E or D; wherein the amino acid residue X3 is selected from F or Y; and wherein the amino acid residue X4 is selected from L or M; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GX1TFSX2X3AX4G (SEQ ID NO: 530); wherein the amino acid residue X1 is selected from R or H; wherein the amino acid residue X2 is selected from E or D; wherein the amino acid residue X3 is selected from F or Y; and wherein the amino acid residue X4 is selected from L or M; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AINWX1GX2WTY (SEQ ID NO: 531); wherein the amino acid residue X1 is selected from G or S; and wherein the amino acid residue X2 is selected from T, G or S; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AINWX1GX2WTY (SEQ ID NO: 531), wherein the amino acid residue X1 is selected from G or S; and wherein the amino acid residue X2 is selected from T, G or S; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AINWX1GX2WTY (SEQ ID NO: 531), wherein the amino acid residue X1 is selected from G or S; and wherein the amino acid residue X2 is selected from T, G or S; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence SX1DYAGGX2X3TGYX4Y (SEQ ID NO: 532); wherein the amino acid residue X1 is selected from S, P or L; wherein the amino acid residue X2 is selected from N, R or S; wherein the amino acid residue X3 is selected from P or S; and wherein the amino acid residue X4 is selected from P, D or A; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SX1DYAGGX2X3TGYX4Y (SEQ ID NO: 532); wherein the amino acid residue X1 is selected from S, P or L; wherein the amino acid residue X2 is selected from N, R or S; wherein the amino acid residue X3 is selected from P or S; and wherein the amino acid residue X4 is selected from P, D or A; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SX1DYAGGX2X3TGYX4Y (SEQ ID NO: 532); wherein the amino acid residue X1 is selected from S, P or L; wherein the amino acid residue X2 is selected from N, R or S; wherein the amino acid residue X3 is selected from P or S; and wherein the amino acid residue X4 is selected from P, D or A. The immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 9; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 10; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 11, or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 234; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 235; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 236,; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 234; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 238; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 239, or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 359; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 357; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 360, or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 234; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 357; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 361. In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149. In one embodiment, the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149. In another embodiment, the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GX1X2X3X4X5YX6X7X8 (SEQ ID NO: 536); wherein the amino acid residue X1 is selected from R or D, the amino acid residue X2 is selected from N or T; wherein the amino acid residue X3 is selected from F or L; wherein the amino acid residue X4 is selected from N, E, G, P, S, or T; wherein the amino acid residue X5 is selected from S , D, or the stretch of the following amino acids: I, N and E; wherein the amino acid residue X6 is selected from D or H; wherein the amino acid residue X7 is selected from L or M; and wherein the amino acid residue X8 is selected from A or G; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GX1X2X3X4X5YX6X7X8 (SEQ ID NO: 536); wherein the amino acid residue X1 is selected from R or D, the amino acid residue X2 is selected from N or T; wherein the amino acid residue X3 is selected from F or L; wherein the amino acid residue X4 is selected from N, E, G, P, S, or T; wherein the amino acid residue X5 is selected from S, D, or the stretch of the following amino acids: I, N and E; wherein the amino acid residue X6 is selected from D or H; wherein the amino acid residue X7 is selected from L or M; and wherein the amino acid residue X8 is selected from A or G; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GX1X2X3X4X5YX6X7X8 (SEQ ID NO: 536); wherein the amino acid residue X1 is selected from R or D, the amino acid residue X2 is selected from N or T; wherein the amino acid residue X3 is selected from F or L; wherein the amino acid residue X4 is selected from N, E, G, P, S, or T; wherein the amino acid residue X5 is selected from S, E, D, or the stretch of the following amino acids: I, N and E; wherein the amino acid residue X6 is selected from D or H; wherein the amino acid residue X7 is selected from L or M; and wherein the amino acid residue X8 is selected from A or G; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AIX1WSX2GX3X4X5 (SEQ ID NO: 537); wherein the amino acid residue X1 is selected from R or W; the amino acid residue X2 is selected from A or T; wherein the amino acid residue X3 is selected from S or N; wherein the amino acid residue X4 is selected from K, R, A or T; and wherein the amino acid residue X5 is selected from I or V; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AIX1WSX2GX3X4X5 (SEQ ID NO: 537); wherein the amino acid residue X1 is selected from R or W; the amino acid residue X2 is selected from A or T; wherein the amino acid residue X3 is selected from S or N; wherein the amino acid residue X4 is selected from K, R, A or T; and wherein the amino acid residue X5 is selected from I or V; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AIX1WSX2GX3X4X5 (SEQ ID NO: 537); wherein the amino acid residue X1 is selected from R or W; the amino acid residue X2 is selected from A or T; wherein the amino acid residue X3 is selected from S or N; wherein the amino acid residue X4 is selected from K, R, A or T; and wherein the amino acid residue X5 is selected from I or V; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence VRX1X2FRPLSTYWKDYDX3 (SEQ ID NO: 538); wherein the amino acid residue X1 is selected from F or P; wherein the amino acid residue X2 is selected from Q or S; and wherein the amino acid residue X3 is selected from I or N; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence VRX1X2FRPLSTYWKDYDX3 (SEQ ID NO: 538); wherein the amino acid residue X1 is selected from F or P; wherein the amino acid residue X2 is selected from Q or S; and wherein the amino acid residue X3 is selected from I or N; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence VRX1X2FRPLSTYWKDYDX3 (SEQ ID NO: 538); wherein the amino acid residue X1 is selected from F or P; wherein the amino acid residue X2 is selected from Q or S; and wherein the amino acid residue X3 is selected from I or N. The immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 255; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 256; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 257; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 284; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 256; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 257; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 285; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 256; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 257; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 286; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 256; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 257; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 287; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 256; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 257; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 288; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 256; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 257; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 363; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 364; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 365; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 368; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 369; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 370; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 376; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 377; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 365; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 378; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 379; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 380. In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NOs: 114, 124-127, 175-208. In one embodiment, the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NOs: 114, 124-127, 175-208. In another embodiment, the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of GX1TX2STYTX3G (SEQ ID NO: 541); wherein the amino acid residue X1 is selected from G or L; wherein the amino acid residue X2 is selected from V or F; and wherein the amino acid residue X3 is selected from V or M; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GX1TX2STYTX3G (SEQ ID NO: 541); wherein the amino acid residue X1 is selected from G or L; wherein the amino acid residue X2 is selected from V or F; and wherein the amino acid residue X3 is selected from V or M; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GX1TX2STYTX3G (SEQ ID NO: 541); wherein the amino acid residue X1 is selected from G or L; wherein the amino acid residue X2 is selected from V or F, and wherein the amino acid residue X3 is selected from V or M; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of X1X2IX3SGSX4TX5 (SEQ ID NO: 542); wherein the amino acid residue X1 is selected from S or A; wherein the amino acid residue X2 is selected from I or M; wherein the amino acid residue X3 is selected from W or Y; wherein the amino acid residue X4 is selected from N or T; and wherein the amino acid residue X5 is selected from V, Y or L; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence X1X2IX3SGSX4TX5 (SEQ ID NO: 542); wherein the amino acid residue X1 is selected from S or A; wherein the amino acid residue X2 is selected from I or M; wherein the amino acid residue X3 is selected from W or Y; wherein the amino acid residue X4 is selected from N or T; and wherein the amino acid residue X5 is selected from V, Y or L; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence X1X2IX3SGSX4TX5 (SEQ ID NO: 542); wherein the amino acid residue X1 is selected from S or A; wherein the amino acid residue X2 is selected from I or M; wherein the amino acid residue X3 is selected from W or Y; wherein the amino acid residue X4 is selected from N or T; and wherein the amino acid residue X5 is selected from V, Y or L; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence QHFGPX1X2X3TTX4GYX5Y (SEQ ID NO: 543); wherein the amino acid residue X1 is selected from V or I; the amino acid residue X2 is selected from S or G; wherein the amino acid residue X3 is selected from L or Q; the amino acid residue X4 is selected from R or K; and wherein the amino acid residue X5 is selected from N, A, F, G, I, L, Y or H; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence QHFGPX1X2X3TTX4GYX5Y (SEQ ID NO: 543); wherein the amino acid residue X1 is selected from V or I; the amino acid residue X2 is selected from S or G; wherein the amino acid residue X3 is selected from L or Q; the amino acid residue X4 is selected from R or K; and wherein the amino acid residue X5 is selected from N, A, F, G, I, L, Y or H; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of QHFGPX1X2X3TTX4GYX5Y (SEQ ID NO: 543); wherein the amino acid residue X1 is selected from V or I; the amino acid residue X2 is selected from S or G; wherein the amino acid residue X3 is selected from L or Q; the amino acid residue X4 is selected from R or K; and wherein the amino acid residue X5 is selected from N, A, F, G, I, L, Y or H. The immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 336; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 339, or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 334; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 337; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 340; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 3; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 33; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYAY (SEQ ID NO: 249); or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYFY (SEQ ID NO: 250); or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYGY (SEQ ID NO: 251), or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYIY (SEQ ID NO: 254); or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYLY (SEQ ID NO: 252); or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO:1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYYY (SEQ ID NO: 253); or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 397; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 398; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 399. In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NOs: 8, 31, 32, 118-119, 130, 150-159, 171- 174. In one embodiment, the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NOs: 8, 31, 32, 118-119, 130, 150-159, 171-174. In another embodiment, the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GGITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E. In an specific embodiment, the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from a) the amino acid sequence GRTFDNX1AMG (SEQ ID NO: 593); wherein the amino acid residue X1 is selected from H, L or E; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTFDNX1AMG (SEQ ID NO: 593); wherein the amino acid residue X1 is selected from H, L or E; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTFDNX1AMG (SEQ ID NO: 593); wherein the amino acid residue X1 is selected from H, L or E; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GGITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E. The immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 594; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 582; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 594; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 583; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 594; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 584; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 594; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 585; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 594; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 586; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 594; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 587; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 594; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 587; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 594; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 588; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 594; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 589; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 594; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 580; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 582; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 595; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 582; or ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 596; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 582. In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NOs: 548, 564-576. In one embodiment, the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NOs: 548, 564-576. In another embodiment, the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 610; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 610; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 610. In a specific embodiment, the immunoglobulin single variable domain of the present technology comprises four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from a) the amino acid sequence GFTFSSYDMS (SEQ ID NO: 611); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GFTFSSYDMS (SEQ ID NO: 611); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GFTFSSYDMS (SEQ ID NO: 611); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence TINRGGSSTS (SEQ ID NO: 612); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GTINRGGSSTS (SEQ ID NO: 612); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence TINRGGSSTS (SEQ ID NO: 612); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GDHRGPWYN (SEQ ID NO: 610); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GDHRGPWYN (SEQ ID NO: 610); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GDHRGPWYN (SEQ ID NO: 610). The immunoglobulin single variable domain of the present technology may comprise four framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 611; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 612; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 610. In some embodiments, the immunoglobulin single variable domain of the present technology has an amino acid sequence with a sequence identity of more than 80%, more than 90% (such as more than 95% or even more then 99%) with one of SEQ ID NOs: 547, 549-563. In one embodiment, the polypeptide of the present technology comprises or consists of the amino acid sequence of SEQ ID NOs: 547, 549-563. In some embodiments, the immunoglobulin single variable domain of the present technology may essentially consist of a VHH, such as a humanized VHH, or a VH, such as a camelized VH, a human VH, a camelized human VH, a domain antibody, a single domain antibody, and/or a dAb. The present technology also relates to polypeptides and constructs comprising such immunoglobulin single variable domain, and optionally further comprising one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers. The immunoglobulin single variable domains of the present technology and polypeptides and constructs comprising said immunoglobulin single variable domains showed a high binding affinity in FACS binding assay on and a high internalization efficacy in FACS internalization assay of BxPC-3 cell line expressing CEACAM5, and could be efficiently produced (e.g., in microbial hosts such as Pichia, e.g., P. pastoris, or in E. coli). In one embodiment, the immunoglobulin single variable domain, polypeptide or construct of the present technology may further comprise one or more other groups, residues, moieties or binding units, optionally linked via one or more peptidic linkers, in which said one or more other groups, residues, moieties or binding units provide the ISVD, polypeptide or construct with increased half- life, compared to the corresponding ISVD, polypeptide or construct without said one or more other groups, residues, moieties or binding units. Said one or more other groups, residues, moieties or binding units that provide the ISVD, polypeptide or construct with increased half-life may be chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that can bind to serum proteins, an Fc portion, and small proteins or peptides that can bind to serum proteins. The binding units that provide the ISVD, polypeptide or construct with increased half-life may be chosen from the group consisting of binding units that can bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG), e.g., human serum albumin. In one embodiment, the binding unit that can bind to serum albumin (such as human serum albumin) is an ISVD. In one embodiment, the ISVD binding to human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which CDR1 is SEQ ID NO: 80, CDR2 is SEQ ID NO: 81, CDR3 is SEQ ID NO: 82. In one embodiment, the ISVD binding to human serum albumin comprises a sequence identity of more than 90% (such as 95%) with SEQ ID NO: 62. In one embodiment, the ISVD binding to human serum albumin comprises or consists of the amino acid sequence of SEQ ID NO: 62. In one embodiment, the ISVD binding to human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 47), ALB23 (SEQ ID NO: 48), ALBX00001 (SEQ ID NO: 61) and ALB23002 (SEQ ID NO: 62). In one embodiment, the ISVD binding to human serum albumin is ALB23002 (SEQ ID NO: 62). Also provided is a nucleic acid molecule capable of expressing the immunoglobulin single variable domain or polypeptide of the present technology, a vector comprising the nucleic acid, and a composition comprising the polypeptide, nucleic acid or vector. Also provided is a (non-human) host or host cell comprising such a nucleic acid. Also provided is a method for producing an immunoglobulin single variable domain or polypeptide of the present technology, said method at least comprising the steps of: a) expressing, in a suitable host cell or (non-human) host organism or in another suitable expression system, a nucleic acid encoding the immunoglobulin single variable domain or polypeptide of the present technology; optionally followed by: b) isolating and/or purifying the ISVD or polypeptide. Also provided is a composition comprising at least one immunoglobulin single variable domain, polypeptide or construct of the present technology, or a nucleic acid encoding an immunoglobulin single variable or polypeptide of the present technology. The composition of the present technology is for use as a medicament. The composition can be a pharmaceutical composition which further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and optionally comprises one or more further pharmaceutically active polypeptides and/or compounds. The immunoglobulin single variable domain, polypeptide or construct of the present technology, a composition comprising the immunoglobulin single variable domain, polypeptide or construct, and a composition comprising a nucleic acid comprising a nucleotide sequence that encodes the immunoglobulin single variable domain or polypeptide can be used as a medicament. The immunoglobulin single variable domain, polypeptide, construct or composition of the present technology can be used in the treatment. More specifically, the immunoglobulin single variable, polypeptide, construct or composition can be used in the treatment of cancer. Accordingly, the present technology also encompasses a method of treating cancer. In some embodiments, the present technology encompasses a method of treating cancer, wherein said method comprises administering, to a subject in need thereof, a pharmaceutically active amount of an immunoglobulin single variable domain, polypeptide or construct of the present technology, a nucleic acid encoding an ISVD or polypeptide of the present technology or a composition comprising the same. Accordingly, the present technology also encompasses the use of an immunoglobulin single domain, polypeptide or construct of the present technology in the preparation of a pharmaceutical composition for treating cancer. 4 Brief Description of Drawings In order to best describe the manner in which the above-described embodiments are implemented, as well as define other advantages and features of the disclosure, a more particular description is provided below and is illustrated in the appended drawings. Understanding that these drawings depict only exemplary embodiments of the invention and are thus not to be considered to be limiting in scope, the examples will be described and explained with additional specificity and detail through the use of the accompanying drawings in which: Figure 1: Characterization by flow cytometry of the binding of anti-CEACAM5 VHHs on MKN45 cells. The FACS assay was conducted with 3 dilutions of non-purified VHHs produced in E. coli as described in Example 8 (section 2.8.1). Figure 2: Quality check of unpurified VHH-HA-His produced in FreeStyle 293-F cells with SDS-PAGE. Following clones are shown: line 1: 14R04-02 ; line 2 : 14R04-03 ; line 3 : 14R04-04; line 4: 14R04- 05; line 5: 14R04-06; line 6: 14R04-07; line 7: 14R04-08; line 8: 14R04-09; line 9: 14R04-10; line 10: 14R04-11; line 11: 14R04-12; line 12: 14R04-13; line 13: 14R04-14; line 14: 14R04-15; line 15: 14R04-16; line 16: 14R04-17; line 17: 14R04-18; line 18: 14R04-19; line 19: 14R04-20; line 20: 14R04-21; line 21: 14R04-22. Figure 3A and 3B: EC50 determination of anti-CEACAM5 VHHs by ELISA on hCEACAM5 and cCEACAM5. The ELISA assay was conducted with serial dilutions of non-purified VHHs produced in FreeStyle 293-F cells. Figure 4A and 4B: Evaluation of the affinity constant (KD) and maximum binding capacity (Bmax) to MKN45 cell line by flow cytometry. The FACS assay was conducted with serial dilutions of non- purified VHHs produced in FreeStyle 293-F cells. Figure 5: EC50 determination of anti-CEACAM5 VHHs by ELISA on (A) hCEACAM5 and (B) hCEACAM6. Figure 6: Characterization by flow cytometry of the binding of anti-CEACAM5 VHHs on LS174T cells. Figure 7a and 7b: Evaluation of the internalization of VHHs on LS174T cell line. The ISVD applied to the cell line are indicated in the legend. pHrhodo: only the pHrhodo anti-Flag antibody was applied; IRR: an ISVD not binding to CEACAM5 was applied to the cell line. Figure 8: Detailed views of interactions between the A2-B2 domains of hCEACAM5 and ISVD T232000134. (A) Epitope-paratope key interacting residues between the A2-B2 domains of hCEACAM5 and T232000134, dotted line represents H-bond interactions (magenta) and salt bridges (dark gray). The residues from T232000134 are indicated with “VHH”. (B) Key interacting residues of paratope located at <3.8Å distance from the hCEACAM5, backbone is in blue, and residues are shown with side chains in Yellow. (C) Key interacting residues of epitope located at < 3.8Å distance from IVSD T232000134, interacting residues are shown in colored in light see green. Figure 9: Detailed views of interactions between the A2-B2 domains of hCEACAM5 and ISVD 2G08. (A) Epitope-paratope key interacting residues between the A2-B2 domains of hCEACAM5 and 2G08, dotted line represents H-bond interactions (dark gray). The residues from ISVD 2G08 are indicated with “VHH”. (B) Key interacting residues of paratope located at <3.8Å distance from the hCEACAM5, backbone is in brown, and residues are shown with side chains in Yellow. (C) Key interacting residues of epitope located at < 3.8Å distance from IVSD 2G08, interacting residues are shown in colored in light see brown. 5 Detailed description of the present technology 5.1 Definitions Unless indicated or defined otherwise, all terms used have their usual meaning in the art, which will be clear to the skilled person. Reference is for example made to the standard handbooks, such as Sambrook et al. (Molecular Cloning: A Laboratory Manual (2nd.Ed.) Vols.1-3, Cold Spring Harbor Laboratory Press, 1989), F. Ausubel et al. (Current protocols in molecular biology, Green Publishing and Wiley Interscience, New York, 1987), Lewin (Genes II, John Wiley & Sons, New York, N.Y., 1985), Old et al. (Principles of Gene Manipulation: An Introduction to Genetic Engineering (2nd edition) University of California Press, Berkeley, CA, 1981); Roitt et al. (Immunology (6th. Ed.) Mosby/Elsevier, Edinburgh, 2001), Roitt et al. (Roitt’s Essential Immunology (10th Ed.) Blackwell Publishing, UK, 2001), and Janeway et al. (Immunobiology (6th Ed.) Garland Science Publishing/Churchill Livingstone, New York, 2005), as well as to the general background art cited herein. Unless indicated otherwise, all methods, steps, techniques and manipulations that are not specifically described in detail can be performed and have been performed in a manner known per se, as will be clear to the skilled person. Reference is for example again made to the standard handbooks and the general background art mentioned herein and to the further references cited therein; as well as to for example the following reviews Presta (Adv. Drug Deliv. Rev.58 (5-6): 640- 56, 2006), Levin and Weiss (Mol. Biosyst. 2(1): 49-57, 2006), Irving et al. (J. Immunol. Methods 248(1-2): 31-45, 2001), Schmitz et al. (Placenta 21 Suppl. A: S106-12, 2000), Gonzales et al. (Tumour Biol. 26(1): 31-43, 2005), which describe techniques for protein engineering, such as affinity maturation and other techniques for improving the specificity and other desired properties of proteins such as immunoglobulins. The term “sequence” as used herein (for example in terms like “immunoglobulin sequence”, “antibody sequence”, “variable domain sequence”, “VHH sequence” or “protein sequence”), should generally be understood to include both the relevant amino acid sequence as well as nucleic acids or nucleotide sequences encoding the same, unless the context requires a more limited interpretation. Amino acid residues will be indicated according to the standard three-letter or one-letter amino acid code. Reference is made to Table A-2 on page 48 of WO 08/020079. A nucleic acid or amino acid is considered to be “(in) (essentially) isolated (form)” - for example, compared to the reaction medium or cultivation medium from which it has been obtained - when it has been separated from at least one other component with which it is usually associated in said source or medium, such as another nucleic acid, another protein/polypeptide, another biological component or macromolecule or at least one contaminant, impurity or minor component. In particular, a nucleic acid or amino acid is considered “(essentially) isolated” when it has been purified at least 2-fold, in particular at least 10-fold, more in particular at least 100-fold, and up to 1000-fold or more. A nucleic acid or amino acid that is “in (essentially) isolated form” is preferably essentially homogeneous, as determined using a suitable technique, such as a suitable chromatographical technique, such as polyacrylamide-gel electrophoresis. When a nucleotide sequence or amino acid sequence is said to “comprise” another nucleotide sequence or amino acid sequence, respectively, or to “essentially consist of” another nucleotide sequence or amino acid sequence, this may mean that the latter nucleotide sequence or amino acid sequence has been incorporated into the first mentioned nucleotide sequence or amino acid sequence, respectively, but more usually this generally means that the first mentioned nucleotide sequence or amino acid sequence comprises within its sequence a stretch of nucleotides or amino acid residues, respectively, that has the same nucleotide sequence or amino acid sequence, respectively, as the latter sequence, irrespective of how the first mentioned sequence has actually been generated or obtained (which may for example be by any suitable method described herein). By means of a non-limiting example, when a polypeptide is said to comprise an immunoglobulin single variable domain, this may mean that said immunoglobulin single variable domain sequence has been incorporated into the sequence of the polypeptide, but more usually this generally means that the polypeptide contains within its sequence the sequence of the immunoglobulin single variable domains irrespective of how said polypeptide has been generated or obtained. Also, when a nucleic acid or nucleotide sequence is said to comprise another nucleotide sequence, the first mentioned nucleic acid or nucleotide sequence is preferably such that, when it is expressed into an expression product (e.g., a polypeptide), the amino acid sequence encoded by the latter nucleotide sequence forms part of said expression product (in other words, that the latter nucleotide sequence is in the same reading frame as the first mentioned, larger nucleic acid or nucleotide sequence). By “(essentially) consist of” is meant that the later nucleic acid sequence or amino acid sequence, either is exactly the same as the polypeptide (e.g., the CDR region; the ISVD) or corresponds to the polypeptide (e.g., the CDR region; the ISVD) which has a limited number of amino acid residues, such as 1-20 amino acid residues, for example 1-10 amino acid residues and preferably 1-6 amino acid residues, such as 1, 2, 3, 4, 5 or 6 amino acid residues, added at the amino terminal end, at the carboxy terminal end, or at both the amino terminal end and the carboxy terminal end of the immunoglobulin single variable domain. For the purposes of comparing two or more amino acid sequences, the percentage of “sequence identity” between a first amino acid sequence and a second amino acid sequence may be calculated by dividing [the number of amino acid residues in the first amino acid sequence that are identical to the amino acid residues at the corresponding positions in the second amino acid sequence] by [the total number of amino acid residues in the first amino acid sequence] and multiplying by [100%], in which each deletion, insertion, substitution or addition of an amino acid residue in the second amino acid sequence - compared to the first amino acid sequence - is considered as a difference at a single amino acid residue (i.e., at a single position). Usually, for the purpose of determining the percentage of “sequence identity” between two amino acid sequences in accordance with the calculation method outlined hereinabove, the amino acid sequence with the greatest number of amino acid residues will be taken as the “first” amino acid sequence, and the other amino acid sequence will be taken as the “second” amino acid sequence. An “amino acid difference” as used herein refers to a deletion, insertion or substitution of a single amino acid residue vis-à-vis a reference sequence. In one embodiment, an “amino acid difference” is a substitution. In one embodiment, amino acid substitutions are conservative substitutions. Such conservative substitutions are substitutions in which one amino acid within the following groups (a) – (e) is substituted by another amino acid residue within the same group: (a) small aliphatic, nonpolar or slightly polar residues: Ala, Ser, Thr, Pro and Gly; (b) polar, negatively charged residues and their (uncharged) amides: Asp, Asn, Glu and Gln; (c) polar, positively charged residues: His, Arg and Lys; (d) large aliphatic, nonpolar residues: Met, Leu, Ile, Val and Cys; and (e) aromatic residues: Phe, Tyr and Trp. In one embodiment, conservative substitutions are as follows: Ala into Gly or into Ser; Arg into Lys; Asn into Gln or into His; Asp into Glu; Cys into Ser; Gln into Asn; Glu into Asp; Gly into Ala or into Pro; His into Asn or into Gln; Ile into Leu or into Val; Leu into Ile or into Val; Lys into Arg, into Gln or into Glu; Met into Leu, into Tyr or into Ile; Phe into Met, into Leu or into Tyr; Ser into Thr; Thr into Ser; Trp into Tyr; Tyr into Trp; and/or Phe into Val, into Ile or into Leu. The “aliphatic index”, as used herein, refers to the relative volume occupied by aliphatic side chains (alanine, valine, isoleucine, and leucine)- The aliphatic index of a protein is calculated according to the following formula:Aliphatic index = X(Ala) + a * X(Val) + b * [X(Ile) + X(Leu)] where X(Ala), X(Val), X(Ile), and X(Leu) are mole percent (100 X mole fraction) of alanine, valine, isoleucine, and leucine. The coefficients a and b are the relative volume of valine side chain (a = 2.9) and of Leu/Ile side chains (b = 3.9) to the side chain of alanine (Ikai, A. "Thermostability and aliphatic index of globular proteins." The Journal of Biochemistry 88.6 (1980): 1895-1898). The “GRAVY value” (grand average of hydropathicity value), as used herein, is calculated as the sum of hydropathy value of all the amino acids, divided by the number of residues in the sequence (Kyte, J. "A simple method for displaying the hydropathic character of a protein." J. Mol. Biol.268 (1993): 10558-10563). A “VHH family”, as used in the present specification refers to a group of VHH sequences that have identical lengths (i.e., they have the same number of amino acids within their sequence) and of which the amino acid sequence between position 8 and position 106 (according to Kabat numbering) has an amino acid sequence identity of 89% or more. The terms “epitope” and “antigenic determinant”, which can be used interchangeably, refer to the part of a macromolecule, such as a polypeptide or protein that is recognized by antigen-binding molecules, such as immunoglobulins, conventional antibodies, or immunoglobulin single variable domains, and more particularly by the antigen-binding site of said molecules. Epitopes define the minimum binding site for an immunoglobulin, and thus represent the target of specificity of an immunoglobulin. The part of an antigen-binding molecule (such as an immunoglobulin, a conventional antibody, an immunoglobulin single variable domain) that recognizes the epitope is called a “paratope”. A polypeptide (such as an immunoglobulin, an antibody, an immunoglobulin single variable domain, or generally an antigen binding molecule or a fragment thereof) that can “bind to” or “specifically bind to”, that “has affinity for” and/or that “has specificity for” a certain epitope, antigen or protein (or for at least one part, fragment or epitope thereof) is said to be "against" or “directed against” said epitope, antigen or protein or is a “binding” molecule with respect to such epitope, antigen or protein, or is said to be “anti”-epitope, “anti”-antigen or “anti”-protein (e.g., “anti”- CEACAM5). The terms “specificity”, “binding specifically” or “specific binding” refer to the number of different target molecules, such as antigens, from the same organism to which a particular binding unit, such as an ISVD, can bind with sufficiently high affinity (see below). “Specificity”, “binding specifically” or “specific binding” are used interchangeably herein with “selectivity”, “binding selectively” or “selective binding”. Binding units, such as ISVDs, specifically bind to their designated targets. The specificity/selectivity of a binding unit can be determined based on affinity. The affinity denotes the strength or stability of a molecular interaction. The affinity is commonly given by the KD, or dissociation constant, which has units of mol/liter (or M). The affinity can also be expressed as an association constant, KA, which equals 1/KD and has units of (mol/liter)-1 (or M-1). The affinity is a measure for the binding strength between a moiety and a binding site on the target molecule: the lower the value of the KD, the stronger the binding strength between a target molecule and a targeting moiety. Typically, binding units used in the present technology, such as ISVDs, will bind to their targets with a dissociation constant (KD) of 10-5 to 10-12 moles/liter or less, 10-7 to 10-12 moles/liter or less, or 10-8 to 10-12 moles/liter (i.e., with an association constant (KA) of 105 to 1012 liter/moles or more, 107 to 1012 liter/moles or more, or 108 to 1012 liter/moles). Any KD value greater than 10-4 mol/liter (or any KA value lower than 104 liters/mol) is generally considered to indicate non-specific binding. The KD for biological interactions, such as the binding of immunoglobulin sequences to an antigen, which are considered specific are typically in the range of 10-5 moles/liter (10000 nM or 10µM) to 10-12 moles/liter (0.001 nM or 1 pM) or less. Accordingly, specific/selective binding may mean that -using the same measurement method, e.g., SPR- a binding unit (or polypeptide comprising the same) binds to CEACAM5 with a KD value of 10- 5 to 10-12 moles/liter or less and binds to related CEACAMs members with a KD value greater than 10-4 moles/liter. An example of a related CEACAMs member is CEACAM1, CEACAM6, CEACAM7 and CEACAM8. Thus, in an embodiment of the present technology, the ISVD binds to (human) CEACAM5 with a KD value of 10-5 to 10-12 moles/liter or less and binds to CEACAM1, CEACAM6, CEACAM7 or CEACAM8 of the same species with a KD value greater than 10-4 moles/liter. Specific binding to a certain target from a certain species does not exclude that the binding unit can also specifically bind to the analogous target from a different species. For example, specific binding to human CEACAM5 does not exclude that the binding unit or a polypeptide comprising the same can also specifically bind to CEACAM5 from cynomolgus monkeys (“cyno”). Specific binding of a binding unit to its designated target can be determined in any suitable manner known per se, including, for example, Scatchard analysis and/or competitive binding assays, such as radioimmunoassays (RIA), enzyme immunoassays (EIA) and sandwich competition assays, and the different variants thereof known per se in the art; as well as the other techniques mentioned further herein. The dissociation constant may be the actual or apparent dissociation constant, as will be clear to the skilled person. Methods for determining the dissociation constant will be clear to the skilled person, and for example include the techniques mentioned herein. In this respect, it will also be clear that it may not be possible to measure dissociation constants of more than 10-4 moles/liter or 10-3 moles/liter (e.g., of 10-2 moles/liter). Optionally, as will also be clear to the skilled person, the (actual or apparent) dissociation constant may be calculated on the basis of the (actual or apparent) association constant (KA), by means of the relationship [KD = 1/KA]. An amino acid sequence is said to be “cross-reactive” for two different antigens or antigenic determinants (such as e.g., serum albumin from two different species of mammal, such as e.g., human serum albumin and cyno serum albumin, such as e.g., CEACAM5 from different species of mammal, such as e.g., human CEACAM5, cyno CEACAM5 and mouse CEACAM5) if it is specific for (as defined herein) these different antigens or antigenic determinants. The terms “block”, “antagonize”, “compete”, “competing” and “competition” are used interchangeably herein to mean the ability of an immunoglobulin, antibody, immunoglobulin single variable domain, polypeptide or other binding agent to interfere with the binding of another protein, polypeptides, ligand or binding agent to a given target. The extent to which an immunoglobulin, antibody, immunoglobulin single variable domain, polypeptide or other binding agent is able to interfere with the binding of another ligand to the target, and therefore whether it can be said to “block”, can be determined using competition binding assays. Particularly suitable quantitative competitive blocking assays are described in the Examples and include, e.g., a fluorescence-activated cell sorting (FACS) binding assay with CEACAM5 expressed on cells. The extent of blocking can be measured by the (reduced) channel fluorescence. The following generally describes a suitable FACS assay for determining whether an immunoglobulin, antibody, immunoglobulin single variable domain, polypeptide or other binding agent blocks or is capable of blocking. It will be appreciated that the assay can be used with any of the immunoglobulin single variable domains and polypeptides described herein. The FACS instrument (e.g., FACS Canto; Becton Dickinson) is operated in line with the manufacturer's recommendations. To evaluate the “blocking” or “competition” between two binding agents (such as an immunoglobulin single variable domain and a natural ligand or another binding agent) for binding CEACAM5, a FACS competition experiment can be performed using cells (such as, e.g., Flp-In™-293 cells) overexpressing human CEACAM5 and the parental cells as background cell line. Different detection reagents can be used including, e.g., monoclonal ANTI-FLAG® M2 antibody (Sigma- Aldrich, cat# F1804), monoclonal anti-C-myc antibody (Sigma-Aldrich, cat# WH0004609M2), monoclonal ANTI-HIS TAG antibody (Sigma-Aldrich, cat# SAB1305538), each labeled differently. A wide range of fluorophores can be used as labels in flow cytometry (such as, e.g., PE (R- Phycoerythrin), 7-aminoactinomycin D (7-AAD), Acridine Orange, various forms of Alexa Fluor, Allophycocyanin (APC), AmCyan, Aminocoumarin, APC Cy5, APC Cy7, APC-H7, APC/Alexa Fluor 750, AsRed2, Azami-Green, Azurite, B ODIPY FL C5-ceramide, BCECF-AM, Bis-oxonol DiBAC2(3), BODIPY- FL, Calcein, Calcein AM, Caroxy-H2DCFDA, Cascade Blue, Cascade Yellow, Cell Tracker Green, Cerulean, CFSE, Chromomycin A3, CM-H2DCFDA, Cy2, Cy3, Cy3.5, Cy3B, Cy5, Cy5.5, Cy7, CyPet, DAF-FM DAF-FM diacetate, DAPI, DCFH (2'7'Dichorodihydrofluorescein), DHR, Dihydrocalcein AM, Dihydrorhoadamine, Dihydrothidium, DiLC1(5), DiOC6(3), DiOC7(3), dKeima-Red, DRAQ5, Dronpa- Green, various forms of DsRed dTomato, various forms of DyLight, E.coli BioParticles AF488, E2- Crimson, E2-Orange, EBFP2, ECFP, various forms of eFluor, EGFP, EGFP*, Emerald, eqFP650, eqFP670, ER-Tracker Blue-White DPX, Ethidium Bromide, Express2, EYFP, Fc OxyBurst Green, Fc OxyBurst Green 123, FITC, Fluo-3, Fluo-4, Fluorescein, Fura-2, Fura-Red, GFPuv, H2DCFDA, HcRed1, Hoechst Blue (33258), Hoechst Red (33342), Hydroxycoumarin, HyPer, Indo-1, Indo-1 Blue (Low Ca2+), Indo-1 Violet (High Ca2+), iRFP, J-Red, JC-1, JC-9, Katushka (TurboFP635), Katushka2 Kusabira-Orange, LDS 751, Lissamine Rhodamine B, various forms of Live/Dead, Lucifer yellow, Lucifer Yellow CH, Lyso Tracker Blue, Lyso Tracker Green, Lyso Tracker Red, mAmertrine, Marina Blue, mBanana, mCFP, mCherry, mCitrine, Methoxycoumarin, mHoneyDew, Midoriishi-Cyan, Mithramycin, Mito Tracker Deep Red, Mito Tracker Green, Mito Tracker Orange, Mito Tracker Red, MitoFluor Green, mKate (TagFP635), mKate2, mKeima, mKeima-Red, mKO, mKOk, mNeptune, Monochlorobimane, mOrange, mOrange2, mRaspberry, mPlum, mRFP1, mStrawberry, mTangerine, mTarquoise, mTFP1, mTFP1 (Teal), NBD, OxyBurst Green H2DCFDA, OxyBurst Green H2HFF BSA, Pacific Blue, PE (R-Phycoerythrin), PE Cy5, PE Cy5.5, PE Cy7, PE Texas Red, PE-Cy5 conjugates, PE-Cy7 conjugates, PerCP (Peridinin chlorphyll protein), PerCP Cy5.5, PhiYFP, PhiYFP-m, Propidium Iodide (PI), various forms of Qdot, Red 613, RFP Tomato, Rhod-2, S65A, S65C, S65L, S65T, Singlet Oxygen Sensor Green, Sirius, SNARF, Superfolder GFP, SYTOX Blue, SYTOX Green, SYTOX Orange, T-Sapphire, TagBFP, TagCFP, TagGFP, TagRFP, TagRFP657, TagYFP, tdTomato, Texas Red, Thiazole Orange, TMRE, TMRM, Topaz, TOTO-1, TO-PRO-1, TRITC, TRITC TruRed, TurboFP602, TurboFP635, TurboGFP, TurboRFP, TurboYFP, Venus, Vybrant CycleDye Violet, Wild Type GFP, X- Rhodamin, Y66F, Y66H, Y66W, YOYO-1, YPet, ZsGreen1, ZsYellow1, Zymosan A BioParticles AF488 (see more at: http://www.thefcn.org/flow-fluorochromes). Fluorophores, or simply “fluors”, are typically attached to the antibody (e.g., the immunoglobulin single variable domain) that recognizes CEACAM5 or to the antibody that is used as detection reagent. Various conjugated antibodies are available, such as (without being limiting) for example antibodies conjugated to Alexa Fluor®, DyLight®, Rhodamine, PE, FITC, and Cy3. Each fluorophore has a characteristic peak excitation and emission wavelength. The combination of labels which can be used will depend on the wavelength of the lamp(s) or laser(s) used to excite the fluorophore and on the detectors available. To evaluate the competition between two test binding agents (termed A and B) for binding to CEACAM5, a dilution series of cold (without any label) binding agent A is added to (e.g., 200000) cells together with the labeled binding agent B*. The concentration of binding agent B* in the test mix should be high enough to readily saturate the binding sites on CEACAM5 expressed on the cells. The concentration of binding agent B* that saturates the binding sites for that binding agent on CEACAM5 expressed on the cells can be determined with a titration series of binding agent B* on the CEACAM5 cells and determination of the EC50 value for binding. In order to work at saturating concentration, binding agent B* can be used at 100x the EC50 concentration. After incubation of the cells with the mixture of binding agent A and binding agent B* and cells wash, read out can be performed on a FACS. First a gate is set on the intact cells as determined from the scatter profile and the total amount of channel fluorescence is recorded. A separate solution of binding agent B* is also prepared. Binding agent B* in this solution should be in the same buffer and at the same concentration as in the test mix (with binding agent A and B*). This separate solution is also added to the cells. After incubation and cells wash, read out can be performed on a FACS. First a gate is set on the intact cells as determined from the scatter profile and the total amount of channel fluorescence is recorded. A reduction of fluorescence for the cells incubated with the mixture of binding agent A and B* compared to the fluorescence for the cells incubated with the separate solution of binding agent B* indicates that binding agent A blocks binding by binding agent B* to CEACAM5 expressed on the cells. A cross-blocking immunoglobulin, antibody, immunoglobulin single variable domain, polypeptide or other binding agent is one which will bind to the CEACAM5 in the above competition FACS such that during the assay and in the presence of the second binding agent the recorded fluorescence is between 80% and 0.1% (e.g., 80% to 4%) of the maximum fluorescence (measured for the separate labelled immunoglobulin, antibody, immunoglobulin single variable domain, polypeptide or other binding agent), specifically between 75% and 0.1% (e.g., 75% to 4%) of the maximum fluorescence, and more specifically between 70% and 0.1% (e.g., 70% to 4%) of maximum fluorescence (as just defined above). The competition between two test binding agents (termed A* and B*) for binding to CEACAM5 can also be evaluated by adding both binding agents, each labeled with a different fluorophore, to the CEACAM5 expressing cells. After incubation and cells wash, read out can be performed on a FACS. A gate is set for each fluorophore and the total amount of channel fluorescence is recorded. Reduction and/or absence of fluorescence of one of the fluorophores indicates blocking by the binding agents for binding to CEACAM5 expressed on the cells. Other methods for determining whether an immunoglobulin, antibody, immunoglobulin single variable domain, polypeptide or other binding agent directed against a target block, is capable of blocking, competitively binds or is competitive as defined herein are described e.g., in Xiao-Chi Jia et al. (Journal of Immunological Methods 288: 91–98, 2004), Miller et al. (Journal of Immunological Methods 365: 118–125, 2011). As used herein, the term "potency" is a measure of the biological activity of an agent, such as an ISVD or polypeptide. Potency of an agent can be determined by any suitable method known in the art, such as for instance as described in the experimental section. Cell culture-based potency assays are often the preferred format for determining biological activity since they measure the physiological response elicited by the agent and can generate results within a relatively short period of time. Various types of cell-based assays, based on the mechanism of action of the product, can be used, such as e.g., in a FACS assay analysing the binding of the immunoglobulin single variable domains of the present technology to human CEACAM5 expressed on BxPC-3 cells, which is a human pancreatic adenocarcinoma cell line (as further described in the Example section). In contrast, the “efficacy” of an agent, such as an ISVD or polypeptide, measures the maximum strength of the effect itself, at saturating agent concentrations. Efficacy indicates the maximum response achievable from the agent. It refers to the ability of the agent to produce the desired (therapeutic) effect. The efficacy of an agent can be evaluated using in vitro functional assays or in vivo models. 5.2 Immunoglobulin single variable domains The present technology aims at providing a novel type of drug for treating diseases associated with CEACAM5. The present inventors have surprisingly found that an immunoglobulin single variable domain comprising a CDR1 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO:1 ; a CDR2 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 2 (AbM); and a CDR3 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 230, or an immunoglobulin single variable domain comprising a CDR1 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 231; a CDR2 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 232; and a CDR3 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 233; or an immunoglobulin single variable domain comprising a CDR1 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 242; a CDR2 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 256; and a CDR3 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 257; or an immunoglobulin single variable domain comprising a CDR1 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 318; a CDR2 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 319; and a CDR3 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 320; or an immunoglobulin single variable domain comprising a CDR1 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 333; a CDR2 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 335; and a CDR3 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 338; or an immunoglobulin single variable domain comprising a CDR1 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 356; a CDR2 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 357; and a CDR3 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 358; or an immunoglobulin single variable domain comprising a CDR1 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 363; a CDR2 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 364; and a CDR3 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 365; or an immunoglobulin single variable domain comprising a CDR1 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 368; a CDR2 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 369; and a CDR3 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 370; or an immunoglobulin single variable domain comprising a CDR1 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 373; a CDR2 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 374; and a CDR3 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 375; or an immunoglobulin single variable domain comprising a CDR1 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 386; a CDR2 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 387; and a CDR3 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 388; or an immunoglobulin single variable domain comprising a CDR1 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 397; a CDR2 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 398; and a CDR3 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 399; or an immunoglobulin single variable domain comprising a CDR1 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 368; a CDR2 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 379; and a CDR3 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 365; or an immunoglobulin single variable domain comprising a CDR1 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 530; a CDR2 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 531; and a CDR3 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 532; or an immunoglobulin single variable domain comprising a CDR1 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 541; a CDR2 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 542; and a CDR3 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 543; or an immunoglobulin single variable domain comprising a CDR1 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 536; a CDR2 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 537; and a CDR3 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 538; or an immunoglobulin single variable domain comprising a CDR1 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 593; a CDR2 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 578; and a CDR3 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 581; or an immunoglobulin single variable domain comprising a CDR1 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 611; a CDR2 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 612; and a CDR3 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 610; can bind to CEACAM5 and internalize cells with a high affinity and potency. Moreover, these immunoglobulin single variable domains are highly specific for CEACAM5 and do not bind related CEACAM family members. They are thus a highly specific tool that can be used in the detection, targeting and/or treatment of diseases associated with CEACAM5. The term “immunoglobulin single variable domain” (ISVD), interchangeably used with “single variable domain”, defines immunoglobulin molecules wherein the antigen binding site is present on, and formed by, a single immunoglobulin domain. This sets immunoglobulin single variable domains apart from “conventional” immunoglobulins (e.g., monoclonal antibodies) or their fragments (such as Fab, Fab’, F(ab’)2, scFv, di-scFv), wherein two immunoglobulin domains, in particular two variable domains, interact to form an antigen binding site. Typically, in conventional immunoglobulins, a heavy chain variable domain (VH) and a light chain variable domain (VL) interact to form an antigen binding site. In this case, the complementarity determining regions (CDRs) of both VH and VL will contribute to the antigen binding site, i.e., a total of 6 CDRs will be involved in antigen binding site formation. In view of the above definition, the antigen-binding domain of a conventional 4-chain antibody (such as an IgG, IgM, IgA, IgD or IgE molecule; known in the art) or of a Fab fragment, a F(ab')2 fragment, an Fv fragment such as a disulfide linked Fv or a scFv fragment, or a diabody (all known in the art) derived from such conventional 4-chain antibody, would normally not be regarded as an immunoglobulin single variable domain, as, in these cases, binding to the respective epitope of an antigen would normally not occur by one (single) immunoglobulin domain but by a pair of (associating) immunoglobulin domains such as light and heavy chain variable domains, i.e., by a VH- VL pair of immunoglobulin domains, which jointly bind to an epitope of the respective antigen. In contrast, immunoglobulin single variable domains are capable of specifically binding to an epitope of the antigen without pairing with an additional immunoglobulin variable domain. The binding site of an immunoglobulin single variable domain is formed by a single VH, a single VHH or single VL domain. As such, the single variable domain may be a light chain variable domain sequence (e.g., a VL- sequence) or a suitable fragment thereof; or a heavy chain variable domain sequence (e.g., a VH- sequence or VHH sequence) or a suitable fragment thereof; as long as it is capable of forming a single antigen binding unit (i.e., a functional antigen binding unit that essentially consists of the single variable domain, such that the single antigen binding domain does not need to interact with another variable domain to form a functional antigen binding unit). An immunoglobulin single variable domain (ISVD) can for example be a heavy-chain ISVD, such as a VHH, including a humanized VHH, a VH, including a camelized VH and a human VH. In one embodiment, it is a VHH, a camelized VH or humanized VHH. Heavy chain ISVDs can be derived from a conventional four-chain antibody or from a heavy chain antibody. For example, the immunoglobulin single variable domain may be a single domain antibody (or an amino acid sequence that is suitable for use as a single domain antibody), a "dAb" or dAb (or an amino acid sequence that is suitable for use as a dAb) or a NANOBODY® ISVD (as defined herein and including but not limited to a VHH); other single variable domains, or any suitable fragment of any one thereof. In particular, the immunoglobulin single variable domain may be a NANOBODY® ISVD (such as a VHH, including a humanized VHH or camelized VH) or a suitable fragment thereof. [Note: NANOBODY ® and NANOBODIES® are registered trademarks of Ablynx N.V.] “VHH domains”, also known as VHHs, VHH antibody fragments, have originally been described as the antigen binding immunoglobulin variable domain of “heavy chain antibodies” (i.e., of “antibodies devoid of light chains”; Hamers-Casterman et al. Nature 363: 446-448, 1993). The term “VHH domain” has been chosen in order to distinguish these variable domains from the heavy chain variable domains that are present in conventional 4-chain antibodies (which are referred to herein as “VH domains”) and from the light chain variable domains that are present in conventional 4- chain antibodies (which are referred to herein as “VL domains”). For a further description of VHH’s, reference is made to the review article by Muyldermans (Reviews in Molecular Biotechnology 74: 277-302, 2001). The generation of immunoglobulin sequences, such as VHHs, has been described extensively in various publications, among which WO 94/04678, Hamers-Casterman et al.1993 and Muyldermans et al. 2001 (Reviews in Molecular Biotechnology 74: 277-302, 2001). In these methods, camelids are immunized with the target antigen in order to induce an immune response against said target antigen. The repertoire of VHHs obtained from said immunization is further screened for VHHs that bind the target antigen. In these instances, the generation of antibodies requires purified antigen for immunization and/or screening. Antigens can be purified from natural sources, or in the course of recombinant production. Immunization and/or screening for immunoglobulin sequences can be performed using peptide fragments of such antigens. Immunoglobulin sequences of different origin, comprising mouse, rat, rabbit, donkey, human and camelid immunoglobulin sequences can be used in the present technology. Also, fully human, humanized or chimeric sequences can be used. For example, camelid immunoglobulin sequences and humanized camelid immunoglobulin sequences, or camelized domain antibodies, e.g., camelized dAb as described by Ward et al. (see for example WO 94/04678 and Riechmann, Febs Lett., 339:285-290, 1994 and Prot. Eng., 9:531-537, 1996) can be used herein. The ISVDs can be fused forming a multivalent and/or multispecific construct (for multivalent and multispecific polypeptides containing one or more VHH domains and their preparation, reference is also made to Conrath et al. 2001 (J. Biol. Chem., Vol. 276, 10. 7346-7350), as well as to for example WO 96/34103 and WO 99/23221) and immunoglobulin sequences comprising tags or other functional moieties, e.g., toxins, labels, radiochemicals, etc., which are derivable from the immunoglobulin sequences of the present technology. However, it should be noted that the ISVD comprised in the present technology is not limited as to the origin of the ISVD sequence (or of the nucleotide sequence used to express it), nor as to the way that the ISVD sequence or nucleotide sequence is (or has been) generated or obtained. Thus, the ISVD sequences may be naturally occurring sequences (from any suitable species) or synthetic or semi-synthetic sequences. In a specific but non-limiting aspect, the ISVD sequence is a naturally occurring sequence (from any suitable species) or a synthetic or semi-synthetic sequence, including but not limited to “humanized” (as defined herein) immunoglobulin sequences (such as partially or fully humanized camelid, mouse or rabbit immunoglobulin sequences, and in particular partially or fully humanized VHH sequences), “camelized” (as defined herein) immunoglobulin sequences (and in particular camelized VH sequences), as well as ISVDs that have been obtained by techniques such as affinity maturation (for example, starting from synthetic, random or naturally occurring immunoglobulin sequences), CDR grafting, veneering, combining fragments derived from different immunoglobulin sequences, PCR assembly using overlapping primers, and similar techniques for engineering immunoglobulin sequences well known to the skilled person; or any suitable combination of any of the foregoing. Similarly, nucleotide sequences may be naturally occurring nucleotide sequences or synthetic or semi-synthetic sequences, and may for example be sequences that are isolated by PCR from a suitable naturally occurring template (e.g., DNA or RNA isolated from a cell), nucleotide sequences that have been isolated from a library (and in particular, an expression library), nucleotide sequences that have been prepared by introducing mutations into a naturally occurring nucleotide sequence (using any suitable technique known per se, such as mismatch PCR), nucleotide sequence that have been prepared by PCR using overlapping primers, or nucleotide sequences that have been prepared using techniques for DNA synthesis known per se. A “humanized VHH” comprises an amino acid sequence that corresponds to the amino acid sequence of a naturally occurring VHH domain, but that has been “humanized”, i.e., by replacing one or more amino acid residues in the amino acid sequence of said naturally occurring VHH sequence (and in particular in the framework sequences) by one or more of the amino acid residues that occur at the corresponding position(s) in a VH domain from a conventional 4-chain antibody from a human being (e.g., indicated above). This can be performed in a manner known per se, which will be clear to the skilled person, for example on the basis of the prior art (e.g., WO 2008/020079). Again, it should be noted that such humanized VHHs can be obtained in any suitable manner known per se and thus are not strictly limited to polypeptides that have been obtained using a polypeptide that comprises a naturally occurring VHH domain as a starting material. A “camelized VH” comprises an amino acid sequence that corresponds to the amino acid sequence of a naturally occurring VH domain, but that has been “camelized”, i.e., by replacing one or more amino acid residues in the amino acid sequence of a naturally occurring VH domain from a conventional 4-chain antibody by one or more of the amino acid residues that occur at the corresponding position(s) in a VHH domain of a (camelid) heavy chain antibody. This can be performed in a manner known per se, which will be clear to the skilled person, for example on the basis of the description in the prior art (e.g., Davies and Riechman (1994 and 1996), supra). Such “camelizing” substitutions are inserted at amino acid positions that form and/or are present at the VH-VL interface, and/or at the so-called Camelidae hallmark residues, as defined herein (see for example WO 94/04678 and Davies and Riechmann (1994 and 1996), supra). In one embodiment, the VH sequence that is used as a starting material or starting point for generating or designing the camelized VH is a VH sequence from a mammal, such as the VH sequence of a human being, such as a VH3 sequence. However, it should be noted that such camelized VH can be obtained in any suitable manner known per se and thus are not strictly limited to polypeptides that have been obtained using a polypeptide that comprises a naturally occurring VH domain as a starting material. The structure of an immunoglobulin single variable domain sequence can be considered to be comprised of four framework regions (“FRs”), which are referred to in the art and herein as “Framework region 1” (“FR1”); as “Framework region 2” (“FR2”); as “Framework region 3” (“FR3”); and as “Framework region 4” (“FR4”), respectively; which framework regions are interrupted by three complementary determining regions (“CDRs”), which are referred to in the art and herein as “Complementarity Determining Region 1” (“CDR1”); as “Complementarity Determining Region 2” (“CDR2”); and as “Complementarity Determining Region 3” (“CDR3”), respectively. As further described in paragraph q) on pages 58 and 59 of WO 08/020079, the amino acid residues of an ISVD can be numbered according to the general numbering for VH domains given by Kabat et al. (“Sequence of proteins of immunological interest”, US Public Health Services, NIH Bethesda, MD, Publication No. 91), as applied to VHH domains from Camelids in the article of Riechmann and Muyldermans, 2000 (J. Immunol. Methods 240 (1-2): 185-195; see for example Figure 2 of this publication). It should be noted that – as is well known in the art for VH domains and for VHH domains – the total number of amino acid residues in each of the CDRs may vary and may not correspond to the total number of amino acid residues indicated by the Kabat numbering. That is, one or more positions according to the Kabat numbering may not be occupied in the actual sequence, or the actual sequence may contain more amino acid residues than the number allowed for by the Kabat numbering. This means that, generally, the numbering according to Kabat may or may not correspond to the actual numbering of the amino acid residues in the actual sequence. The total number of amino acid residues in a VH domain and a VHH domain will usually be in the range of from 110 to 120, often between 112 and 115. It should however be noted that smaller and longer sequences may also be suitable for the purposes described herein. In the present application, unless indicated otherwise, CDR sequences were determined according to the AbM numbering as described in Kontermann and Dübel (Eds. 2010, Antibody Engineering, vol 2, Springer Verlag Heidelberg Berlin, Martin, Chapter 3, pp.33-51). According to this method, FR1 of an ISVD comprises the amino acid residues at positions 1-25, CDR1 of an ISVD comprises the amino acid residues at positions 26-35, FR2 of an ISVD comprises the amino acids at positions 36- 49, CDR2 of an ISVD comprises the amino acid residues at positions 50-58, FR3 of an ISVD comprises the amino acid residues at positions 59-94, CDR3 of an ISVD comprises the amino acid residues at positions 95-102, and FR4 of an ISVD comprises the amino acid residues at positions 103-113. Determination of CDR regions may also be done according to different methods. In the CDR determination according to Kabat, FR1 of an ISVD comprises the amino acid residues at positions 1-30, CDR1 of an ISVD comprises the amino acid residues at positions 31-35, FR2 of an ISVD comprises the amino acids at positions 36-49, CDR2 of an ISVD comprises the amino acid residues at positions 50-65, FR3 of an ISVD comprises the amino acid residues at positions 66-94, CDR3 of an ISVD comprises the amino acid residues at positions 95-102, and FR4 of an ISVD comprises the amino acid residues at positions 103-113. The framework sequences are (a suitable combination of) immunoglobulin framework sequences or framework sequences that have been derived from immunoglobulin framework sequences (for example, by humanization or camelization). For example, the framework sequences may be framework sequences derived from a light chain variable domain (e.g., a VL-sequence) and/or from a heavy chain variable domain (e.g., a VH-sequence or VHH sequence). In one particular aspect, the framework sequences are either framework sequences that have been derived from a VHH- sequence (in which said framework sequences may optionally have been partially or fully humanized) or are conventional VH sequences that have been camelized (as defined herein). In particular, the framework sequences present in the ISVD sequence used in the methods described herein may contain one or more of hallmark residues (as defined herein), such that the ISVD sequence is a NANOBODY® ISVD, such as, e.g., a VHH, including a humanized VHH, or camelized VH. Non-limiting examples of (suitable combinations of) such framework sequences will become clear from the further disclosure herein. Generally, NANOBODY® ISVDs (in particular VHH sequences, including (partially) humanized VHH sequences and camelized VH sequences) can be characterized by the presence of one or more “Hallmark residues” (as described herein) in one or more of the framework sequences (again as further described herein). Thus, generally, a NANOBODY® ISVD can be defined as an immunoglobulin sequence with the (general) structure FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4 in which FR1 to FR4 refer to framework regions 1 to 4, respectively, and in which CDR1 to CDR3 refer to the complementarity determining regions 1 to 3, respectively, and in which one or more of the Hallmark residues are as further defined herein. In particular, a NANOBODY® ISVD can be an immunoglobulin sequence with the (general) structure FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4 in which FR1 to FR4 refer to framework regions 1 to 4, respectively, and in which CDR1 to CDR3 refer to the complementarity determining regions 1 to 3, respectively, and in which the framework sequences are as further defined herein. More in particular, a NANOBODY® ISVD can be an immunoglobulin sequence with the (general) structure FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4 in which FR1 to FR4 refer to framework regions 1 to 4, respectively, and in which CDR1 to CDR3 refer to the complementarity determining regions 1 to 3, respectively, and in which: one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1 below. Table 1: Hallmark Residues in NANOBODY® ISVDs Position Human VH3 Hallmark Residues 11 L, V; predominantly L L, S, V, M, W, F, T, Q, E, A, R, G, K, Y, N, P, I; preferably L 37 V, I, F; usually V F(1), Y, V, L, A, H, S, I, W, C, N, G, D, T, P, preferably F(1) or Y 44(8) G E(3), Q(3), G(2), D, A, K, R, L, P, S, V, H, T, N, W, M, I; preferably G(2), E(3) or Q(3);most preferably G(2) or Q(3) . 45(8) L L(2), R(3), P, H, F, G, Q, S, E, T, Y, C, I, D, V; preferably L(2) or R(3) 47(8) W, Y F(1), L(1) or W(2) G, I, S, A, V, M, R, Y, E, P, T, C, H, K, Q, N, D; preferably W(2) , L(1) or F(1) 83 R or K; usually R R, K(5), T, E(5), Q, N, S, I, V, G, M, L, A, D, Y, H; preferably K or R; most preferably K 84 A, T, D; predominantly A P(5), S, H, L, A, V, I, T, F, D, R, Y, N, Q, G, E; preferably P 103 W W(4), R(6), G, S, K, A, M, Y, L, F, T, N, V, Q, P(6), E, C; preferably W 104 G G, A, S, T, D, P, N, E, C, L; preferably G 108 L, M or T; predominantly L Q, L(7), R, P, E, K, S, T, M, A, H; preferably Q or L(7) Notes: (1) In particular, but not exclusively, in combination with KERE or KQRE at positions 43-46. (2) Usually as GLEW at positions 44-47. (3) Usually as KERE or KQRE at positions 43-46, e.g., as KEREL, KEREF, KQREL, KQREF, KEREG, KQREW or KQREG at positions 43-47. Alternatively, also sequences such as TERE (for example TEREL), TQRE (for example TQREL), KECE (for example KECEL or KECER), KQCE (for example KQCEL), RERE (for example REREG), RQRE (for example RQREL, RQREF or RQREW), QERE (for example QEREG), QQRE, (for example QQREW, QQREL or QQREF), KGRE (for example KGREG), KDRE (for example KDREV) are possible. Some other possible, but less preferred sequences include for example DECKL and NVCEL. (4) With both GLEW at positions 44-47 and KERE or KQRE at positions 43-46. (5) Often as KP or EP at positions 83-84 of naturally occurring VHH domains. (6) In particular, but not exclusively, in combination with GLEW at positions 44-47. (7) With the proviso that when positions 44-47 are GLEW, position 108 is always Q in (non-humanized) VHH sequences that also contain a W at 103. (8) The GLEW group also contains GLEW-like sequences at positions 44-47, such as for example GVEW, EPEW, GLER, DQEW, DLEW, GIEW, ELEW, GPEW, EWLP, GPER, GLER and ELEW. The present technology relates to ISVDs that specifically bind to CEACAM5. Accordingly, the target molecules for the ISVDs is CEACAM5. Examples are mammalian CEACAM5. Besides human CEACAM5 (SEQ ID NO: 26), the versions from other species are also amenable to the present technology, for example CEACAM5 from mice, rats, rabbits, cats, dogs, goats, sheep, horses, pigs, non-human primates, such as cynomolgus monkeys (also referred to herein as “cyno”), or camelids, such as llama or alpaca. In some embodiments, the ISVDs of the present technology bind to human CEACAM5 (hCEACAM5; SEQ ID NO: 26). In some embodiments, the ISVDs of the present technology bind to human CEACAM5 and cyno CEACAM5 (cCEACAM5; SEQ ID NO: 27). Sequences of human, and cyno CEACAM5 are depicted in Table A-1 (SEQ ID NOs: 26 and 27). The immunoglobulin single variable domains of the present technology show a highly affinity on CEACAM5 (e.g., as measured by SPR) as a (monovalent) single variable domain. In some embodiments, the immunoglobulin single variable domains of the present technology show a high potency for binding CEACAM5 on cells (e.g., as measured in (FACS) binding assay) as a (monovalent) single variable domain. In some embodiments, the immunoglobulin single variable domains of the present technology show a high potency for internalization of CEACAM5 expressing cells (e.g., as measured in internalization assay, for example as described herein) as a (monovalent) single variable domain. In some embodiments, the immunoglobulin single variable domains of the present technology are efficiently produced (e.g., in microbial hosts, such as Pichia, e.g., P. pastoris), even when encompassed with binders to other targets, and have good stability. Because of their small size, (monovalent) immunoglobulin single variable domains are more efficient for the penetration of epithelial tissues. In addition, they are easily combined with other cancer target binders in a multivalent polypeptide when the simultaneous targeting of multiple cancer targets is intended, e.g., as multivalent ISVD construct. The high production yields and better stability demonstrated for immunoglobulin single variable domains makes them ideally suited for subcutaneous administration. In some embodiments, the immunoglobulin single variable domains of the present technology show a highly affinity on CEACAM5 as a (monovalent) single variable domain. The affinity of a molecular interaction between two molecules can be measured via different techniques known per se, such as the well-known surface plasmon resonance (SPR) biosensor technique (see for example Ober et al. 2001, Intern. Immunology 13: 1551-1559). The term "surface plasmon resonance" or “SPR”, as used herein, refers to an optical phenomenon that allows for the analysis of real-time biospecific interactions by detection of alterations in protein concentrations within a biosensor matrix, where one molecule is immobilized on the biosensor chip and the other molecule is passed over the immobilized molecule under flow conditions yielding kon, koff measurements and hence KD (or KA) values. This can for example be performed using the well-known BIAcore® system (BIAcore International AB, a GE Healthcare company, Uppsala, Sweden and Piscataway, NJ). For further descriptions, see Jonsson et al. 1993 (Ann. Biol. Clin. 51: 19-26), Jonsson et al. 1991 (Biotechniques 11: 620-627), Johnsson et al. 1995 (J. Mol. Recognit. 8: 125-131), and Johnnson et al.1991 (Anal. Biochem.198: 268-277). Another well-known biosensor technique to determine affinities of biomolecular interactions is bio- layer interferometry (BLI) (see for example Abdiche et al.2008, Anal. Biochem.377: 209-217). The term “bio-layer Interferometry” or “BLI”, as used herein, refers to a label-free optical technique that analyzes the interference pattern of light reflected from two surfaces: an internal reference layer (reference beam) and a layer of immobilized protein on the biosensor tip (signal beam). A change in the number of molecules bound to the tip of the biosensor causes a shift in the interference pattern, reported as a wavelength shift (nm), the magnitude of which is a direct measure of the number of molecules bound to the biosensor tip surface. Since the interactions can be measured in real-time, association and dissociation rates and affinities can be determined. BLI can for example be performed using the well-known Octet® Systems (ForteBio, a division of Pall Life Sciences, Menlo Park, USA). Alternatively, affinities can be measured in Kinetic Exclusion Assay (KinExA) (see for example Drake et al. 2004, Anal. Biochem., 328: 35-43), using the KinExA® platform (Sapidyne Instruments Inc, Boise, USA). The term "KinExA", as used herein, refers to a solution-based method to measure true equilibrium binding affinity and kinetics of unmodified molecules. Equilibrated solutions of an antibody/antigen complex are passed over a column with beads precoated with antigen (or antibody), allowing the free antibody (or antigen) to bind to the coated molecule. Detection of the antibody (or antigen) thus captured is accomplished with a fluorescently labeled protein binding the antibody (or antigen). The GYROLAB® immunoassay system provides a platform for automated bioanalysis and rapid sample turnaround (Fraley et al.2013, Bioanalysis 5: 1765-74). 5.2.1 Embodiment 1 -Family 30 Specific examples of ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of GLTFSTYTMG (SEQ ID NO:1); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GLTFSTYTMG (SEQ ID NO: 1); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences GLTFSTYTMG (SEQ ID NO: 1); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AIIWSGSNTY (SEQ ID NO: 2); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AIIWSGSNTY (SEQ ID NO: 2); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AIIWSGSNTY (SEQ ID NO: 2); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of QHFGPIGLTTRGYXY (SEQ ID NO: 230), wherein the amino acid residue X is selected from N, A, F, G, I, L, Y or H; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of QHFGPIGLTTRGYXY (SEQ ID NO: 230), wherein the amino acid residue X is selected from N, A, F, G, I, L, Y or H; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of QHFGPIGLTTRGYXY (SEQ ID NO: 230), wherein the amino acid residue X is selected from N, A, F, G, I, L Y or H. Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 1, 2, and/or 230. In one embodiment, the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 8, 31, 32, 150-159. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 3. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 33. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 249. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 250. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 251. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 252. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 253. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 254. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315007E07 (SEQ ID NO: 8) and sequence optimized variants thereof in Table A-4 (in addition to the CDRs as defined above). In one embodiment, the ISVD comprises or consists of the full amino acid sequence of A0315007E07 (SEQ ID NO: 8); T028501789 (SEQ ID NO: 31), or T028501789 (E1D) (SEQ ID NO: 32), A031500251 (SEQ ID NO: 150), A031500252 (SEQ ID NO: 151), A031500253 (SEQ ID NO: 152), A031500254 (SEQ ID NO: 153), A031500379 (SEQ ID NO: 154), A031500382 (SEQ ID NO: 155), A031500383 (SEQ ID NO: 156), A031500385 (SEQ ID NO: 157), A031500387 (SEQ ID NO: 158), and A031500394 (SEQ ID NO: 159) (see Table A-2, Table A-4). The SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition. As such in one embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of TYTMG (SEQ ID NO: 17); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of TYTMG (SEQ ID NO: 17); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of TYTMG (SEQ ID NO: 17); and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AIIWSGSNTYYADSVKG (SEQ ID NO: 18); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AIIWSGSNTYYADSVKG (SEQ ID NO: 18); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AIIWSGSNTYYADSVKG (SEQ ID NO: 18); and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of QHFGPIGLTTRGYXY (SEQ ID NO: 230), wherein the amino acid residue X is selected from N, A, F, G, I, L, Y or H; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of QHFGPIGLTTRGYXY (SEQ ID NO: 230), wherein the amino acid residue X is selected from N, A, F, G, I, L, Y or H; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of QHFGPIGLTTRGYXY (SEQ ID NO: 230), wherein the amino acid residue X is selected from N, A, F, G, I, L, Y or H. Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 17, 18, and/or 230. In one embodiment, the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 8, 31, 32, 150-159. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 3. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 33. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 249. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 250. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 251. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 252. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 253. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 254. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315007E07 (SEQ ID NO: 8) and sequence optimized variants thereof in Table A-4 (in addition to the CDRs as defined above). In one embodiment, the ISVD comprises or consists of the full amino acid sequence of A0315007E07 (SEQ ID NO: 8); T028501789 (SEQ ID NO: 31), or T028501789 (E1D) (SEQ ID NO: 32), A031500251 (SEQ ID NO: 150), A031500252 (SEQ ID NO: 151), A031500253 (SEQ ID NO: 152), A031500254 (SEQ ID NO: 153), A031500379 (SEQ ID NO: 154), A031500382 (SEQ ID NO: 155), A031500383 (SEQ ID NO: 156), A031500385 (SEQ ID NO: 157), A031500387 ((SEQ ID NO: 158), and A031500394 (SEQ ID NO: 159) (see Table A-2, Table A-4). In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 8, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 8. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 31, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 31. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 32, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 32. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 150, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 150. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 151, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 151. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 152, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 152. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 153, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 153. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 154, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 154. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 155, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 155. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 156, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 156. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 157, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 157. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 158, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 158. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 159, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 159. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 8, 31, 32, 150-159, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 8, 31, 32, 150-159, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 8, 31, 32, 150-159, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 8, 31, 32, 150-159, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 8, 31, 32, 150-159, the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 8, 31, 32, 150-159, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 8, 31, 32, 150-159, the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 8, 31, 32, 150-159, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 8, 31, 32, 150-159, the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 8, 31, 32, 150-159, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 8, 31, 32, 150-159, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8 or other members of the CEACAM family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-8 to 10-10 moles/litre or less and more preferably 1x10-8 to 1x10-9 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 1.34x10-9 moles/litre or 1.24x10-9 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M-1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, such as between 1x105 M-1s-1 and 5x105 M-1s-1, even more preferably of about 3.17x105 M-1s-1 or 7.16x105 M-1s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a koff rate between 10-1 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-2 s-1 and 1x10-6 s-1, more preferably between 5x10-3 s-1 and 1x10-4 s-1, such as between 5x10-3 s-1 and 5x10-4 s-1even more preferably of about 4.24x10-3 s-1or 8.85x10-4 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (KD) of 10-7 to 10-10 moles/litre or less, and preferably 5x10-8 to 10-9 moles/litre or less and more preferably 5x10-8 to 1x10-8 moles/litre, even more preferably wherein the ISVD specifically binds to cyno CEACAM5 with a KD of about 1.76x10-8 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M-1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, such as between 2x105 M-1s-1 and 1x106 M-1s-1, even more preferably of about 2.17x105 M-1s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-5 s-1 (providing a near irreversible complex with a t1/2 of multiple days), 10-2 s-1 and 10-4 s-1, more preferably between 5 x 10-3 s-1 and 5 x 10-4 s-1, such as between 5 x 10-3 s-1 and 1 x 10-3s-1, even more preferably of about 3.81x10-3 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 100-fold lower affinity (KD). In preferred embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno CEACAM1, CEACAM6, CEACAM7 or CEACAM8. A preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay. For instance, the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a BxPC-3 cell line, which is a human pancreatic adenocarcinoma cell line. VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5. For example, in a FACS binding assay with a BxPC-3 cell line expressing human CEACAM5, the immunoglobulin single variable domains of the present technology may have EC50 values of 10-7 M or lower, more preferably of 10-8 M or lower, or even of 10-9 M or lower. For example, in such FACS assay, the immunoglobulin single variable domains of the present technology may have EC50 values between 10-11 M and 10-8 M, such as between 10- 10 M and 10-8 M, between 5x10-9 M and 10-8 M or between 10-9 M and 10-8 M. In some embodiments, the immunoglobulin single variable domains of the present technology has an CEACAM5-mediated internalization potency (EC50 value) of 10-7 M or lower, more preferably of 5x10-8 M or lower, or even of 10-8 M or lower, such as between 10-7 M and 10-10 M, between 10-7 M and 10-9 M, between 5x10-8 M and 10-9 M or between 5x10-8 M and 10-8 M, for example, as measured in a FACS internalization assay on BxPC-3 cells expressing human CEACAM5. 5.2.2 Embodiment 2 -Family 4 Specific examples of ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of GX1TFSX2YAX3G (SEQ ID NO: 231), wherein the amino acid residue X1 is selected from R or H, the amino acid residue X2 is selected from E or D and the amino acid residue X3 is selected from L or M; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GX1TFSX2YAX3G (SEQ ID NO: 231), wherein the amino acid residue X1 is selected from R or H, the amino acid residue X2 is selected from E or D and the amino acid residue X3 is selected from L or M; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences GX1TFSX2YAX3G (SEQ ID NO: 231), wherein the amino acid residue X1 is selected from R or H, the amino acid residue X2 is selected from E or D and the amino acid residue X3 is selected from L or M; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AINWGGXWTY (SEQ ID NO: 232), wherein the amino acid residue X is selected from T, G or S; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AINWGGXWTY (SEQ ID NO: 232), wherein the amino acid residue X is selected from T, G or S; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AINWGGXWTY (SEQ ID NO: 232), wherein the amino acid residue X is selected from T, G or S); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SX1DYAGGX2PTGYX3Y (SEQ ID NO: 233), wherein the amino acid residue X1 is selected from S, P or L, the amino acid residue X2 is selected from N or S, the amino acid residue X3 is selected from P or A; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SX1DYAGGX2PTGYX3Y (SEQ ID NO: 233), wherein the amino acid residue X1 is selected from S, P or L, the amino acid residue X2 is selected from N or S, the amino acid residue X3 is selected from P or A; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SX1DYAGGX2PTGYX3Y (SEQ ID NO: 233), wherein the amino acid residue X1 is selected from S, P or L, the amino acid residue X2 is selected from N or S, the amino acid residue X3 is selected from P or A. Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 231, 232, and/or 233. In one embodiment, the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 16, 39, 40, 120, 121, 135-149. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 9, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 10 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 11. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 234, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 235 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 236. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 234, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 238 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 239. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315024B02 (SEQ ID NO: 16) and sequence optimized variants thereof in Table A-3 (in addition to the CDRs as defined above). In one embodiment, the ISVD comprises or consists of the full amino acid sequence of A0315024B02 (SEQ ID NO: 16); T028501817 (SEQ ID NO: 39), or T028501817(E1D) (SEQ ID NO: 40), A031500086 (SEQ ID NO: 135), A031500087 (SEQ ID NO: 136), A031500088 (SEQ ID NO: 137), A031500089 (SEQ ID NO: 138), A031500090 (SEQ ID NO: 139), A031500091 (SEQ ID NO: 140), A031500092 (SEQ ID NO: 141), A031500093 (SEQ ID NO: 142), A031500094 (SEQ ID NO: 143), A031500095 (SEQ ID NO: 144), A031500096 (SEQ ID NO: 145, A031500097 (SEQ ID NO: 146), A031500098 (SEQ ID NO: 147), and A031500100 (SEQ ID NO: 148) and A031500101 (SEQ ID NO: 149) (see Table A-2, Table A-3). In other embodiments, the ISVD comprises or consists of the full amino acid sequence of A0315001C02 (SEQ ID NO.: 120) or A0315026D05 (SEQ ID NO.: 121), see Table A-2. The SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition. As such in one embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of X1YAX2G (SEQ ID NO: 240), wherein the amino acid residue X1 is selected from E or D, and the amino acid residue X2 is selected from L or M; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of X1YAX2G (SEQ ID NO: 240), wherein the amino acid residue X1 is selected from E or D, and the amino acid residue X2 is selected from L or M; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of X1YAX2G (SEQ ID NO: 240), wherein the amino acid residue X1 is selected from E or D, and the amino acid residue X2 is selected from L or M; and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AINWGGX1WTYYAX2SVX3G (SEQ ID NO: 241); wherein the amino acid residue X1 is selected from G, S or T, and the amino acid residue X2 is selected from H or D, and the amino acid residue X3 is selected from Q or K; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AINWGGX1WTYYAX2SVX3G (SEQ ID NO: 241); wherein the amino acid residue X1 is selected from G, S or T, and the amino acid residue X2 is selected from H or D, and the amino acid residue X3 is selected from Q or K; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AINWGGX1WTYYAX2SVX3QG (SEQ ID NO: 241); wherein the amino acid residue X1 is selected from G, S or T, and the amino acid residue X2 is selected from H or D, and the amino acid residue X3 is selected from Q or K; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SX1DYAGGX2PTGYX3Y (SEQ ID NO: 233), wherein the amino acid residue X1 is selected from S, P or L, the amino acid residue X2 is selected from N or S, the amino acid residue X3 is selected from P or A; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SX1DYAGGX2PTGYX3Y (SEQ ID NO: 233), wherein the amino acid residue X1 is selected from S, P or L, the amino acid residue X2 is selected from N or S, the amino acid residue X3 is selected from P or A; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SX1DYAGGX2PTGYX3Y (SEQ ID NO: 233), wherein the amino acid residue X1 is selected from S, P or L, the amino acid residue X2 is selected from N or S, the amino acid residue X3 is selected from P or A. Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 240, 241, and/or 233. In one embodiment, the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 16, 39, 40, 120, 121, 135-149. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 21, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 22 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 11. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 21, a CDR2 (Kabat numbering) that is the amino acid sequence of (AINWGGGWTYYADSVKG) SEQ ID NO: 43 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 11. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 243, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 244 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 236. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 243, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 245 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 246. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315024B02 (SEQ ID NO: 16) and sequence optimized variants thereof in Table A-3 (in addition to the CDRs as defined above). In one embodiment, the ISVD comprises or consists of the full amino acid sequence of A0315024B02 (SEQ ID NO: 16); T028501817 (SEQ ID NO: 39), or T028501817(E1D) (SEQ ID NO: 40), A031500086 (SEQ ID NO: 135), A031500087 (SEQ ID NO: 136), A031500088 (SEQ ID NO: 137), A031500089 (SEQ ID NO: 138), A031500090 (SEQ ID NO: 139), A031500091 (SEQ ID NO: 140), A031500092 (SEQ ID NO: 141), A031500093 (SEQ ID NO: 142), A031500094 (SEQ ID NO: 143), A031500095 (SEQ ID NO: 144), A031500096 (SEQ ID NO: 145), A031500097 (SEQ ID NO: 146), A031500098 (SEQ ID NO: 147), and A031500100 (SEQ ID NO: 148) and A031500101 (SEQ ID NO: 149) (see Table A-2, Table A-3). In another embodiment, the ISVD comprises or consists of the full amino acid sequence of A0315001C02 (SEQ ID NO: 120) or A0315026D05 (SEQ ID NO: 121), Table A-2. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 16, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 16. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 39, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 39. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 40, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 40. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 120, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 120. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 121, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 121. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 135, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 135. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 136, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 136. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 137, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 137. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 138, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 138. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 139, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 139. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 140, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 140. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 141, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 141. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 142, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 142. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 143, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 143. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 144, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 144. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 145, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 145. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 146, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 146. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 147, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 147. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 148, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 148. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 149, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 149. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 135-149, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 135-149, wherein the binding affinity is measured using the same method, such as, e.g, SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 135-149, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 135-149, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 135-149, the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 135-149, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 135-149, the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 135- 149, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 135-149, the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 135-149, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 135-149, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with dissociation constant (KD) of 10-7 to 10-10 moles/litre or less, and preferably 5x10-8 to 10-9 moles/litre or less and more preferably 5x10-8 to 5x10-9 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 1.06x10-8moles/litre, 4,86x10-9 moles/litre or 8.9x10-9 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M-1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, such as between 1x105 M-1s-1 and 5x105 M-1s-1, even more preferably of about 1.2x105 M-1s-1, 1.6x105 M-1s-1, 1.98x105 M-1s, or 2.38x105 M-1s , as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 5x10-3 s-1 and 5x10-5 s-1, more preferably between 5x10-3 s-1 and 5x10-4 s-1, such as between 5x10-3 s-1 and 1x10-4 s-1, even more preferably of about 1.08x10-3 s-1, 1.7x10-3 s-1, 9.61x10-4 s-1 or 2.12x10-3 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-8 to 10-10 moles/litre or less and more preferably 5x10-9 to 10-9 moles/litre, even more preferably wherein the ISVD specifically binds to cyno CEACAM5 with a KD of about 6.94x10-9moles/litre, 2.28x10-9moles/litre or 4.86x10-9moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M-1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, such as between 2x105 M-1s-1 and 1x106 M-1s-1, even more preferably of about 5.9x105 M-1s-1, 9.94x105 M-1s-1, or 8.62x105 M-1s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-5 s-1 (providing a near irreversible complex with a t1/2 of multiple days), 10-2 s-1 and 10-4 s-1, more preferably between 5 x 10-3 s-1 and 5 x 10-4 s-1, such as between 5x10-3 s-1 and 1x10-3s-1, even more preferably of about 4,09x10-3 s-1, 2.26x10-3 s-1, or 2.50x10-3 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 100-fold lower affinity (KD). In preferred embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno CEACAM1, CEACAM6, CEACAM7 or CEACAM8. A preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay. For instance, the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a BxPC-3 cell line, which is a human pancreatic adenocarcinoma cell line. VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5. For example, in a FACS assay analysing the binding of the immunoglobulin single variable domains of the present technology to human CEACAM5 expressed on BxPC-3 cells, the immunoglobulin single variable domains of the present technology may have EC50 values of 10-7 M or lower, more preferably of 5x10-8 M or lower, or even of 10-8 M or lower. For example, in such FACS assay, the immunoglobulin single variable domains of the present technology may have EC50 values between 10-11 M and 10-7 M, such as between 10-10 M and 10-7 M, between 10-9 M and 5x10-8 M or between 5x10-9 M and 5x10-8 M. In some embodiments, the immunoglobulin single variable domains of the present technology has an CEACAM5-mediated internalization potency (EC50 value) of 5x10-7 M or lower, more preferably of 10-7 M or lower, or even of 5x10-8 M or lower, such as between 10-7 M and 10-10 M, between 10- 7 M and 10-9 M, between 8x10-8 M and 10-9 M or between 8x10-8 M and 10-8 M, for example, as measured in a FACS internalization assay on BxPC-3 cells expressing human CEACAM5. 5.2.3 Embodiment 3 -Family 1 Specific examples of ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTFXSYDMG (SEQ ID NO: 242), wherein the amino acid residue X is selected from N, E, G, P, S or T; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTFXSYDMG (SEQ ID NO: 242), wherein the amino acid residue X is selected from N, E, G, P, S or T; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTFXSYDMG (SEQ ID NO: 242), wherein the amino acid residue X is selected from N, E, G, P, S or T; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AIRWSAGSTV (SEQ ID NO: 256); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AIRWSAGSTV (SEQ ID NO: 256); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AIRWSAGSTV (SEQ ID NO: 256); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence VRPSFRPLSTYWKDYDN (SEQ ID NO: 257); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence VRPSFRPLSTYWKDYDN (SEQ ID NO: 257); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence VRPSFRPLSTYWKDYDN (SEQ ID NO: 257). Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 242, 256, and/or 257. In one embodiment, the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 114, 175-208. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 255, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 256 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 257. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 284, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 256 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 257. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 285, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 256 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 257. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 286, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 256 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 257. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 287, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 256 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 257. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 288, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 256 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 257. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315001D07 (SEQ ID NO: 114) and sequence optimized variants thereof in Table A-7 (in addition to the CDRs as defined above). In one embodiment, the ISVD comprises or consists of the full amino acid sequence of A031500014 (SEQ ID NO: 175), A031500015 (SEQ ID NO: 176), A031500016 (SEQ ID NO: 177), A031500017 (SEQ ID NO: 178), A031500018 (SEQ ID NO: 179), A031500019 (SEQ ID NO: 180), A031500020 (SEQ ID NO: 181), A031500021 (SEQ ID NO: 182), A031500022 (SEQ ID NO: 183), A031500023 (SEQ ID NO: 184), A031500024 (SEQ ID NO: 185), A031500025 (SEQ ID NO: 186), A031500026 (SEQ ID NO: 187), A031500027 (SEQ ID NO: 188), A031500028 (SEQ ID NO: 189), A031500029 (SEQ ID NO: 190), A031500030 (SEQ ID NO: 191), A031500031 (SEQ ID NO: 192), A031500032 (SEQ ID NO: 193), A031500033 (SEQ ID NO: 194), A031500034 (SEQ ID NO: 195), A031500035 (SEQ ID NO: 196), A031500368 (SEQ ID NO: 197), A031500369 (SEQ ID NO: 198), A031500370 (SEQ ID NO: 199), A031500345 (SEQ ID NO: 200), A031500346 (SEQ ID NO: 201), A031500347 (SEQ ID NO: 202), A031500348 (SEQ ID NO: 203), A031500406 (SEQ ID NO: 204), A031500407 (SEQ ID NO: 205), A031500408 (SEQ ID NO: 206), A031500409 (SEQ ID NO: 207), or A031500410 (SEQ ID NO: 208), (see Table A-7). In another embodiment, the ISVD comprises or consists of the full amino acid sequence of A0315001D07 (SEQ ID NO: 114) (see Table A-2 and Table A-7). The SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition. As such in one embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SYDMG (SEQ ID NO: 289); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SYDMG (SEQ ID NO: 289); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SYDMG (SEQ ID NO: 289); and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AIRWSAGSTVYX1X2SVKG (SEQ ID NO: 290); wherein the amino acid residue X1is selected from G or A and wherein the amino acid residue X2 is selected from N or D; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AIRWSAGSTVYX1X2SVKG (SEQ ID NO: 290); wherein the amino acid residue X1is selected from G or A and wherein the amino acid residue X2 is selected from N or D; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AIRWSAGSTVYX1X2SVKG (SEQ ID NO: 290); wherein the amino acid residue X1is selected from G or A and wherein the amino acid residue X2 is selected from N or D; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of VRPSFRPLSTYWKDYDN (SEQ ID NO: 257); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VRPSFRPLSTYWKDYDN (SEQ ID NO: 257); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of VRPSFRPLSTYWKDYDN (SEQ ID NO: 257). Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 289, 290, and/or 257. In one embodiment, the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 114, 175-208. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 289, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 291 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 257. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 289, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 292 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 257. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 289, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 293 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 257. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 289, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 294 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 257. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315001D07 (SEQ ID NO: 114) and sequence optimized variants thereof in Table A-7 (in addition to the CDRs as defined above). In one embodiment, the ISVD comprises or consists of the full amino acid sequence of A031500014 (SEQ ID NO: 175), A031500015 (SEQ ID NO: 176), A031500016 (SEQ ID NO: 177), A031500017 (SEQ ID NO: 178), A031500018 (SEQ ID NO: 179), A031500019 (SEQ ID NO: 180), A031500020 (SEQ ID NO: 181), A031500021 (SEQ ID NO: 182), A031500022 (SEQ ID NO: 183), A031500023 (SEQ ID NO: 184), A031500024 (SEQ ID NO: 185), A031500025 (SEQ ID NO: 186), A031500026 (SEQ ID NO: 187), A031500027 (SEQ ID NO: 188), A031500028 (SEQ ID NO: 189), A031500029 (SEQ ID NO: 190), A031500030 (SEQ ID NO: 191), A031500031 (SEQ ID NO: 192), A031500032 (SEQ ID NO: 193), A031500033 (SEQ ID NO: 194), A031500034 (SEQ ID NO: 195), A031500035 (SEQ ID NO: 196), A031500368 (SEQ ID NO: 197), A031500369 (SEQ ID NO: 198), A031500370 (SEQ ID NO: 199), A031500345 (SEQ ID NO: 200), A031500346 (SEQ ID NO: 201), A031500347 (SEQ ID NO: 202), A031500348 (SEQ ID NO: 203), A031500406 (SEQ ID NO: 204), A031500407 (SEQ ID NO: 205), A031500408 (SEQ ID NO: 206), A031500409 (SEQ ID NO: 207), or A031500410 (SEQ ID NO: 208), (see Table A-7). In one embodiment, the ISVD comprises or consists of the full amino acid sequence of A0315001D07 (SEQ ID NO: 114) (see Table A-2 and Table A-7). In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 114, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 114. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 175, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 175. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 176, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 176. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 177, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 177. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 178, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 178. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 179, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 179. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 180, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 180. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 181, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 181. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 182, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 182. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 183, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 183. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 184, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 184. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 185, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 185. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 186, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 186. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 187, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 187. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 188, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 188. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 189, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 189. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 190, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 190. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 191, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 191. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 192, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 192. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 193, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 193. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 194, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 194. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 195, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 195. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 196, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 196. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 197, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 197. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 198, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 198. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 199, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 199. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 200, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 200. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 201, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 201. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 202, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 202. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 203, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 203. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 204, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 204. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 205, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 205. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 206, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 206. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 207, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 207. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 208, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 208. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 114, 175-208, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 114, 175-208, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 114, 175-208, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 114, 175-208, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 114, 175-208, the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 114, 175-208, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 114, 175-208, the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 114, 175-208, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 114, 175-208, the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 114, 175-208, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 114, 175-208, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8 or other members of the CEACAM family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-7 to 10-9 moles/litre or less and more preferably 5x10-7 to 1x10-8 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 1.87x10-8 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M-1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, such as between 1x105 M-1s-1 and 5x105 M-1s-1, even more preferably of about 3.96x105 M-1s-1,as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-2 s-1 and 1x10-5 s-1, more preferably between 1x10-2 s-1 and 1x10-3 s-1, such as between 1x10-2 s-1 and 5x10-3 s-1even more preferably of about 7.41x10-3 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (KD) of 10-6 to 10-10 moles/litre or less, and preferably 5x10-7 to 10-9 moles/litre or less and more preferably 5x10-7 to 1x10-8 moles/litre, even more preferably wherein the ISVD specifically binds to cyno CEACAM5 with a KD of about 7.92x10-7 moles/litre or 1.73x10-7 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a koff rate between 10-1 s-1 (t1/2=0.69 s) and 10-5 s-1 (providing a near irreversible complex with a t1/2 of multiple days), 5x10-1 s-1 and 10-4 s-1, more preferably between 1.x 10-2 s-1 and 1 x 10-3 s-1, such as between 1.83 x 10-2 s-1 , as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 100-fold lower affinity (KD). In preferred embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno CEACAM1, CEACAM6, CEACAM7 or CEACAM8. A preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay. For instance, the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a BxPC-3 cell line, which is a human pancreatic adenocarcinoma cell line. VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention. 5.2.4 Embodiment 4 -Family 2 Specific examples of ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), that interacts with one or more amino acids of the CEACAM5 protein selected from K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, D339, E346, S404, D405, P406, V407, I408, N410, L412, P443, P444, and A483. In another specific embodiments, the ISVD interacts with an epitope on CEACAM5 that comprises at least three amino acids selected from K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, D339, E346, S404, D405, P406, V407, I408, N410, L412, P443, P444, and A483. In another specific embodiments, the ISVD interacts with an epitope on CEACAM5 that comprises at least five amino acids selected from K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, D339, E346, S404, D405, P406, V407, I408, N410, L412, P443, P444, and A483. In another specific embodiments, the ISVD interacts with an epitope on CEACAM5 that comprises at least eight amino acids selected from K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, D339, E346, S404, D405, P406, V407, I408, N410, L412, P443, P444, and A483. In another specific embodiments, the ISVD interacts with an epitope on CEACAM5 that comprises at least 10 amino acids selected from K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, D339, E346, S404, D405, P406, V407, I408, N410, L412, P443, P444, and A483. In another specific embodiments, the ISVD interacts with an epitope on CEACAM5 that comprises following amino acids: K324, S329, N330, N331, S332, N333, E346, and D405. In another specific embodiments, the epitope on CEACAM5 that is specifically bound by the ISVDs of the present technology comprises following amino acids: K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, D339, E346, S404, D405, P406, V407, I408, N410, L412, P443, P444, and A483. The interacting amino acids preferably have a distance of <3.8Å, wherein the distance between the amino acids is measured e.g., in Cryogenic-electron microscopy (cryo-EM). The ISVDs specifically binding to this epitope on CEACAM5 form an interaction site (paratope) on CEACAM5 only with the CDR2 and CDR3. As such, only CDR2 and CDR3 of the ISVD participate in the interaction with the CEACAM5 protein. Only CDR2 and CDR3 of the ISVD form part of the paratope (the site with which the ISVD interacts with the CEACAM5 molecule) of the ISVD. In some embodiments, the amino acids that form part of this interaction sites are selected from S52, W52a, R53, S54, I56, and V58 (Kabat numbering) in CDR2. In some embodiments, the amino acids that form part of this interaction sites are selected from Q95, E96, F97, G98, A99, I100, S100a, Y100b, N100c, K100e, G100f, Y100g, F101, Y102 (Kabat numbering) in the CDR3. In some embodiment, the amino acids that form part of this interaction sites are selected from S52, W52a, R53, S54, I56, and V58 (Kabat numbering) in CDR2 and from Q95, E96, F97, G98, A99, I100, S100a, Y100b, N100c, K100e, G100f, Y100g, F101, and Y102 (Kabat numbering) in the CDR3. In some embodiments, the amino acids that form part of this interaction sites are S52, W52a, R53, S54, I56, and V58 (Kabat numbering) in CDR2. In some embodiments, the amino acids that form part of this interaction sites are Q95, F97, I100, S100a, N100c, and K100e (Kabat numbering) in the CDR3. In some embodiments, the amino acids that form part of this interaction sites are Q95, E96, F97, G98, A99, I100, S100a, Y100b, N100c, K100e, G100f, Y100g, F101, and Y102 (Kabat numbering) in the CDR3. In some embodiments, the amino acids that form part of this interaction sites are S52, W52a, R53, S54, I56, and V58 (Kabat numbering) in CDR2 and G98, A99, I100, S100a, Y100b, N100c, K100e, G100f, Y100g, F101, and Y102 (Kabat numbering) in the CDR3. In some embodiments, the amino acids that form part of this interaction sites are Q95, F97, I100, S100a, N100c, or K100e (Kabat numbering) in the CDR3, wherein Q95 forms an interaction site (<3.8Å distance) with N333 in the CEACAM5 epitope, wherein F97 forms an interaction site (<3.8Å distance) with I408 in the CEACAM5 epitope, wherein I100 forms an interaction site (<3.8Å distance) with I327 in the CEACAM epitope, wherein I100 forms an interaction site (<3.8Å distance) with S329 in the CEACAM5 epitope, wherein S100a forms an interaction site (<3.8Å distance) with S329 in the CEACAM5 epitope, wherein N100c forms an interaction site (<3.8Å distance) with N330 in the CEACAM5 epitope and/or wherein K100e forms an interaction site (<3.8Å distance) with S332 in the CEACAM 5 epitope. In some embodiments, the amino acids that form part of this interaction sites are Q95, F97, I100, S100a, N100c, and K100e (Kabat numbering) in the CDR3, wherein Q95 forms an interaction site (<3.8Å distance) with N333 in the CEACAM5 epitope, wherein F97 forms an interaction site (<3.8Å distance) with I408 in the CEACAM5 epitope, wherein I100 forms an interaction site (<3.8Å distance) with I327 in the CEACAM epitope, wherein I100 forms an interaction site (<3.8Å distance) with S329 in the CEACAM5 epitope, wherein S100a forms an interaction site (<3.8Å distance) with S329 in the CEACAM5 epitope, wherein N100c forms an interaction site (<3.8Å distance) with N330 in the CEACAM5 epitope and/or wherein K100e forms an interaction site (<3.8Å distance) with S332 in the CEACAM 5 epitope (wherein the distance between the amino acids is measured e.g., in Cryogenic-electron microscopy (cryo-EM)). The ISVDs specifically binding to this epitope on CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence X1X2SWRSX3X4TV (SEQ ID NO: 319); wherein the amino acid residue X1, X2, X2 or X4 is any amino acid independently chosen, preferably wherein the amino acid residue X4 is I, and/or - CDR3 (AbM numbering) consists of an amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1, X2, X3, X4 and X5 is any amino acid independently chosen, preferably wherein the amino acid residue X1 is E, wherein the amino acid residue X2 is F, wherein the amino acid residue X4 is K and the amino acid residue X5 is Y. The ISVDs specifically binding to this epitope on CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence X1X2SWRSX3X4TV (SEQ ID NO: 319); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E and wherein the amino acid residue X4 is selected from T or I, preferably wherein the amino acid residue X4 is I; and - CDR3 (AbM numbering) consists of an amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y, preferably wherein the amino acid residue X1 is E, the amino acid residue X2 is F, the amino acid residue X4 is K and the amino acid residue X5 is Y. In a preferred embodiment, the ISVDs specifically binding to this epitope on CEACAM5 further comprises a CDR1 (AbM Numbering): a) having a length of 10 amino acids; b) having an aliphatic index of 20.00; c) having a grand average of hydropathicity (GRAVY) of 0.400, -0.010, preferably -0.010; d) comprising no or only one positively-charged amino acid residue; e) comprising 40% hydrophobic, 0% or 10% basic and 50 or 60% neutral amino acids, such as comprising 40% hydrophobic, and 60% neutral amino acids; or comprising 40% hydrophobic, 10% basic and 50% neutral amino acids; f) consisting of a polar neutral amino acid, a basic or polar neutral amino acid, two hydrophobic amino acid, four polar neutral amino acid, and two hydrophobic amino acid, preferably in that order; such as consisting of two polar neutral amino acid, two hydrophobic amino acid, four polar neutral amino acid, and two hydrophobic amino acid, preferably in that order; or consisting of a polar neutral amino acid, a basic amino acid, two hydrophobic amino acid, four polar neutral amino acid, and two hydrophobic amino acid, preferably in that order; and/or g) comprising at least one, preferably all of the amino acids G, A, F, S, Y, A, M, and/or optionally the amino acid R. In some embodiments, the ISVDs specifically binding to this epitope on CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence X1X2SWRSX3X4TV (SEQ ID NO: 319); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E and wherein the amino acid residue X4 is selected from T or I, preferably wherein the amino acid residue X4 is I; and - CDR3 (AbM numbering) consists of an amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y, preferably wherein the amino acid residue X1 is E, the amino acid residue X2 is F, the amino acid residue X4 is K and the amino acid residue X5 is Y, and - CDR1 (AbM Numbering): a) having a length of 10 amino acids; b) having an aliphatic index of 20.00; c) having a grand average of hydropathicity (GRAVY) of 0.400, -0.010, preferably -0.010; d) comprising no or one positively-charged amino acid residue; e) comprising 40% hydrophobic, 0% or 10% basic and 50 or 60% neutral amino acids, such as comprising 40% hydrophobic, and 60% neutral amino acids; or comprising 40% hydrophobic, 10% basic and 50% neutral amino acids; f) consisting of a polar neutral amino acid, a basic or polar neutral amino acid, two hydrophobic amino acid, four polar neutral amino acid, and two hydrophobic amino acid, preferably in that order; such as consisting of two polar neutral amino acid, two hydrophobic amino acid, four polar neutral amino acid, and two hydrophobic amino acid, preferably in that order; or consisting of a polar neutral amino acid, a basic amino acid, two hydrophobic amino acid, four polar neutral amino acid, and two hydrophobic amino acid, preferably in that order; and/or g) comprising at least one, preferably all of the amino acids G, A, F, S, Y, A, M, and/or optionally the amino acid R. In some embodiments, the ISVDs specifically binding to the above specific epitope on CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GXAFSTYTMA (SEQ ID NO: 318), wherein the amino acid residue X is selected from R or G; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GXAFSTYTMA (SEQ ID NO: 318), wherein the amino acid residue X is selected from R or G; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GXAFSTYTMA (SEQ ID NO: 318), wherein the amino acid residue X is selected from R or G; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence X1X2SWRSX3X4TV (SEQ ID NO: 319); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E and wherein the amino acid residue X4 is selected from T or I; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence X1X2SWRSX3X4TV (SEQ ID NO: 319); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E and wherein the amino acid residue X4 is selected from T or I; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence the amino acid X1X2SWRSX3X4TV (SEQ ID NO: 319); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E and wherein the amino acid residue X4 is selected from T or I; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y. It should be noted, however, that the ISVDs specifically binding to CEACAM5 may not necessarily be limited to those binding to the above-specified epitope. Hence, specific examples of ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence X1X2SWRSX3X4TV (SEQ ID NO: 319); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E and wherein the amino acid residue X4 is selected from T or I; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence X1X2SWRSX3X4TV (SEQ ID NO: 319); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E and wherein the amino acid residue X4 is selected from T or I; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence the amino acid X1X2SWRSX3X4TV (SEQ ID NO: 319); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E and wherein the amino acid residue X4 is selected from T or I; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y. The following embodiments, thus, apply to any of the ISVDs described above, i.e., the ISVDs binding specifically to CEACAM5 and which are not necessarily limited to binding to the above specific epitope on CEACAM5 and to ISVDs specifically binding to the above-specified epitope on CEACAM5. In a preferred embodiment, the ISVDs specifically binding to CEACAM5 further comprises a CDR1 (AbM Numbering): a) having a length of 10 amino acids; b) having an aliphatic index of 20.00; c) having a grand average of hydropathicity (GRAVY) of 0.400, -0.010, preferably -0.010; d) comprising no or one positively-charged amino acid residue; e) comprising 40% hydrophobic, 0% or 10% basic and 50 or 60% neutral amino acids, such as comprising 40% hydrophobic, and 60% neutral amino acids; or comprising 40% hydrophobic, 10% basic and 50% neutral amino acids; f) consisting of a polar neutral amino acid, a basic or polar neutral amino acid, two hydrophobic amino acid, four polar neutral amino acid, and two hydrophobic amino acid, preferably in that order; such as consisting of two polar neutral amino acid, two hydrophobic amino acid, four polar neutral amino acid, and two hydrophobic amino acid, preferably in that order; or consisting of a polar neutral amino acid, a basic amino acid, two hydrophobic amino acid, four polar neutral amino acid, and two hydrophobic amino acid, preferably in that order; and/or g) comprising at least one, preferably all of the amino acids G, A, F, S, Y, A, M, and/or and/or optionally the amino acid R. In some embodiments, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence X1X2SWRSX3X4TV (SEQ ID NO: 319); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E and wherein the amino acid residue X4 is selected from T or I; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence X1X2SWRSX3X4TV (SEQ ID NO: 319); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E and wherein the amino acid residue X4 is selected from T or I; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence the amino acid X1X2SWRSX3X4TV (SEQ ID NO: 319); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E and wherein the amino acid residue X4 is selected from T or I; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y; - CDR1 (AbM Numbering): a) having a length of 10 amino acids; b) having an aliphatic index of 20.00; c) having a grand average of hydropathicity (GRAVY) of 0.400, -0.010, preferably -0.010; d) comprising no or one positively-charged amino acid residues; e) comprising 40% hydrophobic, 0% or 10% basic and 50 or 60% neutral amino acids, such as comprising 40% hydrophobic, and 60% neutral amino acids; or comprising 40% hydrophobic, 10% basic and 50% neutral amino acids; f) consisting of a polar neutral amino acid, a basic or polar neutral amino acid, two hydrophobic amino acid, four polar neutral amino acid, and two hydrophobic amino acid, preferably in that order; such as consisting of two polar neutral amino acid, two hydrophobic amino acid, four polar neutral amino acid, and two hydrophobic amino acid, preferably in that order; or consisting of a polar neutral amino acid, a basic amino acid, two hydrophobic amino acid, four polar neutral amino acid, and two hydrophobic amino acid, preferably in that order; and/or g) comprising at least one, preferably all of the amino acids G, A, F, S, Y, A, M, and/or and/or optionally the amino acid R. Specific examples of ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 322 or 325; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 322 or 325 c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 322 or 325; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 323, 326, 327, e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 323, 326, 327; f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 323, 326, 327. In some embodiments, the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 325; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 325; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 325; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 326; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 326; f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 326. In some embodiments, the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 322; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 322; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 322; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 323; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 323; f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 323. In some embodiments, the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 325; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 325; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 325; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 327; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 327; f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 327. Preferably, the CDR2 and CDR3 sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR2 sequences of SEQ ID NOs: 322, or 325 and/or the CDR3 sequences of SEQ ID NOs: 323, 327, 326. In some embodiments, the ISVD comprises a CDR2 and CDR3 (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 115-117, 160-170. In one embodiment, the ISVD comprises a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 322 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 323. In another embodiment, the ISVD comprises a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 325 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 327. In another embodiment, the ISVD comprises a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 325 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 326. The SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition. In some embodiments, the ISVDs specifically binding to this epitope on CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of X1X2SWRSX3X4TVYX5DSVKG (SEQ ID NO: 329); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E, wherein the amino acid residue X4 is selected from T or I, and wherein the amino acid residue X5 is selected from G or A; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of X1X2SWRSX3X4TVYX5DSVKG (SEQ ID NO: 329); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E, wherein the amino acid residue X4 is selected from T or I, and wherein the amino acid residue X5 is selected from G or A; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of X1X2SWRSX3X4TVYX5DSVKG (SEQ ID NO: 329); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E, wherein the amino acid residue X4 is selected from T or I, and wherein the amino acid residue X5 is selected from G or A; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: d) the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y; f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y. In some embodiments, the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 330, 331, 332; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 330, 331, 332; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 330, 331, 332; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 323, 326, 327; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 323, 326, 327; f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 323, 326, 327. In some embodiments, the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 330; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 330; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 330; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 323; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 323; f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 323. In some embodiments, the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 331; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 331; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 331; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 326; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 326; f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 326. In some embodiments, the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 331; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 331; c) amino acid sequences that have3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 331; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 327; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 327; f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 327. In some embodiments, the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 332; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 332; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 332; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 327; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 327; f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 327. Preferably, the CDR2 and CDR3 sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR2 sequences of SEQ ID NOs: 330, 331, 332; and/or the CDR3 sequences of SEQ ID NOs: 323, 327, 326. In one embodiment, the ISVD comprise a CDR2 and CDR3 (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 115-117, 160-170. In one embodiment, the ISVD comprises a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 330 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 323. In another embodiment, the ISVD comprises a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 331 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 326. In another embodiment, the ISVD comprises a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 331 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 327. In another embodiment, the ISVD comprises a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 332 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 327. Specific examples of ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GXAFSTYTMA (SEQ ID NO: 318), wherein the amino acid residue X is selected from R or G; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GXAFSTYTMA (SEQ ID NO: 318), wherein the amino acid residue X is selected from R or G; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GXAFSTYTMA (SEQ ID NO: 318), wherein the amino acid residue X is selected from R or G; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence X1X2SWRSX3X4TV (SEQ ID NO: 319); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E and wherein the amino acid residue X4 is selected from T or I; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence X1X2SWRSX3X4TV (SEQ ID NO: 319); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E and wherein the amino acid residue X4 is selected from T or I; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence the amino acid X1X2SWRSX3X4TV (SEQ ID NO: 319); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E and wherein the amino acid residue X4 is selected from T or I; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y. Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 318, 319, and/or 320. In one embodiment, the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 115-117, 160-170. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 321, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 322 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 323. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 324, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 325 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 326. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 324, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 325 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 327. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315005F01 (SEQ ID NO: 115), A0315006F03 (SEQ ID NO: 116), A0315002G08 (SEQ ID NO: 117) and sequence optimized variants thereof in Table A-5 (in addition to the CDRs as defined above). In one embodiment, the ISVD comprises or consists of the full amino acid sequence of A031500333 (SEQ ID NO: 160); A031500334 (SEQ ID NO: 161), A031500335 (SEQ ID NO: 162), A031500336 (SEQ ID NO: 163), A031500337 (SEQ ID NO: 164), A031500338 (SEQ ID NO: 165), A031500339 (SEQ ID NO: 166), A031500340 (SEQ ID NO: 167), A031500341 (SEQ ID NO: 168), A031500342 (SEQ ID NO: 169), or A031500343 (SEQ ID NO: 170) (see Table A-2, Table A-5). In another embodiment, the ISVD comprises or consists of the full amino acid sequence of A0315005F01 (SEQ ID NO: 115), A0315006F03 (SEQ ID NO: 116), A0315002G08 (SEQ ID NO: 117) (see Table A-2). The SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition. As such in one embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of TYTMA (SEQ ID NO: 328); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of TYTMA (SEQ ID NO: 328); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of TYTMA (SEQ ID NO: 328); and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of X1X2SWRSX3X4TVYX5DSVKG (SEQ ID NO: 329); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E, wherein the amino acid residue X4 is selected from T or I, and wherein the amino acid residue X5 is selected from G or A; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of X1X2SWRSX3X4TVYX5DSVKG (SEQ ID NO: 329); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E, wherein the amino acid residue X4 is selected from T or I, and wherein the amino acid residue X5 is selected from G or A; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of X1X2SWRSX3X4TVYX5DSVKG (SEQ ID NO: 329); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E, wherein the amino acid residue X4 is selected from T or I, and wherein the amino acid residue X5 is selected from G or A; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y. Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 328, 329, and/or 320, as defined above. In one embodiment, the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 115-117, 160-170. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 328, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 330 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 323. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 328, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 331 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 326. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 328, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 331 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 327. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 328, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 332 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 327. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315005F01 (SEQ ID NO: 115), A0315006F03 (SEQ ID NO: 116), A0315002G08 (SEQ ID NO: 117) and sequence optimized variants thereof in Table A-5 (in addition to the CDRs as defined above). In one embodiment, the ISVD comprises or consists of the full amino acid sequence of A031500333 (SEQ ID NO: 160); A031500334 (SEQ ID NO: 161), A031500335 (SEQ ID NO: 162), A031500336 (SEQ ID NO: 163), A031500337 (SEQ ID NO: 164), A031500338 (SEQ ID NO: 165), A031500339 (SEQ ID NO: 166), A031500340 (SEQ ID NO: 167), A031500341 (SEQ ID NO: 168), A031500342 (SEQ ID NO: 169), or A031500343 (SEQ ID NO: 170) (see Table A-2, Table A-5). In another embodiment, the ISVD comprises or consists of the full amino acid sequence of A0315005F01 (SEQ ID NO: 115), A0315006F03 (SEQ ID NO: 116) and A0315002G08 (SEQ ID NO: 117) (see Table A-2). In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 115, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 115. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 116, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 116. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 117, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 117. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 160, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 160. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 161, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 161. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 162, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 162. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 163, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 163. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 164, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 164. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 165, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 165. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 166, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 166. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 167, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 167. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 168, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 168. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 169, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 169. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 170, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 170. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 115-117, 160-170, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 115-117, 160-170, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 10-fold lower affinity (KD). Preferably, the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, or CEACAM7. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 115-117, 160-170, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 115-117, 160-170,, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 10-fold lower affinity (KD). Preferably, the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, or CEACAM7. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 115-117, 160-170, the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 115-117, 160-170, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 115-117, 160-170, the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 115-117, 160-170, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 115-117, 160-170, the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 115-117, 160-170, the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 10-fold lower affinity (KD). Preferably, the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 115-117, 160-170, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, or CEACAM7. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-8 to 10-10 moles/litre or less and more preferably 5x10-8 to 6x10-10 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 1.66x10-9 moles/litre, 5.08x10-10 moles/litre or 3.37x10-9 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M-1s-1 and 107 M-1s-1, more preferably between 1x105 M-1s-1 and 5x106 M- 1s-1, such as between 5x105 M-1s-1 and 5x106 M-1s-1, even more preferably of about 1.93x106 M-1s-1, 1.42x106 M-1s-1, or 1.94x106 M-1s-1as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-2 s-1 and 1x10-5 s-1, more preferably between 1x10-2 s-1 and 1x10-4 s-1, such as between 7x10-3 s-1 and 5x10-4 s- 1 even more preferably of about 3.21x10-3 s-1, 7.23x10-4 s-1, or 6.55 x10-3 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (KD) of 10-7 to 10-10 moles/litre or less, and preferably 10-8 to 10-9 moles/litre or lessand more preferably 5x10-8 to 10-9 moles/litre or less, more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 1.8x10-9 moles/litre, 4.48x10-9 moles/litre or 1.2x10-8 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M-1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 5x106 M-1s-1, such as between 1x105 M-1s-1 and 2x106 M-1s-1, even more preferably of about 1.32x106 M-1s-1, 1.08x106 M-1s-1, or 1.97x105 M-1s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-5 s-1 (providing a near irreversible complex with a t1/2 of multiple days), 10-2 s-1 and 10-4 s-1, more preferably between 5x10-3 s-1 and 1x10-4 s-1, such as between 5x10-3 s-1 and 5x10-3s-1, even more preferably of about 2.36x10-3 s-1, 4.86x10-3 s-1, or 2.37x10-3 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 10-fold lower affinity (KD). In preferred embodiments, the immunoglobulin single variable domains specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno CEACAM1, CEACAM6, or CEACAM7. A preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay. For instance, the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a BxPC-3 cell line, which is a human pancreatic adenocarcinoma cell line. VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5. For example, in a FACS binding assay with a BxPC-3 cell line expressing human CEACAM5., the immunoglobulin single variable domains of the present technology may have EC50 values of 10-7 M or lower, more preferably of 10-8 M or lower, or even of 10-9 M or lower. For example, in such FACS assay, the immunoglobulin single variable domains of the present technology may have EC50 values between 10-11 M and 10-7 M, such as between 10- 10 M and 10-8 M, between 10-9 M and 10-8 M or between 10-9 M and 5x10-8 M. In some embodiments, the immunoglobulin single variable domains of the present technology has an CEACAM5-mediated internalization potency (EC50 value) of 10-7 M or lower, more preferably of 5x10-8 M or lower, or even of 10-8 M or lower, such as between 10-7 M and 10-10 M, between 10-7 M and 10-9 M, between 5x10-8 M and 10-9 M, for example, as measured in a FACS internalization assay on BxPC-3 cells expressing human CEACAM5. 5.2.5 Embodiment 5 -Family 3 Specific examples of ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of GLTFSTYTXG (SEQ ID NO: 333), wherein the amino acid residue X is selected from V or M; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GLTFSTYTXG (SEQ ID NO: 333), wherein the amino acid residue X is selected from V or M; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GLTFSTYTXG (SEQ ID NO: 333), wherein the amino acid residue X is selected from V or M; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SX1IX2SGSNTX3 (SEQ ID NO: 335); wherein the amino acid residue X1 is selected from I or M, wherein the amino acid residue X2 is selected from W or Y, and wherein the amino acid residue X3 is selected from V or L; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence SX1IX2SGSNTX3 (SEQ ID NO: 335); wherein the amino acid residue X1 is selected from I or M, wherein the amino acid residue X2 is selected from W or Y, and wherein the amino acid residue X3 is selected from V or L; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence SX1IX2SGSNTX3 (SEQ ID NO: 335); wherein the amino acid residue X1 is selected from I or M, wherein the amino acid residue X2 is selected from W or Y, and wherein the amino acid residue X3 is selected from V or L; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence QHFGPX1SLTTRGYX2Y (SEQ ID NO: 338); wherein the amino acid residue X1 is selected from V or I, and wherein the amino acid residue X2 is selected from Y or F; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence QHFGPX1SLTTRGYX2Y (SEQ ID NO: 338); wherein the amino acid residue X1 is selected from V or I, and wherein the amino acid residue X2 is selected from Y or F; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence QHFGPX1SLTTRGYX2Y (SEQ ID NO: 338); wherein the amino acid residue X1 is selected from V or I, and wherein the amino acid residue X2 is selected from Y or F. Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 333, 335, and/or 338. In one embodiment, the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 118-119, 171-174. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 336 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 339. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 334, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 337 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 340. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315002G06 (SEQ ID NO: 118), A0315002C10 (SEQ ID NO: 119), and sequence optimized variants thereof in Table A-6 (in addition to the CDRs as defined above). In one embodiment, the ISVD comprises or consists of the full amino acid sequence of A031500010 (SEQ ID NO: 171), A031500011 (SEQ ID NO: 172), A031500012 (SEQ ID NO: 173), or A031500013 (SEQ ID NO: 174) (see Table A-2, Table A-6). In other embodiments, the ISVD comprises or consists of the full amino acid sequence of A0315002G06 (SEQ ID NO: 118) or A0315002C10 (SEQ ID NO: 119) (Table A-2). The SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition. As such in one embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence TYTXG (SEQ ID NO: 341); wherein the amino acid residue X is selected from M or V; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence TYTXG (SEQ ID NO: 341); wherein the amino acid residue X is selected from M or V; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences TYTXG (SEQ ID NO: 341); wherein the amino acid residue X is selected from M or V; and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence SX1IX2SGSNTX3YADSVKG (SEQ ID NO: 343); wherein the amino acid residue X1 is selected from I or M, wherein the amino acid residue X2 is selected from W or Y, and wherein the amino acid residue X3 is selected from V or L; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence SX1IX2SGSNTX3YADSVKG (SEQ ID NO: 343); wherein the amino acid residue X1 is selected from I or M, wherein the amino acid residue X2 is selected from W or Y, and wherein the amino acid residue X3 is selected from V or L; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence SX1IX2SGSNTX3YADSVKG (SEQ ID NO: 343); wherein the amino acid residue X1 is selected from I or M, wherein the amino acid residue X2 is selected from W or Y, and wherein the amino acid residue X3 is selected from V or L; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence QHFGPX1SLTTRGYX2Y (SEQ ID NO: 338); wherein the amino acid residue X1 is selected from V or I, and wherein the amino acid residue X2 is selected from Y or F; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence QHFGPX1SLTTRGYX2Y (SEQ ID NO: 338); wherein the amino acid residue X1 is selected from V or I, and wherein the amino acid residue X2 is selected from Y or F; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence QHFGPX1SLTTRGYX2Y (SEQ ID NO: 338); wherein the amino acid residue X1 is selected from V or I, and wherein the amino acid residue X2 is selected from Y or F. Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 341, 343, and/or 338. In one embodiment, the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 118-119, 171-174. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 334 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 339. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 342, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 345 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 340. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315002G06 (SEQ ID NO: 118), A0315002C10 (SEQ ID NO: 119), and sequence optimized variants thereof in Table A-6 (in addition to the CDRs as defined above). In one embodiment, the ISVD comprises or consists of the full amino acid sequence of A031500010 (SEQ ID NO: 171), A031500011 (SEQ ID NO: 172), A031500012 (SEQ ID NO: 173), or A031500013 (SEQ ID NO: 174) (see Table A-2, Table A-6). In other embodiments, the ISVD comprises or consists of the full amino acid sequence of A0315002G06 (SEQ ID NO: 118) or A0315002C10 (SEQ ID NO: 119) (Table A-2). In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 118, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 118. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 119, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 119. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 171, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 171. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 172, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 172. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 173, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 173. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 174, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 174. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID Nos: 118-119, 171-174, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID Nos: 118-119, 171-174, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with at least 100-fold lower affinity (KD), such as a at least 400-fold lower affinity (KD). Preferably, the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, and CEACAM7. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 118-119, 171-174, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 118-119, 171-174, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with at least 100-fold lower affinity (KD), such as a at least 400-fold lower affinity (KD). Preferably, the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, and CEACAM7. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 118-119, 171-174, the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 118-119, 171-174, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 118-119, 171-174, the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID Nos: 118-119, 171-174, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 118-119, 171-174, the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 118-119, 171-174, the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with at least 100-fold lower affinity (KD), such as a at least 400-fold lower affinity (KD). Preferably, the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 118-119, 171-174, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, and CEACAM7. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-8 to 10-11 moles/litre or less and more preferably 10-8 to 10-10 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 8.83x10-9 moles/litre, or 1.44x10-10 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M-1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 5x106 M-1s-1, even more preferably of about 4.70x105 M-1s-1, or 1.91x106 M-1s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-2 s-1 and 1x10-5 s-1, more preferably between 1x10-2 s-1 and 10-4 s-1, such as between 5x10-3 s-1 and 10-4 s-1 even more preferably of about 4.15x10-3 s-1, or 2.74x10-4 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (KD) of 10-7 to 10-10 moles/litre or less, and preferably 10-7 to 10-9 moles/litre or less and more preferably 5x10-8 to 10-9 moles/litre, even more preferably wherein the ISVD specifically binds to cyno CEACAM5 with a KD of about 3.92x10-8 moles/litre, or 1.56x10-9 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M-1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 5x106 M-1s-1, such as between 2x105 M-1s-1 and 2x106 M-1s-1, even more preferably of about 2.92x105 M-1s-1, or 1.23x106 M-1s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a koff rate between 10-1 s-1 (t1/2=0.69 s) and 10-5 s-1 (providing a near irreversible complex with a t1/2 of multiple days), about 10-2 s-1 and 10-4 s-1, more preferably between about 1x 10-2 s-1 and 5 x 10-4 s-1, such as between about 1x10-2 s-1 and 10-3s-1, even more preferably of about 1.14x10-2 s-1, or 1.92x10-3 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with at least 100-fold lower affinity (KD), such as a at least 400-fold lower affinity (KD). In preferred embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno CEACAM1, CEACAM6, or CEACAM7. A preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay. For instance, the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a BxPC-3 cell line, which is a human pancreatic adenocarcinoma cell line. VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5. For example, in a FACS binding assay with a BxPC-3 cell line expressing human CEACAM5, the immunoglobulin single variable domains of the present technology may have EC50 values of 10-7 M or lower, more preferably of 10-8 M or lower, or even of 10-9 M or lower. For example, in such FACS assay, the immunoglobulin single variable domains of the present technology may have EC50 values between 10-11 M and 10-7 M, such as between 10- 10 M and 10-8 M, between 10-9 M and 5x10-8 M or between 10-9 M and 10-8 M. In some embodiments, the immunoglobulin single variable domains of the present technology has an CEACAM5-mediated internalization potency (EC50 value) of 10-7 M or lower, more preferably of 5x10-8 M or lower, or even of 10-8 M or lower, such as between 10-7 M and 10-10 M, between 10-7 M and 10-9 M, between 5x10-8 M and 10-9 M or between 10-8 M and 10-9 M, for example, as measured in a FACS internalization assay on BxPC-3 cells expressing human CEACAM5. 5.2.6 Embodiment 6 -Family 5 Specific examples of ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTFSDXAMG (SEQ ID NO: 356), wherein the amino acid residue X is selected from F or Y; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTFSDXAMG (SEQ ID NO: 356), wherein the amino acid residue X is selected from F or Y; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTFSDXAMG (SEQ ID NO: 356), wherein the amino acid residue X is selected from F or Y; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AINWSGGWTY (SEQ ID NO: 357); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AINWSGGWTY (SEQ ID NO: 357); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AINWSGGWTY (SEQ ID NO: 357); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence SSDYAGGRSTGYXY (SEQ ID NO: 358); wherein the amino acid residue X is selected from A or D; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence SSDYAGGRSTGYXY (SEQ ID NO: 358); wherein the amino acid residue X is selected from A or D; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence SSDYAGGRSTGYXY (SEQ ID NO: 358); wherein the amino acid residue X is selected from A or D. Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 356, 357, and/or 358. In one embodiment, the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 122 or 123. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 359, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 357 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 360. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 234, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 357 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 361. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315001C11 (SEQ ID NO: 122), A0315004G01 (SEQ ID NO: 123), and sequence optimized variants thereof (in addition to the CDRs as defined above). The SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition. As such in one embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of DXAMG (SEQ ID NO:237), wherein the amino acid residue X is selected from Y or F; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of DXAMG (SEQ ID NO: 237), wherein the amino acid residue X is selected from Y or F; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of DXAMG (SEQ ID NO: 237), wherein the amino acid residue X is selected from Y or F; and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AINWSGGWTYYADSVQG (SEQ ID NO: 362); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AINWSGGWTYYADSVQG (SEQ ID NO: 362); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AINWSGGWTYYADSVQG (SEQ ID NO: 362); and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SSDYAGGRSTGYXY (SEQ ID NO: 358); wherein the amino acid residue X is selected from A or D; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SSDYAGGRSTGYXY (SEQ ID NO: 358); wherein the amino acid residue X is selected from A or D; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SSDYAGGRSTGYXY (SEQ ID NO: 358); wherein the amino acid residue X is selected from A or D. Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 237, 362, and/or 358. In one embodiment, the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 122 or 123. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 229, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 362 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 360. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 243, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 362 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 361. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315001C11 (SEQ ID NO: 122), A0315004G01 (SEQ ID NO: 123), and sequence optimized variants thereof (in addition to the CDRs as defined above). In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 122, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 122. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 123, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 123. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 122 or 123, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 122 or 123, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 100-fold lower affinity (KD). Preferably, the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, and CEACAM8. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 122 or 123, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 122 or 123, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 100-fold lower affinity (KD). Preferably, the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, and CEACAM8. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 122 or 123, the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 122 or 123, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 122 or 123, the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 122 or 123, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 122 or 123, the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 122 or 123, the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 100-fold lower affinity (KD). Preferably, the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 122 or 123, the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 100-fold lower affinity (KD). Preferably, the ISVD specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, and CEACAM8. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-8 to 10-10 moles/litre or less and more preferably 1x10-8 to 1x10-9 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 5.85x10-9 moles/litre, or 6.01x10-9 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a kon-rate of 104 M-1s-1 to about 107 M-1s-1, preferably between 104 M-1s-1 and 106 M-1s-1, more preferably between 104 M-1s-1 and 105 M-1s-1, such as between 5x104 M-1s-1 and 1x105 M-1s-1, even more preferably of about 8.68x104 M-1s-1, or 8.07x104 M-1s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-3 s-1 and 1x10-6 s-1, more preferably between 1x10-3 s-1 and 1x10-5 s-1, such as between 6x10-4 s-1 and 1x10-4 s-1even more preferably of about 5.08x10-4 s-1, or 4.85x10-4 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 1x10-8 to 10-10 moles/litre or less and more preferably 10-8 to 1x10-9 moles/litre, even more preferably wherein the ISVD specifically binds to cyno CEACAM5 with a KD of about 8.16x10-9 moles/litre, or 6.47x10-9 moles/litre, as determined by Surface Plasmon Resonance. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M-1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, such as between 1x105 M-1s-1 and 5x105 M-1s-1, even more preferably of about 3.04x105 M-1s-1, or 3.18x105 M-1s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-5 s-1 (providing a near irreversible complex with a t1/2 of multiple days), 10-2 s-1 and 10-4 s-1, more preferably between 10-2 s-1 and 10-3 s-1, such as between 5x 10-3 s-1 and 1 x 10-3 s-1, even more preferably of about 2.48x10-3 s-1, or 2.06x10-3 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 100-fold lower affinity (KD). In a preferred embodiment, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno CEACAM1, CEACAM6, or CEACAM8. A preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay. For instance, the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a BxPC-3 cell line, which is a human pancreatic adenocarcinoma cell line. VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5. For example, in a FACS binding assay with a BxPC-3 cell line expressing human CEACAM5., the immunoglobulin single variable domains of the present technology may have EC50 values of 10-7 M or lower, more preferably of 10-8 M or lower, or even of 10-9 M or lower. For example, in such FACS assay, the immunoglobulin single variable domains of the present technology may have EC50 values between 10-11 M and 10-7 M, such as between 10- 10 M and 10-7 M, between 10-9 M and 10-7 M or between 5x10-9 M and 10-7 M. In some embodiments, the immunoglobulin single variable domains of the present technology has an CEACAM5-mediated internalization potency (EC50 value) of 10-7 M or lower, more preferably of 5x10-8 M or lower, or even of 10-8 M or lower, such as between 10-7 M and 10-10 M, between 10-7 M and 10-9 M, between 5x10-8 M and 10-9 M or between 5x10-8 M and 10-8 M, for example, as measured in a FACS internalization assay on BxPC-3 cells expressing human CEACAM5. 5.2.7 Embodiment 7 -Family 9 Specific examples of ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTFNINEYHLA (SEQ ID NO: 363); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTFNINEYHLA (SEQ ID NO: 363); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTFNINEYHLA (SEQ ID NO: 363); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AIWWSTGNKI (SEQ ID NO: 364); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence the amino acid AIWWSTGNKI (SEQ ID NO: 364); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AIWWSTGNKI (SEQ ID NO: 364); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence VRFSFRPLSTYWKDYDN (SEQ ID NO: 365); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence VRFSFRPLSTYWKDYDN (SEQ ID NO: 365); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence VRFSFRPLSTYWKDYDN (SEQ ID NO: 365). Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 363, 364, and/or 365. In one embodiment, the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NO: 124. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 363, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 364 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 365. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315025D01 (SEQ ID NO: 124) and sequence optimized variants thereof (in addition to the CDRs as defined above). The SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition. As such in one embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of INEYHLA (SEQ ID NO: 366); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of INEYHLA (SEQ ID NO: 366); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of INEYHLA (SEQ ID NO: 366); and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AIWWSTGNKIVADSVKG (SEQ ID NO: 367); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AIWWSTGNKIVADSVKG (SEQ ID NO: 367); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AIWWSTGNKIVADSVKG (SEQ ID NO: 367); and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of VRFSFRPLSTYWKDYDN (SEQ ID NO: 365); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VRFSFRPLSTYWKDYDN (SEQ ID NO: 365); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of VRFSFRPLSTYWKDYDN (SEQ ID NO: 365). Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 366, 367, and/or 365. In one embodiment, the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NO: 124. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 366, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 367 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 365. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315025D01 (SEQ ID NO: 124) and sequence optimized variants thereof (in addition to the CDRs as defined above). In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 124, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 124. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NO: 124, wherein the binding affinity is measured using the same method, such as e.g. SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NO: 124, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NO: 124, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NO: 124, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 124, the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NO: 124, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 124, the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 124, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 124, the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 124, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 124, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8 or other members of the CEACAM family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-7 to 10-9 moles/litre or less and more preferably 1x10-7 to 1x10-8 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 2.49x10-8 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M-1s-1 and 107 M-1s-1, more preferably between 104 M-1s-1 and 106 M-1s-1, such as between 5x104 M-1s-1 and 5x105 M-1s-1, even more preferably of about 2.01x105 M-1s-1,as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-2 s-1 and 1x10-5 s-1, more preferably between 1x10-2 s-1 and 1x10-3 s-1, such as between 1x10-2 s-1 and 4x10-3 s-1even more preferably of about 5.01x10-3 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (KD) of 10-7 to 10-10 moles/litre or less, and preferably 10-7 to 10-9 moles/litre or less and more preferably 5x10-7 to 1x10-8 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about about 3.65x10-8 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 104 M-1s-1 and 106 M-1s-1, more preferably between 5x104 M-1s-1 and 106 M-1s-1, such as between 5x104 M-1s-1 and 1x105 M-1s-1, even more preferably of about 7.98x104 M-1s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-5 s-1 (providing a near irreversible complex with a t1/2 of multiple days), 10-2 s-1 and 10-4 s-1, more preferably between 1 x 10-2 s-1 and 1x 10-3 s-1, such as between 5x 10-3 s-1 and 1 x 10-3 s-1, even more preferably of about 2.92x10-3 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 100-fold lower affinity (KD). In preferred embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno CEACAM1, CEACAM6, CEACAM7 or CEACAM8. A preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay. For instance, the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a BxPC-3 cell line, which is a human pancreatic adenocarcinoma cell line. VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5. For example, in a FACS binding assay with a BxPC-3 cell line expressing human CEACAM5., the immunoglobulin single variable domains of the present technology may have EC50 values of 10-7 M or lower, more preferably of 10-8 M or lower, or even of 10-9 M or lower. For example, in such FACS assay, the immunoglobulin single variable domains of the present technology may have EC50 values between 10-11 M and 10-7 M, such as between 10- 10 M and 10-7 M, between 5x10-9 M and 8x10-8 M or between 10-9 M and 8x10-8 M. In some embodiments, the immunoglobulin single variable domains of the present technology has an CEACAM5-mediated internalization potency (EC50 value) of 10-7 M or lower, more preferably of 5x10-8 M or lower, or even of 10-8 M or lower, such as between 10-7 M and 10-10 M, between 10-7 M and 10-9 M, between 5x10-8 M and 10-9 M or between 5x10-8 M and 10-8 M, for example, as measured in a FACS internalization assay on BxPC-3 cells expressing human CEACAM5. 5.2.8 Embodiment 8 -Family 17 Specific examples of ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AIWWSTGNRI (SEQ ID NO: 369); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AIWWSTGNRI (SEQ ID NO: 369); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AIWWSTGNRI (SEQ ID NO: 369); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of VRFSFRPLSTYWKDYDI (SEQ ID NO: 370); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VRFSFRPLSTYWKDYDI (SEQ ID NO: 370); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of VRFSFRPLSTYWKDYDI (SEQ ID NO: 370). Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 368, 369, and/or 370. In one embodiment, the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NO: 125. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 368, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 369 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 370. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315020C01 (SEQ ID NO: 125) and sequence optimized variants thereof (in addition to the CDRs as defined above). The SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition. As such in one embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of DYHMA (SEQ ID NO: 371); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of DYHMA (SEQ ID NO: 371); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of DYHMA (SEQ ID NO: 371); and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AIWWSTGNRIVADSVKG (SEQ ID NO: 372); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AIWWSTGNRIVADSVKG (SEQ ID NO: 372); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AIWWSTGNRIVADSVKG (SEQ ID NO: 372); and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of VRFSFRPLSTYWKDYDI (SEQ ID NO: 370); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VRFSFRPLSTYWKDYDI (SEQ ID NO: 370); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of VRFSFRPLSTYWKDYDI (SEQ ID NO: 370). Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 371, 372, and/or 370. In one embodiment, the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NO: 125. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 371, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 372 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 370. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315020C01 (SEQ ID NO: 125) and sequence optimized variants thereof (in addition to the CDRs as defined above). In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 125, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 125. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NO: 125, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NO: 125, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NO: 125, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NO: 125, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 125, the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NO: 125, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 125, the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NO: 125, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 125, the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 125, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 125, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8 or other members of the CEACAM family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-7 to 10-10 moles/litre or less and more preferably 1x10-7 to 1x10-8 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 2.39x10-8 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M-1s-1 and 107 M-1s-1, more preferably between 104 M-1s-1 and 106 M-1s-1, such as between 1x104 M-1s-1 and 5x105 M-1s-1, even more preferably of about 2.19x105 M-1s-1,as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-2 s-1 and 1x10-5 s-1, more preferably between 1x10-2 s-1 and 1x10-4 s-1, such as between 1x10-2 s-1 and 10-3 s-1 even more preferably of about 5.22x10-3 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (KD) of 10-7 to 10-10 moles/litre or less, and preferably 1x10-7 to 10-9 moles/litre or less and more preferably 6x10-8 to 1x10-9 moles/litre, even more preferably wherein the ISVD specifically binds to cyno CEACAM5 with a KD of about 5.81x10-8 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 104 M-1s-1 and 106 M-1s-1, more preferably between 104 M-1s-1 and 5x105 M-1s-1, such as between 5x104 M-1s-1 and 1x105 M-1s-1, even more preferably of about 8.70x104 M-1s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-5 s-1 (providing a near irreversible complex with a t1/2 of multiple days), 10-2 s-1 and 10-4 s-1, more preferably between 1 x 10-2 s-1 and 1 x 10-3 s-1, such as between 8 x 10-3 s-1 and 2 x 10-3 s-1, even more preferably of about 5.05x10-3 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 100-fold lower affinity (KD), In preferred embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno CEACAM1, CEACAM6, CEACAM7 or CEACAM8. A preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay. For instance, the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a BxPC-3 cell line, which is a human pancreatic adenocarcinoma cell line. VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5. For example, in a FACS binding assay with a BxPC-3 cell line expressing human CEACAM5., the immunoglobulin single variable domains of the present technology may have EC50 values of 10-7 M or lower, more preferably of 8x10-8 M or lower, such as 10-8 M or lower, or even of 10-9 M or lower. For example, in such FACS assay, the immunoglobulin single variable domains of the present technology may have EC50 values between 10-11 M and 10-7 M, such as between 10-10 M and 10-7 M, between 5x10-9 M and 8x10-8 M or between 10-9 M and 8x10-8 M. In some embodiments, the immunoglobulin single variable domains of the present technology has an CEACAM5-mediated internalization potency (EC50 value) of 10-6 M or lower, more preferably of 5x10-7 M or lower, or even of 10-7 M or lower, such as between 10-6 M and 10-10 M, between 5x10- 7 M and 10-9 M, between 10-7 M and 10-9 M or between 10-7 M and 10-8 M, for example, as measured in a FACS internalization assay on BxPC-3 cells expressing human CEACAM5.
5.2.9 Embodiment 9 -Family 18 Specific examples of ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GDXLNSYHMA (SEQ ID NO: 373), wherein the amino acid residue X is selected from T or N; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GDXLNSYHMA (SEQ ID NO: 373), wherein the amino acid residue X is selected from T or N; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences GDXLNSYHMA (SEQ ID NO: 373), wherein the amino acid residue X is selected from T or N; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AIWWSTGNXI (SEQ ID NO: 374), wherein the amino acid residue X is selected from A or T; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AIWWSTGNXI (SEQ ID NO: 374), wherein the amino acid residue X is selected from A or T; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AIWWSTGNXI (SEQ ID NO: 374), wherein the amino acid residue X is selected from A or T); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence VRFXFRPLSTYWKDYDN (SEQ ID NO: 375); wherein the amino acid residue X is selected from S or Q; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence VRFXFRPLSTYWKDYDN (SEQ ID NO: 375); wherein the amino acid residue X is selected from S or Q; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence VRFXFRPLSTYWKDYDN (SEQ ID NO: 375); wherein the amino acid residue X is selected from S or Q. Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 373, 374, and/or 375. In one embodiment, the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 126 or 127. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 376, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 377 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 365. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 378, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 379 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 380. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315026B01 (SEQ ID NO: 126) and A0315008B03 (SEQ ID NO: 127), and sequence optimized variants thereof (in addition to the CDRs as defined above). The SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition. As such in one embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence SYHMA (SEQ ID NO: 381); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence SYHMA (SEQ ID NO: 381); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences SYHMA (SEQ ID NO: 381); and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AIWWSTGNXIVADSVKG (SEQ ID NO: 382), wherein the amino acid residue X is selected from A or T; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AIWWSTGNXIVADSVKG (SEQ ID NO: 382), wherein the amino acid residue X is selected from A or T; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AIWWSTGNXIVADSVKG (SEQ ID NO: 382), wherein the amino acid residue X is selected from A or T; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of VRFXFRPLSTYWKDYDN (SEQ ID NO: 375); wherein the amino acid residue X is selected from S or Q; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VRFXFRPLSTYWKDYDN (SEQ ID NO: 375); wherein the amino acid residue X is selected from S or Q; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence VRFXFRPLSTYWKDYDN (SEQ ID NO: 375); wherein the amino acid residue X is selected from S or Q. Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 381, 382, and/or 375. In one embodiment, the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 126 or 127. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 381, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 384 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 365. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 381, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 385 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 380. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315008B03 (SEQ ID NO: 127) and A0315026B01 (SEQ ID NO: 126), and sequence optimized variants thereof (in addition to the CDRs as defined above). In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 126, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 126. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 127, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 127. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 126 or 127, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 126 or 127, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 126 or 127, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 126 or 127, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 126 or 127, the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 126 or 127, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 126 or 127, the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 126 or 127, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 126 or 127, the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 126 or 127, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 126 or 127, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8 or other members of the CEACAM family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-7 to 10-9 moles/litre or less and more preferably 1x10-7 to 1x10-8 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 4.11x10-8 moles/litre, or 2.67x10-8moles/litre, as determined by Surface Plasmon Resonance. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a kon rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M-1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, such as between 1x105 M-1s-1 and 5x105 M-1s-1, even more preferably of about 1.93x105 M-1s-1, or 2.18x105 M-1s-1, as determined by Surface Plasmon Resonance . In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-2 s-1 and 1x10-5 s-1, more preferably between 1x10-2 s-1 and 1x10-4 s-1, such as between 1x10-2 s-1 and 1x10-3 s-1 even more preferably of about 7.94x10-3 s-1, or 5.81x10-3 s-1, as determined by Surface Plasmon Resonance. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (KD) of 10-6 to 10-10 moles/litre or less, and preferably 5x10-7 to 10-9 moles/litre or less and more preferably 5x10-7 to 1x10-8 moles/litre, even more preferably wherein the ISVD specifically binds to cyno CEACAM5 with a KD of about 4.71x10-8 moles/litre, or 2.72x10-7 moles/litre, as determined by Surface Plasmon Resonance. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a kon rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 104 M-1s-1 and 106 M-1s-1, more preferably between 5x104 M-1s-1 and 106 M-1s-1, such as between 5x104 M-1s-1 and 5x105 M-1s-1, even more preferably of about 6.61x104 M-1s-1, or 1.22x105 M-1s-1, as determined by Surface Plasmon Resonance. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a koff rate between 10-1 s-1 (t1/2=0.69 s) and 10-5 s-1 (providing a near irreversible complex with a t1/2 of multiple days), 5x10-2 s-1 and 10-4 s-1, more preferably between 5 x 10-2 s-1 and 1x 10-3 s-1, such as between 5 x 10-2 s-1 and 2x 10-3 s-1, even more preferably of about 3.11x10-3 s-1, or 3.31x10-2 s-1, as determined by Surface Plasmon Resonance. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 100-fold lower affinity (KD). In preferred embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno CEACAM1, CEACAM6, CEACAM7 or CEACAM8. A preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay. For instance, the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a BxPC-3 cell line, which is a human pancreatic adenocarcinoma cell line. VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention. 5.2.10 Embodiment 10 - Family 19 Specific examples of ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GX1TFSX2YAMG (SEQ ID NO: 386), wherein the amino acid residue X1 is selected from G or R, and wherein the amino acid residue X2 is selected from S or N; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GX1TFSX2YAMG (SEQ ID NO: 386), wherein the amino acid residue X1 is selected from G or R, and wherein the amino acid residue X2 is selected from S or N; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences GX1TFSX2YAMG (SEQ ID NO: 386), wherein the amino acid residue X1 is selected from G or R, and wherein the amino acid residue X2 is selected from S or N; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GMSWSGGSTH (SEQ ID NO: 387); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GMSWSGGSTH (SEQ ID NO: 387); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GMSWSGGSTH (SEQ ID NO: 387); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GXNPMGPIATRPSVHDY (SEQ ID NO: 388); wherein the amino acid residue X is selected from Q or R; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GXNPMGPIATRPSVHDY (SEQ ID NO: 388); wherein the amino acid residue X is selected from Q or R; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GXNPMGPIATRPSVHDY (SEQ ID NO: 388); wherein the amino acid residue X is selected from Q or R. Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 386, 387, and/or 388. In one embodiment, the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 128, 129, or 134. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 389, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 387 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 390. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 391, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 387 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 392. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315003D09 (SEQ ID NO: 128), A0315009B07 (SEQ ID NO: 129), and A031500085 (SEQ ID NO: 134), and sequence optimized variants thereof (in addition to the CDRs as defined above). The SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition. As such in one embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence XYAMG (SEQ ID NO: 393), wherein the amino acid residue X is selected from S or N; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence XYAMG (SEQ ID NO: 393), wherein the amino acid residue X is selected from S or N; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences XYAMG (SEQ ID NO: 393), wherein the amino acid residue X is selected from S or N; and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GMSWSGGSTHYADSVKG (SEQ ID NO: 394); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GMSWSGGSTHYADSVKG (SEQ ID NO: 394); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GMSWSGGSTHYADSVKG (SEQ ID NO: 394); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GXNPMGPIATRPSVHDY (SEQ ID NO: 388); wherein the amino acid residue X is selected from Q or R; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GXNPMGPIATRPSVHDY (SEQ ID NO: 388); wherein the amino acid residue X is selected from Q or R; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GXNPMGPIATRPSVHDY (SEQ ID NO: 388); wherein the amino acid residue X is selected from Q or R. Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 393, 394, and/or 388. In one embodiment, the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 128, 129 or 134. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 395, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 394 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 390. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 396, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 394 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 392. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315003D09 (SEQ ID NO: 128), A0315009B07 (SEQ ID NO: 129) and A031500085 (SEQ ID NO: 134), and sequence optimized variants thereof (in addition to the CDRs as defined above). In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 128, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 128. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 129, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 129. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 134, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 134. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 128, 129, or 134, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 128, 129, or 134, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 10-fold lower affinity (KD). Preferably, the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM6 and CEACAM7. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 128, 129, or 134, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 128, 129, or 134, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 10-fold lower affinity (KD). Preferably, the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM6 and CEACAM7. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 128, 129, or 134, the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 128, 129, or 134, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 128, 129, or 134, the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 128, 129, or 134, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 128, 129, or 134, the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 128, 129, or 134, the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 10-fold lower affinity (KD). Preferably, the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 128, 129, or 134, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to, CEACAM6 and CEACAM7 or other members of the CEACAM family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-12 moles/litre or less, and preferably 10-8 to 10-11 moles/litre or less and more preferably 5x10-10 to 5x10-11 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 4.64x10-10 moles/litre, or 9.55x10-11moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M-1s-1 and 107 M-1s-1, more preferably between 104 M-1s-1 and 106 M-1s-1, such as between 1x105 M-1s-1 and 1x106 M-1s-1, even more preferably of about 5.85x105 M-1s-1, or 5.34x105 M-1s-1, as determined by SPR . In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-2 s-1 and 1x10-5 s-1, more preferably between 1x10-3 s-1 and 10-5 s-1, such as between 5x10-4 s-1 and 10-5 s-1 even more preferably of about 2.72x10-4 s-1, or 5.10x10-5 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (KD) of 10-7 to 10-10 moles/litre or less, and preferably 10-8 to 10-10 moles/litre or less and more preferably 1x10-8 to 1x10-9 moles/litre, even more preferably wherein the ISVD specifically binds to cyno CEACAM5 with a KD of about about 4.69x10-9 moles/litre, or 1.93x10-9 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 104 M-1s-1 and 106 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, such as between 1x105 M-1s-1 and 6x105 M-1s-1, even more preferably of about 5.21x105 M-1s-1, or 4.84x105 M-1s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), 10-2 s-1 and 10-5 s-1, more preferably between 10-2 s-1 and 10-4 s-1, such as between 5x10-3 s-1 and 5x10-4 s-1, even more preferably of about 2.45x10-3 s-1, or 9.32x10-4 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 10-fold lower affinity (KD). In preferred embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno, CEACAM6 or CEACAM7. A preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay. For instance, the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a BxPC-3 cell line, which is a human pancreatic adenocarcinoma cell line. VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5. For example, in a FACS binding assay with a BxPC-3 cell line expressing human CEACAM5., the immunoglobulin single variable domains of the present technology may have EC50 values of 10-7 M or lower, more preferably of 10-8 M or lower, or even of 10-9 M or lower. For example, in such FACS assay, the immunoglobulin single variable domains of the present technology may have EC50 values between 10-11 M and 10-8 M, such as between 10- 10 M and 10-8 M, between 10-9 M and 10-8 M or between 5x10-10 M and 5x10-9 M. In some embodiments, the immunoglobulin single variable domains of the present technology has an CEACAM5-mediated internalization potency (EC50 value) of 10-7 M or lower, more preferably of 10-8 M or lower, or even of 5x10-9 M or lower, such as between 10-7 M and 10-10 M, between 10-8 M and 10-10 M, between 5x10-9 M and 10-10 M or between 5x10-9 M and 10-9 M, for example, as measured in a FACS internalization assay on BxPC-3 cells expressing human CEACAM5. 5.2.11 Embodiment 11 -Family 27 Specific examples of ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GGTVSTYTMG (SEQ ID NO: 397); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GGTVSTYTMG (SEQ ID NO: 397); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GGTVSTYTMG (SEQ ID NO: 397); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence SIIWSGSTTV (SEQ ID NO: 398); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence SIIWSGSTTV (SEQ ID NO: 398); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence SIIWSGSTTV (SEQ ID NO: 398); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence QHFGPVSQTTKGYFY (SEQ ID NO: 399); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence QHFGPVSQTTKGYFY (SEQ ID NO: 399); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence QHFGPVSQTTKGYFY (SEQ ID NO: 399). Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 397, 398, and/or 399. In one embodiment, the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NO: 130. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 397, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 398 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 399. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315003F04 (SEQ ID NO: 130) and sequence optimized variants thereof (in addition to the CDRs as defined above). The SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition. As such in one embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of TYTMG (SEQ ID NO: 17); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence TYTMG (SEQ ID NO: 17); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences TYTMG (SEQ ID NO: 17); and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence SIIWSGSTTVYADSVKG (SEQ ID NO: 400); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence SIIWSGSTTVYADSVKG (SEQ ID NO: 400); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence SIIWSGSTTVYADSVKG (SEQ ID NO: 400); and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence QHFGPVSQTTKGYFY (SEQ ID NO: 399); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence QHFGPVSQTTKGYFY (SEQ ID NO: 399); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence QHFGPVSQTTKGYFY (SEQ ID NO: 399). Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 17, 400, and/or 399. In one embodiment, the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NO: 130. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 400 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 399. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315003F04 (SEQ ID NO: 130) and sequence optimized variants thereof (in addition to the CDRs as defined above). In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 130, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 130. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NO: 130, wherein the binding affinity is measured using the same method, such as e.g. SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NO: 130, wherein the binding affinity is measured using the same method, such as e.g. SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 50-fold lower affinity (KD). Preferably, the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM6 and CEACAM7. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NO: 130, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NO: 130, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 50-fold lower affinity (KD). Preferably, the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM6 and CEACAM7. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 130, the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NO: 130, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 130, the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NO: 130, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 130, the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 130, the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 50-fold lower affinity (KD). Preferably, the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 130, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM6 and CEACAM7. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-9 to 10-11 moles/litre or less and more preferably 1x10-9 to 1x10-10 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 7.90x10-10 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a kon rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M-1s-1 and 107 M-1s-1, more preferably between 106 M-1s-1 and 107 M-1s-1, such as between 1x106 M-1s-1 and 5x106 M-1s-1, even more preferably of about 1.19x106 M-1s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-3 s-1 and 1x10-6 s-1, more preferably between 1x10-3 s-1 and 1x10-4 s-1, such as between 1x10-3 s-1 and 5x10-4 s-1 even more preferably of about 9.40x10-4 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (KD) of 10-7 to 10-10 moles/litre or less, and preferably 1x10-8 to 10-10 moles/litre or less and more preferably 1x10-8 to 1x10-9 moles/litre, even more preferably wherein the ISVD specifically binds to cyno CEACAM5 with a KD of about 6.61x10-9 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a kon rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M-1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, such as between 5x105 M-1s-1 and 1x106 M-1s-1, even more preferably of about 9.2x105 M-1s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), 10-2 s-1 and 10-5 s-1, more preferably between 1 x 10-2 s-1 and 1 x 10-4 s-1, such as between 1 x 10-2 s-1 and 1 x 10-3 s-1, even more preferably of about 6.08x10-3 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 50-fold lower affinity (KD). In preferred embodiments, the immunoglobulin single variable domains specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno CEACAM6 or CEACAM7. A preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay. For instance, the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a BxPC-3 cell line, which is a human pancreatic adenocarcinoma cell line. VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5. For example, in a FACS binding assay with a BxPC-3 cell line expressing human CEACAM5., the immunoglobulin single variable domains of the present technology may have EC50 values of 10-7 M or lower, more preferably of 10-8 M or lower, or even of 10-9 M or lower. For example, in such FACS assay, the immunoglobulin single variable domains of the present technology may have EC50 values between 10-11 M and 10-8 M, such as between 10- 10 M and 10-8 M, between 5x10-10 M and 10-8 M or between 10-9 M and 10-8 M. In some embodiments, the immunoglobulin single variable domains of the present technology has an CEACAM5-mediated internalization potency (EC50 value) of 10-7 M or lower, more preferably of 10-8 M or lower, or even of 5x10-9 M or lower, such as between 10-7 M and 10-10 M, between 10-8 M and 10-10 M, between 5x10-9 M and 10-10 M or between 5x10-9 M and 10-9 M, for example, as measured in a FACS internalization assay on BxPC-3 cells expressing human CEACAM5. 5.2.12 Embodiment 12 -Family 28 Specific examples of ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AIWWSTGNTI (SEQ ID NO: 379); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AIWWSTGNTI (SEQ ID NO: 379); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AIWWSTGNTI (SEQ ID NO: 379); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence VRFSFRPLSTYWKDYDN (SEQ ID NO: 365); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence VRFSFRPLSTYWKDYDN (SEQ ID NO: 365); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence VRFSFRPLSTYWKDYDN (SEQ ID NO: 365). Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 368, 379, and/or 365. In one embodiment, the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NO: 131. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 368, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 379 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 365. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315021A01 (SEQ ID NO: 131) and sequence optimized variants thereof (in addition to the CDRs as defined above). The SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition. As such in one embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of DYHMA (SEQ ID NO: 371); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence DYHMA (SEQ ID NO: 371); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences DYHMA (SEQ ID NO: 371); and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AIWWSTGNTIVADSVKG (SEQ ID NO: 385); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AIWWSTGNTIVADSVKG (SEQ ID NO: 385); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AIWWSTGNTIVADSVKG (SEQ ID NO: 385); and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence VRFSFRPLSTYWKDYDN (SEQ ID NO: 365); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence VRFSFRPLSTYWKDYDN (SEQ ID NO: 365); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence VRFSFRPLSTYWKDYDN (SEQ ID NO: 365). Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 371, 385, and/or 365. In one embodiment, the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NO: 131. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 371, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 385 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 365. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315021A01 (SEQ ID NO: 131) and sequence optimized variants thereof (in addition to the CDRs as defined above). In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 131, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 131. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NO: 131, wherein the binding affinity is measured using the same method, such as e.g. SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NO: 131, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NO: 131, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NO: 131, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 131, the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NO: 131, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 131, the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NO: 131, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 131, the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 131, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NO: 131, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8 or other members of the CEACAM family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-7 to 10-9 moles/litre or less and more preferably 1x10-7 to 1x10-8 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 3.12x10-8 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a kon rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M-1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, such as between 1x105 M-1s-1 and 5x105 M-1s-1, even more preferably of about 2.16x105 M-1s-1,as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-2 s-1 and 1x10-5 s-1, more preferably between 8x10-3 s-1 and 1x10-5 s-1, such as between 8x10-3 s-1 and 1x10-4 s-1 even more preferably of about 6.73x10-3 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (KD) of 10-7 to 10-10 moles/litre or less, and preferably 1x10-7 to 10-9 moles/litre or less and more preferably 1x10-7 to 10-8 moles/litre, even more preferably wherein the ISVD specifically binds to cyno CEACAM5 with a KD of about 3.45x10-8 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a kon rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 104 M-1s-1 and 106 M-1s-1, more preferably between 104 M-1s-1 and 105 M-1s-1, such as between 5x104 M-1s-1 and 1x105 M-1s-1, even more preferably of about 7.16x104 M-1s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-2 s-1 and 10-5 s-1, more preferably between 10-2 s-1 and 10-4 s-1, such as between 1x10-2 s-1 and 1x10-3 s-1, even more preferably of about 2.47x10-3 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 100-fold lower affinity (KD). In preferred embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno CEACAM1, CEACAM6, CEACAM7 or CEACAM8. A preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay. For instance, the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a BxPC-3 cell line, which is a human pancreatic adenocarcinoma cell line. VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5. For example, in a FACS binding assay with a BxPC-3 cell line expressing human CEACAM5., the immunoglobulin single variable domains of the present technology may have EC50 values of 10-7 M or lower, more preferably of 10-8 M or lower, or even of 10-9 M or lower. For example, in such FACS assay, the immunoglobulin single variable domains of the present technology may have EC50 values between 10-11 M and 5x10-8 M, such as between 10-10 M and 5x10-8 M, between 5x10-9 M and 5x10-8 M or between 10-9 M and 5x10-8 M. In some embodiments, the immunoglobulin single variable domains of the present technology has an CEACAM5-mediated internalization potency (EC50 value) of 10-6 M or lower, more preferably of 5x10-6 M or lower, or even of 10-7 M or lower, such as between 10-6 M and 10-10 M, between 10-6 M and 10-9 M, between 5x10-6 M and 10-9 M or between 5x10-6 M and 10-8 M, for example, as measured in a FACS internalization assay on BxPC-3 cells expressing human CEACAM5. 5.2.13 Embodiment 13 -Family 4 and 5 Specific examples of ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GX1TFSX2X3AX4G (SEQ ID NO: 530); wherein the amino acid residue X1 is selected from R or H; wherein the amino acid residue X2 is selected from E or D; wherein the amino acid residue X3 is selected from F or Y; and wherein the amino acid residue X4 is selected from L or M; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GX1TFSX2X3AX4G (SEQ ID NO: 530); wherein the amino acid residue X1 is selected from R or H; wherein the amino acid residue X2 is selected from E or D; wherein the amino acid residue X3 is selected from F or Y; and wherein the amino acid residue X4 is selected from L or M; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GX1TFSX2X3AX4G (SEQ ID NO: 530); wherein the amino acid residue X1 is selected from R or H; wherein the amino acid residue X2 is selected from E or D; wherein the amino acid residue X3 is selected from F or Y; and wherein the amino acid residue X4 is selected from L or M; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AINWX1GX2WTY (SEQ ID NO: 531); wherein the amino acid residue X1 is selected from G or S; and wherein the amino acid residue X2 is selected from T, G or S; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AINWX1GX2WTY (SEQ ID NO: 531), wherein the amino acid residue X1 is selected from G or S; and wherein the amino acid residue X2 is selected from T, G or S; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AINWX1GX2WTY (SEQ ID NO: 531), wherein the amino acid residue X1 is selected from G or S; and wherein the amino acid residue X2 is selected from T, G or S; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence SX1DYAGGX2X3TGYX4Y (SEQ ID NO: 532); wherein the amino acid residue X1 is selected from S, P or L; wherein the amino acid residue X2 is selected from N, R or S; wherein the amino acid residue X3 is selected from P or S; and wherein the amino acid residue X4 is selected from P, D or A; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SX1DYAGGX2X3TGYX4Y (SEQ ID NO: 532); wherein the amino acid residue X1 is selected from S, P or L; wherein the amino acid residue X2 is selected from N, R or S; wherein the amino acid residue X3 is selected from P or S; and wherein the amino acid residue X4 is selected from P, D or A; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SX1DYAGGX2X3TGYX4Y (SEQ ID NO: 532); wherein the amino acid residue X1 is selected from S, P or L; wherein the amino acid residue X2 is selected from N, R or S; wherein the amino acid residue X3 is selected from P or S; and wherein the amino acid residue X4 is selected from P, D or A. Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID Nos: 530, 531, and/or 532. In one embodiment, the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 9, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 10 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 11. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 234, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 235 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 236. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 234, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 238 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 239. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 359, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 357 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 360. S‚ In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 234, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 357 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 361. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315024B02 (SEQ ID NO: 16) and sequence optimized variants thereof in Table A-3 (in addition to the CDRs as defined above). In one embodiment, the ISVD comprises or consists of the full amino acid sequence of A0315024B02 (SEQ ID NO: 16); T028501817 (SEQ ID NO: 39), or T028501817(E1D) (SEQ ID NO: 40), A031500086 (SEQ ID NO: 135), A031500087 (SEQ ID NO: 136), A031500088 (SEQ ID NO: 137), A031500089 (SEQ ID NO: 138), A031500090 (SEQ ID NO: 139), A031500091 (SEQ ID NO: 140), A031500092 (SEQ ID NO: 141), A031500093 (SEQ ID NO: 142), A031500094 (SEQ ID NO: 143), A031500095 (SEQ ID NO: 144), A031500096 (SEQ ID NO: 145, A031500097 (SEQ ID NO: 146), A031500098 (SEQ ID NO: 147), and A031500100 (SEQ ID NO: 148) and A031500101 (SEQ ID NO: 149) (see Table A-2, Table A-3). In other embodiments, the ISVD comprises or consists of the full amino acid sequence of A0315001C02 (SEQ ID NO.: 120) or A0315026D05 (SEQ ID NO.: 121), A0315001C11 (SEQ ID NO: 122), or A0315004G01 (SEQ ID NO: 123) see Table A-2. The SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition. As such in one embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence X1X2AX3G (SEQ ID NO: 533); wherein the amino acid residue X1 is selected from E or D, X2 is selected from Y or F; and the amino acid residue X3 is selected from L or M; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence X1X2AX3G (SEQ ID NO: 533); wherein the amino acid residue X1 is selected from E or D, X2 is selected from Y or F; and the amino acid residue X3 is selected from L or M c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence X1X2AX3G (SEQ ID NO: 533); wherein the amino acid residue X1 is selected from E or D, X2 is selected from Y or F; and the amino acid residue X3 is selected from L or M; and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AINWX1GX2WTYYAX3SVX4G (SEQ ID NO: 534); wherein the amino acid residue X1 is selected from G or S; wherein the amino acid residue X2 is selected from G, S or T; wherein the amino acid residue X3 is selected from H or D; and wherein the amino acid residue X4 is selected from Q or K; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AINWX1GX2WTYYAX3SVX4G (SEQ ID NO: 534); wherein the amino acid residue X1 is selected from G or S; wherein the amino acid residue X2 is selected from G, S or T; wherein the amino acid residue X3 is selected from H or D; and wherein the amino acid residue X4 is selected from Q or K; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AINWX1GX2WTYYAX3SVX4G (SEQ ID NO: 534); wherein the amino acid residue X1 is selected from G or S; wherein the amino acid residue X2 is selected from G, S or T; wherein the amino acid residue X3 is selected from H or D; and wherein the amino acid residue X4 is selected from Q or K; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence SX1DYAGGX2X3TGYX4Y (SEQ ID NO: 535); wherein the amino acid residue X1 is selected from S, P or L; wherein the amino acid residue X2 is selected from N, R or S; wherein the amino acid residue X3 is selected from P or S; and wherein the amino acid residue X4 is selected from P, D or A; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence SX1DYAGGX2X3TGYX4Y (SEQ ID NO: 535); wherein the amino acid residue X1 is selected from S, P or L; wherein the amino acid residue X2 is selected from N, R or S; wherein the amino acid residue X3 is selected from P or S; and wherein the amino acid residue X4 is selected from P, D or A; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence SX1DYAGGX2X3TGYX4Y (SEQ ID NO: 535); wherein the amino acid residue X1 is selected from S, P or L; wherein the amino acid residue X2 is selected from N, R or S; wherein the amino acid residue X3 is selected from P or S; and wherein the amino acid residue X4 is selected from P, D or A. Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 533, 534, and/or 535. In one embodiment, the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 21, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 22 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 11. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 21, a CDR2 (Kabat numbering) that is the amino acid sequence of (AINWGGGWTYYADSVKG) SEQ ID NO: 43 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 11. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 243, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 244 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 236. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 243, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 245 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 246. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 229, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 362 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 360. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 243, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 362 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 361. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315024B02 (SEQ ID NO: 16) and sequence optimized variants thereof in Table A-3 (in addition to the CDRs as defined above). In one embodiment, the ISVD comprises or consists of the full amino acid sequence of A0315024B02 (SEQ ID NO: 16); T028501817 (SEQ ID NO: 39), or T028501817(E1D) (SEQ ID NO: 40), A031500086 (SEQ ID NO: 135), A031500087 (SEQ ID NO: 136), A031500088 (SEQ ID NO: 137), A031500089 (SEQ ID NO: 138), A031500090 (SEQ ID NO: 139), A031500091 (SEQ ID NO: 140), A031500092 (SEQ ID NO: 141), A031500093 (SEQ ID NO: 142), A031500094 (SEQ ID NO: 143), A031500095 (SEQ ID NO: 144), A031500096 (SEQ ID NO: 145, A031500097 (SEQ ID NO: 146), A031500098 (SEQ ID NO: 147), and A031500100 (SEQ ID NO: 148) and A031500101 (SEQ ID NO: 149) (see Table A-2, Table A-3). In other embodiments, the ISVD comprises or consists of the full amino acid sequence of A0315001C02 (SEQ ID NO.: 120) or A0315026D05 (SEQ ID NO.: 121), A0315001C11 (SEQ ID NO: 122), or A0315004G01 (SEQ ID NO: 123) see Table A-2. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 16, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 16. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 39, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 39. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 40, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 40. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 120, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 120. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 121, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 121. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 135, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 135. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 136, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 136. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 137, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 137. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 138, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 138. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 139, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 139. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 140, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 140. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 141, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 141. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 142, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 142. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 143, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 143. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 144, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 144. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 145, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 145. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 146, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 146. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 147, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 147. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 148, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 148. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 149, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 149. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 122, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 122. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 123, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 123. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149, wherein the binding affinity is measured using the same method, such as, e.g, SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149, the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149, the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149, the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, and CEACAM8, or other members of the CEACAM family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 5x10-8 to 10-10 moles/litre or less and more preferably 1x10-8 to 1x10-9 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 1.06x10-8moles/litre, 4.86x10-9 moles/litre, 8.9x10-9 moles/litre, 5.85x10-9 moles/litre, or 6.01x10-9 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 104 M-1s-1 and 106 M-1s-1, more preferably between 104 M-1s-1 and 5x105 M-1s-1, such as between 5x104 M-1s-1 and 5x105 M-1s-1, even more preferably of about 1.2x105 M-1s-1, 1.6x105 M-1s-1, 1.98x105 M-1s, 2.38x105 M-1s , 8.68x104 M-1s-1, or 8.07x104 M-1s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 1x10-2 s-1 and 10-5 s-1, more preferably between 5x10-3 s-1 and 5x10-5 s-1, such as between 5x10-3 s-1 and 1x10- 4 s-1, even more preferably of about 1.08x10-3 s-1, 1.7x10-3 s-1, 9.61x10-4 s-1,2.12x10-3 s-1, 5.08x10-4 s- 1, or 4.85x10-4 s-1 as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-8 to 10-10 moles/litre or less and more preferably 10-8 to 1x10-9 moles/litre, even more preferably wherein the ISVD specifically binds to cyno CEACAM5 with a KD of about 6.94x10-9moles/litre, 2.28x10-9moles/litre, 4.86x10-9moles/litre, 8.16x10-9 moles/litre, or 6.47x10- 9 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M-1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, such as between 2x105 M-1s-1 and 1x106 M-1s-1, even more preferably of about 5.9x105 M-1s-1, 9.94x105 M-1s-1, 8.62x105 M-1s-1, 3.04x105 M-1s-1, or 3.18x105 M-1s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-5 s-1 (providing a near irreversible complex with a t1/2 of multiple days), 10-2 s-1 and 10-4 s-1, more preferably between 5 x 10-3 s-1 and 5 x 10-4 s-1, such as between 5x10-3 s-1 and 1x10-3s-1, even more preferably of about 4,09x10-3 s-1, 2.26x10-3 s-1, 2.50x10-3 s-1, 2.48x10-3 s-1, or 2.06x10-3 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 100-fold lower affinity (KD). In preferred embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno CEACAM1, CEACAM6, or CEACAM8. A preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay. For instance, the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a BxPC-3 cell line, which is a human pancreatic adenocarcinoma cell line. VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5. For example, in a FACS assay analysing the binding of the immunoglobulin single variable domains of the present technology to human CEACAM5 expressed on BxPC-3 cells, the immunoglobulin single variable domains of the present technology may have EC50 values of 10-7 M or lower, more preferably of 5x10-8 M or lower, or even of 10-8 M or lower. For example, in such FACS assay, the immunoglobulin single variable domains of the present technology may have EC50 values between 10-11 M and 10-7 M, such as between 10-10 M and 10-7 M, between 10-9 M and 5x10-8 M or between 5x10-9 M and 5x10-8 M. In some embodiments, the immunoglobulin single variable domains of the present technology has an CEACAM5-mediated internalization potency (EC50 value) of 5x10-7 M or lower, more preferably of 10-7 M or lower, or even of 5x10-8 M or lower, such as between 10-7 M and 10-10 M, between 10- 7 M and 10-9 M, between 5x10-8 M and 10-9 M or between 10-7 M and 10-8 M, for example, as measured in a FACS internalization assay on BxPC-3 cells expressing human CEACAM5. 5.2.14 Embodiment 14 -Family 9, 17, 18, 1 Specific examples of ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GX1X2X3X4X5YX6X7X8 (SEQ ID NO: 536); wherein the amino acid residue X1 is selected from R or D, the amino acid residue X2 is selected from N or T; wherein the amino acid residue X3 is selected from F or L; wherein the amino acid residue X4 is selected from N, E, G, P, S, or T; wherein the amino acid residue X5 is selected from S, D, or the stretch of the following amino acids: I, N and E; wherein the amino acid residue X6 is selected from D or H; wherein the amino acid residue X7 is selected from L or M; and wherein the amino acid residue X8 is selected from A or G; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GX1X2X3X4X5YX6X7X8 (SEQ ID NO: 536); wherein the amino acid residue X1 is selected from R or D, the amino acid residue X2 is selected from N or T; wherein the amino acid residue X3 is selected from F or L; wherein the amino acid residue X4 is selected from N, E, G, P, S, or T; wherein the amino acid residue X5 is selected from S, D, or the stretch of the following amino acids: I, N and E; wherein the amino acid residue X6 is selected from D or H; wherein the amino acid residue X7 is selected from L or M; and wherein the amino acid residue X8 is selected from A or G; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GX1X2X3X4X5YX6X7X8 (SEQ ID NO: 536); wherein the amino acid residue X1 is selected from R or D, the amino acid residue X2 is selected from N or T; wherein the amino acid residue X3 is selected from F or L; wherein the amino acid residue X4 is selected from N, E, G, P, S, or T; wherein the amino acid residue X5 is selected from S, D, or the stretch of the following amino acids: I, N and E; wherein the amino acid residue X6 is selected from D or H; wherein the amino acid residue X7 is selected from L or M; and wherein the amino acid residue X8 is selected from A or G; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AIX1WSX2GX3X4X5 (SEQ ID NO: 537); wherein the amino acid residue X1 is selected from R or W; the amino acid residue X2 is selected from A or T; wherein the amino acid residue X3 is selected from S or N; wherein the amino acid residue X4 is selected from K, R, A or T; and wherein the amino acid residue X5 is selected from I or V; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AIX1WSX2GX3X4X5 (SEQ ID NO: 537); wherein the amino acid residue X1 is selected from R or W; the amino acid residue X2 is selected from A or T; wherein the amino acid residue X3 is selected from S or N; wherein the amino acid residue X4 is selected from K, R, A or T; and wherein the amino acid residue X5 is selected from I or V; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AIX1WSX2GX3X4X5 (SEQ ID NO: 537); wherein the amino acid residue X1 is selected from R or W; the amino acid residue X2 is selected from A or T; wherein the amino acid residue X3 is selected from S or N; wherein the amino acid residue X4 is selected from K, R, A or T; and wherein the amino acid residue X5 is selected from I or V; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence VRX1X2FRPLSTYWKDYDX3 (SEQ ID NO: 538); wherein the amino acid residue X1 is selected from F or P; wherein the amino acid residue X2 is selected from Q or S; and wherein the amino acid residue X3 is selected from I or N; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence VRX1X2FRPLSTYWKDYDX3 (SEQ ID NO: 538); wherein the amino acid residue X1 is selected from F or P; wherein the amino acid residue X2 is selected from Q or S; and wherein the amino acid residue X3 is selected from I or N; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence VRX1X2FRPLSTYWKDYDX3 (SEQ ID NO: 538); wherein the amino acid residue X1 is selected from F or P; wherein the amino acid residue X2 is selected from Q or S; and wherein the amino acid residue X3 is selected from I or N. Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 536, 537, and/or 538. In one embodiment, the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 114, 124-127, 175-208. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 255, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 256 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 257. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 284, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 256 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 257. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 285, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 256 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 257. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 286, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 256 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 257. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 287, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 256 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 257. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 288, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 256 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 257. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 363, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 364 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 365. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 368, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 369 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 370. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 376, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 377 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 365. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 378, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 379 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 380. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315001D07 (SEQ ID NO: 114), A0315025D01 (SEQ ID NO: 124), A0315020C01 (SEQ ID NO: 125), A0315026B01 (SEQ ID NO: 126) and A0315008B03 (SEQ ID NO: 127) and sequence optimized variants thereof in Table A-7 (in addition to the CDRs as defined above). In one embodiment, the ISVD comprises or consists of the full amino acid sequence of A031500014 (SEQ ID NO: 175), A031500015 (SEQ ID NO: 176), A031500016 (SEQ ID NO: 177), A031500017 (SEQ ID NO: 178), A031500018 (SEQ ID NO: 179), A031500019 (SEQ ID NO: 180), A031500020 (SEQ ID NO: 181), A031500021 (SEQ ID NO: 182), A031500022 (SEQ ID NO: 183), A031500023 (SEQ ID NO: 184), A031500024 (SEQ ID NO: 185), A031500025 (SEQ ID NO: 186), A031500026 (SEQ ID NO: 187), A031500027 (SEQ ID NO: 188), A031500028 (SEQ ID NO: 189), A031500029 (SEQ ID NO: 190), A031500030 (SEQ ID NO: 191), A031500031 (SEQ ID NO: 192), A031500032 (SEQ ID NO: 193), A031500033 (SEQ ID NO: 194), A031500034 (SEQ ID NO: 195), A031500035 (SEQ ID NO: 196), A031500368 (SEQ ID NO: 197), A031500369 (SEQ ID NO: 198), A031500370 (SEQ ID NO: 199), A031500345 (SEQ ID NO: 200), A031500346 (SEQ ID NO: 201), A031500347 (SEQ ID NO: 202), A031500348 (SEQ ID NO: 203), A031500406 (SEQ ID NO: 204), A031500407 (SEQ ID NO: 205), A031500408 (SEQ ID NO: 206), A031500409 (SEQ ID NO: 207), or A031500410 (SEQ ID NO: 208), (see Table A-7). In another embodiment, the ISVD comprises or consists of the full amino acid sequence of A0315001D07 (SEQ ID NO: 114), A0315025D01 (SEQ ID NO: 124), A0315020C01 (SEQ ID NO: 125), A0315026B01 (SEQ ID NO: 126) and A0315008B03 (SEQ ID NO: 127) (see Table A-2 and Table A-7). The SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition. As such in one embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence X1YX2X3X4 (SEQ ID NO: 539); wherein the amino acid residue X1 is selected from D, S or the stretch of the following amino acids: I, N and E; wherein the amino acid residue X2 is selected from H or D; wherein the amino acid residue X3 is selected from L or M; and wherein the amino acid residue X4 is selected from A or G; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of X1YX2X3X4 (SEQ ID NO: 539); wherein the amino acid residue X1 is selected from D, S or the stretch of the following amino acids: I, N and E; wherein the amino acid residue X2 is selected from H or D; wherein the amino acid residue X3 is selected from L or M; and wherein the amino acid residue X4 is selected from A or G; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of X1YX2X3X4 (SEQ ID NO: 539); wherein the amino acid residue X1 is selected from D, S or the stretch of the following amino acids: I, N and E; wherein the amino acid residue X2 is selected from H or D; wherein the amino acid residue X3 is selected from L or M; and wherein the amino acid residue X4 is selected from A or G; and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AIX1WSX2GX3X4X5X6X7X8SVKG (SEQ ID NO: 540); wherein the amino acid residue X1 is selected from R or W; wherein the amino acid residue X2 is selected from A or T; wherein the amino acid residue X3 is selected from S or N; wherein the amino acid residue X4 is selected from T, K, R, and A; wherein the amino acid residue X5 is selected from V and I; wherein the amino acid residue X6 is selected from Y and V; wherein the amino acid residue X7 is selected from G or A; and wherein the amino acid residue X8 is selected from N or D; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AIX1WSX2GX3X4X5X6X7X8SVKG (SEQ ID NO: 540); wherein the amino acid residue X1 is selected from R or W; wherein the amino acid residue X2 is selected from A or T; wherein the amino acid residue X3 is selected from S or N; wherein the amino acid residue X4 is selected from T, K, R, and A; wherein the amino acid residue X5 is selected from V and I; wherein the amino acid residue X6 is selected from Y and V; wherein the amino acid residue X7 is selected from G or A; and wherein the amino acid residue X8 is selected from N or D; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AIX1WSX2GX3X4X5X6X7X8SVKG (SEQ ID NO: 540); wherein the amino acid residue X1 is selected from R or W; wherein the amino acid residue X2 is selected from A or T; wherein the amino acid residue X3 is selected from S or N; wherein the amino acid residue X4 is selected from T, K, R, and A; wherein the amino acid residue X5 is selected from V and I; wherein the amino acid residue X6 is selected from Y and V; wherein the amino acid residue X7 is selected from G or A; and wherein the amino acid residue X8 is selected from N or D; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence VRX1X2FRPLSTYWKDYDX3 (SEQ ID NO: 538); wherein the amino acid residue X1 is selected from P or F; wherein the amino acid residue X2 is selected from S or Q; and wherein the amino acid residue X3 is selected from I or N; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence VRX1X2FRPLSTYWKDYDX3 (SEQ ID NO: 538); wherein the amino acid residue X1 is selected from P or F; wherein the amino acid residue X2 is selected from S or Q; and wherein the amino acid residue X3 is selected from I or N; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of VRX1X2FRPLSTYWKDYDX3 (SEQ ID NO: 538); wherein the amino acid residue X1 is selected from P or F; wherein the amino acid residue X2 is selected from S or Q; and wherein the amino acid residue X3 is selected from I or N. Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 539, 540, and/or 538. In one embodiment, the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 114, 124-127, 175-208. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 289, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 291 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 257. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 289, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 292 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 257. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 289, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 293 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 257. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 289, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 294 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 257. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 366, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 367 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 365. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 371, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 372 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 370. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 381, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 384 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 365. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 381, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 385 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 380. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315001D07 (SEQ ID NO: 114), A0315025D01 (SEQ ID NO: 124), A0315020C01 (SEQ ID NO: 125), A0315026B01 (SEQ ID NO: 126) and A0315008B03 (SEQ ID NO: 127) and sequence optimized variants thereof in Table A-7 (in addition to the CDRs as defined above). In one embodiment, the ISVD comprises or consists of the full amino acid sequence of A031500014 (SEQ ID NO: 175), A031500015 (SEQ ID NO: 176), A031500016 (SEQ ID NO: 177), A031500017 (SEQ ID NO: 178), A031500018 (SEQ ID NO: 179), A031500019 (SEQ ID NO: 180), A031500020 (SEQ ID NO: 181), A031500021 (SEQ ID NO: 182), A031500022 (SEQ ID NO: 183), A031500023 (SEQ ID NO: 184), A031500024 (SEQ ID NO: 185), A031500025 (SEQ ID NO: 186), A031500026 (SEQ ID NO: 187), A031500027 (SEQ ID NO: 188), A031500028 (SEQ ID NO: 189), A031500029 (SEQ ID NO: 190), A031500030 (SEQ ID NO: 191), A031500031 (SEQ ID NO: 192), A031500032 (SEQ ID NO: 193), A031500033 (SEQ ID NO: 194), A031500034 (SEQ ID NO: 195), A031500035 (SEQ ID NO: 196), A031500368 (SEQ ID NO: 197), A031500369 (SEQ ID NO: 198), A031500370 (SEQ ID NO: 199), A031500345 (SEQ ID NO: 200), A031500346 (SEQ ID NO: 201), A031500347 (SEQ ID NO: 202), A031500348 (SEQ ID NO: 203), A031500406 (SEQ ID NO: 204), A031500407 (SEQ ID NO: 205), A031500408 (SEQ ID NO: 206), A031500409 (SEQ ID NO: 207), or A031500410 (SEQ ID NO: 208), (see Table A-7). In one embodiment, the ISVD comprises or consists of the full amino acid sequence of A0315001D07 (SEQ ID NO: 114), A0315025D01 (SEQ ID NO: 124), A0315020C01 (SEQ ID NO: 125), A0315026B01 (SEQ ID NO: 126) and A0315008B03 (SEQ ID NO: 127) (see Table A-2 and Table A-7). In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 114, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 114. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 175, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 175. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 176, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 176. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 177, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 177. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 178, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 178. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 179, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 179. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 180, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 180. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 181, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 181. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 182, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 182. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 183, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 183. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 184, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 184. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 185, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 185. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 186, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 186. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 187, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 187. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 188, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 188. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 189, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 189. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 190, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 190. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 191, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 191. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 192, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 192. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 193, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 193. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 194, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 194. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 195, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 195. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 196, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 196. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 197, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 197. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 198, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 198. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 199, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 199. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 200, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 200. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 201, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 201. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 202, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 202. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 203, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 203. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 204, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 204. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 205, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 205. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 206, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 206. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 207, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 207. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 208, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 208. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 124, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 124. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 125, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 125. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 126, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 126. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 127, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 127. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 114, 124-127, 175-208, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 114, 124-127, 175-208, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 114, 124-127, 175-208, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 114, 124-127, 175-208, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 114, 124-127, 175-208, the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 114, 124-127, 175-208, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 114, 124-127, 175-208, the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 114, 124-127, 175-208, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 114, 124-127, 175-208, the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 114, 124-127, 175-208, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 114, 124-127, 175-208, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8 or other members of the CEACAM family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-7 to 10-9 moles/litre or less and more preferably 5x10-8 to 5x10-9 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 1.87x10-8 moles/litre, 2.49x10-8 moles/litre, 2.39x10-8 moles/litre, 4.11x10-8 moles/litre, or 2.67x10- 8moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M-1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, such as between 1x105 M-1s-1 and 5x105 M-1s-1, even more preferably of about 3.96x105 M-1s-1, 2.01x105 M-1s-1, 2.19x105 M-1s-1, 1.93x105 M-1s-1, or 2.18x105 M-1s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-2 s-1 and 1x10-5 s-1, more preferably between 1x10-2 s-1 and 1x10-3 s-1, such as between 1x10-2 s-1 and 5x10-3 s-1 even more preferably of about 7.41x10-3 s-1, 5.01x10-3 s-1, 5.22x10-3 s-1, 7.94x10-3 s-1, or 5.81x10-3 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (KD) of 10-6 to 10-10 moles/litre or less, and preferably 5x10-7 to 10-9 moles/litre or less and more preferably 5x10-7 to 10-8 moles/litre, even more preferably wherein the ISVD specifically binds to cyno CEACAM5 with a KD of about 7.92x10-7 moles/litre, 1.73x10-7 moles/litre, 3.65x10-8 moles/litre, 5.81x10-8 moles/litre, 4.71x10- 8 moles/litre, or 2.72x10-7 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 104 M-1s-1 and 106 M-1s-1, more preferably between 5x104 M-1s-1 and 106 M-1s-1, such as between 5x104 M-1s-1 and 5x105 M-1s-1, even more preferably of about 7.98x104 M-1s-1, 8.70x104 M-1s-1, 6.61x104 M-1s-1, or 1.22x105 M-1s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a koff rate between 10-1 s-1 (t1/2=0.69 s) and 10-5 s-1 (providing a near irreversible complex with a t1/2 of multiple days), 5x10-2 s-1 and 10-4 s-1, more preferably between 5x 10-2 s-1 and 1 x 10-3 s-1, even more preferably of about 1.83 x 10-2 s-1 , 2.92x10- 3 s-1, 5.05x10-3 s-1, 3.11x10-3 s-1, or 3.31x10-2 s-1,d as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 100-fold lower affinity (KD). In preferred embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno CEACAM1, CEACAM6, CEACAM7 or CEACAM8. A preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay. For instance, the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a BxPC-3 cell line, which is a human pancreatic adenocarcinoma cell line. VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention. 5.2.15 Embodiment 15 -Family 3, 30, 27 Specific examples of ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of GX1TX2STYTX3G (SEQ ID NO: 541); wherein the amino acid residue X1 is selected from G or L; wherein the amino acid residue X2 is selected from V or F; and wherein the amino acid residue X3 is selected from V or M; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GX1TX2STYTX3G (SEQ ID NO: 541); wherein the amino acid residue X1 is selected from G or L; wherein the amino acid residue X2 is selected from V or F; and wherein the amino acid residue X3 is selected from V or M; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GX1TX2STYTX3G (SEQ ID NO: 541); wherein the amino acid residue X1 is selected from G or L; wherein the amino acid residue X2 is selected from V or F, and wherein the amino acid residue X3 is selected from V or M; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of X1X2IX3SGSX4TX5 (SEQ ID NO: 542); wherein the amino acid residue X1 is selected from S or A; wherein the amino acid residue X2 is selected from I or M; wherein the amino acid residue X3 is selected from W or Y; wherein the amino acid residue X4 is selected from N or T; and wherein the amino acid residue X5 is selected from V, Y or L; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence X1X2IX3SGSX4TX5 (SEQ ID NO: 542); wherein the amino acid residue X1 is selected from S or A; wherein the amino acid residue X2 is selected from I or M; wherein the amino acid residue X3 is selected from W or Y; wherein the amino acid residue X4 is selected from N or T; and wherein the amino acid residue X5 is selected from V, Y or L; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence X1X2IX3SGSX4TX5 (SEQ ID NO: 542); wherein the amino acid residue X1 is selected from S or A; wherein the amino acid residue X2 is selected from I or M; wherein the amino acid residue X3 is selected from W or Y; wherein the amino acid residue X4 is selected from N or T; and wherein the amino acid residue X5 is selected from V, Y or L; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence QHFGPX1X2X3TTX4GYX5Y (SEQ ID NO: 543); wherein the amino acid residue X1 is selected from V or I; the amino acid residue X2 is selected from S or G; wherein the amino acid residue X3 is selected from L or Q; the amino acid residue X4 is selected from R or K; and wherein the amino acid residue X5 is selected from N, A, F, G, I, L, Y or H; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence QHFGPX1X2X3TTX4GYX5Y (SEQ ID NO: 543); wherein the amino acid residue X1 is selected from V or I; the amino acid residue X2 is selected from S or G; wherein the amino acid residue X3 is selected from L or Q; the amino acid residue X4 is selected from R or K; and wherein the amino acid residue X5 is selected from N, A, F, G, I, L, Y or H; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of QHFGPX1X2X3TTX4GYX5Y (SEQ ID NO: 543); wherein the amino acid residue X1 is selected from V or I; the amino acid residue X2 is selected from S or G; wherein the amino acid residue X3 is selected from L or Q; the amino acid residue X4 is selected from R or K; and wherein the amino acid residue X5 is selected from N, A, F, G, I, L, Y or H. Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 541, 542, and/or 543. In one embodiment, the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 8, 31, 32, 118-119, 130, 150-159, 171-174. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 336 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 339. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 334, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 337 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 340. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 3. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 33. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 249. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 250. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 251. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 252. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 253. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 1, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 254. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 397, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 398 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 399. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315002G06 (SEQ ID NO: 118), A0315002C10 (SEQ ID NO: 119), A0315007E07 (SEQ ID NO: 8), A0315003F04 (SEQ ID NO: 130) and sequence optimized variants thereof in Table A-6 (in addition to the CDRs as defined above). In one embodiment, the ISVD comprises or consists of the full amino acid sequence of A031500010 (SEQ ID NO: 171), A031500011 (SEQ ID NO: 172), A031500012 (SEQ ID NO: 173), or A031500013 (SEQ ID NO: 174) (see Table A-2, Table A-6). In other embodiments, the ISVD comprises or consists of the full amino acid sequence of A0315002G06 (SEQ ID NO: 118) or A0315002C10 (SEQ ID NO: 119) (Table A-2). In one embodiment, the ISVD comprises or consists of the full amino acid sequence of T028501789 (SEQ ID NO: 31), or T028501789 (E1D) (SEQ ID NO: 32), A031500251 (SEQ ID NO: 150), A031500252 (SEQ ID NO: 151), A031500253 (SEQ ID NO: 152), A031500254 (SEQ ID NO: 153), A031500379 (SEQ ID NO: 154), A031500382 (SEQ ID NO: 155), A031500383 (SEQ ID NO: 156), A031500385 (SEQ ID NO: 157), A031500387 (SEQ ID NO: 158), and A031500394 (SEQ ID NO: 159) (see Table A-4). In other embodiments, the ISVD comprises or consists of the full amino acid sequence of A0315007E07 (SEQ ID NO: 8) (Table A-2). In other embodiments, the ISVD comprises or consists of the full amino acid sequence of A0315003F04 (SEQ ID NO: 130) (Table A-2). The SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition. As such in one embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence TYTXG (SEQ ID NO: 341); wherein the amino acid residue X is selected from M or V; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence TYTXG (SEQ ID NO: 341); wherein the amino acid residue X is selected from M or V; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences TYTXG (SEQ ID NO: 341); wherein the amino acid residue X is selected from M or V; and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence the amino acid sequence of X1X2IX3SGSX4TX5YADSVKG (SEQ ID NO: 544); wherein the amino acid residue X1 is selected from S or A; wherein the amino acid residue X2 is selected from I or M; wherein the amino acid residue X3 is selected from W or Y; wherein the amino acid residue X4 is selected from N or T; and wherein the amino acid residue X5 is selected from V, Y or L; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence the amino acid sequence X1X2IX3SGSX4TX5YADSVKG (SEQ ID NO: 544); wherein the amino acid residue X1 is selected from S or A; wherein the amino acid residue X2 is selected from I or M; wherein the amino acid residue X3 is selected from W or Y; wherein the amino acid residue X4 is selected from N or T; and wherein the amino acid residue X5 is selected from V, Y or L; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence the amino acid sequence X1X2IX3SGSX4TX5YADSVKG (SEQ ID NO: 544); wherein the amino acid residue X1 is selected from S or A; wherein the amino acid residue X2 is selected from I or M; wherein the amino acid residue X3 is selected from W or Y; wherein the amino acid residue X4 is selected from N or T; and wherein the amino acid residue X5 is selected from V, Y or L; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence QHFGPX1X2X3TTX4GYX5Y (SEQ ID NO: 543); wherein the amino acid residue X1 is selected from V or I; the amino acid residue X2 is selected from S or G; wherein the amino acid residue X3 is selected from L or Q; the amino acid residue X4 is selected from R or K; and wherein the amino acid residue X5 is selected from N, A, F, G, I, L, Y or H; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence QHFGPX1X2X3TTX4GYX5Y (SEQ ID NO: 543); wherein the amino acid residue X1 is selected from V or I; the amino acid residue X2 is selected from S or G; wherein the amino acid residue X3 is selected from L or Q; the amino acid residue X4 is selected from R or K; and wherein the amino acid residue X5 is selected from N, A, F, G, I, L, Y or H; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of QHFGPX1X2X3TTX4GYX5Y (SEQ ID NO: 543); wherein the amino acid residue X1 is selected from V or I; the amino acid residue X2 is selected from S or G; wherein the amino acid residue X3 is selected from L or Q; the amino acid residue X4 is selected from R or K; and wherein the amino acid residue X5 is selected from N, A, F, G, I, L, Y or H. Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 341, 544, and/or 543. In one embodiment, the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 8, 31, 32, 118-119, 130, 150-159, 171-174. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 334 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 339. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 342, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 345 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 340. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 3. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 33. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 249. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 250. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 251. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 252. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 253. In another embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 18 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 254. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 17, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 400 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 399. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for A0315002G06 (SEQ ID NO: 118), A0315002C10 (SEQ ID NO: 119), A0315007E07 (SEQ ID NO: 8), A0315003F04 (SEQ ID NO: 130) and sequence optimized variants thereof in Table A-6 (in addition to the CDRs as defined above). In one embodiment, the ISVD comprises or consists of the full amino acid sequence of A031500010 (SEQ ID NO: 171), A031500011 (SEQ ID NO: 172), A031500012 (SEQ ID NO: 173), or A031500013 (SEQ ID NO: 174) (see Table A-2, Table A-6). In other embodiments, the ISVD comprises or consists of the full amino acid sequence of A0315002G06 (SEQ ID NO: 118) or A0315002C10 (SEQ ID NO: 119) (Table A-2). In one embodiment, the ISVD comprises or consists of the full amino acid sequence of T028501789 (SEQ ID NO: 31), or T028501789 (E1D) (SEQ ID NO: 32), A031500251 (SEQ ID NO: 150), A031500252 (SEQ ID NO: 151), A031500253 (SEQ ID NO: 152), A031500254 (SEQ ID NO: 153), A031500379 (SEQ ID NO: 154), A031500382 (SEQ ID NO: 155), A031500383 (SEQ ID NO: 156), A031500385 (SEQ ID NO: 157), A031500387 (SEQ ID NO: 158), and A031500394 (SEQ ID NO: 159) (see Table A-4). In other embodiments, the ISVD comprises or consists of the full amino acid sequence of A0315007E07 (SEQ ID NO: 8) (Table A-2). In other embodiments, the ISVD comprises or consists of the full amino acid sequence of A0315003F04 (SEQ ID NO: 130) (Table A-2). In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 118, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 118. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 119, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 119. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 171, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 171. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 172, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 172. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 173, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 173. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 174, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 174. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 8, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 8. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 31, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 31. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 32, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 32. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 150, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 150. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 151, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 151. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 152, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 152. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 153, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 153. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 154, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 154. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 155, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 155. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 156, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 156. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 157, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 157. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 158, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 158. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 159, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 159. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 130, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 130. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID Nos: 8, 31, 32, 118-119, 130, 150-159, 171-174, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID Nos: 8, 31, 32, 118-119, 130, 150-159, 171-174, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with at least 100-fold lower affinity (KD), such as a at least 400-fold lower affinity (KD). Preferably, the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM6, and CEACAM7. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 8, 31, 32, 118-119, 130, 150-159, 171-174, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 8, 31, 32, 118-119, 130, 150-159, 171-174, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with at least 100-fold lower affinity (KD), such as a at least 400-fold lower affinity (KD). Preferably, the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, and CEACAM7. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 8, 31, 32, 118-119, 130, 150-159, 171-174, the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 8, 31, 32, 118- 119, 130, 150-159, 171-174, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 8, 31, 32, 118-119, 130, 150-159, 171-174, the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID Nos: 8, 31, 32, 118- 119, 130, 150-159, 171-174, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 8, 31, 32, 118-119, 130, 150-159, 171-174, the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 8, 31, 32, 118-119, 130, 150-159, 171-174, the ISVD still specifically binds to human and cyno CEACAM5 and binds to other members of the CEACAMs family with at least 100-fold lower affinity (KD), such as a at least 400-fold lower affinity (KD). Preferably, the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 8, 31, 32, 118-119, 130, 150-159, 171-174, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, and CEACAM7. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-8 to 10-11 moles/litre or less and more preferably 10-8 to 10-10 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 8.83x10-9 moles/litre, 1.44x10-10 moles/litre, 7.90x10-10 moles/litre, 1.34x10-9 moles/litre or 1.24x10-9 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M-1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 5x106 M-1s-1, even more preferably of about 4.70x105 M-1s-1, or 1.91x106 M-1s-1, 1.19x106 M-1s-1, 3.17x105 M-1s-1 or 7.16x105 M-1s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-2 s-1 and 1x10-5 s-1, more preferably between 1x10-2 s-1 and 10-4 s-1, such as between 5x10-3 s-1 and 10-4 s-1 even more preferably of about 4.15x10-3 s-1, or 2.74x10-4 s-1, 9.40x10-4 s-1, 4.24x10-3 s-1or 8.85x10-4 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (KD) of 10-7 to 10-10 moles/litre or less, and preferably 10-7 to 10-9 moles/litre or less and more preferably 5x10-8 to 10-9 moles/litre, even more preferably wherein the ISVD specifically binds to cyno CEACAM5 with a KD of about 3.92x10-8 moles/litre, or 1.56x10-9 moles/litre, 1.76x10-8 moles/litre, 6.61x10-9 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M-1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 5x106 M-1s-1, such as between 2x105 M-1s-1 and 2x106 M-1s-1, even more preferably of about 2.92x105 M-1s-1, or 1.23x106 M-1s-1, 2.17x105 M-1s-1, 9.2x105 M-1s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a koff rate between 10-1 s-1 (t1/2=0.69 s) and 10-5 s-1 (providing a near irreversible complex with a t1/2 of multiple days), about 10-2 s-1 and 10-4 s-1, more preferably between about 1x 10-2 s-1 and 5 x 10-4 s-1, such as between about 1x10-2 s-1 and 10-3s-1, even more preferably of about 1.14x10-2 s-1, or 1.92x10-3 s-1, 3.81x10-3 s-1, 6.08x10-3 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with at least 100-fold lower affinity (KD), such as a at least 400-fold lower affinity (KD). In preferred embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno CEACAM1, CEACAM6, or CEACAM7. A preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay. For instance, the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a BxPC-3 cell line, which is a human pancreatic adenocarcinoma cell line. VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5. For example, in a FACS binding assay with a BxPC-3 cell line expressing human CEACAM5, the immunoglobulin single variable domains of the present technology may have EC50 values of 10-7 M or lower, more preferably of 10-8 M or lower, or even of 10-9 M or lower. For example, in such FACS assay, the immunoglobulin single variable domains of the present technology may have EC50 values between 10-11 M and 10-7 M, such as between 10- 10 M and 10-8 M, between 10-9 M and 5x10-8 M or between 10-9 M and 10-8 M. In some embodiments, the immunoglobulin single variable domains of the present technology has an CEACAM5-mediated internalization potency (EC50 value) of 10-7 M or lower, more preferably of 5x10-8 M or lower, or even of 10-8 M or lower, such as between 10-7 M and 10-10 M, between 10-7 M and 10-9 M, between 5x10-8 M and 10-9 M or between 10-8 M and 10-9 M, for example, as measured in a FACS internalization assay on BxPC-3 cells expressing human CEACAM5. 5.2.16 Embodiment 16 -Family 13 Specific examples of ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), that interacts with one or more amino acids of the CEACAM5 protein selected from K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, L343, E346, D405, P406, V407, I408, L409, N410, L412, N442, P444, and A483. In another specific embodiments, the ISVD interacts with an epitope on CEACAM5 that comprises at least three amino acids selected K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, L343, E346, D405, P406, V407, I408, L409, N410, L412, N442, P444, and A483. In another specific embodiments, the ISVD interacts with an epitope on CEACAM5 that comprises at least five amino acids selected from K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, L343, E346, D405, P406, V407, I408, L409, N410, L412, N442, P444, and A483. In another specific embodiments, the ISVD interacts with an epitope on CEACAM5 that comprises at least eight amino acids selected from K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, L343, E346, D405, P406, V407, I408, L409, N410, L412, N442, P444, and A483. In another specific embodiments, the ISVD interacts with an epitope on CEACAM5 that comprises at least 10 amino acids selected from K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, L343, E346, D405, P406, V407, I408, L409, N410, L412, N442, P444, and A483. In another specific embodiments, the ISVD interacts with an epitope on CEACAM5 that comprises following amino acids: K324, S329, N330, N331, S332, N333, E346, and D405. In another specific embodiments, the epitope on CEACAM5 that is specifically bound by the ISVDs of the present technology comprises the following amino acids: K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, L343, E346, D405, P406, V407, I408, L409, N410, L412, N442, P444, and A483. The interacting amino acids preferably have a distance of <3.8Å, wherein the distance between the amino acids is measured e.g., in Cryogenic- electron microscopy (cryo-EM). The ISVDs specifically binding to this epitope on CEACAM5 form an interaction site (paratope) on CEACAM5 only with the CDR2 and CDR3. As such, only CDR2 and CDR3 of the ISVD participate in the interaction with the CEACAM5 protein. Only CDR2 and CDR3 of the ISVD form part of the paratope (the site with which the ISVD interacts with the CEACAM5 molecule) of the ISVD. In some embodiments, the amino acids that form part of this interaction sites are selected from T52, W52a, R53, G55, S56, T57, and H58 (Kabat numbering) in CDR2. In some embodiments, the amino acids that form part of this interaction sites are selected from D95, L96, R97, F99, G100, P100a, I100b, T100c, T100d, T100e, Q100f, I100g, and N101 (Kabat numbering) in the CDR3. In some embodiment, the amino acids that form part of this interaction sites are selected from T52, W52a, R53, G55, S56, T57, and H58 (Kabat numbering) in CDR2 and from D95, L96, R97, F99, G100, P100a, I100b, T100c, T100d, T100e, Q100f, I100g, and N101 (Kabat numbering) in the CDR3. In some embodiments, the amino acids that form part of this interaction sites are R53, S56, and H58 (Kabat numbering) in CDR2. In some embodiments, the amino acids that form part of this interaction sites are T52, W52a, R53, G55, S56, T57, and H58 (Kabat numbering) in CDR2. In some embodiments, the amino acids that form part of this interaction sites are D95, I100b, T100d, T100e, Q100f, and N101 (Kabat numbering) in the CDR3. In some embodiments, the amino acids that form part of this interaction sites are D95, L96, R97, F99, G100, P100a, I100b, T100c, T100d, T100e, Q100f, I100g, and N101 (Kabat numbering) in the CDR3. In some embodiments, the amino acids that form part of this interaction sites are R53, S56, and H58 (Kabat numbering) in CDR2 and D95, I100b, T100d, T100e, Q100f, and N101 (Kabat numbering) in the CDR3. In some embodiments, the amino acids that form part of this interaction sites are T52, W52a, R53, G55, S56, T57, and H58 (Kabat numbering) in CDR2 and D95, L96, R97, F99, G100, P100a, I100b, T100c, T100d, T100e, Q100f, I100g, and N101 (Kabat numbering) in the CDR3. In some embodiments, the amino acids that form part of this interaction sites are R53, S56, or H58 (Kabat numbering) in CDR2, wherein R53 forms an interaction site (<3.8Å distance) with D405 in the CEACAM5 epitope, wherein S56 forms an interaction site (<3.8Å distance) with K324 in the CEACAM5 epitope, and/or wherein H58 forms an interaction site (<3.8Å distance) with E346 in the CEACAM5 epitope. In some embodiments, the amino acids that form part of this interaction sites are R53, S56, and H58 (Kabat numbering) in CDR2, wherein R53 forms an interaction site (<3.8Å distance) with D405 in the CEACAM5 epitope, wherein S56 forms an interaction site (<3.8Å distance) with K324 in the CEACAM5 epitope, and/or wherein H58 forms an interaction site (<3.8Å distance) with E346 in the CEACAM 5 epitope (wherein the distance between the amino acids is measured e.g., in Cryogenic-electron microscopy (cryo-EM). In some embodiments, the amino acids that form part of this interaction sites are D95, I100b, T100d, T100e, Q100f, or N101 (Kabat numbering) in the CDR3, wherein D95 forms an interaction site (<3.8Å distance) with S332 in the CEACAM5 epitope, wherein I100b forms an interaction site (<3.8Å distance) with S329 in the CEACAM5 epitope, wherein T100d forms an interaction site (<3.8Å distance) with S329 in the CEACAM epitope, wherein T100e forms an interaction site (<3.8Å distance) with N330 in the CEACAM5 epitope, wherein Q100f forms an interaction site (<3.8Å distance) with N331 in the CEACAM5 epitope, and/or wherein N101 forms an interaction site (<3.8Å distance) with N333 in the CEACAM 5 epitope. In some embodiments, the amino acids that form part of this interaction sites are D95, I100b, T100d, T100e, Q100f, and N101 (Kabat numbering) in the CDR3, wherein D95 forms an interaction site (<3.8Å distance) with S332 in the CEACAM5 epitope, wherein I100b forms an interaction site (<3.8Å distance) with S329 in the CEACAM5 epitope, wherein T100d forms an interaction site (<3.8Å distance) with S329 in the CEACAM epitope, wherein T100e forms an interaction site (<3.8Å distance) with N330 in the CEACAM5 epitope, wherein Q100f forms an interaction site (<3.8Å distance) with N331 in the CEACAM5 epitope, and/or wherein N101 forms an interaction site (<3.8Å distance) with N333 in the CEACAM 5 epitope (wherein the distance between the amino acids is measured e.g., in Cryogenic-electron microscopy (cryo-EM)). In some embodiments, the amino acids that form part of this interaction sites are R53, S56, and H58 (Kabat numbering) in CDR2, and D95, I100b, T100d, T100e, Q100f, and N101 (Kabat numbering) in the CDR3, wherein R53 forms an interaction site (<3.8Å distance) with D405 in the CEACAM5 epitope, wherein S56 forms an interaction site (<3.8Å distance) with K324 in the CEACAM5 epitope, wherein H58 forms an interaction site (<3.8Å distance) with E346 in the CEACAM 5 epitope, wherein D95 forms an interaction site (<3.8Å distance) with S332 in the CEACAM5 epitope, wherein I100b forms an interaction site (<3.8Å distance) with S329 in the CEACAM5 epitope, wherein T100d forms an interaction site (<3.8Å distance) with S329 in the CEACAM5 epitope, wherein T100e forms an interaction site (<3.8Å distance) with N330 in the CEACAM5 epitope, wherein Q100f forms an interaction site (<3.8Å distance) with N331 in the CEACAM5 epitope, and/or wherein N101 forms an interaction site (<3.8Å distance) with N333 in the CEACAM 5 epitope (wherein the distance between the amino acids is measured e.g., in Cryogenic-electron microscopy (cryo-EM)). The ISVDs specifically binding to this epitope on CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is any amino acid independently chosen, preferably wherein the amino acid residue X1 is W, and/or - CDR3 (AbM numbering) consists of an amino acid sequence X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581) wherein X1, X2, X3, X4, X5, and X6 are any amino acid independently chosen, preferably wherein the amino acid residue X1 is D, wherein the amino acid residue X2 is R, wherein the amino acid residue X3 is G, wherein the amino acid residue X4 is T, wherein the amino acid residue X5 is T, and wherein the amino acid residue X6 is N. The ISVDs specifically binding to this epitope on CEACAM5 may also be ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N, preferably wherein the amino acid residue X1 is W; and - CDR3 (AbM numbering) consists of an amino acid sequence X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E, preferably wherein the amino acid residue X1 is D, wherein the amino acid residue X2 is R, wherein the amino acid residue X3 is G, wherein the amino acid residue X4 is T, wherein the amino acid residue X5 is T, and wherein the amino acid residue X6 is N. In a preferred embodiment, the ISVDs specifically binding to this epitope on CEACAM5 further comprises a CDR1 (AbM Numbering) : a) having a length of 10 amino acids; b) having an aliphatic index of 49.00 or 10.00, preferably of 10.00; c) having a grand average of hydropathicity (GRAVY) of -0.970, -0.270, -1.000 preferably -0.970; d) comprising one positively charged and at least one negatively charged residue; e) comprising 30% or 40% hydrophobic, 10% or 20% acid, 20% or 10% basic and 40% neutral amino acids, such as comprising 30% hydrophobic, 10% acid, 20% basic and 40% neutral amino acids; or comprising 40% hydrophobic, 10% acid, 10% basic and 40% neutral amino acids; or comprising 30% hydrophobic, 20% acid, 21% basic and 40% neutral amino acids; f) consisting of a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, a hydrophobic amino acid, an acidic amino acid, a polar neutral amino acid, and a basic, polar neutral or acidic amino acid, two hydrophobic amino acids and a polar neutral amino acid, preferably in that order; such as consisting of a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, a hydrophobic amino acid, an acidic amino acid, a polar neutral amino acid, a basic amino acid, two hydrophobic amino acids and a polar neutral amino acid, preferably in that order; or consisting of a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, a hydrophobic amino acid, an acidic amino acid, a polar neutral amino acid, a polar neutral amino acid, two hydrophobic amino acids and a polar neutral amino acid, preferably in that order; or consisting of a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, a hydrophobic amino acid, an acidic amino acid, a polar neutral amino acid, an acidic amino acid, two hydrophobic amino acids and a polar neutral amino acid, preferably in that order; and/or g) comprising at least one, preferably all of the amino acids G, R, T, F, D, N, A, M, and/or optionally one amino acid selected from H, L, or E. In some embodiment, the ISVDs specifically binding to the above specific epitope on CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N, preferably wherein the amino acid residue X1 is W; and - CDR3 (AbM numbering) consists of an amino acid sequence X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E, preferably wherein the amino acid residue X1 is D, wherein the amino acid residue X2 is R, wherein the amino acid residue X3 is F, wherein the amino acid residue X4 is T, wherein the amino acid residue X5 is T, and wherein the amino acid residue X6 is N; and a - CDR1 (AbM Numbering): a) having a length of 10 amino acids; b) having an aliphatic index of 49.00 or 10.00, preferably of 10.00; c) having a grand average of hydropathicity (GRAVY) of -0.970, -0.270, -1.000 preferably -0.970; d) comprising one positively charged and at least one negatively charged residue; e) comprising 30% or 40% hydrophobic, 10% or 20% acid, 20% or 10% basic and 40% neutral amino acids, such as comprising 30% hydrophobic, 10% acid, 20% basic and 40% neutral amino acids; or comprising 40% hydrophobic, 10% acid, 10% basic and 40% neutral amino acids; or comprising 30% hydrophobic, 20% acid, 21% basic and 40% neutral amino acids; f) consisting of a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, a hydrophobic amino acid, an acidic amino acid, a polar neutral amino acid, and a basic, polar neutral or acidic amino acid, two hydrophobic amino acids and a polar neutral amino acid, preferably in that order; such as consisting of a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, a hydrophobic amino acid, an acidic amino acid, a polar neutral amino acid, a basic amino acid, two hydrophobic amino acids and a polar neutral amino acid, preferably in that order, preferably in that order; or consisting of a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, a hydrophobic amino acid, an acidic amino acid, a polar neutral amino acid, a polar neutral amino acid, two hydrophobic amino acids and a polar neutral amino acid, preferably in that order, preferably in that order; or consisting of a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, a hydrophobic amino acid, an acidic amino acid, a polar neutral amino acid, an acidic amino acid, two hydrophobic amino acids and a polar neutral amino acid, preferably in that order; and/or g) comprising at least one, preferably all of the amino acids G, R, T, F, D, N, A, M, and/or optionally one amino acid selected from H, L, or E. In some embodiments, the ISVDs specifically binding to the above specific epitope on CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTFDNX1AMG (SEQ ID NO: 593); wherein the amino acid residue X1 is selected from H, L or E; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTFDNX1AMG (SEQ ID NO: 593); wherein the amino acid residue X1 is selected from H, L or E; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTFDNX1AMG (SEQ ID NO: 593); wherein the amino acid residue X1 is selected from H, L or E; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E. Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID Nos: 593, 578, and/or 581. In one embodiment, the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 548, 564-576. It should be noted, however, that the ISVDs specifically binding to CEACAM5 may not necessarily be limited to those binding to the above-specified epitope. Hence, specific examples of ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E. The following embodiments, thus, apply to any of the ISVDs described above, i.e., the ISVDs binding specifically binding to CEACAM5 and which are not necessarily limited to binding to the above specific epitope on CEACAM5 and to ISVDs specifically binding to the above-specified epitope on CEACAM5. In a preferred embodiment, the ISVDs specifically binding to CEACAM5 further comprises a CDR1 (AbM Numbering): a) having a length of 10 amino acids; b) having an aliphatic index of 49.00 or 10.00, preferably of 10.00; c) having a grand average of hydropathicity (GRAVY) of -0.970, -0.270, -1.000 preferably -0.970; d) comprising one positively charged and at least one negatively charged residue; e) comprising 30% or 40% hydrophobic, 10% or 20% acid, 20% or 10% basic and 40% neutral amino acids, such as comprising 30% hydrophobic, 10% acid, 20% basic and 40% neutral amino acids; or comprising 40% hydrophobic, 10% acid, 10% basic and 40% neutral amino acids; or comprising 30% hydrophobic, 20% acid, 21% basic and 40% neutral amino acids; f) consisting of a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, a hydrophobic amino acid, an acidic amino acid, a polar neutral amino acid, and a basic, polar neutral or acidic amino acid, two hydrophobic amino acids and a polar neutral amino acid, preferably in that order; such as consisting of a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, a hydrophobic amino acid, an acidic amino acid, a polar neutral amino acid, a basic amino acid, two hydrophobic amino acids and a polar neutral amino acid, preferably in that order; or consisting of a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, a hydrophobic amino acid, an acidic amino acid, a polar neutral amino acid, a polar neutral amino acid, two hydrophobic amino acids and a polar neutral amino acid, preferably in that order; or consisting of a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, a hydrophobic amino acid, an acidic amino acid, a polar neutral amino acid, an acidic amino acid, two hydrophobic amino acids and a polar neutral amino acid, preferably in that order; and/or g) comprising at least one, preferably all of the amino acids G, R, T, F, D, N, A, M, and/or optionally one amino acid selected from H, L, or E. In some embodiments, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E; and a - CDR1 (AbM Numbering): a) having a length of 10 amino acids; b) having an aliphatic index of 49.00 or 10.00, preferably of 10.00; c) having a grand average of hydropathicity (GRAVY) of -0.970, -0.270, -1.000 preferably -0.970; d) comprising one positively charged and at least one negatively charged residue; e) comprising 30% or 40% hydrophobic, 10% or 20% acid, 20% or 10% basic and 40% neutral amino acids, such as comprising 30% hydrophobic, 10% acid, 20% basic and 40% neutral amino acids; or comprising 40% hydrophobic, 10% acid, 10% basic and 40% neutral amino acids; or comprising 30% hydrophobic, 20% acid, 21% basic and 40% neutral amino acids; f) consisting of a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, a hydrophobic amino acid, an acidic amino acid, a polar neutral amino acid, and a basic, polar neutral or acidic amino acid, two hydrophobic amino acids and a polar neutral amino acid, preferably in that order; such as consisting of a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, a hydrophobic amino acid, an acidic amino acid, a polar neutral amino acid, a basic amino acid, two hydrophobic amino acids and a polar neutral amino acid, preferably in that order; or consisting of a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, a hydrophobic amino acid, an acidic amino acid, a polar neutral amino acid, a polar neutral amino acid, two hydrophobic amino acids and a polar neutral amino acid, preferably in that order; or consisting of a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, a hydrophobic amino acid, an acidic amino acid, a polar neutral amino acid, an acidic amino acid, two hydrophobic amino acids and a polar neutral amino acid, preferably in that order; and/or g) comprising at least one, preferably all of the amino acids G, R, T, F, D, N, A, M, and/or optionally one amino acid selected from H, L, or E. Specific examples of ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 579 or 580; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 579 or 580; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 579 or 580; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NOs: 582-589, b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 582-589; c) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 582-589. In some embodiments, the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 579; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 579; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 579; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 582; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 582; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 582. In some embodiments, the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 579; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 579; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 579; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 583; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 583; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 583. In some embodiments, the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 579; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 579; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 579; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 584; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 584; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 584. In some embodiments, the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 579; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 579; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 579; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 585; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 585; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 585. In some embodiments, the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 579; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 579; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 579; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 586; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 586; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 586. In some embodiments, the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 579; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 579; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 579; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 587; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 587; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 587. In some embodiments, the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 579; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 579; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 579; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 588; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 588; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 588. In some embodiments, the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 579; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 579; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 579; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 589; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 589; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 589. In some embodiments, the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 580; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 580; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 580; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 582; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 582; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 582. Preferably, the CDR2 and CDR3 sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR2 sequences of SEQ ID NOs: 579, or 580 and/or the CDR3 sequences of SEQ ID NOs: 582-589. In some embodiments, the ISVD comprise a CDR2 and CDR3 (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 548, 564-576. In one embodiment, the ISVD comprises a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 582. In one embodiment, the ISVD comprises a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 583. In one embodiment, the ISVD comprises a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 584. In one embodiment, the ISVD comprises a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 585. In one embodiment, the ISVD comprises a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 586. In one embodiment, the ISVD comprises a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 587. In one embodiment, the ISVD comprises a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 588. In one embodiment, the ISVD comprises a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 589. In one embodiment, the ISVD comprises a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 580 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 582. The SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition. As such in one embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 591 or 592; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 591 or 592; c) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 591 or 592; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 582-589; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 582-589; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 582-589. In some embodiments, the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 591; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 591; c) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 591; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 582; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 582; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 582. In some embodiments, the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 591; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 591; c) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 591; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 583; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 583; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 583. In some embodiments, the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 591; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 591; c) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 591; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 584; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 584; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 584. In some embodiments, the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 591; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 591; c) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 591; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 585; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 585; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 585. In some embodiments, the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 591; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 591; c) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 591; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 586; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 586; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 586. In some embodiments, the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 591; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 591; c) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 591; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 587; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 587; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 587. In some embodiments, the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 591; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 591; c) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 591; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 588; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 588; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 588. In some embodiments, the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 591; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 591; c) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 591; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 589; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 589; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 589. In some embodiments, the ISVD comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 592; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 592; c) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 592; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: d) the amino acid sequence of SEQ ID NOs: 582; e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 582; f) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 582. Preferably, the CDR2 and CDR3 sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR2 sequences of SEQ ID NOs: 591 or 592 and/or the CDR3 sequences of SEQ ID NOs: 582-589. In one embodiment, the ISVD comprise a CDR2 and CDR3 (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 548, 564-576. In one embodiment, the ISVD comprises a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 582. In one embodiment, the ISVD comprises a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 583. In one embodiment, the ISVD comprises a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 584. In one embodiment, the ISVD comprises a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 585. In one embodiment, the ISVD comprises a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 586. In one embodiment, the ISVD comprises a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 587. In one embodiment, the ISVD comprises a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 588. In one embodiment, the ISVD comprises a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 589. In one embodiment, the ISVD comprises a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 592 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 582. Specific examples of ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTFDNX1AMG (SEQ ID NO: 593); wherein the amino acid residue X1 is selected from H, L or E; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTFDNX1AMG (SEQ ID NO: 593); wherein the amino acid residue X1 is selected from H, L or E; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTFDNX1AMG (SEQ ID NO: 593); wherein the amino acid residue X1 is selected from H, L or E; d) and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E. Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID Nos: 593, 578, and/or 581. In one embodiment, the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 548, 564-576. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 594, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 582. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 594, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 583. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 594, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 584. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 594, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 585. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 594, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 586. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 594, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 587. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 594, CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 588. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 594, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 589. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 594, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 580 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 582. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 595, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 582. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 596, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 582. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for T023200134 (SEQ ID NO: 548) and sequence optimized variants thereof in Table A-17 (in addition to the CDRs as defined above). In one embodiment, the ISVD comprises or consists of the full amino acid sequence of T028500003 (SEQ ID NO: 564), T028500004 (SEQ ID NO: 565), T028500005 (SEQ ID NO: 566), T028500591 (SEQ ID NO: 567), T0285000588 (SEQ ID NO: 568), T028500582 (SEQ ID NO: 569), T028500593 (SEQ ID NO: 570), T028500592 (SEQ ID NO: 571), T028500587 (SEQ ID NO: 572), T028500581 (SEQ ID NO: 573), T028500590 (SEQ ID NO: 574), T028500594 (SEQ ID NO: 575), or T028500583 (SEQ ID NO: 576) (see Table A-2, Table A-17). The SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition. As such in one embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence NX1AMG (SEQ ID NO: 597); wherein the amino acid residue X1 is selected from H, L or E; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence NX1AMG (SEQ ID NO: 597); wherein the amino acid residue X1 is selected from H, L or E; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence NX1AMG (SEQ ID NO: 597); wherein the amino acid residue X1 is selected from H, L or E; and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GITX1RGGSTHYADSVKG (SEQ ID NO: 590), wherein the amino acid residue X1 is selected from W and N; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GITX1RGGSTHYADSVKG (SEQ ID NO: 590), wherein the amino acid residue X1 is selected from W and N; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GITX1RGGSTHYADSVKG (SEQ ID NO: 590), wherein the amino acid residue X1 is selected from W and N; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E. Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 597, 590, and/or 581. In one embodiment, the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 548, 564-576. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 598, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 582. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 598, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 583. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 598, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 584. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 598, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 585. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 598, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 586. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 598, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 587. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 598, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 588. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 598, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 589. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 598, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 592 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 582. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 599, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 582. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 600, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 591 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 582. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for T023200134 (SEQ ID NO: 548) and sequence optimized variants thereof in Table A-17 (in addition to the CDRs as defined above). In one embodiment, the ISVD comprises or consists of the full amino acid sequence of T028500003 (SEQ ID NO: 564), T028500004 (SEQ ID NO: 565), T028500005 (SEQ ID NO: 566), T028500591 (SEQ ID NO: 567), T0285000588 (SEQ ID NO: 568), T028500582 (SEQ ID NO: 569), T028500593 (SEQ ID NO: 570), T028500592 (SEQ ID NO: 571), T028500587 (SEQ ID NO: 572), T028500581 (SEQ ID NO: 573), T028500590 (SEQ ID NO: 574), T028500594 (SEQ ID NO: 575), or T028500583 (SEQ ID NO: 576) (see Table A-2, Table A-17). In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 548, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 548. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 564, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 564. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 565, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 565. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 566, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 556. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 567, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 567. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 568, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 568. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 569, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 569. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 570, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 570. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 571, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 571. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 572, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 572. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 573, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 573. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 574, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 574. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 575, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 575. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 576, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 576. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 548, 564-576, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 548, 564-576, wherein the binding affinity is measured using the same method, such as, e.g, SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 548, 564-576, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 548, 564-576, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 548, 564-576, the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 548, 564-576, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 548, 564-576, the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 548, 564-576, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 548, 564-576, the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 548, 564-576, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 548, 564-576, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM6 or other members of the CEACAM family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 1x10-7 to 10-10 moles/litre or less such as more preferably 1x10-8 to 1x10-10 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 1.20x10-9 moles/litre, 2.82x10-9 moles/litre, 6.51x10-9 moles/litre, 1.27x10-8 moles/litre, 2.44x10-8 moles/litre, 3.07 x10-8 moles/litre, 3.17 x10-8 moles/litre, 7.62 x10-8 moles/litre, 9.28 x10- 8 moles/litre, 1.59 x10-7 moles/litre, or 1.97 x10-7 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 104 M-1s-1 and 106 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, such as between 1x105 M-1s-1 and 5x105 M-1s-1, even more preferably of about 4.3x105 M-1s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 1x10-2 s-1 and 5x10-5 s-1, such as between 5x10-3 s-1 and 10-4 s-1, even more preferably of about 6.4x10-4 s-1, 4.30x10-4 s-1, 4.92x10-4 s-1, 4.71x10-4 s-1, 5.00x10-4 s-1, 5.80 x10-4 s-1, 1.87 x10-3 s-1,1.41 x10-3 s-1,5.87 x10-3 s-1, 1.21 x10-3 s-1,7.41 x10-3 s-1, 6.19 x10-3 s-1, 1.41 x10-2 s-1, 1.28 x10-2 s-1, or 3.42 x10-2 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-7 to 10-10 moles/litre or less and more preferably 5x10-8 to 10-9 moles/litre, even more preferably wherein the ISVD specifically binds to cyno CEACAM5 with a KD of about 1.90x10-9 moles/litre, 3.06x10-9 moles/litre, 6.07x10-9 moles/litre, 8.06x10-9moles/litre, 3.16x10-8 moles/litre, 3.71x10-8moles/litre, 1.65x10-8moles/litre, 7.04x10-8moles/litre, 1.16x10-8moles/litre, 1.55x10-8moles/litre, or 9.68x10-8 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M-1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-5 s-1 (providing a near irreversible complex with a t1/2 of multiple days), more preferably between 1x 10- 2 s-1 and 5 x 10-5 s-1, such as between 5x10-2 s-1 and 10-4 s-1, even more preferably of about 8.96x10- 4 s-1, 8.74x10-4 s-1, 8.96x10-4 s-1, 8.73x10-4 s-1,1.20x10-3 s-1,2.30x10-3 s-1, 1.73x10-3 s-1, 5.02x10-3 s-1, 2.02x10-2 s-1, 1.36x10-2 s-1, 4.44x10-3 s-1 , 1.30x10-2 s-1 , 1.60x10-2 s-1 , 2.78x10-2 s-1 , or 1.80x10-2 s-1 as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 100-fold lower affinity (KD). In preferred embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to human and cyno CEACAM1, CEACAM6, CEACAM7 and CEACAM8. A preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay. For instance, the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a LS174T cell line, which is a human colonic carcinoma cell line. VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention. Alternatively, the internalization can be measured using a Live-Cell Analysis Systems capable of recording fluorescence and bright field images, such as the Incucyte instrument (Sartorius). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5. For example, in a FACS assay analysing the binding of the immunoglobulin single variable domains of the present technology to human CEACAM5 expressed on LS174T cells, the immunoglobulin single variable domains of the present technology may have EC50 values of 10-7 M or lower, more preferably of 5x10-8 M or lower, or even of 10-8 M or lower. For example, in such FACS assay, the immunoglobulin single variable domains of the present technology may have EC50 values between 10-11 M and 10-7 M, such as between 10-10 M and 10-7 M, between 10-9 M and 5x10-8 M or between 10-9 M and 5x10-9 M, such as 1.98x10-9 M, In some embodiments, the immunoglobulin single variable domains of the present technology has an CEACAM5-mediated internalization potency (EC50 value) of 5x10-7 M or lower, more preferably of 10-7 M or lower, or even of 5x10-8 M or lower, such as between 10-7 M and 10-10 M, between 10- 7 M and 10-9 M, between 5x10-8 M and 10-9 M or between 5x10-8 M and 10-8 M, for example, as measured in a fluorescence based internalization assay on LS174T cells expressing human CEACAM5. 5.2.17 Embodiment 17 -Family 14 The ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR3 (AbM numbering) consists of the amino acid sequence GDHRGPWYN (SEQ ID NO: 610). In some embodiments, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 610; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 610; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 610. In a specific embodiment, the ISVDs specifically binding to CEACAM5 may further comprise a CDR1 (AbM numbering): a) having a length of 10 amino acids (AbM numbering); b) having an aliphatic index of 0.00; c) having a grand average of hydropathicity (GRAVY) of -0.080; d) comprising one negatively charged residue; e) comprising 30% hydrophobic, 10% acidic and 60% neutral amino acids; f) consisting of a polar neutral amino acid, a hydrophobic amino acid, a polar neutral amino acid, a hydrophobic amino acid, three polar neutral amino acids, an acidic amino acid, a hydrophobic amino acid, and a polar neutral amino acid; and/or g) comprising at least one, preferably all of the amino acids G, F, T, S, Y, D, or M. In a specific embodiment, the ISVDs specifically binding to CEACAM5 may further comprise a CDR2 (AbM numbering): a) having a length of 10 amino acids (AbM numbering); b) having an aliphatic index of 39.00; c) having a grand average of hydropathicity (GRAVY) of -0.810; d) comprising one positively charged residue; e) comprising 10% hydrophobic, 10% basic and 80% neutral amino acids; f) consisting of a polar neutral amino acid, a hydrophobic amino acid, a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, six polar neutral amino acid, preferably in that order; and/or g) comprising at least one, preferably all of the amino acids T, I, N, R, G, S or T. In some embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 610; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 610; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 610; and - CDR1 (AbM numbering): a) has a length of 10 amino acids; b) has an aliphatic index of 0.00; c) has a grand average of hydropathicity (GRAVY) of -0.080; d) comprises one negatively charged residue; e) comprises 30% hydrophobic, 10% acidic and 60% neutral amino acids; f) consisting of a polar neutral amino acid, a hydrophobic amino acid, a polar neutral amino acid, a hydrophobic amino acid, three polar neutral amino acids, an acidic amino acid, a hydrophobic amino acid, and a polar neutral amino acid; and/or g) comprises at least one, preferably all of the amino acids G, F, T, S, Y, D, or M. In some embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 610; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 610; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 610; and - CDR2 (AbM numbering): a) has a length of 10 amino acids (AbM numbering); b) having an aliphatic index of 39.00; c) having a grand average of hydropathicity (GRAVY) of -0.810; d) comprises one positively charged residue; e) comprises 10% hydrophobic, 10% basic and 80% neutral amino acids; f) consists of a polar neutral amino acid, a hydrophobic amino acid, a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, six polar neutral amino acid, preferably in that order; and/or g) comprises at least one, preferably all of the amino acids T, I, N, R, G, S or T. In some embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 610; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 610; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 610; - CDR1 (AbM numbering): a) has a length of 10 amino acids; b) has an aliphatic index of 0.00; c) has a grand average of hydropathicity (GRAVY) of -0.080; d) comprises one negatively charged residue; e) comprises 30% hydrophobic, 10% acidic and 60% neutral amino acids; f) consists of a polar neutral amino acid, a hydrophobic amino acid, a polar neutral amino acid, a hydrophobic amino acid, three polar neutral amino acids, an acidic amino acid, a hydrophobic amino acid, and a polar neutral amino acid; and/or g) comprises at least one, preferably all of the amino acids G, F, T, S, Y, D, or M; and - CDR2 (AbM numbering): a) has a length of 10 amino acids; b) has an aliphatic index of 39.00; c) has a grand average of hydropathicity (GRAVY) of -0.810; d) comprises one positively charged residue; e) comprises 10% hydrophobic, 10% basic and 80% neutral amino acids; f) consists of a polar neutral amino acid, a hydrophobic amino acid, a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, six polar neutral amino acid, preferably in that order; and/or g) comprises at least one, preferably all of the amino acids T, I, N, R, G, S or T. In some embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR3 (AbM numbering) consists of the amino acid sequence GDHRGPWYN (SEQ ID NO: 610); and - CDR1 (AbM numbering): a) has a length of 10 amino acids; b) has an aliphatic index of 0.00; c) has a grand average of hydropathicity (GRAVY) of -0.080; d) comprises one negatively charged residue; e) comprises 30% hydrophobic, 10% acidic and 60% neutral amino acids; f) consists of a polar neutral amino acid, a hydrophobic amino acid, a polar neutral amino acid, a hydrophobic amino acid, three polar neutral amino acids, an acidic amino acid, a hydrophobic amino acid, and a polar neutral amino acid; and/or g) comprises at least one, preferably all of the amino acids G, F, T, S, Y, D, or M; and - CDR2 (AbM numbering): a) has a length of 10 amino acids; b) has an aliphatic index of 39.00; c) has a grand average of hydropathicity (GRAVY) of -0.810; d) comprises one positively charged residue; e) comprises 10% hydrophobic, 10% basic and 80% neutral amino acids; f) consists of a polar neutral amino acid, a hydrophobic amino acid, a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, six polar neutral amino acid, preferably in that order; and/or g) comprises at least one, preferably all of the amino acids T, I, N, R, G, S or T. In some embodiments, the ISVDs comprise a CDR3 (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 547, 549-563. In an embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - FR1 (AbM numbering) consists of the amino acid sequence EVQLVESGGGXVQPGGSLRLSCAAS (SEQ ID NO: 647); wherein the amino acid residue X is selected from V and L. In an embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - FR1 (AbM numbering) consists of the amino acid sequence EVQLVESGGGXVQPGGSLRLSCAAS (SEQ ID NO: 647); wherein the amino acid residue X is V. In an embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - FR1 (AbM numbering) consists of the amino acid sequence EVQLVESGGGXVQPGGSLRLSCAAS (SEQ ID NO: 647); wherein the amino acid residue X is L. In an embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - FR2 (AbM numbering) consists of the amino acid sequence WVRQX1PGKGX2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P; and wherein the amino acid residue X2 is selected from I and L. In an embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - FR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence WVRQPPGKGIEWVS (SEQ ID NO: 625); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 625; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 625. In an embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein FR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence WVRQAPGKGIEWVS (SEQ ID NO: 626); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 626; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 626. In an embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein FR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence WVRQPPGKGLEWVS (SEQ ID NO: 627); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 627; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 627. In an embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - FR3 (AbM numbering) consists of the amino acid sequence YX1X2X3VX4GRFTISRDNAX5NTLYLQMNSLX6X7EDTAX8YYCTT (SEQ ID NO: 651); wherein the amino acid residue X1 is selected from R and A, wherein the amino acid residue X2 is selected from V and D, wherein the amino acid residue X3 is selected from P and S, wherein the amino acid residue X4 is selected from E and K, wherein the amino acid residue X5 is selected from E and K, wherein the amino acid residue X6 is selected from K and R, wherein the amino acid residue X7 is selected from T, S and P, and wherein the amino acid residue X8 is selected from V and K. In an embodiment, the ISVD specifically binding to CEACAM5 are ISVDs that comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - FR4 (AbM numbering) consists of the amino acid sequence XGQGTLVTVSS (SEQ ID NO: 649); wherein the amino acid residue X is selected from R and W. In one embodiment, the ISVD specifically binding to CEACAM5 are ISVDs that comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 610; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 610; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 610; and at least one, and preferably all of: - FR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence EVQLVESGGGXVQPGGSLRLSCAAS (SEQ ID NO: 647); wherein the amino acid residue X is selected from V and L; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence EVQLVESGGGXVQPGGSLRLSCAAS (SEQ ID NO: 647); wherein the amino acid residue X is selected from V and L; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence EVQLVESGGGXVQPGGSLRLSCAAS (SEQ ID NO: 647); wherein the amino acid residue X is selected from V and L; and/or - FR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence WVRQX1PGKG X2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P, wherein the amino acid residue X2 is selected from I and L; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence WVRQX1PGKG X2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P, wherein the amino acid residue X2 is selected from I and L; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence WVRQX1PGKGX2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P; and wherein the amino acid residue X2 is selected from I and L; and/or - FR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence YX1X2X3VX4GRFTISRDNAX5NTLYLQMNSLX6X7EDTAX8YYCTT (SEQ ID NO: 651); wherein the amino acid residue X1 is selected from R and A, wherein the amino acid residue X2 is selected from V and D, wherein the amino acid residue X3 is selected from P and S, wherein the amino acid residue X4 is selected from E and K, wherein the amino acid residue X5 is selected from E and K, wherein the amino acid residue X6 is selected from K and R, wherein the amino acid residue X7 is selected from T, S and P, and wherein the amino acid residue X8 is selected from V and K; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence YX1X2X3VX4GRFTISRDNAX5NTLYLQMNSLX6X7EDTAX8YYCTT (SEQ ID NO: 651); wherein the amino acid residue X1 is selected from R and A, wherein the amino acid residue X2 is selected from V and D, wherein the amino acid residue X3 is selected from P and S, wherein the amino acid residue X4 is selected from E and K, wherein the amino acid residue X5 is selected from E and K, wherein the amino acid residue X6 is selected from K and R, wherein the amino acid residue X7 is selected from T, S and P, and wherein the amino acid residue X8 is selected from V and K; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence YX1X2X3VX4GRFTISRDNAX5NTLYLQMNSLX6X7EDTAX8YYCTT (SEQ ID NO: 651); wherein the amino acid residue X1 is selected from R and A, wherein the amino acid residue X2 is selected from V and D, wherein the amino acid residue X3 is selected from P and S, wherein the amino acid residue X4 is selected from E and K, wherein the amino acid residue X5 is selected from E and K, wherein the amino acid residue X6 is selected from K and R, wherein the amino acid residue X7 is selected from T, S and P, and wherein the amino acid residue X8 is selected from V and K; and/or - FR4 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of amino acid sequence XGQGTLVTVSS (SEQ ID NO: 649); wherein the amino acid residue X is selected from R and W; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence XGQGTLVTVSS (SEQ ID NO: 649); wherein the amino acid residue X is selected from R and W; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence XGQGTLVTVSS (SEQ ID NO: 649); wherein the amino acid residue X is selected from R and W. In a preferred embodiment, the ISVD specifically binding to CEACAM5 are ISVDs that comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) a) the amino acid sequence of SEQ ID NO: 610; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 610; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 610; and - FR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence WVRQX1PGKGX2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P; and wherein the amino acid residue X2 is selected from I and L; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence WVRQX1PGKGX2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P; and wherein the amino acid residue X2 is selected from I and L; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence WVRQX1PGKGX2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P; and wherein the amino acid residue X2 is selected from I and L. In one preferred embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 610; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 610; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 610; and - FR2 (AbM numbering) consists of an amino acid sequence selected from: I. a) the amino acid sequence WVRQPPGKGIEWVS (SEQ ID NO: 625); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 625; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 625; II. a) the amino acid sequence WVRQAPGKGIEWVS (SEQ ID NO: 626); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 626; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 626; III. a) the amino acid sequence WVRQPPGKGLEWVS (SEQ ID NO: 627); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 627; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 627. In some embodiments, the ISVDs comprise a FR2 and a CDR3 (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR3 and FR2 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 547, 549-563. In one embodiment, the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610 and a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 625. In one embodiment, the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610 and a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 626. In one embodiment, the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610 and a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 627. In some embodiments, the ISVDs comprise a FR1, FR2, FR3 and FR4 and a CDR3 (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR3 and FR1, FR2, FR3, and FR4 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 547, 549- 563. In one embodiment, the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 4, a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 625, a FR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 628, and a FR4 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 640. In one embodiment, the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 34, a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 625, a FR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 629, and a FR4 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 640. In one embodiment, the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 34, a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 625, a FR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 630, and a FR4 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 640. In one embodiment, the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 34, a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 625, a FR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 629, and a FR4 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 7. In one embodiment, the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 34, a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 626, a FR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 631, and a FR4 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 640. In one embodiment, the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 34, a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 626, a FR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 632, and a FR4 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 640. In one embodiment, the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 34, a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 626, a FR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 629, and a FR4 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 640. In one embodiment, the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 34, a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 627, a FR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 629, and a FR4 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 640. In one embodiment, the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 34, a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 625, a FR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 633, and a FR4 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 640. In one embodiment, the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 34, a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 625, a FR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 634, and a FR4 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 640. In one embodiment, the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 34, a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 625, a FR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 635, and a FR4 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 640. In one embodiment, the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 34, a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 625, a FR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 636, and a FR4 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 640. In one embodiment, the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 34, a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 625, a FR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 631, and a FR4 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 640. In one embodiment, the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 34, a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 625, a FR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 637, and a FR4 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 640. In one embodiment, the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 34, a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 625, a FR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 638, and a FR4 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 640. In one embodiment, the ISVD comprises a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 34, a FR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 625, a FR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 639, and a FR4 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 640. The SEQ ID NOs for the CDR and FR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition. In some embodiments, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR3 (Kabat numbering) consists of the amino acid sequence GDHRGPWYN (SEQ ID NO: 610). As such in one embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 610; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 610; c) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 610. In one embodiment, the ISVD comprise a CDR3 (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 547, 549-563. In an embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - FR1 (Kabat numbering) consists of the amino acid sequence EVQLVESGGGXVQPGGSLRLSCAASGFTFS (SEQ ID NO: 650); wherein the amino acid residue X is selected from V and L. In an embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - FR1 (Kabat numbering) consists of the amino acid sequence EVQLVESGGGXVQPGGSLRLSCAASGFTFS (SEQ ID NO: 650); wherein the amino acid residue X is V. In an embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - FR1 (Kabat numbering) consists of the amino acid sequence EVQLVESGGGXVQPGGSLRLSCAASGFTFS (SEQ ID NO: 650); wherein the amino acid residue X is L. In an embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - FR2 (Kabat numbering) consists of the amino acid sequence WVRQX1PGKGX2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P, and wherein the amino acid residue X2 is selected from I and L. In an embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - FR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence WVRQPPGKGIEWVS (SEQ ID NO: 625); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 625; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 625. In an embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein FR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence WVRQAPGKGIEWVS (SEQ ID NO: 626); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 626; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 626. In an embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein FR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence WVRQPPGKGLEWVS (SEQ ID NO: 627); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 627; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 627. In an embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - FR3 (Kabat numbering) consists of an amino acid sequence RFTISRDNAX1NTLYLQMNSLX2X3EDTAX4YYCTT (SEQ ID NO: 648); wherein the amino acid residue X1 is selected from E and K; wherein the amino acid residue X2 is selected from K and R, wherein the amino acid residue X2 is selected from T, S and P; and wherein the amino acid residue X3 is selected from V and K. In an embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - FR4 (Kabat numbering) consists of an amino acid sequence XGQGTLVTVSS (SEQ ID NO: 649); wherein the amino acid residue X is selected from R and W. In one embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 610; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 610; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 610; and at least one, and preferably all of: - FR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of amino acid sequence EVQLVESGGGXVQPGGSLRLSCAASGFTFS (SEQ ID NO: 650); wherein the amino acid residue X is selected from V and L; b) amino acid sequences that have at least 80% amino acid identity with the EVQLVESGGGXVQPGGSLRLSCAASGFTFS (SEQ ID NO: 650); wherein the amino acid residue X is selected from V and L; c) amino acid sequences that have 3, 2, or 1 amino acid difference with EVQLVESGGGXVQPGGSLRLSCAASGFTFS (SEQ ID NO: 650); wherein the amino acid residue X is selected from V and L; - FR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of amino acid sequence WVRQX1PGKGX2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P; and wherein the amino acid residue X2 is selected from I and L; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of amino acid sequence WVRQX1PGKGX2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P; and wherein the amino acid residue X2 is selected from I and L; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of amino acid sequence WVRQX1PGKGX2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P, and wherein the amino acid residue X2 is selected from I and L; and/or - FR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of amino acid sequence RFTISRDNAX1NTLYLQMNSLX2X3EDTAX4YYCTT (SEQ ID NO: 648); wherein the amino acid residue X1 is selected from E and K; wherein the amino acid residue X2 is selected from K and R, wherein the amino acid residue X2 is selected from T, S and P; and wherein the amino acid residue X3 is selected from V and K; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of amino acid sequence RFTISRDNAX1NTLYLQMNSLX2X3EDTAX4YYCTT (SEQ ID NO: 648); wherein the amino acid residue X1 is selected from E and K; wherein the amino acid residue X2 is selected from K and R, wherein the amino acid residue X2 is selected from T, S and P; and wherein the amino acid residue X3 is selected from V and K; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of amino acid sequence RFTISRDNAX1NTLYLQMNSLX2X3EDTAX4YYCTT (SEQ ID NO: 648); wherein the amino acid residue X1 is selected from E and K; wherein the amino acid residue X2 is selected from K and R, wherein the amino acid residue X2 is selected from T, S and P; and wherein the amino acid residue X3 is selected from V and K; and/or - FR4 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of amino acid sequence XGQGTLVTVSS (SEQ ID NO: 649); wherein the amino acid residue X is selected from R and W; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of amino acid sequence XGQGTLVTVSS (SEQ ID NO: 649); wherein the amino acid residue X is selected from R and W; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of amino acid sequence XGQGTLVTVSS (SEQ ID NO: 649); wherein the amino acid residue X is selected from R and W. In a preferred embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 610; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 610; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 610; and - FR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of amino acid sequence WVRQX1PGKG X2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P, and wherein the amino acid residue X2 is selected from I and L; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of amino acid sequence WVRQX1PGKG X2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P, and wherein the amino acid residue X2 is selected from I and L; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of amino acid sequence WVRQX1PGKG X2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P, and wherein the amino acid residue X2 is selected from I and L. In one preferred embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 610; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 610; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 610; and - FR2 (Kabat numbering) consists of an amino acid sequence selected from: I. a) the amino acid sequence WVRQPPGKGIEWVS (SEQ ID NO: 625); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 625; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 625; or II. a) the amino acid sequence WVRQAPGKGIEWVS (SEQ ID NO: 626); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 626; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 626; III. a) the amino acid sequence WVRQPPGKGLEWVS (SEQ ID NO: 627); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 627; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 627. In some embodiments, the ISVDs comprise a FR2 (Kabat numbering) and a CDR3 (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR3 or FR2 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 547, 549-563. In one embodiment, the ISVD comprises a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 610 and a FR2 that is the amino acid sequence of SEQ ID NO: 625. In one embodiment, the ISVD comprises a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 610 and a FR2 that is the amino acid sequence of SEQ ID NO: 626. In one embodiment, the ISVD comprises a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 610 and a FR2 that is the amino acid sequence of SEQ ID NO: 627. In some embodiments, the ISVDs comprise a FR1 to FR4 (Kabat numbering) and a CDR3 (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR3 or FR1 to FR4 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 547, 549-563. In one embodiment, the ISVD comprises a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 623, a FR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 625, a FR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 642, and a FR4 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 640. In one embodiment, the ISVD comprises a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 624, a FR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 625, a FR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 643, and a FR4 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 640. In one embodiment, the ISVD comprises a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 624, a FR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 625, a FR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 644, and a FR4 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 640. In one embodiment, the ISVD comprises a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 624, a FR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 625, a FR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 643, and a FR4 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 7. In one embodiment, the ISVD comprises a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 624, a FR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 626, a FR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 645, and a FR4 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 640. In one embodiment, the ISVD comprises a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 624, a FR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 626, a FR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 643, and a FR4 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 640. In one embodiment, the ISVD comprises a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 624, a FR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 627, a FR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 643, and a FR4 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 640. In one embodiment, the ISVD comprises a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 624, a FR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 625, a FR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 645, and a FR4 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 640. In one embodiment, the ISVD comprises a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 610, a FR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 624, a FR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 625, a FR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 646, and a FR4 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 640. Specific examples of ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GFTFSSYDMS (SEQ ID NO: 611); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GFTFSSYDMS (SEQ ID NO: 611); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GFTFSSYDMS (SEQ ID NO: 611); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence TINRGGSSTS (SEQ ID NO: 612); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence TINRGGSSTS (SEQ ID NO: 612); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence TINRGGSSTS (SEQ ID NO: 612); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GDHRGPWYN (SEQ ID NO: 610); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GDHRGPWYN (SEQ ID NO: 610); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GDHRGPWYN (SEQ ID NO: 610). Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID Nos: 611, 612, and/or 610. In one embodiment, the ISVD comprise CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 547, 549-563. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 611, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 612 and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 610. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for 14R0410/T023200178 (SEQ ID NO: 547) and sequence optimized variants thereof in Table A-16 (in addition to the CDRs as defined above). In one embodiment, the ISVD comprises or consists of the full amino acid sequence of T028500006 (SEQ ID NO: 549), T028500007 (SEQ ID NO: 550), T028500008 (SEQ ID NO: 551), T028500009 (SEQ ID NO: 552), T028500010 (SEQ ID NO: 553), T028500011 (SEQ ID NO: 554), T028500012 (SEQ ID NO: 555), T028500013 (SEQ ID NO: 556), T028500014 (SEQ ID NO: 557), T028500015 (SEQ ID NO: 558), T028500016 (SEQ ID NO: 559), T028500017 (SEQ ID NO: 560), T028500018 (SEQ ID NO: 561), T028500557 (SEQ ID NO: 562), or T028500558 (SEQ ID NO: 563) (see Table A-2, Table A-16). The SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-8). It is noted that the SEQ ID NOs for the CDR sequences defined according to the Kabat definition can likewise be used (see Table A-9). Accordingly, the ISVDs provided by the present technology, specifically binding to CEACAM5 as described above using the AbM definition, can be also described using the Kabat definition. As such in one embodiment, the ISVDs specifically binding to CEACAM5 are ISVDs that comprise 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence SYDMS (SEQ ID NO: 613); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence SYDMS (SEQ ID NO: 613); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence SYDMS (SEQ ID NO: 613); and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence TINRGGSSTSYX1X2X3VX4G (SEQ ID NO: 622), wherein the amino acid residue X1 is selected from A and R, wherein the amino acid residue X2 is selected from D and V, wherein the amino acid residue X3 is selected from S and P, and wherein the amino acid residue X4 is selected from E and K; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of TINRGGSSTSYX1X2X3VX4G (SEQ ID NO: 622), wherein the amino acid residue X1 is selected from A and R, wherein the amino acid residue X2 is selected from D and V, wherein the amino acid residue X3 is selected from S and P, and wherein the amino acid residue X4 is selected from E and K; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of TINRGGSSTSYX1X2X3VX4G (SEQ ID NO: 622), wherein the amino acid residue X1 is selected from A and R, wherein the amino acid residue X2 is selected from D and V, wherein the amino acid residue X3 is selected from S and P, and wherein the amino acid residue X4 is selected from E and K; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GDHRGPWYN (SEQ ID NO: 610); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GDHRGPWYN (SEQ ID NO: 610); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GDHRGPWYN (SEQ ID NO: 610). Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NOs: 613, 622, and/or 610. In one embodiment, the ISVD comprise CDRs (Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 547, 549-563. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 613, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 614 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 610. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 613, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 615 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 610. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 613, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 616 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 610. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 613, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 617 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 610. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 613, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 618 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 610. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 613, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 620 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 610. In one embodiment, the ISVD comprises a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 613, a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 621 and a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 610. Specific examples of such ISVDs that specifically bind to CEACAM5 have one or more, or all, framework regions as indicated for 14R0410/T023200178 (SEQ ID NO: 547) and sequence optimized variants thereof in Table A-16 (in addition to the CDRs as defined above). In one embodiment, the ISVD comprises or consists of the full amino acid sequence of T028500006 (SEQ ID NO: 549), T028500007 (SEQ ID NO: 550), T028500008 (SEQ ID NO: 551), T028500009 (SEQ ID NO: 552), T028500010 (SEQ ID NO: 553), T028500011 (SEQ ID NO: 554), T028500012 (SEQ ID NO: 555), T028500013 (SEQ ID NO: 556), T028500014 (SEQ ID NO: 557), T028500015 (SEQ ID NO: 558), T028500016 (SEQ ID NO: 559), T028500017 (SEQ ID NO: 560), T028500018 (SEQ ID NO: 561), T028500557 (SEQ ID NO: 562), or T028500558 (SEQ ID NO: 563) (see Table A-2, Table A-16). In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 547, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 547. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 549, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 549. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 550, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 550. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 551, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 551. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 552, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 552. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 553, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 553. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 554, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 554. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 555, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 555. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 556, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 556. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 557, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 557. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 558, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 558. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 559, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 559. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 560, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 560. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 561, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 561. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 562, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 562. In another embodiment, the ISVD specifically binding to human CEACAM5 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 563, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to CEACAM5 comprises or consists of the amino acid sequence of SEQ ID NO: 563. The present technology also provides a library comprising at least two ISVDs each comprising 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein the at least two ISVDs each have a FR2 (AbM or Kabat numbering) with SEQ ID NO: 641, or an amino acid sequence that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 641 or an amino acid sequence that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 641. In an embodiment, the present technology provides a library comprising at least two ISVDs each comprising 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein the at least two ISVDs each have a FR2 (AbM or Kabat numbering) consisting of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 625; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 625; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 625. In an embodiment, the present technology provides a library comprising at least two ISVDs each comprising 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein the at least two ISVDs each have a FR2 (AbM or Kabat numbering) consisting of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 626; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 626; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 626. In an embodiment, the present technology provides a library comprising at least two ISVDs each comprising 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein the at least two ISVDs each have a FR2 (AbM or Kabat numbering) consisting of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 627; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 627; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 627. In some embodiments, the present technology provides a library comprising at least two ISVDs that comprise a FR2 (AbM or Kabat numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the FR2 (AbM or Kabat numbering) of the ISVD with the amino acid sequence selected from SEQ ID NOs: 547, 549-563. The library of the present technology may comprise at least two ISVDs according to the present technology, wherein the at least two ISVDs comprised in the library are different in the CDR3, and FR1, FR3, and FR4 region. In some embodiments, the present technology provides a library comprising at least two ISVDs each comprising 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein the at least two ISVDs each have: - FR2 (AbM numbering) that consists of an amino acid sequence selected from: a) the amino acid sequence WVRQX1PGKGX2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P, wherein the amino acid residue X2 is selected from I and L; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence WVRQX1PGKGX2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P, wherein the amino acid residue X2 is selected from I and L; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence WVRQX1PGKGX2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P, wherein the amino acid residue X2 is selected from I and L. In some embodiments, the present technology provides a library comprising at least two ISVDs each comprising 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein the at least two ISVDs each have: - FR2 (AbM numbering) that consists of an amino acid sequence selected from: a) the amino acid sequence WVRQX1PGKGX2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P, wherein the amino acid residue X2 is selected from I and L; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence WVRQX1PGKGX2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P, wherein the amino acid residue X2 is selected from I and L; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence WVRQX1PGKGX2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P, wherein the amino acid residue X2 is selected from I and L; and and at least one, and preferably all of: - FR1 (AbM numbering) that consists of an amino acid sequence selected from: a) the amino acid sequence EVQLVESGGGXVQPGGSLRLSCAAS (SEQ ID NO: 647); wherein the amino acid residue X is selected from V and L; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence EVQLVESGGGXVQPGGSLRLSCAAS (SEQ ID NO: 647); wherein the amino acid residue X is selected from V and L; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence EVQLVESGGGXVQPGGSLRLSCAAS (SEQ ID NO: 647); wherein the amino acid residue X is selected from V and L; and/or - FR3 (AbM numbering) that consists of an amino acid sequence selected from: a) the amino acid sequence YX1X2X3VX4GRFTISRDNAX5NTLYLQMNSLX6X7EDTAX8YYCTT (SEQ ID NO: 651); wherein the amino acid residue X1 is selected from R and A, wherein the amino acid residue X2 is selected from V and D, wherein the amino acid residue X3 is selected from P and S, wherein the amino acid residue X4 is selected from E and K, wherein the amino acid residue X5 is selected from E and K, wherein the amino acid residue X6 is selected from K and R, wherein the amino acid residue X7 is selected from T, S and P, and wherein the amino acid residue X8 is selected from V and K; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence YX1X2X3VX4GRFTISRDNAX5NTLYLQMNSLX6X7EDTAX8YYCTT (SEQ ID NO: 651); wherein the amino acid residue X1 is selected from R and A, wherein the amino acid residue X2 is selected from V and D, wherein the amino acid residue X3 is selected from P and S, wherein the amino acid residue X4 is selected from E and K, wherein the amino acid residue X5 is selected from E and K, wherein the amino acid residue X6 is selected from K and R, wherein the amino acid residue X7 is selected from T, S and P, and wherein the amino acid residue X8 is selected from V and K; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence YX1X2X3VX4GRFTISRDNAX5NTLYLQMNSLX6X7EDTAX8YYCTT (SEQ ID NO: 651); wherein the amino acid residue X1 is selected from R and A, wherein the amino acid residue X2 is selected from V and D, wherein the amino acid residue X3 is selected from P and S, wherein the amino acid residue X4 is selected from E and K, wherein the amino acid residue X5 is selected from E and K, wherein the amino acid residue X6 is selected from K and R, wherein the amino acid residue X7 is selected from T, S and P, and wherein the amino acid residue X8 is selected from V and K; and/or - FR4 (AbM numbering) that consists of an amino acid sequence selected from: a) the amino acid sequence of amino acid sequence XGQGTLVTVSS (SEQ ID NO: 649); wherein the amino acid residue X is selected from R and W; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence XGQGTLVTVSS (SEQ ID NO: 649); wherein the amino acid residue X is selected from R and W; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence XGQGTLVTVSS (SEQ ID NO: 649); wherein the amino acid residue X is selected from R and W. In some embodiments, the present technology provides a library comprising at least two ISVDs each comprising 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein the at least two ISVDs each have: - FR2 (AbM numbering) that consists of an amino acid sequence selected from: a) the amino acid sequence WVRQX1PGKGX2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P, wherein the amino acid residue X2 is selected from I and L; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence WVRQX1PGKGX2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P, wherein the amino acid residue X2 is selected from I and L; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence WVRQX1PGKGX2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P, wherein the amino acid residue X2 is selected from I and L; - FR1 (AbM numbering) that consists of an amino acid sequence selected from: a) the amino acid sequence EVQLVESGGGXVQPGGSLRLSCAAS (SEQ ID NO: 647); wherein the amino acid residue X is selected from V and L; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence EVQLVESGGGXVQPGGSLRLSCAAS (SEQ ID NO: 647); wherein the amino acid residue X is selected from V and L; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence EVQLVESGGGXVQPGGSLRLSCAAS (SEQ ID NO: 647); wherein the amino acid residue X is selected from V and L; - FR3 (AbM numbering) that consists of an amino acid sequence selected from: a) the amino acid sequence YX1X2X3VX4GRFTISRDNAX5NTLYLQMNSLX6X7EDTAX8YYCTT (SEQ ID NO: 651); wherein the amino acid residue X1 is selected from R and A, wherein the amino acid residue X2 is selected from V and D, wherein the amino acid residue X3 is selected from P and S, wherein the amino acid residue X4 is selected from E and K, wherein the amino acid residue X5 is selected from E and K, wherein the amino acid residue X6 is selected from K and R, wherein the amino acid residue X7 is selected from T, S and P, and wherein the amino acid residue X8 is selected from V and K; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence YX1X2X3VX4GRFTISRDNAX5NTLYLQMNSLX6X7EDTAX8YYCTT (SEQ ID NO: 651); wherein the amino acid residue X1 is selected from R and A, wherein the amino acid residue X2 is selected from V and D, wherein the amino acid residue X3 is selected from P and S, wherein the amino acid residue X4 is selected from E and K, wherein the amino acid residue X5 is selected from E and K, wherein the amino acid residue X6 is selected from K and R, wherein the amino acid residue X7 is selected from T, S and P, and wherein the amino acid residue X8 is selected from V and K; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence YX1X2X3VX4GRFTISRDNAX5NTLYLQMNSLX6X7EDTAX8YYCTT (SEQ ID NO: 651); wherein the amino acid residue X1 is selected from R and A, wherein the amino acid residue X2 is selected from V and D, wherein the amino acid residue X3 is selected from P and S, wherein the amino acid residue X4 is selected from E and K, wherein the amino acid residue X5 is selected from E and K, wherein the amino acid residue X6 is selected from K and R, wherein the amino acid residue X7 is selected from T, S and P, and wherein the amino acid residue X8 is selected from V and K; and - FR4 (AbM numbering) that consists of an amino acid sequence selected from: a) the amino acid sequence of amino acid sequence XGQGTLVTVSS (SEQ ID NO: 649); wherein the amino acid residue X is selected from R and W; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence XGQGTLVTVSS (SEQ ID NO: 649); wherein the amino acid residue X is selected from R and W; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence XGQGTLVTVSS (SEQ ID NO: 649); wherein the amino acid residue X is selected from R and W. In some embodiments, the present technology provides a library comprising at least two ISVDs each comprising 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein the at least two ISVDs each have: - FR2 (AbM numbering) that consists of an amino acid sequence selected from: I. a) the amino acid sequence WVRQPPGKGIEWVS (SEQ ID NO: 625); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 625; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 625; II. a) the amino acid sequence WVRQAPGKGIEWVS (SEQ ID NO: 626); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 626; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 626; III. a) the amino acid sequence WVRQPPGKGLEWVS (SEQ ID NO: 627); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 627; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 627. and at least one, and preferably all of: - FR1 (AbM numbering) that consists of an amino acid sequence selected from: I. a) the amino acid sequence EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 4); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 4; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 4; or II. a) the amino acid sequence EVQLVESGGGVVQPGGSLRLSCAAS (SEQ ID NO: 34); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 34; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 34; - FR3 (AbM numbering) that consists of an amino acid sequence selected from: I. a) the amino acid sequence YRVPVEGRFTISRDNAENTLYLQMNSLKTEDTAVYYCTT (SEQ ID NO: 628); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 628; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 628; II. a) the amino acid sequence YRVPVEGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 629); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 629; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 629; III. a) the amino acid sequence YRVPVEGRFTISRDNAENTLYLQMNSLRSEDTALYYCTT (SEQ ID NO: 630); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 630; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 630; IV. a) the amino acid sequence YRVPVEGRFTISRDNAKNTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 631); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 631; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 631; V. a) the amino acid sequence YADSVKGRFTISRDNAKNTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 632); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 632; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 632; VI. a) the amino acid sequence YAVPVEGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 633); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 633; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 633; VII. a) the amino acid sequence YRDPVEGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 634); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 634; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 634; VIII. a) the amino acid sequence YRVSVEGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 635); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 635; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 635; IX. a) the amino acid sequence YRVPVKGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 636); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 636; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 636; X. a) the amino acid sequence YRVPVEGRFTISRDNAENTLYLQMNSLRPEDTALYYCTT (SEQ ID NO: 637); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 637; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 637; XI. a) the amino acid sequence YAVSVKGRFTISRDNAKNTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 638); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 638; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 638; XII. a) the amino acid sequence YAVPVKGRFTISRDNAKNTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 639); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 639; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 639; and/or - FR4 (AbM numbering) that consists of an amino acid sequence selected from: I. a) the amino acid sequence RGQGTLVTVSS (SEQ ID NO: 640); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 640; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 640; II. a) the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 7); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 7; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 7. In some embodiments, the present technology provides a library comprising at least two ISVDs each comprising 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein the at least two ISVDs each have: - FR2 (AbM numbering) that consists of an amino acid sequence selected from: I. a) the amino acid sequence WVRQPPGKGIEWVS (SEQ ID NO: 625); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 625; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 625; II. a) the amino acid sequence WVRQAPGKGIEWVS (SEQ ID NO: 626); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 626; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 626; III. a) the amino acid sequence WVRQPPGKGLEWVS (SEQ ID NO: 627); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 627; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 627. - FR1 (AbM numbering) that consists of an amino acid sequence selected from: I. a) the amino acid sequence EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 4); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 4; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 4; or II. a) the amino acid sequence EVQLVESGGGVVQPGGSLRLSCAAS (SEQ ID NO: 34); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 34; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 34; - FR3 (AbM numbering) that consists of an amino acid sequence selected from: I. a) the amino acid sequence YRVPVEGRFTISRDNAENTLYLQMNSLKTEDTAVYYCTT (SEQ ID NO: 628); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 628; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 628; II. a) the amino acid sequence YRVPVEGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 629); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 629; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 629; III. a) the amino acid sequence YRVPVEGRFTISRDNAENTLYLQMNSLRSEDTALYYCTT (SEQ ID NO: 630); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 630; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 630; IV. a) the amino acid sequence YRVPVEGRFTISRDNAKNTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 631); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 631; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 631; V. a) the amino acid sequence YADSVKGRFTISRDNAKNTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 632); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 632; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 632; VI. a) the amino acid sequence YAVPVEGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 633); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 633; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 633; VII. a) the amino acid sequence YRDPVEGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 634); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 634; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 634; VIII. a) the amino acid sequence YRVSVEGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 635); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 635; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 635; IX. a) the amino acid sequence YRVPVKGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 636); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 636; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 636; X. a) the amino acid sequence YRVPVEGRFTISRDNAENTLYLQMNSLRPEDTALYYCTT (SEQ ID NO: 637); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 637; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 637; XI. a) the amino acid sequence YAVSVKGRFTISRDNAKNTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 638); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 638; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 638; XII. a) the amino acid sequence YAVPVKGRFTISRDNAKNTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 639); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 639; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 639; and - FR4 (AbM numbering) that consists of an amino acid sequence selected from: III. a) the amino acid sequence RGQGTLVTVSS (SEQ ID NO: 640); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 640; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 640; IV. a) the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 7); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 7; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 7. In some embodiments, the present technology provides a library comprising at least two ISVDs each comprising 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein the at least two ISVDs each have: - FR2 (AbM numbering) that consists of an amino acid sequence selected from: I. a) the amino acid sequence WVRQPPGKGIEWVS (SEQ ID NO: 625); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 625; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 625; II. a) the amino acid sequence WVRQAPGKGIEWVS (SEQ ID NO: 626); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 626; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 626; III. a) the amino acid sequence WVRQPPGKGLEWVS (SEQ ID NO: 627); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 627; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 627. - FR1 (AbM numbering) that consists of an amino acid sequence selected from: a) the amino acid sequence EVQLVESGGGVVQPGGSLRLSCAAS (SEQ ID NO: 34); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 34; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 34; - FR3 (AbM numbering) that consists of an amino acid sequence selected from: I. a) the amino acid sequence YRVPVEGRFTISRDNAENTLYLQMNSLKTEDTAVYYCTT (SEQ ID NO: 628); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 628; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 628; II. a) the amino acid sequence YRVPVEGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 629); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 629; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 629; III. a) the amino acid sequence YRVPVEGRFTISRDNAENTLYLQMNSLRSEDTALYYCTT (SEQ ID NO: 630); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 630; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 630; IV. d) the amino acid sequence YRVPVEGRFTISRDNAKNTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 631); e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 631; or f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 631; V. a) the amino acid sequence YADSVKGRFTISRDNAKNTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 632); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 632; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 632; VI. a) the amino acid sequence YAVPVEGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 633); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 633; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 633; VII. d) the amino acid sequence YRDPVEGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 634); e) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 634; or f) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 634; VIII. a) the amino acid sequence YRVSVEGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 635); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 635; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 635; IX. a) the amino acid sequence YRVPVKGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 636); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 636; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 636; X. a) the amino acid sequence YRVPVEGRFTISRDNAENTLYLQMNSLRPEDTALYYCTT (SEQ ID NO: 637); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 637; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 637; XI. a) the amino acid sequence YAVSVKGRFTISRDNAKNTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 638); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 638; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 638; XII. a) the amino acid sequence YAVPVKGRFTISRDNAKNTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 639); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 639; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 639; and - FR4 (AbM numbering) that consists of an amino acid sequence selected from: a) the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 7); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 7; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 7. The library of the present technology may comprise at least two ISVDs according to the present technology, wherein the at least two ISVDs are different at least in the CDR3 sequence. Hence, in some embodiments, the present technology provides a library comprising at least two ISVDs each comprising 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein the at least two ISVDs have: - a FR1 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 647; and - a FR2 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 641; and - a FR3 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 651; and - a FR4 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 649. The present technology also relates to a method for screening an ISVDs specifically binding to a selected target, wherein the method comprises: a) Screening the at least one library comprising at least two ISVDs as described herein for binding to the target; b) Selecting at least one ISVD from the at least one library specifically binding to the target, optionally selecting at least one ISVD based on the affinity to the target. The screening method may be used to screen for ISVDs in the library having variable CDRs. Hence, in an embodiment, the present technology provides a method for screening an ISVDs specifically binding to the selected target, wherein the method comprises: a) Screening a library comprising at least two ISVDs for binding to the selected target, wherein the library comprises at least two ISVDs each comprising 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein the at least two ISVDs have a FR2 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 641, or an amino acid sequence that has at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 641 or an amino acid sequence that has 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 641; b) Selecting at least one ISVD from the library specifically binding to the selected target, optionally selecting at least one ISVD based on the affinity to the selected target. The screening method may be used to screen for ISVDs in the library with variable CDR regions. Hence, in an embodiment, the present technology provides a method for screening an ISVDs specifically binding to a selected target, wherein the method comprises: 1) Screening the at least one library comprising at least two ISVDs for binding to the selected target, wherein the library comprises at least two ISVDs each comprising 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein the at least two ISVDs have: - FR2 (AbM numbering) that consists of an amino acid sequence selected from: a) the amino acid sequence WVRQX1PGKGX2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P, wherein the amino acid residue X2 is selected from I and L; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence WVRQX1PGKGX2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P, wherein the amino acid residue X2 is selected from I and L; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence WVRQX1PGKGX2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P, wherein the amino acid residue X2 is selected from I and L; and and at least one, and preferably all of: - FR1 (AbM numbering) that consists of an amino acid sequence selected from: I. the amino acid sequence EVQLVESGGGXVQPGGSLRLSCAAS (SEQ ID NO: 647); wherein the amino acid residue X is selected from V and L; II. amino acid sequences that have at least 80% amino acid identity with the amino acid sequence EVQLVESGGGXVQPGGSLRLSCAAS (SEQ ID NO: 647); wherein the amino acid residue X is selected from V and L; III. amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence EVQLVESGGGXVQPGGSLRLSCAAS (SEQ ID NO: 647); wherein the amino acid residue X is selected from V and L; and/or - FR3 (AbM numbering) that consists of an amino acid sequence selected from: I. the amino acid sequence YX1X2X3VX4GRFTISRDNAX5NTLYLQMNSLX6X7EDTAX8YYCTT (SEQ ID NO: 651); wherein the amino acid residue X1 is selected from R and A, wherein the amino acid residue X2 is selected from V and D, wherein the amino acid residue X3 is selected from P and S, wherein the amino acid residue X4 is selected from E and K, wherein the amino acid residue X5 is selected from E and K, wherein the amino acid residue X6 is selected from K and R, wherein the amino acid residue X7 is selected from T, S and P, and wherein the amino acid residue X8 is selected from V and K; II. amino acid sequences that have at least 80% amino acid identity with the amino acid sequence YX1X2X3VX4GRFTISRDNAX5NTLYLQMNSLX6X7EDTAX8YYCTT (SEQ ID NO: 651); wherein the amino acid residue X1 is selected from R and A, wherein the amino acid residue X2 is selected from V and D, wherein the amino acid residue X3 is selected from P and S, wherein the amino acid residue X4 is selected from E and K, wherein the amino acid residue X5 is selected from E and K, wherein the amino acid residue X6 is selected from K and R, wherein the amino acid residue X7 is selected from T, S and P, and wherein the amino acid residue X8 is selected from V and K; III. amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence YX1X2X3VX4GRFTISRDNAX5NTLYLQMNSLX6X7EDTAX8YYCTT (SEQ ID NO: 651); wherein the amino acid residue X1 is selected from R and A, wherein the amino acid residue X2 is selected from V and D, wherein the amino acid residue X3 is selected from P and S, wherein the amino acid residue X4 is selected from E and K, wherein the amino acid residue X5 is selected from E and K, wherein the amino acid residue X6 is selected from K and R, wherein the amino acid residue X7 is selected from T, S and P, and wherein the amino acid residue X8 is selected from V and K; and/or - FR4 (AbM numbering) that consists of an amino acid sequence selected from: I. the amino acid sequence of amino acid sequence XGQGTLVTVSS (SEQ ID NO: 649); wherein the amino acid residue X is selected from R and W; II. amino acid sequences that have at least 80% amino acid identity with the amino acid sequence XGQGTLVTVSS (SEQ ID NO: 649); wherein the amino acid residue X is selected from R and W; III. amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence XGQGTLVTVSS (SEQ ID NO: 649); wherein the amino acid residue X is selected from R and W. 2) Selecting at least one ISVD from the at least one library specifically binding to the selected target. In an embodiment, the present technology provides a method for screening an ISVDs specifically binding to a selected target, wherein the method comprises: 1) Screening the at least one library comprising at least two ISVDs for binding to the selected target, wherein the library comprises at least two ISVDs each comprising 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein the at least two ISVDs have: - FR2 (AbM numbering) that consists of an amino acid sequence selected from: I. the amino acid sequence WVRQX1PGKGX2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P, wherein the amino acid residue X2 is selected from I and L; II. amino acid sequences that have at least 80% amino acid identity with the amino acid sequence WVRQX1PGKGX2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P, wherein the amino acid residue X2 is selected from I and L; III. amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence WVRQX1PGKGX2EWVS (SEQ ID NO: 641); wherein the amino acid residue X1 is selected from A and P, wherein the amino acid residue X2 is selected from I and L; - FR1 (AbM numbering) that consists of an amino acid sequence selected from: I. the amino acid sequence EVQLVESGGGXVQPGGSLRLSCAAS (SEQ ID NO: 647); wherein the amino acid residue X is selected from V and L; II. amino acid sequences that have at least 80% amino acid identity with the amino acid sequence EVQLVESGGGXVQPGGSLRLSCAAS (SEQ ID NO: 647); wherein the amino acid residue X is selected from V and L; III. amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence EVQLVESGGGXVQPGGSLRLSCAAS (SEQ ID NO: 647); wherein the amino acid residue X is selected from V and L; - FR3 (AbM numbering) that consists of an amino acid sequence selected from: I. the amino acid sequence YX1X2X3VX4GRFTISRDNAX5NTLYLQMNSLX6X7EDTAX8YYCTT (SEQ ID NO: 651); wherein the amino acid residue X1 is selected from R and A, wherein the amino acid residue X2 is selected from V and D, wherein the amino acid residue X3 is selected from P and S, wherein the amino acid residue X4 is selected from E and K, wherein the amino acid residue X5 is selected from E and K, wherein the amino acid residue X6 is selected from K and R, wherein the amino acid residue X7 is selected from T, S and P, and wherein the amino acid residue X8 is selected from V and K.; II. amino acid sequences that have at least 80% amino acid identity with the amino acid sequence YX1X2X3VX4GRFTISRDNAX5NTLYLQMNSLX6X7EDTAX8YYCTT (SEQ ID NO: 651); wherein the amino acid residue X1 is selected from R and A, wherein the amino acid residue X2 is selected from V and D, wherein the amino acid residue X3 is selected from P and S, wherein the amino acid residue X4 is selected from E and K, wherein the amino acid residue X5 is selected from E and K, wherein the amino acid residue X6 is selected from K and R, wherein the amino acid residue X7 is selected from T, S and P, and wherein the amino acid residue X8 is selected from V and K; III. amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence YX1X2X3VX4GRFTISRDNAX5NTLYLQMNSLX6X7EDTAX8YYCTT (SEQ ID NO: 651); wherein the amino acid residue X1 is selected from R and A, wherein the amino acid residue X2 is selected from V and D, wherein the amino acid residue X3 is selected from P and S, wherein the amino acid residue X4 is selected from E and K, wherein the amino acid residue X5 is selected from E and K, wherein the amino acid residue X6 is selected from K and R, wherein the amino acid residue X7 is selected from T, S and P, and wherein the amino acid residue X8 is selected from V and K; and - FR4 (AbM numbering) that consists of an amino acid sequence selected from: I. the amino acid sequence of amino acid sequence XGQGTLVTVSS (SEQ ID NO: 649); wherein the amino acid residue X is selected from R and W; II. amino acid sequences that have at least 80% amino acid identity with the amino acid sequence XGQGTLVTVSS (SEQ ID NO: 649); wherein the amino acid residue X is selected from R and W; III. amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence XGQGTLVTVSS (SEQ ID NO: 649); wherein the amino acid residue X is selected from R and W. 2) Selecting at least one ISVD from the at least one library specifically binding to the selected target. In an embodiment, the present technology provides a method for screening an ISVDs specifically binding to a selected target, wherein the method comprises: 1) Screening the at least one library comprising at least two ISVDs for binding to the selected target, wherein the library comprises at least two ISVDs each comprising 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein the at least two ISVDs have: - FR2 (AbM numbering) that consists of an amino acid sequence selected from: I. a) the amino acid sequence WVRQPPGKGIEWVS (SEQ ID NO: 625); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 625; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 625; II. a) the amino acid sequence WVRQAPGKGIEWVS (SEQ ID NO: 626); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 626; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 626; III. a) the amino acid sequence WVRQPPGKGLEWVS (SEQ ID NO: 627); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 627; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 627. and at least one, and preferably all of: - FR1 (AbM numbering) that consists of an amino acid sequence selected from: I. a) the amino acid sequence EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 4); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 4; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 4; or II. a) the amino acid sequence EVQLVESGGGVVQPGGSLRLSCAAS (SEQ ID NO: 34); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 34; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 34; - FR3 (AbM numbering) that consists of an amino acid sequence selected from: I. a) the amino acid sequence YRVPVEGRFTISRDNAENTLYLQMNSLKTEDTAVYYCTT (SEQ ID NO: 628); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 628; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 628; II. a) the amino acid sequence YRVPVEGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 629); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 629; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 629; III. a) the amino acid sequence YRVPVEGRFTISRDNAENTLYLQMNSLRSEDTALYYCTT (SEQ ID NO: 630); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 630; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 630; IV. a) the amino acid sequence YRVPVEGRFTISRDNAKNTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 631); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 631; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 631; V. a) the amino acid sequence YADSVKGRFTISRDNAKNTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 632); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 632; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 632; VI. a) the amino acid sequence YAVPVEGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 633); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 633; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 633; VII. a) the amino acid sequence YRDPVEGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 634); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 634; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 634; VIII. a) the amino acid sequence YRVSVEGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 635); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 635; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 635; IX. a) the amino acid sequence YRVPVKGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 636); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 636; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 636; X. a) the amino acid sequence YRVPVEGRFTISRDNAENTLYLQMNSLRPEDTALYYCTT (SEQ ID NO: 637); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 637; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 637; XI. a) the amino acid sequence YAVSVKGRFTISRDNAKNTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 638); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 638; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 638; XII. a) the amino acid sequence YAVPVKGRFTISRDNAKNTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 639); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 639; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 639; and/or - FR4 (AbM numbering) that consists of an amino acid sequence selected from: I. a) the amino acid sequence RGQGTLVTVSS (SEQ ID NO: 640); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 640; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 640; II. a) the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 7); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 7; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 7. 2) Selecting at least one ISVD from the at least one library specifically binding to the selected target. In an embodiment, the present technology provides a method for screening an ISVDs specifically binding to a selected target, wherein the method comprises: 1) Screening the at least one library comprising at least two ISVDs for binding to the selected target, wherein the library comprises at least two ISVDs each comprising 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein the at least two ISVDs have: - FR2 (AbM numbering) that consists of an amino acid sequence selected from: I. a) the amino acid sequence WVRQPPGKGIEWVS (SEQ ID NO: 625); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 625; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 625; II. a) the amino acid sequence WVRQAPGKGIEWVS (SEQ ID NO: 626); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 626; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 626; III. a) the amino acid sequence WVRQPPGKGLEWVS (SEQ ID NO: 627); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 627; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 627. - FR1 (AbM numbering) that consists of an amino acid sequence selected from: I. a) the amino acid sequence EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 4); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 4; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 4; or II. a) the amino acid sequence EVQLVESGGGVVQPGGSLRLSCAAS (SEQ ID NO: 34); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 34; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 34; - FR3 (AbM numbering) that consists of an amino acid sequence selected from: I. a) the amino acid sequence YRVPVEGRFTISRDNAENTLYLQMNSLKTEDTAVYYCTT (SEQ ID NO: 628); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 628; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 628; II. a) the amino acid sequence YRVPVEGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 629); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 629; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 629; III. a) the amino acid sequence YRVPVEGRFTISRDNAENTLYLQMNSLRSEDTALYYCTT (SEQ ID NO: 630); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 630; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 630; IV. a) the amino acid sequence YRVPVEGRFTISRDNAKNTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 631); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 631; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 631; V. a) the amino acid sequence YADSVKGRFTISRDNAKNTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 632); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 632; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 632; VI. a) the amino acid sequence YAVPVEGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 633); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 633; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 633; VII. a) the amino acid sequence YRDPVEGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 634); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 634; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 634; VIII. a) the amino acid sequence YRVSVEGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 635); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 635; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 635; IX. a) the amino acid sequence YRVPVKGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 636); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 636; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 636; X. a) the amino acid sequence YRVPVEGRFTISRDNAENTLYLQMNSLRPEDTALYYCTT (SEQ ID NO: 637); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 637; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 637; XI. a) the amino acid sequence YAVSVKGRFTISRDNAKNTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 638); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 638; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 638; XII. a) the amino acid sequence YAVPVKGRFTISRDNAKNTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 639); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 639; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 639; and - FR4 (AbM numbering) that consists of an amino acid sequence selected from: I. a) the amino acid sequence RGQGTLVTVSS (SEQ ID NO: 640); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 640; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 640; II. a) the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 7); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 7; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 7. 2) Selecting at least one ISVD from the at least one library specifically binding to the selected target. In an embodiment, the present technology provides a method for screening an ISVDs specifically binding to a selected target, wherein the method comprises: 1) Screening the at least one library comprising at least two ISVDs for binding to the selected target, wherein the library comprises at least two ISVDs each comprising 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein the at least two ISVDs have: - FR2 (AbM numbering) that consists of an amino acid sequence selected from: I. a) the amino acid sequence WVRQPPGKGIEWVS (SEQ ID NO: 625); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 625; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 625; II. a) the amino acid sequence WVRQAPGKGIEWVS (SEQ ID NO: 626); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 626; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 626; III. a) the amino acid sequence WVRQPPGKGLEWVS (SEQ ID NO: 627); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 627; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 627. - FR1 (AbM numbering) that consists of an amino acid sequence selected from: a) the amino acid sequence EVQLVESGGGVVQPGGSLRLSCAAS (SEQ ID NO: 34); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 34; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 34; - FR3 (AbM numbering) that consists of an amino acid sequence selected from: I. a) the amino acid sequence YRVPVEGRFTISRDNAENTLYLQMNSLKTEDTAVYYCTT (SEQ ID NO: 628); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 628; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 628; II. a) the amino acid sequence YRVPVEGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 629); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 629; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 629; III. a) the amino acid sequence YRVPVEGRFTISRDNAENTLYLQMNSLRSEDTALYYCTT (SEQ ID NO: 630); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 630; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 630; IV. a) the amino acid sequence YRVPVEGRFTISRDNAKNTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 631); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 631; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 631; V. a) the amino acid sequence YADSVKGRFTISRDNAKNTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 632); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 632; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 632; VI. a) the amino acid sequence YAVPVEGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 633); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 633; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 633; VII. a) the amino acid sequence YRDPVEGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 634); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 634; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 634; VIII. a) the amino acid sequence YRVSVEGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 635); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 635; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 635; IX. a) the amino acid sequence YRVPVKGRFTISRDNAENTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 636); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 636; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 636; X. a) the amino acid sequence YRVPVEGRFTISRDNAENTLYLQMNSLRPEDTALYYCTT (SEQ ID NO: 637); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 637; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 637; XI. a) the amino acid sequence YAVSVKGRFTISRDNAKNTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 638); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 638; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 638; XII. a) the amino acid sequence YAVPVKGRFTISRDNAKNTLYLQMNSLRTEDTALYYCTT (SEQ ID NO: 639); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 639; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 639; and - FR4 (AbM numbering) that consists of an amino acid sequence selected from: a) the amino acid sequence WGQGTLVTVSS (SEQ ID NO: 7); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 7; or c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 7. In specific embodiments, the present technology provides a method for screening an ISVDs specifically binding to the selected target, wherein the method comprises: - Screening the at least one library comprising at least two ISVDs for binding to the selected target, wherein the library comprises at least two ISVDs each comprising 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein the at least two ISVDs have: I. a FR1 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 647; and II. a FR2 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 641; and III. a FR3 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 651; and IV. a FR3 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 649; and - Selecting at least one ISVD from the at least one library specifically binding to the selected target. The present technology also relates to a method for manufacturing an ISVDs specifically binding to a selected target, wherein the method comprises: a) Screening the at least one library comprising at least two ISVDs as described herein for binding to the selected target; b) Selecting at least one ISVD from the at least one library specifically binding to the selected target, optionally selecting at least one ISVD based on the affinity to the selected target. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 547, 549-563, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 547, 549-563, wherein the binding affinity is measured using the same method, such as, e.g, SPR. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when such an ISVD specifically binding to CEACAM5 has 3, 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, or other members of the CEACAM family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 547, 549-563, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 547, 549-563, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the CDRs of such an ISVD specifically binding to CEACAM5 have at least 90% amino acid sequence identity, at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, with a corresponding reference CDR sequence (above), the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, or other members of the CEACAM family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 547, 549-563, the ISVD has at least (essentially) the same binding affinity to human CEACAM5 compared to one of the VHHs with SEQ ID NOs: 547, 549-563, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 547, 549-563, the ISVD has at least (essentially) the same binding affinity to cyno CEACAM5 compared to one of the VHHs with SEQ ID NOs: 547, 549-563, wherein the binding affinity is measured using the same method, such as, e.g., SPR. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 547, 549-563, the ISVD still specifically binds to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 547, 549-563, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. In another embodiment, when the ISVD specifically binding to human CEACAM5 has a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of the VHHs with SEQ ID NOs: 547, 549-563, the ISVD still specifically binds to human and cyno CEACAM5 and does not bind to CEACAM6 or other members of the CEACAM family. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with dissociation constant (KD) of 10-7 to 10-12 moles/litre or less, and preferably 1x10-9 to 10-12 moles/litre or less and more preferably 1x10-10 to 1x10-11 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 9.45x10-11 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 104 M-1s-1 and 106 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, such as between 1x105 M-1s-1 and 5x105 M-1s-1, even more preferably of about 1.64x105 M-1s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 1x10-2 s-1 and 5x10-6 s-1, more preferably between 5x10-3 s-1 and 1x10-6 s-1, such as between 1x10-3 s-1 and 5x10-5 s-1, even more preferably of about 1.55x10-5 s-1, 2.47 x10-4 s-1, 2.67 x10-4 s-1, 2.55 x10-4 s-1, 1.13 x10-3 s-1, 1.09 x10-3 s-1, 1.14 x10-3 s-1, 1.25 x10-3 s-1, 3.09 x10-4 s-1, 1.32 x10-3 s-1, 6.77 x10-4 s-1, 3.54 x10-4 s-1, 2.79 x10-4 s-1, 2.78 x10-4 s-1, 2.37 x10-3 s-1, 4.92 x10-4 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-7 to 10-10 moles/litre or less and more preferably 10-8 to 1x10-10 moles/litre, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M-1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to cyno CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-5 s-1 (providing a near irreversible complex with a t1/2 of multiple days), 10-2 s-1 and 10-4 s-1, more preferably between 2 x 10-2 s-1 and 5 x 10-4 s-1, even more preferably of about 2.95 x10-3 s-1 , 2.96 x10- 3 s-1 , 3.10 x10-3 s-1 , 2.90 x10-2 s-1 , 2.74 x10-2 s-1 , 2.79 x10-2 s-1, 2.56 x10-2 s-1, 8.16 x10-4 s-1, 8.09 x10-3 s-1, 4.29 x10-3 s-1, 2.86 x10-3 s-1, 2.94 x10-3 s-1, 5.06 x10-3 s-1, or 1.24 x10-3 s-1, as determined by SPR. In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and binds to other members of the CEACAMs family with a at least 100-fold lower affinity (KD). In preferred embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human and cyno CEACAM5 and do not bind to other members of the CEACAMs family. A preferred assay for measuring binding and internalization of the ISVD (or polypeptide comprising the ISVD) to CEACAM5 exposed on a cell surface is a FACS assay. For instance, the ISVDs or polypeptides of the present invention can be applied to cancer cell lines overexpressing CEACAM5, such as a MKN45 cell line, which is a human colonic carcinoma cell line. VHH bound to human CEACAM5 can be detected with a fluorophore- labelled anti-VHH antibody and the cells can be analyzed with a flow cytometer to evaluate the binding properties of ISVDs or polypeptides of the present invention. Alternatively, the internalization can be measured using a Live-Cell Analysis Systems capable of recording fluorescence and bright field images, such as the Incucyte instrument (Sartorius). In some embodiments, the immunoglobulin single variable domains of the present technology specifically bind to human CEACAM5. For example, in a FACS assay analysing the binding of the immunoglobulin single variable domains of the present technology to human CEACAM5 expressed on MKN45 cells, the immunoglobulin single variable domains of the present technology may have EC50 values of 10-7 M or lower, more preferably of 5x10-8 M or lower, or even of 10-8 M or lower. For example, in such FACS assay, the immunoglobulin single variable domains of the present technology may have EC50 values between 10-11 M and 10-7 M, such as between 10-10 M and 10-7 M, between 10-10 M and 10-8 M or between 5x10-10 M and 10-8 M.
5.3 Polypeptides and constructs The process of designing/selecting and/or preparing a polypeptide, starting from an immunoglobulin single variable domain such as a VHH, humanized VHH, camelized VH, domain antibody or dAb, is also referred to herein as “formatting” said immunoglobulin single variable domain; and an immunoglobulin single variable domain that is made part of a polypeptide is said to be “formatted” or to be “in the format of” said polypeptide. Examples of ways in which an immunoglobulin single variable domain can be formatted, and examples of such formats will be clear to the skilled person based on the disclosure herein; and such formatted immunoglobulin single variable domain form a further aspect of the present technology. For example, and without limitation, one or more immunoglobulin single variable domains may be used as a “binding unit”, “binding domain” or “building block” (these terms are used interchangeable) for the preparation of a polypeptide, which may optionally contain one or more further immunoglobulin single variable domains that can serve as a binding unit (i.e., against the same or another epitope on CEACAM5 and/or against one or more other antigens, proteins or targets than CEACAM5). The present technology also provides a polypeptide or construct that comprises or essentially consists of one or more immunoglobulin single variable domain. In one embodiment, the polypeptides further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers. The one or more other groups, residues, moieties or binding units can be any groups, residues, moieties or binding units known in the art. In one embodiment the one or more other groups, residues, moieties or binding units are amino acid sequences, so that the resulting polypeptide is a fusion (protein) or fusion (polypeptide). The further groups, residues, moieties, binding units or amino acid sequences may or may not provide further functionality to the ISVD, polypeptide or construct and may or may not modify the properties of the ISVD, polypeptide and/or construct. Such groups, residues, moieties or binding units may for example be chemical groups, residues, moieties, which may or may not by themselves be biologically and/or pharmacologically active. For example, and without limitation, such groups may be linked to the one or more ISVD and/or polypeptide so as to provide a “derivative” of the ISVD and/or polypeptide. The one or more further amino acid sequence may be any suitable and/or desired amino acid sequences. The further amino acid sequences may or may not change, alter or otherwise influence the (biological) properties of the ISVD or polypeptide, and may or may not add further functionality to the ISVD or the polypeptide. Preferably, the further amino acid sequence is such that it confers one or more desired properties or functionalities to the ISVD or the polypeptide. Example of such amino acid sequences will be clear to the skilled person and may generally comprise all amino acid sequences that are used in peptide fusions based on conventional antibodies and fragments thereof (including but not limited to ScFv’s and single domain antibodies). Reference is for example made to the review by Holliger and Hudson, Nature Biotechnology, 23, 9, 1126-1136 (2005). For example, such an amino acid sequence may be an amino acid sequence that increases the half-life, the solubility, or the absorption, reduces the immunogenicity or the toxicity, eliminates or attenuates undesirable side effects, and/or confers other advantageous properties to and/or reduces the undesired properties of the ISVD or polypeptide, compared to the ISVD or polypeptide per se. Some non-limiting examples of such amino acid sequences are serum proteins, such as human serum albumin (see for example WO 00/27435) or haptenic molecules (for example haptens that are recognized by circulating antibodies, see for example WO 98/22141). The further amino acid sequence may also provide a second binding site, which binding site may be directed against any desired protein, polypeptide, antigen, antigenic determinant or epitope (including but not limited to the same protein, polypeptide, antigen, antigenic determinant or epitope against which the ISVD is directed, or a different protein, polypeptide, antigen, antigenic determinant or epitope). In one embodiment, the one or more other groups, residues, moieties or binding units are binding units. In one embodiment the binding unit is an immunoglobulin sequence. In one embodiment the binding unit is an immunoglobulin single variable domain, such as a VHH, humanized VHH, camelized VH, domain antibody, single domain antibody or dAb. Monovalent polypeptides comprise or essentially consist of only one binding unit (such as e.g., immunoglobulin single variable domains). Polypeptides that comprise two or more binding units (such as e.g., immunoglobulin single variable domains) will also be referred to herein as “multivalent” polypeptides, and the binding units/immunoglobulin single variable domains present in such polypeptides will also be referred to herein as being in a “multivalent format”. For example a “bivalent” polypeptide may comprise two immunoglobulin single variable domains, optionally linked via a linker sequence, whereas a “trivalent” polypeptide may comprise three immunoglobulin single variable domains, optionally linked via two linker sequences; whereas a “tetravalent” polypeptide may comprise four immunoglobulin single variable domains, optionally linked via three linker sequences; whereas a “pentavalent” polypeptide may comprise five immunoglobulin single variable domains, optionally linked via four linker sequences; whereas a “hexavalent” polypeptide may comprise six immunoglobulin single variable domains, optionally linked via five linker sequences, etc. Examples of monovalent polypeptides are depicted in Table A- 2, A-3, A-4, A-5, A-6 and A-7 (SEQ ID NOs: 8, 16, 31, 32, 16, 39, 40, 114-120, 121-131, 135-149, 150- 159, 160-170, 171-174, 175-208). Examples of bivalent polypeptides are depicted in Table A-12 (SEQ ID NOs: 109, 110, 211-228). In a multivalent polypeptide, the two or more immunoglobulin single variable domains may be the same or different, and may be directed against the same antigen or antigenic determinant (for example against the same part(s) or epitope(s) or against different parts or epitopes) or may alternatively be directed against different antigens or antigenic determinants; or any suitable combination thereof. Polypeptides that contain at least two binding units (such as e.g., immunoglobulin single variable domains) in which at least one binding unit is directed against a first antigen (i.e., CEACAM5) and at least one binding unit is directed against a second antigen (i.e., different from CEACAM5) will also be referred to as “multispecific” polypeptides, and the binding units (such as e.g., immunoglobulin single variable domains) present in such polypeptides will also be referred to herein as being in a “multispecific format”. Thus, for example, a “bispecific” polypeptide is a polypeptide that comprises at least one immunoglobulin single variable domain directed against a first antigen (i.e., CEACAM5) and at least one further immunoglobulin single variable domain directed against a second antigen (i.e., different from CEACAM5), whereas a “trispecific” polypeptide is a polypeptide that comprises at least one immunoglobulin single variable domain directed against a first antigen (i.e., CEACAM5), at least one further immunoglobulin single variable domain directed against a second antigen (i.e., different from CEACAM5) and at least one further immunoglobulin single variable domain directed against a third antigen (i.e., different from both CEACAM5 and the second antigen); etc. Examples of bispecific polypeptides are depicted in Table A-12 (SEQ ID NOs: 109, 110, 211-228). In one embodiment, the polypeptide may further comprise one or more other groups, residues, moieties or binding units, optionally linked via one or more peptidic linkers, in which said one or more other groups, residues, moieties or binding units provide the polypeptide with increased (in vivo) half-life, compared to the corresponding polypeptide without said one or more other groups, residues, moieties or binding units. In vivo half-life extension means, for example, that the polypeptide has an increased half-life in a mammal, such as a human subject, after administration. Half-life can be expressed for example as t1/2beta. The type of groups, residues, moieties or binding units is not generally restricted and may for example be chosen from the group consisting of a polyethylene glycol molecule, serum proteins or fragments thereof, binding units that can bind to serum proteins, an Fc portion, and small proteins or peptides that can bind to serum proteins. More specifically, said one or more other groups, residues, moieties or binding units that provide the polypeptide with increased half-life can be chosen from the group consisting of binding units that can bind to serum albumin, such as human serum albumin, or a serum immunoglobulin, such as IgG. In one embodiment, said one or more other groups, residues, moieties or binding units that provide the polypeptide with increased half-life is a binding unit that can bind to human serum albumin. In one embodiment, the binding unit is an ISVD. For example, WO 2004/041865 and WO 2006/122787 describes ISVDs binding to serum albumin (and in particular against human serum albumin) that can be linked to other proteins (such as one or more other ISVDs binding to a desired target) in order to increase the half-life of said protein. These ISVDs include the ISVDs called Alb-1 (SEQ ID NO: 52 in WO 2006/122787) and humanized variants thereof, such as Alb-8 (SEQ ID NO: 62 in WO 2006/122787). Again, these can be used to extend the half-life of therapeutic proteins and polypeptide and other therapeutic entities or moieties. Moreover, WO 2012/175400 describes a further improved version of Alb-1, called Alb- 23. In one embodiment, the polypeptide comprises a serum albumin binding moiety selected from Alb- 1, Alb-3, Alb-4, Alb-5, Alb-6, Alb-7, Alb-8, Alb-9, Alb-10 (WO 2006/122787) and Alb-23. In one embodiment, the serum albumin binding moiety is Alb-8 or Alb-23 or its variants, as shown on pages 7-9 of WO 2012/175400. In one embodiment, the serum albumin binding moiety is selected from the albumin binders described in WO 2012/175741, WO 2015/173325, WO 2017/080850, WO 2017/085172, WO 2018/104444, WO 2018/134235, and WO 2018/134234. Some serum albumin binders are also shown in Table A-10. In one embodiment, the serum albumin binder is AlbX00001 (SEQ ID NO: 61). In one embodiment the serum albumin binder is Alb23002 (SEQ ID NO: 62). Examples of polypeptides that comprise ALB23002 are depicted in Table A-12 (SEQ ID NOs: 109, 110, 211-228. In one embodiment, a further component of the polypeptide of the present technology is an ISVD that specially binds to human serum albumin and comprises i. a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 80 or an amino acid sequence with 2 or 1 amino acid difference with SEQ ID NO: 80; ii. a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 81 or an amino acid sequence with 2 or 1 amino acid difference with SEQ ID NO: 81; and iii. a CDR3(AbM numbering) that is the amino acid sequence of SEQ ID NO: 82 or an amino acid sequence with 2 or 1 amino acid difference with SEQ ID NO: 82. In one embodiment, the ISVD that specifically binds to human serum albumin comprises a CDR1 that is the amino acid sequence of SEQ ID NO: 80, a CDR2 that is the amino acid sequence of SEQ ID NO: 81 and a CDR3 that is the amino acid sequence of SEQ ID NO: 82. Examples of such an ISVD that specifically binds to human serum albumin have one or more, or all, framework regions as indicated for ISVD ALB23002 in Table A-8 (in addition to the CDRs as defined above). In one embodiment, it is an ISVD comprising or consisting of the full amino acid sequence of ISVD ALB23002 (SEQ ID NO: 62, see Table A-10 and A-12). The ISVD that specifically binds to human serum albumin can be also described using the Kabat definition for CDR regions. Accordingly, in one embodiment, a further component of the polypeptide of the present technology is an ISVD that specially binds to human serum albumin and comprises i. a CDR1 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 87 or an amino acid sequence with 2 or 1 amino acid difference with SEQ ID NO: 87; ii. a CDR2 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 88 or an amino acid sequence with 2 or 1 amino acid difference with SEQ ID NO: 88; and iii. a CDR3 (Kabat numbering) that is the amino acid sequence of SEQ ID NO: 82 or an amino acid sequence with 2 or 1 amino acid difference with SEQ ID NO: 82. In one embodiment, the ISVD comprises a CDR1 that is the amino acid sequence of SEQ ID NO: 87, a CDR2 that is the amino acid sequence of SEQ ID NO: 88 and a CDR3 that is the amino acid sequence of SEQ ID NO: 82. Examples of such an ISVD that specifically binds to human serum albumin have one or more, or all, framework regions as indicated for construct ALB23002 in Table A-9 (in addition to the CDRs as defined above). In one embodiment, it is an ISVD comprising or consisting of the full amino acid sequence of construct ALB23002 (SEQ ID NO: 62, see Table A-10 and A-12). Also in another embodiment, the amino acid sequence of an ISVD binding to human serum albumin may have a sequence identity of more than 90%, such as more than 95% or more than 99%, with SEQ ID NO: 62, wherein the CDRs are as defined above. In one embodiment, the ISVD binding to human serum albumin comprises or consists of the amino acid sequence of SEQ ID NO: 62. When such an ISVD binding to human serum albumin has 2 or 1 amino acid difference in at least one CDR relative to a corresponding reference CDR sequence (as defined above), the ISVD has at least half of the binding affinity, or at least the same binding affinity, to human serum albumin compared to construct ALB23002 (SEQ ID NO: 62), wherein the binding affinity is measured using the same method, such as SPR. In one embodiment, when such an ISVD binding to human serum albumin has a C-terminal position in the polypeptide or construct, it exhibits a C-terminal extension, such as a C-terminal alanine (A) or glycine (G) extension. In one embodiment such an ISVD is selected from SEQ ID NOs: 49, 50, 52, 54, 55, 56, 57, 58, 59, and 60 (see table A-10). In another embodiment, the ISVD binding to human serum albumin has another position than the C-terminal position in the polypeptide (i.e., is not the C-terminal ISVD of the polypeptide of the technology). In one embodiment such an ISVD is selected from SEQ ID NOs: 47, 48, 51, 53, 61, and 62 (see Table A-10). In one embodiment, the ISVD or polypeptide of the present technology may be linked (optionally via a suitable linker or hinge region) to one or more constant domains (for example, 2 or 3 constant domains that can be used as part of/to form an Fc portion), to an Fc portion and/or to one or more antibody parts, fragments or domains that confer one or more effector functions to the ISVD or polypeptide and/or may confer the ability to bind to one or more Fc receptors. For example, for this purpose, and without being limited thereto, the one or more further amino acid sequences may comprise one or more CH2 and/or CH3 domains of an antibody, such as from a heavy chain antibody (as described herein) and more preferably from a conventional human 4-chain antibody; and/or may form (part of) and Fc region, for example from IgG (e.g., from IgG1, IgG2, IgG3 or IgG4), from IgE or from another human Ig such as IgA, IgD or IgM. For example, WO 94/04678 describes heavy chain antibodies comprising a Camelid VHH domain or a humanized derivative thereof in which the Camelidae CH2 and/or CH3 domain have been replaced by human CH2 and CH3 domains, so as to provide an immunoglobulin that consists of 2 heavy chains each comprising a VHH and human CH2 and CH3 domains (but no CH1 domain), which immunoglobulin has the effector function provided by the CH2 and CH3 domains and which immunoglobulin can function without the presence of any light chains. Other amino acid sequences that can be suitably linked to the ISVD or polypeptide of the present technology so as to provide an effector function will be clear to the skilled person and may be chosen on the basis of the desired effector function(s). Reference is for example made to WO 04/058820, WO 99/42077, WO 02/056910 and WO 05/017148, as well as the review by Holliger and Hudson, supra; and to WO 09/068628. Coupling of ISVD or polypeptide to an Fc portion may also lead to an increased half-life, compared to the corresponding ISVD or polypeptide. For some applications, the use of an Fc portion and/or of constant domains (i.e., CH2 and/or CH3 domains) that confer increased half-life without any biologically significant effector function may also be suitable or even preferred. Other suitable constructs comprising one or more ISVDs or polypeptides and one or more constant domains with increased half-life in vivo will be clear to the skilled person and may for example comprise ISVDs or polypeptides linked to a CH3 domain, optionally via a linker sequence. Generally, any fusion protein or derivatives with increased half-life will preferably have a molecular weight of more than 50 kD, the cut-off value for renal absorption. The components, e.g., the ISVDs, of the polypeptide may be linked to each other by one or more suitable linkers, such as peptidic linkers. The use of linkers to connect two or more (poly)peptides is well known in the art. Exemplary peptidic linkers are shown in Table A-11. One often used class of peptidic linker are known as the “Gly-Ser” or “GS” linkers. These are linkers that essentially consist of glycine (G) and serine (S) residues, and usually comprise one or more repeats of a peptide motif such as the GGGGS (SEQ ID NO: 64) motif (for example, have the formula (Gly-Gly-Gly-Gly- Ser)n in which n may be 1, 2, 3, 4, 5, 6, 7 or more). Some often-used examples of such GS linkers are 9GS linkers (GGGGSGGGS, SEQ ID NO: 67), 15GS linkers (n=3; SEQ ID NO: 69) and 35GS linkers (n=7; SEQ ID NO: 74). Reference is for example made to Chen et al. 2013 (Adv. Drug Deliv. Rev. 65(10): 1357–1369) and Klein et al. 2014 (Protein Eng. Des. Sel. 27 (10): 325-330). In one embodiment, 9GS linkers to link the components of the polypeptide to each other, are used. Examples of ISVD formats with a 9GS linker are depicted in Table A-12 (SEQ ID NOs: 109, 110, 211- 228). In one embodiment, 35GS linkers to link the components of the polypeptide to each other, are used. The present technology also provides sequence optimized ISVDs and polypeptides that show increased stability upon storage during stability studies. In one embodiment, the sequence optimized ISVDs and polypeptides show reduced pyroglutamate post-translational modification of the N-terminus and hence have increased product stability. Pyroglutamaat modification leads to heterogeneity of the final product and needs to be avoided. The possibility of pGlu post- translational modification of the N-terminus was eliminated by changing the N-terminal Glutamic acid (E) into an Aspartic acid (D) which led to increased product stability. Accordingly, the present invention also relates to ISVDs and polypeptides as described above wherein the Glutamic acid at position 1 (said position determined according to Kabat numbering) is changed into an Aspartic acid (E1D). Examples of ISVDs and polypeptides with aspartic acid at position 1 (according to Kabat numbering) are depicted in Table A-4 and A-3 (SEQ ID NOs: 32 and 40). The present technology also provides sequence optimized ISVDs and polypeptides that are “humanized”, i.e., in which one or more amino acid residues in the amino acid sequence of said naturally occurring VHH sequence (and in particular in the framework sequences) are replaced by one or more of the amino acid residues that occur at the corresponding position(s) in a VH domain from a conventional 4-chain antibody from a human being (e.g., indicated above). Accordingly, the present invention also relates to ISVDs and polypeptides as described above that are humanized. Examples of such humanized ISVDs are depicted in Table A-3 to Table A-9 (SEQ ID NOs: 31, 32, 39 and 40, 134-208). The present technology also provides sequence optimized ISVDs and polypeptides that exhibit reduced binding by pre-existing antibodies present in human serum. To this end, in one embodiment, the polypeptide comprises a valine (V) at amino acid position 11 and a leucine (L) at amino acid position 89 (according to Kabat numbering) in at least one ISVD. In one embodiment, the polypeptide comprises a valine (V) at amino acid position 11 and a leucine (L) at amino acid position 89 (according to Kabat numbering) in each ISVD. Accordingly, the present invention also relates to ISVDs and polypeptides as described above that have been sequence optimized with a valine (V) at amino acid position 11 and a leucine (L) at amino acid position 89 (according to Kabat numbering) in at least one ISVD, such as in all ISVDs. Examples of ISVDs and polypeptides that comprises a valine (V) at amino acid position 11 and a leucine (L) at amino acid position 89 (according to Kabat numbering) in at least one ISVD are depicted in Table A-3 to Table A-9 (SEQ ID NOs: 31, 32, 39, 40, and 134-208). In one embodiment, the ISVD or polypeptide has a C-terminal end of the sequence VTVSS(X)n (SEQ ID NO: 91), in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5, and in which each X is an amino acid residue that is independently chosen. In one embodiment, the polypeptide comprises such an ISVD at its C-terminal end. In one embodiment, n is 1 or 2, such as 1. In one embodiment, X is a naturally occurring amino acid. In one embodiment, X is chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I). In another embodiment the polypeptide comprises a lysine (K) or glutamine (Q) at position 110 (according to Kabat numbering) in at least one ISVD. In another embodiment, the ISVD comprises a lysine (K) or glutamine (Q) at position 112 (according to Kabat numbering) in at least one ISVD. In these embodiments, the C-terminus of the ISVD is VKVSS (SEQ ID NO: 92), VQVSS (SEQ ID NO: 93), VTVKS (SEQ ID NO: 94), VTVQS (SEQ ID NO: 95), VKVKS (SEQ ID NO: 96), VKVQS (SEQ ID NO: 97), VQVKS (SEQ ID NO: 98), or VQVQS (SEQ ID NO: 99) such that after addition of a single alanine the C-terminus of the polypeptide for example comprises the sequence VTVSSA (SEQ ID NO: 100), VKVSSA (SEQ ID NO: 101), VQVSSA (SEQ ID NO: 102), VTVKSA (SEQ ID NO: 103), VTVQSA (SEQ ID NO: 104), VKVKSA (SEQ ID NO: 105), VKVQSA (SEQ ID NO: 106), VQVKSA (SEQ ID NO: 107), or VQVQSA (SEQ ID NO: 108). In one embodiment, the polypeptide comprises a valine (V) at amino acid position 11 and a leucine (L) at amino acid position 89 (according to Kabat numbering) in each ISVD, optionally a lysine (K) or glutamine (Q) at position 110 (according to Kabat numbering) in at least one ISVD, and comprises an extension of 1 to 5 (naturally occurring) amino acids (as defined above), such as a single alanine (A) extension, at the C-terminus of the C-terminal ISVD, such that the C-terminus of the polypeptide for example comprises the sequence VTVSSA (SEQ ID NO: 100), VKVSSA (SEQ ID NO: 101) or VQVSSA (SEQ ID NO: 102). See, e.g., WO 2012/175741 and WO 2015/173325 for further information in this regard. In one embodiment, the polypeptide of the present technology comprises or essentially consists of one or more of the ISVDs selected from the group consisting of the amino acid sequence of SEQ ID NOs: 8, 31, 32, 16, 39 and 40, 114-131, 134-208). In one embodiment, the polypeptides further comprises one or more other groups, residues, moieties or binding units (as described herein), optionally linked via one or more linkers. In one embodiment, the polypeptide is selected from the group consisting of the amino acid sequences of SEQ ID NOs: 109, 110, 211-228. In another embodiment, the polypeptide may have a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of SEQ ID NOs: 109, 110, 211-228. In another embodiment, the polypeptide may have a sequence identity of more than 90%, such as more than 95% or more than 99%, with one of SEQ ID NOs: 109, 110, 211-228, wherein the sequences are as defined above. In one embodiment, the polypeptide comprises or consists of any one of the amino acid sequences of SEQ ID NOs: 109, 110, 211-228. In some embodiments, the polypeptide or construct of the present technology specifically bind to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-8 to 10-11 moles/litre or less and more preferably 1x10-8 to 1x10-9 moles/litre, such as a KD of less/better than 10-7 moles/litre, less/better than 10-8 moles/litre, less/better than 10-9 moles/litre, or even less/better than 10-10 moles/litre, such as 1.34x10-9 moles/litre or 1.06x10-8 moles/litre, as determined by SPR. In some embodiments, the polypeptide or construct of the present technology specifically bind to human CEACAM5 with a kon rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M-1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, such as between 1x105 M- 1s-1 and 5x105 M-1s-1, such as a kon of 105 M-1s-1 or higher, or even 106 M-1s-1 or higher, such as 3.17x105 M-1s-1 or 1.6x105 M-1s, as determined by SPR. In some embodiments, the polypeptide or construct of the present technology specifically bind to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-5 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-2 s-1 and 10-4 s-1, more preferably between 5x10-3 s-1 and 5.10-4 s-1, such as between 5x10-3 s-1 and 10-3 s-1, such as a koff of less/better than 10-2 s-1, less/better than 10-3 s-1 or even less/better than 10-4 s-1 such as 4.24x10-3 s- 1 or 1.7x10-3 s-1 M-1s, as determined by SPR. In some embodiments, the polypeptide or construct of the present technology specifically bind to cyno CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 5x10-8 to 10-10 moles/litre or less and more preferably 5x10-8 to 10-9 moles/litre, such as 2.28x10- 9 moles/litre or 1.76x10-8 moles/litre, as determined by SPR. In some embodiments, the polypeptide or construct of the present technology specifically bind to cyno CEACAM5 with a kon rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M- 1s-1 and 107 M-1s-1, such as between 105 M-1s-1 and 106 M-1s-1, such as between 2x105 M-1s-1 and 1x106 M-1s-1, such as 2.17x105 M-1s-1 or 9.94x105 M-1s, as determined by SPR. In some embodiments, the polypeptide or construct of the present technology specifically bind to cyno CEACAM5 with a koff rate between 10-1s-1 (t1/2=0.69 s) and 10-5 s-1 (providing a near irreversible complex with a t1/2 of multiple days), 10-2s-1 and 10-4s-1, between 5 x 10-3 s-1 and 5 x 10-4 s-1, such as between 5 x 10-3 s-1 and 1 x 10-3s-1, such as 3.81x10-3 s-1 or 2.26x10-3 s-1 M-1s, as determined by SPR . In some embodiments, the polypeptide or construct of the present technology specifically bind to human CEACAM5 and cyno CEACAM5 with less than 10-fold difference in affinity (KD). In some embodiments, the polypeptide or construct of the present technology specifically bind to human and cyno CEACAM5 and do not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAM family. In some embodiments, the polypeptide or construct of the present technology has an CEACAM5- mediated internalization potency (EC50 value) of 10-7 M or lower, more preferably of 5x10-8 M or lower, or even of 10-8 M or lower, such as between 10-11 M and 10-7 M, between 10-10 M and 5x10- 8 M, between 10-10 M and 10-8 M or between 10-11 M and 5x10-9 M, for example, as measured in a FACS internalization assay on BxPC-3 cells expressing human CEACAM5 In some embodiments, the polypeptide or construct of the present technology specifically bind to human CEACAM5. For example, in a FACS assay analysing the binding of the immunoglobulin single variable domains of the present technology to human CEACAM5 expressed on BxPC-3 cells, the immunoglobulin single variable domains of the present technology may have EC50 values of 10-7 M or lower, more preferably of 10-8 M or lower, 5x10-9 M or lower or even of 10-9 M or lower. For example, in such FACS binding assay the immunoglobulin single variable domains of the present technology may have EC50 values between 10-11 M and 10-7 M, such as between 10-10 M and 5x10- 8 M, such as between 10-10 M and 10-8 M, between 10-9 M and 10-8 M or between 10-11 M and 10-9 M. In one embodiment, the one or more other groups, residues, or moieties comprise the introduction of one or more detectable labels or other signal-generating groups or moieties, depending on the intended use of the labelled ISVD. Suitable labels and techniques for attaching, using and detecting them will be clear to the skilled person, and for example include, but are not limited to, fluorescent labels (such as fluorescein, isothiocyanate, rhodamine, phycoerythrin, phycocyanin, allophycocyanin, o-phthaldehyde, and fluorescamine and fluorescent metals such as 152Eu or others metals from the lanthanide series), phosphorescent labels, chemiluminescent labels or bioluminescent labels (such as luminal, isoluminol, theromatic acridinium ester, imidazole, acridinium salts, oxalate ester, dioxetane or GFP and its analogs), radio-isotopes (such as 3H, 125I, 32P, 35S, 14C, 51Cr, 36Cl, 57Co, 58Co, 59Fe, and 75Se), metals, metal chelates or metallic cations (for example metallic cations such as 99mTc, 123I, 111In, 131I, 97Ru, 67Cu, 67Ga, and 68Ga or other metals or metallic cations that are particularly suited for use in in vivo, in vitro or in situ diagnosis and imaging, such as (157Gd, 55Mn, 162Dy, 52Cr, and 56Fe), as well as chromophores and enzymes (such as malate dehydrogenase, staphylococcal nuclease, delta-V-steroid isomerase, yeast alcohol dehydrogenase, alpha-glycerophosphate dehydrogenase, triose phosphate isomerase, biotinavidin peroxidase, horseradish peroxidase, alkaline phosphatase, asparaginase, glucose oxidase, beta-galactosidase, ribonuclease, urease, catalase, glucose-VI-phosphate dehydrogenase, glucoamylase and acetylcholine esterase). Other suitable labels will be clear to the skilled person, and for example include moieties that can be detected using NMR or ESR spectroscopy. Such labelled ISVDs and polypeptides may for example be used for in vitro, in vivo or in situ assays (including immunoassays known per se such as ELISA, RIA, EIA and other “sandwich assays”, etc.) as well as in vivo diagnostic and imaging purposes, depending on the choice of the specific label. Another modification may involve the introduction of a chelating group, for example to chelate one of the metals or metallic cations referred to above. Suitable chelating groups for example include, without limitation, diethyl-enetriaminepentaacetic acid (DTPA) or ethylenediaminetetraacetic acid (EDTA). 5.4 Nucleic acid molecules Also provided is a nucleic acid molecule encoding the ISVD and/or polypeptide of the present technology. A “nucleic acid molecule” (used interchangeably with “nucleic acid”) is a chain of nucleotide monomers linked to each other via a phosphate backbone to form a nucleotide sequence. A nucleic acid may be used to transform/transfect a host cell or host organism, e.g., for expression and/or production of a polypeptide. Suitable hosts or host cells for production purposes will be clear to the skilled person, and may for example be any suitable fungal, prokaryotic or eukaryotic cell or cell line or any suitable fungal, prokaryotic or eukaryotic organism. A host or host cell comprising a nucleic acid encoding the polypeptide of the present technology is also encompassed by the present technology. A nucleic acid may be for example DNA, RNA, or a hybrid thereof, and may also comprise (e.g., chemically) modified nucleotides, like PNA. It can be single- or double-stranded. In one embodiment, it is in the form of double-stranded DNA. For example, the nucleotide sequences of the present technology may be genomic DNA, cDNA. The nucleic acids of the present technology can be prepared or obtained in a manner known per se, and/or can be isolated from a suitable natural source. Nucleotide sequences encoding naturally occurring (poly)peptides can for example be subjected to site-directed mutagenesis, so as to provide a nucleic acid molecule encoding polypeptide with sequence variation. Also, as will be clear to the skilled person, to prepare a nucleic acid, also several nucleotide sequences, such as at least one nucleic acid with a nucleotide sequence encoding a targeting moiety and for example a nucleic acid with a nucleotide sequence encoding one or more linkers can be linked together in a suitable manner. Techniques for generating nucleic acids will be clear to the skilled person and may for instance include, but are not limited to, automated DNA synthesis; site-directed mutagenesis; combining two or more naturally occurring and/or synthetic sequences (or two or more parts thereof), introduction of mutations that lead to the expression of a truncated expression product; introduction of one or more restriction sites (e.g., to create cassettes and/or regions that may easily be digested and/or ligated using suitable restriction enzymes), and/or the introduction of mutations by means of a PCR reaction using one or more “mismatched” primers. 5.5 Vectors Also provided is a vector comprising the nucleic acid molecule encoding the ISVD and/or polypeptide of the present technology. A vector as used herein is a vehicle suitable for carrying genetic material into a cell. A vector includes naked nucleic acids, such as plasmids or mRNAs, or nucleic acids embedded into a bigger structure, such as liposomes or viral vectors. In some embodiments, vectors comprise at least one nucleic acid that is optionally linked to one or more regulatory elements, such as for example one or more suitable promoter(s), enhancer(s), terminator(s), etc.). In one embodiment, the vector is an expression vector, i.e., a vector suitable for expressing an encoded polypeptide or construct under suitable conditions, e.g., when the vector is introduced into a (e.g., human) cell. DNA-based vectors include the presence of elements for transcription (e.g., a promoter and a polyA signal) and translation (e.g., Kozak sequence). In one embodiment, in the vector, said at least one nucleic acid and said regulatory elements are “operably linked” to each other, by which is generally meant that they are in a functional relationship with each other. For instance, a promoter is considered “operably linked” to a coding sequence if said promoter is able to initiate or otherwise control/regulate the transcription and/or the expression of a coding sequence (in which said coding sequence should be understood as being “under the control of” said promotor). Generally, when two nucleotide sequences are operably linked, they will be in the same orientation and usually also in the same reading frame. They will usually also be essentially contiguous, although this may also not be required. In one embodiment, any regulatory elements of the vector are such that they are capable of providing their intended biological function in the intended host cell or host organism. For instance, a promoter, enhancer or terminator should be “operable” in the intended host cell or host organism, by which is meant that for example said promoter should be capable of initiating or otherwise controlling/regulating the transcription and/or the expression of a nucleotide sequence - e.g., a coding sequence - to which it is operably linked. 5.6 Compositions The present technology also provides a composition comprising at least one ISVD of the present technology, at least one polypeptide or construct of the present technology, at least one nucleic acid molecule encoding a polypeptide of the present technology or at least one vector comprising such a nucleic acid molecule. The composition may be a pharmaceutical composition. The composition may further comprise at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and optionally comprise one or more further pharmaceutically active polypeptides and/or compounds. 5.7 Host organisms The present technology also pertains to (non-human) host cells or (non-human) host organisms capable of expressing the ISVD and/or polypeptide of the present technology, or comprising the nucleic acid encoding the ISVD and/or polypeptide of the present technology, and/or the vector comprising the nucleic acid molecule encoding the ISVD and/or polypeptide of the present technology. Suitable host cells or host organisms are clear to the skilled person, and are for example any suitable fungal, prokaryotic or eukaryotic cell or cell line or any suitable fungal, prokaryotic or eukaryotic organism. Specific examples include HEK293 cells, CHO cells, Escherichia coli or Pichia pastoris. In one embodiment, the host is Pichia pastoris. 5.8 Methods and uses of the polypeptide The present technology also provides a method for producing the ISVD and/or polypeptide of the present technology. The method may comprise transforming/transfecting a (non-human) host cell or host organism with a nucleic acid encoding the ISVD and/or polypeptide, expressing the ISVD and/or polypeptide in the host, optionally followed by one or more isolation and/or purification steps. In an embodiment, the method may comprise: a) expressing, in a suitable host cell or (non-human) host organism or in another suitable expression system, a nucleic acid sequence or genetic construct encoding the ISVD and/or polypeptide; optionally followed by: b) isolating and/or purifying the ISVD and/or polypeptide. In another embodiment, the method may comprise: a) cultivating and/or maintaining a (non-human) host or host cell that is capable of expressing the ISVD and/or polypeptide of the present technology and/or that comprises a nucleic acid or a genetic construct encoding the ISVD and/or polypeptide of the present technology, under suitable circumstances that are such that said (non-human) host or host cell is expresses the ISVD and/or polypeptide of the present technology; optionally followed by: b) isolating and/or purifying the ISVD and/or polypeptide produced. Suitable (non-human) host cells or host organisms for production purposes will be clear to the skilled person, and may for example be any suitable fungal, prokaryotic or eukaryotic cell or cell line or any suitable fungal, prokaryotic or eukaryotic organism. Specific examples include HEK293 cells, CHO cells, Escherichia coli or Pichia pastoris. In one embodiment, the host is Pichia pastoris. The ISVD of the present technology, the polypeptide or construct of the present technology, the nucleic acid molecule or vector as described, or the composition comprising the ISVD, polypeptide, construct, nucleic acid molecule or vector of the present technology are useful as a medicament. Accordingly, the present technology provides the ISVD of the present technology, the polypeptide or construct of the present technology, the nucleic acid molecule or vector as described, or the composition comprising the ISVD, polypeptide, construct, nucleic acid molecule or vector of the present technology for use as a medicament. Also provided is the ISVD of the present technology, the polypeptide or construct of the present technology, the nucleic acid molecule or vector as described, or the composition comprising the ISVD, polypeptide, construct, nucleic acid molecule or vector of the present technology for use in the diagnosis, prevention and/or treatment. Also provided is the ISVD of the present technology, the polypeptide or construct of the present technology, the nucleic acid molecule or vector as described, or the composition comprising the ISVD, polypeptide, construct, nucleic acid molecule or vector of the present technology for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder. Also provided is the ISVD of the present technology, the polypeptide or construct of the present technology, the nucleic acid molecule or vector as described, or the composition comprising the ISVD, polypeptide, construct, nucleic acid molecule or vector of the present technology, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved. CEACAM5 is known to play a role in several epithelial tumour types. These cancers are marked by an overexpression of CEACAM5. As such, also provided is the ISVD of the present technology, the polypeptide or construct of the present technology, the nucleic acid molecule or vector as described, or the composition comprising the ISVD, polypeptide, construct, nucleic acid molecule or vector of the present technology for use in the diagnosis, prevention and/or treatment of a cancer. Therefore, also provided is the ISVD of the present technology, the polypeptide or construct of the present technology, the nucleic acid molecule or vector as described, or the composition comprising the ISVD, polypeptide, construct, nucleic acid molecule or vector of the present technology for use in the diagnosis, prevention and/or treatment of cancer. Further provided is a method for the diagnosis, prevention and/or treatment of at least one disease and/or disorder, comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of at least one ISVD of the present technology, at least one polypeptide or construct of the present technology, the nucleic acid molecule or vector as described, or a composition comprising the ISVD, polypeptide, construct, nucleic acid molecule or vector of the present technology. Further provided is a method for the diagnosis, prevention and/or treatment of at least one disease or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved, said method comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of at least one ISVD of the present technology, at least one polypeptide or construct of the present technology, the nucleic acid molecule or vector as described, or a composition comprising the ISVD, polypeptide, construct, nucleic acid molecule or vector of the present technology. Also provided is the ISVD of the present technology, the polypeptide or construct of the present technology, the nucleic acid molecule or vector as described, or the composition comprising the ISVD, polypeptide, construct, nucleic acid molecule or vector of the present technology for use in the internalization of a cell, preferably a human cell. Also provided is the ISVD of the present technology, the polypeptide or construct of the present technology, the nucleic acid molecule or vector as described, or the composition comprising the ISVD, polypeptide, construct, nucleic acid molecule or vector of the present technology for use in the for the intracellular delivery, preferably intracellular delivery in a human cell. Further provided is a method for the internalization of a cell, preferably a human cell, said method comprising the administration of a at least one ISVD of the present technology, at least one polypeptide or construct of the present technology, the nucleic acid molecule or vector as described, or a composition comprising the ISVD, polypeptide, construct, nucleic acid molecule or vector of the present technology. Further provided is a method for intracellular delivery, preferably intracellular delivery in a human cell, said method comprising the administration of a at least one ISVD of the present technology, at least one polypeptide or construct of the present technology, the nucleic acid molecule or vector as described, or a composition comprising the ISVD, polypeptide, construct, nucleic acid molecule or vector of the present technology. Further provided is a method for the diagnosis, prevention and/or treatment of at least one epithelial tumour, said method comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of at least one ISVD of the present technology, at least one polypeptide or construct of the present technology, the nucleic acid molecule or vector as described, or a composition comprising the ISVD, polypeptide, construct, nucleic acid molecule or vector of the present technology. Further provided is the use of the ISVD of the present technology in an in vivo or in vitro diagnostic method of detecting the presence of a cancer in a subject, comprising the steps consisting of: a) administering an ISVD according to the invention labelled to a patient; b) detecting localisation of said labelled ISVD in the patient by imaging. “Labelled ISVD” in this context may refer to the introduction of one or more detectable labels or other signal-generating groups or moieties to the at least one polypeptide or construct of the present technology. Suitable labels and techniques for attaching, using and detecting them will be clear to the skilled person, and for example include, but are not limited to, the fluorescent labels, phosphorescent labels, chemiluminescent labels, bioluminescent labels, radioisotopes, metals, metal chelates, metallic cations, chromophores and enzymes, such as those mentioned on page 109 of WO 08/020079 and e.g., as described earlier. Other suitable labels will be clear to the skilled person, and for example include moieties that can be detected using NMR or ESR spectroscopy. The labelled polypeptide or construct of the present technology may for example be used for in vitro, in vivo or in situ assays (including immunoassays known per se such as ELISA, RIA, EIA and other "sandwich assays", etc.) as well as in vivo diagnostic and imaging purposes, depending on the choice of the specific label to detect the presence of the biomarker CEACAM5. As such, the ISVD of the present technology can be used in an in vitro assay comprising the step of detecting and/or measuring the level of CEACAM 5 in a subject’s sample; and optionally, correlating the measured level of CEACAM5 with the subject disease status. Further provided is a method for the diagnosis, prevention and/or treatment of cancer, said method comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of at least one ISVD of the present technology, at least one polypeptide or construct of the present technology, the nucleic acid molecule or vector as described, or a composition comprising the ISVD, polypeptide, construct, nucleic acid molecule or vector of the present technology. Further provided is the use of the ISVD of the present technology, the polypeptide of the present technology, the nucleic acid molecule or vector as described, or a composition comprising the ISVD, polypeptide, construct, nucleic acid molecule or vector in the preparation of a pharmaceutical composition for the diagnosis, prevention and/or treatment of at least one disease or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved. Further provided is the use of the ISVD of the present technology, the polypeptide of the present technology, the nucleic acid molecule or vector as described, or a composition comprising the ISVD, polypeptide, construct, nucleic acid molecule or vector in the preparation of a pharmaceutical composition for the diagnosis, prevention and/or treatment of at least one cancer. Further provided is the use of the ISVD of the present technology, the polypeptide of the present technology, the nucleic acid molecule or vector as described, or a composition comprising the ISVD, polypeptide, construct, nucleic acid molecule or vector in the preparation of a pharmaceutical composition for the diagnosis, prevention and/or treatment of cancer. A “subject” as referred to in the context of the present technology can be any animal. In one embodiment, the subject is a mammal. Among mammals, a distinction can be made between humans and non-human mammals. Non-human animals may be for example companion animals (e.g., dogs, cats), livestock (e.g., bovine, equine, ovine, caprine, or porcine animals), or animals used generally for research purposes and/or for producing antibodies (e.g., mice, rats, rabbits, cats, dogs, goats, sheep, horses, pigs, non-human primates, such as cynomolgus monkeys, or camelids, such as llama or alpaca). In one embodiment, the subject is a human subject. Substances, including the ISVDs, polypeptides, constructs, nucleic acid molecules and vectors of the present technology, or compositions comprising the same may be administered to a subject by any suitable route of administration, for example by parenteral administration, such as intramuscular, subcutaneous or intradermal, administration. In one embodiment, subcutaneous administration is used. An effective amount of an ISVD, a polypeptide, a construct, a nucleic acid molecule or vector as described herein, or a composition comprising the ISVD, polypeptide, construct, nucleic acid molecule or vector can be administered to a subject in order to provide the intended diagnosis, prevention and/or treatment results. One or more doses can be administered. If more than one dose is administered, the doses can be administered in suitable intervals in order to maximize the effect of the ISVD, polypeptide, construct, composition, nucleic acid molecule or vector.
5.9 Tables Table A-1: Amino acid sequences of the human, and cyno CEACAM5 (“ID” refers to the SEQ ID NO as used herein) Name ID Amino acid sequence Human CEACAM5 26 KLTIESTPFNVAEGKEVLLLVHNLPQHLFGYSWYKGERVDGNRQIIGYVIGTQQ ATPGPAYSGREIIYPNASLLIQNIIQNDTGFYTLHVIKSDLVNEEATGQFRVYPELP KPSISSNNSKPVEDKDAVAFTCEPETQDATYLWWVNNQSLPVSPRLQLSNGNR TLTLFNVTRNDTASYKCETQNPVSARRSDSVILNVLYGPDAPTISPLNTSYRSGE NLNLSCHAASNPPAQYSWFVNGTFQQSTQELFIPNITVNNSGSYTCQAHNSDT GLNRTTVTTITVYAEPPKPFITSNNSNPVEDEDAVALTCEPEIQNTTYLWWVNN QSLPVSPRLQLSNDNRTLTLLSVTRNDVGPYECGIQNELSVDHSDPVILNVLYGP DDPTISPSYTYYRPGVNLSLSCHAASNPPAQYSWLIDGNIQQHTQELFISNITEK NSGLYTCQANNSASGHSRTTVKTITVSAELPKPSISSNNSKPVEDKDAVAFTCEP EAQNTTYLWWVNGQSLPVSPRLQLSNGNRTLTLFNVTRNDARAYVCGIQNSV SANRSDPVTLDVLYGPDTPIISPPDSSYLSGANLNLSCHSASNPSPQYSWRINGIP QQHTQVLFIAKITPNNNGTYACFVSNLATGRNNSIVKSITVSASGTSPGLSA Cyno CEACAM5 27 QLTIESRPFNVAEGKEVLLLAHNVSQNLFGYIWYKGERVDASRRIGSCVIRTQQI TPGPAHSGRETIDFNASLLIQNVTQSDTGSYTIQVIKEDLVNEEATGQFRVYPEL PKPYITSNNSNPIEDKDAVALTCEPETQDTTYLWWVNNQSLPVSPRLELSSDNR TLTVFNIPRNDTTSYKCETQNPVSVRRSDPVTLNVLYGPDAPTISPLNTPYRAGE YLNLTCHAASNPTAQYFWFVNGTFQQSTQELFIPNITVNNSGSYMCQAHNSA TGLNRTTVTAITVYAELPKPYITSNNSNPIEDKDAVTLTCEPETQDTTYLWWVN NQRLSVSSRLELSNDNRTLTVFNIPRNDTTFYECETQNPVSVRRSDPVTLNVLYG PDAPTISPLNTPYRAGENLNLSCHAASNPAAQYFWFVNGTFQQSTQELFIPNIT VNNSGSYMCQAHNSATGLNRTTVTAITVYVELPKPYISSNNSNPIEDKDAVTLT CEPVAENTTYLWWVNNQSLSVSPRLQLSNGNRILTLLSVTRNDTGPYECGIQNS ESAKRSDPVTLNVTYGPDTPIISPPDLSYRSGANLNLSCHSDSNPSPQYSWLING TLRQHTQVLFISKITSNNNGAYACFVSNLATGRNNSIVKNISVSSGDSAPGSSGL SA Human CEACAM5 577 KLTIESTPFNVAEGKEVLLLVHNLPQHLFGYSWYKGERVDGNRQIIGYVIGTQQ ATPGPAYSGREIIYPNASLLIQNIIQNDTGFYTLHVIKSDLVNEEATGQFRVYPELP KPSISSNNSKPVEDKDAVAFTCEPETQDATYLWWVNNQSLPVSPRLQLSNGNR TLTLFNVTRNDTASYKCETQNPVSARRSDSVILNVLYGPDAPTISPLNTSYRSGE NLNLSCHAASNPPAQYSWFVNGTFQQSTQELFIPNITVNNSGSYTCQAHNSDT GLNRTTVTTITVYAEPPKPFITSNNSNPVEDEDAVALTCEPEIQNTTYLWWVNN QSLPVSPRLQLSNDNRTLTLLSVTRNDVGPYECGIQNELSVDHSDPVILNVLYGP DDPTISPSYTYYRPGVNLSLSCHAASNPPAQYSWLIDGNIQQHTQELFISNITEK NSGLYTCQANNSASGHSRTTVKTITVSAELPKPSISSNNSKPVEDKDAVAFTCEP EAQNTTYLWWVNGQSLPVSPRLQLSNGNRTLTLFNVTRNDARAYVCGIQNSV SANRSDPVTLDVLYGPDTPIISPPDSSYLSGANLNLSCHSASNPSPQYSWRINGIP QQHTQVLFIAKITPNNNGTYACFVSNLATGRNNSIVKSITVSASGTSPGLSAHH HHHH Table A-2: Amino acid sequences of the ISVDs binding CEACAM5 (“ID” refers to the SEQ ID NO as used herein) Name ID Amino acid sequence 1D07 (ISVD20) 114 EVQLVESGGGLAQTGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVSAIRWS FAM1 AGSTVYGNSVKGRFAIARTNANNIMYLQMNSLKPEDTAVYYCAAVRPSFRPLSTY WKDYDNWGQGTLVTVSS 5F01 (ISVD11) 115 EVQLVESGGGLVQTGGSLRLSCAASGGAFSTYTMAWFRQTPGNEREFVAALSW FAM2 RSGTTVYGDSVKGRFTISRVIAENTVYLQMNSLKPEDTAVYFCAAQQYGAISYNRN GFFYWGQGTLVTVSS 6F03 (ISVD12) 116 EVQLVESGGGLVQAGGSLRLSCVASGRAFSTYTMAWFRQTPGNEREFVATISWR FAM2 SEITVYGDSVKGRFTISRDKAENTVYLQMNSLKPEDTAVYFCAAQEFGAISYNTKG YFYWGQGTLVTVSS 2G08 (ISVD16) 117 EVQLVESGGGLVQAGGSLRLSCAASGRAFSTYTMAWFRQTPGNEREFVATISWR FAM2 SEITVYGDSVKGRFTISRDNAENTVYLQMNSLRPEDTAVYFCAAQEFGAISYNRKG YFYWGQGTLVTVSS 2G06 (ISVD19) 118 EVQLVESGGGLVQAGDSLRLSCAASGLTFSTYTMGWFRQAPGKEREFVASIIWSG FAM3 SNTVYADSVKGRFTISRENAKNTVYLQMNSLKPEDTAVYHCAAQHFGPVSLTTRG YYYWGQGTLVTVSS 2C10 (ISVD7) 119 EVQLVESGGGLVQAGDSLRLSCAASGLTFSTYTVGWFRQAPGKEREFVGSMIYSG FAM3 SNTLYADSVKGRFTISRDNAKNTVFLQMNSLKPEDTAVYHCAAQHFGPISLTTRGY FYWGQGTLVTVSS 1C02 (ISVD1) 120 EVQLVESGGGLVQAGDSLRLSCSASGRTFSDYAMGWFRQAPGMEREFVAAINW FAM4 GGTWTYYAHSVQGRFTISRGNAKNTLYLQMNSLKPEDTAGYYCAASLDYAGGSP TGYAYWGQGTLVTVSS 24B02 (ISVD3) 16 EVQLVESGGGLVQAGDSLRLSCSASGHTFSEYALGWFRQAPGMEREFVAAINW FAM4 GGGWTYYADSVQGRFTISRDNAKNTLYLQMNSLKPGDTAGYYCAASSDYAGGN PTGYPYWGQGTLVTVSS 26D05 (ISVD13) 121 EVQLVESGGGLVLAGDSLRLSCSASGRTFSDYAMGWFRQAPGMEREFVAAINW FAM4 GGSWTYYAHSVQGRFTISRDNAKNTLYLQMNSLKPEDTASYYCAASPDYAGGNP TGYAYWGQGTLVTVSS 1C11 (ISVD6) 122 EVQLVESGGGLVQAGDSLRLSCLASGRTFSDFAMGWFRQAPGMEREFVAAINW FAM5 SGGWTYYADSVQGRFTISRDNTKNTLYLQMNSLKPEDTAAYYCAASSDYAGGRS TGYDYWGQGTLVTVSS 4G01 (ISVD10) 123 EVQLVESGGGLVQAGDSLRLSCSASGRTFSDYAMGWFRQAPGMEREFVAAINW FAM5 SGGWTYYADSVQGRFTISRDNTKNTLYLQMNSLKPEDTAAYYCAASSDYAGGRS TGYAYWGQGTLVTVSS 25D01 (ISVD5) 124 EVQLVESGGGLVQTGGSLILSCAASGRTFNINEYHLAWFRQAPGKEREFLAAIWW FAM9 STGNKIVADSVKGRFAISRSSRINTVNLQMNNLKREDTAVYYCAAVRFSFRPLSTY WKDYDNWGQGTLVTVSS 20C01 (ISVD2) 125 EVQLVESGGGLVQTGGSLRLSCAASGRTLNDYHMAWFRQAPGKEREFQAAIW FAM17 WSTGNRIVADSVKGRFAVSRSNAGNTIYLQMNSLKPEDTAVYYCAAVRFSFRPLS TYWKDYDIWGQGTLVTVSS 26B01 (ISVD15) 126 EVQLVESGGGSVQTGGSLRLSCAASGDTLNSYHMAWFRQAPRKEREFLSAIWW FAM18 STGNAIVADSVKGRFAISKSNALNTVYLQMNSLKPEDTAVYYCAAVRFSFRPLSTY WKDYDNWGQGTLVTVSS Name ID Amino acid sequence 8B03 (ISVD17) 127 EVQLVESGGGSVQTGGSLRLSCAASGDNLNSYHMAWFRQAPGKNRDFLSAIW FAM18 WSTGNTIVADSVKGRFAISKSNALNTVYLQMNTLKPEDTAVYYCAAVRFQFRPLS TYWKDYDNWGQGTLVTVSS 3D09 (ISVD8) 128 EVQLVESGGGLVQAGGSLRLSCAASGGTFSSYAMGWFRQAPGKEREFVAGMS FAM19 WSGGSTHYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCTRGQNPMGPI ATRPSVHDYWGQGTLVTVSS 9B07 (ISVD18) 129 EVQLVESGGGLVQAGGSLRLSCAASGRTFSNYAMGWFRQAPGKEREFVAGMS FAM19 WSGGSTHYADSVKGRFAISRDNAKNTVYLQMNSLKPEDTAVYYCTVGRNPMGPI ATRPSVHDYWGQGTLVTVSS 3F04 (ISVD9) 130 EVQLVESGGGLVRAGDSLRLSCAASGGTVSTYTMGWFRQAPGKEREFVGSIIWS FAM27 GSTTVYADSVKGRSTISRDNAKNTVYLQMNSLKPEDTAVYYCAAQHFGPVSQTTK GYFYWGQGTLVTVSS 21A01 (ISVD14) 131 EVQLVESGGGLVQTGGSLRLSCAASGRTLNDYHMAWFRQAPGKEREFLSAIWW FAM28 STGNTIVADSVKGRFASSKTNAGVYLQMNSLKPEDTAVYYCAAVRFSFRPLSTYW KDYDNWGQGTLVTVSS 7E07 (ISVD4) 8 EVQLVESGGGLVQPGGSLRLSCAASGLTFSTYTMGWFRQAPGKEREFVAAIIWSG FAM30 SNTYYADSVKGRFTISRDNAKSTVYLQMNNLEPEDTAVYHCAAQHFGPIGLTTRG YNYWGQGTLVTVSS 14R0410 547 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQPPGKGIEWVSTINRG FAM 14 GSSTSYRVPVEGRFTISRDNAENTLYLQMNSLKTEDTAVYYCTTGDHRGPWYNRG QGTLVTVSS T232000134 548 EVQLVESGGGLVQAGGSLRLSCAASGRTFDNHAMGWFRQTPGKEREFVAGITW FAM 13 RGGSTHYADSVKGRFTISRDNAKNTLYLEMNSLKPEDTAVYYCTADLRPFGPITTT PQRINYWGQGTLVTVSS
Table A-3: Amino acid sequences of the 24B02-based sequence optimized ISVDs binding CEACAM5 (“ID” refers to the SEQ ID NO as used herein) – FAM4 Name Description ID Amino acid sequence 24B02 (ISVD3) Parental 16 EVQLVESGGGLVQAGDSLRLSCSASGHTFSEYALGWFRQAPGMEREFVAAINWGGGWTYYAD SVQGRFTISRDNAKNTLYLQMNSLKPGDTAGYYCAASSDYAGGNPTGYPYWGQGTLVTVSS A031500086 24B02(L11V,A14P,D16G,K83R,G89 135 EVQLVESGGGVVQPGGSLRLSCSASGHTFSEYALGWFRQAPGMEREFVAAINWGGGWTYYAD L) SVQGRFTISRDNAKNTLYLQMNSLRPGDTALYYCAASSDYAGGNPTGYPYWGQGTLVTVSS A031500087 24B02(L11V,A14P,D16G,K83R,G85 136 EVQLVESGGGVVQPGGSLRLSCSASGHTFSEYALGWFRQAPGMEREFVAAINWGGGWTYYAD E,G89L) SVQGRFTISRDNAKNTLYLQMNSLRPEDTALYYCAASSDYAGGNPTGYPYWGQGTLVTVSS A031500088 24B02(L11V,A14P,D16G,Q64K,K83 137 EVQLVESGGGVVQPGGSLRLSCSASGHTFSEYALGWFRQAPGMEREFVAAINWGGGWTYYAD R,G89L) SVKGRFTISRDNAKNTLYLQMNSLRPGDTALYYCAASSDYAGGNPTGYPYWGQGTLVTVSS A031500089 24B02(L11V,A14P,D16G,M43K,K83 138 EVQLVESGGGVVQPGGSLRLSCSASGHTFSEYALGWFRQAPGKEREFVAAINWGGGWTYYAD R,G89L) SVQGRFTISRDNAKNTLYLQMNSLRPGDTALYYCAASSDYAGGNPTGYPYWGQGTLVTVSS A031500090 24B02(L11V,A14P,D16G,M43K,K83 139 EVQLVESGGGVVQPGGSLRLSCSASGHTFSEYALGWFRQAPGKEREFVAAINWGGGWTYYAD R,G85E,G89L) SVQGRFTISRDNAKNTLYLQMNSLRPEDTALYYCAASSDYAGGNPTGYPYWGQGTLVTVSS A031500091 24B02(L11V,A14P,D16G,M43K,Q6 140 EVQLVESGGGVVQPGGSLRLSCSASGHTFSEYALGWFRQAPGKEREFVAAINWGGGWTYYAD 4K,K83R,G89L) SVKGRFTISRDNAKNTLYLQMNSLRPGDTALYYCAASSDYAGGNPTGYPYWGQGTLVTVSS A031500092 24B02(L11V,A14P,D16G,S23A,K83 141 EVQLVESGGGVVQPGGSLRLSCAASGHTFSEYALGWFRQAPGMEREFVAAINWGGGWTYYA R,G89L) DSVQGRFTISRDNAKNTLYLQMNSLRPGDTALYYCAASSDYAGGNPTGYPYWGQGTLVTVSS A031500093 24B02(L11V,A14P,D16G,S23A,K83 142 EVQLVESGGGVVQPGGSLRLSCAASGHTFSEYALGWFRQAPGMEREFVAAINWGGGWTYYA R,G85E,G89L) DSVQGRFTISRDNAKNTLYLQMNSLRPEDTALYYCAASSDYAGGNPTGYPYWGQGTLVTVSS A031500094 24B02(L11V,A14P,D16G,S23A,Q64 143 EVQLVESGGGVVQPGGSLRLSCAASGHTFSEYALGWFRQAPGMEREFVAAINWGGGWTYYA K,K83R,G89L) DSVKGRFTISRDNAKNTLYLQMNSLRPGDTALYYCAASSDYAGGNPTGYPYWGQGTLVTVSS A031500095 24B02(L11V,A14P,D16G,S23A,Q64 144 EVQLVESGGGVVQPGGSLRLSCAASGHTFSEYALGWFRQAPGMEREFVAAINWGGGWTYYA K,K83R,G85E,G89L) DSVKGRFTISRDNAKNTLYLQMNSLRPEDTALYYCAASSDYAGGNPTGYPYWGQGTLVTVSS A031500096 24B02(L11V,A14P,D16G,S23A,M43 145 EVQLVESGGGVVQPGGSLRLSCAASGHTFSEYALGWFRQAPGKEREFVAAINWGGGWTYYAD K,K83R,G89L) SVQGRFTISRDNAKNTLYLQMNSLRPGDTALYYCAASSDYAGGNPTGYPYWGQGTLVTVSS A031500097 24B02(L11V,A14P,D16G,S23A,M43 146 EVQLVESGGGVVQPGGSLRLSCAASGHTFSEYALGWFRQAPGKEREFVAAINWGGGWTYYAD K,K83R,G85E,G89L) SVQGRFTISRDNAKNTLYLQMNSLRPEDTALYYCAASSDYAGGNPTGYPYWGQGTLVTVSS
Name Description ID Amino acid sequence A031500098 24B02(L11V,A14P,D16G,S23A,M43 147 EVQLVESGGGVVQPGGSLRLSCAASGHTFSEYALGWFRQAPGKEREFVAAINWGGGWTYYAD K,Q64K,K83R,G89L) SVKGRFTISRDNAKNTLYLQMNSLRPGDTALYYCAASSDYAGGNPTGYPYWGQGTLVTVSS A031500099 (ISVD21) 24B02(L11V,A14P,D16G,S23A,M43 39 EVQLVESGGGVVQPGGSLRLSCAASGHTFSEYALGWFRQAPGKEREFVAAINWGGGWTYYAD T028501817 K,Q64K,K83R,G85E,G89L) SVKGRFTISRDNAKNTLYLQMNSLRPEDTALYYCAASSDYAGGNPTGYPYWGQGTLVTVSS A031500099 (E1D) 24B02(E1D,L11V,A14P,D16G,S23A, 40 DVQLVESGGGVVQPGGSLRLSCAASGHTFSEYALGWFRQAPGKEREFVAAINWGGGWTYYAD T028501817(E1D) M43K,Q64K,K83R,G85E,G89L) SVKGRFTISRDNAKNTLYLQMNSLRPEDTALYYCAASSDYAGGNPTGYPYWGQGTLVTVSS A031500100 24B02(L11V,A14P,D16G,M43K,Q6 148 EVQLVESGGGVVQPGGSLRLSCSASGHTFSEYALGWFRQAPGKEREFVAAINWGGGWTYYAD 4K,K83R,G85E,G89L) SVKGRFTISRDNAKNTLYLQMNSLRPEDTALYYCAASSDYAGGNPTGYPYWGQGTLVTVSS A031500101 24B02(L11V,A14P,D16G,Q64K,K83 149 EVQLVESGGGVVQPGGSLRLSCSASGHTFSEYALGWFRQAPGMEREFVAAINWGGGWTYYAD R,G85E,G89L) SVKGRFTISRDNAKNTLYLQMNSLRPEDTALYYCAASSDYAGGNPTGYPYWGQGTLVTVSS
Table A-4: Amino acid sequences of the 7E07-based sequence optimized ISVDs binding CEACAM5 (“ID” refers to the SEQ ID NO as used herein) – FAM30 Name ID Amino acid sequence 7E07 (ISVD4) Parental 8 EVQLVESGGGLVQPGGSLRLSCAASGLTFSTYTMGWFRQAPGKEREFVAAIIWSGSNTYYADSVKGRFTIS RDNAKSTVYLQMNNLEPEDTAVYHCAAQHFGPIGLTTRGYNYWGQGTLVTVSS A031500251 7E07(L11V,N82bS,E83R,V89L) 150 EVQLVESGGGVVQPGGSLRLSCAASGLTFSTYTMGWFRQAPGKEREFVAAIIWSGSNTYYADSVKGRFTIS RDNAKSTVYLQMNSLRPEDTALYHCAAQHFGPIGLTTRGYNYWGQGTLVTVSS A031500252 7E07(L11V,S76N,N82bS,E83R, 151 EVQLVESGGGVVQPGGSLRLSCAASGLTFSTYTMGWFRQAPGKEREFVAAIIWSGSNTYYADSVKGRFTIS V89L) RDNAKNTVYLQMNSLRPEDTALYHCAAQHFGPIGLTTRGYNYWGQGTLVTVSS A031500253 7E07(L11V,N82bS,E83R,V89L, 152 EVQLVESGGGVVQPGGSLRLSCAASGLTFSTYTMGWFRQAPGKEREFVAAIIWSGSNTYYADSVKGRFTIS H91Y) RDNAKSTVYLQMNSLRPEDTALYYCAAQHFGPIGLTTRGYNYWGQGTLVTVSS A031500254 7E07(L11V,S76N,N82bS,E83R, 153 EVQLVESGGGVVQPGGSLRLSCAASGLTFSTYTMGWFRQAPGKEREFVAAIIWSGSNTYYADSVKGRFTIS V89L,H91Y) RDNAKNTVYLQMNSLRPEDTALYYCAAQHFGPIGLTTRGYNYWGQGTLVTVSS A031500379 7E07(L11V,S76N,N82bS,E83R, 154 EVQLVESGGGVVQPGGSLRLSCAASGLTFSTYTMGWFRQAPGKEREFVAAIIWSGSNTYYADSVKGRFTIS V89L,H91Y,N101A) RDNAKNTVYLQMNSLRPEDTALYYCAAAQHFGPIGLTTRGYAYWGQGTLVTVSS A031500382 7E07(L11V,S76N,N82bS,E83R, 155 EVQLVESGGGVVQPGGSLRLSCAASGLTFSTYTMGWFRQAPGKEREFVAAIIWSGSNTYYADSVKGRFTIS V89L,H91Y,N101F) RDNAKNTVYLQMNSLRPEDTALYYCAAQHFGPIGLTTRGYFYWGQGTLVTVSS A031500383 7E07(L11V,S76N,N82bS,E83R, 156 EVQLVESGGGVVQPGGSLRLSCAASGLTFSTYTMGWFRQAPGKEREFVAAIIWSGSNTYYADSVKGRFTIS V89L,H91Y,N101G) RDNAKNTVYLQMNSLRPEDTALYYCAAQHFGPIGLTTRGYGYWGQGTLVTVSS A031500384 7E07(L11V,S76N,N82bS,E83R, 31 EVQLVESGGGVVQPGGSLRLSCAASGLTFSTYTMGWFRQAPGKEREFVAAIIWSGSNTYYADSVKGRFTIS (ISVD22) V89L,H91Y,N101H) RDNAKNTVYLQMNSLRPEDTALYYCAAQHFGPIGLTTRGYHYWGQGTLVTVSS T028501789 A031500384 (E1D) 7E07(E1D, 32 DVQLVESGGGVVQPGGSLRLSCAASGLTFSTYTMGWFRQAPGKEREFVAAIIWSGSNTYYADSVKGRFTIS T028501789(E1D) L11V,S76N,N82bS,E83R,V89L, RDNAKNTVYLQMNSLRPEDTALYYCAAQHFGPIGLTTRGYHYWGQGTLVTVSS H91Y,N101H) A031500385 7E07(L11V,S76N,N82bS,E83R, 157 EVQLVESGGGVVQPGGSLRLSCAASGLTFSTYTMGWFRQAPGKEREFVAAIIWSGSNTYYADSVKGRFTIS V89L,H91Y,N101I) RDNAKNTVYLQMNSLRPEDTALYYCAAQHFGPIGLTTRGYIYWGQGTLVTVSS A031500387 7E07(L11V,S76N,N82bS,E83R, 158 EVQLVESGGGVVQPGGSLRLSCAASGLTFSTYTMGWFRQAPGKEREFVAAIIWSGSNTYYADSVKGRFTIS V89L,H91Y,N101L) RDNAKNTVYLQMNSLRPEDTALYYCAAQHFGPIGLTTRGYLYWGQGTLVTVSS
Name ID Amino acid sequence A031500394 7E07(L11V,S76N,N82bS,E83R, 159 EVQLVESGGGVVQPGGSLRLSCAASGLTFSTYTMGWFRQAPGKEREFVAAIIWSGSNTYYADSVKGRFTIS V89L,H91Y,N101Y) RDNAKNTVYLQMNSLRPEDTALYYCAAQHFGPIGLTTRGYYYWGQGTLVTVSS
Table A-5: Amino acid sequences of the 2G08-based sequence optimized ISVDs binding CEACAM5 (“ID” refers to the SEQ ID NO as used herein) – FAM2 Name ID Amino acid sequence 2G08 (ISVD16) Parental 117 EVQLVESGGGLVQAGGSLRLSCAASGRAFSTYTMAWFRQTPGNEREFVATISWRSEITVYGDSVKGRFTI SRDNAENTVYLQMNSLRPEDTAVYFCAAQEFGAISYNRKGYFYWGQGTLVTVSS A031500333 2G08(L11V,A14P,V89L) 160 EVQLVESGGGVVQPGGSLRLSCAASGRAFSTYTMAWFRQTPGNEREFVATISWRSEITVYGDSVKGRFTI SRDNAENTVYLQMNSLRPEDTALYFCAAQEFGAISYNRKGYFYWGQGTLVTVSS A031500334 2G08(L11V,A14P,T40A,V89L,F91Y) 161 EVQLVESGGGVVQPGGSLRLSCAASGRAFSTYTMAWFRQAPGNEREFVATISWRSEITVYGDSVKGRFTI SRDNAENTVYLQMNSLRPEDTALYYCAAQEFGAISYNRKGYFYWGQGTLVTVSS A031500335 2G08(L11V,A14P,T40A,E75K,V89L, 162 EVQLVESGGGVVQPGGSLRLSCAASGRAFSTYTMAWFRQAPGNEREFVATISWRSEITVYGDSVKGRFTI F91Y) SRDNAKNTVYLQMNSLRPEDTALYYCAAQEFGAISYNRKGYFYWGQGTLVTVSS A031500336 2G08(L11V,A14P,T40A,G60A,V89L, 163 EVQLVESGGGVVQPGGSLRLSCAASGRAFSTYTMAWFRQAPGNEREFVATISWRSEITVYADSVKGRFTI F91Y) SRDNAENTVYLQMNSLRPEDTALYYCAAQEFGAISYNRKGYFYWGQGTLVTVSS A031500337 2G08(L11V,A14P,T40A,G60A,E75K, 164 EVQLVESGGGVVQPGGSLRLSCAASGRAFSTYTMAWFRQAPGNEREFVATISWRSEITVYADSVKGRFTI V89L,F91Y) SRDNAKNTVYLQMNSLRPEDTALYYCAAQEFGAISYNRKGYFYWGQGTLVTVSS A031500338 2G08(L11V,A14P,T40A,N43K,V89L, 165 EVQLVESGGGVVQPGGSLRLSCAASGRAFSTYTMAWFRQAPGKEREFVATISWRSEITVYGDSVKGRFTI F91Y) SRDNAENTVYLQMNSLRPEDTALYYCAAQEFGAISYNRKGYFYWGQGTLVTVSS A031500339 2G08(L11V,A14P,T40A,N43K,E75K, 166 EVQLVESGGGVVQPGGSLRLSCAASGRAFSTYTMAWFRQAPGKEREFVATISWRSEITVYGDSVKGRFTI V89L,F91Y) SRDNAKNTVYLQMNSLRPEDTALYYCAAQEFGAISYNRKGYFYWGQGTLVTVSS A031500340 2G08(L11V,A14P,T40A,N43K,G60A 167 EVQLVESGGGVVQPGGSLRLSCAASGRAFSTYTMAWFRQAPGKEREFVATISWRSEITVYADSVKGRFTI ,V89L,F91Y) SRDNAENTVYLQMNSLRPEDTALYYCAAQEFGAISYNRKGYFYWGQGTLVTVSS A031500341 2G08(L11V,A14P,T40A,N43K,G60A 168 EVQLVESGGGVVQPGGSLRLSCAASGRAFSTYTMAWFRQAPGKEREFVATISWRSEITVYADSVKGRFTI (ISVD23) ,E75K,V89L,F91Y) SRDNAKNTVYLQMNSLRPEDTALYYCAQEFGAISYNRKGYFYWGQGTLVTVSS A031500342 2G08(L11V,A14P,T40A,V89L) 169 EVQLVESGGGVVQPGGSLRLSCAASGRAFSTYTMAWFRQAPGNEREFVATISWRSEITVYGDSVKGRFTI SRDNAENTVYLQMNSLRPEDTALYFCAAQEFGAISYNRKGYFYWGQGTLVTVSS A031500343 2G08(L11V,A14P,V89L,F91Y) 170 EVQLVESGGGVVQPGGSLRLSCAASGRAFSTYTMAWFRQTPGNEREFVATISWRSEITVYGDSVKGRFTI SRDNAENTVYLQMNSLRPEDTALYYCAAQEFGAISYNRKGYFYWGQGTLVTVSS
Table A-6: Amino acid sequences of the 2G06-based sequence optimized ISVDs binding CEACAM5 (“ID” refers to the SEQ ID NO as used herein) – FAM3 Name ID Amino acid sequence 2G06 (ISVD19) 118 EVQLVESGGGLVQAGDSLRLSCAASGLTFSTYTMGWFRQAPGKEREFVASIIWSGSNTVYADSVKGRFTIS RENAKNTVYLQMNSLKPEDTAVYHCAAQHFGPVSLTTRGYYYWGQGTLVTVSS A031500010 2G06(L11V,A14P,D16G,K83R, 171 EVQLVESGGGVVQPGGSLRLSCAASGLTFSTYTMGWFRQAPGKEREFVASIIWSGSNTVYADSVKGRFTIS V89L) RENAKNTVYLQMNSLRPEDTALYHCAAQHFGPVSLTTRGYYYWGQGTLVTVSS A031500011 2G06(L11V,A14P,D16G,E72D, 172 EVQLVESGGGVVQPGGSLRLSCAASGLTFSTYTMGWFRQAPGKEREFVASIIWSGSNTVYADSVKGRFTIS K83R,V89L) RDNAKNTVYLQMNSLRPEDTALYHCAAQHFGPVSLTTRGYYYWGQGTLVTVSS A031500012 2G06(L11V,A14P,D16G,K83R, 173 EVQLVESGGGVVQPGGSLRLSCAASGLTFSTYTMGWFRQAPGKEREFVASIIWSGSNTVYADSVKGRFTIS V89L,H91Y) RENAKNTVYLQMNSLRPEDTALYYCAAQHFGPVSLTTRGYYYWGQGTLVTVSS A031500013 2G06(L11V,A14P,D16G,E72D, 174 EVQLVESGGGVVQPGGSLRLSCAASGLTFSTYTMGWFRQAPGKEREFVASIIWSGSNTVYADSVKGRFTIS (ISVD24) K83R,V89L,H91Y) RDNAKNTVYLQMNSLRPEDTALYYCAAQHFGPVSLTTRGYYYWGQGTLVTVSS
Table A-7: Amino acid sequences of the 1D07-based sequence optimized ISVDs binding CEACAM5 (“ID” refers to the SEQ ID NO as used herein) - FAM1 Name ID Amino acid sequence 1D07 (ISVD20) Parental 114 EVQLVESGGGLAQTGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVSAIRWSAGSTVYGNSVKGRF AIARTNANNIMYLQMNSLKPEDTAVYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS A031500014 1D07(L11V,A12V,T14P,K83R,V89L) EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVSAIRWSAGSTVYGNSVKGRF 175 AIARTNANNIMYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS A031500015 1D07(L11V,A12V,T14P,S49A,K83R,V EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVAAIRWSAGSTVYGNSVKGRF 89L) 176 AIARTNANNIMYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS A031500016 1D07(L11V,A12V,T14P,G60A,K83R,V EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVSAIRWSAGSTVYANSVKGRF 89L) 177 AIARTNANNIMYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS A031500017 1D07(L11V,A12V,T14P,N61D,K83R,V EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVSAIRWSAGSTVYGDSVKGRF 89L) 178 AIARTNANNIMYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS A031500018 1D07(L11V,A12V,T14P,A68T,K83R,V EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVSAIRWSAGSTVYGNSVKGRF 89L) 179 TIARTNANNIMYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS A031500019 1D07(L11V,A12V,T14P,A70S,K83R,V EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVSAIRWSAGSTVYGNSVKGRF 89L) 180 AISRTNANNIMYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS A031500020 1D07(L11V,A12V,T14P,T72D,K83R,V EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVSAIRWSAGSTVYGNSVKGRF 89L) 181 AIARDNANNIMYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS A031500021 1D07(L11V,A12V,T14P,N75K,K83R,V EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVSAIRWSAGSTVYGNSVKGRF 89L) 182 AIARTNAKNIMYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS A031500022 1D07(L11V,A12V,T14P,I77T,K83R,V8 EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVSAIRWSAGSTVYGNSVKGRF 9L) 183 AIARTNANNTMYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS A031500023 1D07(L11V,A12V,T14P,M78V,K83R, EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVSAIRWSAGSTVYGNSVKGRF V89L) 184 AIARTNANNIVYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS A031500024 1D07(L11V,A12V,T14P,M78L,K83R,V EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVSAIRWSAGSTVYGNSVKGRF 89L) 185 AIARTNANNILYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS A031500025 1D07(L11V,A12V,T14P,G60A,N61D, EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVSAIRWSAGSTVYADSVKGRF K83R,V89L) 186 AIARTNANNIMYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS
Name ID Amino acid sequence A031500026 1D07(L11V,A12V,T14P,A68T,A70S,K EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVSAIRWSAGSTVYGNSVKGRF 83R,V89L) 187 TISRTNANNIMYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS A031500027 1D07(L11V,A12V,T14P,A68T,A70S,N EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVSAIRWSAGSTVYGNSVKGRF 75K,K83R,V89L) 188 TISRTNAKNIMYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS A031500028 1D07(L11V,A12V,T14P,A68T,A70S,N EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVSAIRWSAGSTVYGNSVKGRF 75K,I77T,K83R,V89L) 189 TISRTNAKNTMYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS A031500029 1D07(L11V,A12V,T14P,A68T,A70S,T EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVSAIRWSAGSTVYGNSVKGRF 72D,N75K,I77T,K83R,V89L) 190 TISRDNAKNTMYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS A031500030 1D07(L11V,A12V,T14P,G60A,A68T,A EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVSAIRWSAGSTVYANSVKGRF 70S,T72D,N75K,I77T,K83R,V89L) 191 TISRDNAKNTMYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS A031500031 1D07(L11V,A12V,T14P,G60A,N61D, EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVSAIRWSAGSTVYADSVKGRF A68T,A70S,T72D,N75K,I77T,K83R,V8 TISRDNAKNTMYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS 9L) 192 A031500032 1D07(L11V,A12V,T14P,G60A,N61D, EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVSAIRWSAGSTVYADSVKGRF A68T,A70S,T72D,N75K,I77T,M78V,K TISRDNAKNTVYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS 83R,V89L) 193 A031500033 1D07(L11V,A12V,T14P,G60A,N61D, EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVSAIRWSAGSTVYADSVKGRF A68T,A70S,T72D,N75K,I77T,M78L,K TISRDNAKNTLYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS 83R,V89L) 194 A031500034 1D07(L11V,A12V,T14P,A68T,A70S,T EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVSAIRWSAGSTVYGNSVKGRF 72D,N75K,I77T,M78V,K83R,V89L) 195 TISRDNAKNTVYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS A031500035 1D07(L11V,A12V,T14P,A68T,A70S,T EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVSAIRWSAGSTVYGNSVKGRF 72D,N75K,I77T,M78L,K83R,V89L) 196 TISRDNAKNTLYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS A031500368 1D07(L11V,A12V,T14P,G60A,N61D, EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVSAIRWSAGSTVYADSVKGRF A68T,A70S,M78L,K83R,V89L) 197 TISRTNANNILYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS A031500369 1D07(L11V,A12V,T14P,S49A,G60A,N EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVAAIRWSAGSTVYADSVKGRF 61D,A68T,A70S,M78L,K83R,V89L) 198 TISRTNANNILYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS
Name ID Amino acid sequence A031500370 1D07(L11V,A12V,T14P,G60A,N61D, EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVSAIRWSAGSTVYADSVKGRF A68T,A70S,T72D,M78L,K83R,V89L) 199 TISRDNANNILYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS A031500345 1D07(L11V,A12V,T14P,S49A,G60A,N EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVAAIRWSAGSTVYADSVKGRF 61D,A68T,A70S,T72D,I77T,M78L,K8 TISRDNANNTLYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS 3R,V89L) 200 A031500346 1D07(L11V,A12V,T14P,S49A,G60A,N EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVAAIRWSAGSTVYADSVKGRF 61D,A68T,A70S,T72D,N75K,M78L,K TISRDNAKNILYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS 83R,V89L) 201 A031500347 1D07(L11V,A12V,T14P,S49A,G60A,N EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVAAIRWSAGSTVYADSVKGRF 61D,A68T,A70S,T72D,M78L,K83R,V8 TISRDNANNILYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS 9L) 202 A031500348 1D07(L11V,A12V,T14P,S49A,G60A,N EVQLVESGGGVVQPGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVAAIRWSAGSTVYADSVKGRF 61D,A68T,A70S,T72D,N75K,I77T,M7 TISRDNAKNTLYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS 8L,K83R,V89L) 203 A031500406 1D07(L11V,A12V,T14P,N30E,G60A, EVQLVESGGGVVQPGGSLRLSCAASGRTFESYDMGWFRQAPGKEREFVSAIRWSAGSTVYADSVKGRF N61D,A68T,A70S,M78L,K83R,V89L) 204 TISRTNANNILYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS A031500407 1D07(L11V,A12V,T14P,N30G,G60A, EVQLVESGGGVVQPGGSLRLSCAASGRTFGSYDMGWFRQAPGKEREFVSAIRWSAGSTVYADSVKGRF N61D,A68T,A70S,M78L,K83R,V89L) 205 TISRTNANNILYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS A031500408 1D07(L11V,A12V,T14P,N30P,G60A, EVQLVESGGGVVQPGGSLRLSCAASGRTFPSYDMGWFRQAPGKEREFVSAIRWSAGSTVYADSVKGRF N61D,A68T,A70S,M78L,K83R,V89L) 206 TISRTNANNILYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS A031500409 1D07(L11V,A12V,T14P,N30S,G60A,N EVQLVESGGGVVQPGGSLRLSCAASGRTFSSYDMGWFRQAPGKEREFVSAIRWSAGSTVYADSVKGRF (ISVD25) 61D,A68T,A70S,M78L,K83R,V89L) 207 TISRTNANNILYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS A031500410 1D07(L11V,A12V,T14P,N30T,G60A, EVQLVESGGGVVQPGGSLRLSCAASGRTFTSYDMGWFRQAPGKEREFVSAIRWSAGSTVYADSVKGRF N61D,A68T,A70S,M78L,K83R,V89L) 208 TISRTNANNILYLQMNSLRPEDTALYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSS
Table A-8: Sequences for CDRs according to AbM numbering and frameworks (“ID” refers to the given SEQ ID NO) ID VHH ID FR1 ID CDR1 ID FR2 ID CDR2 ID FR3 ID CDR3 ID FR4 120 A0315001C0401 EVQLVESGGGLV 234 GRTFSDY 13 WFRQAPG 235 AINWGG 402 YAHSVQGRFTISRGNAKNTLY 236 SLDYAGGSPT 7 WGQGT 2 QAGDSLRLSCSAS AMG MEREFVA TWTY LQMNSLKPEDTAGYYCAA GYAY LVTVSS 16 A0315024B012 EVQLVESGGGLV 9 GHTFSEY 13 WFRQAPG 10 AINWGG 14 YADSVQGRFTISRDNAKNTLY 11 SSDYAGGNP 7 WGQGT 2 QAGDSLRLSCAAS ALG MEREFVA GWTY LQMNSLKPGDTAGYYCAA TGYPY LVTVSS 121 A0315026D0403 EVQLVESGGGLVL 234 GRTFSDY 13 WFRQAPG 238 AINWGG 404 YAHSVQGRFTISRDNAKNTLY 239 SPDYAGGNP 7 WGQGT 5 AGDSLRLSCSAS AMG MEREFVA SWTY LQMNSLKPEDTASYYCAA TGYAY LVTVSS 122 A0315001C1405 EVQLVESGGGLV 359 GRTFSDF 13 WFRQAPG 357 AINWSG 406 YADSVQGRFTISRDNTKNTLY 360 SSDYAGGRST 7 WGQGT 1 QAGDSLRLSCLAS AMG MEREFVA GWTY LQMNSLKPEDTAAYYCAA GYDY LVTVSS 123 A0315004G0401 EVQLVESGGGLV 234 GRTFSDY 13 WFRQAPG 357 AINWSG 406 YADSVQGRFTISRDNTKNTLY 361 SSDYAGGRST 7 WGQGT 1 QAGDSLRLSCSAS AMG MEREFVA GWTY LQMNSLKPEDTAAYYCAA GYAY LVTVSS 124 A0315025D0407 EVQLVESGGGLV 363 GRTFNIN 408 WFRQAPG 364 AIWWST 409 VADSVKGRFAISRSSRINTVNL 365 VRFSFRPLST 7 WGQGT 1 QTGGSLILSCAAS EYHLA KEREFLA GNKI QMNNLKREDTAVYYCAA YWKDYDN LVTVSS 125 A0315020C0346 EVQLVESGGGLV 368 GRTLNDY 412 WFRQAPG 369 AIWWST 410 VADSVKGRFAVSRSNAGNTIY 370 VRFSFRPLST 7 WGQGT 1 QTGGSLRLSCAAS HMA KEREFQA GNRI LQMNSLKPEDTAVYYCAA YWKDYDI LVTVSS 126 A0315026B0411 EVQLVESGGGSV 376 GDTLNSY 413 WFRQAPR 377 AIWWST 414 VADSVKGRFAISKSNALNTVY 365 VRFSFRPLST 7 WGQGT 1 QTGGSLRLSCAAS HMA KEREFLS GNAI LQMNSLKPEDTAVYYCAA YWKDYDN LVTVSS 127 A0315008B0411 EVQLVESGGGSV 378 GDNLNSY 415 WFRQAPG 379 AIWWST 416 VADSVKGRFAISKSNALNTVY 380 VRFQFRPLST 7 WGQGT 3 QTGGSLRLSCAAS HMA KNRDFLS GNTI LQMNTLKPEDTAVYYCAA YWKDYDN LVTVSS 128 A0315003D0351 EVQLVESGGGLV 389 GGTFSSY 5 WFRQAPG 387 GMSWSG 418 YADSVKGRFTISRDNAKNTVY 390 GQNPMGPIA 7 WGQGT 9 QAGGSLRLSCAAS AMG KEREFVA GSTH LQMNSLKPEDTAVYYCTR TRPSVHDY LVTVSS 129 A0315009B0351 EVQLVESGGGLV 391 GRTFSNY 5 WFRQAPG 387 GMSWSG 417 YADSVKGRFAISRDNAKNTVY 392 GRNPMGPIA 7 WGQGT 7 QAGGSLRLSCAAS AMG KEREFVA GSTH LQMNSLKPEDTAVYYCTV TRPSVHDY LVTVSS 130 A0315003F0 419 EVQLVESGGGLV 397 GGTVSTY 353 WFRQAPG 398 SIIWSGST 420 YADSVKGRSTISRDNAKNTVY 399 QHFGPVSQT 7 WGQGT 4 RAGDSLRLSCAAS TMG KEREFVG TV LQMNSLKPEDTAVYYCAA TKGYFY LVTVSS 131 A0315021A0346 EVQLVESGGGLV 368 GRTLNDY 421 WFRQAPG 379 AIWWST 422 VADSVKGRFASSKTNAGVYL 365 VRFSFRPLST 7 WGQGT 1 QTGGSLRLSCAAS HMA KEREFLS GNTI QMNSLKPEDTAVYYCAA YWKDYDN LVTVSS
ID VHH ID FR1 ID CDR1 ID FR2 ID CDR2 ID FR3 ID CDR3 ID FR4 8 A0315007E04 EVQLVESGGGLV 1 GLTFSTYT 5 WFRQAPG 2 AIIWSGS 6 YADSVKGRFTISRDNAKSTVY 3 QHFGPIGLTT 7 WGQGT 7 QPGGSLRLSCAAS MG KEREFVA NTY LQMNNLEPEDTAVYHCAA RGYNY LVTVSS 134 A031500085 34 EVQLVESGGGVV 389 GGTFSSY 5 WFRQAPG 387 GMSWSG 423 YADSVKGRFTISRDNAKNTVY 390 GQNPMGPIA 7 WGQGT QPGGSLRLSCAAS AMG KEREFVA GSTH LQMNSLRPEDTALYYCTR TRPSVHDY LVTVSS 135 A031500086 424 EVQLVESGGGVV 9 GHTFSEY 13 WFRQAPG 10 AINWGG 425 YADSVQGRFTISRDNAKNTLY 11 SSDYAGGNP 7 WGQGT QPGGSLRLSCSAS ALG MEREFVA GWTY LQMNSLRPGDTALYYCAA TGYPY LVTVSS 136 A031500087 424 EVQLVESGGGVV 9 GHTFSEY 13 WFRQAPG 10 AINWGG 426 YADSVQGRFTISRDNAKNTLY 11 SSDYAGGNP 7 WGQGT QPGGSLRLSCSAS ALG MEREFVA GWTY LQMNSLRPEDTALYYCAA TGYPY LVTVSS 137 A031500088 424 EVQLVESGGGVV 9 GHTFSEY 13 WFRQAPG 10 AINWGG 427 YADSVKGRFTISRDNAKNTLY 11 SSDYAGGNP 7 WGQGT QPGGSLRLSCSAS ALG MEREFVA GWTY LQMNSLRPGDTALYYCAA TGYPY LVTVSS 138 A031500089 424 EVQLVESGGGVV 9 GHTFSEY 5 WFRQAPG 10 AINWGG 425 YADSVQGRFTISRDNAKNTLY 11 SSDYAGGNP 7 WGQGT QPGGSLRLSCSAS ALG KEREFVA GWTY LQMNSLRPGDTALYYCAA TGYPY LVTVSS 139 A031500090 424 EVQLVESGGGVV 9 GHTFSEY 5 WFRQAPG 10 AINWGG 426 YADSVQGRFTISRDNAKNTLY 11 SSDYAGGNP 7 WGQGT QPGGSLRLSCSAS ALG KEREFVA GWTY LQMNSLRPEDTALYYCAA TGYPY LVTVSS 140 A031500091 424 EVQLVESGGGVV 9 GHTFSEY 5 WFRQAPG 10 AINWGG 427 YADSVKGRFTISRDNAKNTLY 11 SSDYAGGNP 7 WGQGT QPGGSLRLSCSAS ALG KEREFVA GWTY LQMNSLRPGDTALYYCAA TGYPY LVTVSS 141 A031500092 34 EVQLVESGGGVV 9 GHTFSEY 13 WFRQAPG 10 AINWGG 425 YADSVQGRFTISRDNAKNTLY 11 SSDYAGGNP 7 WGQGT QPGGSLRLSCAAS ALG MEREFVA GWTY LQMNSLRPGDTALYYCAA TGYPY LVTVSS 142 A031500093 34 EVQLVESGGGVV 9 GHTFSEY 13 WFRQAPG 10 AINWGG 426 YADSVQGRFTISRDNAKNTLY 11 SSDYAGGNP 7 WGQGT QPGGSLRLSCAAS ALG MEREFVA GWTY LQMNSLRPEDTALYYCAA TGYPY LVTVSS 143 A031500094 34 EVQLVESGGGVV 9 GHTFSEY 13 WFRQAPG 10 AINWGG 427 YADSVKGRFTISRDNAKNTLY 11 SSDYAGGNP 7 WGQGT QPGGSLRLSCAAS ALG MEREFVA GWTY LQMNSLRPGDTALYYCAA TGYPY LVTVSS 144 A031500095 34 EVQLVESGGGVV 9 GHTFSEY 13 WFRQAPG 10 AINWGG 41 YADSVKGRFTISRDNAKNTLY 11 SSDYAGGNP 7 WGQGT QPGGSLRLSCAAS ALG MEREFVA GWTY LQMNSLRPEDTALYYCAA TGYPY LVTVSS 145 A031500096 34 EVQLVESGGGVV 9 GHTFSEY 5 WFRQAPG 10 AINWGG 425 YADSVQGRFTISRDNAKNTLY 11 SSDYAGGNP 7 WGQGT QPGGSLRLSCAAS ALG KEREFVA GWTY LQMNSLRPGDTALYYCAA TGYPY LVTVSS 146 A031500097 34 EVQLVESGGGVV 9 GHTFSEY 5 WFRQAPG 10 AINWGG 426 YADSVQGRFTISRDNAKNTLY 11 SSDYAGGNP 7 WGQGT QPGGSLRLSCAAS ALG KEREFVA GWTY LQMNSLRPEDTALYYCAA TGYPY LVTVSS
ID VHH ID FR1 ID CDR1 ID FR2 ID CDR2 ID FR3 ID CDR3 ID FR4 147 A031500098 34 EVQLVESGGGVV 9 GHTFSEY 5 WFRQAPG 10 AINWGG 427 YADSVKGRFTISRDNAKNTLY 11 SSDYAGGNP 7 WGQGT QPGGSLRLSCAAS ALG KEREFVA GWTY LQMNSLRPGDTALYYCAA TGYPY LVTVSS 39 A03150009934 EVQLVESGGGVV 9 GHTFSEY 5 WFRQAPG 10 AINWGG 41 YADSVKGRFTISRDNAKNTLY 11 SSDYAGGNP 7 WGQGT T028501817 QPGGSLRLSCAAS ALG KEREFVA GWTY LQMNSLRPEDTALYYCAA TGYPY LVTVSS 40 A03150009942 DVQLVESGGGVV 9 GHTFSEY 5 WFRQAPG 10 AINWGG 41 YADSVKGRFTISRDNAKNTLY 11 SSDYAGGNP 7 WGQGT (E1D) QPGGSLRLSCAAS ALG KEREFVA GWTY LQMNSLRPEDTALYYCAA TGYPY LVTVSS T028501817( E1D) 148 A031500100 424 EVQLVESGGGVV 9 GHTFSEY 5 WFRQAPG 10 AINWGG 41 YADSVKGRFTISRDNAKNTLY 11 SSDYAGGNP 7 WGQGT QPGGSLRLSCSAS ALG KEREFVA GWTY LQMNSLRPEDTALYYCAA TGYPY LVTVSS 149 A031500101 424 EVQLVESGGGVV 9 GHTFSEY 13 WFRQAPG 10 AINWGG 41 YADSVKGRFTISRDNAKNTLY 11 SSDYAGGNP 7 WGQGT QPGGSLRLSCSAS ALG MEREFVA GWTY LQMNSLRPEDTALYYCAA TGYPY LVTVSS 150 A031500251 34 EVQLVESGGGVV 1 GLTFSTYT 5 WFRQAPG 2 AIIWSGS 428 YADSVKGRFTISRDNAKSTVY 3 QHFGPIGLTT 7 WGQGT QPGGSLRLSCAAS MG KEREFVA NTY LQMNSLRPEDTALYHCAA RGYNY LVTVSS 151 A031500252 34 EVQLVESGGGVV 1 GLTFSTYT 5 WFRQAPG 2 AIIWSGS 429 YADSVKGRFTISRDNAKNTVY 3 QHFGPIGLTT 7 WGQGT QPGGSLRLSCAAS MG KEREFVA NTY LQMNSLRPEDTALYHCAA RGYNY LVTVSS 152 A031500253 34 EVQLVESGGGVV 1 GLTFSTYT 5 WFRQAPG 2 AIIWSGS 430 YADSVKGRFTISRDNAKSTVY 3 QHFGPIGLTT 7 WGQGT QPGGSLRLSCAAS MG KEREFVA NTY LQMNSLRPEDTALYYCAA RGYNY LVTVSS 153 A031500254 34 EVQLVESGGGVV 1 GLTFSTYT 5 WFRQAPG 2 AIIWSGS 6 YADSVKGRFTISRDNAKNTVY 3 QHFGPIGLTT 7 WGQGT QPGGSLRLSCAAS MG KEREFVA NTY LQMNSLRPEDTALYYCAA RGYNY LVTVSS 154 A031500379 34 EVQLVESGGGVV 1 GLTFSTYT 5 WFRQAPG 2 AIIWSGS 6 YADSVKGRFTISRDNAKNTVY 249 QHFGPIGLTT 7 WGQGT QPGGSLRLSCAAS MG KEREFVA NTY LQMNSLRPEDTALYYCAA RGYAY LVTVSS 155 A031500382 34 EVQLVESGGGVV 1 GLTFSTYT 5 WFRQAPG 2 AIIWSGS 6 YADSVKGRFTISRDNAKNTVY 250 QHFGPIGLTT 7 WGQGT QPGGSLRLSCAAS MG KEREFVA NTY LQMNSLRPEDTALYYCAA RGYFY LVTVSS 156 A031500383 34 EVQLVESGGGVV 1 GLTFSTYT 5 WFRQAPG 2 AIIWSGS 6 YADSVKGRFTISRDNAKNTVY 251 QHFGPIGLTT 7 WGQGT QPGGSLRLSCAAS MG KEREFVA NTY LQMNSLRPEDTALYYCAA RGYGY LVTVSS 31 A03150038434 EVQLVESGGGVV 1 GLTFSTYT 5 WFRQAPG 2 AIIWSGS 6 YADSVKGRFTISRDNAKNTVY 33 QHFGPIGLTT 7 WGQGT T028501789 QPGGSLRLSCAAS MG KEREFVA NTY LQMNSLRPEDTALYYCAA RGYHY LVTVSS
ID VHH ID FR1 ID CDR1 ID FR2 ID CDR2 ID FR3 ID CDR3 ID FR4 32 A03150038435 DVQLVESGGGVV 1 GLTFSTYT 5 WFRQAPG 2 AIIWSGS 6 YADSVKGRFTISRDNAKNTVY 33 QHFGPIGLTT 7 WGQGT (E1D) QPGGSLRLSCAAS MG KEREFVA NTY LQMNSLRPEDTALYYCAA RGYHY LVTVSS T028501789( E1D) 157 A031500385 34 EVQLVESGGGVV 1 GLTFSTYT 5 WFRQAPG 2 AIIWSGS 6 YADSVKGRFTISRDNAKNTVY 254 QHFGPIGLTT 7 WGQGT QPGGSLRLSCAAS MG KEREFVA NTY LQMNSLRPEDTALYYCAA RGYIY LVTVSS 158 A031500387 34 EVQLVESGGGVV 1 GLTFSTYT 5 WFRQAPG 2 AIIWSGS 6 YADSVKGRFTISRDNAKNTVY 252 QHFGPIGLTT 7 WGQGT QPGGSLRLSCAAS MG KEREFVA NTY LQMNSLRPEDTALYYCAA RGYLY LVTVSS 159 A031500394 34 EVQLVESGGGVV 1 GLTFSTYT 5 WFRQAPG 2 AIIWSGS 6 YADSVKGRFTISRDNAKNTVY 253 QHFGPIGLTT 7 WGQGT QPGGSLRLSCAAS MG KEREFVA NTY LQMNSLRPEDTALYYCAA RGYYY LVTVSS 115 A0315005F0 346 EVQLVESGGGLV 321 GGAFSTY 347 WFRQTPG 322 ALSWRS 348 YGDSVKGRFTISRVIAENTVYL 323 QQYGAISYN 7 WGQGT 1 QTGGSLRLSCAAS TMA NEREFVA GTTV QMNSLKPEDTAVYFCAA RNGFFY LVTVSS 116 A0315006F0 349 EVQLVESGGGLV 324 GRAFSTY 347 WFRQTPG 325 TISWRSEI 350 YGDSVKGRFTISRDKAENTVY 326 QEFGAISYNT 7 WGQGT 3 QAGGSLRLSCVAS TMA NEREFVA TV LQMNSLKPEDTAVYFCAA KGYFY LVTVSS 117 A0315002G0351 EVQLVESGGGLV 324 GRAFSTY 347 WFRQTPG 325 TISWRSEI 352 YGDSVKGRFTISRDNAENTVY 327 QEFGAISYNR 7 WGQGT 8 QAGGSLRLSCAAS TMA NEREFVA TV LQMNSLRPEDTAVYFCAA KGYFY LVTVSS 160 A031500333 34 EVQLVESGGGVV 324 GRAFSTY 347 WFRQTPG 325 TISWRSEI 277 YGDSVKGRFTISRDNAENTVY 327 QEFGAISYNR 7 WGQGT QPGGSLRLSCAAS TMA NEREFVA TV LQMNSLRPEDTALYFCAA KGYFY LVTVSS 161 A031500334 34 EVQLVESGGGVV 324 GRAFSTY 480 WFRQAPG 325 TISWRSEI 431 YGDSVKGRFTISRDNAENTVY 327 QEFGAISYNR 7 WGQGT QPGGSLRLSCAAS TMA NEREFVA TV LQMNSLRPEDTALYYCAA KGYFY LVTVSS 162 A031500335 34 EVQLVESGGGVV 324 GRAFSTY 480 WFRQAPG 325 TISWRSEI 432 YGDSVKGRFTISRDNAKNTVY 327 QEFGAISYNR 7 WGQGT QPGGSLRLSCAAS TMA NEREFVA TV LQMNSLRPEDTALYYCAA KGYFY LVTVSS 163 A031500336 34 EVQLVESGGGVV 324 GRAFSTY 480 WFRQAPG 325 TISWRSEI 433 YADSVKGRFTISRDNAENTVY 327 QEFGAISYNR 7 WGQGT QPGGSLRLSCAAS TMA NEREFVA TV LQMNSLRPEDTALYYCAA KGYFY LVTVSS 164 A031500337 34 EVQLVESGGGVV 324 GRAFSTY 480 WFRQAPG 325 TISWRSEI 6 YADSVKGRFTISRDNAKNTVY 327 QEFGAISYNR 7 WGQGT QPGGSLRLSCAAS TMA NEREFVA TV LQMNSLRPEDTALYYCAA KGYFY LVTVSS 165 A031500338 34 EVQLVESGGGVV 324 GRAFSTY 5 WFRQAPG 325 TISWRSEI 431 YGDSVKGRFTISRDNAENTVY 327 QEFGAISYNR 7 WGQGT QPGGSLRLSCAAS TMA KEREFVA TV LQMNSLRPEDTALYYCAA KGYFY LVTVSS
ID VHH ID FR1 ID CDR1 ID FR2 ID CDR2 ID FR3 ID CDR3 ID FR4 166 A031500339 34 EVQLVESGGGVV 324 GRAFSTY 5 WFRQAPG 325 TISWRSEI 432 YGDSVKGRFTISRDNAKNTVY 327 QEFGAISYNR 7 WGQGT QPGGSLRLSCAAS TMA KEREFVA TV LQMNSLRPEDTALYYCAA KGYFY LVTVSS 167 A031500340 34 EVQLVESGGGVV 324 GRAFSTY 5 WFRQAPG 325 TISWRSEI 433 YADSVKGRFTISRDNAENTVY 327 QEFGAISYNR 7 WGQGT QPGGSLRLSCAAS TMA KEREFVA TV LQMNSLRPEDTALYYCAA KGYFY LVTVSS 168 A031500341 34 EVQLVESGGGVV 324 GRAFSTY 5 WFRQAPG 325 TISWRSEI 6 YADSVKGRFTISRDNAKNTVY 327 QEFGAISYNR 7 WGQGT QPGGSLRLSCAAS TMA KEREFVA TV LQMNSLRPEDTALYYCAA KGYFY LVTVSS 169 A031500342 34 EVQLVESGGGVV 324 GRAFSTY 480 WFRQAPG 325 TISWRSEI 277 YGDSVKGRFTISRDNAENTVY 327 QEFGAISYNR 7 WGQGT QPGGSLRLSCAAS TMA NEREFVA TV LQMNSLRPEDTALYFCAA KGYFY LVTVSS 170 A031500343 34 EVQLVESGGGVV 324 GRAFSTY 347 WFRQTPG 325 TISWRSEI 431 YGDSVKGRFTISRDNAENTVY 327 QEFGAISYNR 7 WGQGT QPGGSLRLSCAAS TMA NEREFVA TV LQMNSLRPEDTALYYCAA KGYFY LVTVSS 118 A0315002G012 EVQLVESGGGLV 1 GLTFSTYT 5 WFRQAPG 336 SIIWSGS 354 YADSVKGRFTISRENAKNTVY 339 QHFGPVSLTT 7 WGQGT 6 QAGDSLRLSCAAS MG KEREFVA NTV LQMNSLKPEDTAVYHCAA RGYYY LVTVSS 119 A0315002C112 EVQLVESGGGLV 334 GLTFSTYT 353 WFRQAPG 337 SMIYSGS 355 YADSVKGRFTISRDNAKNTVF 340 QHFGPISLTT 7 WGQGT 0 QAGDSLRLSCAAS VG KEREFVG NTL LQMNSLKPEDTAVYHCAA RGYFY LVTVSS 171 A031500010 34 EVQLVESGGGVV 1 GLTFSTYT 5 WFRQAPG 336 SIIWSGS 434 YADSVKGRFTISRENAKNTVY 339 QHFGPVSLTT 7 WGQGT QPGGSLRLSCAAS MG KEREFVA NTV LQMNSLRPEDTALYHCAA RGYYY LVTVSS 172 A031500011 34 EVQLVESGGGVV 1 GLTFSTYT 5 WFRQAPG 336 SIIWSGS 429 YADSVKGRFTISRDNAKNTVY 339 QHFGPVSLTT 7 WGQGT QPGGSLRLSCAAS MG KEREFVA NTV LQMNSLRPEDTALYHCAA RGYYY LVTVSS 173 A031500012 34 EVQLVESGGGVV 1 GLTFSTYT 5 WFRQAPG 336 SIIWSGS 435 YADSVKGRFTISRENAKNTVY 339 QHFGPVSLTT 7 WGQGT QPGGSLRLSCAAS MG KEREFVA NTV LQMNSLRPEDTALYYCAA RGYYY LVTVSS 174 A031500013 34 EVQLVESGGGVV 1 GLTFSTYT 5 WFRQAPG 336 SIIWSGS 6 YADSVKGRFTISRDNAKNTVY 339 QHFGPVSLTT 7 WGQGT QPGGSLRLSCAAS MG KEREFVA NTV LQMNSLRPEDTALYYCAA RGYYY LVTVSS 114 A0315001D0258 EVQLVESGGGLA 255 GRTFNSY 259 WFRQAPG 256 AIRWSAG 260 YGNSVKGRFAIARTNANNIM 257 VRPSFRPLST 7 WGQGT 7 QTGGSLRLSCAAS DMG KEREFVS STV YLQMNSLKPEDTAVYYCAA YWKDYDN LVTVSS 175 A031500014 34 EVQLVESGGGVV 255 GRTFNSY 259 WFRQAPG 256 AIRWSAG 436 YGNSVKGRFAIARTNANNIM 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV YLQMNSLRPEDTALYYCAA YWKDYDN LVTVSS 176 A031500015 34 EVQLVESGGGVV 255 GRTFNSY 5 WFRQAPG 256 AIRWSAG 436 YGNSVKGRFAIARTNANNIM 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVA STV YLQMNSLRPEDTALYYCAA YWKDYDN LVTVSS
ID VHH ID FR1 ID CDR1 ID FR2 ID CDR2 ID FR3 ID CDR3 ID FR4 177 A031500016 34 EVQLVESGGGVV 255 GRTFNSY 259 WFRQAPG 256 AIRWSAG 261 YANSVKGRFAIARTNANNIM 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV YLQMNSLRPEDTALYYCAA YWKDYDN LVTVSS 178 A031500017 34 EVQLVESGGGVV 255 GRTFNSY 259 WFRQAPG 256 AIRWSAG 262 YGDSVKGRFAIARTNANNIM 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV YLQMNSLRPEDTALYYCAA YWKDYDN LVTVSS 179 A031500018 34 EVQLVESGGGVV 255 GRTFNSY 259 WFRQAPG 256 AIRWSAG 263 YGNSVKGRFTIARTNANNIM 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV YLQMNSLRPEDTALYYCAA YWKDYDN LVTVSS 180 A031500019 34 EVQLVESGGGVV 255 GRTFNSY 259 WFRQAPG 256 AIRWSAG 264 YGNSVKGRFAISRTNANNIM 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV YLQMNSLRPEDTALYYCAA YWKDYDN LVTVSS 181 A031500020 34 EVQLVESGGGVV 255 GRTFNSY 259 WFRQAPG 256 AIRWSAG 265 YGNSVKGRFAIARDNANNIM 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV YLQMNSLRPEDTALYYCAA YWKDYDN LVTVSS 182 A031500021 34 EVQLVESGGGVV 255 GRTFNSY 259 WFRQAPG 256 AIRWSAG 266 YGNSVKGRFAIARTNAKNIM 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV YLQMNSLRPEDTALYYCAA YWKDYDN LVTVSS 183 A031500022 34 EVQLVESGGGVV 255 GRTFNSY 259 WFRQAPG 256 AIRWSAG 267 YGNSVKGRFAIARTNANNTM 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV YLQMNSLRPEDTALYYCAA YWKDYDN LVTVSS 184 A031500023 34 EVQLVESGGGVV 255 GRTFNSY 259 WFRQAPG 256 AIRWSAG 268 YGNSVKGRFAIARTNANNIVY 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV LQMNSLRPEDTALYYCAA YWKDYDN LVTVSS 185 A031500024 34 EVQLVESGGGVV 255 GRTFNSY 259 WFRQAPG 256 AIRWSAG 269 YGNSVKGRFAIARTNANNILY 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV LQMNSLRPEDTALYYCAA YWKDYDN LVTVSS 186 A031500025 34 EVQLVESGGGVV 255 GRTFNSY 259 WFRQAPG 256 AIRWSAG 270 YADSVKGRFAIARTNANNIM 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV YLQMNSLRPEDTALYYCAA YWKDYDN LVTVSS 187 A031500026 34 EVQLVESGGGVV 255 GRTFNSY 259 WFRQAPG 256 AIRWSAG 271 YGNSVKGRFTISRTNANNIMY 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV LQMNSLRPEDTALYYCAA YWKDYDN LVTVSS 188 A031500027 34 EVQLVESGGGVV 255 GRTFNSY 259 WFRQAPG 256 AIRWSAG 272 YGNSVKGRFTISRTNAKNIMY 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV LQMNSLRPEDTALYYCAA YWKDYDN LVTVSS 189 A031500028 34 EVQLVESGGGVV 255 GRTFNSY 259 WFRQAPG 256 AIRWSAG 273 YGNSVKGRFTISRTNAKNTM 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV YLQMNSLRPEDTALYYCAA YWKDYDN LVTVSS 190 A031500029 34 EVQLVESGGGVV 255 GRTFNSY 259 WFRQAPG 256 AIRWSAG 274 YGNSVKGRFTISRDNAKNTM 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV YLQMNSLRPEDTALYYCAA YWKDYDN LVTVSS
ID VHH ID FR1 ID CDR1 ID FR2 ID CDR2 ID FR3 ID CDR3 ID FR4 191 A031500030 34 EVQLVESGGGVV 255 GRTFNSY 259 WFRQAPG 256 AIRWSAG 275 YANSVKGRFTISRDNAKNTM 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV YLQMNSLRPEDTALYYCAA YWKDYDN LVTVSS 192 A031500031 34 EVQLVESGGGVV 255 GRTFNSY 259 WFRQAPG 256 AIRWSAG 276 YADSVKGRFTISRDNAKNTM 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV YLQMNSLRPEDTALYYCAA YWKDYDN LVTVSS 193 A031500032 34 EVQLVESGGGVV 255 GRTFNSY 259 WFRQAPG 256 AIRWSAG 6 YADSVKGRFTISRDNAKNTVY 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV LQMNSLRPEDTALYYCAA YWKDYDN LVTVSS 194 A031500033 34 EVQLVESGGGVV 255 GRTFNSY 259 WFRQAPG 256 AIRWSAG 41 YADSVKGRFTISRDNAKNTLY 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV LQMNSLRPEDTALYYCAA YWKDYDN LVTVSS 195 A031500034 34 EVQLVESGGGVV 255 GRTFNSY 259 WFRQAPG 256 AIRWSAG 278 YGNSVKGRFTISRDNAKNTVY 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV LQMNSLRPEDTALYYCAA YWKDYDN LVTVSS 196 A031500035 34 EVQLVESGGGVV 255 GRTFNSY 259 WFRQAPG 256 AIRWSAG 279 YGNSVKGRFTISRDNAKNTLY 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV LQMNSLRPEDTALYYCAA YWKDYDN LVTVSS 197 A031500368 34 EVQLVESGGGVV 255 GRTFNSY 259 WFRQAPG 256 AIRWSAG 280 YADSVKGRFTISRTNANNILYL 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV QMNSLRPEDTALYYCAA YWKDYDN LVTVSS 198 A031500369 34 EVQLVESGGGVV 255 GRTFNSY 5 WFRQAPG 256 AIRWSAG 280 YADSVKGRFTISRTNANNILYL 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVA STV QMNSLRPEDTALYYCAA YWKDYDN LVTVSS 199 A031500370 34 EVQLVESGGGVV 255 GRTFNSY 259 WFRQAPG 256 AIRWSAG 281 YADSVKGRFTISRDNANNILYL 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV QMNSLRPEDTALYYCAA YWKDYDN LVTVSS 200 A031500345 34 EVQLVESGGGVV 255 GRTFNSY 5 WFRQAPG 256 AIRWSAG 282 YADSVKGRFTISRDNANNTLY 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVA STV LQMNSLRPEDTALYYCAA YWKDYDN LVTVSS 201 A031500346 34 EVQLVESGGGVV 255 GRTFNSY 5 WFRQAPG 256 AIRWSAG 283 YADSVKGRFTISRDNAKNILYL 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVA STV QMNSLRPEDTALYYCAA YWKDYDN LVTVSS 202 A031500347 34 EVQLVESGGGVV 255 GRTFNSY 5 WFRQAPG 256 AIRWSAG 281 YADSVKGRFTISRDNANNILYL 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVA STV QMNSLRPEDTALYYCAA YWKDYDN LVTVSS 203 A031500348 34 EVQLVESGGGVV 255 GRTFNSY 5 WFRQAPG 256 AIRWSAG 41 YADSVKGRFTISRDNAKNTLY 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVA STV LQMNSLRPEDTALYYCAA YWKDYDN LVTVSS 204 A031500406 34 EVQLVESGGGVV 284 GRTFESY 259 WFRQAPG 256 AIRWSAG 280 YADSVKGRFTISRTNANNILYL 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV QMNSLRPEDTALYYCAA YWKDYDN LVTVSS
ID VHH ID FR1 ID CDR1 ID FR2 ID CDR2 ID FR3 ID CDR3 ID FR4 205 A031500407 34 EVQLVESGGGVV 285 GRTFGSY 259 WFRQAPG 256 AIRWSAG 280 YADSVKGRFTISRTNANNILYL 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV QMNSLRPEDTALYYCAA YWKDYDN LVTVSS 206 A031500408 34 EVQLVESGGGVV 286 GRTFPSY 259 WFRQAPG 256 AIRWSAG 280 YADSVKGRFTISRTNANNILYL 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV QMNSLRPEDTALYYCAA YWKDYDN LVTVSS 207 A031500409 34 EVQLVESGGGVV 287 GRTFSSY 259 WFRQAPG 256 AIRWSAG 280 YADSVKGRFTISRTNANNILYL 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV QMNSLRPEDTALYYCAA YWKDYDN LVTVSS 208 A031500410 34 EVQLVESGGGVV 288 GRTFTSY 259 WFRQAPG 256 AIRWSAG 280 YADSVKGRFTISRTNANNILYL 257 VRPSFRPLST 7 WGQGT QPGGSLRLSCAAS DMG KEREFVS STV QMNSLRPEDTALYYCAA YWKDYDN LVTVSS 547 14R0410 4 EVQLVESGGGLV 611 GFTFSSY 625 WVRQPPG 612 TINRGGS 628 YRVPVEGRFTISRDNAENTLY 610 GDHRGPWY 640 RGQGTL T023200178 QPGGSLRLSCAAS DMS KGIEWVS STS LQMNSLKTEDTAVYYCTT N VTVSS 549 34 EVQLVESGGGVV 611 GFTFSSY 625 WVRQPPG 612 TINRGGS 629 YRVPVEGRFTISRDNAENTLY 610 GDHRGPWY 640 RGQGTL T028500006 QPGGSLRLSCAAS DMS KGIEWVS STS LQMNSLRTEDTALYYCTT N VTVSS 550 34 EVQLVESGGGVV 611 GFTFSSY 625 WVRQPPG 612 TINRGGS 630 YRVPVEGRFTISRDNAENTLY 610 GDHRGPWY 640 RGQGTL T028500007 QPGGSLRLSCAAS DMS KGIEWVS STS LQMNSLRSEDTALYYCTT N VTVSS 551 34 EVQLVESGGGVV 611 GFTFSSY 625 WVRQPPG 612 TINRGGS 629 YRVPVEGRFTISRDNAENTLY 610 GDHRGPWY 7 WGQGT T028500008 QPGGSLRLSCAAS DMS KGIEWVS STS LQMNSLRTEDTALYYCTT N LVTVSS 552 34 EVQLVESGGGVV 611 GFTFSSY 626 WVRQAPG 612 TINRGGS 631 YRVPVEGRFTISRDNAKNTLY 610 GDHRGPWY 640 RGQGTL T028500009 QPGGSLRLSCAAS DMS KGIEWVS STS LQMNSLRTEDTALYYCTT N VTVS 553 34 EVQLVESGGGVV 611 GFTFSSY 626 WVRQAPG 612 TINRGGS 632 YADSVKGRFTISRDNAKNTLY 610 GDHRGPWY 640 RGQGTL T028500010 QPGGSLRLSCAAS DMS KGIEWVS STS LQMNSLRTEDTALYYCTT N VTVSS 554 34 EVQLVESGGGVV 611 GFTFSSY 626 WVRQAPG 612 TINRGGS 629 YRVPVEGRFTISRDNAENTLY 610 GDHRGPWY 640 RGQGTL T028500011 QPGGSLRLSCAAS DMS KGIEWVS STS LQMNSLRTEDTALYYCTT N VTVSS 555 34 EVQLVESGGGVV 611 GFTFSSY 627 WVRQPPG 612 TINRGGS 629 YRVPVEGRFTISRDNAENTLY 610 GDHRGPWY 640 RGQGTL T028500012 QPGGSLRLSCAAS DMS KGLEWVS STS LQMNSLRTEDTALYYCTT N VTVSS 556 34 EVQLVESGGGVV 611 GFTFSSY 625 WVRQPPG 612 TINRGGS 633 YAVPVEGRFTISRDNAENTLY 610 GDHRGPWY 640 RGQGTL T028500013 QPGGSLRLSCAAS DMS KGIEWVS STS LQMNSLRTEDTALYYCTT N VTVSS
ID VHH ID FR1 ID CDR1 ID FR2 ID CDR2 ID FR3 ID CDR3 ID FR4 557 34 EVQLVESGGGVV 611 GFTFSSY 625 WVRQPPG 612 TINRGGS 634 YRDPVEGRFTISRDNAENTLY 610 GDHRGPWY 640 RGQGTL T028500014 QPGGSLRLSCAAS DMS KGIEWVS STS LQMNSLRTEDTALYYCTT N VTVSS 558 34 EVQLVESGGGVV 611 GFTFSSY 625 WVRQPPG 612 TINRGGS 635 YRVSVEGRFTISRDNAENTLYL 610 GDHRGPWY 640 RGQGTL T028500015 QPGGSLRLSCAAS DMS KGIEWVS STS QMNSLRTEDTALYYCTT N VTVSS 559 34 EVQLVESGGGVV 611 GFTFSSY 625 WVRQPPG 612 TINRGGS 636 YRVPVKGRFTISRDNAENTLY 610 GDHRGPWY 640 RGQGTL T028500016 QPGGSLRLSCAAS DMS KGIEWVS STS LQMNSLRTEDTALYYCTT N VTVSS 560 34 EVQLVESGGGVV 611 GFTFSSY 625 WVRQPPG 612 TINRGGS 631 YRVPVEGRFTISRDNAKNTLY 610 GDHRGPWY 640 RGQGTL T028500017 QPGGSLRLSCAAS DMS KGIEWVS STS LQMNSLRTEDTALYYCTT N VTVSS 561 34 EVQLVESGGGVV 611 GFTFSSY 625 WVRQPPG 612 TINRGGS 637 YRVPVEGRFTISRDNAENTLY 610 GDHRGPWY 640 RGQGTL T028500018 QPGGSLRLSCAAS DMS KGIEWVS STS LQMNSLRPEDTALYYCTT N VTVSS 562 34 EVQLVESGGGVV 611 GFTFSSY 625 WVRQPPG 612 TINRGGS 638 YAVSVKGRFTISRDNAKNTLY 610 GDHRGPWY 640 RGQGTL T028500557 QPGGSLRLSCAAS DMS KGIEWVS STS LQMNSLRTEDTALYYCTT N VTVSS 563 T028500558 34 EVQLVESGGGVV 611 GFTFSSY 625 WVRQPPG 612 TINRGGS 639 YAVPVKGRFTISRDNAKNTLY 610 GDHRGPWY 640 RGQGTL QPGGSLRLSCAAS DMS KGIEWVS STS LQMNSLRTEDTALYYCTT N VTVSS 548 T023200134 351 EVQLVESGGGLV 594 GRTFDN 603 WFRQTPG 579 GITWRG 604 YADSVKGRFTISRDNAKNTLY 582 DLRPFGPITT 7 WGQGT QAGGSLRLSCAAS HAMG KEREFVA GSTH LEMNSLKPEDTAVYYCTA TPQRINY LVTVSS 564 T028500003 34 EVQLVESGGGVV 594 GRTFDN 603 WFRQTPG 579 GITWRG 605 YADSVKGRFTISRDNAKNTLY 582 DLRPFGPITT 7 WGQGT QPGGSLRLSCAAS HAMG KEREFVA GSTH LEMNSLRPEDTALYYCTA TPQRINY LVTVSS 565 T028500004 34 EVQLVESGGGVV 594 GRTFDN 603 WFRQTPG 579 GITWRG 606 YADSVKGRFTISRDNAKNTLY 582 DLRPFGPITT 7 WGQGT QPGGSLRLSCAAS HAMG KEREFVA GSTH LQMNSLRPEDTALYYCTA TPQRINY LVTVSS 566 T028500005 34 EVQLVESGGGVV 594 GRTFDN 603 WFRQAPG 579 GITWRG 606 YADSVKGRFTISRDNAKNTLY 582 DLRPFGPITT 7 WGQGT QPGGSLRLSCAAS HAMG KEREFVA GSTH LQMNSLRPEDTALYYCTA TPQRINY LVTVSS 567 T028500591 34 EVQLVESGGGVV 594 GRTFDN 603 WFRQAPG 579 GITWRG 606 YADSVKGRFTISRDNAKNTLY 583 DLVPFGPITT 7 WGQGT QPGGSLRLSCAAS HAMG KEREFVA GSTH LQMNSLRPEDTALYYCTA TPQRINY LVTVSS 568 T028500058 34 EVQLVESGGGVV 595 GRTFDNL 603 WFRQAPG 579 GITWRG 606 YADSVKGRFTISRDNAKNTLY 582 DLRPFGPITT 7 WGQGT 8 QPGGSLRLSCAAS AMG KEREFVA GSTH LQMNSLRPEDTALYYCTA TPQRINY LVTVSS 569 T028500582 34 EVQLVESGGGVV 594 GRTFDN 603 WFRQAPG 579 GITWRG 606 YADSVKGRFTISRDNAKNTLY 584 DLRPFAPITT 7 WGQGT QPGGSLRLSCAAS HAMG KEREFVA GSTH LQMNSLRPEDTALYYCTA TPQRINY LVTVSS
ID VHH ID FR1 ID CDR1 ID FR2 ID CDR2 ID FR3 ID CDR3 ID FR4 570 T028500593 34 EVQLVESGGGVV 594 GRTFDN 603 WFRQAPG 579 GITWRG 606 YADSVKGRFTISRDNAKNTLY 585 DLRPFGPITQ 7 WGQGT QPGGSLRLSCAAS HAMG KEREFVA GSTH LQMNSLRPEDTALYYCTA TPQRINY LVTVSS 571 T028500592 34 EVQLVESGGGVV 594 GRTFDN 603 WFRQAPG 579 GITWRG 606 YADSVKGRFTISRDNAKNTLY 586 DLRPFGPITT 7 WGQGT QPGGSLRLSCAAS HAMG KEREFVA GSTH LQMNSLRPEDTALYYCTA EPQRINY LVTVSS 572 T028500587 34 EVQLVESGGGVV 596 GRTFDNE 603 WFRQAPG 579 GITWRG 606 YADSVKGRFTISRDNAKNTLY 582 DLRPFGPITT 7 WGQGT QPGGSLRLSCAAS AMG KEREFVA GSTH LQMNSLRPEDTALYYCTA TPQRINY LVTVSS 573 T028500581 34 EVQLVESGGGVV 594 GRTFDN 603 WFRQAPG 579 GITWRG 606 YADSVKGRFTISRDNAKNTLY 587 VLRPFGPITT 7 WGQGT QPGGSLRLSCAAS HAMG KEREFVA GSTH LQMNSLRPEDTALYYCTA TPQRINY LVTVSS 574 T028500590 34 EVQLVESGGGVV 594 GRTFDN 603 WFRQAPG 579 GITWRG 606 YADSVKGRFTISRDNAKNTLY 588 DLRPFGPITT 7 WGQGT QPGGSLRLSCAAS HAMG KEREFVA GSTH LQMNSLRPEDTALYYCTA TPQRIEY LVTVSS 575 T028500594 34 EVQLVESGGGVV 594 GRTFDN 603 WFRQAPG 580 GITNRGG 606 YADSVKGRFTISRDNAKNTLY 582 DLRPFGPITT 7 WGQGT QPGGSLRLSCAAS HAMG KEREFVA STH LQMNSLRPEDTALYYCTA TPQRINY LVTVSS T028500583 34 EVQLVESGGGVV 594 GRTFDN 603 WFRQAPG 579 GITWRG 606 YADSVKGRFTISRDNAKNTLY 589 DLRPFFPITTT 7 WGQGT QPGGSLRLSCAAS HAMG KEREFVA GSTH LQMNSLRPEDTALYYCTA PQRINY LVTVSS 62 ALB23002 83 EVQLVESGGGVV 80 GFTFRSF 84 WVRQAPG 81 SISGSGS 85 YADSVKGRFTISRDNSKNTLYL 82 GGSLSR 86 SSQGTL QPGGSLRLSCAAS GMS KGPEWVS DTL QMNSLRPEDTALYYCTI VTVSS
Table A-9: Sequences for CDRs according to Kabat numbering and frameworks (“ID” refers to the given SEQ ID NO) ID VHH ID FR1 ID CDR1 ID FR2 ID CDR2 ID FR3 ID CDR3 ID FR4 120 A03150 447 EVQLVESGGGLVQAG 243 DYAMG 13 WFRQAPGM 244 AINWGGTW 448 RFTISRGNAKNTLYLQM 236 SLDYAGGSP 7 WGQGT 01C02 DSLRLSCSASGRTFS EREFVA TYYAHSVQG NSLKPEDTAGYYCAA TGYAY LVTVSS 16 A03150 24 EVQLVESGGGLVQAG 21 EYALG 13 WFRQAPGM 22 AINWGGGW 25 RFTISRDNAKNTLYLQM 11 SSDYAGGN 7 WGQGT 24B02 DSLRLSCSASGHTFS EREFVA TYYADSVQG NSLKPGDTAGYYCAA PTGYPY LVTVSS 121 A03150 449 EVQLVESGGGLVLAG 243 DYAMG 13 WFRQAPGM 245 AINWGGSW 450 RFTISRDNAKNTLYLQM 246 SPDYAGGN 7 WGQGT 26D05 DSLRLSCSASGRTFS EREFVA TYYAHSVQG NSLKPEDTASYYCAA PTGYAY LVTVSS 122 A03150 451 EVQLVESGGGLVQAG 229 DFAMG 13 WFRQAPGM 362 AINWSGGW 452 RFTISRDNTKNTLYLQM 360 SSDYAGGR 7 WGQGT 01C11 DSLRLSCLASGRTFS EREFVA TYYADSVQG NSLKPEDTAAYYCAA STGYDY LVTVSS 123 A03150 447 EVQLVESGGGLVQAG 243 DYAMG 13 WFRQAPGM 362 AINWSGGW 452 RFTISRDNTKNTLYLQM 361 SSDYAGGR 7 WGQGT 04G01 DSLRLSCSASGRTFS EREFVA TYYADSVQG NSLKPEDTAAYYCAA STGYAY LVTVSS 124 A03150 453 EVQLVESGGGLVQTG 366 INEYHLA 408 WFRQAPGKE 367 AIWWSTGN 454 RFAISRSSRINTVNLQM 365 VRFSFRPLS 7 WGQGT 25D01 GSLILSCAASGRTFN REFLA KIVADSVKG NNLKREDTAVYYCAA TYWKDYDN LVTVSS 125 A03150 455 EVQLVESGGGLVQTG 371 DYHMA 412 WFRQAPGKE 372 AIWWSTGN 456 RFAVSRSNAGNTIYLQ 370 VRFSFRPLS 7 WGQGT 20C01 GSLRLSCAASGRTLN REFQA RIVADSVKG MNSLKPEDTAVYYCAA TYWKDYDI LVTVSS 126 A03150 457 EVQLVESGGGSVQTG 381 SYHMA 413 WFRQAPRKE 384 AIWWSTGN 458 RFAISKSNALNTVYLQM 365 VRFSFRPLS 7 WGQGT 26B01 GSLRLSCAASGDTLN REFLS AIVADSVKG NSLKPEDTAVYYCAA TYWKDYDN LVTVSS 127 A03150 459 EVQLVESGGGSVQTG 381 SYHMA 415 WFRQAPGK 385 AIWWSTGNT 460 RFAISKSNALNTVYLQM 380 VRFQFRPLS 7 WGQGT 08B03 GSLRLSCAASGDNLN NRDFLS IVADSVKG NTLKPEDTAVYYCAA TYWKDYDN LVTVSS 128 A03150 461 EVQLVESGGGLVQAG 395 SYAMG 5 WFRQAPGKE 394 GMSWSGGS 462 RFTISRDNAKNTVYLQ 390 GQNPMGPI 7 WGQGT 03D09 GSLRLSCAASGGTFS REFVA THYADSVKG MNSLKPEDTAVYYCTR ATRPSVHD LVTVSS Y 129 A03150 463 EVQLVESGGGLVQAG 396 NYAMG 5 WFRQAPGKE 394 GMSWSGGS 464 RFAISRDNAKNTVYLQ 392 GRNPMGPI 7 WGQGT 09B07 GSLRLSCAASGRTFS REFVA THYADSVKG MNSLKPEDTAVYYCTV ATRPSVHD LVTVSS Y
ID VHH ID FR1 ID CDR1 ID FR2 ID CDR2 ID FR3 ID CDR3 ID FR4 130 A03150 465 EVQLVESGGGLVRAG 17 TYTMG 353 WFRQAPGKE 400 SIIWSGSTTV 466 RSTISRDNAKNTVYLQ 399 QHFGPVSQ 7 WGQGT 03F04 DSLRLSCAASGGTVS REFVG YADSVKG MNSLKPEDTAVYYCAA TTKGYFY LVTVSS 131 A03150 455 EVQLVESGGGLVQTG 371 DYHMA 421 WFRQAPGKE 385 AIWWSTGNT 467 RFASSKTNAGVYLQMN 365 VRFSFRPLS 7 WGQGT 21A01 GSLRLSCAASGRTLN REFLS IVADSVKG SLKPEDTAVYYCAA TYWKDYDN LVTVSS 8 A03150 19 EVQLVESGGGLVQPG 17 TYTMG 5 WFRQAPGKE 18 AIIWSGSNTY 20 RFTISRDNAKSTVYLQM 3 QHFGPIGLT 7 WGQGT 07E07 GSLRLSCAASGLTFS REFVA YADSVKG NNLEPEDTAVYHCAA TRGYNY LVTVSS 134 A03150 468 EVQLVESGGGVVQPG 395 SYAMG 5 WFRQAPGKE 394 GMSWSGGS 469 RFTISRDNAKNTVYLQ 390 GQNPMGPI 7 WGQGT 0085 GSLRLSCAASGGTFS REFVA THYADSVKG MNSLRPEDTALYYCTR ATRPSVHD LVTVSS Y 135 A03150 470 EVQLVESGGGVVQPG 21 EYALG 13 WFRQAPGM 22 AINWGGGW 471 RFTISRDNAKNTLYLQM 11 SSDYAGGN 7 WGQGT 0086 GSLRLSCSASGHTFS EREFVA TYYADSVQG NSLRPGDTALYYCAA PTGYPY LVTVSS 136 A03150 470 EVQLVESGGGVVQPG 21 EYALG 13 WFRQAPGM 22 AINWGGGW 45 RFTISRDNAKNTLYLQM 11 SSDYAGGN 7 WGQGT 0087 GSLRLSCSASGHTFS EREFVA TYYADSVQG NSLRPEDTALYYCAA PTGYPY LVTVSS 137 A03150 470 EVQLVESGGGVVQPG 21 EYALG 13 WFRQAPGM 43 AINWGGGW 471 RFTISRDNAKNTLYLQM 11 SSDYAGGN 7 WGQGT 0088 GSLRLSCSASGHTFS EREFVA TYYADSVKG NSLRPGDTALYYCAA PTGYPY LVTVSS 138 A03150 470 EVQLVESGGGVVQPG 21 EYALG 5 WFRQAPGKE 22 AINWGGGW 471 RFTISRDNAKNTLYLQM 11 SSDYAGGN 7 WGQGT 0089 GSLRLSCSASGHTFS REFVA TYYADSVQG NSLRPGDTALYYCAA PTGYPY LVTVSS 139 A03150 470 EVQLVESGGGVVQPG 21 EYALG 5 WFRQAPGKE 22 AINWGGGW 45 RFTISRDNAKNTLYLQM 11 SSDYAGGN 7 WGQGT 0090 GSLRLSCSASGHTFS REFVA TYYADSVQG NSLRPEDTALYYCAA PTGYPY LVTVSS 140 A03150 470 EVQLVESGGGVVQPG 21 EYALG 5 WFRQAPGKE 43 AINWGGGW 471 RFTISRDNAKNTLYLQM 11 SSDYAGGN 7 WGQGT 0091 GSLRLSCSASGHTFS REFVA TYYADSVKG NSLRPGDTALYYCAA PTGYPY LVTVSS 141 A03150 44 EVQLVESGGGVVQPG 21 EYALG 13 WFRQAPGM 22 AINWGGGW 471 RFTISRDNAKNTLYLQM 11 SSDYAGGN 7 WGQGT 0092 GSLRLSCAASGHTFS EREFVA TYYADSVQG NSLRPGDTALYYCAA PTGYPY LVTVSS 142 A03150 44 EVQLVESGGGVVQPG 21 EYALG 13 WFRQAPGM 22 AINWGGGW 45 RFTISRDNAKNTLYLQM 11 SSDYAGGN 7 WGQGT 0093 GSLRLSCAASGHTFS EREFVA TYYADSVQG NSLRPEDTALYYCAA PTGYPY LVTVSS 143 A03150 44 EVQLVESGGGVVQPG 21 EYALG 13 WFRQAPGM 43 AINWGGGW 471 RFTISRDNAKNTLYLQM 11 SSDYAGGN 7 WGQGT 0094 GSLRLSCAASGHTFS EREFVA TYYADSVKG NSLRPGDTALYYCAA PTGYPY LVTVSS
ID VHH ID FR1 ID CDR1 ID FR2 ID CDR2 ID FR3 ID CDR3 ID FR4 144 A03150 44 EVQLVESGGGVVQPG 21 EYALG 13 WFRQAPGM 43 AINWGGGW 45 RFTISRDNAKNTLYLQM 11 SSDYAGGN 7 WGQGT 0095 GSLRLSCAASGHTFS EREFVA TYYADSVKG NSLRPEDTALYYCAA PTGYPY LVTVSS 145 A03150 44 EVQLVESGGGVVQPG 21 EYALG 5 WFRQAPGKE 22 AINWGGGW 471 RFTISRDNAKNTLYLQM 11 SSDYAGGN 7 WGQGT 0096 GSLRLSCAASGHTFS REFVA TYYADSVQG NSLRPGDTALYYCAA PTGYPY LVTVSS 146 A03150 44 EVQLVESGGGVVQPG 21 EYALG 5 WFRQAPGKE 22 AINWGGGW 45 RFTISRDNAKNTLYLQM 11 SSDYAGGN 7 WGQGT 0097 GSLRLSCAASGHTFS REFVA TYYADSVQG NSLRPEDTALYYCAA PTGYPY LVTVSS 147 A03150 44 EVQLVESGGGVVQPG 21 EYALG 5 WFRQAPGKE 43 AINWGGGW 471 RFTISRDNAKNTLYLQM 11 SSDYAGGN 7 WGQGT 0098 GSLRLSCAASGHTFS REFVA TYYADSVKG NSLRPGDTALYYCAA PTGYPY LVTVSS 39 A03150 44 EVQLVESGGGVVQPG 21 EYALG 5 WFRQAPGKE 43 AINWGGGW 45 RFTISRDNAKNTLYLQM 11 SSDYAGGN 7 WGQGT 0099 GSLRLSCAASGHTFS REFVA TYYADSVKG NSLRPEDTALYYCAA PTGYPY LVTVSS T028501 817 40 A03150 46 DVQLVESGGGVVQP 21 EYALG 5 WFRQAPGKE 43 AINWGGGW 45 RFTISRDNAKNTLYLQM 11 SSDYAGGN 7 WGQGT 0099 GGSLRLSCAASGHTFS REFVA TYYADSVKG NSLRPEDTALYYCAA PTGYPY LVTVSS (E1D) T028501 817(E1D ) 148 A03150 470 EVQLVESGGGVVQPG 21 EYALG 5 WFRQAPGKE 43 AINWGGGW 45 RFTISRDNAKNTLYLQM 11 SSDYAGGN 7 WGQGT 0100 GSLRLSCSASGHTFS REFVA TYYADSVKG NSLRPEDTALYYCAA PTGYPY LVTVSS 149 A03150 470 EVQLVESGGGVVQPG 21 EYALG 13 WFRQAPGM 43 AINWGGGW 45 RFTISRDNAKNTLYLQM 11 SSDYAGGN 7 WGQGT 0101 GSLRLSCSASGHTFS EREFVA TYYADSVKG NSLRPEDTALYYCAA PTGYPY LVTVSS 150 A03150 36 EVQLVESGGGVVQPG 17 TYTMG 5 WFRQAPGKE 18 AIIWSGSNTY 472 RFTISRDNAKSTVYLQM 3 QHFGPIGLT 7 WGQGT 0251 GSLRLSCAASGLTFS REFVA YADSVKG NSLRPEDTALYHCAA TRGYNY LVTVSS 151 A03150 36 EVQLVESGGGVVQPG 17 TYTMG 5 WFRQAPGKE 18 AIIWSGSNTY 473 RFTISRDNAKNTVYLQ 3 QHFGPIGLT 7 WGQGT 0252 GSLRLSCAASGLTFS REFVA YADSVKG MNSLRPEDTALYHCAA TRGYNY LVTVSS
ID VHH ID FR1 ID CDR1 ID FR2 ID CDR2 ID FR3 ID CDR3 ID FR4 152 A03150 36 EVQLVESGGGVVQPG 17 TYTMG 5 WFRQAPGKE 18 AIIWSGSNTY 474 RFTISRDNAKSTVYLQM 3 QHFGPIGLT 7 WGQGT 0253 GSLRLSCAASGLTFS REFVA YADSVKG NSLRPEDTALYYCAA TRGYNY LVTVSS 153 A03150 36 EVQLVESGGGVVQPG 17 TYTMG 5 WFRQAPGKE 18 AIIWSGSNTY 37 RFTISRDNAKNTVYLQ 3 QHFGPIGLT 7 WGQGT 0254 GSLRLSCAASGLTFS REFVA YADSVKG MNSLRPEDTALYYCAA TRGYNY LVTVSS 154 A03150 36 EVQLVESGGGVVQPG 17 TYTMG 5 WFRQAPGKE 18 AIIWSGSNTY 37 RFTISRDNAKNTVYLQ 249 QHFGPIGLT 7 WGQGT 0379 GSLRLSCAASGLTFS REFVA YADSVKG MNSLRPEDTALYYCAA TRGYAY LVTVSS 155 A03150 36 EVQLVESGGGVVQPG 17 TYTMG 5 WFRQAPGKE 18 AIIWSGSNTY 37 RFTISRDNAKNTVYLQ 250 QHFGPIGLT 7 WGQGT 0382 GSLRLSCAASGLTFS REFVA YADSVKG MNSLRPEDTALYYCAA TRGYFY LVTVSS 156 A03150 36 EVQLVESGGGVVQPG 17 TYTMG 5 WFRQAPGKE 18 AIIWSGSNTY 37 RFTISRDNAKNTVYLQ 251 QHFGPIGLT 7 WGQGT 0383 GSLRLSCAASGLTFS REFVA YADSVKG MNSLRPEDTALYYCAA TRGYGY LVTVSS 31 A03150 36 EVQLVESGGGVVQPG 17 TYTMG 5 WFRQAPGKE 18 AIIWSGSNTY 37 RFTISRDNAKNTVYLQ 33 QHFGPIGLT 7 WGQGT 0384 GSLRLSCAASGLTFS REFVA YADSVKG MNSLRPEDTALYYCAA TRGYHY LVTVSS T028501 789 32 A03150 38 DVQLVESGGGVVQP 17 TYTMG 5 WFRQAPGKE 18 AIIWSGSNTY 37 RFTISRDNAKNTVYLQ 33 QHFGPIGLT 7 WGQGT 0384 GGSLRLSCAASGLTFS REFVA YADSVKG MNSLRPEDTALYYCAA TRGYHY LVTVSS (E1D) T028501 789(E1D ) 157 A03150 36 EVQLVESGGGVVQPG 17 TYTMG 5 WFRQAPGKE 18 AIIWSGSNTY 37 RFTISRDNAKNTVYLQ 254 QHFGPIGLT 7 WGQGT 0385 GSLRLSCAASGLTFS REFVA YADSVKG MNSLRPEDTALYYCAA TRGYIY LVTVSS 158 A03150 36 EVQLVESGGGVVQPG 17 TYTMG 5 WFRQAPGKE 18 AIIWSGSNTY 37 RFTISRDNAKNTVYLQ 252 QHFGPIGLT 7 WGQGT 0387 GSLRLSCAASGLTFS REFVA YADSVKG MNSLRPEDTALYYCAA TRGYLY LVTVSS 159 A03150 36 EVQLVESGGGVVQPG 17 TYTMG 5 WFRQAPGKE 18 AIIWSGSNTY 37 RFTISRDNAKNTVYLQ 253 QHFGPIGLT 7 WGQGT 0394 GSLRLSCAASGLTFS REFVA YADSVKG MNSLRPEDTALYYCAA TRGYYY LVTVSS
ID VHH ID FR1 ID CDR1 ID FR2 ID CDR2 ID FR3 ID CDR3 ID FR4 115 A03150 438 EVQLVESGGGLVQTG 328 TYTMA 347 WFRQTPGNE 330 ALSWRSGTT 439 RFTISRVIAENTVYLQM 323 QQYGAISY 7 WGQGT 05F01 GSLRLSCAASGGAFS REFVA VYGDSVKG NSLKPEDTAVYFCAA NRNGFFY LVTVSS 116 A03150 440 EVQLVESGGGLVQAG 328 TYTMA 347 WFRQTPGNE 331 TISWRSEITV 441 RFTISRDKAENTVYLQM 326 QEFGAISYN 7 WGQGT 06F03 GSLRLSCVASGRAFS REFVA YGDSVKG NSLKPEDTAVYFCAA TKGYFY LVTVSS 117 A03150 442 EVQLVESGGGLVQAG 328 TYTMA 347 WFRQTPGNE 331 TISWRSEITV 443 RFTISRDNAENTVYLQ 327 QEFGAISYN 7 WGQGT 02G08 GSLRLSCAASGRAFS REFVA YGDSVKG MNSLRPEDTAVYFCAA RKGYFY LVTVSS 160 A03150 476 EVQLVESGGGVVQPG 328 TYTMA 347 WFRQTPGNE 331 TISWRSEITV 475 RFTISRDNAENTVYLQ 327 QEFGAISYN 7 WGQGT 0333 GSLRLSCAASGRAFS REFVA YGDSVKG MNSLRPEDTALYFCAA RKGYFY LVTVSS 161 A03150 476 EVQLVESGGGVVQPG 328 TYTMA 480 WFRQAPGN 331 TISWRSEITV 477 RFTISRDNAENTVYLQ 327 QEFGAISYN 7 WGQGT 0334 GSLRLSCAASGRAFS EREFVA YGDSVKG MNSLRPEDTALYYCAA RKGYFY LVTVSS 162 A03150 476 EVQLVESGGGVVQPG 328 TYTMA 480 WFRQAPGN 331 TISWRSEITV 37 RFTISRDNAKNTVYLQ 327 QEFGAISYN 7 WGQGT 0335 GSLRLSCAASGRAFS EREFVA YGDSVKG MNSLRPEDTALYYCAA RKGYFY LVTVSS 163 A03150 476 EVQLVESGGGVVQPG 328 TYTMA 480 WFRQAPGN 332 TISWRSEITV 477 RFTISRDNAENTVYLQ 327 QEFGAISYN 7 WGQGT 0336 GSLRLSCAASGRAFS EREFVA YADSVKG MNSLRPEDTALYYCAA RKGYFY LVTVSS 164 A03150 476 EVQLVESGGGVVQPG 328 TYTMA 480 WFRQAPGN 332 TISWRSEITV 37 RFTISRDNAKNTVYLQ 327 QEFGAISYN 7 WGQGT 0337 GSLRLSCAASGRAFS EREFVA YADSVKG MNSLRPEDTALYYCAA RKGYFY LVTVSS 165 A03150 476 EVQLVESGGGVVQPG 328 TYTMA 5 WFRQAPGKE 331 TISWRSEITV 477 RFTISRDNAENTVYLQ 327 QEFGAISYN 7 WGQGT 0338 GSLRLSCAASGRAFS REFVA YGDSVKG MNSLRPEDTALYYCAA RKGYFY LVTVSS 166 A03150 476 EVQLVESGGGVVQPG 328 TYTMA 5 WFRQAPGKE 331 TISWRSEITV 37 RFTISRDNAKNTVYLQ 327 QEFGAISYN 7 WGQGT 0339 GSLRLSCAASGRAFS REFVA YGDSVKG MNSLRPEDTALYYCAA RKGYFY LVTVSS 167 A03150 476 EVQLVESGGGVVQPG 328 TYTMA 5 WFRQAPGKE 332 TISWRSEITV 477 RFTISRDNAENTVYLQ 327 QEFGAISYN 7 WGQGT 0340 GSLRLSCAASGRAFS REFVA YADSVKG MNSLRPEDTALYYCAA RKGYFY LVTVSS 168 A03150 476 EVQLVESGGGVVQPG 328 TYTMA 5 WFRQAPGKE 332 TISWRSEITV 37 RFTISRDNAKNTVYLQ 327 QEFGAISYN 7 WGQGT 0341 GSLRLSCAASGRAFS REFVA YADSVKG MNSLRPEDTALYYCAA RKGYFY LVTVSS 169 A03150 476 EVQLVESGGGVVQPG 328 TYTMA 480 WFRQAPGN 331 TISWRSEITV 475 RFTISRDNAENTVYLQ 327 QEFGAISYN 7 WGQGT 0342 GSLRLSCAASGRAFS EREFVA YGDSVKG MNSLRPEDTALYFCAA RKGYFY LVTVSS
ID VHH ID FR1 ID CDR1 ID FR2 ID CDR2 ID FR3 ID CDR3 ID FR4 170 A03150 476 EVQLVESGGGVVQPG 328 TYTMA 347 WFRQTPGNE 331 TISWRSEITV 477 RFTISRDNAENTVYLQ 327 QEFGAISYN 7 WGQGT 0343 GSLRLSCAASGRAFS REFVA YGDSVKG MNSLRPEDTALYYCAA RKGYFY LVTVSS 118 A03150 444 EVQLVESGGGLVQAG 17 TYTMG 5 WFRQAPGKE 344 SIIWSGSNTV 445 RFTISRENAKNTVYLQM 339 QHFGPVSL 7 WGQGT 02G06 DSLRLSCAASGLTFS REFVA YADSVKG NSLKPEDTAVYHCAA TTRGYYY LVTVSS 119 A03150 444 EVQLVESGGGLVQAG 342 TYTVG 353 WFRQAPGKE 345 SMIYSGSNTL 446 RFTISRDNAKNTVFLQ 340 QHFGPISLT 7 WGQGT 02C10 DSLRLSCAASGLTFS REFVG YADSVKG MNSLKPEDTAVYHCAA TRGYFY LVTVSS 171 A03150 36 EVQLVESGGGVVQPG 17 TYTMG 5 WFRQAPGKE 344 SIIWSGSNTV 478 RFTISRENAKNTVYLQM 339 QHFGPVSL 7 WGQGT 0010 GSLRLSCAASGLTFS REFVA YADSVKG NSLRPEDTALYHCAA TTRGYYY LVTVSS 172 A03150 36 EVQLVESGGGVVQPG 17 TYTMG 5 WFRQAPGKE 344 SIIWSGSNTV 473 RFTISRDNAKNTVYLQ 339 QHFGPVSL 7 WGQGT 0011 GSLRLSCAASGLTFS REFVA YADSVKG MNSLRPEDTALYHCAA TTRGYYY LVTVSS 173 A03150 36 EVQLVESGGGVVQPG 17 TYTMG 5 WFRQAPGKE 344 SIIWSGSNTV 479 RFTISRENAKNTVYLQM 339 QHFGPVSL 7 WGQGT 0012 GSLRLSCAASGLTFS REFVA YADSVKG NSLRPEDTALYYCAA TTRGYYY LVTVSS 174 A03150 36 EVQLVESGGGVVQPG 17 TYTMG 5 WFRQAPGKE 344 SIIWSGSNTV 37 RFTISRDNAKNTVYLQ 339 QHFGPVSL 7 WGQGT 0013 GSLRLSCAASGLTFS REFVA YADSVKG MNSLRPEDTALYYCAA TTRGYYY LVTVSS 114 A03150 437 EVQLVESGGGLAQTG 289 SYDMG 259 WFRQAPGKE 291 AIRWSAGST 295 RFAIARTNANNIMYLQ 257 VRPSFRPLS 7 WGQGT 01D07 GSLRLSCAASGRTFN REFVS VYGNSVKG MNSLKPEDTAVYYCAA TYWKDYDN LVTVSS 175 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 291 AIRWSAGST 296 RFAIARTNANNIMYLQ 257 VRPSFRPLS 7 WGQGT 0014 GSLRLSCAASGRTFN REFVS VYGNSVKG MNSLRPEDTALYYCAA TYWKDYDN LVTVSS 176 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 5 WFRQAPGKE 291 AIRWSAGST 296 RFAIARTNANNIMYLQ 257 VRPSFRPLS 7 WGQGT 0015 GSLRLSCAASGRTFN REFVA VYGNSVKG MNSLRPEDTALYYCAA TYWKDYDN LVTVSS 177 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 292 AIRWSAGST 296 RFAIARTNANNIMYLQ 257 VRPSFRPLS 7 WGQGT 0016 GSLRLSCAASGRTFN REFVS VYANSVKG MNSLRPEDTALYYCAA TYWKDYDN LVTVSS 178 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 293 AIRWSAGST 296 RFAIARTNANNIMYLQ 257 VRPSFRPLS 7 WGQGT 0017 GSLRLSCAASGRTFN REFVS VYGDSVKG MNSLRPEDTALYYCAA TYWKDYDN LVTVSS 179 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 291 AIRWSAGST 297 RFTIARTNANNIMYLQ 257 VRPSFRPLS 7 WGQGT 0018 GSLRLSCAASGRTFN REFVS VYGNSVKG MNSLRPEDTALYYCAA TYWKDYDN LVTVSS
ID VHH ID FR1 ID CDR1 ID FR2 ID CDR2 ID FR3 ID CDR3 ID FR4 180 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 291 AIRWSAGST 298 RFAISRTNANNIMYLQ 257 VRPSFRPLS 7 WGQGT 0019 GSLRLSCAASGRTFN REFVS VYGNSVKG MNSLRPEDTALYYCAA TYWKDYDN LVTVSS 181 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 291 AIRWSAGST 299 RFAIARDNANNIMYLQ 257 VRPSFRPLS 7 WGQGT 0020 GSLRLSCAASGRTFN REFVS VYGNSVKG MNSLRPEDTALYYCAA TYWKDYDN LVTVSS 182 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 291 AIRWSAGST 300 RFAIARTNAKNIMYLQ 257 VRPSFRPLS 7 WGQGT 0021 GSLRLSCAASGRTFN REFVS VYGNSVKG MNSLRPEDTALYYCAA TYWKDYDN LVTVSS 183 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 291 AIRWSAGST 301 RFAIARTNANNTMYLQ 257 VRPSFRPLS 7 WGQGT 0022 GSLRLSCAASGRTFN REFVS VYGNSVKG MNSLRPEDTALYYCAA TYWKDYDN LVTVSS 184 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 291 AIRWSAGST 302 RFAIARTNANNIVYLQ 257 VRPSFRPLS 7 WGQGT 0023 GSLRLSCAASGRTFN REFVS VYGNSVKG MNSLRPEDTALYYCAA TYWKDYDN LVTVSS 185 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 291 AIRWSAGST 303 RFAIARTNANNILYLQM 257 VRPSFRPLS 7 WGQGT 0024 GSLRLSCAASGRTFN REFVS VYGNSVKG NSLRPEDTALYYCAA TYWKDYDN LVTVSS 186 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 294 AIRWSAGST 296 RFAIARTNANNIMYLQ 257 VRPSFRPLS 7 WGQGT 0025 GSLRLSCAASGRTFN REFVS VYADSVKG MNSLRPEDTALYYCAA TYWKDYDN LVTVSS 187 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 291 AIRWSAGST 304 RFTISRTNANNIMYLQ 257 VRPSFRPLS 7 WGQGT 0026 GSLRLSCAASGRTFN REFVS VYGNSVKG MNSLRPEDTALYYCAA TYWKDYDN LVTVSS 188 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 291 AIRWSAGST 305 RFTISRTNAKNIMYLQ 257 VRPSFRPLS 7 WGQGT 0027 GSLRLSCAASGRTFN REFVS VYGNSVKG MNSLRPEDTALYYCAA TYWKDYDN LVTVSS 189 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 291 AIRWSAGST 306 RFTISRTNAKNTMYLQ 257 VRPSFRPLS 7 WGQGT 0028 GSLRLSCAASGRTFN REFVS VYGNSVKG MNSLRPEDTALYYCAA TYWKDYDN LVTVSS 190 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 291 AIRWSAGST 307 RFTISRDNAKNTMYLQ 257 VRPSFRPLS 7 WGQGT 0029 GSLRLSCAASGRTFN REFVS VYGNSVKG MNSLRPEDTALYYCAA TYWKDYDN LVTVSS 191 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 292 AIRWSAGST 30z RFTISRDNAKNTMYLQ 257 VRPSFRPLS 7 WGQGT 0030 GSLRLSCAASGRTFN REFVS VYANSVKG MNSLRPEDTALYYCAA TYWKDYDN LVTVSS 192 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 294 AIRWSAGST 307 RFTISRDNAKNTMYLQ 257 VRPSFRPLS 7 WGQGT 0031 GSLRLSCAASGRTFN REFVS VYADSVKG MNSLRPEDTALYYCAA TYWKDYDN LVTVSS
ID VHH ID FR1 ID CDR1 ID FR2 ID CDR2 ID FR3 ID CDR3 ID FR4 193 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 294 AIRWSAGST 37 RFTISRDNAKNTVYLQ 257 VRPSFRPLS 7 WGQGT 0032 GSLRLSCAASGRTFN REFVS VYADSVKG MNSLRPEDTALYYCAA TYWKDYDN LVTVSS 194 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 294 AIRWSAGST 45 RFTISRDNAKNTLYLQM 257 VRPSFRPLS 7 WGQGT 0033 GSLRLSCAASGRTFN REFVS VYADSVKG NSLRPEDTALYYCAA TYWKDYDN LVTVSS 195 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 291 AIRWSAGST 37 RFTISRDNAKNTVYLQ 257 VRPSFRPLS 7 WGQGT 0034 GSLRLSCAASGRTFN REFVS VYGNSVKG MNSLRPEDTALYYCAA TYWKDYDN LVTVSS 196 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 291 AIRWSAGST 45 RFTISRDNAKNTLYLQM 257 VRPSFRPLS 7 WGQGT 0035 GSLRLSCAASGRTFN REFVS VYGNSVKG NSLRPEDTALYYCAA TYWKDYDN LVTVSS 197 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 294 AIRWSAGST 308 RFTISRTNANNILYLQM 257 VRPSFRPLS 7 WGQGT 0368 GSLRLSCAASGRTFN REFVS VYADSVKG NSLRPEDTALYYCAA TYWKDYDN LVTVSS 198 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 5 WFRQAPGKE 294 AIRWSAGST 308 RFTISRTNANNILYLQM 257 VRPSFRPLS 7 WGQGT 0369 GSLRLSCAASGRTFN REFVA VYADSVKG NSLRPEDTALYYCAA TYWKDYDN LVTVSS 199 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 294 AIRWSAGST 309 RFTISRDNANNILYLQM 257 VRPSFRPLS 7 WGQGT 0370 GSLRLSCAASGRTFN REFVS VYADSVKG NSLRPEDTALYYCAA TYWKDYDN LVTVSS 200 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 5 WFRQAPGKE 294 AIRWSAGST 310 RFTISRDNANNTLYLQ 257 VRPSFRPLS 7 WGQGT 0345 GSLRLSCAASGRTFN REFVA VYADSVKG MNSLRPEDTALYYCAA TYWKDYDN LVTVSS 201 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 5 WFRQAPGKE 294 AIRWSAGST 311 RFTISRDNAKNILYLQM 257 VRPSFRPLS 7 WGQGT 0346 GSLRLSCAASGRTFN REFVA VYADSVKG NSLRPEDTALYYCAA TYWKDYDN LVTVSS 202 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 5 WFRQAPGKE 294 AIRWSAGST 309 RFTISRDNANNILYLQM 257 VRPSFRPLS 7 WGQGT 0347 GSLRLSCAASGRTFN REFVA VYADSVKG NSLRPEDTALYYCAA TYWKDYDN LVTVSS 203 A03150 312 EVQLVESGGGVVQPG 289 SYDMG 5 WFRQAPGKE 294 AIRWSAGST 45 RFTISRDNAKNTLYLQM 257 VRPSFRPLS 7 WGQGT 0348 GSLRLSCAASGRTFN REFVA VYADSVKG NSLRPEDTALYYCAA TYWKDYDN LVTVSS 204 A03150 313 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 294 AIRWSAGST 308 RFTISRTNANNILYLQM 257 VRPSFRPLS 7 WGQGT 0406 GSLRLSCAASGRTFE REFVS VYADSVKG NSLRPEDTALYYCAA TYWKDYDN LVTVSS 205 A03150 314 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 294 AIRWSAGST 308 RFTISRTNANNILYLQM 257 VRPSFRPLS 7 WGQGT 0407 GSLRLSCAASGRTFG REFVS VYADSVKG NSLRPEDTALYYCAA TYWKDYDN LVTVSS
ID VHH ID FR1 ID CDR1 ID FR2 ID CDR2 ID FR3 ID CDR3 ID FR4 206 A03150 315 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 294 AIRWSAGST 308 RFTISRTNANNILYLQM 257 VRPSFRPLS 7 WGQGT 0408 GSLRLSCAASGRTFP REFVS VYADSVKG NSLRPEDTALYYCAA TYWKDYDN LVTVSS 207 A03150 316 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 294 AIRWSAGST 308 RFTISRTNANNILYLQM 257 VRPSFRPLS 7 WGQGT 0409 GSLRLSCAASGRTFS REFVS VYADSVKG NSLRPEDTALYYCAA TYWKDYDN LVTVSS 208 A03150 314 EVQLVESGGGVVQPG 289 SYDMG 259 WFRQAPGKE 294 AIRWSAGST 308 RFTISRTNANNILYLQM 257 VRPSFRPLS 7 WGQGT 0410 GSLRLSCAASGRTFT REFVS VYADSVKG NSLRPEDTALYYCAA TYWKDYDN LVTVSS 54714R0410 623 EVQLVESGGGLVQPG 613 SYDMS 625 WVRQPPGK 614 TINRGGSSTS 642 RFTISRDNAENTLYLQM 610 GDHRGPW 640 RGQGTL T023200 GSLRLSCAASGFTFS GIEWVS YRVPVEG NSLKTEDTAVYYCTT YN VTVSS 178 549 T028500 624 EVQLVESGGGVVQPG 613 SYDMS 625 WVRQPPGK 614 TINRGGSSTS 643 RFTISRDNAENTLYLQM 610 GDHRGPW 640 RGQGTL 006 GSLRLSCAASGFTFS GIEWVS YRVPVEG NSLRTEDTALYYCTT YN VTVSS 550 T028500 624 EVQLVESGGGVVQPG 613 SYDMS 625 WVRQPPGK 614 TINRGGSSTS 644 RFTISRDNAENTLYLQM 610 GDHRGPW 640 RGQGTL 007 GSLRLSCAASGFTFS GIEWVS YRVPVEG NSLRSEDTALYYCTT YN VTVSS 551 T028500 624 EVQLVESGGGVVQPG 613 SYDMS 625 WVRQPPGK 614 TINRGGSSTS 643 RFTISRDNAENTLYLQM 610 GDHRGPW 7 WGQGTL 008 GSLRLSCAASGFTFS GIEWVS YRVPVEG NSLRTEDTALYYCTT YN VTVSS 552 T028500 624 EVQLVESGGGVVQPG 613 SYDMS 626 WVRQAPGK 614 TINRGGSSTS 645 RFTISRDNAKNTLYLQM 610 GDHRGPW 640 RGQGTL 009 GSLRLSCAASGFTFS GIEWVS YRVPVEG NSLRTEDTALYYCTT YN VTVSS 553 T028500 624 EVQLVESGGGVVQPG 613 SYDMS 626 WVRQAPGK 615 TINRGGSSTS 645 RFTISRDNAKNTLYLQM 610 GDHRGPW 640 RGQGTL 010 GSLRLSCAASGFTFS GIEWVS YADSVKG NSLRTEDTALYYCTT YN VTVSS 554 T028500 624 EVQLVESGGGVVQPG 613 SYDMS 626 WVRQAPGK 614 TINRGGSSTS 643 RFTISRDNAENTLYLQM 610 GDHRGPW 640 RGQGTL 011 GSLRLSCAASGFTFS GIEWVS YRVPVEG NSLRTEDTALYYCTT YN VTVSS 555 T028500 624 EVQLVESGGGVVQPG 613 SYDMS 627 WVRQPPGK 614 TINRGGSSTS 643 RFTISRDNAENTLYLQM 610 GDHRGPW 640 RGQGTL 012 GSLRLSCAASGFTFS GLEWVS YRVPVEG NSLRTEDTALYYCTT YN VTVSS 556 T028500 624 EVQLVESGGGVVQPG 613 SYDMS 625 WVRQPPGK 616 TINRGGSSTS 643 RFTISRDNAENTLYLQM 610 GDHRGPW 640 RGQGTL 013 GSLRLSCAASGFTFS GIEWVS YAVPVEG NSLRTEDTALYYCTT YN VTVSS 557 T028500 624 EVQLVESGGGVVQPG 613 SYDMS 625 WVRQPPGK 617 TINRGGSSTS 643 RFTISRDNAENTLYLQM 610 GDHRGPW 640 RGQGTL 014 GSLRLSCAASGFTFS GIEWVS YRDPVEG NSLRTEDTALYYCTT YN VTVSS
ID VHH ID FR1 ID CDR1 ID FR2 ID CDR2 ID FR3 ID CDR3 ID FR4 558 T028500 624 EVQLVESGGGVVQPG 613 SYDMS 625 WVRQPPGK 618 TINRGGSSTS 643 RFTISRDNAENTLYLQM 610 GDHRGPW 640 RGQGTL 015 GSLRLSCAASGFTFS GIEWVS YRVSVEG NSLRTEDTALYYCTT YN VTVSS 559 T028500 624 EVQLVESGGGVVQPG 613 SYDMS 625 WVRQPPGK 620 TINRGGSSTS 643 RFTISRDNAENTLYLQM 610 GDHRGPW 640 RGQGTL 016 GSLRLSCAASGFTFS GIEWVS YRVPVKG NSLRTEDTALYYCTT YN VTVSS 560 T028500 624 EVQLVESGGGVVQPG 613 SYDMS 625 WVRQPPGK 614 TINRGGSSTS 645 RFTISRDNAKNTLYLQM 610 GDHRGPW 640 RGQGTL 017 GSLRLSCAASGFTFS GIEWVS YRVPVEG NSLRTEDTALYYCTT YN VTVSS 561 T028500 624 EVQLVESGGGVVQPG 613 SYDMS 625 WVRQPPGK 614 TINRGGSSTS 646 RFTISRDNAENTLYLQM 610 GDHRGPW 640 RGQGTL 018 GSLRLSCAASGFTFS GIEWVS YRVPVEG NSLRPEDTALYYCTT YN VTVSS 562 T028500 624 EVQLVESGGGVVQPG 613 SYDMS 625 WVRQPPGK 620 TINRGGSSTS 645 RFTISRDNAKNTLYLQM 610 GDHRGPW 640 RGQGTL 557 GSLRLSCAASGFTFS GIEWVS YAVSVKG NSLRTEDTALYYCTT YN VTVSS 563 T028500 624 EVQLVESGGGVVQPG 613 SYDMS 625 WVRQPPGK 621 TINRGGSSTS 645 RFTISRDNAKNTLYLQM 610 GDHRGPW 640 RGQGTL 558 GSLRLSCAASGFTFS GIEWVS YAVPVKG NSLRTEDTALYYCTT YN VTVSS 548 T023200 601 EVQLVESGGGLVQAG 598 NHAMG 603 WFRQTPGKE 591 GITWRGGST 607 RFTISRDNAKNTLYLEM 582 DLRPFGPIT 7 WGQGTL 134 GSLRLSCAASGRTFD REFVA HYADSVKG NSLKPEDTAVYYCTA TTPQRINY VTVSS 564 T028500 602 EVQLVESGGGVVQPG 598 NHAMG 603 WFRQTPGKE 591 GITWRGGST 608 FTISRDNAKNTLYLEMN 582 DLRPFGPIT 7 WGQGTL 003 GSLRLSCAASGRTFD REFVA HYADSVKGR SLRPEDTALYYCTA TTPQRINY VTVSS 565 T028500 602 EVQLVESGGGVVQPG 598 NHAMG 603 WFRQTPGKE 591 GITWRGGST 609 RFTISRDNAKNTLYLQM 582 DLRPFGPIT 7 WGQGTL 004 GSLRLSCAASGRTFD REFVA HYADSVKG NSLRPEDTALYYCTA TTPQRINY VTVSS 566 T028500 602 EVQLVESGGGVVQPG 598 NHAMG 5 WFRQAPGKE 591 GITWRGGST 609 RFTISRDNAKNTLYLQM 582 DLRPFGPIT 7 WGQGTL 005 GSLRLSCAASGRTFD REFVA HYADSVKG NSLRPEDTALYYCTA TTPQRINY VTVSS 567 T028500 602 EVQLVESGGGVVQPG 598 NHAMG 5 WFRQAPGKE 591 GITWRGGST 609 RFTISRDNAKNTLYLQM 583 DLVPFGPIT 7 WGQGTL 591 GSLRLSCAASGRTFD REFVA HYADSVKG NSLRPEDTALYYCTA TTPQRINY VTVSS 568 T028500 602 EVQLVESGGGVVQPG 599 NLAMG 5 WFRQAPGKE 591 GITWRGGST 609 RFTISRDNAKNTLYLQM 582 DLRPFGPIT 7 WGQGTL 0588 GSLRLSCAASGRTFD REFVA HYADSVKG NSLRPEDTALYYCTA TTPQRINY VTVSS 569 T028500 602 EVQLVESGGGVVQPG 598 NHAMG 5 WFRQAPGKE 591 GITWRGGST 609 RFTISRDNAKNTLYLQM 584 DLRPFAPIT 7 WGQGTL 582 GSLRLSCAASGRTFD REFVA HYADSVKG NSLRPEDTALYYCTA TTPQRINY VTVSS
ID VHH ID FR1 ID CDR1 ID FR2 ID CDR2 ID FR3 ID CDR3 ID FR4 570 T028500 602 EVQLVESGGGVVQPG 598 NHAMG 591 GITWRGGST 609 RFTISRDNAKNTLYLQM 585 DLRPFGPIT 7 WGQGTL 593 GSLRLSCAASGRTFD
Figure imgf000400_0001
Figure imgf000400_0002
571 T028500 602 EVQLVESGGGVVQPG 598 NHAMG 591 GITWRGGST 609 RFTISRDNAKNTLYLQM 586 DLRPFGPIT 7 WGQGTL 592 GSLRLSCAASGRTFD
Figure imgf000400_0003
Figure imgf000400_0004
572 T028500 602 EVQLVESGGGVVQPG 600 NEAMG 591 GITWRGGST 609 RFTISRDNAKNTLYLQM 582 DLRPFGPIT 7 WGQGTL 587 GSLRLSCAASGRTFD
Figure imgf000400_0005
Figure imgf000400_0006
573 T028500 602 EVQLVESGGGVVQPG 598 NHAMG 591 GITWRGGST 609 RFTISRDNAKNTLYLQM 587 VLRPFGPIT 7 WGQGTL 581 GSLRLSCAASGRTFD
Figure imgf000400_0008
Figure imgf000400_0009
574 T028500 602 EVQLVESGGGVVQPG 598 NHAMG 591 GITWRGGST 609 RFTISRDNAKNTLYLQM 588 DLRPFGPIT 7 WGQGTL 590 GSLRLSCAASGRTFD
Figure imgf000400_0010
Figure imgf000400_0011
575 T028500 602 EVQLVESGGGVVQPG 598 NHAMG 592 GITNRGGST 609 RFTISRDNAKNTLYLQM 582 DLRPFGPIT 7 WGQGTL 594 GSLRLSCAASGRTFD
Figure imgf000400_0013
Figure imgf000400_0012
576 T028500 602 EVQLVESGGGVVQPG 598 NHAMG 591 GITWRGGST 609 RFTISRDNAKNTLYLQM 589 DLRPFFPITT 7 WGQGTL 583 GSLRLSCAASGRTFD
Figure imgf000400_0007
Figure imgf000400_0014
TPQRINY
Figure imgf000400_0015
62 ALB230079 EVQLVESGGGVVQPG 87 SFGMS 84 WVRQAPGK 88 SISGSGSDTL 90 RFTISRDNSKNTLYLQM 82 GGSLSR 86 SSQGTL 2
Figure imgf000400_0016
Table A-10: Serum albumin binding ISVD sequences (“ID” refers to the SEQ ID NO as used herein) Name ID Amino acid sequence Alb8 47 EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDT LYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSS Alb23 48 EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDT LYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSS Alb129 49 EVQLVESGGGVVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDT LYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTATYYCTIGGSLSRSSQGTLVTVSSA Alb132 50 EVQLVESGGGVVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSD TLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTATYYCTIGGSLSRSSQGTLVTVSSA Alb11 51 EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDT LYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSS Alb11 52 EVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDT (S112K)-A LYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVKVSSA Alb82 53 EVQLVESGGGVVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDT LYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTALYYCTIGGSLSRSSQGTLVTVSS Alb82-A 54 EVQLVESGGGVVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDT LYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTALYYCTIGGSLSRSSQGTLVTVSSA Alb82-AA 55 EVQLVESGGGVVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDT LYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTALYYCTIGGSLSRSSQGTLVTVSSAA Alb82-AAA 56 EVQLVESGGGVVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDT LYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTALYYCTIGGSLSRSSQGTLVTVSSAAA Alb82-G 57 EVQLVESGGGVVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDT LYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTALYYCTIGGSLSRSSQGTLVTVSSG Alb82-GG 58 EVQLVESGGGVVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDT LYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTALYYCTIGGSLSRSSQGTLVTVSSGG Alb82-GGG 59 EVQLVESGGGVVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDT LYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTALYYCTIGGSLSRSSQGTLVTVSSGGG Alb223 60 EVQLVESGGGVVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSD TLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTALYYCTIGGSLSRSSQGTLVTVSSA AlbX00001 61 EVQLVESGGGVVQPGGSLRLSCAASGLTFSSYAMGWFRQAPGKERERVVSISRGGGYT YYADSVKGRFTISRDNSENTVYLQMNSLRPEDTALYYCAAARYWATGSEYEFDYWGQG TLVTVSS Alb23002 62 EVQLVESGGGVVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSD TLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTALYYCTIGGSLSRSSQGTLVTVSS Table A-11: Linker sequences (“ID” refers to the SEQ ID NO as used herein) Name ID Amino acid sequence 3A linker 63 AAA 5GS linker 64 GGGGS 7GS linker 65 SGGSGGS 8GS linker 66 GGGGSGGS 9GS linker 67 GGGGSGGGS 10GS linker 68 GGGGSGGGGS 15GS linker 69 GGGGSGGGGSGGGGS 18GS linker 70 GGGGSGGGGSGGGGSGGS 20GS linker 71 GGGGSGGGGSGGGGSGGGGS 25GS linker 72 GGGGSGGGGSGGGGSGGGGSGGGGS 30GS linker 73 GGGGSGGGGSGGGGSGGGGSGGGGSGGGGS 35GS linker 74 GGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGS 40GS linker 75 GGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGS G1 hinge 76 EPKSCDKTHTCPPCP 9GS-G1 hinge 77 GGGGSGGGSEPKSCDKTHTCPPCP Llama upper long EPKTPKPQPAAA hinge region 78 G3 hinge ELKTPLGDTTHTCPRCPEPKSCDTPPPCPRCPEPKSCDTPPPCPRCPEPKSCD 79 TPPPCPRCP
Table A-12: Different formats of anti-hCEACAM5 VHH (“ID” refers to the SEQ ID NO as used herein) Construct ID Description Sequence ISVD125 211 1D07-9GS-ALB23002 EVQLVESGGGLAQTGGSLRLSCAASGRTFNSYDMGWFRQAPGKEREFVSAIRWSAGSTVYGNSVKGRFAIARTNA NNIMYLQMNSLKPEDTAVYYCAAVRPSFRPLSTYWKDYDNWGQGTLVTVSSGGGGSGGGSEVQLVESGGGVVQP GGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDT ALYYCTIGGSLSRSSQGTLVTVSS A031500053 212 5F01-9GS-ALB23002 EVQLVESGGGLVQTGGSLRLSCAASGGAFSTYTMAWFRQTPGNEREFVAALSWRSGTTVYGDSVKGRFTISRVIAE (ISVD116) NTVYLQMNSLKPEDTAVYFCAAQQYGAISYNRNGFFYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGVVQPGGS LRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTALY YCTIGGSLSRSSQGTLVTVSS A031500054 213 6F03-9GS-ALB23002 EVQLVESGGGLVQAGGSLRLSCVASGRAFSTYTMAWFRQTPGNEREFVATISWRSEITVYGDSVKGRFTISRDKAEN (ISVD117) TVYLQMNSLKPEDTAVYFCAAQEFGAISYNTKGYFYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGVVQPGGSLR LSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTALYYC TIGGSLSRSSQGTLVTVSS A031500062 214 2G08-9GS-ALB23002 EVQLVESGGGLVQAGGSLRLSCAASGRAFSTYTMAWFRQTPGNEREFVATISWRSEITVYGDSVKGRFTISRDNAEN (ISVD121) TVYLQMNSLRPEDTAVYFCAAQEFGAISYNRKGYFYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGVVQPGGSLR LSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTALYYC TIGGSLSRSSQGTLVTVSS ISVD124 215 2G06-9GS-ALB23002 EVQLVESGGGLVQAGDSLRLSCAASGLTFSTYTMGWFRQAPGKEREFVASIIWSGSNTVYADSVKGRFTISRENAKN TVYLQMNSLKPEDTAVYHCAAQHFGPVSLTTRGYYYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGVVQPGGSL RLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTALYY CTIGGSLSRSSQGTLVTVSS A031500049 216 2C10-9GS-ALB23002 EVQLVESGGGLVQAGDSLRLSCAASGLTFSTYTVGWFRQAPGKEREFVGSMIYSGSNTLYADSVKGRFTISRDNAKN (ISVD112) TVFLQMNSLKPEDTAVYHCAAQHFGPISLTTRGYFYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGVVQPGGSLR LSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTALYYC TIGGSLSRSSQGTLVTVSS A031500047 217 1C02-9GS-ALB23002 EVQLVESGGGLVQAGDSLRLSCSASGRTFSDYAMGWFRQAPGMEREFVAAINWGGTWTYYAHSVQGRFTISRGN (ISVD106) AKNTLYLQMNSLKPEDTAGYYCAASLDYAGGSPTGYAYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGVVQPGG
SLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAL YYCTIGGSLSRSSQGTLVTVSS A031500056 109 24B02-9GS-ALB23002 EVQLVESGGGLVQAGDSLRLSCSASGHTFSEYALGWFRQAPGMEREFVAAINWGGGWTYYADSVQGRFTISRDNA (ISVD108) KNTLYLQMNSLKPGDTAGYYCAASSDYAGGNPTGYPYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGVVQPGGS LRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTALY YCTIGGSLSRSSQGTLVTVSS A031500057 218 26D05-9GS-ALB23002 EVQLVESGGGLVLAGDSLRLSCSASGRTFSDYAMGWFRQAPGMEREFVAAINWGGSWTYYAHSVQGRFTISRDN (ISVD118) AKNTLYLQMNSLKPEDTASYYCAASPDYAGGNPTGYAYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGVVQPGG SLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAL YYCTIGGSLSRSSQGTLVTVSS A031500048 219 1C11-9GS-ALB23002 EVQLVESGGGLVQAGDSLRLSCLASGRTFSDFAMGWFRQAPGMEREFVAAINWSGGWTYYADSVQGRFTISRDN (ISVD111) TKNTLYLQMNSLKPEDTAAYYCAASSDYAGGRSTGYDYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGVVQPGG SLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAL YYCTIGGSLSRSSQGTLVTVSS A031500052 220 4G01-9GS-ALB23002 EVQLVESGGGLVQAGDSLRLSCSASGRTFSDYAMGWFRQAPGMEREFVAAINWSGGWTYYADSVQGRFTISRDN (ISVD115) TKNTLYLQMNSLKPEDTAAYYCAASSDYAGGRSTGYAYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGVVQPGG SLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAL YYCTIGGSLSRSSQGTLVTVSS A031500060 221 25D01-9GS-ALB23002 EVQLVESGGGLVQTGGSLILSCAASGRTFNINEYHLAWFRQAPGKEREFLAAIWWSTGNKIVADSVKGRFAISRSSRI (ISVD110) NTVNLQMNNLKREDTAVYYCAAVRFSFRPLSTYWKDYDNWGQGTLVTVSSGGGGSGGGSEVQLVESGGGVVQP GGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDT ALYYCTIGGSLSRSSQGTLVTVSS A031500058 222 20C01-9GS-ALB23002 EVQLVESGGGLVQTGGSLRLSCAASGRTLNDYHMAWFRQAPGKEREFQAAIWWSTGNRIVADSVKGRFAVSRSN (ISVD107) AGNTIYLQMNSLKPEDTAVYYCAAVRFSFRPLSTYWKDYDIWGQGTLVTVSSGGGGSGGGSEVQLVESGGGVVQP GGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDT ALYYCTIGGSLSRSSQGTLVTVSS A031500061 223 26B01-9GS-ALB23002 EVQLVESGGGSVQTGGSLRLSCAASGDTLNSYHMAWFRQAPRKEREFLSAIWWSTGNAIVADSVKGRFAISKSNAL (ISVD120) NTVYLQMNSLKPEDTAVYYCAAVRFSFRPLSTYWKDYDNWGQGTLVTVSSGGGGSGGGSEVQLVESGGGVVQPG
GSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTA LYYCTIGGSLSRSSQGTLVTVSS A031500063 224 8B03-9GS-ALB23002 EVQLVESGGGSVQTGGSLRLSCAASGDNLNSYHMAWFRQAPGKNRDFLSAIWWSTGNTIVADSVKGRFAISKSNA (ISVD122) LNTVYLQMNTLKPEDTAVYYCAAVRFQFRPLSTYWKDYDNWGQGTLVTVSSGGGGSGGGSEVQLVESGGGVVQP GGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDT ALYYCTIGGSLSRSSQGTLVTVSS A031500050 225 3D09-9GS-ALB23002 EVQLVESGGGLVQAGGSLRLSCAASGGTFSSYAMGWFRQAPGKEREFVAGMSWSGGSTHYADSVKGRFTISRDN (ISVD113) AKNTVYLQMNSLKPEDTAVYYCTRGQNPMGPIATRPSVHDYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGVVQ PGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPED TALYYCTIGGSLSRSSQGTLVTVSS A031500064 226 9B07-9GS-ALB23002 EVQLVESGGGLVQAGGSLRLSCAASGRTFSNYAMGWFRQAPGKEREFVAGMSWSGGSTHYADSVKGRFAISRDN (ISVD123) AKNTVYLQMNSLKPEDTAVYYCTVGRNPMGPIATRPSVHDYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGVVQ PGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPED TALYYCTIGGSLSRSSQGTLVTVSS A031500051 227 3F04-9GS-ALB23002 EVQLVESGGGLVRAGDSLRLSCAASGGTVSTYTMGWFRQAPGKEREFVGSIIWSGSTTVYADSVKGRSTISRDNAKN (ISVD114) TVYLQMNSLKPEDTAVYYCAAQHFGPVSQTTKGYFYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGVVQPGGSL RLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTALYY CTIGGSLSRSSQGTLVTVSS A031500059 228 21A01-9GS-ALB23002 EVQLVESGGGLVQTGGSLRLSCAASGRTLNDYHMAWFRQAPGKEREFLSAIWWSTGNTIVADSVKGRFASSKTNA (ISVD119) GVYLQMNSLKPEDTAVYYCAAVRFSFRPLSTYWKDYDNWGQGTLVTVSSGGGGSGGGSEVQLVESGGGVVQPGG SLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAL YYCTIGGSLSRSSQGTLVTVSS A031500055 110 7E07-9GS-ALB23002 EVQLVESGGGLVQPGGSLRLSCAASGLTFSTYTMGWFRQAPGKEREFVAAIIWSGSNTYYADSVKGRFTISRDNAKS (ISVD109) TVYLQMNNLEPEDTAVYHCAAQHFGPIGLTTRGYNYWGQGTLVTVSSGGGGSGGGSEVQLVESGGGVVQPGGSL RLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTALYY CTIGGSLSRSSQGTLVTVSS
Table A-13: ISVD C-terminus (“ID” refers to the SEQ ID NO as used herein) SEQ ID NO: Sequence 91 VTVSS(X)n 92 VKVSS 93 VQVSS 94 VTVKS 95 VTVQS 96 VKVKS 97 VKVQS 98 VQVKS 99 VQVQS 100 VTVSSA 101 VKVSSA 102 VQVSSA 103 VTVKSA 104 VTVQSA 105 VKVKSA 106 VKVQSA 107 VQVKSA 108 VQVQSA Table A-14. CEACAM5 epitopes (“ID” refers to the SEQ ID NO as used herein) Description SEQ ID Sequence NO: 111 ELPKPSISSNNSKPVEDKDAVAFTCEPETQDATYLWWVNNQSLPVSPRL A1-B1 QLSNGNRTLTLFNVTRNDTASYKCETQNPVSARRSDSVILNVLYGPDAPT (hCEACAM5_143-320 ISPLNTSYRSGENLNLSCHAASNPPAQYSWFVNGTFQQSTQELFIPNITV NNSGSYTCQAHNSDTGLNRTTVTTITVYAHHHHHH 112 EPPKPFITSNNSNPVEDEDAVALTCEPEIQNTTYLWWVNNQSLPVSPRL A2-B2 QLSNDNRTLTLLSVTRNDVGPYECGIQNELSVDHSDPVILNVLYGPDDPT (hCEACAM5_321- ISPSYTYYRPGVNLSLSCHAASNPPAQYSWLIDGNIQQHTQELFISNITEK 498) NSGLYTCQANNSASGHSRTTVKTITVSAHHHHHH A2-B2 545 EPPKPFITSNNSNPVEDEDAVALTCEPEIQNTTYLWWVNNQSLPVSPRL (hCEACAM5_321- QLSNDNRTLTLLSVTRNDVGPYECGIQNELSVDHSDPVILNVLYGPDDPT 488) ISPSYTYYRPGVNLSLSCHAASNPPAQYSWLIDGNIQQHTQELFISNITEK NSGLYTCQANNSASGHSR 113 ELPKPSISSNNSKPVEDKDAVAFTCEPEAQNTTYLWWVNGQSLPVSPRL A3-B3 QLSNGNRTLTLFNVTRNDARAYVCGIQNSVSANRSDPVTLDVLYGPDTP (hCEACAM5_499- IISPPDSSYLSGANLNLSCHSASNPSPQYSWRINGIPQQHTQVLFIAKITP 685) NNNGTYACFVSNLATGRNNSIVKSITVSASGTSPGLSAHHHHHH 546 KLTIESTPFNVAEGKEVLLLVHNLPQHLFGYSWYKGERVDGNRQIIGYVIGTQ QATPGPAYSGREIIYPNASLLIQNIIQNDTGFYTLHVIKSDLVNEEATGQFRVY N-A1B1 PELPKPSISSNNSKPVEDKDAVAFTCEPETQDATYLWWVNNQSLPVSPRLQL (hCEACAM5_35-320) SNGNRTLTLFNVTRNDTASYKCETQNPVSARRSDSVILNVLYGPDAPTISPLN TSYRSGENLNLSCHAASNPPAQYSWFVNGTFQQSTQELFIPNITVNNSGSYT CQAHNSDTGLNRTTVTTITVYA Table A-15: Amino acid sequences of CEACAM1, CEACAM6, CEACAM7 and CEACAM8 (“ID” refers to the SEQ ID NO as used herein) Name ID Amino acid sequence TPP- 15 KLTIESTPFNVAEGKEVLLLAHNLPQNRIGYSWYKGERVDGNSLIVGYVIG 2484|hCEACAM6_1to3 TQQATPGPAYSGRETIYPNASLLIQNVTQNDTGFYTLQVIKSDLVNEEATG 27, mature_chain_1 QFHVYPELPKPSISSNNSNPVEDKDAVAFTCEPEVQNTTYLWWVNGQSL PVSPRLQLSNGNMTLTLLSVKRNDAGSYECEIQNPASANRSDPVTLNVLY GPDGPTISPSKANYRPGENLNLSCHAASNPPAQYSWFINGTFQQSTQELF IPNITVNNSGSYMCQAHNSATGLNRTTVTMITVSGSAPVLSA TPP- 28 QLTTESMPFNVAEGKEVLLLVHNLPQQLFGYSWYKGERVDGNRQIVGYA 2476|hCEACAM1_1to4 IGTQQATPGPANSGRETIYPNASLLIQNVTQNDTGFYTLQVIKSDLVNEEA 28, mature_chain_1 TGQFHVYPELPKPSISSNNSNPVEDKDAVAFTCEPETQDTTYLWWINNQ SLPVSPRLQLSNGNRTLTLLSVTRNDTGPYECEIQNPVSANRSDPVTLNVT YGPDTPTISPSDTYYRPGANLSLSCYAASNPPAQYSWLINGTFQQSTQELF IPNITVNNSGSYTCHANNSVTGCNRTTVKTIIVTELSPVVAKPQIKASKTTV TGDKDSVNLTCSTNDTGISIRWFFKNQSLPSSERMKLSQGNTTLSINPVKR EDAGTYWCEVFNPISKNQSDPIMLNVNYNALPQENGLSPG CEACAM7 247 TNIDVVPFNVAEGKEVLLVVHNESQNLYGYNWYKGERVHANYRIIGYVK NISQENAPGPAHNGRETIYPNGTLLIQNVTHNDAGIYTLHVIKENLVNEEV TRQFYVFSEPPKPSITSNNFNPVENKDIVVLTCQPETQNTTYLWWVNNQ SLLVSPRLLLSTDNRTLVLLSATKNDIGPYECEIQNPVGASRSDPVTLNVRY ESVQASSPDLSA CEACAM8 248 QLTIEAVPSNAAEGKEVLLLVHNLPQDPRGYNWYKGETVDANRRIIGYVI SNQQITPGPAYSNRETIYPNASLLMRNVTRNDTGSYTLQVIKLNLMSEEV TGQFSVHPETPKPSISSNNSNPVEDKDAVAFTCEPETQNTTYLWWVNGQ SLPVSPRLQLSNGNRTLTLLSVTRNDVGPYECEIQNPASANFSDPVTLNVL YGPDAPTISPSDTYYHAGVNLNLSCHAASNPPSQYSWSVNGTFQQYTQK LFIPNITTKNSGSYACHTTNSATGRNRTTVRMITVSDALVQGSSPGLSA Table A-16: Amino acid sequences of the 14R04-10-based sequence optimized ISVDs binding CEACAM5 (“ID” refers to the SEQ ID NO as used herein) Name ID Amino acid sequence 14R0410 Parental 547 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYDMSWVRQPPGKGIEWVSTINRGGSSTSYRVPVEGRFTI (T023200178) SRDNAENTLYLQMNSLKTEDTAVYYCTTGDHRGPWYNRGQGTLVTVSS 549 EVQLVESGGGVVQPGGSLRLSCAASGFTFSSYDMSWVRQPPGKGIEWVSTINRGGSSTSYRVPVEGRFTI T028500006 14R0410(L11V,K83R,V89L) SRDNAENTLYLQMNSLRTEDTALYYCTTGDHRGPWYNRGQGTLVTVSS 550 EVQLVESGGGVVQPGGSLRLSCAASGFTFSSYDMSWVRQPPGKGIEWVSTINRGGSSTSYRVPVEGRFTI T028500007 14R0410(L11V,K83R,T84S,V89L) SRDNAENTLYLQMNSLRSEDTALYYCTTGDHRGPWYNRGQGTLVTVSS 551 EVQLVESGGGVVQPGGSLRLSCAASGFTFSSYDMSWVRQPPGKGIEWVSTINRGGSSTSYRVPVEGRFTI T028500008 14R0410(L11V,K83R,V89L,R103W) SRDNAENTLYLQMNSLRTEDTALYYCTTGDHRGPWYNWGQGTLVTVSS 14R0410(L11V,P40A,E75K,K83R,V89 552 EVQLVESGGGVVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGIEWVSTINRGGSSTSYRVPVEGRFTI T028500009 L) SRDNAKNTLYLQMNSLRTEDTALYYCTTGDHRGPWYNRGQGTLVTVSS 14R0410(L11V,P40A,R60A,V61D,P62 553 EVQLVESGGGVVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGIEWVSTINRGGSSTSYADSVKGRFT T028500010 S,E64K,E75K,K83R,V89L) ISRDNAKNTLYLQMNSLRTEDTALYYCTTGDHRGPWYNRGQGTLVTVSS 554 EVQLVESGGGVVQPGGSLRLSCAASGFTFSSYDMSWVRQAPGKGIEWVSTINRGGSSTSYRVPVEGRFTI T028500011 14R0410(L11V,P40A,K83R,V89L) SRDNAENTLYLQMNSLRTEDTALYYCTTGDHRGPWYNRGQGTLVTVSS 555 EVQLVESGGGVVQPGGSLRLSCAASGFTFSSYDMSWVRQPPGKGLEWVSTINRGGSSTSYRVPVEGRFT T028500012 14R0410(L11V,I45L,K83R,V89L) ISRDNAENTLYLQMNSLRTEDTALYYCTTGDHRGPWYNRGQGTLVTVSS 556 EVQLVESGGGVVQPGGSLRLSCAASGFTFSSYDMSWVRQPPGKGIEWVSTINRGGSSTSYAVPVEGRFTI T028500013 14R0410(L11V,R60A,K83R,V89L) SRDNAENTLYLQMNSLRTEDTALYYCTTGDHRGPWYNRGQGTLVTVSS 557 EVQLVESGGGVVQPGGSLRLSCAASGFTFSSYDMSWVRQPPGKGIEWVSTINRGGSSTSYRDPVEGRFTI T028500014 14R0410(L11V,V61D,K83R,V89L) SRDNAENTLYLQMNSLRTEDTALYYCTTGDHRGPWYNRGQGTLVTVSS 558 EVQLVESGGGVVQPGGSLRLSCAASGFTFSSYDMSWVRQPPGKGIEWVSTINRGGSSTSYRVSVEGRFTI T028500015 14R0410(L11V,P62S,K83R,V89L) SRDNAENTLYLQMNSLRTEDTALYYCTTGDHRGPWYNRGQGTLVTVSS 14R0410(L11V,E64K,K83R,V89L)- 559 EVQLVESGGGVVQPGGSLRLSCAASGFTFSSYDMSWVRQPPGKGIEWVSTINRGGSSTSYRVPVKGRFTI T028500016 FLAG3-HIS6 SRDNAENTLYLQMNSLRTEDTALYYCTTGDHRGPWYNRGQGTLVTVSS 560 EVQLVESGGGVVQPGGSLRLSCAASGFTFSSYDMSWVRQPPGKGIEWVSTINRGGSSTSYRVPVEGRFTI T028500017 14R0410(L11V,E75K,K83R,V89L) SRDNAKNTLYLQMNSLRTEDTALYYCTTGDHRGPWYNRGQGTLVTVSS
Name ID Amino acid sequence 561 EVQLVESGGGVVQPGGSLRLSCAASGFTFSSYDMSWVRQPPGKGIEWVSTINRGGSSTSYRVPVEGRFTI T028500018 14R0410(L11V,K83R,T84P,V89L) SRDNAENTLYLQMNSLRPEDTALYYCTTGDHRGPWYNRGQGTLVTVSS 14R0410(L11V,R60A,P62S,E64K,E75 562 EVQLVESGGGVVQPGGSLRLSCAASGFTFSSYDMSWVRQPPGKGIEWVSTINRGGSSTSYAVSVKGRFTI T028500557 K,K83R,V89L) SRDNAKNTLYLQMNSLRTEDTALYYCTTGDHRGPWYNRGQGTLVTVSS T028500558 14R0410 (L11V, R60A, E64K, E75K, 563 EVQLVESGGGVVQPGGSLRLSCAASGFTFSSYDMSWVRQPPGKGIEWVSTINRGGSSTSYAVPVKGRFTI K83R, V89L) SRDNAKNTLYLQMNSLRTEDTALYYCTTGDHRGPWYNRGQGTLVTVSS
Table A-17: Amino acid sequences of the T0232000134-based sequence optimized ISVDs binding CEACAM5 (“ID” refers to the SEQ ID NO as used herein) Name ID Amino acid sequence T023200134 Parental 548 EVQLVESGGGLVQAGGSLRLSCAASGRTFDNHAMGWFRQTPGKEREFVAGITWRGGSTHYADSVKGR FTISRDNAKNTLYLEMNSLKPEDTAVYYCTADLRPFGPITTTPQRINYWGQGTLVTVSS T028500003 T232000134(L11V,A14P,K83R,V89L) 564 EVQLVESGGGVVQPGGSLRLSCAASGRTFDNHAMGWFRQTPGKEREFVAGITWRGGSTHYADSVKGR FTISRDNAKNTLYLEMNSLRPEDTALYYCTADLRPFGPITTTPQRINYWGQGTLVTVSS T028500004 T232000134(L11V,A14P,E81Q,K83R, 565 EVQLVESGGGVVQPGGSLRLSCAASGRTFDNHAMGWFRQTPGKEREFVAGITWRGGSTHYADSVKGR V89L) FTISRDNAKNTLYLQMNSLRPEDTALYYCTADLRPFGPITTTPQRINYWGQGTLVTVSS T028500005 T232000134(L11V,A14P,T40A,E81Q, 566 EVQLVESGGGVVQPGGSLRLSCAASGRTFDNHAMGWFRQAPGKEREFVAGITWRGGSTHYADSVKGR K83R,V89L) FTISRDNAKNTLYLQMNSLRPEDTALYYCTADLRPFGPITTTPQRINYWGQGTLVTVSS T028500591 T232000134 567 EVQLVESGGGVVQPGGSLRLSCAASGRTFDNHAMGWFRQAPGKEREFVAGITWRGGSTHYADSVKGR (L11V,A14P,T40A,E81Q,K83R,V89L,R FTISRDNAKNTLYLQMNSLRPEDTALYYCTADLVPFGPITTTPQRINYWGQGTLVTVSS 97V) T028500588 T232000134(L11V, A14P, H32L, 568 EVQLVESGGGVVQPGGSLRLSCAASGRTFDNLAMGWFRQAPGKEREFVAGITWRGGSTHYADSVKGR T40A, E81Q, K83R, V89L) FTISRDNAKNTLYLQMNSLRPEDTALYYCTADLRPFGPITTTPQRINYWGQGTLVTVSS T028500582 T232000134 569 EVQLVESGGGVVQPGGSLRLSCAASGRTFDNHAMGWFRQAPGKEREFVAGITWRGGSTHYADSVKGR (L11V,A14P,T40A,E81Q,K83R,V89L, FTISRDNAKNTLYLQMNSLRPEDTALYYCTADLRPFAPITTTPQRINYWGQGTLVTVSS G100A) T028500593 T232000134 570 EVQLVESGGGVVQPGGSLRLSCAASGRTFDNHAMGWFRQAPGKEREFVAGITWRGGSTHYADSVKGR (L11V,A14P,T40A,E81Q,K83R,V89L,T FTISRDNAKNTLYLQMNSLRPEDTALYYCTADLRPFGPITQTPQRINYWGQGTLVTVSS 100dQ) T028500592 T232000134 571 EVQLVESGGGVVQPGGSLRLSCAASGRTFDNHAMGWFRQAPGKEREFVAGITWRGGSTHYADSVKGR (L11V,A14P,T40A,E81Q,K83R,V89L,T FTISRDNAKNTLYLQMNSLRPEDTALYYCTADLRPFGPITTEPQRINYWGQGTLVTVSS 100dE) T028500587 T232000134 572 EVQLVESGGGVVQPGGSLRLSCAASGRTFDNEAMGWFRQAPGKEREFVAGITWRGGSTHYADSVKGR (L11V,A14P,H32E,T40A,E81Q,K83R, FTISRDNAKNTLYLQMNSLRPEDTALYYCTADLRPFGPITTTPQRINYWGQGTLVTVSS V89L)
Name ID Amino acid sequence T028500581 T232000134 573 EVQLVESGGGVVQPGGSLRLSCAASGRTFDNHAMGWFRQAPGKEREFVAGITWRGGSTHYADSVKGR (L11V,A14P,T40A,E81Q,K83R,V89L,D FTISRDNAKNTLYLQMNSLRPEDTALYYCTAVLRPFGPITTTPQRINYWGQGTLVTVSS 95V) T028500590 T232000134 574 EVQLVESGGGVVQPGGSLRLSCAASGRTFDNHAMGWFRQAPGKEREFVAGITWRGGSTHYADSVKGR (L11V,A14P,T40A,E81Q,K83R,V89L, FTISRDNAKNTLYLQMNSLRPEDTALYYCTADLRPFGPITTTPQRIEYWGQGTLVTVSS N101E) T028500594 T232000134 575 EVQLVESGGGVVQPGGSLRLSCAASGRTFDNHAMGWFRQAPGKEREFVAGITNRGGSTHYADSVKGR (L11V,A14P,T40A,W52aN,E81Q,K83 FTISRDNAKNTLYLQMNSLRPEDTALYYCTADLRPFGPITTTPQRINYWGQGTLVTVSS R,V89L) T028500583 T232000134 576 EVQLVESGGGVVQPGGSLRLSCAASGRTFDNHAMGWFRQAPGKEREFVAGITWRGGSTHYADSVKGR (L11V,A14P,T40A,E81Q,K83R,V89L, FTISRDNAKNTLYLQMNSLRPEDTALYYCTADLRPFFPITTTPQRINYWGQGTLVTVSS G100F)-FLAG3-HIS6
6 Examples 6.1 Example 1: Generation of human CEACAM5 binding ISVD compounds 6.1.1 Immunizations Camelids were immunized with a cocktail of antigens using Freund's complete adjuvant (first injection) and Freund's incomplete adjuvant (subsequent injections) as described in WO2003/035694. 6.1.2 Library constructions and phage display selections Immune blood samples were taken and total RNA was prepared from the isolated PBL. From these blood samples, peripheral blood mononuclear cells (PBMCs) were prepared using Ficoll-Hypaque according to the manufacturer’s instructions (Amersham Biosciences, Piscataway, NJ, US). From the PBMCs, total RNA was extracted and used as starting material for RT-PCR to amplify the VHH- encoding DNA segments, essentially as described in WO 2005/044858. Subsequently, phages were prepared according to standard protocols (see for example the prior art and applications filed by Ablynx N.V. cited herein) and stored after filter sterilization at 4 °C for further use. For general phage display selection techniques, reference is made to Antibody Phage Display: Methods and Protocols (First Edition, 2002, O’Brian and Aitken eds., Humana Press, Totowa, NJ). Two or three rounds of panning phage display selections were performed using the llama immune library in selection rounds on cynomolgus CEACAM5 protein. The output from the selection were plated onto LB/amp/2%glu plates. Colonies were picked and grown in 96 deep well plates (1 ml volume) and induced by adding IPTG for VHH expression. Periplasmic extracts (PEs, volume: ~ 80 ^l) were prepared according to standard methods (see for example the prior art and applications filed by applicant cited herein). 6.1.3 Primary screening and sequencing Primary screening of 830 PEs was performed by ELISA on human (SEQ ID NO: 26) and cynomolgus (SEQ ID NO: 27) CEACAM5 proteins (in-house produced). To verify specific binding, all PEs were tested for binding on human CEACAM1 (SEQ ID NO: 28) and human CEACAM6 (SEQ ID NO: 15) (in- house produced) as well. Any non-specific binders were discarded. In short, the binding of PE containing anti-CECAM5 VHHs to recombinantly expressed human and cynomolgus CEACAM5 was evaluated in ELISA. 384-well ELISA plates were overnight coated with human CEACAM5, CEACAM1, CEACAM6 and cynomolgus CEACAM5 at final concentrations of 1 μg/ml in PBS buffer. After blocking with 1% Casein, final dilutions of 1/10 of the PE were applied and allowed to incubate for 2 hours at room temperature. After extensive washing, the binding of VHHs on coated CEACAM5 proteins was detected by an anti-FLAG-HRP conjugate (Sigma).239 VHHs returned binding values > 3x over non-binding controls on human and cynomolgus CEACAM5 while showing binding values < or equal to 3x over non-binding controls to human CEACAM1 and CEACAM6. These were further tested in an off-rate analysis. 6.2 Example 2: Initial characterization of the unique sequences 6.2.1 Off-rate analysis of binders All 239 specific binders in ELISA were subjected to off-rate analysis towards human (SEQ ID NO: 26) and cynomolgus CEACAM5 (SEQ ID NO: 27) by Surface Plasmon Resonance (SPR) on a ProteOn XPR36 instrument (Bio-Rad Laboratories). Again, human CEACAM1 (SEQ ID NO: 28) and CEACAM6 (SEQ ID NO: 15), see Table A-10, were taken along as off-targets. The experiment was performed at 25°C. As assay buffer PBS pH7.4 containing 0.005% Tween 20 (Bio-Rad Laboratories) was used. Human CEACAM5, CEACAM1, CEACAM6 and cynomolgus CEACAM5 were immobilized on different ligand lanes from a GLC sensor chip (Bio-Rad Laboratories) with the ProteOn Amine Coupling Kit (Bio-Rad Laboratories) according to the manufacturer’s instructions. One ligand lane served as a reference surface where no target was immobilized. PEs diluted 1:10 in running buffer were flowed over for 2 minutes, followed by a constant flow of the assay buffer for 10 minutes. Between sample injections, the surfaces were regenerated with 2 pulses (20 seconds) of 10 mM glycine pH 1.5. Several buffer blanks were injected for double referencing. Data was analysed with the ProteOn Manager 3.1.0 software (Bio-Rad Laboratories), off-rates were determined based on the 1:1 interaction model (Langmuir binding model). The further selected VHHs showed a maximal difference of 10-fold between human and cynomolgus CEACAM5 off-rates while not binding to human CEACAM1 and CEACAM6. Sequence analysis of those VHHs was done according to commonly known procedures (Pardon et al. 2014, Nat. Protoc. 9: 674) and returned 30 distinct (based on CDR3 sequence similarities) VHH families (table A-2 and table B-0). Table B-0: Results off-rate analysis of 5 selected ISVDs Human CEACAM5 Cynomolgus CEACAM5 Ratio Kd Sample ID kd [1/s] kd [1/s] cyno/human 1D07 (ISVD20) 1.03E-02 1.83E-02 1.8 5F01 (ISVD11) 1.65E-03 1.65E-03 1.0 6F03 (ISVD12) 6.91E-04 4.24E-03 6.1 2G08 (ISVD16) 7.16E-03 5.80E-02 8.0 2G06 (ISVD19) 4.41E-03 1.52E-02 3.4 2C10 (ISVD7) 2.58E-04 1.53E-03 5.9 1C02 (ISVD1) 1.0 E-03 2.4 E-03 2.4 24B02 (ISVD3) 1.4E-03 4.1E-03 2.9 26D05 (ISVD13) 8.8E-04 2.3E-03 2.6 1C11 (ISVD6) 6.77E-04 1.90E-03 2.8 4G01 (ISVD10) 5.77E-04 1.58E-03 2.7 25D01 (ISVD5) 2.9E-03 4.3E-03 1.3 20C01 (ISVD2) 2.3E-03 3.8E-03 1.64 26B01 (ISVD15) 2.8E-03 2.5E-03 0.9 8B03 (ISVD17) 6.00E-03 4.48E-02 7.5 3D09 (ISVD8) 2.43E-04 2.06E-03 8.5 9B07 (ISVD18) 5.92E-05 8.43E-04 14.2 3F04 (ISVD9) 7.57E-04 7.30E-03 9.6 21A01 (ISVD14) 2.7E-03 3.4E-03 1.2 7E07 (ISVD4) 4.40E-04 3.5E-03 7.9 T028500588 5.00E-04 8.00E-04 1.6 T028500558 4.92E-04 1.24E-03 2.5 6.3 Example 3: Generation of VHH expressing constructs VHH-containing DNA fragments, obtained by PCR with specific combinations of forward FR1 and reverse FR4 primers each carrying a unique restriction site, were digested with the appropriate restriction enzymes and ligated into the matching cloning cassettes of VHH expression vectors (described below). The ligation mixtures were then transformed to electrocompetent Escherichia coli TG1 (60502, Lucigen, Middleton, WI) or TOP10 (C404052, ThermoFisher Scientific, Waltham, MA) cells which were then grown under the appropriate antibiotic selection pressure (kanamycin or Zeocin). Resistant clones were verified by Sanger sequencing of plasmid DNA (LGC Genomics, Berlin, Germany). VHHs were expressed in E. coli TG1 from a plasmid expression vector containing the lac promoter, a resistance gene for kanamycin, an E. coli replication origin and a VHH cloning site preceded by the coding sequence for the OmpA signal peptide. In frame with the VHH coding sequence, the vector codes for a C-terminal FLAG3 and HIS6 tag. The signal peptide directs the expressed VHH to the periplasmic compartment of the bacterial host. HIS6-tagged VHHs were purified by immobilized metal affinity chromatography (IMAC) followed by a desalting step. The purity and integrity of the VHHs was verified by SDS-PAGE and mass spectrometry. These monovalent VHHs were consequently assessed for melting temperature (Tm) and relative binding sites. 6.3.1 Determination of Tm (Thermal Shift assay) The thermal shift assay (TSA) was performed in a 96-well plate on a qPCR machine (LightCycler 480II, Roche). Each ISVD was analyzed in 20 mM phosphate (pH 7) buffer. Per well, 5 µL of sample (0.8 mg/mL in D-PBS) was added to 5 µL of Sypro Orange (40× in MilliQ water; Invitrogen) and 10 µL of buffer. A temperature gradient (37 to 99°C at a rate of 0.03°C/s) was applied, which induced unfolding of the ISVD proteins, and hence exposure of hydrophobic patches. Binding of Sypro Orange to those hydrophobic patches, caused increase in fluorescence intensity, which was measured (Ex/Em = 465/580 nm). The inflection point of the first derivative of the fluorescence intensity curve at pH 7 served as a measure of the melting temperature (Tm). The determined Tm values for 5 selected ISVDs are shown in table B-1. Table B-1 Tm values for selected ISVDs Sample ID Tm, [oC] 1D07 (ISVD20) 69 5F01 (ISVD11) 74 6F03 (ISVD12) 69 2G08 (ISVD16) 68 2G06 (ISVD19) 69 2C10 (ISVD7) 68 1C02 (ISVD1) 58 24B02 (ISVD3) 65 26D05 (ISVD13) 79 1C11 (ISVD6) 71 4G01 (ISVD10) 74 25D01 (ISVD5) 80 20C01 (ISVD2) 76 26B01 (ISVD15) 78 8B03 (ISVD17) nd 3D09 (ISVD8) 70 9B07 (ISVD18) nd 3F04 (ISVD9) 73 21A01 (ISVD14) 76 7E07 (ISVD4) 75 T028500588 70 nd: not determined 6.3.2 Epitope binning of selected VHH In order to determine the relative binding sites of the selected ISVDs, an epitope binning was performed on the OctetRED384 (Sartorius). Human CEACAM5 (in-house produced) was in-vitro biotinylated (EZ-Link NHS Biotin; Thermo Fisher Scientific) and subsequently captured on a SA Biosensor to allow epitope binning following a classical tandem approach. In short, SA Biosensors were first loaded with biotinylated human CEACAM5, after which a first ISVD was allowed to bind until saturation, interspersed by a short 5 s dip into assay buffer (HBS-EP+), the Biosensor was subsequently dipped into the 2nd ISVD solution for 500 s. Each ISVD was assayed at a concentration of 1 μM. Binding levels at the end of association of the first ISVD and the second ISVD were subtracted from each other and compared to an assessment in which first and second ISVD was the same molecule (self-binning). In case additional binding above 3-fold of the self-binning value was detected, both first and second ISVD were considered to bind non-overlapping epitopes. We could identify 2 distinct epitope bins that are populated by 5 and 15 ISVDs respectively (table B-2). Table B-2 Epitope bin and epitope mapping of the selected ISVDs. Sample ID Epitope bin Epitope mapping Binding > OD 0.2 Binding < OD 0.2 at 1000, 100, 10, 1 nM at 1000, 100, 10, 1 nM 1D07 (ISVD20) A Full length A3-B3 A1-B1** A2-B2 5F01 (ISVD11) A Full length A1-B1 A2-B2 A3-B3 6F03 (ISVD12) A Full length A3-B3 A1-B1* A2-B2 2G08 (ISVD16) A nd nd 2G06 (ISVD19) A Full length A1-B1 A2-B2 A3-B3 2C10 (ISVD7) A Full length A3-B3 A1-B1* A2-B2 1C02 (ISVD1) C Full length A3-B3 A1-B1 A2-B2 24B02 (ISVD3) C Full length A3-B3 A1-B1 A2-B2 26D05 (ISVD13) C Full length A2-B2 A1-B1 A3-B3 1C11 (ISVD6) C Full length A3-B3 A1-B1 A2-B2* 4G01 (ISVD10) C Full length A3-B3 A1-B1 A2-B2 25D01 (ISVD5) A Full length A3-B3 A1-B1* A2-B2 20C01 (ISVD2) A Full length A1-B1 A2-B2 A3-B3 26B01 (ISVD15) A Full length A1-B1 A2-B2* A3-B3 8B03 (ISVD17) A nd nd 3D09 (ISVD8) A Full length A3-B3 A1-B1* A2-B2 9B07 (ISVD18) A nd nd 3F04 (ISVD9) A Full length A3-B3 A1-B1** A2-B2 21A01 (ISVD14) A Full length A3-B3 A1-B1** A2-B2 7E07 (ISVD4) A Full length A1-B1 A2-B2 A3-B3 T023200134 A Full length A1-B2 A2-B2 T028500558 B Full length A2-B2 A3-B3 *Only binding at 1000, 100 and 10 nM; **Only binding at 1000 and 100 nM; nd: not determined 6.3.3 Epitope binning of binders An epitope mapping assay was set up to determine the binding site of each ISVD in a domain resolution. In short, 3 truncated extracellular domains of human CEACAM5 were prepared, representing the isolated A1-B1(SEQ ID NO: 111), A2-B2(SEQ ID NO: 112), and A3-B3 (SEQ ID NO: 113) domains, respectively, see table A-14.384-well ELISA plates were overnight coated with the full-length extracellular domain, A1-B1, A2-B2 and the A3-B3 domains at final concentrations of 1 μg/ml in PBS buffer. After blocking with 1% Casein, final concentrations of 1000 nM, 100 nM, 10 nM and 1nM were applied and allowed to incubate for 1 hour at room temperature. After extensive washing, the binding of VHHs on coated CEACAM5 proteins was detected by an anti-FLAG-HRP conjugate (Sigma). An overview of the binding values with the assigned binding domain is shown in table B-2. 6.4 Example 4: Formatting of ISVDs 6.4.1 Preparation of VHH formats Each monovalent VHH was formatted as a bivalent VHH construct with a C-terminally appended ISVD binding to Human Serum Albumin (ALB23002, SEQ ID NO.: 62) (Table A-12 and Table B-3). Table B-3 Formatted anti-CEACAM5 VHH constructs Construct ID BB1 Linker BB2 ISVD125 1D07 (ISVD20) 9GS ALB23002 A031500053 (ISVD116) 5F01 (ISVD11) 9GS ALB23002 A031500054 (ISVD117) 6F03 (ISVD12) 9GS ALB23002 A031500062 (ISVD121) 2G08 (ISVD16) 9GS ALB23002 ISVD124 2G06 (ISVD19) 9GS ALB23002 A031500049 (ISVD112) 2C10 (ISVD7) 9GS ALB23002 A031500047 (ISVD106) 1C02 (ISVD1) 9GS ALB23002 A031500056 (ISVD108) 24B02 (ISVD3) 9GS ALB23002 A031500057 (ISVD118) 26D05 (ISVD13) 9GS ALB23002 A031500048 (ISVD111) 1C11 (ISVD6) 9GS ALB23002 A031500052 (ISVD115) 4G01 (ISVD10) 9GS ALB23002 A031500060 (ISVD110) 25D01 (ISVD5) 9GS ALB23002 A031500058 (ISVD107) 20C01 (ISVD2) 9GS ALB23002 A031500061 (ISVD120) 26B01 (ISVD15) 9GS ALB23002 A031500063 (ISVD122) 8B03 (ISVD17) 9GS ALB23002 A031500050 (ISVD113) 3D09 (ISVD8) 9GS ALB23002 A031500064 (ISVD123) 9B07 (ISVD18) 9GS ALB23002 A031500051 (ISVD114) 3F04 (ISVD9) 9GS ALB23002 A031500059 (ISVD119) 21A01 (ISVD14) 9GS ALB23002 A031500055 (ISVD109) 7E07 (ISVD4) 9GS ALB23002 6.4.2 FACS analysis on cells expressing human CEACAM5 Binding of purified anti-CEACAM5 VHH constructs to human CEACAM5 on a BxPC-3 cell line was evaluated in flow cytometry. A serial dilution of VHH constructs starting at 1000nM was applied to the cells in presence of 50 µM Human Serum Albumin. VHH constructs were allowed to associate for 30 minutes at 4°C in cold FACS buffer (D-PBS supplemented with 10% 2% HI-FBS and 0.05 % Sodium Azide). Cells were washed twice by centrifugation (300g; 4°C; 2 minutes; wash by addition of cold FACS buffer) and probed with a Alexa647- labelled mouse anti-VHH antibody (in-house generated) for 30 minutes at 4°C in dark, to detect VHH construct bound to human CEACAM5. Cells were washed twice by centrifugation (300g; 4°C; 2 minutes; wash by addition of cold FACS buffer). PI dead stain was added to the cells and the binding on the cells was then analysed via a MACSQuant X device (Miltenyi Biotec) (table B-4). Table B-4: Results of FACS analysis of purified VHHs on BxPC-3 cells Construct anti-CEACAM5 VHH in EC50 [nM] construct ISVD125 1D07 (ISVD20) >100 A031500053 (ISVD116) 5F01 (ISVD11) 3 A031500054 (ISVD117) 6F03 (ISVD12) 1 A031500062 (ISVD121) 2G08 (ISVD16) 19 ISVD124 2G06 (ISVD19) >100 A031500049 (ISVD112) 2C10 (ISVD7) 2 A031500047 (ISVD106) 1C02 (ISVD1) >100 A031500056 (ISVD108) 24B02 (ISVD3) 27 A031500057 (ISVD118) 26D05 (ISVD13) 15 A031500048 (ISVD111) 1C11 (ISVD6) 36 A031500052 (ISVD115) 4G01 (ISVD10) >100 A031500060 (ISVD110) 25D01 (ISVD5) 62 A031500058 (ISVD107) 20C01 (ISVD2) 65 A031500061 (ISVD120) 26B01 (ISVD15) no binding A031500063 (ISVD122) 8B03 (ISVD17) >100 A031500050 (ISVD113) 3D09 (ISVD8) 3 A031500064 (ISVD123) 9B07 (ISVD18) nd A031500051 (ISVD114) 3F04 (ISVD9) 1 A031500059 (ISVD119) 21A01 (ISVD14) 36 A031500055 (ISVD109) 7E07 (ISVD4) 9 nd: not determined 6.5 Example 5: Affinity determination of selected bivalent VHHs on CEACAM5 The affinity (KD) of the indicated VHH constructs (tables B-3 and A-12) towards human and cynomolgus CEACAM5 was determined via SPR on a ProteOn XPR36 instrument (Bio-Rad Laboratories). The experiment was performed at 25°C, as assay buffer PBS pH7.4 containing 0.005% Tween 20 (Bio-Rad Laboratories) was used. Human CEACAM1 (SEQ ID NO.:28), CEACAM5 (SEQ ID NO.:26), CEACAM7 (SEQ ID NO.:247), CEACAM8 (SEQ ID NO.:248) and cynomolgus CEACAM5 (SEQ ID NO.:27), were immobilized onto different ligand lanes from a GLC sensorchip (Bio-Rad Laboratories) with the ProteOn Amine Coupling Kit (Bio-Rad Laboratories) according to the manufacturer’s instructions. One ligand lane served as an empty reference surface where no target was immobilized. Six different ISVD analyte concentrations ranging from 1000 nM to 0.9 nM diluted in running buffer were flowed over the respective targets and reference surface in multi-cycle kinetics for 2 minutes, followed by a constant flow of the assay buffer for 15 minutes. Between the different injections, the surfaces were regenerated with 10 mM Glycine pH 1.5 (Cytiva). Several buffer blanks were injected for double referencing. Data were analyzed with the ProteOn Manager 3.1.0 software (Bio-Rad Laboratories). The kinetic rate constants (ka and kd) were calculated by fitting the sensorgrams via the Langmuir 1:1 interaction ligand binding model. The equilibrium dissociation constant KD was calculated as the kd/ka ratio. Results are shown in Table B-5. Table B-5: Kinetic analysis of selected VHH constructs on human and cynomolgus CEACAM5 Construct CEACAM5 binder Target Ka (kon) Kd (koff) KD in the construct 1/Ms 1/s M ISVD125 1D07 (ISVD20) hCEACAM5 3.96E+05 7.41E-03 1.87E-08 cCEACAM5 Heterogenous binding profile hCEACAM1 no binding hCEACAM6 no binding hCEACAM7 no binding hCEACAM8 no binding A031500053 5F01 (ISVD11) hCEACAM5 1.93E+06 3.21E-03 1.66E-09 (ISVD116) cCEACAM5 1.32E+06 2.36E-03 1.80E-09 hCEACAM1 no binding hCEACAM6 no binding hCEACAM7 no binding hCEACAM8 2.11E+05 2.98E-02 1.41E-07 A031500054 6F03 (ISVD12) hCEACAM5 1.42E+06 7.23E-04 5.08E-10 (ISVD117) cCEACAM5 1.08E+06 4.86E-03 4.48E-09 hCEACAM1 no binding hCEACAM6 no binding hCEACAM7 no binding hCEACAM8 1.24E+05 3.24E-03 2.62E-08 A031500062 2G08 (ISVD16) hCEACAM5 1.94E+06 6.55E-03 3.37E-09 (ISVD121) cCEACAM5 1.97E+05 2.37E-03 1.20E-08 hCEACAM1 no binding hCEACAM6 no binding hCEACAM7 no binding hCEACAM8 no binding ISVD124 2G06 (ISVD19) hCEACAM5 4.70E+05 4.15E-03 8.83E-09 cCEACAM5 2.92E+05 1.14E-02 3.92E-08 hCEACAM1 no binding hCEACAM6 no binding hCEACAM7 no binding hCEACAM8 no binding A031500049 2C10 (ISVD7) hCEACAM5 1.91E+06 2.74E-04 1.44E-10 (ISVD112) cCEACAM5 1.23E+06 1.92E-03 1.56E-09 hCEACAM1 binding below 10 RU at highest concentration hCEACAM6 no binding hCEACAM7 no binding hCEACAM8 4.18E+05 3.03E-01 7.26E-07 A031500047 1C02 (ISVD1) hCEACAM5 1.20E+05 1.08E-03 8.95E-09 (ISVD106) cCEACAM5 5.90E+05 4.09E-03 6.94E-09 hCEACAM1 no binding hCEACAM6 no binding hCEACAM7 no binding hCEACAM8 no binding A031500056 24B02 (ISVD3) hCEACAM5 1.60E+05 1.70E-03 1.06E-08 (ISVD108) cCEACAM5 9.94E+05 2.26E-03 2.28E-09 hCEACAM1 no binding hCEACAM6 no binding hCEACAM7 no binding hCEACAM8 no binding A031500057 26D05 (ISVD13) hCEACAM5 1.98E+05 9.61E-04 4.86E-09 (ISVD118) cCEACAM5 8.62E+05 2.50E-03 2.90E-09 hCEACAM1 no binding hCEACAM6 no binding hCEACAM7 no binding hCEACAM8 no binding A031500048 1C11 (ISVD6) hCEACAM5 8.68E+04 5.08E-04 5.85E-09 (ISVD111) cCEACAM5 3.04E+05 2.48E-03 8.16E-09 hCEACAM1 no binding hCEACAM6 no binding hCEACAM7 1.47E+05 2.06E-01 1.40E-06 hCEACAM8 no binding A031500052 4G01 (ISVD10) hCEACAM5 8.07E+04 4.85E-04 6.01E-09 (ISVD115) cCEACAM5 3.18E+05 2.06E-03 6.47E-09 hCEACAM1 no binding hCEACAM6 no binding hCEACAM7 2.03E+05 1.89E-01 9.33E-07 hCEACAM8 no binding A031500060 25D01 (ISVD5) hCEACAM5 2.01E+05 5.01E-03 2.49E-08 (ISVD110) cCEACAM5 7.98E+04 2.92E-03 3.65E-08 hCEACAM1 no binding hCEACAM6 no binding hCEACAM7 no binding hCEACAM8 no binding A031500058 20C01 (ISVD2) hCEACAM5 2.19E+05 5.22E-03 2.39E-08 (ISVD107) cCEACAM5 8.70E+04 5.05E-03 5.81E-08 hCEACAM1 no binding hCEACAM6 no binding hCEACAM7 no binding hCEACAM8 no binding A031500061 26B01 (ISVD15) hCEACAM5 1.93E+05 7.94E-03 4.11E-08 (ISVD120) cCEACAM5 6.61E+04 3.11E-03 4.71E-08 hCEACAM1 no binding hCEACAM6 no binding hCEACAM7 no binding hCEACAM8 no binding A031500063 8B03 (ISVD17) hCEACAM5 2.18E+05 5.81E-03 2.67E-08 (ISVD122) cCEACAM5 1.22E+05 3.31E-02 2.72E-07 hCEACAM1 no binding hCEACAM6 no binding hCEACAM7 no binding hCEACAM8 no binding A031500050 3D09 (ISVD8) hCEACAM5 5.85E+05 2.72E-04 4.64E-10 (ISVD113) cCEACAM5 5.21E+05 2.45E-03 4.69E-09 hCEACAM1 no binding hCEACAM6 no binding hCEACAM7 no binding hCEACAM8 8.10E+04 1.18E-02 1.45E-07 A031500064 9B07 (ISVD18) hCEACAM5 5.34E+05 5.10E-05 9.55E-11 (ISVD123) cCEACAM5 4.84E+05 9.32E-04 1.93E-09 hCEACAM1 6.08E+04 6.85E-03 1.13E-07 cCEACAM1 no binding cCEACAM6 no binding cCEACAM7 no binding cCEACAM8 7.33E+04 2.08E-03 2.83E-08 A031500051 3F04 (ISVD9) hCEACAM5 1.19E+06 9.40E-04 7.90E-10 (ISVD114) cCEACAM5 9.20E+05 6.08E-03 6.61E-09 cCEACAM1 5.38E+05 6.74E-01 1.25E-06 cCEACAM6 no binding cCEACAM7 no binding cCEACAM8 9.11E+04 4.46E-02 4.89E-07 A031500059 21A01 (ISVD14) hCEACAM5 2.16E+05 6.73E-03 3.12E-08 (ISVD119) cCEACAM5 7.16E+04 2.47E-03 3.45E-08 cCEACAM1 no binding cCEACAM6 no binding cCEACAM7 no binding cCEACAM8 no binding A031500055 7E07 (ISVD4) hCEACAM5 3.17E+05 4.24E-03 1.34E-09 (ISVD109) cCEACAM5 2.17E+05 3.81E-03 1.76E-08 cCEACAM1 no binding cCEACAM6 no binding cCEACAM7 no binding cCEACAM8 binding below 10 RU at highest concentration 6.5.1 Functional testing of selected bivalent VHHs in CEACAM5-mediated internalization The selected VHH constructs were tested for internalization on human CEACAM5-expressing BxPC- 3 cells exploiting the pH-dependent fluorescence of the dye pHAb (Promega). Prior to the assessment, Human Serum Albumin (HSA) was labelled with pHAb Amine Reactive Dye (Promega) according to the manufacturer’s protocol. The degree of labelling varied between 1.5 to 2.5 for different batches. Each internalization experiment was initiated at day 1 with seeding of ~ 12000 BxPC-3 cells in each well of a 96-well F-bottom plate and incubated at 37°C at 5% CO2 for 40 hours. On day 2 VHH / HSA-pHAb mix’ were prepared and allowed to incubate overnight at 4°C in the dark. On day 3, these pre-mixed VHH/HSA-pHAb solutions were added to the incubated BxPC-3 cells and incubated for 3 hours at 370C; 5% CO2. Subsequently, cells were washed with D-PBS, detached with TrypLE™ Express and transferred to 96-well V-bottom plate. Cells were washed twice by centrifugation (300g; 4°C; 2 minutes; wash by addition of D-PBS), followed by addition of Zombie NIR™ Fixable Viability Kit (Biolegend). After 15 minutes incubation at room temperature, cells were washed twice by centrifugation (300g; 4°C; 2 minutes; wash by addition of cold FACS buffer (D-PBS supplemented with 2% HI-FBS and 0.05 % Sodium Azide)). Final fluorescence read-out in cold FACS buffer was done on FACS Array III (BD Biosciences) at yellow and NIR wavelengths. Data was subsequently analysed using GraphPad Prism, applying a 4 PL model fit to obtain the EC50 values in table B-6. Table B-6: EC50 internalization values of selected VHH constructs on BxPC-3 cells Construct Top VHH construct (MFI)/ CEACAM5 binder Top non-binding control in construct EC50 (nM) (MFI) at 0.5 μM ISVD125 1D07 (ISVD20) nd nd A031500053 (ISVD116) 5F01 (ISVD11) 3 3.6 A031500054 (ISVD117) 6F03 (ISVD12) >200 nd A031500062 (ISVD121) 2G08 (ISVD16) 13 2.8 ISVD124 2G06 (ISVD19) nd nd A031500049 (ISVD112) 2C10 (ISVD7) 2 7.8 A031500047 (ISVD106) 1C02 (ISVD1) 82 4.1 A031500056 (ISVD108) 24B02 (ISVD3) 79 4 A031500057 (ISVD118) 26D05 (ISVD13) 25 2.9 A031500048 (ISVD111) 1C11 (ISVD6) 13 2.4 A031500052 (ISVD115) 4G01 (ISVD10) 15 2.8 A031500060 (ISVD110) 25D01 (ISVD5) 23 1.3 A031500058 (ISVD107) 20C01 (ISVD2) 106 3 A031500061 (ISVD120) 26B01 (ISVD15) >200 1.4* A031500063 (ISVD122) 8B03 (ISVD17) >200 2* A031500050 (ISVD113) 3D09 (ISVD8) 3 3.8 A031500064 (ISVD123) 9B07 (ISVD18) nd nd A031500051 (ISVD114) 3F04 (ISVD9) 3 5.3 A031500059 (ISVD119) 21A01 (ISVD14) >200 1.7* A031500055 (ISVD109) 7E07 (ISVD4) 13 7.1 *ratio at 500 nM while no full dose response curve was seen; nd: not determined 6.6 Example 6: Sequence optimization of selected ISVDs 6.6.1 Sequence optimization ISVDs 24B02, 7E07, 2G08, 2G06 and 1D07 were further sequence optimized to improve chemical stability, to reduce binding by pre-existing antibodies to the ISVD and to make the ISVD more human like. The optimized sequences are depicted in Tables A-3, Tables A-4, Tables A-5, Tables A- 6, Tables A-7 respectively. 6.6.2 Binding kinetics of sequence optimized ISVDs The affinity (KD) of selected sequence optimized ISVDs to their respective ligands, recombinant human CEACAM5 (in-house production) and human serum albumin (Sigma catn. A8763), was determined via SPR on a Biacore 8K+ (Cytiva). The experiment was performed at 25°C and as running buffer HBS-EP+ 1 x (GE Healthcare, cat#BR-1006-69) was used. The ligands were directly immobilized (amine coupling) on Flow Cell 2 (FC) of a Series S Sensor Chip CM5 for CEACAM5 and C1 for human serum albumin. Flow rate during activation, immobilization and deactivation was 10 µl/min. An affinity determination was set up with a 9-point dilution series (2500-1.64 nM). Affinity determination was performed using a 1:1 binding fit model. Samples were applied to the respective targets in multi-cycle kinetics for 2 minutes, followed by a constant flow of the running buffer for 10 minutes. Between the different injections, the surfaces were regenerated with 10 mM Glycin pH 1.5. The equilibrium dissociation constant KD was calculated as the kd/ka ratio. Results are shown in Table B-7. Table B-7: Results affinity analysis of sequence optimized ISVDs Human CEACAM5 Cynomolgus CEACAM5 Sample ID KD[M] KD [M] A031500099 (ISVD21) 8.40E-09 1.30E-08 (parental 24B02/ISVD3) (1.62E-08) (3.28E-08) A031500384 (ISVD22) 1.34E-09 2.23E-08 (parental 7E07/ISVD4) (1.15E-09) (3.20E-08) A031500341 (ISVD23) 2.43E-09 6.59E-08 (parental 2G08/ISVD16) (5.79E-09) (1.35E-07) A031500013 (ISVD24) 6.60E-09 5.80E-08 (parental 2G06/ISVD19) A031500409 (ISVD25) 1.18E-07 7.92E-07 (parental 1D07/ISVD20) (2.27E-08) (1.73E-07) 6.6.3 Thermal stability of sequence optimized ISVDs A thermal shift assay (TSA) was performed as described in 6.3.1. The determined Tm values for 5 selected ISVDs are shown in table B-8. Table B-8: Tm values for selected ISVDs Sample ID Tm, [oC] A031500099 (ISVD21) (parental 24B02/ISVD3) 82 A031500384 (ISVD22) (parental 7E07/ISVD4) 80 A031500341 (ISVD23) (parental 2G08/ISVD16) 77 A031500013 (ISVD24) (parental 2G06/ISVD19) 76 A031500409 (ISVD25) (parental 1D07/ISVD20) 70 6.7 Example 7: Generation of human CEACAM5 binding ISVD compounds 6.7.1 Immunizations Camelids (Camelus bactrianus) were immunized with a cocktail of antigens (among which huCEACAM535-685 (SEQ ID NO: 577; KLTIESTPFNVAEGKEVLLLVHNLPQHLFGYSWYKGERVDGNRQIIGYVIGTQQATPGPAYSGREIIYPNASLLIQ NIIQNDTGFYTLHVIKSDLVNEEATGQFRVYPELPKPSISSNNSKPVEDKDAVAFTCEPETQDATYLWWVNNQS LPVSPRLQLSNGNRTLTLFNVTRNDTASYKCETQNPVSARRSDSVILNVLYGPDAPTISPLNTSYRSGENLNLSCH AASNPPAQYSWFVNGTFQQSTQELFIPNITVNNSGSYTCQAHNSDTGLNRTTVTTITVYAEPPKPFITSNNSNP VEDEDAVALTCEPEIQNTTYLWWVNNQSLPVSPRLQLSNDNRTLTLLSVTRNDVGPYECGIQNELSVDHSDPVI LNVLYGPDDPTISPSYTYYRPGVNLSLSCHAASNPPAQYSWLIDGNIQQHTQELFISNITEKNSGLYTCQANNSAS GHSRTTVKTITVSAELPKPSISSNNSKPVEDKDAVAFTCEPEAQNTTYLWWVNGQSLPVSPRLQLSNGNRTLTLF NVTRNDARAYVCGIQNSVSANRSDPVTLDVLYGPDTPIISPPDSSYLSGANLNLSCHSASNPSPQYSWRINGIPQ QHTQVLFIAKITPNNNGTYACFVSNLATGRNNSIVKSITVSASGTSPGLSAHHHHHH) produced in HEK293 cells) using Freund's complete adjuvant (first injection) and Freund's incomplete adjuvant (subsequent injections) according to the scheme listed below: Immunization Protocol: Day Procedure 1 Pre-bleed.20 ml serum per animal. Inject the antigens mixed 1:1with CFA. 21 Inject antigen mixed with Incomplete Freund's adjuvant of the same equal volume 42 Inject antigen mixed with Incomplete Freund's adjuvant of the same equal volume 70 Inject antigen mixed with Incomplete Freund's adjuvant of the same equal volume 90 Inject antigen mixed with Incomplete Freund's adjuvant of the same equal volume 98 Production bleed.300 ml whole blood Na EDTA for B-Cell Isolation, 200mL for serum production 6.7.2 mRNA isolation, library constructions and phage display selections Using the classical Ficoll Hypaque density gradient centrifugation method, up to 4^108 PBLs were collected and subjected to total RNA isolation with the TriZol method. RT-PCR was performed using Oligo dT as the primer. A first round of PCR amplification of the VH-CH1-Fc and VHH-Fc gene was conducted using an Fc downstream primer and a VH/VHH-FR1 upstream primer using 200× diluted cDNA as the template. Two bands were amplified of which the smaller band (the VHH band) was recovered and subjected to a second round of PCR. The second round of PCR amplified the VHH gene using a VHH-FR4 downstream primer and a VHH-FR1 upstream primer. The second round PCR product was then digested with BssHII and NheI, purified with the Qiagen kit, and cloned between the BssHII and NheI sites of the phagemid vector upstream the myc and 6xHis tags using the NEB’s T4 DNA ligase. The ligation products were desalted before being electro- transformed into TG1 host cells. An end library of 6.0×108 diversity was constructed after 4 transformations. By colony PCR, the random clones from the end library were QC tested. All of 20 clones contained the DNA insert of the right VHH size.20 clones were subsequently subjected to DNA sequencing. No identical sequences were found among these clones. 6.7.3 Selections For general phage display selection techniques, reference is made to Antibody Phage Display: Methods and Protocols (First Edition, 2002, O’Brian and Aitken eds., Humana Press, Totowa, NJ). huCEACAM5 protein was coated on ELISA plates or on streptavidin beads (via biotin capture) and 2 rounds of panning were conducted using the camel immune library. The output from selection was added to exponentially growing TG1 bacteria before plating on 2YTAG plates (2xYT medium, Ampicillin 100 μg/mL, Glucose 2%). Individual TG1 colonies were randomly picked using a colony picker (Molecular Device) and grown overnight in 2YTAG at 37°C. Overnight culture was then used to inoculate 2YTA medium in new 96-well plates. After growing for 2-3 h at 37°C, the production of VHH was induced by the addition of 1 mM IPTG (isopropyl β-D-1-thiogalactopyranoside) followed by overnight incubation at 37°C. Supernatant containing VHHs was harvested and used for the primary screening of the non-purified VHH. 6.7.4 Primary screening and sequencing Primary screening of 380 supernatants was performed by ELISA on human (SEQ ID NO: 577) CEACAM5 proteins (in-house produced).384-well ELISA plates were coated overnight at 4°C with human CEACAM5 at final concentration of 1 μg/ml in PBS buffer. After blocking with PBS (incl. 0.1%Tween, 20-2% milk) a final dilution of 1/2 of TG1 supernatants was applied and allowed to incubate for 1 h at room temperature. After washing, the binding of myc-tagged VHHs on coated CEACAM5 was detected by an anti-myc-HRP conjugate (Roche). All but 5 clones were binders to CEACAM5, even after the first round, showing a strong enrichment. Due to the high enrichment in round 1, 760 clones from the immune library were picked and tested for binding to huCEACAM5 by ELISA, resulting in the identification of 20 positive clones. All positive clones from the immune library or post selection were then Sanger-sequenced. From these, 23 unique sequences were obtained divided into 17 different clusters (based on 90% sequence identity). 6.8 Example 8: Further characterization of the human CEACAM5-binding ISVD compounds expressed in E. coli 6.8.1 Binding to CEACAM5-expressing cells The 23 clones were further tested for their capacity to bind human CEACAM5 expressed on cell surface by flow cytometry. In short, three dilutions of non-purified TG1 supernatants (dilution ½, 1/10 and 1/100) were applied to live MKN45 cells (DSMZ, ref ACC409). VHHs were allowed to associate for 1h at 4°C in FACS buffer (PBS supplemented with 3% BSA). Cells were washed by centrifugation and incubated for 1h at 4°C with DAPI (Life Technologies) to stain for dead cells together with the Penta·His Alexa Fluor 647 Conjugate (Qiagen) to detect VHH bound to CEACAM5. The cells were then analysed via a MACSQuant cytometer (Miltenyi Biotec). Results of the binding FACS are shown in Figure 1.21 out of the 23 VHHs could bind MKN45 cells in a dose-dependent manner. 6.8.2 Domain mapping, specificity and cross-reactivity The 23 clones were further characterized for specificity and crossreactivity, and an epitope mapping assay was run to determine the binding site of each VHH in a domain resolution. In short, 4 truncated extracellular domains of human CEACAM5 were prepared, representing the isolated N- A1B1 (SEQ ID NO: 546), A1-B1(SEQ ID NO: 111), A2-B2(SEQ ID NO: 112), and A3-B3 (SEQ ID NO: 113) domains, respectively. 384-well ELISA plates were overnight coated with the full-length extracellular domain of human CEACAM1, CEACAM5, CEACAM6 or cyno CEACAM5, as well as with the N-A1B1, A1-B1, A2-B2 and the A3-B3 domains at final concentrations of 1 μg/ml in PBS buffer. After blocking with PBS (supplemented with 0.1%Tween, 20-2% milk), a final dilution of 1/2 of TG1 supernatants was applied and incubated for 1 h at room temperature. After washing, the binding of myc-tagged VHHs on coated CEACAM5 was detected by an anti-myc-HRP conjugate (Roche). Results of the ELISA are shown in Table B-9. The two clones that did not bind to MKN45 were also negative in the ELISA assay (14R01-19 and 14R01-24). The majority of the remaining 21 VHHs were specific to huCEACAM5 while 3 out of the 23 bound to cyno CEACAM5. Most of the VHHs bound only one of the 4 domains, their majority binding to the N-terminal domain (domain 35-320). Finally, one VHH was found to be both specific and cross-reactive. Table B-9: Specificity, cross reactivity and epitope mapping of the selected VHHs N-A1B1 A1B1 A2B2 A3B3 A2B2 N-A1B1 hCEACAM5 hCEACAM5 hCEACAM5 hCEACAM5 and and 35-320 143-320 321-498 499-685 A3B3 A2B2 14 1 2 1 1 2 Specific to 8 0 1 1 1 2 huCEACAM5 Binding to both 1 1 1* human and cyno CEACAM5 Specific and 1* crossreactive *lower OD signal on cyno CEACAM5 vs human CEACAM5 2.8.3 Affinity of the selected ISVDs for human CEACAM5 The EC50 of the 21 VHHs binding to huCEACAM5 was then determined using unpurified periplasmatic extracts (PE) from TG1. The concentration of VHH in PE was first determined. Then their binding to recombinantly expressed human CEACAM5 was evaluated in ELISA.384-well ELISA plates were overnight coated with human CEACAM5 at a final concentration of 1 μg/ml in PBS buffer. After blocking with PBS (supplemented with 0.1%Tween, 20-2% milk), serial dilutions of the PE containing anti-CEACAM5 VHHs were applied and allowed to incubate for 1 hour at room temperature. After extensive washing, the VHHs bound to coated CEACAM5 were detected by an anti-cMyc-HRP (Roche) and the EC50 were determined. Results are shown in Table B-10. Table B-10: EC50 values determined by ELISA on recombinant huCEACAM5 E.coli clone ID EC50 on immobilized huCEACAM5 (nM) 14R04-11 0.05 14R04-18 0.06 14R0410 0.07 (T023200178) 14R04-20 0.07 14R04-13 0.07 14R04-15 0.08 14R04-09 0.11 14R04-14 0.11 14R04-17 0.12 14R04-03 0.12 14R04-07 0.12 14R04-12 0.13 14R04-08 0.14 14R04-04 0.2 14R04-22 0.35 14R04-05 0.37 14R04-06 0.37 14R01-16 0.52 6.9 Example 9: Further characterization of the human CEACAM5-binding ISVD compounds expressed in mammalian cells 6.9.1 Production of the human CEACAM5-binding ISVD compounds in mammalian cells and quantification The 23 VHHs were cloned into a mammalian expression vector for production in FreeStyle 293-F cells (Invitrogen). To facilitate detection and purification, the VHH binders were extended with the influenza hemagglutinin (HA) and 6xhistidine (His) tags.21 out of the 23 expected plasmids were recovered and purified using NucleoBond Macherey-Nalgel kits and Sanger sequenced, before transfection in FS293-F cells. Supernatants were harvested 7 days later. To assess the quantity and quality of unpurified VHH-HA-His in supernatants, ELISA and SDS-PAGE techniques were used. For ELISA titration, 384-well ELISA plates were coated overnight with the anti-tetra-His antibody (Qiagen) at a final concentration of 2.5 μg/ml in PBS buffer. After blocking with 2% BSA, serial dilutions of the supernatants containing unpurified VHH-HA-His were applied and allowed to incubate for 1 hour at room temperature. A purified VHH-HA-His (clone 13R05-10) was used as standard in the assay. After extensive washing, the VHHs captured by the coated anti-tetra-His antibody were detected by an anti-HA-HRP (Sigma) and their concentration was determined. Results are shown in Table B-11. Concentrations ranged between 0 and 48µg/ml (for clones 14R04- 21 and 14R04-05 respectively), with an average of 19.47 +/- 11.8 µg/ml, showing variability in expression levels. Table B-11: Quantification by ELISA of VHHs produced in mammalian cells Mammalian clone ID Supernatant concentration (µg/ml) 14R04-02 21.09 14R04-03 8.64 14R04-04 2.13 14R04-05 48.06 14R04-06 5.78 14R04-07 33.53 14R04-08 25.25 14R04-09 25.83 14R0410 (T023200178) 22.03 14R04-11 7.77 14R04-12 27.44 14R04-13 29.83 14R04-14 44.17 14R04-15 6.85 14R04-16 25.22 14R04-17 5.44 14R04-18 35.78 14R04-19 12.60 14R04-20 9.56 14R04-21 0.00 14R04-22 12.04 SDS-PAGE is a method that separates proteins by size, giving a visual profile of samples on a gel. Results are shown on Figure 2. The VHHs in lanes 3, 5, 10, 14, 16 and 20 show low band intensity at the expected molecular weight (between 15 and 20kDa), corresponding to the lowest concentrations measured by ELISA. Overall, there is a good correlation between the results of SDS- page and ELISA, supporting the reliability of the data. 2.9.2 Affinity of the selected ISVDs for huCEACAM5 and cyCEACAM5 The affinity of the VHHs produced in mammalian cells for recombinant proteins (huCEA and cyCEA), was assessed via ELISA.96-well ELISA plates were overnight coated with recombinant antigen at a final concentration of 1 µg/ml in PBS buffer. After blocking with 2% Milk, serially diluted supernatants containing VHHs were applied and allowed to incubate for 1 hour at room temperature. After extensive washing, the VHHs bound to coated recombinant antigen were detected by an anti-HA-HRP (sigma). Results are shown in Figure 3. Three clones (14R04-13,18 and 19) did not show binding to huCEACAM5, while the remaining 17 clones had EC50 values for huCEACAM5 binding below 1 nM. Additionally, two clones, 14R04-06 and 14R04-10, were confirmed to bind to cynoCEACAM5 with EC50 values of 2.1 and 2.9 nM, respectively. 6.9.2 Binding kinetics of ISVD constructs The affinity constants (ka, kd, and KD) for human CEACAM5 of the VHHs produced in mammalian cells was determined via SPR on a T200 instrument. An anti-His antibody was covalently immobilized on a Sensor Chip CM5 (Cytiva LifeSciences, Biacore). Following surface preparation, FS293-F supernatants containing VHH were injected to allow for their capture via their His tag. Various concentrations of recombinant huCECAM5 were then injected, and dissociation was monitored for over 10 minutes. Results are shown in Table B-12. Clones 14R04-3, 14R04-4, 14R04- 9, 14R04-14, and 20 could not be measured accurately because their affinity values exceeded the instrument's detection limits due to extremely high affinity. Extended dissociation time was required. In line with the EC50 measurements obtained from ELISA, clones 14R04-13, 14R04-18, and 14R04-19 displayed no binding to huCEACAM5. The other clones showed an overall high affinity for huCEACAM5. Indeed, 17 clones showed KD between 0.01 nM and 2 nM and 11 clones showed a dissociation rate (kd) lower than 2.10-4 s-1. Table B-12: Results of the affinity analysis by SPR of the VHHs Clone ka (1/Ms) kd (1/s) KD (M) 14R04-09 1.52E+05 9.31E-09 6.13E-14 14R04-20 1.14E+05 3.28E-08 2.88E-13 14R04-04 9.69E+04 7.45E-08 7.69E-13 14R04-14 1.79E+05 1.49E-07 8.32E-13 14R04-03 1.14E+05 4.22E-06 3.70E-11 14R0410 1.64E+05 1.55E-05 9.45E-11 (T023200178) 14R04-12 9.23E+04 1.88E-05 2.04E-10 14R04-02 1.09E+05 3.96E-05 3.63E-10 14R04-06 1.88E+05 7.32E-05 3.89E-10 14R04-15 2.66E+05 1.31E-04 4.92E-10 14R04-11 3.49E+05 1.66E-04 4.76E-10 14R04-05 2.43E+05 1.77E-04 7.28E-10 14R04-07 3.93E+05 2.97E-04 7.56E-10 14R04-22 4.70E+05 4.25E-04 9.04E-10 14R04-16 2.14E+05 5.92E-04 2.77E-09 14R04-08 3.98E+05 7.76E-04 1.95E-09 14R04-17 6.73E+05 1.27E-03 1.89E-09 14R04-13 No binding 14R04-18 No binding 14R04-19 No binding 6.9.3 FACS analysis on cells expressing human CEACAM5 The ability of FS293-F cell supernatants to bind to MKN45 cells expressing the CEACAM5 antigen was assessed, by measuring the affinity constant (EC50) and maximum binding capacity (Bmax) by flow cytometry. Cells were incubated with serial dilutions of FS293-F supernatants containing VHH for 1h at 4°C in FACS buffer (PBS supplemented with 3% BSA). Cells were washed by centrifugation and probed for 1 hour at 4°C with DAPI (Life Technologies) to stain for dead cells together with the Penta·His Alexa Fluor 647 Conjugate (Qiagen) to detect VHH bound to CEACAM5. Cells were washed by centrifugation and then analysed with a MACSQuant cytometer (Miltenyi Biotec). Results are shown on Figure 4. Seventeen VHHs bound to MKN45 cells. Of these 17 VHHs, 11 were specifically directed against CEACAM5, while 6 clones could also bind to CEACAM6, or CEACAM6 and CEACAM1. EC50 values ranged from 0.6 nM to 11 nM. Bmax values ranged from 10,000 to 225,000, with the highest values observed for clones binding to CEACAM6, which is highly expressed on MKN45 cells. 6.10 Example 10: Sequence optimization of ISVD 14R0410 (T023200178) 6.10.1 Sequence optimization ISVDs 14R0410 (T023200178) was further sequence optimized to improve chemical stability, to reduce binding by pre-existing antibodies to the ISVD and to make the ISVD more human like. The optimized sequences are depicted in Tables A-16. 6.10.2 Binding kinetics of sequence optimized ISVDs All optimized sequences were subjected to off-rate analysis towards human (SEQ ID NO: 26) and cynomolgus CEACAM5 (SEQ ID NO: 27) by Surface Plasmon Resonance (SPR) on a ProteOn XPR36 instrument (Bio-Rad Laboratories). The experiment was performed at 25°C. As assay buffer PBS pH7.4 containing 0.005% Tween 20 (Bio-Rad Laboratories) was used. Human CEACAM5 and cynomolgus CEACAM5 were immobilized on different ligand lanes from a GLC sensor chip (Bio-Rad Laboratories) with the ProteOn Amine Coupling Kit (Bio-Rad Laboratories) according to the manufacturer’s instructions. One ligand lane served as a reference surface where no target was immobilized. Pes diluted 1:10 in running buffer were flowed over for 2 minutes, followed by a constant flow of the assay buffer for 10 minutes. Between sample injections, the surfaces were regenerated with 2 pulses (20 seconds) of 10 mM glycine pH 1.5. Several buffer blanks were injected for double referencing. Data was analysed with the ProteOn Manager 3.1.0 software (Bio-Rad Laboratories), off-rates were determined based on the 1:1 interaction model (Langmuir binding model). Results are shown in Table B-13. Table B-13: Off-rates of the sequence optimized ISVDs of ISVDs 14R0410 (T023200178) Human CEACAM5 Cynomolgus CEACAM5 Sample ID Kd [1/s] Kd [1/s] T023200178 2.47E-04 2.95E-03 T028500006 2.67E-04 2.96E-03 T028500007 2.55E-04 3.10E-03 T028500008 1.13E-03 2.90E-02 T028500009 1.09E-03 2.74E-02 T028500011 1.14E-03 2.79E-02 T028500012 1.25E-03 2.56E-02 T028500013 3.09E-04 8.16E-04 T028500014 1.32E-03 nd T028500015 6.77E-04 8.09E-03 T028500016 3.54E-04 4.29E-03 T028500017 2.79E-04 2.86E-03 T028500018 2.78E-04 2.94E-03 T028500557 2.37E-03 5.06E-03 T028500558 4.92E-04 1.24E-03 nd: not determined 6.10.3 Thermal stability of sequence optimized ISVDs A thermal shift assay (TSA) was performed as described in 6.3.1. The determined Tm values for the sequence optimized ISVDs are shown in Table B-14. Table B-14: Tm values for selected ISVDs Sample ID Tm, [oC] T023200178 63 T028500006 62 T028500007 60 T028500008 60 T028500009 63 T028500010 74 T028500011 60 T028500012 62 T028500013 69 T028500014 61 T028500015 70 T028500016 63 T028500017 63 T028500018 61 T028500557 74 T028500558 72 6.11 Example 11: Generation of human CEACAM5 binding ISVD compounds 6.11.1 Immunizations Camelids were immunized with a cocktail of antigens using Freund's complete adjuvant (first injection) and Freund's incomplete adjuvant (subsequent injections) as described in WO2003/035694. 6.11.2 Library constructions and phage display selections Immune blood samples were taken and total RNA was prepared from the isolated peripheral blood lymphocytes (PLBs). From these blood samples, peripheral blood mononuclear cells (PBMCs) were prepared using Ficoll-Hypaque according to the manufacturer’s instructions (Amersham Biosciences, Piscataway, NJ, US). From the PBMCs, total RNA was extracted and used as starting material for RT-PCR to amplify the VHH-encoding DNA segments, essentially as described in WO 2005/044858. Subsequently, phages were prepared according to standard protocols (see for example the prior art and applications filed by Ablynx N.V. cited herein) and stored after filter sterilization at 4 °C for further use. For general phage display selection techniques, reference is made to Antibody Phage Display: Methods and Protocols (First Edition, 2002, O’Brian and Aitken eds., Humana Press, Totowa, NJ). Two or three rounds of panning phage display selections were performed using the llama immune library in selection rounds on CEACAM5 protein. The output from the selection were plated onto LB/amp/2%glu plates. Colonies were picked and grown in 96 deep well plates (1 ml volume) and induced by adding IPTG for VHH expression. Periplasmic extracts (PEs, volume: ~ 80 ^l) were prepared according to standard methods (see for example the prior art and applications filed by applicant cited herein). 6.11.3 Primary screening Primary screening of PEs was performed by ELISA on human CEACAM5 proteins (in-house produced). 96-well ELISA plates were coated overnight at 4°C with human CEACAM5 at final concentration of 1 μg/ml in PBS buffer. After blocking with PBS-0.1%Tween20-2% milk, a final dilution of 1/2 of TG1 supernatants was applied and allowed to incubate for 1 h at room temperature. After washing, the binding of myc-tagged VHHs on coated CEACAM5 was detected by an anti-myc-HRP conjugate (Roche). 6.12 Example 12: Further characterization of the human CEACAM5-binding ISVD compounds 6.12.1 Binding kinetics of the ISVD constructs The affinity constants (ka, kd, and KD) for human CEACAM5 of the VHHs was determined via SPR on a ProteOn XPR36 instrument (Bio-Rad Laboratories). Human CEACAM5 (SEQ ID NO: 27) was immobilized on a a GLC sensorchip (Bio-Rad Laboratories) with the ProteOn Amine Coupling Kit (Bio-Rad Laboratories) according to the manufacturer’s instructions. Various VHH analyte concentrations were then injected and dissociation was monitored for over 10 minutes. Data were analyzed with the ProteOn Manager 3.1.0 software (Bio-Rad Laboratories). The kinetic rate constants (ka and kd) were calculated by fitting the sensorgrams via the Langmuir 1:1 interaction ligand binding model. The equilibrium dissociation constant KD was calculated as the kd/ka ratio. Results are shown in Table B-15. Table B-15: Results of the affinity analysis by SPR of the VHHs ID ka (1/Ms) kd (1/s) KD (nM) T023200001 9.9E+05 5.1E-04 0.51 T023200005 1.1E+06 3.3E-03 3.1 T023200134 4.3E+05 6.4E-04 1.5 T023200137 3.9E+05 4.1E-03 10.5 T023200133 3.4E+05 1.2E-02 51.8 T023200136 1.7E+05 6.2E-03 36.5 T023200129 1.2E+05 1.1E-03 90 Benchmark 4.2E+05 7.6E-03 18 (T023200009) 6.12.2 Binding of the selected ISVDs to recombinant CEACAM5 and CEACAM6 The binding of the VHHs for recombinant proteins (hCEACAM5 and hCEACAM6), was assessed via ELISA.96-well ELISA plates were overnight coated with recombinant antigen at a final concentration of 1 µg/ml in PBS buffer. After blocking with 1% Milk, serially diluted supernatants containing VHHs were applied and allowed to incubate for 1 hour at room temperature. After extensive washing, the VHHs bound to coated recombinant antigen were detected by an anti-FLAG-HRP (Sigma). Results are shown in Table B-16 and Figure 5. Binding to hCEACAM5 was confirmed for all the clones, including 5 clones with EC50 values below 1 nM, and 2 clones (T023200001 and T023200134) with EC50 values below 0.1 nM. Additionally, two clones, T023200129 and T023200136, were cross-reactive with hCEACAM6. Table B-16: EC50 values of the VHH clones for binding hCEACAM5 and hCEACAM6 as determined in ELISA ID CEACAM5 CEACAM6 EC50 (M) EC50 (M) T023200001 2.7E-11 T023200009 3.1E-10 T023200129 1.5E-10 1.7E-09 T023200130 4.1E-08 T023200133 6.1E-10 T023200134 6.2E-11 T023200135 3.8E-10 T023200136 4.9E-10 2.2E-09 T023200137 1.3E-09 (T023200009) 6.12.3 Binding of the selected ISVDs to cells expressing human CEACAM5 Binding of purified CEACAM5 VHHs to human CEACAM5 expressed on LS174T cells was assessed by flow cytometry. Cells were incubated with serial dilutions of VHHs for 30 min at 4°C in FACS buffer (D-PBS supplemented with 10% FBS and 0.05 % Sodium Azide). Cells were washed by centrifugation and probed for 30 minutes at 4°C with a primary anti-FLAG mouse monoclonal antibody (Sigma Aldrich), washed and subsequently incubated for again 30 minutes at 4°C with a secondary goat anti-mouse -APC labelled polyclonal antibody (Jackson Immuno Research) in the dark to detect VHH bound to CEACAM5. Cells were washed by centrifugation. PI dead stain was added to the cells and the binding on the cells was then analysed with a BD FACS Canto cytometer (BD Biosciences). Results are shown on Figure 6 and Table B-17. Nine VHHs bound to LS174T cells. EC50 values ranged from 0.91 nM to 85 nM. Only two VHHs (T023200001 and T023200134) have value below 2nM. Table B-17: EC50 (M) values of the VHH clones for binding CEACAM5 expressed on LS174T cell line as determined by flow cytometry ID FACS (LS174T) EC50 (M) T023200001 9.1E-10 T023200005 5.3E-09 T023200134 1.98E-09 T023200137 9.17E-09 T023200133 1.88E-08 T023200135 8.50E-08 T023200136 2.22E-08 T023200129 8.47E-09 Benchmark 1.52E-08 2.12.4 Functional testing of selected VHHs in CEACAM5-mediated internalization The selected monovalent anti-CEACAM5 VHHs (Flag3-His6 tagged) were tested for internalization on human LS174T cells using the pH-dependent fluorescence of the dye pHrodo. Each internalization experiment was initiated on day 1 with seeding of ~30,000 LS174T cells in each well of a 96-well F-bottom plate and incubated at 37°C with 5% CO2 overnight. On day 2, the VHHs (final concentration: 62.5 nM) were pre-mixed with an anti-FLAG pHrodo-labeled (in-house prepared, final concentration: 500 nM) monoclonal antibody. Cells were subsequently incubated at 37°C with 5% CO2 for 90 hours in the Incucyte instrument (Sartorius). Every hour, the pHrodo-specific fluorescence was measured, images of the cells were taken at several time points to allow assessment of the viability of the cells throughout the experiment. 6.13 Example 13: Sequence optimization of ISVD T023200134 6.13.1 Sequence optimization ISVDs T023200134 was further sequence optimized to improve chemical stability, to reduce binding by pre-existing antibodies to the ISVD, to make the ISVD more human like and/or to affinity demature the ISVD. The optimized sequences are depicted in Tables A-17. 6.13.2 Binding kinetics of sequence optimized ISVDs All optimized sequences were subjected to off-rate analysis towards human (SEQ ID NO: 26) and cynomolgus CEACAM5 (SEQ ID NO: 27) by Surface Plasmon Resonance (SPR) on a ProteOn XPR36 instrument (Bio-Rad Laboratories). The experiment was performed at 25°C. As assay buffer PBS pH 7.4 containing 0.005% Tween 20 (Bio-Rad Laboratories) was used. Human CEACAM5 and cynomolgus CEACAM5 were immobilized on different ligand lanes from a GLC sensor chip (Bio-Rad Laboratories) with the ProteOn Amine Coupling Kit (Bio-Rad Laboratories) according to the manufacturer’s instructions. One ligand lane served as a reference surface where no target was immobilized. PEs diluted 1:10 in running buffer were flowed over for 2 minutes, followed by a constant flow of the assay buffer for 10 minutes. Between sample injections, the surfaces were regenerated with 2 pulses (20 seconds) of 10 mM glycine pH 1.5. Several buffer blanks were injected for double referencing. Data was analysed with the ProteOn Manager 3.1.0 software (Bio-Rad Laboratories), off-rates were determined based on the 1:1 interaction model (Langmuir binding model). Results are shown in Table B-18 and B-19. Table B-18: Off-rates of the sequence optimized ISVDs of ISVD T023200134 Human CEACAM5 Cynomolgus CEACAM5 Sample ID Kd [1/s] Kd [1/s] T023200134 4.30E-04 8.96E-04 T028500003 4.92E-04 8.74E-04 T028500004 4.71E-04 8.96E-04 T028500005 5.00E-04 8.73E-04 Table B-19: Off-rates of the sequence optimized ISVDs of ISVD T023200134 Human CEACAM5 Cynomolgus CEACAM5 Sample ID Kd [1/s] Kd [1/s] T023200134 5.80E-04 1.20E-03 T028500591 1.87E-03 2.30E-03 T028500588 1.41E-03 1.73E-03 T028500582 5.87E-03 5.02E-03 T028500593 1.21E-02 2.02E-02 T028500592 7.41E-03 1.36E-02 T028500587 6.19E-03 4.44E-03 T028500581 1.41E-02 1.30E-02 T028500590 1.41E-02 1.60E-02 T028500594 1.28E-02 2.78E-02 T028500583 3.42E-02 1.80E-02 2.13.2 Thermal stability of sequence optimized ISVDs A thermal shift assay (TSA) was performed as described in 6.3.1. The determined Tm values for 5 selected ISVDs are shown in Table B-20. Table B-20 Tm values for selected ISVDs Sample ID Tm, [oC] T023200134 70 T028500003 68 T028500004 68 T028500005 69 T028500591 69 T028500588 70 T028500582 68 T028500593 67 T028500592 67 T028500587 66 T028500581 70 T028500590 69 T028500594 68 T028500583 69 6.13.3 Binding kinetics of the sequence optimized ISVD constructs The affinity constants (KD) of the VHHs for binding to human and cyno CEACAM5 was determined via SPR as described in 6.2.1. Results are shown in Table B-21. Table B-21: Results of the affinity analysis by SPR of the sequence optimized VHHs ID KD (nM) KD (nM) hCEACAM5 cCEACAM5 T023200134 1.20E-09 1.90E-09 T028500591 2.82E-09 3.06E-09 T028500588 6.51E-09 6.07E-09 T028500582 1.27E-08 8.06E-09 T028500593 2.44E-08 3.16E-08 T028500592 3.07E-08 3.71E-08 T028500587 3.17E-08 1.65E-08 T028500581 7.62E-08 7.04E-08 T028500590 9.28E-08 1.16E-07 T028500594 1.59E-07 1.55E-07 T028500583 1.97E-07 9.68E-08 6.14 Example 12: Determination of the structure of the T023200134/CEACAM5 interaction site by Cryogenic electron microscopy (cryo-EM) 1290 pmol of the ISVD T023200134 was incubated with 1580 pmol of A2-B2 domain of CEACAM5 (EPPKPFITSNNSNPVEDEDAVALTCEPEIQNTTYLWWVNNQSLPVSPRLQLSNDNRTLTLLSVTRNDVGPYEC GIQNELSVDHSDPVILNVLYGPDDPTISPSYTYYRPGVNLSLSCHAASNPPAQYSWLIDGNIQQHTQELFISNITE KNSGLYTCQANNSASGHSRTTVKTITVSAHHHHHH; SEQ ID NO: 112) and 1520 pmol of an anti-Nb Fab TPP-38000 (in house generated) to obtain the high-resolution structure, in a total volume of 88.12 µL PBS. The final stoichiometric ratio was 1:1.2:1.2 (ISVD:CEACAM5:Fab). The complex was incubated for 30 minutes at 4 °C temperature and purified via size exclusion chromatography on a Superdex20010/300 GL increase column (Cytiva) with injected volume of 60 µL and collecting 0.1 µL fractions. Peak fractions were collected, and centre peak fraction was used for sample preparation. The concentration of the sample was determined to be 0.33 mg/mL via absorption at 280 nm using a Nanodrop spectrophotometer (Thermo). CryoEM samples were prepared on 0.6/1.0 UltraFoil grids, 300 mesh (Quantifoil) using 4 µL per grid, vitrifying with a Thermo Fisher Vitrobot-IV. With blot force of 5, and blot time of 4 second was used at 4°C temperatures and a humidity of 100%. Grids were screened on Thermo Fisher Glacios 200 keV transmission electron microscope equipped with a Falcon4 direct electron detector. 6779 movies were collected on Thermo Fisher Krios 300 keV transmission electron microscope equipped with a Falcon4i direct electron detector and Selectris X energy filter. The electron microscope was operated at 300 kV, and data were collected in counting mode using EPU software (version 3.1) using a defocus range between −0.6 and −2.2 µm with a pixel size of 0.74 Å. Each movie contained 60 frames with a dose per frame of 1 electron/Å2 and a total exposure time of 3.2 seconds. Data were processed with CryoSPARC (version 4.2). Full-frame motion correction and estimation of contrast-transfer function (CTF) parameters were carried out using the built-in patch-motion correction and patch-CTF estimation routines, respectively. From 5760 manually selected movies 2,956,933 particles were auto picked. After 2–3 rounds of 2D classification 683,394 selected particles were further used for ab initio 3D model generation with four classes. Followed by non-uniform refinement with 107,632 particles, which resulted in a map at 3.24 Å map which could be improved to 3.11 Å resolution with local refinement to improve the density in epitope-paratope region. For modelling structures into the cryoEM map, predicted structures were obtained from AlphaFold for the ISVD T023200134 and TPP-38000. For modelling CEACAM5 into the map a deposited structure of CEACAM5 was used PDB-ID 8BW0 (Kumar, Anand, et al. "Structural insights into epitope-paratope interactions of a monoclonal antibody targeting CEACAM5-expressing tumors." Nature Communications 15.1 (2024): 9377). All three components were fitted manually into the cryoEM map using ChimeraX (USFC) (Pettersen, Eric F., et al. "UCSF ChimeraX: Structure visualization for researchers, educators, and developers." Protein science 30.1 (2021): 70-82). Furthermore, side chains were manually adjusted using Coot (version 0.9.4.1) (Casañal, Ana, Bernhard Lohkamp, and Paul Emsley. "Current developments in Coot for macromolecular model building of Electron Cryo-microscopy and Crystallographic Data." Protein Science 29.4 (2020): 1055- 1064) and model was real-space refined in PHENIX (version 1.19.2) (Afonine, Pavel V., et al. "Real- space refinement in PHENIX for cryo-EM and crystallography." Acta Crystallographica Section D: Structural Biology 74.6 (2018): 531-544.). A view of the structure of the interaction of T023200134 is given in Figure 8, interactions were calculated using Proteins, Interfaces, Structures, and Assemblies (PISA). T023200134 binds primarily to the A2 domain of CEACAM5 and has weak interaction with the B2 domain. Analysis of the obtained structure of the interaction between T023200134 and CEACAM5 showed involvement in binding by following amino acids: • CEACAM5 epitope: K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, L343, E346, D405, P406, V407, I408, L409, N410, L412, N442, P444, A483 • T023200134 paratope: T52, W53, R54, G56, S57, T58, H59, D99, L100, R101, F103, G104, P105, I106, T107, T108, T109, Q111, I113, N114, which corresponds to T52, W52a, R53, G55, S56, T57, H58, D95, L96, R97, F99, G100, P100a, I100b, T100c, T100d, T100e, Q100f, I100g, N101 according to Kabat numbering. 6.15 Example 13: Determination of the structure of the 2G08/CEACAM5 interaction site by Cryogenic electron microscopy (cryo-EM) 2510 pmol of the ISVD A037900128 (2G08) was incubated with 3150 pmol of A2-B2 domain of CEACAM5 (SEQ ID NO: P06731, 321-498) and 3040 pmol of an anti-Nb Fab TPP-64219 to obtain the high-resolution structure, in a total volume of 100 uL PBS. The final stoichiometric ratio was 1:1.2:1.2 (ISVD:CEACAM5:Fab). The complex was incubated for 30 minutes at 4°C temperature and purified via size exclusion chromatography on a Superdex20010/300 GL increase column (Cytiva) with injected volume of 90 µL and collecting 0.1 µL fractions. Peak fractions were collected, and center peak fraction was used for sample preparation. The concentration of the sample was determined to be 0.6 mg/mL via absorption at 280 nm using a Nanodrop spectrophotometer (Thermo). CryoEM samples were prepared on 1.2/1.3 QuantiFoil grids, 300 mesh (Quantifoil) using 4 µL sample per grid, vitrifying with a Thermo Fisher Vitrobot-IV. With blot force of 5, and blot time of 4 second was used at 4°C temperatures and a humidity of 100%. Grids were screened and 7908 movies were collected on Thermo Fisher Krios 300 keV transmission electron microscope equipped with a Falcon4i direct electron detector and Selectris X energy filter. Protein particles nicely distributed on the cryo-EM specimen, and specimen ice was optimum for data collection. The electron microscope was operated at 300 kV, and data were collected in counting mode using EPU software (version 3.1) using a defocus range between −0.6 and −2.2 µm with a pixel size of 0.74 Å. Each movie contained 40 frames with a dose per frame of ~1 electron/Å2 and a total exposure time of 2.34 seconds. Data were processed with CryoSPARC (version 4.2). Full-frame motion correction and estimation of contrast-transfer function (CTF) parameters were carried out using the built-in patch-motion correction and patch-CTF estimation routines, respectively. From 4556 manually selected movies 2,225,971 particles were auto picked using TOPAZ (Bepler, Tristan, et al. "Positive-unlabeled convolutional neural networks for particle picking in cryo-electron micrographs." Nature methods 16.11 (2019): 1153-1160). After first round of 2D classification 420,756 selected particles were further used for ab initio 3D model generation and heterogenous refinement cycles. Followed by non-uniform refinement with 69,438 particles which resulted to 3.06Å resolution map. To further improve the resolution, we used focused map for local refinement to remove the flexible region and obtained a 3.02 Å map with a locally higher resolution at epitope- paratope region. For modelling structures into the cryoEM map, predicted structures were obtained from AlphaFold for the ISVD 2G08 and TPP-64219. For modelling CEACAM5 into the map a deposited structure of CEACAM5 was used PDB-ID 8BW0 (Kumar, Anand, et al. "Structural insights into epitope-paratope interactions of a monoclonal antibody targeting CEACAM5-expressing tumors." Nature Communications 15.1 (2024): 9377). All three components were fitted manually into the cryoEM map using ChimeraX (Pettersen, Eric F., et al. "UCSF ChimeraX: Structure visualization for researchers, educators, and developers." Protein science 30.1 (2021): 70-82). Furthermore, side chains were manually adjusted using Coot (version 0.9.4.1) (Casañal, Ana, Bernhard Lohkamp, and Paul Emsley. "Current developments in Coot for macromolecular model building of Electron Cryo- microscopy and Crystallographic Data." Protein Science 29.4 (2020): 1055-1064) and model was real-space refined in PHENIX (version 1.19.2) (Afonine, Pavel V., et al. "Real-space refinement in PHENIX for cryo-EM and crystallography." Acta Crystallographica Section D: Structural Biology 74.6 (2018): 531-544). A view of the structure of the interaction of 2G08 is given in Figure 9, interactions were calculated using with Proteins, Interfaces, Structures, and Assemblies (PISA). 2G08 binds primarily to the A2 domain of CEACAM5 and has weak interaction with the B2 domain. Analysis of the obtained structure of the interaction between 2G08 and CEACAM5 showed involvement in binding by following amino acids: • CEACAM5 epitope: K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, D339, E346, S404, D405, P406, V407, I408, N410, L412, P443, P444, A483 • 2G08 paratope: D1, S52, W53, R54, S55, I57, V59, Q99, E100, F101, G102, A103, I104, S105, Y106, N107, K109, G110, Y111, F112, Y113, which corresponds to D1, S52, W52a, R53, S54, I56, V58, Q95, E96, F97, G98, A99, I100, S100a, Y100b, N100c, K100e, G100f, Y100g, F101, Y102 according to Kabat numbering.
7 Industrial applicability The ISVDs, polypeptides, constructs, nucleic acid molecules encoding the same, vectors comprising the nucleic acids and compositions described herein may be used for example in the treatment, such as treatment of subjects suffering from cancer.
Items 7.1 Embodiment 1 -Family 30 1. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of GLTFSTYTMG (SEQ ID NO:1); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GLTFSTYTMG (SEQ ID NO: 1); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences GLTFSTYTMG (SEQ ID NO: 1); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AIIWSGSNTY (SEQ ID NO: 2); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AIIWSGSNTY (SEQ ID NO: 2); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AIIWSGSNTY (SEQ ID NO: 2); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of QHFGPIGLTTRGYXY (SEQ ID NO: 230), wherein the amino acid residue X is selected from N, A, F, G, I, L, Y or H; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AQHFGPIGLTTRGYXY (SEQ ID NO: 230), wherein the amino acid residue X is selected from N, A, F, G, I, L, Y or H; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AQHFGPIGLTTRGYXY (SEQ ID NO: 230), wherein the amino acid residue X is selected from N, A, F, G, I, L, Y or H. 2. The ISVD according to item 1, in which the amino acid sequences of the CDRs (AbM numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 8, 31, 32, 150-159. The ISVD according to any one of items 1 or 2, in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 3; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 33; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYAY (SEQ ID NO: 249); or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYFY (SEQ ID NO: 250); or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYGY (SEQ ID NO: 251), or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYIY (SEQ ID NO: 254); or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYLY (SEQ ID NO: 252); or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO:1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYYY (SEQ ID NO: 253). 4. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of TYTMG (SEQ ID NO: 17); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of TYTMG (SEQ ID NO: 17); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of TYTMG (SEQ ID NO: 17); and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AIIWSGSNTYYADSVKG (SEQ ID NO: 18); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AIIWSGSNTYYADSVKG (SEQ ID NO: 18); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AIIWSGSNTYYADSVKG (SEQ ID NO: 18); and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of QHFGPIGLTTRGYXY (SEQ ID NO: 230), wherein the amino acid residue X is selected from N, A, F, G, I, L, Y or H; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of QHFGPIGLTTRGYXY (SEQ ID NO: 230), wherein the amino acid residue X is selected from N, A, F, G, I, L, Y or H; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of QHFGPIGLTTRGYXY (SEQ ID NO: 230), wherein the amino acid residue X is selected from N, A, F, G, I, L, Y or H. 5. The ISVD according to item 4, in which the amino acid sequences of the CDRs (Kabat numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 8, 31, 32, 150-159. 6. The ISVD according to any one of items 4 or 5, in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 17; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 18; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 3; or in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 17; ^ CDR2 (Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 18; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 33; or in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO:17; ^ CDR2 (Kabat numbering) consists of the amino acid sequences of SEQ ID NO: 18; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of QHFGPIGLTTRGYAY (SEQ ID NO: 249); or in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO:17; ^ CDR2 (Kabat numbering) consists of the amino acid sequences of SEQ ID NO: 18; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of QHFGPIGLTTRGYFY (SEQ ID NO: 250); or in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO:17; ^ CDR2 (Kabat numbering) consists of the amino acid sequences of SEQ ID NO: 18; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of QHFGPIGLTTRGYGY (SEQ ID NO: 251); or in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO:17; ^ CDR2 (Kabat numbering) consists of the amino acid sequences of SEQ ID NO: 18; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of QHFGPIGLTTRGYIY (SEQ ID NO: 254); or in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO:17; ^ CDR2 (Kabat numbering) consists of the amino acid sequences of SEQ ID NO: 18; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of QHFGPIGLTTRGYLY (SEQ ID NO: 252); or in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO:17; ^ CDR2 (Kabat numbering) consists of the amino acid sequences of SEQ ID NO: 18; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of QHFGPIGLTTRGYYY (SEQ ID NO: 253). 7. The ISVD according to any of one items 1 to 6, which amino acid sequence i) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NOs: 8, 31, 32, 150-159, in which, for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded; and in which: ii) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1. 8. The ISVD according to any one of items 1 to 7, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consist of a heavy chain variable domain sequence that is derived from heavy chain antibody. 9. The ISVD according to any one of items 1 to 8, that essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb. 10. The ISVD according to any one of items 1 to 9, which is a humanized ISVD that is chosen from the group consisting of SEQ ID NOs: 31, 32, 150-159 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID NOs: 8, 31, 32, 150-159. 11. The ISVD according to any one of items 1 to 10, in which the amino acid sequence is chosen from the group consisting of SEQ ID NOs: 8, 31, 32, 150-159. 12. The ISVD according to any one of items 1 to 11, wherein the ISVD specifically binds to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-8 to 10-10 moles/litre or less and more preferably 1x10-8 to 1x10-9 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 1.34x10- 9 moles/litre or 1.24x10-9 moles/litre, as determined by Surface Plasmon Resonance. 13. The ISVD according to any one of items 1 to 12, wherein the ISVD specifically binds to human CEACAM5 with a kon rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M- 1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, such as between 1x105 M-1s-1 and 8x105 M-1s-1, even more preferably of about 3.17x105 M-1s-1 or 7.16x105 M-1s, as determined by Surface Plasmon Resonance. 14. The ISVD according to any one of items 1 to 13, wherein the ISVD specifically binds to human CEACAM5 with a koff rate between 10-1 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-2 s-1 and 1x10-5 s-1, more preferably between 5x10-3 s-1 and 1x10-4 s-1, such as between 5x10-3 s-1 and 5x10-4 s-1even more preferably of about 4.24x10-3 s-1or 8.85x10-4 s-1, as determined by Surface Plasmon Resonance. 15. The ISVD according to any one of items 1 to 14, wherein the ISVD specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAMs family. 16. The ISVD according to any one of items 1 to 15, wherein the ISVD internalizes upon binding to CEACAM5. 17. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to any one of items 1 to 16, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers. 18. The polypeptide or construct according to item 17, in which said one or more other groups, residues, moieties or binding units are amino acid sequences. 19. The polypeptide or construct according to any one of items 17 to 18, in which said one or more linkers are one or more amino acid sequences. 20. The polypeptide or construct according to any one of items 17 to 19, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences. 21. The polypeptide or construct according to any one of items 17 to 20, in which said one or more other groups, residues, moieties or binding units are ISVDs. 22. The polypeptide or construct according to any one of items 17 to 21, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs. 23. The polypeptide or construct according to any one of items 17 to 22, which is a multivalent construct. 24. The polypeptide or construct according to any one of items 17 to 23, which is a multispecific construct. 25. The polypeptide or construct according to any one of items 17 to 24, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half-life, compared to the ISVD without the one or more other groups, residues, moieties or binding units. 26. The polypeptide or construct according to item 25, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins. 27. The polypeptide or construct according to item 26, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof. 28. The polypeptide or construct according to item 27, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). 29. The polypeptide or construct according to item 28, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). 30. The polypeptide or construct according to item 29, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin. 31. The polypeptide or construct according to item 30, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which: - CDR1 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 80; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 80; and c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 80; and - CDR2 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 81; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 81; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 81; and - CDR3 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 82; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 82; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 82. 32. The polypeptide or construct according to item 31, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 80, CDR2 consists of the amino acid sequence of SEQ ID NO: 81, and CDR3 consists of the amino acid sequence of SEQ ID NO: 82. 33. The polypeptide or construct according to item 32, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 47), ALB23 (SEQ ID NO: 48), ALBX00001 (SEQ ID NO: 61) and ALB23002 (SEQ ID NO: 62). 34. The polypeptide or construct according to anyone of items 17 to 33, wherein said linker is chosen from the group consisting of SEQ ID NOs: 63 to 79. 35. The polypeptide or construct according to any of items 17 to 34, further comprising a C- terminal extension. 36. The polypeptide or construct according to item 35, wherein said C-terminal extension is a C- terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I). 37. A nucleic acid that encodes an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36. 38. The nucleic acid according to item 37, that is in the form of a genetic construct. 39. A non-human host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36; and/or that comprises the nucleic acid according to any one of items 37 or 38. 40. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, at least comprising the steps of: a) expressing, in a suitable host cell or non-human host organism or in another suitable expression system, a nucleic acid according to any one of items 37 or 38; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or the polypeptide according to any one of items 17 to 36. 41. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, said method at least comprising the steps of: a) cultivating and/or maintaining a non-human host or host cell according to item 39 under conditions that are such that said non-human host or host cell expresses and/or produces at least one ISVD according to any one of items 1 to 16, or at least one polypeptide according to any one of items 17 to 36; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or polypeptide according to any one of items 17 to 36. A composition comprising at least one ISVD according to any one of items 1 to 16, at least one polypeptide or construct according to any one of items 17 to 36, or at least one nucleic acid according to any one of items 37 or 38. The composition according to item 42, which is a pharmaceutical composition. The composition according to any one of items 42 or 43, which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and/or compounds. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use as a medicament. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of cancer. A method for the diagnosis, prevention and/or treatment of at least one disease and/or disorder, comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of an ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or a composition according to any one of items 42 to 44. The method according to item 49, for the diagnosis, prevention and/or treatment of at least one disease or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or composition according to any one of items 42 to 44. The method according to any one of items 49 or 50, for the diagnosis, prevention and/or treatment of cancer, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or a composition according to any one of items 42 to 44. Embodiment 2-Family 4 An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of GX1TFSX2YAX3G (SEQ ID NO: 231), wherein the amino acid residue X1 is selected from R or H, the amino acid residue X2 is selected from E or D and the amino acid residue X3 is selected from L or M; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GX1TFSX2YAX3G (SEQ ID NO: 231), wherein the amino acid residue X1 is selected from R or H, the amino acid residue X2 is selected from E or D and the amino acid residue X3 is selected from L or M, c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences GX1TFSX2YAX3G (SEQ ID NO: 231), wherein the amino acid residue X1 is selected from R or H, the amino acid residue X2 is selected from E or D and the amino acid residue X3 is selected from L or M; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AINWGGXWTY (SEQ ID NO: 232), wherein the amino acid residue X is selected from T, G or S; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AINWGGXWTY (SEQ ID NO: 232), wherein the amino acid residue X is selected from T, G or S; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AINWGGXWTY (SEQ ID NO: 232), wherein the amino acid residue X is selected from T, G or S); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SX1DYAGGX2PTGYX3Y (SEQ ID NO: 233), wherein the amino acid residue X1 is selected from S, P or L, the amino acid residue X2 is selected from N or S, the amino acid residue X4 is selected from P or A; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SX1DYAGG X2PTGY X3Y (SEQ ID NO: 233), wherein the amino acid residue X1 is selected from S, P or L, the amino acid residue X2 is selected from N or S, the amino acid residue X3 is selected from P or A; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SX1DYAGG X2PTGY X3Y (SEQ ID NO: 233), wherein the amino acid residue X1 is selected from S, P or L, the amino acid residue X2 is selected from N or S, the amino acid residue X3 is selected from P or A. 2. The ISVD according to item 1, in which the amino acid sequences of the CDRs (AbM numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 16, 39, 40, 120, 121, 135-149. 3. The ISVD according to any one of items 1 or 2, in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 9; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 10; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 11; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO:234; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 235; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 236; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO:234; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 238; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 239. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of X1YAX2G (SEQ ID NO: 240), wherein the amino acid residue X1 is selected from E or D, and the amino acid residue X2 is selected from L or M; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of X1YAX2G (SEQ ID NO: 240), wherein the amino acid residue X1 is selected from E or D, and the amino acid residue X2 is selected from L or M; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of X1YAX2G (SEQ ID NO: 240), wherein the amino acid residue X1 is selected from E or D, and the amino acid residue X2 is selected from L or M; and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AINWGGX1WTYYAX2SVX3G (SEQ ID NO: 241); wherein the amino acid residue X1 is selected from G, S or T, the amino acid residue X2 is selected from H or D, and the amino acid residue X3 is selected from Q or K; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AINWGGX1WTYYAX2SVX3G (SEQ ID NO: 241); wherein the amino acid residue X1 is selected from G, S or T, the amino acid residue X2 is selected from H or D, and the amino acid residue X3 is selected from Q or K; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AINWGGX1WTYYAX2SVX3G (SEQ ID NO: 241); wherein the amino acid residue X1 is selected from G, S or T, the amino acid residue X2 is selected from H or D, and the amino acid residue X3 is selected from Q or K; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SX1DYAGGX2PTGYX3Y (SEQ ID NO: 233), wherein the amino acid residue X1 is selected from S, P or L, the amino acid residue X2 is selected from N or S, the amino acid residue X3 is selected from P or A; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SX1DYAGGX2PTGYX3Y (SEQ ID NO: 233), wherein the amino acid residue X1 is selected from S, P or L, the amino acid residue X2 is selected from N or S, the amino acid residue X3 is selected from P or A; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SX1DYAGGX2PTGYX3Y (SEQ ID NO: 233), wherein the amino acid residue X1 is selected from S, P or L, the amino acid residue X2 is selected from N or S, the amino acid residue X3 is selected from P or A. The ISVD according to item 4, in which the amino acid sequences of the CDRs (Kabat numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 16, 39, 40, 120, 121, 135-149. The ISVD according to any one of items 4 or 5, in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 21; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 22; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 11; or in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 21; ^ CDR2 (Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 43; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 11; or in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 243; ^ CDR2 (Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 244; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 236. or in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 243; ^ CDR2 (Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 245; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 246. 7. The ISVD according to any of one items 1 to 6, which amino acid sequence i) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NOs: 16, 39, 40, 120, 121, 135-149, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded; and in which: ii) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1. 8. The ISVD according to any one of items 1 to 7, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consist of a heavy chain variable domain sequence that is derived from heavy chain antibody. 9. The ISVD according to any one of items 1 to 8, that essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb. 10. The ISVD according to any one of items 1 to 9, which is a humanized ISVD that is chosen from the group consisting of SEQ ID NOs: 16, 39, 40, 120, 121, 135-149 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID Nos: 16, 39, 40, 120, 121, 135-149. 11. The ISVD according to any one of items 1 to 10, in which the amino acid sequence is chosen from the group consisting of SEQ ID NOs: 16, 39, 40, 120, 121, 135-149. 12. The ISVD according to any one of items 1 to 11, wherein the ISVD specifically binds to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-10 moles/litre or less, and preferably 5x10-8 to 10-9 moles/litre or less and more preferably 5x10-8 to 5x10-9 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 1.06x10- 8moles/litre, 4.86x10-9 moles/litre or 8.9x10-9 moles/litre, as determined by Surface Plasmon Resonance. 13. The ISVD according to any one of items 1 to 12, wherein the ISVD specifically binds to human CEACAM5 with kon rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M- 1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, such as between 1x105 M-1s-1 and 5x105 M-1s-1, even more preferably of about 1.2x105 M-1s-1, 1.6x105 M-1s-1, 1.98x105 M-1s, or 2.38x105 M-1s, as determined by Surface Plasmon Resonance. 14. The ISVD according to any one of items 1 to 13, wherein the ISVD specifically binds to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 5x10-3 s-1 and 5x10-5 s-1, more preferably between 5x10-3 s-1 and 5x10-4 s-1, such as between 5x10-3 s-1 and 1x10-4 s-1, even more preferably of about 1.08x10-3 s-1, 1.7x10-3 s-1, 9.61x10-4 s-1 or 2.12x10-3 s-1, as determined by Surface Plasmon Resonance. 15. The ISVD according to any one of items 1 to 14, wherein the ISVD specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8 or other members of the CEACAMs family. 16. The ISVD according to any one of items 1 to 15, wherein the ISVD internalizes upon binding to CEACAM5. 17. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to any one of items 1 to 16, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers. 18. The polypeptide or construct according to item 17, in which said one or more other groups, residues, moieties or binding units are amino acid sequences. 19. The polypeptide or construct according to any one of items 17 to 18, in which said one or more linkers are one or more amino acid sequences. 20. The polypeptide or construct according to any one of items 17 to 19, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences. 21. The polypeptide or construct according to any one of items 17 to 20, in which said one or more other groups, residues, moieties or binding units are ISVDs. 22. The polypeptide or construct according to any one of items 17 to 21, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs. 23. The polypeptide or construct according to any one of items 17 to 22, which is a multivalent construct. 24. The polypeptide or construct according to any one of items 17 to 23, which is a multispecific construct. 25. The polypeptide or construct according to any one of items 17 to 24, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half-life, compared to the ISVD without the one or more other groups, residues, moieties or binding units. 26. The polypeptide or construct according to item 25, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins. 27. The polypeptide or construct according to item 26, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof. 28. The polypeptide or construct according to item 27, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). 29. The polypeptide or construct according to item 28, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). 30. The polypeptide or construct according to item 29, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin. 31. The polypeptide or construct according to item 30, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which: - CDR1 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 80; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 80; and c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 80; and - CDR2 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 81; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 81; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 81; and - CDR3 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 82; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 82; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 82. 32. The polypeptide or construct according to item 31, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 80, CDR2 consists of the amino acid sequence of SEQ ID NO: 81, and CDR3 consists of the amino acid sequence of SEQ ID NO: 82. 33. The polypeptide or construct according to item 32, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 47), ALB23 (SEQ ID NO: 48), ALBX00001 (SEQ ID NO: 61) and ALB23002 (SEQ ID NO: 62). 34. The polypeptide or construct according to anyone of items 17 to 33, wherein said linker is chosen from the group consisting of SEQ ID NOs: 63 to 79. 35. The polypeptide or construct according to any of items 17 to 34, further comprising a C- terminal extension. 36. The polypeptide or construct according to item 35, wherein said C-terminal extension is a C- terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I). 37. A nucleic acid that encodes an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36. 38. The nucleic acid according to item 37, that is in the form of a genetic construct. 39. A non-human host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36; and/or that comprises the nucleic acid according to any one of items 37 or 38. 40. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, at least comprising the steps of: a) expressing, in a suitable host cell or non-human host organism or in another suitable expression system, a nucleic acid according to any one of items 37 or 38; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or the polypeptide according to any one of items 17 to 36. 41. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, said method at least comprising the steps of: a) cultivating and/or maintaining a non-human host or host cell according to item 39 under conditions that are such that said non-human host or host cell expresses and/or produces at least one ISVD according to any one of items 1 to 16, or at least one polypeptide according to any one of items 17 to 36; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or polypeptide according to any one of items 17 to 36. A composition comprising at least one ISVD according to any one of items 1 to 16, at least one polypeptide or construct according to any one of items 17 to 36, or at least one nucleic acid according to any one of items 37 or 38. The composition according to item 42, which is a pharmaceutical composition. The composition according to any one of items 42 or 43, which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and/or compounds. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use as a medicament. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of cancer. A method for the diagnosis, prevention and/or treatment of at least one disease and/or disorder, comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of an ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or a composition according to any one of items 42 to 44. 50. The method according to item 49, for the diagnosis, prevention and/or treatment of at least one disease or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or composition according to any one of items 42 to 44. 51. The method according to any one of items 49 or 50, for the diagnosis, prevention and/or treatment of cancer, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or a composition according to any one of items 42 to 44. 7.3 Embodiment 3-Family 1 1. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTFXSYDMG (SEQ ID NO: 242), wherein the amino acid residue X is selected from N, E, G, P, S or T; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTFXSYDMG (SEQ ID NO: 242), wherein the amino acid residue X is selected from N, E, G, P, S or T; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences GRTFXSYDMG (SEQ ID NO: 242), wherein the amino acid residue X is selected from N, E, G, P, S or T; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AIRWSAGSTV (SEQ ID NO: 256); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AIRWSAGSTV (SEQ ID NO: 256); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AIRWSAGSTV (SEQ ID NO: 256); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence VRPSFRPLSTYWKDYDN (SEQ ID NO: 257); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AVRPSFRPLSTYWKDYDN (SEQ ID NO: 257); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AQHFGPIGLTTRGYXY (SEQ ID NO: 230), wherein the amino acid residue X is selected from N, A, F, G, I, L, Y or H. The ISVD according to item 1, in which the amino acid sequences of the CDRs (AbM numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 114, 175-208. The ISVD according to any one of items 1 or 2, in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 255; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 256; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 257; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 284; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 256; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 257; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 285; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 256; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 257; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 286; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 256; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 257; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 287; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 256; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 257; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 288; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 256; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 257. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SYDMG (SEQ ID NO: 289); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SYDMG (SEQ ID NO: 289); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SYDMG (SEQ ID NO: 289); and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AIRWSAGSTVYX1X2SVKG (SEQ ID NO: 290); wherein the amino acid residue X1is selected from G or A and wherein the amino acid residue X2 is selected from N or D; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AIRWSAGSTVYX1X2SVKG (SEQ ID NO: 290); wherein the amino acid residue X1is selected from G or A and wherein the amino acid residue X2 is selected from N or D; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AIRWSAGSTVYX1X2SVKG (SEQ ID NO: 290); wherein the amino acid residue X1is selected from G or A and wherein the amino acid residue X2 is selected from N or D; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of VRPSFRPLSTYWKDYDN (SEQ ID NO: 257); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VRPSFRPLSTYWKDYDN (SEQ ID NO: 257); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of QHFGPIGLTTRGYXY (SEQ ID NO: 230), wherein the amino acid residue X is selected from N, A, F, G, I, L, Y or H. The ISVD according to item 4, in which the amino acid sequences of the CDRs (Kabat numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 114, 175-208. The ISVD according to any one of items 4 or 5, in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 289; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 291; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 257; or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 289; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 292; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 257; or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 289; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 293; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 257; or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 289; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 294; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 257. 7. The ISVD according to any of one items 1 to 6, which amino acid sequence i) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NOs: 114, 175-208, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded; and in which: ii) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1. 8. The ISVD according to any one of items 1 to 7, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consist of a heavy chain variable domain sequence that is derived from heavy chain antibody. 9. The ISVD according to any one of items 1 to 8, that essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb. 10. The ISVD according to any one of items 1 to 9, which is a humanized ISVD that is chosen from the group consisting of SEQ ID NOs: 114, 175-208 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID NOs: 114, 175-208. 11. The ISVD according to any one of items 1 to 10, in which the amino acid sequence is chosen from the group consisting of SEQ ID NOs: 114, 175-208. 12. The ISVD according to any one of items 1 to 11, wherein the ISVD specifically binds to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-7 to 10-9 moles/litre or less and more preferably 5x10-7 to 1x10-8 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 1.87x10- 8 moles/litre, as determined by Surface Plasmon Resonance. 13. The ISVD according to any one of items 1 to 12, wherein the ISVD specifically binds to human CEACAM5 with a kon rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M- 1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, such as between 1x105 M-1s-1 and 8x105 M-1s-1, even more preferably of about 3.96x105 M-1s, as determined by Surface Plasmon Resonance. 14. The ISVD according to any one of items 1 to 13, wherein the ISVD specifically binds to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-2 s-1 and 1x10-5 s-1, more preferably between 1x10-2 s-1 and 1x10-3 s-1, such as between 1x10-2 s-1 and 5x10-3 s-1even more preferably of about 7.41x10-3 s-1, as determined by Surface Plasmon Resonance. 15. The ISVD according to any one of items 1 to 14, wherein the ISVD specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAMs family. 16. The ISVD according to any one of items 1 to 15, wherein the ISVD internalizes upon binding to CEACAM5. 17. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to any one of items 1 to 16, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers. 18. The polypeptide or construct according to item 17, in which said one or more other groups, residues, moieties or binding units are amino acid sequences. 19. The polypeptide or construct according to any one of items 17 to 18, in which said one or more linkers are one or more amino acid sequences. 20. The polypeptide or construct according to any one of items 17 to 19, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences. 21. The polypeptide or construct according to any one of items 17 to 20, in which said one or more other groups, residues, moieties or binding units are ISVDs. 22. The polypeptide or construct according to any one of items 17 to 21, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs. 23. The polypeptide or construct according to any one of items 17 to 22, which is a multivalent construct. 24. The polypeptide or construct according to any one of items 17 to 23, which is a multispecific construct. 25. The polypeptide or construct according to any one of items 17 to 24, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half-life, compared to the ISVD without the one or more other groups, residues, moieties or binding units. 26. The polypeptide or construct according to item 25, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins. The polypeptide or construct according to item 26, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof. The polypeptide or construct according to item 27, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). The polypeptide or construct according to item 28, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). The polypeptide or construct according to item 29, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin. The polypeptide or construct according to item 30, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which: - CDR1 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 80; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 80; and c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 80; and - CDR2 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 81; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 81; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 81; and - CDR3 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 82; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 82; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 82. The polypeptide or construct according to item 31, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 80, CDR2 consists of the amino acid sequence of SEQ ID NO: 81, and CDR3 consists of the amino acid sequence of SEQ ID NO: 82. The polypeptide or construct according to item 32, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 47), ALB23 (SEQ ID NO: 48), ALBX00001 (SEQ ID NO: 61) and ALB23002 (SEQ ID NO: 62). The polypeptide or construct according to anyone of items 17 to 33, wherein said linker is chosen from the group consisting of SEQ ID NOs: 63 to 79. The polypeptide or construct according to any of items 17 to 34, further comprising a C- terminal extension. The polypeptide or construct according to item 35, wherein said C-terminal extension is a C- terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I). A nucleic acid that encodes an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36. The nucleic acid according to item 37, that is in the form of a genetic construct. A non-human host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36; and/or that comprises the nucleic acid according to any one of items 37 or 38. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, at least comprising the steps of: a) expressing, in a suitable host cell or non-human host organism or in another suitable expression system, a nucleic acid according to any one of items 37 or 38; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or the polypeptide according to any one of items 17 to 36. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, said method at least comprising the steps of: a) cultivating and/or maintaining a non-human host or host cell according to item 39 under conditions that are such that said non-human host or host cell expresses and/or produces at least one ISVD according to any one of items 1 to 16, or at least one polypeptide according to any one of items 17 to 36; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or polypeptide according to any one of items 17 to 36. A composition comprising at least one ISVD according to any one of items 1 to 16, at least one polypeptide or construct according to any one of items 17 to 36, or at least one nucleic acid according to any one of items 37 or 38. The composition according to item 42, which is a pharmaceutical composition. 44. The composition according to any one of items 42 or 43, which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and/or compounds. 45. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use as a medicament. 46. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder. 47. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved. 48. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of cancer. 49. A method for the diagnosis, prevention and/or treatment of at least one disease and/or disorder, comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of an ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or a composition according to any one of items 42 to 44. 50. The method according to item 49, for the diagnosis, prevention and/or treatment of at least one disease or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or composition according to any one of items 42 to 44. 51. The method according to any one of items 49 or 50, for the diagnosis, prevention and/or treatment of cancer, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or a composition according to any one of items 42 to 44. 7.4 Embodiment 4 -Family 2 1. An immunoglobulin single variable domain (ISVD) specifically binding to human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), that interacts with one or more amino acids of the CEACAM5 protein selected from K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, D339, E346, S404, D405, P406, V407, I408, N410, L412, P443, P444, and A483. 2. The immunoglobulin single variable domain (ISVD) of item 1, that interacts with following amino acids of the CEACAM5 protein: K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, D339, E346, S404, D405, P406, V407, I408, N410, L412, P443, P444, and A483. 3. The immunoglobulin single variable domain (ISVD) of item 1 or 2, in which CDR2 and CDR3 interact with one or more amino acids of the CEACAM5 protein selected from K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, D339, E346, S404, D405, P406, V407, I408, N410, L412, P443, P444, and A483. 4. The immunoglobulin single variable domain (ISVD) of any of items 1 to 3, in which CDR2 and CDR3 interact with following amino acids of the CEACAM5 protein: K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, D339, E346, S404, D405, P406, V407, I408, N410, L412, P443, P444, and A483. 5. The immunoglobulin single variable domain (ISVD) of any of items 1 to 4, in which S52, W52a, R53, S54, I56, and V58 (Kabat numbering) in CDR2 form the interaction site with the amino acids of the CEACAM5 protein. 6. The immunoglobulin single variable domain (ISVD) of any of items 1 to 5, in which G98, A99, I100, S100a, Y100b, N100c, K100e, G100f, Y100g, F101, and Y102(Kabat numbering) in CDR3 form the interaction site with the amino acids of the CEACAM5 protein. 7. The immunoglobulin single variable domain (ISVD) of any of items 1 to 6, in which S52, W52a, R53, S54, I56, and V58 (Kabat numbering) in CDR2 and G98, A99, I100, S100a, Y100b, N100c, K100e, G100f, Y100g, F101, and Y102(Kabat numbering) in CDR3 form the interaction site with the epitope on the CEACAM5 protein. 8. The immunoglobulin single variable domain (ISVD) of any of items 1 to 7, in which S52, W52a, R53, S54, I56, and V58 (Kabat numbering) in CDR2 and G98, A99, I100, S100a, Y100b, N100c, K100e, G100f, Y100g, F101, and Y102(Kabat numbering) in CDR3 form the interaction site with one or more amino acids of the CEACAM5 protein selected from K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, L343, E346, D405, P406, V407, I408, L409, N410, L412, N442, P444, and A483. 9. The immunoglobulin single variable domain (ISVD) of any of items 1 to 8, in which S52, W52a, R53, S54, I56, and V58 (Kabat numbering) in CDR2 and G98, A99, I100, S100a, Y100b, N100c, K100e, G100f, Y100g, F101, and Y102 (Kabat numbering) in CDR3 form the interaction site with following amino acids of the CEACAM5 protein: K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, L343, E346, D405, P406, V407, I408, L409, N410, L412, N442, P444, and A483. 10. The immunoglobulin single variable domain (ISVD) according to items 1-9, wherein - CDR2 (AbM numbering) consists of an amino acid sequence X1X2SWRSX3X4TV (SEQ ID NO: 319); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E and wherein the amino acid residue X4 is selected from T or I, preferably wherein the amino acid residue X4 is I; and - CDR3 (AbM numbering) consists of an amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y, preferably wherein the amino acid residue X1 is E, the amino acid residue X2 is F, the amino acid residue X4 is K and the amino acid residue X5 is Y. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 322 or 325; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 322 or 325; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 322 or 325; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NOs: 323, 326, 327; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 323, 326, 327; c) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 323, 326, 327. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: -CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of X1X2SWRSX3X4TV (SEQ ID NO: 319); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E and wherein the amino acid residue X4 is selected from T or I; b) amino acid sequences that have at least 80% amino acid identity with the acid sequence of X1X2SWRSX3X4TV (SEQ ID NO: 319); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E and wherein the amino acid residue X4 is selected from T or I; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the acid sequence of X1X2SWRSX3X4TV (SEQ ID NO: 319); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E and wherein the amino acid residue X4 is selected from T or I; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y. 13. The immunoglobulin single variable domain (ISVD) according to any one of items 10 to12, in which CDR1 (AbM Numbering): a) has a length of 10 amino acids; b) has an aliphatic index of 20.00; c) has a grand average of hydropathicity (GRAVY) of 0.400, -0.010, preferably -0.010; d) comprises no or one positively charged; e) comprises 40% hydrophobic, 0% or 10% basic and 50 or 60% neutral amino acids, such as 40% hydrophobic, and 60% neutral amino acids; or comprises 40% hydrophobic, 10% basic and 50% neutral amino acids; f) consists of a polar neutral amino acid, a basic or polar neutral amino acid, two hydrophobic amino acid, four polar neutral amino acid, and two hydrophobic amino acid, preferably in that order; such as consists of two polar neutral amino acid, two hydrophobic amino acid, four polar neutral amino acid, and two hydrophobic amino acid, preferably in that order; or consiss of a polar neutral amino acid, a basic amino acid, two hydrophobic amino acid, four polar neutral amino acid, and two hydrophobic amino acid, preferably in that order; and/or g) comprises at least one, preferably all of the amino acids G, A, F, S, Y, A, M, and/or optionally the amino acid R. 14. The ISVD according to any one of items 10 to 13, in which the amino acid sequences of the CDR2 and CDR3 (AbM numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 115-117, 160-170. 15. The ISVD according to any one of items 10 to 14, in which ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 322; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 323, or in which ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 325; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 326, or in which ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 325; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 327. 16. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GXAFSTYTMA (SEQ ID NO: 318), wherein the amino acid residue X is selected from R or G; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GXAFSTYTMA (SEQ ID NO: 318), wherein the amino acid residue X is selected from R or G; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GXAFSTYTMA (SEQ ID NO: 318), wherein the amino acid residue X is selected from R or G; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence X1X2SWRSX3X4TV (SEQ ID NO: 319); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E and wherein the amino acid residue X4 is selected from T or I; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence X1X2SWRSX3X4TV (SEQ ID NO: 319); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E and wherein the amino acid residue X4 is selected from T or I; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence X1X2SWRSX3X4TV (SEQ ID NO: 319); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E and wherein the amino acid residue X4 is selected from T or I; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y. The ISVD according to item 16, in which the amino acid sequences of the CDRs (AbM numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 115-117, 160-170. The ISVD according to any one of items 16 or 17, in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 321; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 322; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 323, or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 324; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 325; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 326, or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 324; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 325; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 327. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of TYTMA (SEQ ID NO: 328); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of TYTMA (SEQ ID NO: 328); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of TYTMA (SEQ ID NO: 328); - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of X1X2SWRSX3X4TVYX5DSVKG (SEQ ID NO: 329); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E, wherein the amino acid residue X4 is selected from T or I, and wherein the amino acid residue X5 is selected from G or A; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of X1X2SWRSX3X4TVYX5DSVKG (SEQ ID NO: 329); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E, wherein the amino acid residue X4 is selected from T or I, and wherein the amino acid residue X5 is selected from G or A; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of X1X2SWRSX3X4TVYX5DSVKG (SEQ ID NO: 329); wherein the amino acid residue X1 is selected from A or T, wherein the amino acid residue X2 is selected from L or I, wherein the amino acid residue X3 is selected from G or E, wherein the amino acid residue X4 is selected from T or I, and wherein the amino acid residue X5 is selected from G or A; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence QX1X2GAISYNX3X4GX5FY (SEQ ID NO: 320); wherein the amino acid residue X1 is selected from Q or E, wherein the amino acid residue X2 is selected from Y or F, wherein the amino acid residue X3 is selected from T or R and wherein the amino acid residue X4 is selected from N or K, and wherein the amino acid residue X5 is selected from F or Y. The ISVD according to item 19 in which the amino acid sequences of the CDRs (Kabat numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 115-117, 160-170. The ISVD according to any one of items 19 or 20, in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 328; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 330; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 323, or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 328; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 331; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 326, or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 328; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 331; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 327, or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 328; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 332; and CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 327. 22. The ISVD according to any of one items 1 to 21, which amino acid sequence i) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NOs: 115-117, 160-170, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded; and in which: ii) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1. 23. The ISVD according to any one of items 1 to 22, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consist of a heavy chain variable domain sequence that is derived from heavy chain antibody. 24. The ISVD according to any one of items 1 to 23, that essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb. 25. The ISVD according to any one of items 1 to 24, which is a humanized ISVD that is chosen from the group consisting of SEQ ID NOs: 160-170or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID NOs: 115-117, 160-170. 26. The ISVD according to any one of items 1 to 25, in which the amino acid sequence is chosen from the group consisting of SEQ ID NOs: 115-117, 160-170. 27. The ISVD according to any one of items 1 to 26, wherein the ISVD specifically binds to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-8 to 10-10 moles/litre or less and more preferably 5x10-8 to 6x10-10 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 1.66x10- 9 moles/litre, 5.08x10-10 moles/litre or 3.37x10-9 moles/litre, as determined by Surface Plasmon Resonance. 28. The ISVD according to any one of items 1 to 27, wherein the ISVD specifically binds to human CEACAM5 with a kon rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M- 1s-1 and 107 M-1s-1, more preferably between 1x105 M-1s-1 and 5x106 M-1s-1, such as between 5x105 M-1s-1 and 5x106 M-1s-1, even more preferably of about 1.93x106 M-1s-1, 1.42x106 M-1s-1, or 1.94x106 M-1s-1as determined by Surface Plasmon Resonance. 29. The ISVD according to any one of items 1 to 28, wherein the ISVD specifically binds to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-2 s-1 and 1x10-6 s-1, more preferably between 1x10-2 s-1 and 1x10-4 s-1, such as between 7x10-3 s-1 and 5x10-4 s-1 even more preferably of about 3.21x10-3 s-1, 7.23x10-4 s-1, or 6.55 x10-3 s-1, as determined by Surface Plasmon Resonance. 30. The ISVD according to any one of items 1 to 29, wherein the ISVD specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, or CEACAM7. 31. The ISVD according to any one of items 1 to 30, wherein the ISVD internalizes upon binding to CEACAM5. 32. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to any one of items 1 to 31, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers. 33. The polypeptide or construct according to item 32, in which said one or more other groups, residues, moieties or binding units are amino acid sequences. 34. The polypeptide or construct according to any one of items 32 to 33, in which said one or more linkers are one or more amino acid sequences. 35. The polypeptide or construct according to any one of items 32 to 34, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences. 36. The polypeptide or construct according to any one of items 32 to 35, in which said one or more other groups, residues, moieties or binding units are ISVDs. 37. The polypeptide or construct according to any one of items 32 to 36, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs. 38. The polypeptide or construct according to any one of items 32 to 37, which is a multivalent construct. 39. The polypeptide or construct according to any one of items 32 to 38, which is a multispecific construct. 40. The polypeptide or construct according to any one of items 32 to 39, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half-life, compared to the ISVD without the one or more other groups, residues, moieties or binding units. 41. The polypeptide or construct according to item 40, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins. The polypeptide or construct according to item 41, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof. The polypeptide or construct according to item 42, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). The polypeptide or construct according to item 43, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). The polypeptide or construct according to item 44, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin. The polypeptide or construct according to item 45, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which: - CDR1 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 80; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 80; and c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 80; and - CDR2 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 81; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 81; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 81; and - CDR3 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NOs: 82; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 82; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 82. The polypeptide or construct according to item 46, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 80, CDR2 consists of the amino acid sequence of SEQ ID NO: 81, and CDR3 consists of the amino acid sequence of SEQ ID NO: 82. The polypeptide or construct according to item 47, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 47), ALB23 (SEQ ID NO: 48), ALBX00001 (SEQ ID NO: 61) and ALB23002 (SEQ ID NO: 62). The polypeptide or construct according to anyone of items 32 to 48, wherein said linker is chosen from the group consisting of SEQ ID NOs: 63 to 79. The polypeptide or construct according to any of items 32 to 49, further comprising a C- terminal extension. The polypeptide or construct according to item 50, wherein said C-terminal extension is a C- terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I). A nucleic acid that encodes an ISVD according to any one of items 1 to 31, or a polypeptide according to any one of items 32 to 51. The nucleic acid according to item 52, that is in the form of a genetic construct. A non-human host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD according to any one of items 1 to 31, or a polypeptide according to any one of items 32 to 51; and/or that comprises the nucleic acid according to any one of items 52 or 53. A method for producing an ISVD according to any one of items 1 to 31, or a polypeptide according to any one of items 32 to 51, at least comprising the steps of: a) expressing, in a suitable host cell or non-human host organism or in another suitable expression system, a nucleic acid according to any one of items 52 or 53; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 31, or the polypeptide according to any one of items 32 to 51. A method for producing an ISVD according to any one of items 1 to 31, or a polypeptide according to any one of items 32 to 51, said method at least comprising the steps of: a) cultivating and/or maintaining a non-human host or host cell according to item 39 under conditions that are such that said non-human host or host cell expresses and/or produces at least one ISVD according to any one of items 1 to 31, or at least one polypeptide according to any one of items 32 to 51; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 31, or polypeptide according to any one of items 32 to 51. A composition comprising at least one ISVD according to any one of items 1 to 31, at least one polypeptide or construct according to any one of items 32 to 51, or at least one nucleic acid according to any one of items 52 or 53. The composition according to item 57, which is a pharmaceutical composition. 59. The composition according to any one of items 57 or 58, which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and/or compounds. 60. The ISVD according to any one of items 1 to 31, the polypeptide or construct according to any one of items 32 to 51, or the composition according to any one of items 57 to 59, for use as a medicament. 61. The ISVD according to any one of items 1 to 31, the polypeptide or construct according to any one of items 32 to 51, or the composition according to any one of items 57 to 59, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder. 62. The ISVD according to any one of items 1 to 31, the polypeptide or construct according to any one of items 32 to 51, or the composition according to any one of items 57 to 59, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved. 63. The ISVD according to any one of items 1 to 31, the polypeptide or construct according to any one of items 32 to 51, or the composition according to any one of items 57 to 59, for use in the diagnosis, prevention and/or treatment of cancer. 64. A method for the diagnosis, prevention and/or treatment of at least one disease and/or disorder, comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of an ISVD according to any one of items 1 to 31, a polypeptide or construct according to any one of items 32 to 51, or a composition according to any one of items 57 to 59. 65. The method according to item 64, for the diagnosis, prevention and/or treatment of at least one disease or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 31, a polypeptide or construct according to any one of items 32 to 51, or composition according to any one of items 57 to 59. 66. The method according to any one of items 64 or 65 for the diagnosis, prevention and/or treatment of cancer, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 31, a polypeptide or construct according to any one of items 32 to 51, or a composition according to any one of items 57 to 59. 7.5 Embodiment 5 -Family 3 1. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of GLTFSTYTXG (SEQ ID NO: 333), wherein the amino acid residue X is selected from V or M; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GLTFSTYTXG (SEQ ID NO: 333), wherein the amino acid residue X is selected from V or M; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences GLTFSTYTXG (SEQ ID NO: 333), wherein the amino acid residue X is selected from V or M; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SX1IX2SGSNTX3 (SEQ ID NO: 335); wherein the amino acid residue X1 is selected from I or M, wherein the amino acid residue X2 is selected from W or Y, and wherein the amino acid residue X3 is selected from V or L; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of the amino acid sequence of SX1IX2SGSNTX3 (SEQ ID NO: 335); wherein the amino acid residue X1 is selected from I or M, wherein the amino acid residue X2 is selected from W or Y, and wherein the amino acid residue X3 is selected from V or L; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of the amino acid sequence of SX1IX2SGSNTX3 (SEQ ID NO: 335); wherein the amino acid residue X1 is selected from I or M, wherein the amino acid residue X2 is selected from W or Y, and wherein the amino acid residue X3 is selected from V or L; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of QHFGPX1SLTTRGYX2Y (SEQ ID NO: 338); wherein the amino acid residue X1 is selected from V or I, and wherein the amino acid residue X2 is selected from Y or F; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of QHFGPX1SLTTRGYX2Y (SEQ ID NO: 338); wherein the amino acid residue X1 is selected from V or I, and wherein the amino acid residue X2 is selected from Y or F; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of QHFGPX1SLTTRGYX2Y (SEQ ID NO: 338); wherein the amino acid residue X1 is selected from V or I, and wherein the amino acid residue X2 is selected from Y or F. 2. The ISVD according to item 1, in which the amino acid sequences of the CDRs (AbM numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 118-119, 171-174. 3. The ISVD according to any one of items 1 or 2, in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 336; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 339; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 334; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 337; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 340. 4. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of TYTXG (SEQ ID NO: 341); wherein the amino acid residue X is selected from M or V; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of TYTXG (SEQ ID NO: 341); wherein the amino acid residue X is selected from M or V; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of TYTXG (SEQ ID NO: 341); wherein the amino acid residue X is selected from M or V; and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SX1IX2SGSNTX3YADSVKG (SEQ ID NO: 343); wherein the amino acid residue X1 is selected from I or M, wherein the amino acid residue X2 is selected from W or Y, and wherein the amino acid residue X3 is selected from V or L; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SX1IX2SGSNTX3YADSVKG (SEQ ID NO: 343); wherein the amino acid residue X1 is selected from I or M, wherein the amino acid residue X2 is selected from W or Y, and wherein the amino acid residue X3 is selected from V or L; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SX1IX2SGSNTX3YADSVKG (SEQ ID NO: 343); wherein the amino acid residue X1 is selected from I or M, wherein the amino acid residue X2 is selected from W or Y, and wherein the amino acid residue X3 is selected from V or L; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of QHFGPX1SLTTRGYX2Y (SEQ ID NO: 338); wherein the amino acid residue X1 is selected from V or I, and wherein the amino acid residue X2 is selected from Y or F; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of QHFGPX1SLTTRGYX2Y (SEQ ID NO: 338); wherein the amino acid residue X1 is selected from V or I, and wherein the amino acid residue X2 is selected from Y or F; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of QHFGPX1SLTTRGYX2Y (SEQ ID NO: 338); wherein the amino acid residue X1 is selected from V or I, and wherein the amino acid residue X2 is selected from Y or F. 5. The ISVD according to item 4, in which the amino acid sequences of the CDRs (Kabat numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 118-119, 171-174. 6. The ISVD according to any one of items 4 or 5, in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 17; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 334; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 339; or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 342; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 345; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 340. 7. The ISVD according to any of one items 1 to 6, which amino acid sequence i) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NOs: 118-119, 171-174, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded; and in which: ii) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1. 8. The ISVD according to any one of items 1 to 7, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consist of a heavy chain variable domain sequence that is derived from heavy chain antibody. 9. The ISVD according to any one of items 1 to 8, that essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb. 10. The ISVD according to any one of items 1 to 9, which is a humanized ISVD that is chosen from the group consisting of SEQ ID Nos: 171-174 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID NOs: 118-119, 171-174. 11. The ISVD according to any one of items 1 to 10, in which the amino acid sequence is chosen from the group consisting of SEQ ID NOs: 118-119, 171-174. 12. The ISVD according to any one of items 1 to 11, wherein the ISVD specifically binds to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-8 to 10-11 moles/litre or less and more preferably 10-8 to 10-10 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 8.83x10- 9 moles/litre, or 1.44x10-10 moles/litre, as determined by Surface Plasmon Resonance. 13. The ISVD according to any one of items 1 to 12, wherein the ISVD specifically binds to human CEACAM5 with a kon rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M- 1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 5x106 M-1s-1, even more preferably of about 4.70x105 M-1s-1, or 1.91x106 M-1s-1, as determined by Surface Plasmon Resonance. 14. The ISVD according to any one of items 1 to 13, wherein the ISVD specifically binds to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-2 s-1 and 1x10-5 s-1, more preferably between 1x10-2 s-1 and 10-4 s-1, such as between 5x10-3 s-1 and 10-4 s-1 even more preferably of about 4.15x10-3 s-1, or 2.74x10-4 s-1, as determined by Surface Plasmon Resonance. 15. The ISVD according to any one of items 1 to 14, wherein the ISVD specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, and CEACAM7. 16. The ISVD according to any one of items 1 to 15, wherein the ISVD internalizes upon binding to CEACAM5. 17. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to any one of items 1 to 16, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers. 18. The polypeptide or construct according to item 17, in which said one or more other groups, residues, moieties or binding units are amino acid sequences. 19. The polypeptide or construct according to any one of items 17 to 18, in which said one or more linkers are one or more amino acid sequences. 20. The polypeptide or construct according to any one of items 17 to 19, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences. 21. The polypeptide or construct according to any one of items 17 to 20, in which said one or more other groups, residues, moieties or binding units are ISVDs. The polypeptide or construct according to any one of items 17 to 21, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs. The polypeptide or construct according to any one of items 17 to 22, which is a multivalent construct. The polypeptide or construct according to any one of items 17 to 23, which is a multispecific construct. The polypeptide or construct according to any one of items 17 to 24, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half-life, compared to the ISVD without the one or more other groups, residues, moieties or binding units. The polypeptide or construct according to item 25, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins. The polypeptide or construct according to item 26, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof. The polypeptide or construct according to item 27, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). The polypeptide or construct according to item 28, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). 30. The polypeptide or construct according to item 29, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin. 31. The polypeptide or construct according to item 30, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which: - CDR1 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 80; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 80; and c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 80; and - CDR2 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 81; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 81; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 81; and - CDR3 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NOs: 82; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 82; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 82. 32. The polypeptide or construct according to item 31, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 80, CDR2 consists of the amino acid sequence of SEQ ID NO: 81, and CDR3 consists of the amino acid sequence of SEQ ID NO: 82. 33. The polypeptide or construct according to item 32, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 47), ALB23 (SEQ ID NO: 48), ALBX00001 (SEQ ID NO: 61) and ALB23002 (SEQ ID NO: 62). 34. The polypeptide or construct according to anyone of items 17 to 33, wherein said linker is chosen from the group consisting of SEQ ID NOs: 63 to 79. 35. The polypeptide or construct according to any of items 17 to 34, further comprising a C- terminal extension. 36. The polypeptide or construct according to item 35, wherein said C-terminal extension is a C- terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I). 37. A nucleic acid that encodes an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36. 38. The nucleic acid according to item 37, that is in the form of a genetic construct. 39. A non-human host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36; and/or that comprises the nucleic acid according to any one of items 37 or 38. 40. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, at least comprising the steps of: a) expressing, in a suitable host cell or non-human host organism or in another suitable expression system, a nucleic acid according to any one of items 37 or 38; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or the polypeptide according to any one of items 17 to 36. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, said method at least comprising the steps of: a) cultivating and/or maintaining a non-human host or host cell according to item 39 under conditions that are such that said non-human host or host cell expresses and/or produces at least one ISVD according to any one of items 1 to 16, or at least one polypeptide according to any one of items 17 to 36; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or polypeptide according to any one of items 17 to 36. A composition comprising at least one ISVD according to any one of items 1 to 16, at least one polypeptide or construct according to any one of items 17 to 36, or at least one nucleic acid according to any one of items 37 or 38. The composition according to item 42, which is a pharmaceutical composition. The composition according to any one of items 42 or 43, which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and/or compounds. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use as a medicament. 46. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder. 47. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved. 48. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of cancer. 49. A method for the diagnosis, prevention and/or treatment of at least one disease and/or disorder, comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of an ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or a composition according to any one of items 42 to 44. 50. The method according to item 49, for the diagnosis, prevention and/or treatment of at least one disease or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or composition according to any one of items 42 to 44. 51. The method according to any one of items 49 or 50, for the diagnosis, prevention and/or treatment of cancer, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or a composition according to any one of items 42 to 44. 7.6 Embodiment 6 -Family 5 1. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTFSDXAMG (SEQ ID NO: 356), wherein the amino acid residue X is selected from F or Y; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTFSDXAMG (SEQ ID NO: 356), wherein the amino acid residue X is selected from F or Y; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTFSDXAMG (SEQ ID NO: 356), wherein the amino acid residue X is selected from F or Y; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AINWSGGWTY (SEQ ID NO: 357); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AINWSGGWTY (SEQ ID NO: 357); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AINWSGGWTY (SEQ ID NO: 357); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence SSDYAGGRSTGYXY (SEQ ID NO: 358); wherein the amino acid residue X is selected from A or D; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence SSDYAGGRSTGYXY (SEQ ID NO: 358); wherein the amino acid residue X is selected from A or D; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence SSDYAGGRSTGYXY (SEQ ID NO: 358); wherein the amino acid residue X is selected from A or D. 2. The ISVD according to item 1, in which the amino acid sequences of the CDRs (AbM numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 122 or 123. 3. The ISVD according to any one of items 1 or 2, in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 359; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 357; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 360; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 234; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 357; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 361. 4. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of DXAMG (SEQ ID NO: 237), wherein the amino acid residue X is selected from Y or F; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of DXAMG (SEQ ID NO:237), wherein the amino acid residue X is selected from Y or F; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of DXAMG (SEQ ID NO:237), wherein the amino acid residue X is selected from Y or F; and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AINWSGGWTYYADSVQG (SEQ ID NO: 362); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AINWSGGWTYYADSVQG (SEQ ID NO: 362); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AINWSGGWTYYADSVQG (SEQ ID NO: 362); and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SSDYAGGRSTGYXY (SEQ ID NO: 358); wherein the amino acid residue X is selected from A or D; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SSDYAGGRSTGYXY (SEQ ID NO: 358); wherein the amino acid residue X is selected from A or D; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SSDYAGGRSTGYXY (SEQ ID NO: 358); wherein the amino acid residue X is selected from A or D. 5. The ISVD according to item 4, in which the amino acid sequences of the CDRs (Kabat numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 122 or 123. 6. The ISVD according to any one of items 4 or 5, in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 229; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 362; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 360; or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 243; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 362; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 361. 7. The ISVD according to any of one items 1 to 6, which amino acid sequence i) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NOs: 122 or 123, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded; and in which: ii) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1. 8. The ISVD according to any one of items 1 to 7, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consist of a heavy chain variable domain sequence that is derived from heavy chain antibody. 9. The ISVD according to any one of items 1 to 8, that essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb. 10. The ISVD according to any one of items 1 to 9, which is a humanized ISVD that is chosen from the group consisting of SEQ ID Nos: 171-174 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID NOs: 122 or 123. 11. The ISVD according to any one of items 1 to 10, in which the amino acid sequence is chosen from the group consisting of SEQ ID NOs: 122 or 123. 12. The ISVD according to any one of items 1 to 11, wherein the ISVD specifically binds to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-8 to 10-10 moles/litre or less and more preferably 1x10-8 to 1x10-9 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 5.85x10- 9 moles/litre, or 6.01x10-9 moles/litre, as determined by Surface Plasmon Resonance. 13. The ISVD according to any one of items 1 to 12, wherein the ISVD specifically binds to human CEACAM5 with a kon rate of 104 M-1s-1 to about 107 M-1s-1, preferably between 104 M-1s-1 and 106 M-1s-1, more preferably between 104 M-1s-1 and 105 M-1s-1, such as between 5x104 M-1s-1 and 1x105 M-1s-1, even more preferably of about 8.68x104 M-1s-1, or 8.07x104 M-1s-1, as determined by Surface Plasmon Resonance. 14. The ISVD according to any one of items 1 to 13, wherein the ISVD specifically binds to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-3 s-1 and 1x10-6 s-1, more preferably between 1x10-3 s-1 and 1x10-5 s-1, such as between 6x10-4 s-1 and 1x10-4 s-1even more preferably of about 5.08x10-4 s-1, or 4.85x10-4 s-1, as determined by Surface Plasmon Resonance. 15. The ISVD according to any one of items 1 to 14, wherein the ISVD specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, and CEACAM8. 16. The ISVD according to any one of items 1 to 15, wherein the ISVD internalizes upon binding to CEACAM5. 17. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to any one of items 1 to 16, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers. 18. The polypeptide or construct according to item 17, in which said one or more other groups, residues, moieties or binding units are amino acid sequences. 19. The polypeptide or construct according to any one of items 17 to 18, in which said one or more linkers are one or more amino acid sequences. 20. The polypeptide or construct according to any one of items 17 to 19, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences. 21. The polypeptide or construct according to any one of items 17 to 20, in which said one or more other groups, residues, moieties or binding units are ISVDs. The polypeptide or construct according to any one of items 17 to 21, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs. The polypeptide or construct according to any one of items 17 to 22, which is a multivalent construct. The polypeptide or construct according to any one of items 17 to 23, which is a multispecific construct. The polypeptide or construct according to any one of items 17 to 24, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half-life, compared to the ISVD without the one or more other groups, residues, moieties or binding units. The polypeptide or construct according to item 25, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins. The polypeptide or construct according to item 26, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof. The polypeptide or construct according to item 27, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). The polypeptide or construct according to item 28, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). 30. The polypeptide or construct according to item 29, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin. 31. The polypeptide or construct according to item 30, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which: - CDR1 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 80; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 80; and c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 80; and - CDR2 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 81; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 81; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 81; and - CDR3 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NOs: 82; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 82; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 82. 32. The polypeptide or construct according to item 31, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 80, CDR2 consists of the amino acid sequence of SEQ ID NO: 81, and CDR3 consists of the amino acid sequence of SEQ ID NO: 82. 33. The polypeptide or construct according to item 32, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 47), ALB23 (SEQ ID NO: 48), ALBX00001 (SEQ ID NO: 61) and ALB23002 (SEQ ID NO: 62). 34. The polypeptide or construct according to anyone of items 17 to 33, wherein said linker is chosen from the group consisting of SEQ ID NOs: 63 to 79. 35. The polypeptide or construct according to any of items 17 to 34, further comprising a C- terminal extension. 36. The polypeptide or construct according to item 35, wherein said C-terminal extension is a C- terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I). 37. A nucleic acid that encodes an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36. 38. The nucleic acid according to item 37, that is in the form of a genetic construct. 39. A non-human host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36; and/or that comprises the nucleic acid according to any one of items 37 or 38. 40. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, at least comprising the steps of: a) expressing, in a suitable host cell or non-human host organism or in another suitable expression system, a nucleic acid according to any one of items 37 or 38; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or the polypeptide according to any one of items 17 to 36. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, said method at least comprising the steps of: a) cultivating and/or maintaining a non-human host or host cell according to item 39 under conditions that are such that said non-human host or host cell expresses and/or produces at least one ISVD according to any one of items 1 to 16, or at least one polypeptide according to any one of items 17 to 36; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or polypeptide according to any one of items 17 to 36. A composition comprising at least one ISVD according to any one of items 1 to 16, at least one polypeptide or construct according to any one of items 17 to 36, or at least one nucleic acid according to any one of items 37 or 38. The composition according to item 42, which is a pharmaceutical composition. The composition according to any one of items 42 or 43, which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and/or compounds. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use as a medicament. 46. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder. 47. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved. 48. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of cancer. 49. A method for the diagnosis, prevention and/or treatment of at least one disease and/or disorder, comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of an ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or a composition according to any one of items 42 to 44. 50. The method according to item 49, for the diagnosis, prevention and/or treatment of at least one disease or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or composition according to any one of items 42 to 44. 51. The method according to any one of items 49 or 50, for the diagnosis, prevention and/or treatment of cancer, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or a composition according to any one of items 42 to 44. 7.7 Embodiment 7 -Family 9 1. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTFNINEYHLA (SEQ ID NO: 363); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTFNINEYHLA (SEQ ID NO: 363); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTFNINEYHLA (SEQ ID NO: 363); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AIWWSTGNKI (SEQ ID NO: 364); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AIWWSTGNKI (SEQ ID NO: 364); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AIWWSTGNKI (SEQ ID NO: 364); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence VRFSFRPLSTYWKDYDN (SEQ ID NO: 365); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence VRFSFRPLSTYWKDYDN (SEQ ID NO: 365); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence VRFSFRPLSTYWKDYDN (SEQ ID NO: 365). 2. The ISVD according to item 1, in which the amino acid sequences of the CDRs (AbM numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NO: 124. 3. The ISVD according to any one of items 1 or 2, in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 363; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 364; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 365. 4. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of INEYHLA (SEQ ID NO: 366); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of INEYHLA (SEQ ID NO: 366); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of INEYHLA (SEQ ID NO: 366); and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AIWWSTGNKIVADSVKG (SEQ ID NO: 367); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AIWWSTGNKIVADSVKG (SEQ ID NO: 367); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AIWWSTGNKIVADSVKG (SEQ ID NO: 367); and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of VRFSFRPLSTYWKDYDN (SEQ ID NO: 365); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VRFSFRPLSTYWKDYDN (SEQ ID NO: 365); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of VRFSFRPLSTYWKDYDN (SEQ ID NO: 365). 5. The ISVD according to item 4, in which the amino acid sequences of the CDRs (Kabat numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NO: 124. 6. The ISVD according to any one of items 4 or 5, in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 366; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 367; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 365. 7. The ISVD according to any of one items 1 to 6, which amino acid sequence i) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NO: 124, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded; and in which: ii) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1. 8. The ISVD according to any one of items 1 to 7, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consist of a heavy chain variable domain sequence that is derived from heavy chain antibody. 9. The ISVD according to any one of items 1 to 8, that essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb. 10. The ISVD according to any one of items 1 to 9, which is a humanized ISVD that is chosen from the group consisting of SEQ ID No: 124 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID NO: 124. 11. The ISVD according to any one of items 1 to 10, in which the amino acid sequence is chosen from the group consisting of SEQ ID NO: 124. 12. The ISVD according to any one of items 1 to 11, wherein the ISVD specifically binds to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-7 to 10-9 moles/litre or less and more preferably 1x10-7 to 1x10-8 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 2.49x10- 8 moles/litre, as determined by Surface Plasmon Resonance. 13. The ISVD according to any one of items 1 to 12, wherein the ISVD specifically binds to human CEACAM5 with a kon rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M- 1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, such as between 1x105 M-1s-1 and 8x105 M-1s-1, even more preferably of about of about 2.01x105 M-1s-1, as determined by Surface Plasmon Resonance. 14. The ISVD according to any one of items 1 to 13, wherein the ISVD specifically binds to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-2 s-1 and 1x10-5 s-1, more preferably between 1x10-2 s-1 and 1x10-3 s-1, such as between 1x10-2 s-1 and 4x10-3 s-1even more preferably of about 5.01x10-3 s-1, as determined by Surface Plasmon Resonance. 15. The ISVD according to any one of items 1 to 14, wherein the ISVD specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAMs family. 16. The ISVD according to any one of items 1 to 15, wherein the ISVD internalizes upon binding to CEACAM5. 17. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to any one of items 1 to 16, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers. 18. The polypeptide or construct according to item 17, in which said one or more other groups, residues, moieties or binding units are amino acid sequences. 19. The polypeptide or construct according to any one of items 17 to 18, in which said one or more linkers are one or more amino acid sequences. 20. The polypeptide or construct according to any one of items 17 to 19, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences. 21. The polypeptide or construct according to any one of items 17 to 20, in which said one or more other groups, residues, moieties or binding units are ISVDs. 22. The polypeptide or construct according to any one of items 17 to 21, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs. 23. The polypeptide or construct according to any one of items 17 to 22, which is a multivalent construct. 24. The polypeptide or construct according to any one of items 17 to 23, which is a multispecific construct. 25. The polypeptide or construct according to any one of items 17 to 24, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half-life, compared to the ISVD without the one or more other groups, residues, moieties or binding units. 26. The polypeptide or construct according to item 25, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins. 27. The polypeptide or construct according to item 26, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof. 28. The polypeptide or construct according to item 27, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). 29. The polypeptide or construct according to item 28, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). 30. The polypeptide or construct according to item 29, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin. 31. The polypeptide or construct according to item 30, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which: - CDR1 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 80; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 80; and c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 80; and - CDR2 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 81; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 81; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 81; and - CDR3 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NOs: 82; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 82; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 82. 32. The polypeptide or construct according to item 31, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 80, CDR2 consists of the amino acid sequence of SEQ ID NO: 81, and CDR3 consists of the amino acid sequence of SEQ ID NO: 82. 33. The polypeptide or construct according to item 32, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 47), ALB23 (SEQ ID NO: 48), ALBX00001 (SEQ ID NO: 61) and ALB23002 (SEQ ID NO: 62). 34. The polypeptide or construct according to anyone of items 17 to 33, wherein said linker is chosen from the group consisting of SEQ ID NOs: 63 to 79. 35. The polypeptide or construct according to any of items 17 to 34, further comprising a C- terminal extension. 36. The polypeptide or construct according to item 35, wherein said C-terminal extension is a C- terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I). 37. A nucleic acid that encodes an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36. 38. The nucleic acid according to item 37, that is in the form of a genetic construct. 39. A non-human host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36; and/or that comprises the nucleic acid according to any one of items 37 or 38. 40. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, at least comprising the steps of: a) expressing, in a suitable host cell or non-human host organism or in another suitable expression system, a nucleic acid according to any one of items 37 or 38; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or the polypeptide according to any one of items 17 to 36. 41. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, said method at least comprising the steps of: a) cultivating and/or maintaining a non-human host or host cell according to item 39 under conditions that are such that said non-human host or host cell expresses and/or produces at least one ISVD according to any one of items 1 to 16, or at least one polypeptide according to any one of items 17 to 36; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or polypeptide according to any one of items 17 to 36. 42. A composition comprising at least one ISVD according to any one of items 1 to 16, at least one polypeptide or construct according to any one of items 17 to 36, or at least one nucleic acid according to any one of items 37 or 38. 43. The composition according to item 42, which is a pharmaceutical composition. 44. The composition according to any one of items 42 or 43, which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and/or compounds. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use as a medicament. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of cancer. A method for the diagnosis, prevention and/or treatment of at least one disease and/or disorder, comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of an ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or a composition according to any one of items 42 to 44. The method according to item 49, for the diagnosis, prevention and/or treatment of at least one disease or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or composition according to any one of items 42 to 44. 51. The method according to any one of items 49 or 50, for the diagnosis, prevention and/or treatment of cancer, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or a composition according to any one of items 42 to 44. 7.8 Embodiment 8 -Family 17 1. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AIWWSTGNRI (SEQ ID NO: 369); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AIWWSTGNRI (SEQ ID NO: 369); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AIWWSTGNRI (SEQ ID NO: 369); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence VRFSFRPLSTYWKDYDI (SEQ ID NO: 370); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence VRFSFRPLSTYWKDYDI (SEQ ID NO: 370); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence VRFSFRPLSTYWKDYDI (SEQ ID NO: 370). 2. The ISVD according to item 1, in which the amino acid sequences of the CDRs (AbM numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NO: 125. 3. The ISVD according to any one of items 1 or 2, in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 368; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 369; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 370. 4. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of DYHMA (SEQ ID NO: 371); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of DYHMA (SEQ ID NO: 371); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of DYHMA (SEQ ID NO: 371); and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AIWWSTGNRIVADSVKG (SEQ ID NO: 372); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AIWWSTGNRIVADSVKG (SEQ ID NO: 372); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AIWWSTGNRIVADSVKG (SEQ ID NO: 372); and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of VRFSFRPLSTYWKDYDI (SEQ ID NO: 370); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VRFSFRPLSTYWKDYDI (SEQ ID NO: 370); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of VRFSFRPLSTYWKDYDI (SEQ ID NO: 370). The ISVD according to item 4, in which the amino acid sequences of the CDRs (Kabat numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NO: 125. The ISVD according to any one of items 4 or 5, in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 371; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 372; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 370. The ISVD according to any of one items 1 to 6, which amino acid sequence i) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NO: 125, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded; and in which: ii) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1. The ISVD according to any one of items 1 to 7, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consist of a heavy chain variable domain sequence that is derived from heavy chain antibody. The ISVD according to any one of items 1 to 8, that essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb. The ISVD according to any one of items 1 to 9, which is a humanized ISVD that is chosen from the group consisting of SEQ ID NO: 125 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID NO: 125. The ISVD according to any one of items 1 to 10, in which the amino acid sequence is chosen from the group consisting of SEQ ID NO: 125. The ISVD according to any one of items 1 to 11, wherein the ISVD specifically binds to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-7 to 10-9 moles/litre or less and more preferably 1x10-7 to 1x10-8 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 2.39x10- 8 moles/litre, as determined by Surface Plasmon Resonance. The ISVD according to any one of items 1 to 12, wherein the ISVD specifically binds to human CEACAM5 with a kon rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M- 1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, such as between 1x105 M-1s-1 and 8x105 M-1s-1, even more preferably of about of about 2.19x105 M-1s-1, as determined by Surface Plasmon Resonance. The ISVD according to any one of items 1 to 13, wherein the ISVD specifically binds to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-2 s-1 and 1x10-5 s-1, more preferably between 1x10-2 s-1 and 1x10-4 s-1, such as between 1x10-2 s-1 and 2x10-3 s-1 even more preferably of about 5.22x10-3 s-1, as determined by Surface Plasmon Resonance The ISVD according to any one of items 1 to 14, wherein the ISVD specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAMs family. 16. The ISVD according to any one of items 1 to 15, wherein the ISVD internalizes upon binding to CEACAM5. 17. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to any one of items 1 to 16, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers. 18. The polypeptide or construct according to item 17, in which said one or more other groups, residues, moieties or binding units are amino acid sequences. 19. The polypeptide or construct according to any one of items 17 to 18, in which said one or more linkers are one or more amino acid sequences. 20. The polypeptide or construct according to any one of items 17 to 19, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences. 21. The polypeptide or construct according to any one of items 17 to 20, in which said one or more other groups, residues, moieties or binding units are ISVDs. 22. The polypeptide or construct according to any one of items 17 to 21, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs. 23. The polypeptide or construct according to any one of items 17 to 22, which is a multivalent construct. 24. The polypeptide or construct according to any one of items 17 to 23, which is a multispecific construct. 25. The polypeptide or construct according to any one of items 17 to 24, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half-life, compared to the ISVD without the one or more other groups, residues, moieties or binding units. 26. The polypeptide or construct according to item 25, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins. 27. The polypeptide or construct according to item 26, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof. 28. The polypeptide or construct according to item 27, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). 29. The polypeptide or construct according to item 28, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). 30. The polypeptide or construct according to item 29, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin. 31. The polypeptide or construct according to item 30, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which: - CDR1 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 80; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 80; and c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 80; and - CDR2 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 81; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 81; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 81; and - CDR3 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NOs: 82; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 82; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 82. 32. The polypeptide or construct according to item 31, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 80, CDR2 consists of the amino acid sequence of SEQ ID NO: 81, and CDR3 consists of the amino acid sequence of SEQ ID NO: 82. 33. The polypeptide or construct according to item 32, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 47), ALB23 (SEQ ID NO: 48), ALBX00001 (SEQ ID NO: 61) and ALB23002 (SEQ ID NO: 62). 34. The polypeptide or construct according to anyone of items 17 to 33, wherein said linker is chosen from the group consisting of SEQ ID NOs: 63 to 79. 35. The polypeptide or construct according to any of items 17 to 34, further comprising a C- terminal extension. 36. The polypeptide or construct according to item 35, wherein said C-terminal extension is a C- terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I). 37. A nucleic acid that encodes an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36. 38. The nucleic acid according to item 37, that is in the form of a genetic construct. 39. A non-human host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36; and/or that comprises the nucleic acid according to any one of items 37 or 38. 40. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, at least comprising the steps of: a) expressing, in a suitable host cell or non-human host organism or in another suitable expression system, a nucleic acid according to any one of items 37 or 38; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or the polypeptide according to any one of items 17 to 36. 41. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, said method at least comprising the steps of: a) cultivating and/or maintaining a non-human host or host cell according to item 39 under conditions that are such that said non-human host or host cell expresses and/or produces at least one ISVD according to any one of items 1 to 16, or at least one polypeptide according to any one of items 17 to 36; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or polypeptide according to any one of items 17 to 36. A composition comprising at least one ISVD according to any one of items 1 to 16, at least one polypeptide or construct according to any one of items 17 to 36, or at least one nucleic acid according to any one of items 37 or 38. The composition according to item 42, which is a pharmaceutical composition. The composition according to any one of items 42 or 43, which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and/or compounds. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use as a medicament. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of cancer. A method for the diagnosis, prevention and/or treatment of at least one disease and/or disorder, comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of an ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or a composition according to any one of items 42 to 44. 50. The method according to item 49, for the diagnosis, prevention and/or treatment of at least one disease or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or composition according to any one of items 42 to 44. 51. The method according to any one of items 49 or 50, for the diagnosis, prevention and/or treatment of cancer, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or a composition according to any one of items 42 to 44. 7.9 Embodiment 9 -Family 18 1. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of GDXLNSYHMA (SEQ ID NO: 373), wherein the amino acid residue X is selected from T or N; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GDXLNSYHMA (SEQ ID NO: 373), wherein the amino acid residue X is selected from T or N; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of GDXLNSYHMA (SEQ ID NO: 373), wherein the amino acid residue X is selected from T or N; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AIWWSTGNXI (SEQ ID NO: 374), wherein the amino acid residue X is selected from A or T; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AIWWSTGNXI (SEQ ID NO: 374), wherein the amino acid residue X is selected from A or T; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AIWWSTGNXI (SEQ ID NO: 374), wherein the amino acid residue X is selected from A or T); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence VRFXFRPLSTYWKDYDN (SEQ ID NO: 375); wherein the amino acid residue X is selected from S or Q; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence VRFXFRPLSTYWKDYDN (SEQ ID NO: 375); wherein the amino acid residue X is selected from S or Q; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence VRFXFRPLSTYWKDYDN (SEQ ID NO: 375); wherein the amino acid residue X is selected from S or Q. 2. The ISVD according to item 1, in which the amino acid sequences of the CDRs (AbM numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 126 or 127. 3. The ISVD according to any one of items 1 or 2, in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 376; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 377; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 365; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 378; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 379; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 380. 4. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence SYHMA (SEQ ID NO: 381); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence SYHMA (SEQ ID NO: 381); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences SYHMA (SEQ ID NO: 381); and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AIWWSTGNXIVADSVKG (SEQ ID NO: 382), wherein the amino acid residue X is selected from A or T; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AIWWSTGNXIVADSVKG (SEQ ID NO: 382), wherein the amino acid residue X is selected from A or T; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AIWWSTGNXIVADSVKG (SEQ ID NO: 382), wherein the amino acid residue X is selected from A or T; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of VRFXFRPLSTYWKDYDN (SEQ ID NO: 375); wherein the amino acid residue X is selected from S or Q; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VRFXFRPLSTYWKDYDN (SEQ ID NO: 375); wherein the amino acid residue X is selected from S or Q; a) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence VRFXFRPLSTYWKDYDN (SEQ ID NO: 375); wherein the amino acid residue X is selected from S or Q. 5. The ISVD according to item 4, in which the amino acid sequences of the CDRs (Kabat numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 126 or 127. 6. The ISVD according to any one of items 4 or 5, in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 381; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 384; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 365; or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 381; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 385; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 380. 7. The ISVD according to any of one items 1 to 6, which amino acid sequence i) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NOs: 126 or 127, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded; and in which: ii) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1. 8. The ISVD according to any one of items 1 to 7, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consist of a heavy chain variable domain sequence that is derived from heavy chain antibody. 9. The ISVD according to any one of items 1 to 8, that essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb. 10. The ISVD according to any one of items 1 to 9, which is a humanized ISVD that is chosen from the group consisting of SEQ ID Nos: 171-174 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID NOs: 126 or 127. 11. The ISVD according to any one of items 1 to 10, in which the amino acid sequence is chosen from the group consisting of SEQ ID NOs: 126 or 127. 12. The ISVD according to any one of items 1 to 11, wherein the ISVD specifically binds to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-7 to 10-10 moles/litre or less and more preferably 10-7 to 10-9 moles/litre or less and more preferably 1x10-7 to 1x10-8 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 4.11x10-8 moles/litre, or 2.67x10-8moles/litre, as determined by Surface Plasmon Resonance. 13. The ISVD according to any one of items 1 to 12, wherein the ISVD specifically binds to human CEACAM5 with a kon rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M- 1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, such as between 1x105 M-1s-1 and 5x105 M-1s-1, even more preferably of about 1.93x105 M-1s-1, or 2.18x105 M-1s-1, as determined by Surface Plasmon Resonance. 14. The ISVD according to any one of items 1 to 13, wherein the ISVD specifically binds to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-2 s-1 and 1x10-5 s-1, more preferably between 1x10-2 s-1 and 1x10-4 s-1, such as between 1x10-2 s-1 and 1x10-3 s-1 even more preferably of about 7.94x10-3 s-1, or 5.81x10-3 s-1, as determined by Surface Plasmon Resonance. 15. The ISVD according to any one of items 1 to 14, wherein the ISVD specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAMs family. 16. The ISVD according to any one of items 1 to 15, wherein the ISVD internalizes upon binding to CEACAM5. 17. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to any one of items 1 to 16, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers. 18. The polypeptide or construct according to item 17, in which said one or more other groups, residues, moieties or binding units are amino acid sequences. 19. The polypeptide or construct according to any one of items 17 to 18, in which said one or more linkers are one or more amino acid sequences. 20. The polypeptide or construct according to any one of items 17 to 19, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences. 21. The polypeptide or construct according to any one of items 17 to 20, in which said one or more other groups, residues, moieties or binding units are ISVDs. 22. The polypeptide or construct according to any one of items 17 to 21, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs. 23. The polypeptide or construct according to any one of items 17 to 22, which is a multivalent construct. 24. The polypeptide or construct according to any one of items 17 to 23, which is a multispecific construct. The polypeptide or construct according to any one of items 17 to 24, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half-life, compared to the ISVD without the one or more other groups, residues, moieties or binding units. The polypeptide or construct according to item 25, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins. The polypeptide or construct according to item 26, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof. The polypeptide or construct according to item 27, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). The polypeptide or construct according to item 28, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). The polypeptide or construct according to item 29, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin. 31. The polypeptide or construct according to item 30, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which: - CDR1 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 80; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 80; and c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 80; and - CDR2 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 81; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 81; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 81; and - CDR3 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NOs: 82; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 82; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 82. 32. The polypeptide or construct according to item 31, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 80, CDR2 consists of the amino acid sequence of SEQ ID NO: 81, and CDR3 consists of the amino acid sequence of SEQ ID NO: 82. 33. The polypeptide or construct according to item 32, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 47), ALB23 (SEQ ID NO: 48), ALBX00001 (SEQ ID NO: 61) and ALB23002 (SEQ ID NO: 62). The polypeptide or construct according to anyone of items 17 to 33, wherein said linker is chosen from the group consisting of SEQ ID NOs: 63 to 79. The polypeptide or construct according to any of items 17 to 34, further comprising a C- terminal extension. The polypeptide or construct according to item 35, wherein said C-terminal extension is a C- terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I). A nucleic acid that encodes an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36. The nucleic acid according to item 37, that is in the form of a genetic construct. A non-human host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36; and/or that comprises the nucleic acid according to any one of items 37 or 38. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, at least comprising the steps of: a) expressing, in a suitable host cell or non-human host organism or in another suitable expression system, a nucleic acid according to any one of items 37 or 38; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or the polypeptide according to any one of items 17 to 36. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, said method at least comprising the steps of: a) cultivating and/or maintaining a non-human host or host cell according to item 39 under conditions that are such that said non-human host or host cell expresses and/or produces at least one ISVD according to any one of items 1 to 16, or at least one polypeptide according to any one of items 17 to 36; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or polypeptide according to any one of items 17 to 36. 42. A composition comprising at least one ISVD according to any one of items 1 to 16, at least one polypeptide or construct according to any one of items 17 to 36, or at least one nucleic acid according to any one of items 37 or 38. 43. The composition according to item 42, which is a pharmaceutical composition. 44. The composition according to any one of items 42 or 43, which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and/or compounds. 45. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use as a medicament. 46. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder. 47. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved. 48. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of cancer. 49. A method for the diagnosis, prevention and/or treatment of at least one disease and/or disorder, comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of an ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or a composition according to any one of items 42 to 44. 50. The method according to item 49, for the diagnosis, prevention and/or treatment of at least one disease or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or composition according to any one of items 42 to 44. 51. The method according to any one of items 49 or 50, for the diagnosis, prevention and/or treatment of cancer, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or a composition according to any one of items 42 to 44. 7.10 Embodiment 10 -Family 19 1. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GX1TFSX2YAMG (SEQ ID NO: 386), wherein the amino acid residue X1 is selected from G or R, and wherein the amino acid residue X2 is selected from S or N; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GX1TFSX2YAMG (SEQ ID NO: 386), wherein the amino acid residue X1 is selected from G or R, and wherein the amino acid residue X2 is selected from S or N; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences GX1TFSX2YAMG (SEQ ID NO: 386), wherein the amino acid residue X1 is selected from G or R, and wherein the amino acid residue X2 is selected from S or N; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GMSWSGGSTH (SEQ ID NO: 387); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GMSWSGGSTH (SEQ ID NO: 387); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GMSWSGGSTH (SEQ ID NO: 387); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GXNPMGPIATRPSVHDY (SEQ ID NO: 388); wherein the amino acid residue X is selected from Q or R; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GXNPMGPIATRPSVHDY (SEQ ID NO: 388); wherein the amino acid residue X is selected from Q or R; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GXNPMGPIATRPSVHDY (SEQ ID NO: 388); wherein the amino acid residue X is selected from Q or R. 2. The ISVD according to item 1, in which the amino acid sequences of the CDRs (AbM numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 128, 129 or 134. 3. The ISVD according to any one of items 1 or 2, in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 389; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 387; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 390; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 391; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 387; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 392. 4. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence XYAMG (SEQ ID NO: 393), wherein the amino acid residue X is selected from S or N; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence XYAMG (SEQ ID NO: 393), wherein the amino acid residue X is selected from S or N; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences XYAMG (SEQ ID NO: 393), wherein the amino acid residue X is selected from S or N; and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GMSWSGGSTHYADSVKG (SEQ ID NO: 394); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GMSWSGGSTHYADSVKG (SEQ ID NO: 394); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GMSWSGGSTHYADSVKG (SEQ ID NO: 394); and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GXNPMGPIATRPSVHDY (SEQ ID NO: 388); wherein the amino acid residue X is selected from Q or R; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GXNPMGPIATRPSVHDY (SEQ ID NO: 388); wherein the amino acid residue X is selected from Q or R; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GXNPMGPIATRPSVHDY (SEQ ID NO: 388); wherein the amino acid residue X is selected from Q or R. 5. The ISVD according to item 4, in which the amino acid sequences of the CDRs (Kabat numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 128, 129 or 134. 6. The ISVD according to any one of items 4 or 5, in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 395; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 394; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 390; or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 396; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 394; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 392. 7. The ISVD according to any of one items 1 to 6, which amino acid sequence i) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NOs: 128, 129 or 134, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded; and in which: ii) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1. 8. The ISVD according to any one of items 1 to 7, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consist of a heavy chain variable domain sequence that is derived from heavy chain antibody. 9. The ISVD according to any one of items 1 to 8, that essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb. 10. The ISVD according to any one of items 1 to 9, which is a humanized ISVD that is chosen from the group consisting of SEQ ID Nos: 171-174 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID NOs: 128, 129 or 134. 11. The ISVD according to any one of items 1 to 10, in which the amino acid sequence is chosen from the group consisting of SEQ ID NOs: 128, 129 or 134. 12. The ISVD according to any one of items 1 to 11, wherein the ISVD specifically binds to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-12 moles/litre or less, and preferably 10-8 to 10-11 moles/litre or less and more preferably 5x10-10 to 5x10-11 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 4.64x10- 10 moles/litre, or 9.55x10-11moles/litre, as determined by Surface Plasmon Resonance. 13. The ISVD according to any one of items 1 to 12, wherein the ISVD specifically binds to human CEACAM5 with a kon rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M- 1s-1 and 107 M-1s-1, more preferably between 104 M-1s-1 and 106 M-1s-1, such as between 1x105 M-1s-1 and 1x106 M-1s-1, even more preferably of about 5.85x105 M-1s-1, or 5.34x105 M-1s-1, as determined by Surface Plasmon Resonance. 14. The ISVD according to any one of items 1 to 13, wherein the ISVD specifically binds to human CEACAM5 with koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-2 s-1 and 1x10-5 s-1, more preferably between 1x10-3 s-1 and 10-5 s-1, such as between 5x10-4 s-1 and 10-5 s-1 even more preferably of about 2.72x10-4 s-1, or 5.10x10-5 s-1, as determined by Surface Plasmon Resonance. 15. The ISVD according to any one of items 1 to 14, wherein the ISVD specifically binds to human and cyno CEACAM5 and does not bind to CEACAM6 and CEACAM7. 16. The ISVD according to any one of items 1 to 15, wherein the ISVD internalizes upon binding to CEACAM5. 17. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to any one of items 1 to 16, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers. 18. The polypeptide or construct according to item 17, in which said one or more other groups, residues, moieties or binding units are amino acid sequences. 19. The polypeptide or construct according to any one of items 17 to 18, in which said one or more linkers are one or more amino acid sequences. 20. The polypeptide or construct according to any one of items 17 to 19, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences. 21. The polypeptide or construct according to any one of items 17 to 20, in which said one or more other groups, residues, moieties or binding units are ISVDs. 22. The polypeptide or construct according to any one of items 17 to 21, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs. 23. The polypeptide or construct according to any one of items 17 to 22, which is a multivalent construct. 24. The polypeptide or construct according to any one of items 17 to 23, which is a multispecific construct. 25. The polypeptide or construct according to any one of items 17 to 24, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half-life, compared to the ISVD without the one or more other groups, residues, moieties or binding units. 26. The polypeptide or construct according to item 25, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins. 27. The polypeptide or construct according to item 26, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof. 28. The polypeptide or construct according to item 27, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). 29. The polypeptide or construct according to item 28, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). 30. The polypeptide or construct according to item 29, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin. 31. The polypeptide or construct according to item 30, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which: - CDR1 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 80; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 80; and c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 80; and - CDR2 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 81; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 81; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 81; and - CDR3 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NOs: 82; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 82; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 82. 32. The polypeptide or construct according to item 31, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 80, CDR2 consists of the amino acid sequence of SEQ ID NO: 81, and CDR3 consists of the amino acid sequence of SEQ ID NO: 82. 33. The polypeptide or construct according to item 32, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 47), ALB23 (SEQ ID NO: 48), ALBX00001 (SEQ ID NO: 61) and ALB23002 (SEQ ID NO: 62). The polypeptide or construct according to anyone of items 17 to 33, wherein said linker is chosen from the group consisting of SEQ ID NOs: 63 to 79. The polypeptide or construct according to any of items 17 to 34, further comprising a C- terminal extension. The polypeptide or construct according to item 35, wherein said C-terminal extension is a C- terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I). A nucleic acid that encodes an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36. The nucleic acid according to item 37, that is in the form of a genetic construct. A non-human host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36; and/or that comprises the nucleic acid according to any one of items 37 or 38. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, at least comprising the steps of: a) expressing, in a suitable host cell or non-human host organism or in another suitable expression system, a nucleic acid according to any one of items 37 or 38; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or the polypeptide according to any one of items 17 to 36. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, said method at least comprising the steps of: a) cultivating and/or maintaining a non-human host or host cell according to item 39 under conditions that are such that said non-human host or host cell expresses and/or produces at least one ISVD according to any one of items 1 to 16, or at least one polypeptide according to any one of items 17 to 36; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or polypeptide according to any one of items 17 to 36. 42. A composition comprising at least one ISVD according to any one of items 1 to 16, at least one polypeptide or construct according to any one of items 17 to 36, or at least one nucleic acid according to any one of items 37 or 38. 43. The composition according to item 42, which is a pharmaceutical composition. 44. The composition according to any one of items 42 or 43, which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and/or compounds. 45. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use as a medicament. 46. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder. 47. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved. 48. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of cancer. 49. A method for the diagnosis, prevention and/or treatment of at least one disease and/or disorder, comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of an ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or a composition according to any one of items 42 to 44. 50. The method according to item 49, for the diagnosis, prevention and/or treatment of at least one disease or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or composition according to any one of items 42 to 44. 51. The method according to any one of items 49 or 50, for the diagnosis, prevention and/or treatment of cancer, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or a composition according to any one of items 42 to 44. 7.11 Embodiment 11 -Family 27 1. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GGTVSTYTMG (SEQ ID NO: 397); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GGTVSTYTMG (SEQ ID NO: 397); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GGTVSTYTMG (SEQ ID NO: 397); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence SIIWSGSTTV (SEQ ID NO: 398); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence SIIWSGSTTV (SEQ ID NO: 398); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence SIIWSGSTTV (SEQ ID NO: 398); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence QHFGPVSQTTKGYFY (SEQ ID NO: 399); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence QHFGPVSQTTKGYFY (SEQ ID NO: 399); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence QHFGPVSQTTKGYFY (SEQ ID NO: 399). 2. The ISVD according to item 1, in which the amino acid sequences of the CDRs (AbM numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NO: 130. 3. The ISVD according to any one of items 1 or 2, in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 397; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 398; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 399. 4. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence TYTMG (SEQ ID NO: 17); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence TYTMG (SEQ ID NO: 17); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences TYTMG (SEQ ID NO: 17); and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence SIIWSGSTTVYADSVKG (SEQ ID NO: 400); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence SIIWSGSTTVYADSVKG (SEQ ID NO: 400); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence SIIWSGSTTVYADSVKG (SEQ ID NO: 400); and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of QHFGPVSQTTKGYFY (SEQ ID NO: 399); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of QHFGPVSQTTKGYFY (SEQ ID NO: 399); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of QHFGPVSQTTKGYFY (SEQ ID NO: 399). 5. The ISVD according to item 4, in which the amino acid sequences of the CDRs (Kabat numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NO: 130. 6. The ISVD according to any one of items 4 or 5, in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 17; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 400; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 399. 7. The ISVD according to any of one items 1 to 6, which amino acid sequence i) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NO: 130, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded; and in which: ii) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1. 8. The ISVD according to any one of items 1 to 7, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consist of a heavy chain variable domain sequence that is derived from heavy chain antibody. 9. The ISVD according to any one of items 1 to 8, that essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb. 10. The ISVD according to any one of items 1 to 9, which is a humanized ISVD that is chosen from the group consisting of SEQ ID NO: 130 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID NO: 130. 11. The ISVD according to any one of items 1 to 10, in which the amino acid sequence is chosen from the group consisting of SEQ ID NO: 130. 12. The ISVD according to any one of items 1 to 11, wherein the ISVD specifically binds to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-8 to 10-10 moles/litre or less and more preferably 1x10-8 to 1x10-9 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 7.90x10- 10 moles/litre, as determined by Surface Plasmon Resonance. 13. The ISVD according to any one of items 1 to 12, wherein the ISVD specifically binds to human CEACAM5 with a kon rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M- 1s-1 and 107 M-1s-1, more preferably between 106 M-1s-1 and 107 M-1s-1, such as between 1x106 M-1s-1 and 5x106 M-1s-1, even more preferably of about 1.19x106 M-1s-1,as determined by Surface Plasmon Resonance. 14. The ISVD according to any one of items 1 to 13, wherein the ISVD specifically binds to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-3 s-1 and 1x10-6 s-1, more preferably between 1x10-3 s-1 and 1x10-4 s-1, such as between 1x10-3 s-1 and 5x10-4 s-1 even more preferably of about 9.40x10-4 s-1, as determined by Surface Plasmon Resonance. 15. The ISVD according to any one of items 1 to 14, wherein the ISVD specifically binds to human and cyno CEACAM5 and does not bind to CEACAM6 and CEACAM7. 16. The ISVD according to any one of items 1 to 15, wherein the ISVD internalizes upon binding to CEACAM5. 17. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to any one of items 1 to 16, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers. 18. The polypeptide or construct according to item 17, in which said one or more other groups, residues, moieties or binding units are amino acid sequences. 19. The polypeptide or construct according to any one of items 17 to 18, in which said one or more linkers are one or more amino acid sequences. 20. The polypeptide or construct according to any one of items 17 to 19, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences. 21. The polypeptide or construct according to any one of items 17 to 20, in which said one or more other groups, residues, moieties or binding units are ISVDs. 22. The polypeptide or construct according to any one of items 17 to 21, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs. 23. The polypeptide or construct according to any one of items 17 to 22, which is a multivalent construct. 24. The polypeptide or construct according to any one of items 17 to 23, which is a multispecific construct. 25. The polypeptide or construct according to any one of items 17 to 24, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half-life, compared to the ISVD without the one or more other groups, residues, moieties or binding units. 26. The polypeptide or construct according to item 25, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins. 27. The polypeptide or construct according to item 26, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof. 28. The polypeptide or construct according to item 27, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). 29. The polypeptide or construct according to item 28, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). The polypeptide or construct according to item 29, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin. The polypeptide or construct according to item 30, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which: - CDR1 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 80; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 80; and c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 80; and - CDR2 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 81; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 81; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 81; and - CDR3 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NOs: 82; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 82; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 82. 32. The polypeptide or construct according to item 31, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 80, CDR2 consists of the amino acid sequence of SEQ ID NO: 81, and CDR3 consists of the amino acid sequence of SEQ ID NO: 82. 33. The polypeptide or construct according to item 32, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 47), ALB23 (SEQ ID NO: 48), ALBX00001 (SEQ ID NO: 61) and ALB23002 (SEQ ID NO: 62). 34. The polypeptide or construct according to anyone of items 17 to 33, wherein said linker is chosen from the group consisting of SEQ ID NOs: 63 to 79. 35. The polypeptide or construct according to any of items 17 to 34, further comprising a C- terminal extension. 36. The polypeptide or construct according to item 35, wherein said C-terminal extension is a C- terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I). 37. A nucleic acid that encodes an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36. 38. The nucleic acid according to item 37, that is in the form of a genetic construct. 39. A non-human host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36; and/or that comprises the nucleic acid according to any one of items 37 or 38. 40. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, at least comprising the steps of: a) expressing, in a suitable host cell or non-human host organism or in another suitable expression system, a nucleic acid according to any one of items 37 or 38; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or the polypeptide according to any one of items 17 to 36. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, said method at least comprising the steps of: a) cultivating and/or maintaining a non-human host or host cell according to item 39 under conditions that are such that said non-human host or host cell expresses and/or produces at least one ISVD according to any one of items 1 to 16, or at least one polypeptide according to any one of items 17 to 36; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or polypeptide according to any one of items 17 to 36. A composition comprising at least one ISVD according to any one of items 1 to 16, at least one polypeptide or construct according to any one of items 17 to 36, or at least one nucleic acid according to any one of items 37 or 38. The composition according to item 42, which is a pharmaceutical composition. The composition according to any one of items 42 or 43, which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and/or compounds. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use as a medicament. 46. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder. 47. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved. 48. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of cancer. 49. A method for the diagnosis, prevention and/or treatment of at least one disease and/or disorder, comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of an ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or a composition according to any one of items 42 to 44. 50. The method according to item 49, for the diagnosis, prevention and/or treatment of at least one disease or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or composition according to any one of items 42 to 44. 51. The method according to any one of items 49 or 50, for the diagnosis, prevention and/or treatment of cancer, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or a composition according to any one of items 42 to 44. 7.12 Embodiment 12 -Family 28 1. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTLNDYHMA (SEQ ID NO: 368); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AIWWSTGNTI (SEQ ID NO: 379); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AIWWSTGNTI (SEQ ID NO: 379); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AIWWSTGNTI (SEQ ID NO: 379); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence VRFSFRPLSTYWKDYDN (SEQ ID NO: 365); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence VRFSFRPLSTYWKDYDN (SEQ ID NO: 365); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence VRFSFRPLSTYWKDYDN (SEQ ID NO: 365). 2. The ISVD according to item 1, in which the amino acid sequences of the CDRs (AbM numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NO: 131. 3. The ISVD according to any one of items 1 or 2, in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 368; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 379; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 365. 4. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence DYHMA (SEQ ID NO: 371); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence DYHMA (SEQ ID NO: 371); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences DYHMA (SEQ ID NO: 371); and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AIWWSTGNTIVADSVKG (SEQ ID NO: 385); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AIWWSTGNTIVADSVKG (SEQ ID NO: 385); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AIWWSTGNTIVADSVKG (SEQ ID NO: 385); and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of VRFSFRPLSTYWKDYDN (SEQ ID NO: 365); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VRFSFRPLSTYWKDYDN (SEQ ID NO: 365); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of VRFSFRPLSTYWKDYDN (SEQ ID NO: 365). 5. The ISVD according to item 4, in which the amino acid sequences of the CDRs (Kabat numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NO: 131. 6. The ISVD according to any one of items 4 or 5, in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 371; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 385; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 365. 7. The ISVD according to any of one items 1 to 6, which amino acid sequence i) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NO: 131, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded; and in which: ii) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1. 8. The ISVD according to any one of items 1 to 7, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consist of a heavy chain variable domain sequence that is derived from heavy chain antibody. 9. The ISVD according to any one of items 1 to 8, that essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb. 10. The ISVD according to any one of items 1 to 9, which is a humanized ISVD that is chosen from the group consisting of SEQ ID NO: 131 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID NO: 131. 11. The ISVD according to any one of items 1 to 10, in which the amino acid sequence is chosen from the group consisting of SEQ ID NO: 131. 12. The ISVD according to any one of items 1 to 11, wherein the ISVD specifically binds to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-7 to 10-9 moles/litre or less and more preferably 1x10-7 to 5x10-8 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 3.12x10- 8 moles/litre, as determined by Surface Plasmon Resonance. 13. The ISVD according to any one of items 1 to 12, wherein the ISVD specifically binds to human CEACAM5 with a kon rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M- 1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, such as between 1x105 M-1s-1 and 5x105 M-1s-1, even more preferably of about 2.16x105 M-1s-1, as determined by Surface Plasmon Resonance. 14. The ISVD according to any one of items 1 to 13, wherein the ISVD specifically binds to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-2 s-1 and 1x10-5 s-1, more preferably between 8x10-3 s-1 and 1x10-5 s-1, such as between 8x10-3 s-1 and 1x10-4 s-1 even more preferably of about 6.73x10-3 s-1, as determined by Surface Plasmon Resonance. 15. The ISVD according to any one of items 1 to 14, wherein the ISVD specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAMs family. 16. The ISVD according to any one of items 1 to 15, wherein the ISVD internalizes upon binding to CEACAM5. 17. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to any one of items 1 to 16, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers. 18. The polypeptide or construct according to item 17, in which said one or more other groups, residues, moieties or binding units are amino acid sequences. 19. The polypeptide or construct according to any one of items 17 to 18, in which said one or more linkers are one or more amino acid sequences. 20. The polypeptide or construct according to any one of items 17 to 19, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences. 21. The polypeptide or construct according to any one of items 17 to 20, in which said one or more other groups, residues, moieties or binding units are ISVDs. 22. The polypeptide or construct according to any one of items 17 to 21, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs. 23. The polypeptide or construct according to any one of items 17 to 22, which is a multivalent construct. 24. The polypeptide or construct according to any one of items 17 to 23, which is a multispecific construct. 25. The polypeptide or construct according to any one of items 17 to 24, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half-life, compared to the ISVD without the one or more other groups, residues, moieties or binding units. 26. The polypeptide or construct according to item 25, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins. 27. The polypeptide or construct according to item 26, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof. 28. The polypeptide or construct according to item 27, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). 29. The polypeptide or construct according to item 28, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). 30. The polypeptide or construct according to item 29, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin. 31. The polypeptide or construct according to item 30, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which - CDR1 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 80; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 80; and c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 80; and - CDR2 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 81; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 81; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 81; and - CDR3 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NOs: 82; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 82; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 82. 32. The polypeptide or construct according to item 31, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 80, CDR2 consists of the amino acid sequence of SEQ ID NO: 81, and CDR3 consists of the amino acid sequence of SEQ ID NO: 82. 33. The polypeptide or construct according to item 32, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 47), ALB23 (SEQ ID NO: 48), ALBX00001 (SEQ ID NO: 61) and ALB23002 (SEQ ID NO: 62). 34. The polypeptide or construct according to anyone of items 17 to 33, wherein said linker is chosen from the group consisting of SEQ ID NOs: 63 to 79. 35. The polypeptide or construct according to any of items 17 to 34, further comprising a C- terminal extension. 36. The polypeptide or construct according to item 35, wherein said C-terminal extension is a C- terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I). 37. A nucleic acid that encodes an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36. 38. The nucleic acid according to item 37, that is in the form of a genetic construct. 39. A non-human host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36; and/or that comprises the nucleic acid according to any one of items 37 or 38. 40. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, at least comprising the steps of: a) expressing, in a suitable host cell or non-human host organism or in another suitable expression system, a nucleic acid according to any one of items 37 or 38; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or the polypeptide according to any one of items 17 to 36. 41. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, said method at least comprising the steps of: a) cultivating and/or maintaining a non-human host or host cell according to item 39 under conditions that are such that said non-human host or host cell expresses and/or produces at least one ISVD according to any one of items 1 to 16, or at least one polypeptide according to any one of items 17 to 36; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or polypeptide according to any one of items 17 to 36. 42. A composition comprising at least one ISVD according to any one of items 1 to 16, at least one polypeptide or construct according to any one of items 17 to 36, or at least one nucleic acid according to any one of items 37 or 38. 43. The composition according to item 42, which is a pharmaceutical composition. 44. The composition according to any one of items 42 or 43, which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and/or compounds. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use as a medicament. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of cancer. A method for the diagnosis, prevention and/or treatment of at least one disease and/or disorder, comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of an ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or a composition according to any one of items 42 to 44. The method according to item 49, for the diagnosis, prevention and/or treatment of at least one disease or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or composition according to any one of items 42 to 44. The method according to any one of items 49 or 50, for the diagnosis, prevention and/or treatment of cancer, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or a composition according to any one of items 42 to 44. Embodiment 13-Family 4 and 5 An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (AbM numbering) consists of an amino acid sequence selected from a) the amino acid sequence GX1TFSX2X3AX4G (SEQ ID NO: 530); wherein the amino acid residue X1 is selected from R or H; wherein the amino acid residue X2 is selected from E or D; wherein the amino acid residue X3 is selected from F or Y; and wherein the amino acid residue X4 is selected from L or M; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GX1TFSX2X3AX4G (SEQ ID NO: 530); wherein the amino acid residue X1 is selected from R or H; wherein the amino acid residue X2 is selected from E or D; wherein the amino acid residue X3 is selected from F or Y; and wherein the amino acid residue X4 is selected from L or M; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GX1TFSX2X3AX4G (SEQ ID NO: 530); wherein the amino acid residue X1 is selected from R or H; wherein the amino acid residue X2 is selected from E or D; wherein the amino acid residue X3 is selected from F or Y; and wherein the amino acid residue X4 is selected from L or M; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AINWX1GX2WTY (SEQ ID NO: 531); wherein the amino acid residue X1 is selected from G or S; and wherein the amino acid residue X2 is selected from T, G or S; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AINWX1GX2WTY (SEQ ID NO: 531); wherein the amino acid residue X1 is selected from G or S; and wherein the amino acid residue X2 is selected from T, G or S; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AINWX1GX2WTY (SEQ ID NO: 531); wherein the amino acid residue X1 is selected from G or S; and wherein the amino acid residue X2 is selected from T, G or S; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence SX1DYAGGX2X3TGYX4Y (SEQ ID NO: 532); wherein the amino acid residue X1 is selected from S, P or L; wherein the amino acid residue X2 is selected from N, R or S; wherein the amino acid residue X3 is selected from P or S; and wherein the amino acid residue X4 is selected from P, D or A; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SX1DYAGGX2X3TGYX4Y (SEQ ID NO: 532); wherein the amino acid residue X1 is selected from S, P or L; wherein the amino acid residue X2 is selected from N, R or S; wherein the amino acid residue X3 is selected from P or S; and wherein the amino acid residue X4 is selected from P, D or A; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SX1DYAGGX2X3TGYX4Y (SEQ ID NO: 532); wherein the amino acid residue X1 is selected from S, P or L; wherein the amino acid residue X2 is selected from N, R or S; wherein the amino acid residue X3 is selected from P or S; and wherein the amino acid residue X4 is selected from P, D or A. The ISVD according to item 1, in which the amino acid sequences of the CDRs (AbM numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149. The ISVD according to any one of items 1 or 2, in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 9; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 10; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 11, or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 234; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 235; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 236,; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 234; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 238; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 239, or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 359; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 357; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 360, or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 234; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 357; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 361. 4. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence X1X2AX3G (SEQ ID NO: 532), wherein the amino acid residue X1 is selected from E or D, X2 is selected from Y or F, and the amino acid residue X3 is selected from L or M; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence X1X2AX3G (SEQ ID NO: 532), wherein the amino acid residue X1 is selected from E or D, X3 is selected from Y or F, and the amino acid residue X2 is selected from L or M; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence X1X2AX3G (SEQ ID NO: 532), wherein the amino acid residue X1 is selected from E or D, X2 is selected from Y or F, and the amino acid residue X3is selected from L or M; and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AINWX1GX2WTYYAX3SVX4G (SEQ ID NO: 534); wherein the amino acid residue X1 is selected from G or S; wherein the amino acid residue X2 is selected from G, S or T; wherein the amino acid residue X3 is selected from H or D; and wherein the amino acid residue X4 is selected from Q or K; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AINWX1GX2WTYYAX3SVX4G (SEQ ID NO: 534); wherein the amino acid residue X1 is selected from G or S; wherein the amino acid residue X2 is selected from G, S or T; wherein the amino acid residue X3 is selected from H or D; and wherein the amino acid residue X4 is selected from Q or K; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AINWX1GX2WTYYAX3SVX4G (SEQ ID NO: 534); wherein the amino acid residue X1 is selected from G or S; wherein the amino acid residue X2 is selected from G, S or T; wherein the amino acid residue X3 is selected from H or D; and wherein the amino acid residue X4 is selected from Q or K; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence SX1DYAGGX2X3TGYX4Y (SEQ ID NO: 535); wherein the amino acid residue X1 is selected from S, P or L; wherein the amino acid residue X2 is selected from N, R or S; wherein the amino acid residue X3 is selected from P or S; and wherein the amino acid residue X4 is selected from P, D or A; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence SX1DYAGGX2X3TGYX4Y (SEQ ID NO: 535); wherein the amino acid residue X1 is selected from S, P or L; wherein the amino acid residue X2 is selected from N, R or S; wherein the amino acid residue X3 is selected from P or S; and wherein the amino acid residue X4 is selected from P, D or A; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence SX1DYAGGX2X3TGYX4Y (SEQ ID NO: 535); wherein the amino acid residue X1 is selected from S, P or L; wherein the amino acid residue X2 is selected from N, R or S; wherein the amino acid residue X3 is selected from P or S; and wherein the amino acid residue X4 is selected from P, D or A. 5. The ISVD according to item 4, in which the amino acid sequences of the CDRs (Kabat numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149. 6. The ISVD according to any one of items 4 or 5, in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 21; ^ CDR2 (Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 22; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 11, or in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 21; ^ CDR2 (Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 43; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 11. or in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 243; ^ CDR2 (Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 244; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 236; or in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 243; ^ CDR2 (Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 245; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 246; or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 229; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 362; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 360, or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 243; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 362; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 361. 7. The ISVD according to any of one items 1 to 6, which amino acid sequence i) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded; and in which: ii) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1. 8. The ISVD according to any one of items 1 to 7, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consist of a heavy chain variable domain sequence that is derived from heavy chain antibody. 9. The ISVD according to any one of items 1 to 8, that essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb. 10. The ISVD according to any one of items 1 to 9, which is a humanized ISVD that is chosen from the group consisting of SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID Nos: 16, 39, 40, 120, 121, 122, 123, 135-149. 11. The ISVD according to any one of items 1 to 10, in which the amino acid sequence is chosen from the group consisting of SEQ ID NOs: 16, 39, 40, 120, 121, 122, 123, 135-149. 12. The ISVD according to any one of items 1 to 11, wherein the ISVD specifically binds to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 5x10-8 to 10-10 moles/litre or less and more preferably 1x10-8 to 1x10-9 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 1.06x10- 8moles/litre, 4.86x10-9 moles/litre, 8.9x10-9 moles/litre, 5.85x10-9 moles/litre, or 6.01x10- 9 moles/litre, as determined by Surface Plasmon Resonance. 13. The ISVD according to any one of items 1 to 12, wherein the ISVD specifically binds to human CEACAM5 with kon rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 104 M- 1s-1 and 106 M-1s-1, more preferably between 104 M-1s-1 and 5x105 M-1s-1, such as between 5x104 M-1s-1 and 5x105 M-1s-1, even more preferably of about 1.2x105 M-1s-1, 1.6x105 M-1s-1, 1.98x105 M-1s, 2.38x105 M-1s , 8.68x104 M-1s-1, or 8.07x104 M-1s-1, as determined by Surface Plasmon Resonance. 14. The ISVD according to any one of items 1 to 13, wherein the ISVD specifically binds to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 1x10-2 s-1 and 10-5 s-1, more preferably between 5x10-3 s-1 and 5x10-5 s-1, such as between 5x10-3 s-1 and 1x10-4 s-1, even more preferably of about 1.08x10-3 s-1, 1.7x10-3 s-1, 9.61x10-4 s-1,2.12x10-3 s-1, 5.08x10-4 s-1, or 4.85x10-4 s -1, as determined by Surface Plasmon Resonance. 15. The ISVD according to any one of items 1 to 14, wherein the ISVD specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, and CEACAM8 or other members of the CEACAMs family. 16. The ISVD according to any one of items 1 to 15, wherein the ISVD internalizes upon binding to CEACAM5. 17. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to any one of items 1 to 16, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers. 18. The polypeptide or construct according to item 17, in which said one or more other groups, residues, moieties or binding units are amino acid sequences. 19. The polypeptide or construct according to any one of items 17 to 18, in which said one or more linkers are one or more amino acid sequences. 20. The polypeptide or construct according to any one of items 17 to 19, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences. 21. The polypeptide or construct according to any one of items 17 to 20, in which said one or more other groups, residues, moieties or binding units are ISVDs. 22. The polypeptide or construct according to any one of items 17 to 21, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs. 23. The polypeptide or construct according to any one of items 17 to 22, which is a multivalent construct. 24. The polypeptide or construct according to any one of items 17 to 23, which is a multispecific construct. 25. The polypeptide or construct according to any one of items 17 to 24, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half-life, compared to the ISVD without the one or more other groups, residues, moieties or binding units. The polypeptide or construct according to item 25, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins. The polypeptide or construct according to item 26, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof. The polypeptide or construct according to item 27, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). The polypeptide or construct according to item 28, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). The polypeptide or construct according to item 29, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin. The polypeptide or construct according to item 30, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which: - CDR1 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 80; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 80; and c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 80; and - CDR2 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 81; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 81; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 81; and - CDR3 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 82; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 82; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 82. The polypeptide or construct according to item 31, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 80, CDR2 consists of the amino acid sequence of SEQ ID NO: 81, and CDR3 consists of the amino acid sequence of SEQ ID NO: 82. The polypeptide or construct according to item 32, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 47), ALB23 (SEQ ID NO: 48), ALBX00001 (SEQ ID NO: 61) and ALB23002 (SEQ ID NO: 62). The polypeptide or construct according to anyone of items 17 to 33, wherein said linker is chosen from the group consisting of SEQ ID NOs: 63 to 79. The polypeptide or construct according to any of items 17 to 34, further comprising a C- terminal extension. The polypeptide or construct according to item 35, wherein said C-terminal extension is a C- terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I). 37. A nucleic acid that encodes an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36. 38. The nucleic acid according to item 37, that is in the form of a genetic construct. 39. A non-human host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36; and/or that comprises the nucleic acid according to any one of items 37 or 38. 40. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, at least comprising the steps of: a) expressing, in a suitable host cell or non-human host organism or in another suitable expression system, a nucleic acid according to any one of items 37 or 38; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or the polypeptide according to any one of items 17 to 36. 41. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, said method at least comprising the steps of: a) cultivating and/or maintaining a non-human host or host cell according to item 39 under conditions that are such that said non-human host or host cell expresses and/or produces at least one ISVD according to any one of items 1 to 16, or at least one polypeptide according to any one of items 17 to 36; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or polypeptide according to any one of items 17 to 36. 42. A composition comprising at least one ISVD according to any one of items 1 to 16, at least one polypeptide or construct according to any one of items 17 to 36, or at least one nucleic acid according to any one of items 37 or 38. 43. The composition according to item 42, which is a pharmaceutical composition. 44. The composition according to any one of items 42 or 43, which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and/or compounds. 45. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use as a medicament. 46. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder. 47. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved. 48. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of cancer. 49. A method for the diagnosis, prevention and/or treatment of at least one disease and/or disorder, comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of an ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or a composition according to any one of items 42 to 44. The method according to item 49, for the diagnosis, prevention and/or treatment of at least one disease or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or composition according to any one of items 42 to 44. The method according to any one of items 49 or 50, for the diagnosis, prevention and/or treatment of cancer, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or a composition according to any one of items 42 to 44. Embodiment 14 -Family 9, 17, 18, 1 An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GX1X2X3X4X5YX6X7X8 (SEQ ID NO: 536); wherein the amino acid residue X1 is selected from R or D, the amino acid residue X2 is selected from N or T; wherein the amino acid residue X3 is selected from F or L; wherein the amino acid residue X4 is selected from N, E, G, P, S, or T; wherein the amino acid residue X5 is selected from S, D, or the stretch of the following amino acids: I, N and E; wherein the amino acid residue X6 is selected from D or H; wherein the amino acid residue X7 is selected from L or M; and wherein the amino acid residue X8 is selected from A or G; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GX1X2X3X4X5YX6X7X8 (SEQ ID NO: 536); wherein the amino acid residue X1 is selected from R or D, the amino acid residue X2 is selected from N or T; wherein the amino acid residue X3 is selected from F or L; wherein the amino acid residue X4 is selected from N, E, G, P, S, or T; wherein the amino acid residue X5 is selected from S, D, or the stretch of the following amino acids: I, N and E; wherein the amino acid residue X6 is selected from D or H; wherein the amino acid residue X7 is selected from L or M; and wherein the amino acid residue X8 is selected from A or G; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GX1X2X3X4X5YX6X7X8 (SEQ ID NO: 536); wherein the amino acid residue X1 is selected from R or D, the amino acid residue X2 is selected from N or T; wherein the amino acid residue X3 is selected from F or L; wherein the amino acid residue X4 is selected from N, E, G, P, S, or T; wherein the amino acid residue X5 is selected from S, D, or the stretch of the following amino acids: I, N and E; wherein the amino acid residue X6 is selected from D or H; wherein the amino acid residue X7 is selected from L or M; and wherein the amino acid residue X8 is selected from A or G; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence AIX1WSX2GX3X4X5 (SEQ ID NO: 537); wherein the amino acid residue X1 is selected from R or W; the amino acid residue X2 is selected from A or T; wherein the amino acid residue X3 is selected from S or N; wherein the amino acid residue X4 is selected from K, R, A or T; and wherein the amino acid residue X5 is selected from I or V; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence AIX1WSX2GX3X4X5 (SEQ ID NO: 537); wherein the amino acid residue X1 is selected from R or W; the amino acid residue X2 is selected from A or T; wherein the amino acid residue X3 is selected from S or N; wherein the amino acid residue X4 is selected from K, R, A or T; and wherein the amino acid residue X5 is selected from I or V; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence AIX1WSX2GX3X4X5 (SEQ ID NO: 537); wherein the amino acid residue X1 is selected from R or W; the amino acid residue X2 is selected from A or T; wherein the amino acid residue X3 is selected from S or N; wherein the amino acid residue X4 is selected from K, R, A or T; and wherein the amino acid residue X5 is selected from I or V; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence VRX1X2FRPLSTYWKDYDX3 (SEQ ID NO: 538); wherein the amino acid residue X1 is selected from F or P; wherein the amino acid residue X2 is selected from Q or S; and wherein the amino acid residue X3 is selected from I or N; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence VRX1X2FRPLSTYWKDYDX3 (SEQ ID NO: 538); wherein the amino acid residue X1 is selected from F or P; wherein the amino acid residue X2 is selected from Q or S; and wherein the amino acid residue X3 is selected from I or N; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence VRX1X2FRPLSTYWKDYDX3 (SEQ ID NO: 538); wherein the amino acid residue X1 is selected from F or P; wherein the amino acid residue X2 is selected from Q or S; and wherein the amino acid residue X3 is selected from I or N. 2. The ISVD according to item 1, in which the amino acid sequences of the CDRs (AbM numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 114, 124-127, 175-208. 3. The ISVD according to any one of items 1 or 2, in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 255; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 256; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 257; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 284; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 256; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 257; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 285; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 256; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 257; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 286; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 256; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 257; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 287; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 256; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 257; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 288; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 256; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 257; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 363; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 364; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 365; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 368; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 369; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 370; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 376; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 377; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 365; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 378; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 379; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 380. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of X1YX2X3X4 (SEQ ID NO: 539); wherein the amino acid residue X1 is selected from D, S or the stretch of the following amino acids: I, N and E; wherein the amino acid residue X2 is selected from H or D; wherein the amino acid residue X3 is selected from L or M; and wherein the amino acid residue X4 is selected from A or G; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of X1YX2X3X4 (SEQ ID NO: 539); wherein the amino acid residue X1 is selected from D, S or the stretch of the following amino acids: I, N and E; wherein the amino acid residue X2 is selected from H or D; wherein the amino acid residue X3 is selected from L or M; and wherein the amino acid residue X4 is selected from A or G; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of X1YX2X3X4 (SEQ ID NO: 539); wherein the amino acid residue X1 is selected from D, S or the stretch of the following amino acids: I, N and E; wherein the amino acid residue X2 is selected from H or D; wherein the amino acid residue X3 is selected from L or M; and wherein the amino acid residue X4 is selected from A or G; and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of AIX1WSX2GX3X4X5X6X7X8SVKG (SEQ ID NO: 540); wherein the amino acid residue X1 is selected from R or W; wherein the amino acid residue X2 is selected from A or T; wherein the amino acid residue X3 is selected from S or N; wherein the amino acid residue X4 is selected from T, K, R, and A; wherein the amino acid residue X5 is selected from V and I; wherein the amino acid residue X6 is selected from Y and V; wherein the amino acid residue X7 is selected from G or A; and wherein the amino acid residue X8 is selected from N or D; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of AIX1WSX2GX3X4X5X6X7X8SVKG (SEQ ID NO: 540wherein the amino acid residue X1 is selected from R or W; wherein the amino acid residue X2 is selected from A or T; wherein the amino acid residue X3 is selected from S or N; wherein the amino acid residue X4 is selected from T, K, R, and A; wherein the amino acid residue X5 is selected from V and I; wherein the amino acid residue X6 is selected from Y and V; wherein the amino acid residue X7 is selected from G or A; and wherein the amino acid residue X8 is selected from N or D; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of AIX1WSX2GX3X4X5X6X7X8SVKG (SEQ ID NO: 540); wherein the amino acid residue X1 is selected from R or W; wherein the amino acid residue X2 is selected from A or T; wherein the amino acid residue X3 is selected from S or N; wherein the amino acid residue X4 is selected from T, K, R, and A; wherein the amino acid residue X5 is selected from V and I; wherein the amino acid residue X6 is selected from Y and V; wherein the amino acid residue X7 is selected from G or A; and wherein the amino acid residue X8 is selected from N or D; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of VRX1X2FRPLSTYWKDYDX3 (SEQ ID NO: 538); wherein the amino acid residue X1 is selected from P or F; wherein the amino acid residue X2 is selected from S or Q; and wherein the amino acid residue X3 is selected from I or N N; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of VRX1X2FRPLSTYWKDYDX3 (SEQ ID NO: 538); wherein the amino acid residue X1 is selected from P or F; wherein the amino acid residue X2 is selected from S or Q; and wherein the amino acid residue X3 is selected from I or N; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of VRX1X2FRPLSTYWKDYDX3 (SEQ ID NO: 538); wherein the amino acid residue X1 is selected from P or F; wherein the amino acid residue X2 is selected from S or Q; and wherein the amino acid residue X3 is selected from I or N. 5. The ISVD according to item 4, in which the amino acid sequences of the CDRs (Kabat numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 114, 124-127, 175-208. 6. The ISVD according to any one of items 4 or 5, in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 289; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 291; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 257; or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 289; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 292; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 257; or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 289; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 293; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 257; or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 289; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 294; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 257; or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 366; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 367; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 365; or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 371; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 372; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 370; or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 381; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 384; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 365; or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 381; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 385; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 380. 7. The ISVD according to any of one items 1 to 6, which amino acid sequence i) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NOs: 114, 124-127, 175-208, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded; and in which: ii) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1. 8. The ISVD according to any one of items 1 to 7, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consist of a heavy chain variable domain sequence that is derived from heavy chain antibody. 9. The ISVD according to any one of items 1 to 8, that essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb. 10. The ISVD according to any one of items 1 to 9, which is a humanized ISVD that is chosen from the group consisting of SEQ ID NOs: 114, 124-127, 175-208 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID NOs: 114, 124-127, 175-208. 11. The ISVD according to any one of items 1 to 10, in which the amino acid sequence is chosen from the group consisting of SEQ ID NOs: 114, 124-127, 175-208. 12. The ISVD according to any one of items 1 to 11, wherein the ISVD specifically binds to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-7 to 10-9 moles/litre or less and more preferably 5x10-8 to 5x10-9 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 1.87x10- 8 moles/litre, 2.49x10-8 moles/litre, 2.39x10-8 moles/litre, 4.11x10-8 moles/litre, or 2.67x10- 8moles/litre, as determined by Surface Plasmon Resonance. 13. The ISVD according to any one of items 1 to 12, wherein the ISVD specifically binds to human CEACAM5 with a kon rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M- 1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, such as between 1x105 M-1s-1 and 8x105 M-1s-1, even more preferably of about 3.96x105 M-1s-1, 2.01x105 M-1s-1, 2.19x105 M-1s-1, 1.93x105 M-1s-1, or 2.18x105 M-1s-1, as determined by Surface Plasmon Resonance. 14. The ISVD according to any one of items 1 to 13, wherein the ISVD specifically binds to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-2 s-1 and 1x10-5 s-1, more preferably between 1x10-2 s-1 and 1x10-3 s-1, such as between 1x10-2 s-1 and 5x10-3 s-1 even more preferably of about 7.41x10-3 s-1, 5.01x10-3 s-1, 5.22x10-3 s-1, 7.94x10-3 s-1, or 5.81x10-3 s-1, as determined by Surface Plasmon Resonance. 15. The ISVD according to any one of items 1 to 14, wherein the ISVD specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8, or other members of the CEACAMs family. 16. The ISVD according to any one of items 1 to 15, wherein the ISVD internalizes upon binding to CEACAM5. 17. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to any one of items 1 to 16, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers. 18. The polypeptide or construct according to item 17, in which said one or more other groups, residues, moieties or binding units are amino acid sequences. 19. The polypeptide or construct according to any one of items 17 to 18, in which said one or more linkers are one or more amino acid sequences. 20. The polypeptide or construct according to any one of items 17 to 19, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences. 21. The polypeptide or construct according to any one of items 17 to 20, in which said one or more other groups, residues, moieties or binding units are ISVDs. 22. The polypeptide or construct according to any one of items 17 to 21, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs. 23. The polypeptide or construct according to any one of items 17 to 22, which is a multivalent construct. 24. The polypeptide or construct according to any one of items 17 to 23, which is a multispecific construct. The polypeptide or construct according to any one of items 17 to 24, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half-life, compared to the ISVD without the one or more other groups, residues, moieties or binding units. The polypeptide or construct according to item 25, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins. The polypeptide or construct according to item 26, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof. The polypeptide or construct according to item 27, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). The polypeptide or construct according to item 28, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). The polypeptide or construct according to item 29, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin. 31. The polypeptide or construct according to item 30, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which: - CDR1 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 80; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 80; and c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 80; and - CDR2 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 81; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 81; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 81; and - CDR3 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 82; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 82; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 82. 32. The polypeptide or construct according to item 31, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 80, CDR2 consists of the amino acid sequence of SEQ ID NO: 81, and CDR3 consists of the amino acid sequence of SEQ ID NO: 82. 33. The polypeptide or construct according to item 32, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 47), ALB23 (SEQ ID NO: 48), ALBX00001 (SEQ ID NO: 61) and ALB23002 (SEQ ID NO: 62). The polypeptide or construct according to anyone of items 17 to 33, wherein said linker is chosen from the group consisting of SEQ ID NOs: 63 to 79. The polypeptide or construct according to any of items 17 to 34, further comprising a C- terminal extension. The polypeptide or construct according to item 35, wherein said C-terminal extension is a C- terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I). A nucleic acid that encodes an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36. The nucleic acid according to item 37, that is in the form of a genetic construct. A non-human host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36; and/or that comprises the nucleic acid according to any one of items 37 or 38. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, at least comprising the steps of: a) expressing, in a suitable host cell or non-human host organism or in another suitable expression system, a nucleic acid according to any one of items 37 or 38; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or the polypeptide according to any one of items 17 to 36. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, said method at least comprising the steps of: a) cultivating and/or maintaining a non-human host or host cell according to item 39 under conditions that are such that said non-human host or host cell expresses and/or produces at least one ISVD according to any one of items 1 to 16, or at least one polypeptide according to any one of items 17 to 36; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or polypeptide according to any one of items 17 to 36. 42. A composition comprising at least one ISVD according to any one of items 1 to 16, at least one polypeptide or construct according to any one of items 17 to 36, or at least one nucleic acid according to any one of items 37 or 38. 43. The composition according to item 42, which is a pharmaceutical composition. 44. The composition according to any one of items 42 or 43, which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and/or compounds. 45. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use as a medicament. 46. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder. 47. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved. 48. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of cancer. 49. A method for the diagnosis, prevention and/or treatment of at least one disease and/or disorder, comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of an ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or a composition according to any one of items 42 to 44. 50. The method according to item 49, for the diagnosis, prevention and/or treatment of at least one disease or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or composition according to any one of items 42 to 44. 7.15 Embodiment 15 -Family 3, 30, 27 1. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of GX1TX2STYTX3G (SEQ ID NO: 541); wherein the amino acid residue X1 is selected from G or L; wherein the amino acid residue X2 is selected from V or F; and wherein the amino acid residue X3 is selected from V or M; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GX1TX2STYTX3G (SEQ ID NO: 541); wherein the amino acid residue X1 is selected from G or L; wherein the amino acid residue X2 is selected from V or F; and wherein the amino acid residue X3 is selected from V or M; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GX1TX2STYTX3G (SEQ ID NO: 541); wherein the amino acid residue X1 is selected from G or L; wherein the amino acid residue X2 is selected from V or F; and wherein the amino acid residue X3 is selected from V or M; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of X1X2IX3SGSX4TX5 (SEQ ID NO: 542); wherein the amino acid residue X1 is selected from S or A; wherein the amino acid residue X2 is selected from I or M; wherein the amino acid residue X3 is selected from W or Y; wherein the amino acid residue X4 is selected from N or T; and wherein the amino acid residue X5 is selected from V, Y or L; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence X1X2IX3SGSX4TX5 (SEQ ID NO: 542); wherein the amino acid residue X1 is selected from S or A; wherein the amino acid residue X2 is selected from I or M; wherein the amino acid residue X3 is selected from W or Y; wherein the amino acid residue X4 is selected from N or T; and wherein the amino acid residue X5 is selected from V, Y or L; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence X1X2IX3SGSX4TX5 (SEQ ID NO: 542); wherein the amino acid residue X1 is selected from S or A; wherein the amino acid residue X2 is selected from I or M; wherein the amino acid residue X3 is selected from W or Y; wherein the amino acid residue X4 is selected from N or T; and wherein the amino acid residue X5 is selected from V, Y or L; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence QHFGPX1X2X3TTX4GYX5Y (SEQ ID NO: 543); wherein the amino acid residue X1 is selected from V or I, the amino acid residue X2 is selected from S or G, wherein the amino acid residue X3 is selected from L or Q, the amino acid residue X4 is selected from R or K, and wherein the amino acid residue X5 is selected from N, A, F, G, I, L, Y or H; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence QHFGPX1X2X3TTX4GYX5Y (SEQ ID NO: 543); wherein the amino acid residue X1 is selected from V or I, the amino acid residue X2 is selected from S or G, wherein the amino acid residue X3 is selected from L or Q, the amino acid residue X4 is selected from R or K, and wherein the amino acid residue X5 is selected from N, A, F, G, I, L, Y or H; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of QHFGPX1X2X3TTX4GYX5Y (SEQ ID NO: 543); wherein the amino acid residue X1 is selected from V or I, the amino acid residue X2 is selected from S or G, wherein the amino acid residue X3 is selected from L or Q, the amino acid residue X4 is selected from R or K, and wherein the amino acid residue X5 is selected from N, A, F, G, I, L, Y or H. The ISVD according to item 1, in which the amino acid sequences of the CDRs (AbM numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 8, 31, 32, 118-119, 130, 150-159, 171-174. The ISVD according to any one of items 1 or 2, in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 336; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 339, or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 334; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 337; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 340; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 3; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 33; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYAY (SEQ ID NO: 249); or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYFY (SEQ ID NO: 250); or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYGY (SEQ ID NO: 251), or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYIY (SEQ ID NO: 254); or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYLY (SEQ ID NO: 252); or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO:1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYYY (SEQ ID NO: 253); Or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 397; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 398; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 399. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence TYTXG (SEQ ID NO: 341); wherein the amino acid residue X is selected from M or V; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence TYTXG (SEQ ID NO: 341); wherein the amino acid residue X is selected from M or V; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences TYTXG (SEQ ID NO: 341); wherein the amino acid residue X is selected from M or V; and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence the amino acid sequence of X1X2IX3SGSX4TX5YADSVKG (SEQ ID NO: 544); wherein the amino acid residue X1 is selected from S or A; wherein the amino acid residue X2 is selected from I or M; wherein the amino acid residue X3 is selected from W or Y; wherein the amino acid residue X4 is selected from N or T; and wherein the amino acid residue X5 is selected from V, Y or L; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence the amino acid sequence X1X2IX3SGSX4TX5YADSVKG (SEQ ID NO: 544); wherein the amino acid residue X1 is selected from S or A; wherein the amino acid residue X2 is selected from I or M; wherein the amino acid residue X3 is selected from W or Y; wherein the amino acid residue X4 is selected from N or T; and wherein the amino acid residue X5 is selected from V, Y or L; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence the amino acid sequence X1X2IX3SGSX4TX5YADSVKG (SEQ ID NO: 544); wherein the amino acid residue X1 is selected from S or A; wherein the amino acid residue X2 is selected from I or M; wherein the amino acid residue X3 is selected from W or Y; wherein the amino acid residue X4 is selected from N or T; and wherein the amino acid residue X5 is selected from V, Y or L; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence QHFGPX1X2X3TTX4GYX5Y (SEQ ID NO: 543); wherein the amino acid residue X1 is selected from V or I; the amino acid residue X2 is selected from S or G; wherein the amino acid residue X3 is selected from L or Q; the amino acid residue X4 is selected from R or K; and wherein the amino acid residue X5 is selected from N, A, F, G, I, L, Y or H b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence QHFGPX1X2X3TTX4GYX5Y (SEQ ID NO: 543); wherein the amino acid residue X1 is selected from V or I; the amino acid residue X2 is selected from S or G; wherein the amino acid residue X3 is selected from L or Q; the amino acid residue X4 is selected from R or K; and wherein the amino acid residue X5 is selected from N, A, F, G, I, L, Y or H; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of QHFGPX1X2X3TTX4GYX5Y (SEQ ID NO: 543); wherein the amino acid residue X1 is selected from V or I; the amino acid residue X2 is selected from S or G; wherein the amino acid residue X3 is selected from L or Q; the amino acid residue X4 is selected from R or K; and wherein the amino acid residue X5 is selected from N, A, F, G, I, L, Y or H. 5. The ISVD according to item 4, in which the amino acid sequences of the CDRs (Kabat numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 8, 31, 32, 118-119, 130, 150-159, 171-174. 6. The ISVD according to any one of items 4 or 5, in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 17; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 334; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 339, or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 342; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 345; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 340; or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 17; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 18; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 3; or in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 17; ^ CDR2 (Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 18; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 33; or in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO:17; ^ CDR2 (Kabat numbering) consists of the amino acid sequences of SEQ ID NO: 18; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of QHFGPIGLTTRGYAY (SEQ ID NO: 249); or in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO:17; ^ CDR2 (Kabat numbering) consists of the amino acid sequences of SEQ ID NO: 18; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of QHFGPIGLTTRGYFY (SEQ ID NO: 250); or in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO:17; ^ CDR2 (Kabat numbering) consists of the amino acid sequences of SEQ ID NO: 18; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of QHFGPIGLTTRGYGY (SEQ ID NO: 251); or in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO:17; ^ CDR2 (Kabat numbering) consists of the amino acid sequences of SEQ ID NO: 18; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of QHFGPIGLTTRGYIY (SEQ ID NO: 254); or in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO:17; ^ CDR2 (Kabat numbering) consists of the amino acid sequences of SEQ ID NO: 18; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of QHFGPIGLTTRGYLY (SEQ ID NO: 252); or in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO:17; ^ CDR2 (Kabat numbering) consists of the amino acid sequences of SEQ ID NO: 18; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of QHFGPIGLTTRGYYY (SEQ ID NO: 253); or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 17; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 400; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 399. The ISVD according to any of one items 1 to 6, which amino acid sequence iii) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NOs: 8, 31, 32, 118-119, 130, 150-159, 171-174, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded; and in which: iv) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1. The ISVD according to any one of items 1 to 7, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consist of a heavy chain variable domain sequence that is derived from heavy chain antibody. The ISVD according to any one of items 1 to 8, that essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb. 10. The ISVD according to any one of items 1 to 9, which is a humanized ISVD that is chosen from the group consisting of SEQ ID Nos: 150-159, 171-174 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID NOs: 8, 31, 32, 118-119, 130, 150-159, 171-174. 11. The ISVD according to any one of items 1 to 10, in which the amino acid sequence is chosen from the group consisting of SEQ ID NOs: 8, 31, 32, 118-119, 130, 150-159, 171-174. 12. The ISVD according to any one of items 1 to 11, wherein the ISVD specifically binds to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-8 to 10-11 moles/litre or less and more preferably 10-8 to 10-10 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 8.83x10- 9 moles/litre, or 1.44x10-10 moles/litre, 7.90x10-10 moles/litre, 1.34x10-9 moles/litre or 1.24x10- 9 moles/litre, as determined by Surface Plasmon Resonance. 13. The ISVD according to any one of items 1 to 12, wherein the ISVD specifically binds to human CEACAM5 with a kon rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M- 1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 5x106 M-1s-1, even more preferably of about 4.70x105 M-1s-1, or 1.91x106 M-1s-1, 1.19x106 M-1s-1, 3.17x105 M-1s-1 or 7.16x105 M-1s-1, as determined by Surface Plasmon Resonance. 14. The ISVD according to any one of items 1 to 13, wherein the ISVD specifically binds to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 10-2 s-1 and 1x10-5 s-1, more preferably between 1x10-2 s-1 and 10-4 s-1, such as between 5x10-3 s-1 and 10-4 s-1 even more preferably of about 4.15x10-3 s-1, or 2.74x10-4 s-1, 9.40x10-4 s-1, 4.24x10-3 s-1or 8.85x10-4 s-1, as determined by Surface Plasmon Resonance. 15. The ISVD according to any one of items 1 to 14, wherein the ISVD specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, and CEACAM7. 16. The ISVD according to any one of items 1 to 15, wherein the ISVD internalizes upon binding to CEACAM5. 17. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to any one of items 1 to 16, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers. 18. The polypeptide or construct according to item 17, in which said one or more other groups, residues, moieties or binding units are amino acid sequences. 19. The polypeptide or construct according to any one of items 17 to 18, in which said one or more linkers are one or more amino acid sequences. 20. The polypeptide or construct according to any one of items 17 to 19, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences. 21. The polypeptide or construct according to any one of items 17 to 20, in which said one or more other groups, residues, moieties or binding units are ISVDs. 22. The polypeptide or construct according to any one of items 17 to 21, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs. 23. The polypeptide or construct according to any one of items 17 to 22, which is a multivalent construct. 24. The polypeptide or construct according to any one of items 17 to 23, which is a multispecific construct. 25. The polypeptide or construct according to any one of items 17 to 24, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half-life, compared to the ISVD without the one or more other groups, residues, moieties or binding units. 26. The polypeptide or construct according to item 25, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins. 27. The polypeptide or construct according to item 26, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof. 28. The polypeptide or construct according to item 27, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). 29. The polypeptide or construct according to item 28, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). 30. The polypeptide or construct according to item 29, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin. 31. The polypeptide or construct according to item 30, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which: - CDR1 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 80; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 80; and c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 80; and - CDR2 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 81; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 81; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 81; and - CDR3 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NOs: 82; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 82; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 82. 32. The polypeptide or construct according to item 31, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 80, CDR2 consists of the amino acid sequence of SEQ ID NO: 81, and CDR3 consists of the amino acid sequence of SEQ ID NO: 82. 33. The polypeptide or construct according to item 32, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 47), ALB23 (SEQ ID NO: 48), ALBX00001 (SEQ ID NO: 61) and ALB23002 (SEQ ID NO: 62). 34. The polypeptide or construct according to anyone of items 17 to 33, wherein said linker is chosen from the group consisting of SEQ ID NOs: 63 to 79. 35. The polypeptide or construct according to any of items 17 to 34, further comprising a C- terminal extension. 36. The polypeptide or construct according to item 35, wherein said C-terminal extension is a C- terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I). 37. A nucleic acid that encodes an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36. 38. The nucleic acid according to item 37, that is in the form of a genetic construct. 39. A non-human host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36; and/or that comprises the nucleic acid according to any one of items 37 or 38. 40. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, at least comprising the steps of: a) expressing, in a suitable host cell or non-human host organism or in another suitable expression system, a nucleic acid according to any one of items 37 or 38; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or the polypeptide according to any one of items 17 to 36. 41. A method for producing an ISVD according to any one of items 1 to 16, or a polypeptide according to any one of items 17 to 36, said method at least comprising the steps of: a) cultivating and/or maintaining a non-human host or host cell according to item 39 under conditions that are such that said non-human host or host cell expresses and/or produces at least one ISVD according to any one of items 1 to 16, or at least one polypeptide according to any one of items 17 to 36; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 16, or polypeptide according to any one of items 17 to 36. A composition comprising at least one ISVD according to any one of items 1 to 16, at least one polypeptide or construct according to any one of items 17 to 36, or at least one nucleic acid according to any one of items 37 or 38. The composition according to item 42, which is a pharmaceutical composition. The composition according to any one of items 42 or 43, which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and/or compounds. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use as a medicament. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved. The ISVD according to any one of items 1 to 16, the polypeptide or construct according to any one of items 17 to 36, or the composition according to any one of items 42 to 44, for use in the diagnosis, prevention and/or treatment of cancer. A method for the diagnosis, prevention and/or treatment of at least one disease and/or disorder, comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of an ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or a composition according to any one of items 42 to 44. The method according to item 49, for the diagnosis, prevention and/or treatment of at least one disease or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or composition according to any one of items 42 to 44. The method according to any one of items 49 or 50, for the diagnosis, prevention and/or treatment of cancer, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 16, a polypeptide or construct according to any one of items 17 to 36, or a composition according to any one of items 42 to 44. Embodiment 16-Family 13 An immunoglobulin single variable domain (ISVD) specifically binding to human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), that interacts with one or more amino acids of the CEACAM5 protein selected from K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, L343, E346, D405, P406, V407, I408, L409, N410, L412, N442, P444, A483. The immunoglobulin single variable domain (ISVD) of item 1, that interacts with following amino acids of the CEACAM5 protein: K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, L343, E346, D405, P406, V407, I408, L409, N410, L412, N442, P444, and A483. The immunoglobulin single variable domain (ISVD) of item 1 or 2, in which CDR2 and CDR3 interact with one or more amino acids of the CEACAM5 protein selected from K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, L343, E346, D405, P406, V407, I408, L409, N410, L412, N442, P444, and A483. The immunoglobulin single variable domain (ISVD) of any of items 1 to 3, in which CDR2 and CDR3 interact with following amino acids of the CEACAM5 protein: K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, L343, E346, D405, P406, V407, I408, L409, N410, L412, N442, P444, and A483. 5. The immunoglobulin single variable domain (ISVD) of any of items 1 to 4, in which T52, W52a, R53, G55, S56, T57, and H58 (Kabat numbering) in CDR2 form the interaction site with the amino acids of the CEACAM5 protein. 6. The immunoglobulin single variable domain (ISVD) of any of items 1 to 5, in which D95, L96, R97, F99, G100, P100a, I100b, T100c, T100d, T100e, Q100f, I100g, and N101 (Kabat numbering) in CDR3 form the interaction site with the amino acids of the CEACAM5 protein. 7. The immunoglobulin single variable domain (ISVD) of any of items 1 to 6, in which T52, W52a, R53, G55, S56, T57, and H58 (Kabat numbering) in CDR2 and D95, L96, R97, F99, G100, P100a, I100b, T100c, T100d, T100e, Q100f, I100g, and N101 (Kabat numbering) in CDR3 form the interaction site with the epitope on the CEACAM5 protein. 8. The immunoglobulin single variable domain (ISVD) of any of items 1 to 7, in which T52, W52a, R53, G55, S56, T57, and H58 (Kabat numbering) in CDR2 and D95, L96, R97, F99, G100, P100a, I100b, T100c, T100d, T100e, Q100f, I100g, and N101 (Kabat numbering) in CDR3 form the interaction site with one or more amino acids of the CEACAM5 protein selected from K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, L343, E346, D405, P406, V407, I408, L409, N410, L412, N442, P444, and A483. 9. The immunoglobulin single variable domain (ISVD) of any of items 1 to 8, in which T52, W52a, R53, G55, S56, T57, and H58 (Kabat numbering) in CDR2 and D95, L96, R97, F99, G100, P100a, I100b, T100c, T100d, T100e, Q100f, I100g, and N101 (Kabat numbering) in CDR3 form the interaction site with following amino acids of the CEACAM5 protein: K324, P325, F326, I327, T328, S329, N330, N331, S332, N333, L343, E346, D405, P406, V407, I408, L409, N410, L412, N442, P444, and A483. 10. The immunoglobulin single variable domain (ISVD) according to any of items 1 to 9, wherein - CDR2 (AbM numbering) consists of an amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; and - CDR3 (AbM numbering) consists of an amino acid sequence X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E, preferably wherein the amino acid residue X1 is D, wherein the amino acid residue X2 is R, wherein the amino acid residue X3 is F, wherein the amino acid residue X4 is T, wherein the amino acid residue X5 is T, and wherein the amino acid residue X6 is N. 11. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 579 or 580; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 579 or 580; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 579 or 580; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NOs: 582-589; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 582-589; c) amino acid sequences that have 4, 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 582-589. 12. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; b) amino acid sequences that have at least 80% amino acid identity with the acid sequence of GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the acid sequence of GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E. 13. The immunoglobulin single variable domain (ISVD) according to any one of items 10 to 12, in which CDR1 (AbM Numbering): a) has a length of 10 amino acids; b) has an aliphatic index of 49.00 or 10.00, preferably of 10.00; c) has a grand average of hydropathicity (GRAVY) of -0.970, -0.270, -1.000 preferably -0.970; d) comprises one positively charged and at least one negatively charged residue; e) comprises 30% or 40% hydrophobic, 10% or 20% acid, 20% or 10% basic and 40% neutral amino acids, such as comprises 30% hydrophobic, 10% acid, 20% basic and 40% neutral amino acids; or comprises 40% hydrophobic, 10% acid, 10% basic and 40% neutral amino acids; or comprises 30% hydrophobic, 20% acid, 21% basic and 40% neutral amino acids; f) consists of a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, a hydrophobic amino acid, an acidic amino acid, a polar neutral amino acid, and a basic, polar neutral or acidic amino acid, two hydrophobic amino acids and a polar neutral amino acid, preferably in that order; such as consists of a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, a hydrophobic amino acid, an acidic amino acid, a polar neutral amino acid, a basic amino acid, two hydrophobic amino acids and a polar neutral amino acid, preferably in that order; or consists of a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, a hydrophobic amino acid, an acidic amino acid, a polar neutral amino acid, a polar neutral amino acid, two hydrophobic amino acids and a polar neutral amino acid, preferably in that order; or consists of a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, a hydrophobic amino acid, an acidic amino acid, a polar neutral amino acid, an acidic amino acid, two hydrophobic amino acids and a polar neutral amino acid, preferably in that order; and/or g) comprises at least one, preferably all of the amino acids G, R, T, F, D, N, A, M, and/or optionally one amino acid selected from H, L, or E. The ISVD according to any one of items 10 to 13, in which the amino acid sequences of the CDR2 and CDR3 (AbM numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR2 and CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 548, 564-576. The ISVD according to any one of items 10 to 14, in which ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 582, or in which ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 583, or in which ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 584, or in which ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 585, or in which ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 586, or in which ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 587, or in which ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 588, or in which ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 589, or in which ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 580; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 582. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (AbM numbering) consists of an amino acid sequence selected from a) the amino acid sequence GRTFDNX1AMG (SEQ ID NO: 593); wherein the amino acid residue X1 is selected from H, L or E; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GRTFDNX1AMG (SEQ ID NO: 593); wherein the amino acid residue X1 is selected from H, L or E; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GRTFDNX1AMG (SEQ ID NO: 593); wherein the amino acid residue X1 is selected from H, L or E; and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GGITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GITX1RGGSTH (SEQ ID NO: 578), wherein the amino acid residue X1 is selected from W and N; and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E. 17. The ISVD according to item 16, in which the amino acid sequences of the CDRs (AbM numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 548, 564-576. 18. The ISVD according to any one of items 16 or 17, in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 594; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 582; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 594; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 583; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 594; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 584; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 594; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 585; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 594; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 586; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 594; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 587; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 594; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 587; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 594; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 588; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 594; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 589; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 594; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 580; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 582; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 595; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 582; or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 596; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 579; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 582. 19. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence NX1AMG (SEQ ID NO: 597); wherein the amino acid residue X1 is selected from H, L or E; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence NX1AMG (SEQ ID NO: 597); wherein the amino acid residue X1 is selected from H, L or E; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence NX1AMG (SEQ ID NO: 597); wherein the amino acid residue X1 is selected from H, L or E; and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GITX1RGGSTHYADSVKG (SEQ ID NO: 590), wherein the amino acid residue X1 is selected from W and N; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GITX1RGGSTHYADSVKG (SEQ ID NO: 590), wherein the amino acid residue X1 is selected from W and N; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GITX1RGGSTHYADSVKG (SEQ ID NO: 590), wherein the amino acid residue X1 is selected from W and N; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence X1LX2PFX3PITX4X5PQRIX6Y (SEQ ID NO: 581), wherein the amino acid residue X1 is selected from D and V, wherein the amino acid residue X2 is selected from R and V, wherein the amino acid residue X3 is selected from G, A, and F, wherein the amino acid residue X4 is selected from Q and T, wherein the amino acid residue X5 is selected from T and E, and wherein the amino acid residue X6 is selected from N and E. 20. The ISVD according to item 19, in which the amino acid sequences of the CDRs (Kabat numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 548, 564-576. 21. The ISVD according to any one of items 19 or 20, in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 598; ^ CDR2 (Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 591; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 582; or in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 598; ^ CDR2 (Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 591; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 583; or in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 598; ^ CDR2 (Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 591; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 584; or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 598; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 591; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 585; or in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 598; ^ CDR2 (Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 591; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 586; or in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 598; ^ CDR2 (Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 591; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 587; or in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 598; ^ CDR2 (Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 591; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 588; or in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 598; ^ CDR2 (Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 591; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 589; or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 598; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 592; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 582; or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 599; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 591; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 582; or in which ^ CDR1 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 600; ^ CDR2 (Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 591; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 582. The ISVD according to any of one items 1 to 21, which amino acid sequence i) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NOs: 548, 564-576, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded; and in which: ii) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1. The ISVD according to any one of items 1 to 22, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consist of a heavy chain variable domain sequence that is derived from heavy chain antibody. The ISVD according to any one of items 1 to 23, that essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb. 25. The ISVD according to any one of items 1 to 24, which is a humanized ISVD that is chosen from the group consisting of SEQ ID NOs: 564-576 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID Nos: 548, 564-576. 26. The ISVD according to any one of items 1 to 25, in which the amino acid sequence is chosen from the group consisting of SEQ ID NOs: 548, 564-576. 27. The ISVD according to any one of items 1 to 26, wherein the ISVD specifically binds to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 1x10-7 to 10-10 moles/litre or less such as more preferably 1x10-8 to 1x10-10 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 1.20x10-9 moles/litre, 2.82x10-9 moles/litre, 6.51x10-9 moles/litre, 1.27x10-8 moles/litre, 2.44x10-8 moles/litre, 3.07 x10-8 moles/litre, 3.17 x10-8 moles/litre, 7.62 x10-8 moles/litre, 9.28 x10-8 moles/litre, 1.59 x10-7 moles/litre, or 1.97 x10-7 moles/litre, as determined by SPR. 28. The ISVD according to any one of items 1 to 27, wherein the ISVD specifically binds to human CEACAM5 with kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 104 M- 1s-1 and 106 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, such as between 1x105 M-1s-1 and 5x105 M-1s-1, even more preferably of about 4.3x105 M-1s-1, as determined by SPR. 29. The ISVD according to any one of items 1 to 28, wherein the ISVD specifically binds to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 1x10-2 s-1 and 5x10-5 s-1, such as between 5x10-3 s-1 and 10-4 s-1, even more preferably of about 6.4x10-4 s-1, 4.30x10-4 s-1, 4.92x10-4 s-1, 4.71x10-4 s-1, 5.00x10-4 s-1, 5.80 x10-4 s-1, 1.87 x10-3 s-1,1.41 x10-3 s-1, 5.87 x10-3 s-1, 1.21 x10-3 s-1, 7.41 x10-3 s-1, 6.19 x10-3 s-1, 1.41 x10-2 s-1, 1.28 x10-2 s-1, or 3.42 x10-2 s-1, as determined by SPR. 30. The ISVD according to any one of items 1 to 29, wherein the ISVD specifically binds to human and cyno CEACAM5 and does not bind to other members of the CEACAMs family. 31. The ISVD according to any one of items 1 to 30, wherein the ISVD internalizes upon binding to CEACAM5. 32. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to any one of items 1 to 31, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers. 33. The polypeptide or construct according to item 32, in which said one or more other groups, residues, moieties or binding units are amino acid sequences. 34. The polypeptide or construct according to any one of items 32 to 33, in which said one or more linkers are one or more amino acid sequences. 35. The polypeptide or construct according to any one of items 32 to 34, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences. 36. The polypeptide or construct according to any one of items 32 to 35, in which said one or more other groups, residues, moieties or binding units are ISVDs. 37. The polypeptide or construct according to any one of items 32 to 36, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs. 38. The polypeptide or construct according to any one of items 32 to 37, which is a multivalent construct. 39. The polypeptide or construct according to any one of items 17 to 38, which is a multispecific construct. 40. The polypeptide or construct according to any one of items 32 to 39, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half-life, compared to the ISVD without the one or more other groups, residues, moieties or binding units. 41. The polypeptide or construct according to item 40, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins. 42. The polypeptide or construct according to item 41, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof. 43. The polypeptide or construct according to item 42, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). 44. The polypeptide or construct according to item 43, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). 45. The polypeptide or construct according to item 44, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin. 46. The polypeptide or construct according to item 45, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which: - CDR1 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 80; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 80; and c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 80; and - CDR2 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 81; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 81; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 81; and - CDR3 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 82; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 82; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 82. 47. The polypeptide or construct according to item 46, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 80, CDR2 consists of the amino acid sequence of SEQ ID NO: 81, and CDR3 consists of the amino acid sequence of SEQ ID NO: 82. 48. The polypeptide or construct according to item 47, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 47), ALB23 (SEQ ID NO: 48), ALBX00001 (SEQ ID NO: 61) and ALB23002 (SEQ ID NO: 62). 49. The polypeptide or construct according to anyone of items 32 to 48, wherein said linker is chosen from the group consisting of SEQ ID NOs: 63 to 79. 50. The polypeptide or construct according to any of items 32 to 49, further comprising a C- terminal extension. The polypeptide or construct according to item 50, wherein said C-terminal extension is a C- terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I). A nucleic acid that encodes an ISVD according to any one of items 1 to 31, or a polypeptide according to any one of items 32 to 51. The nucleic acid according to item 52, that is in the form of a genetic construct. A non-human host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD according to any one of items 1 to 31, or a polypeptide according to any one of items 32 to 51; and/or that comprises the nucleic acid according to any one of items 52 or 53. A method for producing an ISVD according to any one of items 1 to 31, or a polypeptide according to any one of items 32 to 51, at least comprising the steps of: a) expressing, in a suitable host cell or non-human host organism or in another suitable expression system, a nucleic acid according to any one of items 52 or 53; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 31, or the polypeptide according to any one of items 32 to 51. A method for producing an ISVD according to any one of items 1 to 31, or a polypeptide according to any one of items 32 to 51, said method at least comprising the steps of: a) cultivating and/or maintaining a non-human host or host cell according to item 39 under conditions that are such that said non-human host or host cell expresses and/or produces at least one ISVD according to any one of items 1 to 31, or at least one polypeptide according to any one of items 32 to 51; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 31, or polypeptide according to any one of items 32 to 51. 57. A composition comprising at least one ISVD according to any one of items 1 to 31, at least one polypeptide or construct according to any one of items 32 to 51, or at least one nucleic acid according to any one of items 52 or 53. 58. The composition according to item 57, which is a pharmaceutical composition. 59. The composition according to any one of items 57 or 58, which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and/or compounds. 60. The ISVD according to any one of items 1 to 31, the polypeptide or construct according to any one of items 32 to 51, or the composition according to any one of items 57 to 59, for use as a medicament. 61. The ISVD according to any one of items 1 to 31, the polypeptide or construct according to any one of items 32 to 51, or the composition according to any one of items 57 to 59, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder. 62. The ISVD according to any one of items 1 to 31, the polypeptide or construct according to any one of items 32 to 51, or the composition according to any one of items 57 to 59, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved. 63. The ISVD according to any one of items 1 to 31, the polypeptide or construct according to any one of items 32 to 51, or the composition according to any one of items 57 to 59, for use in the diagnosis, prevention and/or treatment of cancer. 64. A method for the diagnosis, prevention and/or treatment of at least one disease and/or disorder, comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of an ISVD according to any one of items 1 to 31, a polypeptide or construct according to any one of items 32 to 51, or a composition according to any one of items 57 to 59. 65. The method according to item 64, for the diagnosis, prevention and/or treatment of at least one disease or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 31, a polypeptide or construct according to any one of items 32 to 51, or composition according to any one of items 57 to 59. 66. The method according to any one of items 64 or 65, for the diagnosis, prevention and/or treatment of cancer, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 31, a polypeptide or construct according to any one of items 32 to 51, or a composition according to any one of items 57 to 59. 7.17 Embodiment 17 -Family 14 1. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 610; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 610; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 610. 2. The immunoglobulin single variable domain (ISVD) according to item 1, wherein - CDR3 (AbM numbering) consists of an amino acid sequence GDHRGPWYN (SEQ ID NO: 610). 3. The immunoglobulin single variable domain (ISVD) according to any one of items 1 to2, in which CDR1 (AbM Numbering): a) has a length of 10 amino acids; b) has an aliphatic index of 0.00; c) has a grand average of hydropathicity (GRAVY) of -0.080; d) comprises one negatively charged residue; e) comprises 30% hydrophobic, 10% acidic and 60% neutral amino acids; f) consists of a polar neutral amino acid, a hydrophobic amino acid, a polar neutral amino acid, a hydrophobic amino acid, three polar neutral amino acids, an acidic amino acid, a hydrophobic amino acid, and a polar neutral amino acid; and/or g) comprises at least one, preferably all of the amino acids G, F, T, S, Y, D, or M. 4. The immunoglobulin single variable domain (ISVD) according to any one of items 1 to 3, in which CDR2 (AbM Numbering): a) has a length of 10 amino acids; b) has an aliphatic index of 39.00; c) has a grand average of hydropathicity (GRAVY) of -0.810; d) comprises one positively charged residue; e) comprises 10% hydrophobic, 10% basic and 80% neutral amino acids; f) consists of a polar neutral amino acid, a hydrophobic amino acid, a polar neutral amino acid, a basic amino acid, a polar neutral amino acid, six polar neutral amino acid, preferably in that order; and/or g) comprises at least one, preferably all of the amino acids T, I, N, R, G, S or T. 5. The ISVD according to any one of items 1 to 4, in which the amino acid sequences of CDR3 (AbM numbering) has at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDR3 of the ISVD with the amino acid sequence selected from SEQ ID NOs: 547, 549-563. 6. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (AbM numbering) consists of an amino acid sequence selected from a) the amino acid sequence GFTFSSYDMS (SEQ ID NO: 611); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GFTFSSYDMS (SEQ ID NO: 611); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GFTFSSYDMS (SEQ ID NO: 611); and - CDR2 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence TINRGGSSTS (SEQ ID NO: 612); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GTINRGGSSTS (SEQ ID NO: 612); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence TINRGGSSTS (SEQ ID NO: 612); and - CDR3 (AbM numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GDHRGPWYN (SEQ ID NO: 610); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GDHRGPWYN (SEQ ID NO: 610); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GDHRGPWYN (SEQ ID NO: 610). 7. The ISVD according to item 6, in which the amino acid sequences of the CDRs (AbM numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 547, 549-563. 8. The ISVD according to any one of items 6 or 7, in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 611; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 612; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 610. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence SYDMS (SEQ ID NO: 613); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence SYDMS (SEQ ID NO: 613); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence SYDMS (SEQ ID NO: 613); and - CDR2 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence TINRGGSSTSYX1X2X3VX4G (SEQ ID NO: 622), wherein the amino acid residue X1 is selected from A and R, wherein the amino acid residue X2 is selected from D and V, wherein the amino acid residue X3 is selected from S and P, wherein the amino acid residue X4 is selected from E and K; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of TINRGGSSTSYX1X2X3VX4G (SEQ ID NO: 622), wherein the amino acid residue X1 is selected from A and R, wherein the amino acid residue X2 is selected from D and V, wherein the amino acid residue X3 is selected from S and P, wherein the amino acid residue X4 is selected from E and K; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of TINRGGSSTSYX1X2X3VX4G (SEQ ID NO: 622), wherein the amino acid residue X1 is selected from A and R, wherein the amino acid residue X2 is selected from D and V, wherein the amino acid residue X3 is selected from S and P, wherein the amino acid residue X4 is selected from E and K; and - CDR3 (Kabat numbering) consists of an amino acid sequence selected from: a) the amino acid sequence GDHRGPWYN (SEQ ID NO: 610); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GDHRGPWYN (SEQ ID NO: 610); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of GDHRGPWYN (SEQ ID NO: 610). The ISVD according to item 9, in which the amino acid sequences of the CDRs (Kabat numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 547, 549-563. The ISVD according to any one of items 19 or 20, in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 613; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 614; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 610; or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 613; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 615; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 610; or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 613; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 616; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 610; or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 613; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 617; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 610; or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 613; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 618; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 610; or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 613; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 620; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 610; or in which ^ CDR1(Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 598; ^ CDR2(Kabat numbering) consists of one of the amino acid sequences of SEQ ID NO: 621; and ^ CDR3 (Kabat numbering) consists of the amino acid sequence of SEQ ID NO: 588. 12. The ISVD according to any of one items 1 to 11, which amino acid sequence iii) has 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NOs: 547, 549-563, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded; and in which: iv) preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1. The ISVD according to any one of items 1 to 12, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consist of a heavy chain variable domain sequence that is derived from heavy chain antibody. The ISVD according to any one of items 1 to 13, that essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb. The ISVD according to any one of items 1 to 14, which is a humanized ISVD that is chosen from the group consisting of SEQ ID NOs: 547, 549-563 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID Nos: 547, 549-563. The ISVD according to any one of items 1 to 15, in which the amino acid sequence is chosen from the group consisting of SEQ ID NOs: 547, 549-563. The ISVD according to any one of items 1 to 16, wherein the ISVD specifically binds to human CEACAM5 with a dissociation constant (KD) of 10-7 to 10-12 moles/litre or less, and preferably 1x10-9 to 10-12 moles/litre or less and more preferably 1x10-10 to 1x10-11 moles/litre, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 9.45x10-11 moles/litre, as determined by SPR. The ISVD according to any one of items 1 to 17, wherein the ISVD specifically binds to human CEACAM5 with kon-rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 104 M- 1s-1 and 106 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, such as between 1x105 M-1s-1 and 5x105 M-1s-1, even more preferably of about 1.64x105 M-1s-1, as determined by SPR. 19. The ISVD according to any one of items 1 to 18, wherein the ISVD specifically binds to human CEACAM5 with a koff rate between 10-2 s-1 (t1/2=0.69 s) and 10-6 s-1 (providing a near irreversible complex with a t1/2 of multiple days), preferably between 1x10-2 s-1 and 5x10-5 s-1, more preferably between 5x10-3 s-1 and 1x10-5 s-1, such as between 2x10-2 s-1 and 5x10-5 s-1, even more preferably of about 1.55x10-5 s-1, 2.47 x10-4 s-1, 2.67 x10-4 s-1, 2.55 x10-4 s-1, 1.13 x10-3 s-1, 1.09 x10-3 s-1, 1.14 x10-3 s-1, 1.25 x10-3 s-1, 3.09 x10-4 s-1, 1.32 x10-3 s-1, 6.77 x10-4 s-1, 3.54 x10-4 s- 1, 2.79 x10-4 s-1, 2.78 x10-4 s-1, 2.37 x10-3 s-1, 4.92 x10-4 s-1, as determined by SPR. 20. The ISVD according to any one of items 1 to 19, wherein the ISVD specifically binds to human and cyno CEACAM5 and does not bind CEACAM1, CEACAM6, or to other members of the CEACAMs family. 21. The ISVD according to any one of items 1 to 20, wherein the ISVD internalizes upon binding to CEACAM5. 22. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to any one of items 1 to 21, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers. 23. The polypeptide or construct according to item 22, in which said one or more other groups, residues, moieties or binding units are amino acid sequences. 24. The polypeptide or construct according to any one of items 22 to 23, in which said one or more linkers are one or more amino acid sequences. 25. The polypeptide or construct according to any one of items 22 to 24, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences. 26. The polypeptide or construct according to any one of items 22 to 25, in which said one or more other groups, residues, moieties or binding units are ISVDs. 27. The polypeptide or construct according to any one of items 22 to 25, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs. The polypeptide or construct according to any one of items 22 to 27, which is a multivalent construct. The polypeptide or construct according to any one of items 22 to 28, which is a multispecific construct. The polypeptide or construct according to any one of items 22 to 28, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half-life, compared to the ISVD without the one or more other groups, residues, moieties or binding units. The polypeptide or construct according to item 30, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins. The polypeptide or construct according to item 31, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof. The polypeptide or construct according to item 32, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). The polypeptide or construct according to item 33, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG). The polypeptide or construct according to item 34, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin. 36. The polypeptide or construct according to item 35, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which: - CDR1 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 80; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 80; and c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 80; and - CDR2 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 81; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 81; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 81; and - CDR3 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 82; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 82; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 82. 37. The polypeptide or construct according to item 36, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 80, CDR2 consists of the amino acid sequence of SEQ ID NO: 81, and CDR3 consists of the amino acid sequence of SEQ ID NO: 82. 38. The polypeptide or construct according to item 37, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 47), ALB23 (SEQ ID NO: 48), ALBX00001 (SEQ ID NO: 61) and ALB23002 (SEQ ID NO: 62). 39. The polypeptide or construct according to anyone of items 22 to 38, wherein said linker is chosen from the group consisting of SEQ ID NOs: 63 to 79. 40. The polypeptide or construct according to any of items 22 to 39, further comprising a C- terminal extension. 41. The polypeptide or construct according to item 40, wherein said C-terminal extension is a C- terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I). 42. A nucleic acid that encodes an ISVD according to any one of items 1 to 21, or a polypeptide according to any one of items 22 to 41. 43. The nucleic acid according to item 42, that is in the form of a genetic construct. 44. A non-human host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD according to any one of items 1 to 21, or a polypeptide according to any one of items 22 to 41; and/or that comprises the nucleic acid according to any one of items 42 or 43. 45. A method for producing an ISVD according to any one of items 1 to 21, or a polypeptide according to any one of items 22 to 41, at least comprising the steps of: a) expressing, in a suitable host cell or non-human host organism or in another suitable expression system, a nucleic acid according to any one of items 42 or 43; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 21, or the polypeptide according to any one of items 22 to 41. 46. A method for producing an ISVD according to any one of items 1 to 21, or a polypeptide according to any one of items 22 to 41, said method at least comprising the steps of: a) cultivating and/or maintaining a non-human host or host cell according to item 39 under conditions that are such that said non-human host or host cell expresses and/or produces at least one ISVD according to any one of items 1 to 21, or at least one polypeptide according to any one of items 22 to 41; optionally followed by: b) isolating and/or purifying the ISVD according to any one of items 1 to 21, or polypeptide according to any one of items 22 to 41. 47. A composition comprising at least one ISVD according to any one of items 1 to 21, at least one polypeptide or construct according to any one of items 22 to 41, or at least one nucleic acid according to any one of items 42 or 43. 48. The composition according to item 47, which is a pharmaceutical composition. 49. The composition according to any one of items 47 or 48, which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and/or compounds. 50. The ISVD according to any one of items 1 to 21, the polypeptide or construct according to any one of items 22 to 41, or the composition according to any one of items 47 to 49, for use as a medicament. 51. The ISVD according to any one of items 1 to 21, the polypeptide or construct according to any one of items 22 to 41, or the composition according to any one of items 47 to 49, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder. 52. The ISVD according to any one of items 1 to 21, the polypeptide or construct according to any one of items 22 to 41, or the composition according to any one of items 47 to 49, for use in the diagnosis, prevention and/or treatment of at least one disease and/or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved. 53. The ISVD according to any one of items 1 to 21, the polypeptide or construct according to any one of items 22 to 41, or the composition according to any one of items 47 to 49, for use in the diagnosis, prevention and/or treatment of cancer. 54. A method for the diagnosis, prevention and/or treatment of at least one disease and/or disorder, comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of an ISVD according to any one of items 1 to 21, a polypeptide or construct according to any one of items 22 to 41, or a composition according to any one of items 47 to 49. 55. The method according to item 54, for the diagnosis, prevention and/or treatment of at least one disease or disorder that is associated with CEACAM5, with its biological or pharmacological activity, and/or with the biological pathways or signalling in which CEACAM5 is involved, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 21, a polypeptide or construct according to any one of items 22 to 41, or composition according to any one of items 47 to 49. The method according to any one of items 54 or 55, for the diagnosis, prevention and/or treatment of cancer, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of items 1 to 21, a polypeptide or construct according to any one of items 22 to 41, or a composition according to any one of items 47 to 49.

Claims

1. An immunoglobulin single variable domain (ISVD) specifically binding human CEACAM5, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which: - CDR1 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 1; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 1; and c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 1; and - CDR2 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 2; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 2; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 2; and - CDR3 (AbM numbering) has an amino acid sequence selected from: a) the amino acid sequence of QHFGPIGLTTRGYXY (SEQ ID NO: 230), wherein the amino acid residue X is selected from N, A, F, G, I, L, Y or H; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of QHFGPIGLTTRGYXY (SEQ ID NO: 230), wherein the amino acid residue X is selected from N, A, F, G, I, L, Y or H; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of QHFGPIGLTTRGYXY (SEQ ID NO: 230), wherein the amino acid residue X is selected from N, A, F, G, I, L, Y or H. 2. The ISVD according to claim 1, in which the amino acid sequences of the CDRs (AbM numbering) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 8, 31, 32, 150-159. 3. The ISVD according to any one of claims 1 or 2, in which ^ CDR1 consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 consists of one of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 consists of the amino acid sequence of SEQ ID NO: 3, or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO:1; ^ CDR2 (AbM numbering) consists of one of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 33, or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYAY (SEQ ID NO: 249); or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYFY (SEQ ID NO: 250); or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYGY (SEQ ID NO: 251), or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYIY (SEQ ID NO: 254); or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO: 1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYLY (SEQ ID NO: 252); or in which ^ CDR1 (AbM numbering) consists of the amino acid sequence of SEQ ID NO:1; ^ CDR2 (AbM numbering) consists of the amino acid sequences of SEQ ID NO: 2; and ^ CDR3 (AbM numbering) consists of the amino acid sequence of QHFGPIGLTTRGYYY (SEQ ID NO: 253). 4. The ISVD according to any one of claims 1 to 3, that essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb. 5. The ISVD according to any one of claims 1 to 4, wherein the ISVD specifically binds to human CEACAM5: a. with a dissociation constant (KD) of 10-7 to 10-11 moles/litre or less, and preferably 10-8 to 10-10 moles/litre or less and more preferably 1x10-8 to 1x10-9 moles/litre or less, even more preferably wherein the ISVD specifically binds to human CEACAM5 with a KD of about 1.34x10-9 moles/litre or 1.24x10-9 moles/litre, and/or b. with a kon rate of between 104 M-1s-1 to about 107 M-1s-1, preferably between 105 M-1s-1 and 107 M-1s-1, more preferably between 105 M-1s-1 and 106 M-1s-1, such as between 1x105 M-1s-1 and 8x105 M-1s-1, even more preferably of about 3.17x105 M-1s-1 or about7.16x105 M-1s, and/or c. with a koff rate between 10-3 s-1 and 10-6 s-1, preferably between 10-2 s-1 and 1x10-5 s-1, more preferably between 5x10-3 s-1 and 1x10-4 s-1, such as between 5x10-3 s-1 and 5x10-4 s-1, even more preferably of about 4.24x10-3 s-1or 8.85x10-4 s-1, as determined by Surface Plasmon Resonance. 6. The ISVD according to any one of claims 1 to 5, wherein the ISVD specifically binds to human and cyno CEACAM5 and does not bind to CEACAM1, CEACAM6, CEACAM7 and CEACAM8 or other members of the CEACAMs family.
7. The ISVD according to any one of claims 1 to 6, wherein the ISVD internalizes upon binding to CEACAM5. 8. The ISVD according to any one of claims 1 to 7, which is a humanized ISVD that is chosen from the group consisting of SEQ ID NOs: 31, 32, 150-159 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID NOs: 8, 31, 32, 150-159. 9. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to any one of claims 1 to 8, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers, in which said one or more other groups, residues, moieties or binding units are ISVDs. 10. The polypeptide or construct according to claim 9, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased half- life, compared to the ISVD without the one or more other groups, residues, moieties or binding units. 11. The polypeptide or construct according to claim 10, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin, optionally wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 47), ALB23 (SEQ ID NO: 48), ALBX00001 (SEQ ID NO: 61) and ALB23002 (SEQ ID NO: 62). 12. A nucleic acid that encodes an ISVD according to any one of claims 1 to 8, or a polypeptide according to any one of claims 9 to 11. 13. A non-human host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD according to any one of claims 1 to 8, or a polypeptide according to any one of claims 9 to 10; and/or that comprises the nucleic acid according to claim 12.
14. A method for producing an ISVD according to any one of claims 1 to 8, or a polypeptide according to any one of claims 9 to 11, at least comprising the steps of: a) expressing, in a suitable non-human host cell or host organism or in another suitable expression system, a nucleic acid according to claim 11; optionally followed by: b) isolating and/or purifying the ISVD according to any one of claims 1 to 8, or the polypeptide according to any one of claims 9 to 11. 15. A composition comprising at least one ISVD according to any one of claims 1 to 8, at least one polypeptide or construct according to any one of claims 9 to 11, or at least one nucleic acid according to claim 12; which optionally is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and/or compounds.
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