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WO2023227594A1 - Nouvelles chaînes de récepteurs de cellules t delta et chaînes de récepteurs de cellules t gamma ou parties de celles-ci - Google Patents

Nouvelles chaînes de récepteurs de cellules t delta et chaînes de récepteurs de cellules t gamma ou parties de celles-ci Download PDF

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WO2023227594A1
WO2023227594A1 PCT/EP2023/063776 EP2023063776W WO2023227594A1 WO 2023227594 A1 WO2023227594 A1 WO 2023227594A1 EP 2023063776 W EP2023063776 W EP 2023063776W WO 2023227594 A1 WO2023227594 A1 WO 2023227594A1
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amino acid
acid sequence
seq
cell receptor
sequence
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Laurens SAND
Stefania GOBESSI
Haakan NORELL
Peter REININK
Karin VAN VEGHEL
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Gadeta Bv
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Gadeta Bv
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/7051—T-cell receptor (TcR)-CD3 complex
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16041—Use of virus, viral particle or viral elements as a vector
    • C12N2740/16043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2840/00—Vectors comprising a special translation-regulating system
    • C12N2840/20—Vectors comprising a special translation-regulating system translation of more than one cistron

Definitions

  • Novel deltaT-cell receptor chains qammaT-cell receptor chains, or parts thereof
  • the present invention relates to bT-cell (or yT-cell) receptor chains, yQTCRs, parts thereof, and cells comprising or expressing them.
  • the invention is useful for anti-tumour and anti-infective therapeutics.
  • our immune system utilizes different lines of defence to protect us from infections as well as cancer.
  • our adaptive immune system has the possibility to raise up to 10 16 apTCR combinations as well as 10 11 variations in immunoglobulins (Chien YH, et al, 2014. Annu.Rev.lmmunol.).
  • TCRbs have even the highest potential diversity in the CDR3 loop (approximately 10 16 combinations for murine TCR6) owing to the presence of multiple D gene segments (two in mice, three in human, and up to five in cattle) that can join together. Each D gene segment can be read in all three open reading frames, and N nucleotides can be inserted into the junctions of the joining segments.
  • the potential diversity generated at the combined CDR3 junctions is still higher than that of apTCRs ( ⁇ 10 16 ) and immunoglobulins ( ⁇ 10 11 ).
  • TCR6 and TCRy chains may be particularly useful for immunotherapeutics against cancer and infections. Accordingly, there is still a need for identifying new yT- and bT-cell receptor chains, and ybT-cell receptors, that will mediate an anti-tumour response. There is still a need for identifying new yT- and bT-cell receptor chains, and ybT-cell receptors, that will mediate an anti-infective response. There is still a need for improved treatments utilizing yT- and bT-cell receptor chains, and ybT-cell receptors.
  • FIG. 2A-2B ybTCR clone 1 displays tumour specifc reactivity.
  • TEGs expressing ybTCR clone 1 SEQ ID NO: 12, 16
  • TEGnc negative control ybTCR
  • Both TEGs are produced from the same matched apT-cells.
  • Co-culture was performed at effector to target (E/T) ratio 1 :1.
  • Cytotoxicity (Fig. 2A) was measured by LDH release from target cells and plotted as LDH fold change (LDH TEG ybTCR/LDH TEGnc). Bars represent mean +SD of triplicates in a single experiment. IFNy levels were measured by ELISA (Fig. 2B). Graphs describe data from two TEG batches. *”*P ⁇ 0.0001.
  • FIG. 3A-3B ybTCR clone 2 displays tumour specifc reactivity.
  • TEGs expressing ybTCR clone 2 SEQ ID NO: 20, 24
  • TEGnc negative control ybTCR
  • Both TEGs are produced from the same matched apT-cells.
  • Co-culture was performed at effector to target (E/T) ratio 1 :1.
  • Cytotoxicity (Fig. 3A) was measured by LDH release from target cells and plotted as LDH fold change (LDH TEG ybTCR/LDH TEGnc).
  • yQTCR clone 3 displays tumour specifc reactivity.
  • TEGs expressing yQTCR clone 3 SEQ ID NO: 28, 32
  • TEGnc negative control ydTCR
  • FIG. 5A-5B yQTCR clone 4 displays tumour specifc reactivity.
  • TEGs expressing yQTCR clone 4 SEQ ID NO: 36, 40
  • TEGnc negative control yQTCR
  • Both TEGs are produced from the same matched a[3T-cells.
  • Co-culture was performed at effector to target (E/T) ratio 1 :1.
  • Cytotoxicity (Fig. 5A) was measured by LDH release from target cells and plotted as LDH fold change (LDH TEG yQTCR/LDH TEGnc).
  • FIG. 6A-6B ybTCR clone 5 displays tumour specifc reactivity.
  • TEGs expressing ybTCR clone 5 SEQ ID NO: 4, 8) or negative control ybTCR (TEGnc) which does not react to any of the target cells tested.
  • Both TEGs are produced from the same matched a[3T-cells.
  • Co-culture was performed at effectorto target (E/T) ratio 1 :1 .
  • Cytotoxicity (Fig. 6A) was measured by LDH release from target cells and plotted as LDH fold change (LDH TEG ybTCR/LDH TEGnc). Bars represent mean +SD of triplicates in a single experiment. IFNy levels were measured by ELISA (Fig. 6B). Graphs describe data from two TEG batches. ****P ⁇ 0.0001.
  • FIG. 7A-7B ybTCR clone 6 displays tumour specifc reactivity.
  • Fourtumor cell lines and 6 healthy primary cells were co-cultured for 48hr with TEGs expressing ybTCR clone 6 (SEQ ID NO: 44, 48) or negative control gdTCR (TEGnc) which does not react to any of the target cells tested. Both TEGs are produced from the same matched a[3T-cells. Co-culture was performed at effectorto target (E/T) ratio 1 :1 . Cytotoxicity (Fig. 7A) was measured by LDH release from target cells and plotted as LDH fold change (LDH TEG ybTCR/LDH TEGnc). Bars represent mean +SD of triplicates in a single experiment. IFNy levels were measured by ELISA (Fig. 7B). Graphs describe data from two TEG batches. ****P ⁇ 0.0001.
  • FIG. 8A-8B ybTCR clone 7 displays tumour specifc reactivity.
  • TEGs expressing ybTCR clone 7 SEQ ID NO: 52, 56
  • TEGnc negative control ybTCR
  • Both TEGs are produced from the same matched a[3T-cells.
  • Co-culture was performed at effector to target (E/T) ratio 1 :1.
  • Cytotoxicity (Fig. 8A) was measured by LDH release from target cells and plotted as LDH fold change (LDH TEG ybTCR/LDH TEGnc). Bars represent mean +SD of triplicates in a single experiment. IFNy levels were measured by ELISA (Fig. 8B). Graphs describe data from two TEG batches. ****P ⁇ 0.0001.
  • TEGs expressing ybTCRs clones 1-7 or Fel l Tumour specific reactivity of TEGs expressing ybTCRs clones 1-7 or Fel l (SEQ ID NO: 217,
  • TEGs were produced from donor matched a[3T-cells. Co-culture was performed at effector to target (E/T) ratio 1 :1 for 48h. Cytolysis/cytot oxi city was measured in a luciferased- based cytotoxicity assay (Fig. 9A). IFNy levels were measured by ELISA (Fig. 9B). Untransduced a[3T-cells were used as negative control.
  • Fig. 10A-10B Tumour specific reactivity of TEGs expressing ybTCRs clones 1-7 or Fel l (SEQ ID NO: 217, 218) against Luc-Tom OVCAR-3 cells. All TEGs were produced from donor matched a[3T-cells. Coculture was performed at effector to target (E/T) ratio 1 :1 for 48h. Cytolysis/cytotoxicity was measured in a luciferased-based cytotoxicity assay (Fig. 10A). IFNy levels were measured by ELISA (Fig. 10B). Untransduced a[3T-cells were used as negative control.
  • Fig. 11A-11 B Tumour specific reactivity of TEGs expressing ybTCRs clones 1-7 or Fel l (SEQ ID NO: 217, 218) against Luc-Tom MDA-MB-231 cells. All TEGs were produced from donor matched a[3T-cells. Co-culture was performed at effector to target (E/T) ratio 1 :1 for 48h. Cytolysis/cytotoxicity was measured in a luciferased-based cytotoxicity assay (Fig. 11 A). IFNy levels were measured by ELISA (Fig. 11 B). Untransduced a[3T-cells were used as negative control.
  • Fig. 12A-12D Tumour specific reactivity of TEGs co-expressing ybTCR clone 5 (SEQ ID NO: 4, 8) and chimeric bidirectional signaling transmembrane protein (MIDIS; 41 BBL-OX40; SEQ ID NO: 105) vs. TEGs expressing ybTCR clone 5 alone against Luc-Tom MDA-MB-231 over 6 stimulation rounds.
  • Co-culture in each round was performed at effector to target (E/T) ratio 1 :1 (Fig. 12A), 1 :2 (Fig. 12B), 1 :4 (Fig. 12C), and 1 :8 (Fig. 1 :8) for 3-4 days.
  • E/T effector to target
  • effector T-cells were harvested and transferred to a new cell culture plate containing fresh Luc-Tom tumour cells, for a new round of target exposure/stimulation, and cytolysis/cytotoxicity was measured in a luciferased-based cytotoxicity assay.
  • Fig. 13 Illustrative example of function of a chimeric bidirectional signaling transmembrane protein (MIDIS) described herein.
  • a MIDIS protein is expressed by an engineered cell. Binding of the extracellular ligand domain to an interaction partner induces multi-directional signaling comprising at least one “inside out’’ signal mediated by an intracellular signaling domain of the interaction partner (signal 1) and at least one “outside-in’’ signal mediated by the heterologous intracellular signaling domain of the MIDIS protein (signal 2).
  • the first signaling pathway and the second signaling pathway can jointly induce a target biological outcome.
  • a bT-cell receptor chain or a part thereof comprising a CDR3 region, wherein said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 4 amino acid modifications relative to the amino acid sequence of SEQ ID NO: 1 , 9, 17, 25, 33, 41 , or 49.
  • a yT-cell receptor chain or a part thereof comprising a CDR3 region, wherein yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 1 modifications relative to the amino acid sequence of SEQ ID NO: 5, 13, 21 , 29, 37, 45, or 53.
  • a ybT-cell receptor or a part thereof wherein said receptor or part thereof comprises: - a 6T-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said 6T-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 80% sequence identity or similarity with the amino acid sequence of SEQ ID NO: 1 , 9, 17, 25, 33, 41 , or 49, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 80% sequence identity or similarity with the amino acid sequence of SEQ ID NO: 5, 13, 21 , 29, 37, 45, or 53.
  • the ydT-cell receptor or part thereof comprises A, B, C, D, E, F, or G:
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 80% sequence identity or similarity with the amino acid sequence of SEQ ID NO: 5,
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 80% sequence identity or similarity with the amino acid sequence of SEQ ID NO: 13,
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 80% sequence identity or similarity with the amino acid sequence of SEQ ID NO: 21 ,
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 80% sequence identity or similarity with the amino acid sequence of SEQ ID NO: 29,
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 80% sequence identity or similarity with the amino acid sequence of SEQ ID NO: 37,
  • yT-cell receptor chain or part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 80% sequence identity or similarity with the amino acid sequence of SEQ ID NO: 45, G. - a bT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 80% sequence identity or similarity with the amino acid sequence of SEQ ID NO: 49, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 80% sequence identity or similarity with the amino acid sequence of SEQ ID NO: 53.
  • the ybT-cell receptor or part thereof further comprises A2, B2, C2, D2, E2, F2, or G2:
  • A2 -a 5CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 209
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 195, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 202,
  • -a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 213
  • -a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 199, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 206,
  • -a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 210
  • -a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 216
  • SEQ ID NO: 216
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 196, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 203,
  • -a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 211
  • -a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with the amino acid sequence QGS
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 197, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 204, E2.
  • -a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 212
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 198, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 205,
  • -a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 214
  • -a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with the amino acid sequence QGS
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 200, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 207,
  • G2 -a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 215, -a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 201 , and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 208.
  • the a ybT-cell receptor or a part thereof is such that:
  • the bT-cell receptor chain or part thereof is selected from the group consisting of a 61 T-, 62T-, 63T-, and 65T-cell receptor chain, preferably from a 61T- and 63T-cell receptor chain, and/or;
  • the yT-cell receptor chain or part thereof is selected from the group consisting of a y1 T-, y2T-, y3T-, y4T-, y5T-, y8T-, y9T-, y10T-, and y11 T-cell receptor chain, preferably from a y2T-, y3T-, y5T-, and y8T-cell receptor chain.
  • the 6T-cell receptor chain or part thereof, the yT-cell receptor chain or part thereof, or the y6T-cell receptor or part thereof is such that said 6T-cell receptor chain, yT-cell receptor chain, y6T- cell receptor, or part thereof mediates an anti-tumour or an anti-infective response.
  • the 6T-cell receptor chain or part thereof, the yT-cell receptor chain or part thereof, or the y6T-cell receptor or part thereof is a soluble polypeptide.
  • a conjugate comprising a 6T-cell receptor chain or a part thereof, a yT-cell receptor chain or a part thereof, or a y6T-cell receptor or a part thereof, as defined herein, linked to an agent, wherein the agent is preferably selected from the group consisting of a diagnostic agent, a therapeutic agent, an anti-cancer agent, a chemical, a nanoparticle, a chemotherapeutic agent, a radionuclide, a fluorescent protein and an enzyme whose catalytic activity can be detected.
  • nucleic acid molecule encoding a ybT-cell receptor or a part thereof as defined herein, wherein said nucleic acid molecule comprises a nucleotide sequence comprising:
  • nucleotide sequence comprising at least 80% sequence identity with the nucleotide sequence of SEQ ID NO: 2, 3, 10, 11 , 18, 19, 26, 27, 34, 35, 42, 43, 50, or 51 , and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 80% amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2, 3, 10, 11 , 18, 19, 26, 27, 34, 35, 42, 43, 50, or 51 , and/or;
  • nucleic acid molecule is such that it comprises a nucleotide sequence comprising A1 , B1 , C1 , D1 , E1 , F1 , or G1 :
  • A1. a nucleotide sequence comprising at least 80% sequence identity with the nucleotide sequence of SEQ ID NO: 2 or 3, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 80% amino acid identity orsimilarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2 or 3, and/or;
  • nucleotide sequence comprising at least 80% sequence identity with the nucleotide sequence of SEQ ID NO: 6 or 7, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 80% amino acid identity orsimilarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6 or 7,
  • nucleotide sequence comprising at least 80% sequence identity with the nucleotide sequence of SEQ ID NO: 10 or 11 , and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 80% amino acid identity orsimilarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 10 or 11 , and/or;
  • nucleotide sequence comprising at least 80% sequence identity with the nucleotide sequence of SEQ ID NO: 14 or 15, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 80% amino acid identity orsimilarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 14 or 15,
  • nucleotide sequence comprising at least 80% sequence identity with the nucleotide sequence of SEQ ID NO: 18 or 19, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 80% amino acid identity orsimilarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 18 or 19, and/or;
  • nucleotide sequence comprising at least 80% sequence identity with the nucleotide sequence of SEQ ID NO: 22 or 23, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 80% amino acid identity orsimilarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 22 or 23,
  • nucleotide sequence comprising at least 80% sequence identity with the nucleotide sequence of SEQ ID NO: 26 or 27, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 80% amino acid identity orsimilarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26 or 27, and/or; - a nucleotide sequence comprising at least 80% sequence identity with the nucleotide sequence of SEQ ID NO: 30 or 31 , and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 80% amino acid identity orsimilarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30 or 31 ,
  • nucleotide sequence comprising at least 80% sequence identity with the nucleotide sequence of SEQ ID NO: 34 or 35, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 80% amino acid identity orsimilarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34 or 35, and/or;
  • nucleotide sequence comprising at least 80% sequence identity with the nucleotide sequence of SEQ ID NO: 38 or 39, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 80% amino acid identity orsimilarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 38 or 39,
  • nucleotide sequence comprising at least 80% sequence identity with the nucleotide sequence of SEQ ID NO: 42 or 43, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 80% amino acid identity orsimilarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 42 or 43, and/or;
  • nucleotide sequence comprising at least 80% sequence identity with the nucleotide sequence of SEQ ID NO: 46 or 47, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 80% amino acid identity orsimilarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 46 or 47,
  • G1 . - a nucleotide sequence comprising at least 80% sequence identity with the nucleotide sequence of SEQ ID NO: 50 or 51 , and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 80% amino acid identity orsimilarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 50 or 51 , and/or;
  • nucleotide sequence comprising at least 80% sequence identity with the nucleotide sequence of SEQ ID NO: 54 or 55, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 80% amino acid identity orsimilarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 54 or 55.
  • nucleic acid construct comprising a nucleic acid molecule as defined herein.
  • a vector comprising a nucleic acid molecule or comprising a nucleic acid construct, as defined herein, preferably wherein said vector is a retroviral or lentiviral vector.
  • a T-cell expressing a bT-cell receptor chain or a part thereof, a yT-cell receptor chain or a part thereof, a ybT-cell receptor or a part thereof, or comprising a nucleic acid molecule, a nucleic acid construct, or a vector, as defined herein, preferably wherein said T-cell is an apT-cell or an NK cell.
  • the T-cell is such that it further comprises a polynucleotide encoding a chimeric bidirectional signaling transmembrane protein able to transduce at least two intracellular signals, said protein comprising:
  • extracellular ligand domain able to interact with the extracellular domain of its interaction partner, said extracellular ligand domain preferably comprising an amino acid sequence from 41 BBL, OX40L, CD86, RANK, or CD70; -a transmembrane domain, and;
  • heterologous intracellular signaling domain transducing a first signal after binding of the extracellular ligand domain to its interaction partner, said heterologous intracellular signaling domain preferably comprising 0X40, 41 BB, NKp80, IL18RAP, or IL2RB.
  • composition preferably a pharmaceutical composition, comprising a 6T- cell receptor chain or a part thereof, a yT-cell receptor chain or a part thereof, a ybT-cell receptor or a part thereof, a conjugate, a nucleic acid molecule, a nucleic acid construct, a vector, or a T-cell, as defined herein.
  • a bT-cell receptor chain or a part thereof a yT-cell receptor chain or a part thereof, a ybT-cell receptor or a part thereof, a conjugate, a nucleic acid molecule, a nucleic acid construct, a vector, a T-cell, or a composition, as defined herein for use as a medicament.
  • T-cell receptor In the context of the invention the term “part” of a yT-cell or bT-cell receptor chain may be replaced by the term “fragment”, the two terms being interchangeable. As used herein, the term “T-cell receptor” may be abbreviated as "TCR”.
  • polypeptides comprising a bT-cell receptor chain, a variant, or a part thereof.
  • the invention provides a bT-cell receptor chain or a part thereof, comprising a CDR3 region, and which bT-cell receptor chain or part thereof comprises an amino acid sequence as defined herein.
  • the bT-cell receptor chain is a 61T-, 62T-, 63T-, or 65T- cell receptor chain, preferably a 61T- or 63T-cell receptor chain.
  • polypeptides comprising a yT-cell receptor chain, a variant, or a part thereof.
  • the invention provides a yT-cell receptor chain or a part thereof, comprising a CDR3 region, and which yT-cell receptor chain or part thereof comprises an amino acid sequence as defined herein.
  • the yT-cell receptor chain is a y1T-, y2T-, y3T-, y4T-, y5T-, y8T-, y9T-, y10T-, or yUT-cell receptor chain, preferably a y2T-, y3T-, y5T-, or y8T-cell receptor chain.
  • polypeptides comprising a ybT-cell receptor, a variant, or a part thereof.
  • the invention provides a ybT-cell receptor or a part thereof, and which ybT-cell receptor or part thereof comprises a bT-cell receptor chain or a part thereof, comprising a CDR3 region, and a yT-cell receptor chain or a part thereof, comprising a CDR3 region.
  • Each of the bT-cell receptor chain or part thereof and yT-cell receptor chain or part thereof may comprise an amino acid sequence as defined herein.
  • a "variant” polypeptide as used herein refers to a polypeptide comprising an amino acid modification as compared to the amino sequence of the polypeptide it is derived from. A definition of amino acid modification is provided later herein.
  • a part or fragment of a polypeptide may correspond to at least 1 %, at least 2%, at least 3 %, at least 4%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40% of the length of a polypeptide, such as represented by an amino acid sequence with a specific SEQ ID NO, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90% of the length of the polypeptide.
  • a part or fragment of a polypeptide may correspond to an extracellular domain of a polypeptide, such as a yT-cell receptor chain, a bT-cell receptor chain, or a ybT-cell receptor, or part of said extracellular domain, as discussed later herein.
  • a part or fragment of a polypeptide may correspond to a complete variable region and/or a fragment or part of a constant region of a yT-cell receptor chain, a bT-cell receptor chain, or a ybT-cell receptor.
  • a part or frag me nt of a polypeptide may correspond to a part or fragment of a variable region and/or a fragment or part of a constant region of a yT-cell receptor chain, a bT-cell receptor chain, or a ybT-cell receptor.
  • a part or fragment of a polypeptide may correspond to a CDR3 region of a yT-cell receptor chain, a bT-cell receptor chain, or a ybT-cell receptor.
  • a part or fragment of a polypeptide may correspond to a soluble polypeptide, such as a soluble yT-cell receptor chain, a soluble bT-cell receptor chain, or a soluble ybT-cell receptor, as described later herein.
  • a part or fragment of a polypeptide is preferably a functional part or fragment thereof. It may mean that this part or fragment exhibits a similar activity as the original polypeptide it is derived from. In the context of the invention, an activity may for example be the mediation of an antitumour or an anti-infective response as explained later herein.
  • a similar anti-tumour or anti-infective response may mean that the part or fragment of the polypeptide mediates at least 50% of said anti-tumour or anti-infective response, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or more, or at least 110% or at least 120%, or more, as compared to the original polypeptide it is derived from.
  • a part or fragment of a yT-cell receptor chain, bT-cell receptor chain, or ybT-cell receptor corresponds to an extracellular domain or part or fragment thereof, as described later herein.
  • Each bT-cell receptor chain, variant, or part thereof described herein may also be represented by its coding nucleic acid sequence instead of the amino acid sequence it comprises. Therefore, the invention also relates to a nucleic acid molecule encoding said receptor chain or part thereof. The same holds for each yT-cell receptor chain, variant, or part thereof described herein.
  • Each ybT-cell receptor, variant, or part thereof described herein may be identified by the yT- and/or bT-cell receptor chains (or parts thereof) it comprises or by the nucleic acid molecules encoding the yT- and/or 6T- cell chains (or parts thereof) it comprises.
  • Each T cell expressing a bT-cell receptor chain or a part thereof, a yT-cell receptor chain or a part thereof, or a ybT-cell receptor, or a variant, or a part thereof, as described herein may be identified by the yT- and/or bT-cell receptor chains (or parts thereof) it comprises or by the nucleic acid molecules encoding the yT- and/or bT-cell chains (or parts thereof) it comprises.
  • each bT-cell receptor chain, yT-cell receptor chain, ybT-cell receptor, variant, or part thereof is a mammalian, preferably human, bT-cell receptor chain, yT-cell receptor chain, ybT-cell receptor, variant, or part thereof.
  • Each bT-cell receptor chain, yT-cell receptor chain, ybT-cell receptor, variant, or part thereof may be an isolated polypeptide.
  • Each bT-cell receptor chain, yT-cell receptor chain, ydT-cell receptor, variant, or part thereof may be synthetically made.
  • Each bT-cell receptor chain, yT-cell receptor chain, ybT-cell receptor, variant, or part thereof may be comprised, preferably expressed, by a cell as described later herein, for example in a cellular membrane.
  • a cell may alternatively express the bT-cell receptor chain, yT-cell receptor chain, ybT-cell receptor, variant, or part thereof as a soluble polypeptide, as described later herein.
  • the bT-cell receptor chain, yT-cell receptor chain, ybT-cell receptor, variant, or part thereof is comprised, preferably expressed, by a cell
  • said bT-cell receptor chain, yT-cell receptor chain, ybT-cell receptor, variant, or part thereof is preferably exogenous to said cell.
  • Exogenous in this context refers to the corresponding polypeptide being introduced to said cell, for example using one of the methods as described later herein.
  • An "exogenous” polypeptide is understood to refer to a polypeptide that is not naturally expressed by the cell it is introduced to.
  • an exogenous yT-cell receptor chain, ybT-cell receptor, variant, or part thereof is not naturally present in the cell it is introduced in.
  • yT-cell receptor chains bT-cell receptor chains, ybT- cell receptors, or parts thereof described herein are associated with at least one, at least two, or all of the following advantages:
  • the yT-cell receptor chains, bT-cell receptor chains, ybT-cell receptors or parts thereof described herein solve at least some of the problems discussed herein.
  • a bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8 amino acid modifications relative to the amino acid sequence of SEQ ID NO: 1 , 9, 17, 25, 33, 41 , or 49.
  • the amino acid sequence comprises from 0 to 7 amino acid modifications relative to the amino acid sequence of SEQ ID NO: 1 , 9, 17, 25, 33, 41 , or 49.
  • the amino acid sequence comprises from 0 to 6 amino acid modifications relative to the amino acid sequence of SEQ ID NO: 1 , 9, 17, 25, 33, 41 , or 49.
  • the amino acid sequence comprises from 0 to 5 amino acid modifications relative to the amino acid sequence of SEQ ID NO: 1 , 9, 17, 25, 33, 41 , or 49. In some embodiments, the amino acid sequence comprises from 0 to 4 amino acid modifications relative to the amino acid sequence of SEQ ID NO: 1 , 9, 17, 25, 33, 41 , or 49. In some embodiments, the amino acid sequence comprises from 0 to 3 amino acid modifications relative to the amino acid sequence of SEQ ID NO: 1 , 9, 17, 25, 33, 41 , or 49. In some embodiments, the amino acid sequence comprises from 0 to 2 amino acid modifications relative to the amino acid sequence of SEQ ID NO: 1 , 9, 17, 25, 33, 41 , or 49.
  • the amino acid sequence comprises from 0 to 1 amino acid modifications relative to the amino acid sequence of SEQ ID NO: 1 , 9, 17, 25, 33, 41 , or 49. In some embodiments, the amino acid sequence comprises no amino acid modifications, i.e. the amino acid sequence corresponds to the amino acid sequence of SEQ ID NO: 1 , 9, 17, 25, 33, 41 , or 49. In some embodiments, the amino acid sequence comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight amino acid modifications relative to the amino acid sequence of SEQ ID NO 1 , 9, 17, 25, 33, 41 , or 49. SEQ ID NOs: 1 , 9, 17, 25, 33, 41 , and 49 represent CDR3 regions of bT-cell receptor chains.
  • the bT-cell receptor chain or a part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 1.
  • the bT-cell receptor chain or a part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 9.
  • the bT-cell receptor chain or a part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to
  • the bT-cell receptor chain or a part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 25.
  • the bT-cell receptor chain or a part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 33.
  • the bT-cell receptor chain or a part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 41.
  • the bT-cell receptor chain or a part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 49.
  • a yT-cell receptor chain or a part thereof comprising a CDR3 region
  • yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6 amino acid modifications relative to the amino acid sequence of SEQ ID NO: 5, 13, 21 , 29, 37, 45, or 53.
  • the amino acid sequence comprises from 0 to 5 amino acid modifications relative to the amino acid sequence of SEQ ID NO: 5, 13, 21 , 29, 37, 45, or 53.
  • the amino acid sequence comprises from 0 to 4 amino acid modifications relative to the amino acid sequence of SEQ ID NO: 5, 13, 21 , 29, 37, 45, or 53.
  • the amino acid sequence comprises from 0 to 3 amino acid modifications relative to the amino acid sequence of SEQ ID NO: 5, 13, 21 , 29, 37, 45, or 53. In some embodiments, the amino acid sequence comprises from 0 to 2 amino acid modifications relative to the amino acid sequence of SEQ ID NO: 5, 13, 21 , 29, 37, 45, or 53. In some embodiments, the amino acid sequence comprises from 0 to 1 amino acid modifications relative to the amino acid sequence of SEQ ID NO: 5, 13, 21 , 29, 37, 45, or 53. In some embodiments, the amino acid sequence comprises no amino acid modifications, i.e. the amino acid sequence corresponds to the amino acid sequence of SEQ ID NO: 5, 13, 21 , 29, 37, 45, or 53.
  • the amino acid sequence comprises at least one, at least two, at least three, at least four, at least five, or at least six amino acid modifications relative to the amino acid sequence of SEQ ID NO: 5, 13, 21 , 29, 37, 45, or 53.
  • the yT-cell receptor chain or a part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 5.
  • the yT-cell receptor chain or a part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 13.
  • the yT-cell receptor chain or a part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 21 .
  • the yT-cell receptor chain or a part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 29.
  • the yT-cell receptor chain or a part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 37.
  • the yT-cell receptor chain or a part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 45.
  • the yT-cell receptor chain or a part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 53.
  • the CDR3 regions of ybT-cell receptors are known to be the most variable and to be the determinant sequences in specific antigen-recognition. These sequences can bind to their cognate antigens even in the absence of the remainder of the ybTCR sequence (Xu et al., Molecular Immunology 44 (2007) 302-310, incorporated herein by reference in its entirety). Further, transplanting of a ybCDR3 region to a different ybTCR can change the ybTCR’s binding characteristics to the ones of the transplanted ybCDR3 region (Adams et al., Nature Immunology (2008) (7): 777-784, incorporated herein by reference in its entirety).
  • the CDR1 and CDR2 regions of ybT-cell receptors are generally conserved in each yT- and bT-cell receptor chain type, and are not the determinant factors in specific antigen-recognition.
  • each of the CDR1 , CDR2, and CDR3 region in a respective yT-cell receptor chain or bT-cell receptor chain can easily be identified using corresponding anchor amino acid positions according to IMGT numbering (Lefranc, M.-P., The Immunologist 7:132-136 (1999); Lefranc, M.-P., Dev Comp Immunol 29(3):185-203 (2005), both of which are incorporated herein by reference in their entireties).
  • a y2CDR1 region is represented by the amino acid sequence EGSNGY (SEQ ID NO: 196, 197, 201).
  • a y3CDR1 region is represented by the amino acid sequence VTNTFY (SEQ ID NO: 198, 200).
  • a y5CDR1 region is represented by the amino acid sequence VINAFY (SEQ ID NO: 195).
  • a y8CDR1 region is represented by the amino acid sequence VENAVY (SEQ ID NO: 199).
  • a 61 CDR1 region is represented by the amino acid sequence TSWWSYY (SEQ ID NO: 209, 211 , 212, 213, 214, 215).
  • a 63CDR1 region is represented by the amino acid sequence TVYSNPD (SEQ ID NO: 210).
  • a y2CDR2 region is represented by the amino acid sequence YDSYNSKV (SEQ ID NO: 203, 204, 208).
  • a y3CDR2 region is represented by the amino acid sequence YDVSTARD (SEQ ID NO: 205, 207).
  • a y5CDR2 region is represented by the amino acid sequence YDVSNSKD (SEQ ID NO: 202).
  • a y8CDR2 region is represented by the amino acid sequence YDSYNSRV (SEQ ID NO: 206).
  • a 61 CDR2 region is represented by the amino acid sequence QGS.
  • a 63CDR2 region is represented by the amino acid sequence GDNSRS (SEQ ID NO: 216).
  • the bT-cell receptor chain or part thereof further comprises a CDR1 region represented by an amino acid sequence comprising from 0 to 3 amino acid modifications relative to the amino acid sequence of SEQ ID NOs: 209-215. In some embodiments, the bT-cell receptor chain or part thereof further comprises a CDR1 region represented by an amino acid sequence comprising from 0 to 2 amino acid modifications relative to the amino acid sequence of SEQ ID NOs: 209-215. In some embodiments, the bT-cell receptor chain or part thereof further comprises a CDR1 region represented by an amino acid sequence comprising from 0 to 1 amino acid modifications relative to the amino acid sequence of SEQ ID NOs: 209-215.
  • the bT-cell receptor chain or part thereof further comprises a CDR1 region represented by an amino acid sequence comprising no amino acid modifications relative to the amino acid sequence of SEQ ID NOs: 209-215, i.e. , the amino acid sequence corresponds to the amino acid sequence of SEQ ID NOs: 209-215.
  • the 6CDR1 region comprises at least one, at least two, or at least three amino acid modifications relative to amino acid sequence of SEQ ID NOs: 209-215.
  • the bT-cell receptor chain or part thereof further comprises a CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NOs: 209, 211 , 212, 213, 214, or 215.
  • the bT-cell receptor chain or part thereof further comprises a CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 210.
  • the bT-cell receptor chain or part thereof further comprises a CDR2 region represented by an amino acid sequence comprising from 0 to 3 amino acid modifications relative to the amino acid sequence of SEQ ID NO: 216 or QGS. In some embodiments, the bT-cell receptor chain or part thereof further comprises a CDR2 region represented by an amino acid sequence comprising from 0 to 2 amino acid modifications relative to the amino acid sequence of SEQ ID NO: 216 or QGS. In some embodiments, the bT-cell receptor chain or part thereof further comprises a CDR2 region represented by an amino acid sequence comprising from 0 to 1 amino acid modifications relative to the amino acid sequence of SEQ ID NO: 216 or QGS.
  • the bT-cell receptor chain or part thereof further comprises a CDR2 region represented by an amino acid sequence comprising no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 216 or QGS, i.e., the amino acid sequence corresponds to the amino acid sequence of SEQ ID NO: 216 or QGS.
  • the 6CDR2 region comprises at least one, at least two, or at least three amino acid modifications relative to amino acid sequence of SEQ ID NO: 216 or QGS.
  • the yT-cell receptor chain or part thereof further comprises a CDR1 region represented by an amino acid sequence comprising from 0 to 3 amino acid modifications relative to the amino acid sequence of SEQ ID NOs: 195-201. In some embodiments, the yT-cell receptor chain or part thereof further comprises a CDR1 region represented by an amino acid sequence comprising from 0 to 2 amino acid modifications relative to the amino acid sequence of SEQ ID NOs: 195-201. In some embodiments, the yT-cell receptor chain or part thereof further comprises a CDR1 region represented by an amino acid sequence comprising from 0 to 1 amino acid modifications relative to the amino acid sequence of SEQ ID NOs: 195-201.
  • the yT-cell receptor chain or part thereof further comprises a CDR1 region represented by an amino acid sequence comprising no amino acid modifications relative to the amino acid sequence of SEQ ID NOs: 195-201 , i.e. the amino acid sequence corresponds to the amino acid sequence of SEQ ID NOs: 195-201 .
  • the yCDR1 region comprises at least one, at least two, or at least three amino acid modifications relative to the amino acid sequence of SEQ ID NOs: 195-201.
  • the yT-cell receptor chain or part thereof further comprises a CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 195. In some embodiments, the yT-cell receptor chain or part thereof further comprises a CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NOs: 196, 197, or 201.
  • the yT-cell receptor chain or part thereof further comprises a CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NOs: 198 or 200. In some embodiments, the yT-cell receptor chain or part thereof further comprises a CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 199.
  • the yT-cell receptor chain or part thereof further comprises a CDR2 region represented by an amino acid sequence comprising from 0 to 3 amino acid modifications relative to the amino acid sequence of SEQ ID NOs: 202-208. In some embodiments, the yT-cell receptor chain or part thereof further comprises a CDR1 region represented by an amino acid sequence comprising from 0 to 2 amino acid modifications relative to the amino acid sequence of SEQ ID NOs: 202-208. In some embodiments, the yT-cell receptor chain or part thereof further comprises a CDR1 region represented by an amino acid sequence comprising from 0 to 1 amino acid modifications relative to the amino acid sequence of SEQ ID NOs: 202-208.
  • the yT-cell receptor chain or part thereof further comprises a CDR1 region represented by an amino acid sequence comprising no amino acid modifications relative to the amino acid sequence of SEQ ID NOs: 202-208, i.e. the amino acid sequence corresponds to the amino acid sequence of SEQ ID NOs: 202-208.
  • the yCDR2 region comprises at least one, at least two, or at least three amino acid modifications relative to the amino acid sequence of SEQ ID NOs: 202-208.
  • the yT-cell receptor chain or part thereof further comprises a CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 202. In some embodiments, the yT-cell receptor chain or part thereof further comprises a CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NOs: 203, 204, or 208.
  • the yT-cell receptor chain or part thereof further comprises a CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NOs: 205 or 207. In some embodiments, the yT-cell receptor chain or part thereof further comprises a CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 206.
  • amino acid modification may refer to a modification resulting in an amino acid sequence being modified (altered). Such a modification may, for example, be an amino acid substitution, insertion and/or deletion.
  • An amino acid substitution refers to a sequence modification that replaces an amino acid residue in a parent (reference) amino acid sequence (or a nucleotide in a nucleotide sequence comprised by a nucleic acid encoding the amino acid sequence) which results in a variant (mutant or derivative) sequence that has the same number of amino acids.
  • An amino acid substitution may correspond to a substitution by any other amino acid.
  • An amino acid substitution may correspond to a substitution of an L-amino acid by a D-amino acid.
  • amino acid substitution may correspond to a substitution by a nonnatural amino acid.
  • An amino acid substitution may be conservative.
  • a definition of "conservative” amino acid substitutions is provided later herein.
  • multiple amino acids are substituted, they may correspond to consecutive positions, to positions that are not consecutive, or to positions that are spatially apart in the amino acid sequence.
  • amino acid modifications in the context of the invention may be combined, e.g., an amino acid sequence may comprise an amino acid substitution and an amino acid insertion and/or deletion relative to an amino acid sequence having a SEQ ID NO as described herein.
  • a bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 1 , 4, 9, 12, 17, 20, 25, 28, 33, 36, 41 , 44, 49, or 52, preferably of SEQ ID NO: 1 , 9, 17, 25, 33, 41 , or 49.
  • a bT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the CDR3 region comprised in SEQ ID NO: 4, 12, 20, 28, 36, 44, or 52.
  • the bT-cell receptor chain or part thereof further comprises a CDR1 and a CDR2 region comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to, respectively, the CDR1 and CDR2 regions comprised in SEQ ID NO: 4, 12, 20, 28, 36, 44, or 52.
  • a bT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the CDR3 region comprised in SEQ ID NO: 4 and optionally further comprising a CDR1 and a CDR2 region comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to, respectively, the CDR1 and CDR2 regions comprised in SEQ ID NO: 4.
  • a bT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the CDR3 region comprised in SEQ ID NO: 12 and optionally further comprising a CDR1 and a CDR2 region comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to, respectively, the CDR1 and CDR2 regions comprised in SEQ ID NO: 12.
  • a bT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the CDR3 region comprised in SEQ ID NO: 20 and optionally further comprising a CDR1 and a CDR2 region comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to, respectively, the CDR1 and CDR2 regions comprised in SEQ ID NO: 20.
  • a bT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the CDR3 region comprised in SEQ ID NO: 28 and optionally further comprising a CDR1 and a CDR2 region comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to, respectively, the CDR1 and CDR2 regions comprised in SEQ ID NO: 28.
  • a bT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the CDR3 region comprised in SEQ ID NO: 36 and optionally further comprising a CDR1 and a CDR2 region comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to, respectively, the CDR1 and CDR2 regions comprised in SEQ ID NO: 36.
  • a bT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the CDR3 region comprised in SEQ ID NO: 44 and optionally further comprising a CDR1 and a CDR2 region comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to, respectively, the CDR1 and CDR2 regions comprised in SEQ ID NO: 44.
  • a bT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the CDR3 region comprised in SEQ ID NO: 52 and optionally further comprising a CDR1 and a CDR2 region comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to, respectively, the CDR1 and CDR2 regions comprised in SEQ ID NO: 52.
  • a bT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with a CDR3 region comprised in SEQ ID NO: 4, 12, 20, 28, 36, 44, or 52.
  • the bT-cell receptor chain or part thereof further comprises a CDR1 region and a CDR2 region comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with, respectively, a CDR1 region and a CDR2 region comprised in SEQ ID NO: 4, 12, 20, 28, 36, 44, or 52.
  • a bT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with the CDR3 region comprised in SEQ ID NO: 4 and optionally further comprising a CDR1 region and a CDR2 region comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with, respectively, the CDR1 region and the CDR2 region comprised in SEQ ID NO: 4.
  • a bT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with the CDR3 region comprised in SEQ ID NO: 12 and optionally further comprising a CDR1 region and a CDR2 region comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with, respectively, the CDR1 region and the CDR2 region comprised in SEQ ID NO: 12.
  • a bT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with the CDR3 region comprised in SEQ ID NO: 20 and optionally further comprising a CDR1 region and a CDR2 region comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with, respectively, the CDR1 region and the CDR2 region comprised in SEQ ID NO: 20.
  • a bT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with the CDR3 region comprised in SEQ ID NO: 28 and optionally further comprising a CDR1 region and a CDR2 region comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with, respectively, the CDR1 region and the CDR2 region comprised in SEQ ID NO: 28.
  • a bT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with the CDR3 region comprised in SEQ ID NO: 36 and optionally further comprising a CDR1 region and a CDR2 region comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with, respectively, the CDR1 region and the CDR2 region comprised in SEQ ID NO: 36.
  • a bT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with the CDR3 region comprised in SEQ ID NO: 44 and optionally further comprising a CDR1 region and a CDR2 region comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with, respectively, the CDR1 region and the CDR2 region comprised in SEQ ID NO: 44.
  • a bT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with the CDR3 region comprised in SEQ ID NO: 52 and optionally further comprising a CDR1 region and a CDR2 region comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with, respectively, the CDR1 region and the CDR2 region comprised in SEQ ID NO: 52.
  • the identity or similarity is at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least
  • a yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with the amino acid sequence of SEQ ID NO: 5, 8, 13, 16, 21 , 24, 29, 32, 37, 40, 45, 48, 53, or 56, preferably of 5, 13, 21 , 29, 37, 45, or 53.
  • a yT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the CDR3 region comprised in SEQ ID NO: 8, 16, 24, 32, 40, 48, or 56.
  • the yT-cell receptor chain or part thereof further comprises a CDR1 and a CDR2 region comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to, respectively, the CDR1 and CDR2 regions comprised in SEQ ID NO: 8, 16, 24, 32, 40, 48, or 56.
  • a yT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the CDR3 region comprised in SEQ ID NO: 8 and optionally further comprising a CDR1 and a CDR2 region comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to, respectively, the CDR1 and CDR2 regions comprised in SEQ ID NO: 8.
  • a yT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the CDR3 region comprised in SEQ ID NO: 16 and optionally further comprising a CDR1 and a CDR2 region comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to, respectively, the CDR1 and CDR2 regions comprised in SEQ ID NO: 16.
  • a yT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the CDR3 region comprised in SEQ ID NO: 24 and optionally further comprising a CDR1 and a CDR2 region comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to, respectively, the CDR1 and CDR2 regions comprised in SEQ ID NO: 24.
  • a yT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the CDR3 region comprised in SEQ ID NO: 32 and optionally further comprising a CDR1 and a CDR2 region comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to, respectively, the CDR1 and CDR2 regions comprised in SEQ ID NO: 32.
  • a yT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the CDR3 region comprised in SEQ ID NO: 40 and optionally further comprising a CDR1 and a CDR2 region comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to, respectively, the CDR1 and CDR2 regions comprised in SEQ ID NO: 40.
  • a yT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the CDR3 region comprised in SEQ ID NO: 48 and optionally further comprising a CDR1 and a CDR2 region comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to, respectively, the CDR1 and CDR2 regions comprised in SEQ ID NO: 48.
  • a yT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the CDR3 region comprised in SEQ ID NO: 56 and optionally further comprising a CDR1 and a CDR2 region comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to, respectively, the CDR1 and CDR2 regions comprised in SEQ ID NO: 56.
  • a yT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with a CDR3 region comprised in SEQ ID NO: 8, 16, 24, 32, 40, 48, or 56.
  • the yT-cell receptor chain or part thereof further comprises a CDR1 region and a CDR2 region comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with, respectively, a CDR1 region and a CDR2 region comprised in SEQ ID NO: 8, 16, 24, 32, 40, 48, or 56.
  • a yT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with the CDR3 region comprised in SEQ ID NO: 8 and optionally further comprising a CDR1 region and a CDR2 region comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with, respectively, the CDR1 region and the CDR2 region comprised in SEQ ID NO: 8.
  • a yT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with the CDR3 region comprised in SEQ ID NO: 16 and optionally further comprising a CDR1 region and a CDR2 region comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with, respectively, the CDR1 region and the CDR2 region comprised in SEQ ID NO: 16.
  • a yT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with the CDR3 region comprised in SEQ ID NO: 24 and optionally further comprising a CDR1 region and a CDR2 region comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with, respectively, the CDR1 region and the CDR2 region comprised in SEQ ID NO: 24.
  • a yT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with the CDR3 region comprised in SEQ ID NO: 32 and optionally further comprising a CDR1 region and a CDR2 region comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with, respectively, the CDR1 region and the CDR2 region comprised in SEQ ID NO: 32.
  • a yT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with the CDR3 region comprised in SEQ ID NO: 40 and optionally further comprising a CDR1 region and a CDR2 region comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with, respectively, the CDR1 region and the CDR2 region comprised in SEQ ID NO: 40.
  • a yT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with the CDR3 region comprised in SEQ ID NO: 48 and optionally further comprising a CDR1 region and a CDR2 region comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with, respectively, the CDR1 region and the CDR2 region comprised in SEQ ID NO: 48.
  • a yT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with the CDR3 region comprised in SEQ ID NO: 56 and optionally further comprising a CDR1 region and a CDR2 region comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with, respectively, the CDR1 region and the CDR2 region comprised in SEQ ID NO: 56.
  • the identity or similarity is at least 61 %, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least
  • a ybT-cell receptor or a part thereof comprising:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 1 , 4, 9, 12, 17, 20, 25, 28, 33, 36, 41 , 44, 49, or 52, preferably relative to SEQ ID NO: 1 , 9, 17, 25, 33, 41 , or 49, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 5, 8, 13, 16, 21 , 24, 29, 32, 37, 40, 45, 48, 53, or 56, preferably relative to SEQ ID NO: 5, 13, 21 , 29, 37, 45, or 53.
  • a ybT-cell receptor or a part thereof comprising:
  • bT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein the CDR3 region comprises from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the CDR3 region comprised in SEQ ID NO: 4, 12, 20, 28, 36, 44, or 52, and/or
  • a yT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the CDR3 region comprised in SEQ ID NO: 8, 16, 24, 32, 40, 48, or 56.
  • the bT-cell receptor chain or part thereof further comprises a CDR1 and a CDR2 region comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no modifications relative to, respectively, the CDR1 and CDR2 region comprised in SEQ ID NO: 4, 12, 20, 28, 36, 44, or 52 and the yT-cell receptor chain or part thereof further comprises a CDR1 and a CDR2 region comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no modifications relative to the CDR1 and a CDR2 region comprised in SEQ ID NO: 8, 16, 24, 32, 40, 48, or 56.
  • a ybT-cell receptor or a part thereof comprising:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 1 , 4, 9, 12, 17, 20, 25, 28, 33, 36, 41 , 44, 49, or 52, preferably of SEQ ID NO: 1 , 9, 17, 25, 33, 41 , or 49, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 5, 8, 13, 16, 21 , 24, 29, 32, 37, 40, 45, 48, 53, or 56, preferably of 5, 13, 21 , 29, 37, 45, or 53.
  • a ydT-cell receptor or a part thereof comprising:
  • a bT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with a CDR3 region comprised in SEQ ID NO: 4, 12, 20, 28, 36, 44, or 52, and/or
  • a yT-cell receptor chain or a part thereof comprising a CDR3 region, wherein the CDR3 region comprises at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with a CDR3 region comprised in SEQ ID NO: 8, 16, 24, 32, 40, 48, or 56.
  • the bT-cell receptor chain or part thereof further comprises a CDR1 and a CDR2 region comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with a CDR1 and a CDR2 region comprised in SEQ ID NO: 4, 12, 20, 28, 36, 44, or 52 and the yT-cell receptor chain or part thereof further comprises a CDR1 and a CDR2 region comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, sequence identity or similarity with, respectively, a CDR1 and a CDR2 region comprised in SEQ ID NO: 8, 16, 24, 32, 40, 48, or 56.
  • the identity or similarity is at least 61 %, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%.
  • the ybT-cell receptor or part thereof comprises:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 1 or 4, preferably relative to SEQ ID NO: 1 , and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 5 or 8, preferably relative to SEQ ID NO: 5.
  • the ybT-cell receptor or part thereof further comprises:
  • -a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 209,
  • -a 6CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 195, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 202.
  • the ybT-cell receptor or part thereof comprises:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 1 or 4, preferably of SEQ ID NO: 1 , and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 5 or 8, preferably of SEQ ID NO: 5.
  • the ybT-cell receptor or part thereof further comprises:
  • -a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 209,
  • -a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 195, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 202.
  • the identity or similarity is at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least
  • the ybT-cell receptor or part thereof comprises:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 9 or 12, preferably relative to SEQ ID NO: 9, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 13 or 16, preferably relative to SEQ ID NO: 13.
  • the ybT-cell receptor or part thereof further comprises:
  • -a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 213,
  • -a 6CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 199, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 206.
  • the ybT-cell receptor or part thereof comprises:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 9 or 12, preferably of SEQ ID NO: 9, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 13 or 16, preferably of SEQ ID NO: 13.
  • the ybT-cell receptor or part thereof further comprises:
  • -a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 213, and/or;
  • -a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 199, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 206.
  • the identity or similarity is at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least
  • the ybT-cell receptor or part thereof comprises:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 17 or 20, preferably relative to SEQ ID NO: 17, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 21 or 24, preferably relative to SEQ ID NO: 21 .
  • the ybT-cell receptor or part thereof further comprises:
  • -a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 210,
  • -a 6CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 216,
  • -a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 196, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 203.
  • the ybT-cell receptor or part thereof comprises:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 17 or 20, preferably of SEQ ID NO: 17, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 21 or 24, preferably of SEQ ID NO: 21 .
  • the ybT-cell receptor or part thereof further comprises:
  • -a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 210,
  • -a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 216,
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 196, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 203.
  • the identity or similarity is at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least
  • the ybT-cell receptor or part thereof comprises:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 25 or 28, preferably relative to SEQ ID NO: 25, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 29 or 32, preferably relative to SEQ ID NO: 29.
  • the ybT-cell receptor or part thereof further comprises:
  • -a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 211 ,
  • -a 6CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 197, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 204.
  • the ybT-cell receptor or part thereof comprises:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 25 or 28, preferably of SEQ ID NO: 25, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 29 or 32 preferably of SEQ ID NO: 29.
  • the y6T-cell receptor or part thereof further comprises:
  • -a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 211 ,
  • -a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 197, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 204.
  • the identity or similarity is at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least
  • the y6T-cell receptor or part thereof comprises:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 33 or 36, preferably relative to SEQ ID NO: 33, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 37 or 40, preferably relative to SEQ ID NO: 37.
  • the ybT-cell receptor or part thereof further comprises:
  • -a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 212,
  • -a 6CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 198, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 205.
  • the ybT-cell receptor or part thereof comprises:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 33 or 36, preferably of SEQ ID NO: 33, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 37 or 40, preferably of SEQ ID NO: 37.
  • the y6T-cell receptor or part thereof further comprises:
  • -a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 212,
  • -a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 198, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 205.
  • the identity or similarity is at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least
  • the ybT-cell receptor or part thereof comprises:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 41 or 44, preferably relative to SEQ ID NO: 41 , and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 45 or 48, preferably relative to SEQ ID NO: 45.
  • the ybT-cell receptor or part thereof further comprises:
  • -a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 214,
  • -a 6CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 200, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 207.
  • the ybT-cell receptor or part thereof comprises:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 41 or 44, preferably of SEQ ID NO: 41 , and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 45 or 48, preferably of SEQ ID NO: 45.
  • the y6T-cell receptor or part thereof further comprises:
  • -a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 214,
  • -a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 200, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 207.
  • the identity or similarity is at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least
  • the ybT-cell receptor or part thereof comprises:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 49 or 52, preferably relative to SEQ ID NO: 49, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 53 or 56, preferably relative to SEQ ID NO: 53.
  • the ybT-cell receptor or part thereof further comprises:
  • -a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 215,
  • -a 6CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 201 , and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 208.
  • the ybT-cell receptor or part thereof comprises:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 49 or 52, preferably of SEQ ID NO: 49, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 53 or 56, preferably of SEQ ID NO: 53.
  • the y6T-cell receptor or part thereof further comprises:
  • -a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 215,
  • -a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 201 , and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 208.
  • the identity or similarity is at least 61 %, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%.
  • the y6T-cell receptor or part thereof comprises A, B, C, D, E, F, or G:
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 5 or 8, preferably of SEQ ID NO: 5,
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 13 or 16, preferably of SEQ ID NO: 13,
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 17 or 20, preferably of SEQ ID NO: 17, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 21 or 24, preferably of SEQ ID NO: 21 ,
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 29 or 32, preferably of SEQ ID NO: 29,
  • bT-cell receptor chain or a part thereof comprising a CDR3 region, wherein said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 33 or 36, preferably of SEQ ID NO: 33, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 37 or 40, preferably of SEQ ID NO: 37,
  • bT-cell receptor chain or a part thereof comprising a CDR3 region, wherein said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 41 or 44, preferably of SEQ ID NO: 41 , and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 45 or 48, preferably of SEQ ID NO: 45,
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 53 or 56, preferably of SEQ ID NO: 53.
  • the ybT-cell receptor or part thereof further comprises A2, B2, C2, D2, E2, F2, or G2:
  • A2 -a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 209
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 195, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 202,
  • -a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 199, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 206,
  • C2. -a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 210,
  • -a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 216,
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 196, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 203,
  • -a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 197, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 204,
  • -a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 198, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 205,
  • F2. -a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 214,
  • -a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 200, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 207,
  • G2 -a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 215, -a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 201 , and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 208.
  • the identity or similarity is at least 61 %, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%.
  • a 6T-cell receptor chain or a part thereof as described herein is selected from the group consisting of a 61T-, 62T-, 63T-, and 65T-cell receptor chain, preferably from a 61T- and 63T-cell receptor chain.
  • a yT-cell receptor chain or a part thereof as described herein is selected from the group consisting of a y1T-, y2T-, y3T-, y4T-, y5T-, y8T-, y9T-, yl OT-, and yUT-cell receptor chain, preferably from a y2T-, y3T-, y5T-, and y8T-cell receptor chain.
  • a y6T-cell receptor or a part thereof as described herein comprises:
  • -a bT-cell receptor chain or part thereof selected from the group consisting of a 61 T-, 62T-, 63T-, and 65T- cell receptor chain, preferably from a 61T- and 63T-cell receptor chain, and/or;
  • y6T-cell receptor or a part thereof selected from the group consisting of a y1 T-, y2T-, y3T-, y4T-, y5T- , y8T-, y9T-, y10T-, and yUT-cell receptor chain, preferably from a y2T-, y3T-, y5T-, and y8T-cell receptor chain.
  • the y6T-cell receptor or a part thereof is a y161T-cell receptor or a part thereof.
  • the y6T-cell receptor or a part thereof is a y162T-cell receptor or a part thereof.
  • the y6T-cell receptor or a part thereof is a y163T-cell receptor or a part thereof. In some embodiments the y6T-cell receptor or a part thereof is a y165T-cell receptor or a part thereof. In some embodiments the YbT-cell receptor or a part thereof is a y261 T-cell receptor or a part thereof. In some embodiments the YbT-cell receptor or a part thereof is a y262T-cell receptor or a part thereof. In some embodiments the ybT-cell receptor or a part thereof is a y263T-cell receptor or a part thereof. In some embodiments the y6T-cell receptor or a part thereof is a y265T-cell receptor or a part thereof.
  • the ybT-cell receptor or a part thereof is a y361T-cell receptor or a part thereof. In some embodiments the ybT-cell receptor or a part thereof is a y362T-cell receptor or a part thereof. In some embodiments the ybT-cell receptor or a part thereof is a y363T-cell receptor or a part thereof. In some embodiments the ybT-cell receptor or a part thereof is a y365T-cell receptor or a part thereof.
  • the ybT-cell receptor or a part thereof is a y461T-cell receptor or a part thereof. In some embodiments the ybT-cell receptor or a part thereof is a y462T-cell receptor or a part thereof. In some embodiments the ybT-cell receptor or a part thereof is a y463T-cell receptor or a part thereof. In some embodiments the y6T-cell receptor or a part thereof is a y465T-cell receptor or a part thereof.
  • the y6T-cell receptor or a part thereof is a y561T-cell receptor or a part thereof. In some embodiments the y6T-cell receptor or a part thereof is a y562T-cell receptor or a part thereof. In some embodiments the y6T-cell receptor or a part thereof is a y563T-cell receptor or a part thereof. In some embodiments the y6T-cell receptor or a part thereof is a y565T-cell receptor or a part thereof.
  • the y6T-cell receptor or a part thereof is a y861T-cell receptor or a part thereof. In some embodiments the y6T-cell receptor or a part thereof is a y862T-cell receptor or a part thereof. In some embodiments the y6T-cell receptor or a part thereof is a y863T-cell receptor or a part thereof. In some embodiments the y6T-cell receptor or a part thereof is a y865T-cell receptor or a part thereof.
  • the y6T-cell receptor or a part thereof is a y961T-cell receptor or a part thereof. In some embodiments the y6T-cell receptor or a part thereof is a y962T-cell receptor or a part thereof. In some embodiments the y6T-cell receptor or a part thereof is a y963T-cell receptor or a part thereof. In some embodiments the y6T-cell receptor or a part thereof is a y965T-cell receptor or a part thereof.
  • the y6T-cell receptor or a part thereof is a y1061 T-cell receptor or a part thereof. In some embodiments the y6T-cell receptor or a part thereof is a y1062T-cell receptor or a part thereof. In some embodiments the y6T-cell receptor or a part thereof is a y1063T-cell receptor or a part thereof. In some embodiments the y6T-cell receptor or a part thereof is a y1065T-cell receptor or a part thereof.
  • the y6T-cell receptor or a part thereof is a y1161 T-cell receptor or a part thereof. In some embodiments the y6T-cell receptor or a part thereof is a y1162T-cell receptor or a part thereof. In some embodiments the y6T-cell receptor or a part thereof is a y1163T-cell receptor or a part thereof. In some embodiments the y6T-cell receptor or a part thereof is a y1165T-cell receptor or a part thereof.
  • y6T-cell receptors or parts thereof described herein y261 , y263, y361 , y561 , and y861T-cell receptors are preferred.
  • a polypeptide described herein is a soluble polypeptide.
  • a "soluble” polypeptide as used herein refers to a polypeptide that may be in solution, i.e. , a polypeptide that is not embedded in a cellular membrane.
  • a soluble polypeptide comprises or consists of the extracellular domain of a yT-cell receptor chain, a 6T-cell receptor chain, a y6T-cell receptor, or a part thereof, optionally fused to additional domains, as described herein.
  • IMGT standardized nomenclature such as IMGT to pinpoint the exact amino acids correponding to the domain.
  • IMGT nomenclature is described in Lefranc et al., 2005 (Nucl Acids Res 33: D593-D597) and Lefranc et al., 2014 (Front Immunol 5:22), both of which are incorporated herein in their entireties, and is further described in the public database available at imgt.org.
  • transmembrane domains of human yT- and 6T-cell receptor chains are generally conserved and their sequences are available to the skilled person; see Uniprot Ref: P0CF51 for TRGC1 chains, Uniprot Ref: P03986 for TRGC2 chains, and Uniprot Ref: B7Z8K6 for TRDC chains. Using this information, the skilled person may easily arrive at yT-cell receptor chains, 6T-cell receptor chains, y6T-cell receptors, or parts thereof, which do not comprise a transmembrane domain and/or a cytoplasmic domain.
  • a soluble polypeptide does not comprise a transmembrane domain of a yT-cell receptor chain, a 6T-cell receptor chain, or a y6T-cell receptor, or a part thereof. In some embodiments, a soluble polypeptide does not comprise a transmembrane domain and a cytoplasmic domain of a yT-cell receptor chain, a 6T-cell receptor chain, ora y6T-cell receptor, or a part thereof. In some embodiments, a soluble polypeptide does not comprise SEQ ID NO: 192 or a part thereof. In some embodiments, a soluble polypeptide does not comprise SEQ ID NO: 193 or a part thereof. In some embodiments, a soluble polypeptide does not comprise SEQ ID NO: 194 or a part thereof.
  • a polypeptide preferably a soluble polypeptide, comprises a bT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 1 , 150, 151 , or 152, preferably with SEQ ID NO: 1 or SEQ ID NO: 151 , more preferably with SEQ ID NO: 1.
  • a polypeptide preferably a soluble polypeptide, comprises a bT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 1 , 150, 151 , or 152, preferably relative to SEQ ID NO: 1 or SEQ ID NO: 151 , more preferably relative to SEQ ID NO: 1 .
  • a polypeptide preferably a soluble polypeptide, comprises a yT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 5, 153, 154, 155, 221 , or 222, preferably with SEQ ID NO: 5 or SEQ ID NO: 154, more preferably with SEQ ID NO: 5.
  • a polypeptide preferably a soluble polypeptide, comprises a yT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 5, 153, 154, 155, 221 , or 222, preferably relative to SEQ ID NO: 5 or SEQ ID NO: 154, more preferably relative to SEQ ID NO: 5.
  • a polypeptide preferably a soluble polypeptide, comprises:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 1 , 150, 151 , or 152, preferably with SEQ ID NO: 1 or SEQ ID NO: 151 , more preferably with SEQ ID NO: 1 , and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 5, 153, 154, 155, 221 , or 222, preferably with SEQ ID NO: 5 or SEQ ID NO: 154, more preferably with SEQ ID NO: 5.
  • the bT-cell receptor chain or part thereof further comprises a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 209 and/or a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with the amino acid sequence QGS, and the yT-cell receptor chain or part thereof further comprises a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 195 and/or a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 202.
  • a polypeptide preferably a soluble polypeptide, comprises:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 1 , 150, 151 , or 152, preferably relative to SEQ ID NO: 1 or SEQ ID NO: 151 , more preferably relative to SEQ ID NO: 1 , and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 5, 153, 154, 155, 221 , or 222, preferably relative to SEQ ID NO: 5 or SEQ ID NO: 154, more preferably relative to SEQ ID NO: 5.
  • the bT-cell receptor chain or part thereof further comprises a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 209 and/or a 6CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence QGS, and the yT-cell receptor chain or part thereof further comprises a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 195 and/or a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 202.
  • a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 ,
  • a polypeptide preferably a soluble polypeptide, comprises a bT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 9, 156, 157, or 158, preferably with SEQ ID NO: 9 or SEQ ID NO: 157, more preferably with SEQ ID NO: 9.
  • a polypeptide preferably a soluble polypeptide, comprises a bT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 9, 156, 157, or 158, preferably relative to SEQ ID NO: 9 or SEQ ID NO: 157, more preferably relative to SEQ ID NO: 9.
  • a polypeptide preferably a soluble polypeptide, comprises a yT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 13, 159, 160, or 161 , preferably with SEQ ID NO: 13 or SEQ ID NO: 160, more preferably with SEQ ID NO: 13.
  • a polypeptide preferably a soluble polypeptide, comprises a yT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 13, 159, 160, or 161 , preferably relative to SEQ ID NO: 13 or SEQ ID NO: 160, more preferably relative to SEQ ID NO: 13.
  • a polypeptide preferably a soluble polypeptide, comprises:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 9, 156, 157, or 158, preferably with SEQ ID NO: 9 or SEQ ID NO: 157, more preferably with SEQ ID NO: 9, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 13, 159, 160, or 161 , preferably with SEQ ID NO: 13 or SEQ ID NO: 160, more preferably with SEQ ID NO: 13.
  • the bT-cell receptor chain or part thereof further comprises a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 213 and/or a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with the amino acid sequence QGS, and the yT-cell receptor chain or part thereof further comprises a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 199 and/or a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 206.
  • a polypeptide preferably a soluble polypeptide, comprises:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 9, 156, 157, or 158, preferably relative to SEQ ID NO: 9 or SEQ ID NO: 157, more preferably relative to SEQ ID NO: 9, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 13, 159, 160, or 161 , preferably relative to SEQ ID NO: 13 or SEQ ID NO: 160, more preferably relative to SEQ ID NO: 13.
  • the bT-cell receptor chain or part thereof further comprises a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 213 and/or a 6CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence QGS, and the yT-cell receptor chain or part thereof further comprises a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 199 and/or a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 206.
  • a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 ,
  • a polypeptide preferably a soluble polypeptide, comprises a bT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 17, 162, 163, or 164, preferably with SEQ ID NO: 17 or SEQ ID NO: 163, more preferably with SEQ ID NO: 17.
  • a polypeptide preferably a soluble polypeptide, comprises a bT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 17, 162, 163, or 164, preferably relative to SEQ ID NO: 17 or SEQ ID NO: 163, more preferably relative to SEQ ID NO: 17.
  • a polypeptide preferably a soluble polypeptide, comprises a yT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 21 , 165, 166, 167, 223, or 224, preferably with SEQ ID NO: 21 or SEQ ID NO: 166, more preferably with SEQ ID NO: 21.
  • a polypeptide preferably a soluble polypeptide, comprises a yT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 21 , 165, 166, 167, 223, or 224, preferably relative to SEQ ID NO: 21 or SEQ ID NO: 166, more preferably relative to SEQ ID NO: 21 .
  • a polypeptide preferably a soluble polypeptide, comprises:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 17, 162, 163, or 164, preferably with SEQ ID NO: 17 or SEQ ID NO: 163, more preferably with SEQ ID NO: 17, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 21 , 165, 166, 167, 223, or 224, preferably with SEQ ID NO: 21 or SEQ ID NO: 166, more preferably with SEQ ID NO: 21.
  • the bT-cell receptor chain or part thereof further comprises a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 210 and/or a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 216, and the yT-cell receptor chain or part thereof further comprises a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 196 and/or a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 203.
  • a polypeptide preferably a soluble polypeptide, comprises:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 17, 162, 163, or 164, preferably relative to SEQ ID NO: 17 or SEQ ID NO: 163, more preferably relative to SEQ ID NO: 17, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 21 , 165, 166, 167, 223, or 224, preferably relative to SEQ ID NO: 21 or SEQ ID NO: 166, more preferably relative to SEQ ID NO: 21.
  • the bT-cell receptor chain or part thereof further comprises a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 210 and/or a 6CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 216
  • the yT-cell receptor chain or part thereof further comprises a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 196 and/or a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 203.
  • a polypeptide preferably a soluble polypeptide, comprises a bT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 25, 168, 169, or 170, preferably with SEQ ID NO: 25 or SEQ ID NO: 169, more preferably with SEQ ID NO: 25.
  • a polypeptide preferably a soluble polypeptide, comprises a bT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 25, 168, 169, or 170, preferably relative to SEQ ID NO: 25 or SEQ ID NO: 169, more preferably relative to SEQ ID NO: 25.
  • a polypeptide preferably a soluble polypeptide, comprises a yT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 29, 171 , 172, 173, 225, or 226, preferably with SEQ ID NO: 29 or SEQ ID NO: 172, more preferably with SEQ ID NO: 29.
  • a polypeptide preferably a soluble polypeptide, comprises a yT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 29, 171 , 172, 173, 225, or 226, preferably relative to SEQ ID NO: 29 or SEQ ID NO: 172, more preferably relative to SEQ ID NO: 29.
  • a polypeptide preferably a soluble polypeptide, comprises:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 25, 168, 169, or 170, preferably with SEQ ID NO: 25 or SEQ ID NO: 170, more preferably with SEQ ID NO: 25, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 29, 171 , 172, 173, 225, or 226, preferably with SEQ ID NO: 29 or SEQ ID NO: 172, more preferably with SEQ ID NO: 29.
  • the bT-cell receptor chain or part thereof further comprises a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 211 and/or a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with the amino acid sequence QGS, and the yT-cell receptor chain or part thereof further comprises a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 197 and/or a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 204.
  • a polypeptide preferably a soluble polypeptide, comprises:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 25, 168, 169, or 170, preferably relative to SEQ ID NO: 25 or SEQ ID NO: 170, more preferably relative to SEQ ID NO: 25, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 29, 171 , 172, 173, 225, or 226, preferably relative to SEQ ID NO: 29 or SEQ ID NO: 172, more preferably relative to SEQ ID NO: 29.
  • the bT-cell receptor chain or part thereof further comprises a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 211 and/or a 6CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence QGS, and the yT-cell receptor chain or part thereof further comprises a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 197 and/or a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 204.
  • a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 ,
  • a polypeptide preferably a soluble polypeptide, comprises a bT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 33, 174, 175, or 176, preferably with SEQ ID NO: 33 or SEQ ID NO: 175, more preferably with SEQ ID NO: 33.
  • a polypeptide preferably a soluble polypeptide, comprises a bT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 33, 174, 175, or 176, preferably relative to SEQ ID NO: 33 or SEQ ID NO: 175, more preferably relative to SEQ ID NO: 33.
  • a polypeptide preferably a soluble polypeptide, comprises a yT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 37, 177, 178, 179, 227, or 228, preferably with SEQ ID NO: 37 or SEQ ID NO: 178, more preferably with SEQ ID NO: 37.
  • a polypeptide preferably a soluble polypeptide, comprises a yT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 37, 177, 178, 179, 227, or 228, preferably relative to SEQ ID NO: 37 or SEQ ID NO: 178, more preferably relative to SEQ ID NO: 37.
  • a polypeptide preferably a soluble polypeptide, comprises:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 33, 174, 175, or 176, preferably with SEQ ID NO: 33 or SEQ ID NO: 175, more preferably with SEQ ID NO: 33, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 37, 177, 178, 179, 227, or 228, preferably with SEQ ID NO: 37 or SEQ ID NO: 178, more preferably with SEQ ID NO: 37.
  • the bT-cell receptor chain or part thereof further comprises a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 212 and/or a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with the amino acid sequence QGS, and the yT-cell receptor chain or part thereof further comprises a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 198 and/or a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 205.
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 33, 174, 175, or 176, preferably relative to SEQ ID NO: 33 or SEQ ID NO: 175, more preferably relative to SEQ ID NO: 33, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 37, 177, 178, 179, 227, or 228, preferably relative to SEQ ID NO: 37 or SEQ ID NO: 178, more preferably relative to SEQ ID NO: 37.
  • the bT-cell receptor chain or part thereof further comprises a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 212 and/or a 6CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence QGS, and the yT-cell receptor chain or part thereof further comprises a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 198 and/or a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 205.
  • a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 ,
  • a polypeptide preferably a soluble polypeptide, comprises a bT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 41 , 180, 181 , or 182, preferably with SEQ ID NO: 41 or SEQ ID NO: 181 , more preferably with SEQ ID NO: 41 .
  • a polypeptide preferably a soluble polypeptide, comprises a bT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 41 , 180, 181 , or 182, preferably relative to SEQ ID NO: 41 or SEQ ID NO: 181 , more preferably relative to SEQ ID NO: 41 .
  • a polypeptide preferably a soluble polypeptide, comprises a yT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 45, 183, 184, 185, 229, or 230, preferably with SEQ ID NO: 45 or SEQ ID NO: 184, more preferably with SEQ ID NO: 45.
  • a polypeptide preferably a soluble polypeptide, comprises a yT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 45, 183, 184, 185, 229, or 230, preferably relative to SEQ ID NO: 45 or SEQ ID NO: 184, more preferably relative to SEQ ID NO: 45.
  • a polypeptide preferably a soluble polypeptide, comprises:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 41 , 180, 181 , or 182, preferably with SEQ ID NO: 41 or SEQ ID NO: 181 , preferably with SEQ ID NO: 41 , and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 45, 183, 184, 185, 229, or 230, preferably with SEQ ID NO: 45 or SEQ ID NO: 184, more preferably with SEQ ID NO: 45.
  • the bT-cell receptor chain or part thereof further comprises a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 214 and/or a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with the amino acid sequence QGS, and the yT-cell receptor chain or part thereof further comprises a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 200 and/or a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 207.
  • a 6CDR1 region represented by
  • a polypeptide preferably a soluble polypeptide, comprises:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 41 , 180, 181 , or 182, preferably relative to SEQ ID NO: 41 or SEQ ID NO: 181 , more preferably relative to SEQ ID NO: 41 , and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 45, 183, 184, 185, 229, or 230, preferably relative to SEQ ID NO: 45 or SEQ ID NO: 184, more preferably relative to SEQ ID NO: 45.
  • the bT-cell receptor chain or part thereof further comprises a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 214 and/or a 6CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence QGS, and the yT-cell receptor chain or part thereof further comprises a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 200 and/or a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 207.
  • a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or
  • a polypeptide preferably a soluble polypeptide, comprises a bT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 49, 186, 187, or 188, preferably with SEQ ID NO: 49 or SEQ ID NO: 187, more preferably with SEQ ID NO: 49.
  • a polypeptide preferably a soluble polypeptide, comprises a bT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 49, 186, 187, or 188, preferably relative to SEQ ID NO: 49 or SEQ ID NO: 187, more preferably relative to SEQ ID NO: 49.
  • a polypeptide preferably a soluble polypeptide, comprises a yT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 53, 189, 190, 191 , 231 , or 232, preferably with SEQ ID NO: 53 or SEQ ID NO: 190, more preferably with SEQ ID NO: 53.
  • a polypeptide preferably a soluble polypeptide, comprises a yT-cell receptor chain or a part thereof, comprising a CDR3 region, wherein said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 53, 189, 190, 191 , 231 , or 232, preferably relative to SEQ ID NO: 53 or SEQ ID NO: 190, more preferably relative to SEQ ID NO: 53.
  • a polypeptide preferably a soluble polypeptide, comprises:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 49, 186, 187, or 188, preferably with SEQ ID NO: 49 or SEQ ID NO: 187, more preferably with SEQ ID NO: 49, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 53, 189, 190, 191 , 231 , or 232, preferably with SEQ ID NO: 53 or SEQ ID NO: 190, more preferably with SEQ ID NO: 53.
  • the bT-cell receptor chain or part thereof further comprises a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 215 and/or a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with the amino acid sequence QGS, and the yT-cell receptor chain or part thereof further comprises a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 201 and/or a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 208.
  • a poly(vinyl)
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 49, 186, 187, or 188, preferably relative to SEQ ID NO: 49 or SEQ ID NO: 187, more preferably relative to SEQ ID NO: 49, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence of SEQ ID NO: 53, 189, 190, 191 , 231 , or 232, preferably relative to SEQ ID NO: 53 or SEQ ID NO: 190, more preferably relative to SEQ ID NO: 53.
  • the bT-cell receptor chain or part thereof further comprises a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 215 and/or a 6CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence QGS, and the yT-cell receptor chain or part thereof further comprises a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 201 and/or a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 208.
  • a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 ,
  • the identity or similarity is at least 61 %, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least
  • a soluble polypeptide described herein may in some embodiments be a chimeric polypeptide, i.e., a polypeptide that comprises various forms or parts of binding entities such as, but not limited to, a yT-cell receptor chain, a bT-cell receptor chain, a ybT-cell receptor (or parts thereof such as extracellular domains or parts thereof), an antibody, an scFv, a B-cell receptor, a VHH, or any combination thereof.
  • ybTCR-antibody chimeric polypeptides can be generated and tested before arriving at a desired chimeric polypeptide, by replacing the heavy and light chain variable domains of an antibody by ybTCR-variable domains.
  • the soluble polypeptide comprises a yT-cell receptor chain, a bT-cell receptor chain, a ybT-cell receptor, or a part thereof (such as e.g., an extracellular domain or part thereof), that is fused with a T-cell- and/or NK-cell-binding domain.
  • a soluble polypeptide may be called a bispecific polypeptide.
  • Such a bispecific polypeptide may be advantageous, as it may first bind to a T- and/or NK-cell and then recruit the cell to a tumour cell, or to an infection site, thus mediating an anti-tumour or an anti- infective response without the requirement for its expression in a cellular membrane of an engineered T- and/or NK-cell.
  • a T-cell- and/or NK-cell-binding domain is to be understood as a domain that specifically binds to a T-cell and/or NK-cell, for example via binding to an antigen that is present on or displayed by the T-cell and/or NK-cell.
  • the T-cell and/or NK-cell is a mammalian cell, preferably a human cell.
  • binding of a T-cell- or NK-cell-binding domain to the respective T-cell or NK-cell results in the activation of the T-cell or NK-cell.
  • the T-cell- and/or NK-cell-binding domain is derived from, or is, an antibody, a single heavy chain variable domain antibody (such as for example a camelid VHH), a shark immunoglobulinderived variable new antigen receptor, an scFv, a tandem scFv, a Fab, an Fc domain of an antibody, an scFab, an antibody mimetic (such as for example a designed ankyrin repeat protein), a binding protein based on a Z domain of protein A, a binding protein based on a fibronectin type III domain, a lipocalin, and combinations thereof.
  • a single heavy chain variable domain antibody such as for example a camelid VHH
  • a shark immunoglobulinderived variable new antigen receptor such as for example a camelid VHH
  • an scFv such as for example a camelid VHH
  • a shark immunoglobulinderived variable new antigen receptor such as for example a camelid VHH
  • the T-cell- and/or NK-cell-binding domain is of mammalian origin, preferably of human origin. In some embodiments, the T-cell- and/or NK-cell-binding domain is selected from the group of CD3-, CD4-, CD8-, CD16-, CD56-, CD103-, CD154-, CD314-binding domains, and combinations thereof. In some embodiments, a T-cell- and/or NK-cell-binding domain is a CD3-binding domain, also referred to herein as an ”anti-CD3” binding domain.
  • binding domains are known to the skilled person, and are further described in e.g., W02007/062245, Liao et al., 2000 (Gene Ther 7: 339-47), W02001/051644, Arakawa et al., 1996 (J Biochem 120: 657-62), Adair et al., 1994 (Human Antibodies 5: 41-47), Kipriyanov et al., 1997 (Protein Engin Design Selection 10:445), van Diest et al., 2021 (J Immunother Cancer 2021 ;9:e003850), and WO2019/156566, all of which are incorporated herein by reference in their entireties.
  • a soluble polypeptide is a chimeric polypeptide comprising a yT-cell receptor chain, a bT-cell receptor chain, a ybT-cell receptor, or a part thereof (such as e.g., an extracelllular domain or part thereof), and an scFv domain, preferably an anti-CD3 scFv domain.
  • a soluble polypeptide is a chimeric polypeptide comprising a yT-cell receptor chain, a bT-cell receptor chain, a ybT-cell receptor, or a part thereof (such as e.g., an extracellular domain or part thereof), and an Fc domain of an antibody.
  • the yT-cell receptor chain, bT-cell receptor chain, ybT-cell receptor, or part thereof (such as e.g., extracellular domain or part thereof) comprised in the soluble, such as chimeric, polypeptides described herein are fused to an extracellular domain of an immune checkpoint-related molecule (or part thereof), such as for example an immune checkpoint inhibitor.
  • an immune checkpoint inhibitor refers to polypeptides, such as, but not limited to, inhibitory receptors, expressed by T- and/or NK-cells.
  • a soluble polypeptide is a chimeric polypeptide comprising a yT-cell receptor chain, a bT-cell receptor chain, a ybT-cell receptor, or a part thereof (such as e.g., an extracellular domain or part thereof), an extracellular immune checkpoint inhibitor domain, and a T-cell- and/or NK-cell- binding domain, preferably an anti-CD3 scFv or Fc domain.
  • a soluble polypeptide may be called a trispecific polypeptide.
  • Suitable extracellular immune checkpoint inhibitor domains may be derived from, but are not limited to, the group consisting of the adenosine A2A receptor, programmed death 1 (PD1) receptor, T-cell immunoglobulin domain, mucin domain 3, and V-domain Ig suppressor of T cell activation (TIGIT).
  • PD1 programmed death 1
  • T-cell immunoglobulin domain T-cell immunoglobulin domain
  • mucin domain 3 V-domain Ig suppressor of T cell activation
  • TAGIT V-domain Ig suppressor of T cell activation
  • the presence of the extracellular PD1 domain (or part thereof) in a trispecific polypeptide may interact with the PD-L1 ligand in a tumour cell, thereby enhancing the anti-tumour response of the T- and/or NK-cell that is recruited to the tumour cell via the binding domain of the polypeptide.
  • a soluble polypeptide is a chimeric polypeptide comprising a yT-cell receptor chain, a bT-cell receptor chain, a ybT-cell receptor, or a part thereof (such as e.g., an extracellular domain or part thereof), an extracellular domain of PD1 , and a T-cell- and/or NK-cell- binding domain, preferably an anti-CD3 scFv or Fc domain.
  • a soluble, such as a chimeric, polypeptide described herein may optionally further comprise a linker between the domains which provides conformational flexibility to the chimeric polypeptide.
  • Suitable linkers are known to the skilled person, and may for example be selected from polypeptides comprising from 1 to 60 amino acid residues, from 5 to 40 amino acid residues, or from 10 to 20 amino acid residues. Examples of suitable linkers are described in e.g., WO1999/42077, W02006/040153, W02006/122825, WO2011/001152A1 , and WO2019/156566, all of which are incorporated herein by reference in their entireties. Additional examples of suitable linkers are Gly-Ser linkers, such as, but not limited to, (Gly4Ser)3, (Gly4Ser)7, or (Gly3Ser2)3. Additional examples of suitable linkers are provided in Table 5 later herein.
  • a soluble, such as a chimeric, polypeptide as described herein may optionally comprise additional domains, for example a domain facilitating polypeptide excretion (in embodiments wherein the soluble polypeptide is produced by a cell, i.e., a signal peptide), and/or polypeptide isolation and/or purification and/or stability.
  • additional domains for example a domain facilitating polypeptide excretion (in embodiments wherein the soluble polypeptide is produced by a cell, i.e., a signal peptide), and/or polypeptide isolation and/or purification and/or stability.
  • Such domains and their applications are known in the art and are further described in standard handbooks such as Sambrook and Green, Molecular Cloning. A Laboratory Manual, 4th Edition, Cold Spring Harbor Laboratory Press (2012); Ausubel et al., Current Protocols in Molecular Biology, 3 rd edition, John Wiley & Sons Inc (2003), both of which are incorporated herein by reference in their entireties.
  • suitable domains facilitating polypeptide isolation and/or purification, and/or stability may be derived from a His-tag, c-myc domain, hemagglutinin tag, glutathione-S-transferase, maltose-binding protein, FLAG tag peptide, biotin acceptor peptide, streptravidin-binding peptide, calmodulin-binding peptide, bovine serum albumin, and others.
  • a T-cell- and/or NK-cell-binding domain, an immune checkpoint inhibitor domain, and/or an additional domain may be fused to a yT-cell receptor chain, a bT-cell receptor chain, a ybT-cell receptor, or a part thereof (such as e.g., an extracellular domain or part thereof) at the N-terminus or C-terminus of the receptor chain, receptor, or part thereof.
  • a part thereof such as e.g., an extracellular domain or part thereof
  • each additional domain may also be fused at the N-terminus or C-terminus of the domain it is fused to.
  • linkers may be comprised between the domains as described earlier herein.
  • a soluble, such as chimeric, polypeptide as described herein is a dimer, or a higher multimer such as a trimer.
  • dimerization or multimerization is facilitated by the inclusion of a dimerization or multimerization domain in the polypepide, for example a leucine zipper, a juntos interaction domain (such as for example described in Pack and Pliickthun, 1992, Biochemistry 31 , 1579- 1584; de Kruif and Logtenberg, 1996. JBC 271 : 7630-7634, incorporated herein by reference in their entireties), or any other suitable such domain known to the skilled person.
  • a dimerization or multimerization domain for example a leucine zipper, a juntos interaction domain (such as for example described in Pack and Pliickthun, 1992, Biochemistry 31 , 1579- 1584; de Kruif and Logtenberg, 1996. JBC 271 : 7630-7634, incorporated herein by reference in their entireties), or any other suitable
  • a bivalent or multivalent polypeptide may be generated via chemical cross-linking using standard methods, also described in standard handbooks such as Wong S. S, Chemistry of Protein Conjugation and Cross-Linking, 1 st edition, CRC Press (1991), incorporated herein by reference in its entirety.
  • a dimer or a higher multimer as described herein may be a dimer or multimer of polypeptides comprising the same or different yT-cell receptor chains, bT-cell receptor chains, ybT-cell receptors, or parts thereof (such as e.g., extracellulardomains or parts thereof), and/or T-cell and/or NK-cell-binding domains, said polypeptides and/or domains optionally having different targets.
  • the skilled person may arrive at the soluble, such as chimeric, polypeptides described herein utilizing standard moleculartoolbox techniques, for example as described in standard handbooks such as Sambrook and Green (2012, supra) and Ausubel et al. (2003, supra).
  • a soluble, such as a chimeric, polypeptide described herein may be synthetic or may be produced by an engineered cell, as described later herein.
  • the soluble, such as chimeric polypeptide may be exogenous to the engineered cell.
  • a soluble, such as a chimeric polypeptide may be excreted by the cell.
  • a soluble, such as a chimeric polypeptide may be produced in vitro, for example using isolated and/or purified cellular components (cell-free extracts) comprising the necessary transcription and translation machinery.
  • the polypeptide may be isolated and/or purified after its production.
  • Suitable downstream processing methods for isolation and/or purification of polypeptides from cell cultures are well-known in the art and are described in standard handbooks such as Wesselingh, J.A and Krijgsman, J., 1st edition, Downstream Processing in Biotechnology, Delft Academic Press (2013), incorporated herein by reference in its entirety.
  • suitable isolation and/or purification techniques are chromatographic methods such as high performance liquid chromatography, size exclusion chromatography, ion exchange chromatography, affinity chromatography (such as for example utilizing His-tags or protein A), immunoaffinity chromatography, immunoprecipitation, and the like.
  • a chimeric polypeptide comprising a yT-cell receptor chain, a bT-cell receptor chain, a ybT-cell receptor, or a part thereof (such as e.g., an extracellular domain or part thereof), and a T- and/or NK-cell-binding domain (for example an anti-CD3 scFv or Fc domain) may be produced by HEK293 cells and subsequently purified using protein A affinity chromatography followed by size exclusion chromatography. A proper folding of the chimeric polypeptide can be probed using conformational-specific antibodies that can target y and 6 variable domains.
  • Chimeric polypeptides may then be used in antibody dependent cell mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) assays to determine functional efficacy. After performing in vitro assays, functional efficacy of chimeric polypeptides can be tested in vitro and/or in vivo.
  • ADCC antibody dependent cell mediated cytotoxicity
  • CDC complement dependent cytotoxicity
  • a conjugate comprising a yT-cell receptor chain, a bT-cell receptor chain, a ybT-cell receptor, or a part thereof (such as e.g., an extracellular domain or part thereof), as described herein, which is linked to an agent.
  • agent e.g., an extracellular domain or part thereof
  • Such a conjugate may, for example, be linked to a substrate (e.g. chemicals, radionuclides, nanoparticles) and may be used e.g., to administer chemotherapy or radiotherapy to a target of interest.
  • diagnostics expression of defined ligands may be tested by taking advantage of the soluble ybTCRs linked to fluorochromes which are used as staining tool or for the biochemical isolation of the ligand, or linked to radionuclides used for the same purpose.
  • the agent is selected from the group consisting of a diagnostic agent, a therapeutic agent, an anti-cancer agent, a chemical, a nanoparticle, a chemotherapeutic agent, a fluorescent protein, and an enzyme whose catalytic activity could be detected.
  • the agent is selected from the group consisting of a diagnostic agent, a therapeutic agent, an anti-cancer agent, a chemical, a nanoparticle, a chemotherapeutic agent, a radionuclide, a fluorescent protein, and an enzyme whose catalytic activity could be detected.
  • the agent is a chemotherapeutic agent.
  • the agent is a radionuclide.
  • the fluorescent protein is selected from the group consisting of: green fluorescent protein (GFP), yellow fluorescent protein (YFP), red fluorescent protein (RFP), Blue fluorescent protein (BFP, Heim R substitu et al. (1994), Proc. Natl. Acad. Sci., 20;91 (26): 12501-12504, and Heim RNase et al (1996) Curr. Biol., 1 ;6(2): 178-182), a cyan fluorescent variant known as CFP (Heim R., et al. (1996) supra; Tsien R., et al, (1998) Annu. Rev. Biochem., 67: 509-544); a yellow fluorescent variant known as YFP (Ormo M., et al.
  • a fluorescent reporter is detected using flow cytometry.
  • the enzyme whose activity could be detected is selected from the group consisting of luciferase, beta galactosidase, beta-lactamase, catalase, alkaline phosphatase, and the like.
  • luciferase activity can be detected by commercially available assays, e.g., by the Luciferase 1000 Assay System, Nano-Gio or the Bio-Gio (Promega, Wl, US).
  • the Luciferase 1000 Assay System contains coenzyme A (CoA) besides luciferin as a substrate, resulting in a strong light intensity lasting for at least one minute when the manufacturer’s protocol is followed.
  • CoA coenzyme A
  • D-luciferin can also be utilized.
  • D-luciferin can also be utilized prior to an intracellular luciferase assay.
  • a Luciferase assay is used wherein the luciferase is secreted from the cells.
  • the assay can be performed without lysis of the cells.
  • the invention further provides nucleic acid molecules enconding the polypeptides described herein.
  • a nucleic acid molecule described herein may in some cases be a synthetic nucleic acid molecule or be part of a synthetic construct.
  • a nucleic acid molecule described herein may in some cases be a codon optimized molecule, preferably for expression in a mammalian cell, more preferably in a human cell. A definition of codon optimization is provided later herein. Accordingly, in an aspect, there is provided a nucleic acid molecule encoding a bT-cell receptor chain or part thereof as described herein.
  • the nucleic acid molecule is such that it comprises a nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 2, 3, 10, 11 , 18, 19, 26, 27, 34, 35, 42, 43, 50, or 51 , and/or with a nucleotide sequence that encodes an amino acid sequence that has (comprises) at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2, 3, 10, 11 , 18, 19, 26, 27, 34, 35, 42, 43, 50, or 51.
  • nucleic acid molecule encoding a yT-cell receptor chain or part thereof as described herein.
  • the nucleic acid molecule is such that it comprises a nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 6, 7, 14, 15, 22, 23, 30, 31 , 38, 39, 46, 47, 54, or 55, and/or with a nucleotide sequence that encodes an amino acid sequence that has (comprises) at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6, 7, 14, 15, 22, 23, 30, 31 , 38, 39, 46, 47, 54, or 55.
  • nucleic acid molecule encoding a ydT-cell receptor or a part thereof as described herein.
  • the nucleic acid molecule is such that it comprises:
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 2, 3, 10, 11 , 18, 19, 26, 27, 34, 35, 42, 43, 50, or 51 , and/or with a nucleotide sequence that encodes an amino acid sequence that has (comprises) at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2, 3, 10, 11 , 18, 19, 26, 27, 34, 35, 42, 43, 50, or 51 , and/or;
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 6, 7, 14, 15, 22, 23, 30, 31 , 38, 39, 46, 47, 54, or 55, and/or with a nucleotide sequence that encodes an amino acid sequence that has (comprises) at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6, 7, 14, 15, 22, 23, 30, 31 , 38, 39, 46, 47, 54, or 55.
  • the nucleic acid molecule is such that it comprises:
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 2 or 3, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2 or 3, and/or;
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 6 or 7, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6 or 7.
  • the nucleic acid molecule is such that it comprises:
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 10 or 11 , and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 10 or 11 , and/or;
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 14 or 15, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 14 or 15.
  • the nucleic acid molecule is such that it comprises:
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 18 or 19, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 18 or 19, and/or;
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 22 or 23, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 22 or 23.
  • the nucleic acid molecule is such that it comprises:
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 26 or 27, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26 or 27, and/or;
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 30 or 31 , and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30 or 31 .
  • the nucleic acid molecule is such that it comprises:
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 34 or 35, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34 or 35, and/or;
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 38 or 39, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 38 or 39.
  • the nucleic acid molecule is such that it comprises:
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 42 or 43, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 42 or 43, and/or;
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 46 or 47, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 46 or 47.
  • the nucleic acid molecule is such that it comprises: - a nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 50 or 51 , and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 50 or 51 , and/or;
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 54 or 55, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 54 or 55.
  • the nucleic acid molecule is such that it comprises a nucleotide sequence comprising A1 , B1 , C1 , D1 , E1 , F1 , or G1 :
  • A1 . - a nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 2 or 3, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2 or 3, and/or;
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 6 or 7, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6 or 7,
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 10 or 11 , and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 10 or 11 , and/or;
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 14 or 15, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 14 or 15,
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 18 or 19, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 18 or 19, and/or;
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 22 or 23, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 22 or 23,
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 26 or 27, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26 or 27, and/or;
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 30 or 31 , and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30 or 31 ,
  • E1 . - a nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 34 or 35, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34 or 35, and/or;
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 38 or 39, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 38 or 39,
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 42 or 43, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 42 or 43, and/or;
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 46 or 47, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 46 or 47,
  • G1 . - a nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 50 or 51 , and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 50 or 51 , and/or;
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 54 or 55, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 54 or 55.
  • nucleic acid molecule encoding a soluble polypeptide as described herein.
  • a nucleic acid molecule described herein may be comprised in a nucleic acid construct.
  • a nucleic acid construct may be alternatively referred to herein as an "expression construct”.
  • a nucleic acid construct comprising a nucleic acid molecule as described herein.
  • the skilled person understands that the nucleic acid molecule comprised in the nucleic acid constructs described herein may be operably linked to a regulatory sequence.
  • a definition of "operably linked” is provided later herein.
  • a regulatory sequence refers to any genetic element that is known to the skilled person to drive or otherwise regulate expression of nucleic acids in a cell.
  • nucleic acid construct comprises a nucleic acid molecule operably linked to a promoter.
  • Non-limiting examples of suitable promoters include EF1a, MSCV, EIF alpha-HTLV-1 hybrid promoter, Moloney murine leukemia virus (MoMuLV or MMLV), Gibbon Ape Leukemia virus (GALV), murine mammary tumor virus (MuMTV or MMTV), Rous sarcoma virus (RSV), MHC class II, clotting Factor IX, insulin promoter, PDX1 promoter, CD11 , CD4, CD2, gp47 promoter, PGK, Beta-globin, UbC, MND, and derivatives (i.e. variants) thereof, of which the MSCV promoter is preferred.
  • MoMuLV or MMLV Moloney murine leukemia virus
  • GALV Gibbon Ape Leukemia virus
  • MuMTV or MMTV murine mammary tumor virus
  • RSV Rous sarcoma virus
  • MHC class II MHC class II
  • clotting Factor IX insulin promoter
  • a nucleic acid construct may comprise additional nucleic acid molecules, for example encoding a chimeric bidirectional signaling transmembrane protein or a 2A-self cleaving peptide as described later herein.
  • the nucleic acid construct may be comprised in a vector as described herein.
  • a nucleic acid molecule or nucleic acid construct described herein may be comprised in a vector. Accordingly, the in a further aspect, there is provided a vector comprising a nucleic acid molecule or nucleic acid construct as described herein.
  • a preferred vector is a viral vector, preferably a retroviral or lentiviral vector. Suitable vectors are known to the skilled person and further information is provided later herein.
  • the vector is a good manufacturing practices (GMP) compatible vector.
  • GMP good manufacturing practices
  • a GMP vector can be purer than a non-GMP vector.
  • purity can be measured by bioburden.
  • bioburden can be the presence or absence of aerobes, anaerobes, sporeformers, fungi, or combinations thereof in a vector composition.
  • a pure vector can be endotoxin low or endotoxin free. Purity can also be measured by double-stranded primer-walking sequencing. Plasmid identity can be a source of determining purity of a vector.
  • a GMP vector of the invention can be from 10% to 99% more pure than a non-GMP vector.
  • a GMP vector can be from 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% more pure than a non-GMP vectoras measured by the presence of bioburden, endotoxin, sequencing, or combinations thereof.
  • Each of the bT-cell receptor chains, yT-cell receptor chains, ybT-cell receptors, or parts thereof (such as e.g., extracellular domains or parts thereof), and polypeptides comprising them (such as soluble polypeptides), described herein, or encoded by the nucleic acid molecules, constructs, and vectors described herein, are preferably able to mediate an anti-tumour activity/response and/or an anti-infective activity/response as explained later herein. Accordingly, they are preferably suitable for designing a medicament, such as for example for preventing, treating, regressing, curing and/or delaying a cancer or an infection in a subject, preferably in a human being.
  • Table 1 provides non-limiting examples of sequences described herein.
  • a cell expressing a polypeptide and/or comprising a nucleic acid molecule, a nucleic acid construct, and/or a vector as described herein.
  • a cell may be called an engineered cell.
  • the cell expresses a bT-cell receptor chain, a yT-cell receptor chain, a ybT-cell receptor, or a part thereof, as described herein.
  • the cell expresses the bT-cell receptor chain, yT-cell receptor chain, ybT-cell receptor, or part thereof, in its cellular membrane.
  • the cell expresses (produces) a soluble, such as a chimeric, polypeptide as described herein.
  • the cell is a mammalian cell, preferably a human cell.
  • the cell is an immune (immunoresponsive) cell such as a T-cell, an a
  • the cell is a T-cell, preferably an apT-cell.
  • an apT-cell may be a CD4+ or CD8+ apT-cell .
  • the cell is a T-cell, preferably an a
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 1 or 4, preferably relative to SEQ ID NO: 1 , and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 5 or 8, preferably relative to SEQ ID NO: 5.
  • the ybT-cell receptor or part thereof further comprises:
  • -a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 209,
  • -a 6CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 195, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 202.
  • the cell is a T-cell, preferably an a
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 9 or 12, preferably relative to SEQ ID NO: 9, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 13 or 16, preferably relative to SEQ ID NO: 13.
  • the ybT-cell receptor or part thereof further comprises:
  • -a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 213,
  • -a 6CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 199, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 206.
  • the cell is a T-cell, preferably an a
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 17 or 20, preferably relative to SEQ ID NO: 17, and/or;
  • the ydT-cell receptor or part thereof further comprises:
  • -a 5CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 210,
  • -a 6CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 216,
  • -a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 196, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 203.
  • the cell is a T-cell, preferably an a
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 25 or 28, preferably relative to SEQ ID NO: 25, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 29 or 32, preferably relative to SEQ ID NO: 29.
  • the ybT-cell receptor or part thereof further comprises:
  • -a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 211 ,
  • -a 6CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 197, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 204.
  • the cell is a T-cell, preferably an a
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 33 or 36, preferably relative to SEQ ID NO: 33, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 37 or 40, preferably relative to SEQ ID NO: 37.
  • the ybT-cell receptor or part thereof further comprises: -a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 212,
  • -a 5CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 198, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 205.
  • the cell is a T-cell, preferably an a
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 41 or 44, preferably relative to SEQ ID NO: 41 , and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 45 or 48, preferably relative to SEQ ID NO: 45.
  • the ybT-cell receptor or part thereof further comprises:
  • -a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 214,
  • -a 6CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 200, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 207.
  • the cell is a T-cell, preferably an a
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 49 or 52, preferably relative to SEQ ID NO: 49, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 53 or 56, preferably relative to SEQ ID NO: 53.
  • the ybT-cell receptor or part thereof further comprises:
  • -a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 215,
  • -a 6CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 201 , and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 208.
  • the cell is a T-cell, preferably an a
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 5 or 8, preferably of SEQ ID NO: 5,
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 13 or 16, preferably of SEQ ID NO: 13,
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 17 or 20, preferably of SEQ ID NO: 17, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 21 or 24, preferably of SEQ ID NO: 21 ,
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 29 or 32, preferably of SEQ ID NO: 29,
  • bT-cell receptor chain or a part thereof comprising a CDR3 region, wherein said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 33 or 36, preferably of SEQ ID NO: 33, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 37 or 40, preferably of SEQ ID NO: 37,
  • bT-cell receptor chain or a part thereof comprising a CDR3 region, wherein said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 41 or 44, preferably of SEQ ID NO: 41 , and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 45 or 48, preferably of SEQ ID NO: 45,
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 53 or 56, preferably of SEQ ID NO: 53.
  • the ybT-cell receptor or part thereof comprised by the T-cell preferably apT-cell, further comprises A2, B2, C2, D2, E2, F2, or G2:
  • A2 -a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 209
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 195, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 202,
  • -a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 213
  • -a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 199, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 206,
  • -a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 210
  • -a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 216
  • SEQ ID NO: 216
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 196, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 203,
  • -a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 211
  • -a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with the amino acid sequence QGS
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 197, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 204,
  • -a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 212
  • -a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with the amino acid sequence QGS
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 198, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 205,
  • -a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 214
  • -a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with the amino acid sequence QGS
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 200, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 207,
  • G2 -a 6CDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 215, -a 6CDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 201 , and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% sequence identity or similarity with SEQ ID NO: 208.
  • the cell is a T-cell, preferably an apT-cell, and comprises a nucleic acid molecule encoding a ybT-cell receptor or a part thereof as described herein, the nucleic acid molecule being such that it comprises a nucleotide sequence comprising A1 , B1 , C1 , D1 , E1 , F1 , or G1 :
  • A1 . - a nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 2 or 3, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 2 or 3, and/or;
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 6 or 7, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 6 or 7,
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 10 or 11 , and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 10 or 11 , and/or;
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 14 or 15, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 14 or 15,
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 18 or 19, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 18 or 19, and/or;
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 22 or 23, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 22 or 23,
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 26 or 27, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 26 or 27, and/or;
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 30 or 31 , and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 30 or 31 ,
  • E1 . - a nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 34 or 35, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 34 or 35, and/or;
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 38 or 39, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 38 or 39,
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 42 or 43, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 42 or 43, and/or;
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 46 or 47, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 46 or 47,
  • G1 . - a nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 50 or 51 , and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 50 or 51 , and/or;
  • nucleotide sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity with the nucleotide sequence of SEQ ID NO: 54 or 55, and/or with a nucleotide sequence that encodes an amino acid sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, amino acid identity or similarity with an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 54 or 55.
  • T-cells alternatively called T-lymphocytes, belong to a group of white blood cells named lymphocytes, which play a role in cell-mediated immunity. T-cells originate from hematopoietic stem cells in the bone marrow, mature in the thymus, and gain their full function in peripheral lymphoid tissues.
  • CD4'CD8‘ T-cells (negative for both the CD4 and CD8 co-receptor) are committed either to an ap or yb fate as a result of an initial pTCR or 6TCR gene rearrangement. Cells that undergo early p-chain rearrangement express a pre-TCR structure composed of a complete p-chain and a pre-TCRa chain on the cell surface.
  • Such cells switch to a CD4 + CD8 + state, rearrange the TCRa-chain locus, and express a mature apTCR on the surface.
  • CD4'CD8 _ T-cells that successfully complete the y gene rearrangement before the p-gene rearrangement express a functional ybTCR and remain CD4'CD8 _ (Claudio Tripodo et al. Gamma delta T cell lymphomas Nature Reviews Clinical Oncology 6, 707-717, December 2009).
  • the T-cell receptor associates with the CD3 protein complex.
  • Mature T-cells i.e. , expressing a apTCR or a ybTCR, express the T-cell receptor complex on the cell surface.
  • ybT-cells which constitute about 1-5% of the total population of T-cells, can be divided in further subpopulations which, in humans, is based on TCRb-chain expression.
  • aPT-cells apT cells may be defined with respect to function as T lymphocytes that express an apTCR, which recognize peptides bound to MHC molecules (major histocompatibility complex), which are expressed on the surface of various cells.
  • MHC molecules present peptides derived from the proteins of a cell.
  • a T cells may be functionally defined as being cells capable of recognizing peptides bound to MHC molecules.
  • apT cells may be selected from peripheral blood for example via the CD3 antigen.
  • apT cells may also be selected with an antibody specific for the apTCR, many of which are commercially available such as the ones offered by ThermoFisher Scientific (Waltham, MA, USA).
  • apT cells may also be defined as being cells naturally comprising a nucleic acid (or amino acid) sequence corresponding to an aT-cell receptor chain and/or the pT-cell receptor chain.
  • apT-cells described herein express an endogenous apTCR.
  • apT-cells described herein may have decreased or no expression of an endogenous apTCR.
  • Decreased expression may correspond to at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%, decreased expression of an apTCR relative to an otherwise comparable apT-cell not comprising a genomic modification or not having been subjected to selective expansion.
  • an apT-cell may comprise a higher ratio of an exogenous ybTCR as compared to an endogenous (naturally expressed) apTCR.
  • decreased expression of an endogenous apTCR and/or a higher ratio of an exogenous ybTCR to an endogenous apTCR may be achieved by way of preferential expansion of said T-cells, benefitting the growth and survival of said T-cells.
  • T-cells comprising an exogenous ybTCR may be stimulated by anti-CD3/CD28 antibodies, by contact with antigens that are specific for the exogenous ybTCR, or with cells expressing such antigens, optionally the stimulation being serial stimulation.
  • the preferential expansion may result in a population of said T-cells with limited or absent cell surface expression of the endogenous apTCR, while expressing sufficient amounts of the exogenous ybTCR (referred to as a population enriched for a single positive phenotype).
  • Such cells may have reduced alloreactivity (e.g., graft versus host disease) as compared to cells having surface expression of the endogenous apTCR. Reduced alloreactivity may result in improved therapeutic applications with decreased side-effects.
  • decreased expression of an endogenous apTCR and/or a higher ratio of an exogenous ybTCR to an endogenous apTCR may be achieved by way of preferential expansion of apT-cells also expressing a chimeric bidirectional signaling transmembrane protein (as described herein), benefitting the growth and survival of said T-cells.
  • decreased exoression of an endogenous apTCR and/or a higher ratio of an exogenous ybTCR to an endogenous apTCR may be achieved by preferential expansion of apT-cells expressing a chimeric signaling protein combined with stimulation as discussed above, optionally the stimulation being serial stimulation, benefitting the growth and survival of said T-cells.
  • decreased expression of an endogenous apTCR and/or a higher ratio of an exogenous yQTCR to an endogenous apTCR can be achieved by positively or negatively selecting for cells that express the exogenous yQTCR and have reduced surface expression of the endogenous receptor or lack the endogenous receptor.
  • genomic modification for example a genomic modification which results in the reduction or elimination of surface expression of the endogenous apTCR.
  • a genomic modification may be combined with preferential expansion and/or selection as discussed above. Genomic modification techniques are discussed later herein.
  • an apT-cell of the invention may comprise a ratio of an exogenous yQTCR to an endogenous apTCR that is at least 0.5:1 , at least 1 :1 , at least 2:1 , at least 3:1 , at least 4:1 , at least 5:1 , at least 6:1 , at least 7:1 , at least 8:1 , at least 9:1 , at least 10:1 , at least 11 :1 , at least 12:1 , at least 13:1 , at least 14, :1 at least 15:1 , at least 20:1 , at least 30:1 , at least 40:1 , at least 50:1 , at least 60:1 , at least 70:1 , at least 80:1 , at least 90:1 , at least 100:1 , at least 150:1 , at least 200:1 , at least 250:1 , or at least 300:1 .
  • v6T-cells ybT-cells may be functionally defined in that they are specifically and rapidly activated by e.g., (but not limited to) a set of non-peptidic phosphorylated isoprenoid precursors, collectively named phosphoantigens or stress signals medicated by non-classical HLA molecules like CD1 (this is for example the case for the Vy962 T-cell subset).
  • Phosphoantigens are produced by virtually all living cells, though the levels are usually very low in healthy cells, and increased in transformed I malignant cells or cells infected by e.g., Mycobacterium tuberculosis, which deliver a derivate of phosphoantigens.
  • Activation of y6T-cells comprises clonal expansion, cytotoxic activity and expression and release of cytokines.
  • y6T-cells are also defined by expression of the y6T-cell receptor.
  • cells may be selected using an antibody specific for the ybT-cell receptor, many of which are commercially available such as the ones offered by ThermoFisher Scientific (Waltham, MA, USA). From such selected cells, the nucleic acid (or amino acid sequence) sequence corresponding to the yT-cell receptor chain and/or the bT-cell receptor chain may be determined by sequencing using standard methods available in the art.
  • ybT-cells may also be defined as being cells naturally comprising a nucleic acid (or amino acid) sequence corresponding to a yT-cell receptor chain and/or a bT-cell receptor chain.
  • a ybT-cell expresses a ybTCR.
  • the person skilled in the art is well capable of selecting and/or identifying cell populations characterized by expression of an antigen or receptor on the surface of the cell such as described throughout herein. It is understood that with regard to expression on the surface of cells, such as expression of CD3, CD4, CD8, apTCR, and ybTCR, and parts thereof, this typically involves a population of cells of which a portion of cells have a much higher level of expression of the respective polypeptide when compared to cells having a lower level of expression. Hence, the terms positive or negative are to be understood as being relative, i.e., positive cells have a much higher expression level as compared to cells being negative. Cells being negative in this sense may thus still have an expression level which may be detectable.
  • FACS Fluorescence Activated Cell Sorting
  • apTCR e.g., targeting CD3, CD4, CD8, apTCR, ybTCR, that are suitable for such FACS analysis, many of which are commercially available, such as the ones offered by ThermoFisher Scientific (Waithan, MA, USA).
  • apT cells can also be defined and selected as being positive for apTCR expression in FACS.
  • ybT cells and ybTCR expression Conditions that allow the selection of negative and/or positive cells may be according to the manufacturer’s protocols.
  • additional techniques such as magnetic bead separation may be utilized.
  • antibodies that may be suitable for selection of T-cells described herein are available from BD Pharmingen (BD, Franklin Lakes, NJ USA) such as V62-FITC (clone B6, # 555738), or from Thermofisher Scientific (Waltham, MA, USA) such as Vy1-PE-Cy7 (clone TS8.2, #25-5679-42), or from Biolegend (San Diego, CA, USA) such as a0TCR-BV785 (clone IP26, #306742), or from Beckman Coulter (Brea, CA, USA) such as pan-ybTCR-PE (clone IMMU510, # IM1418U), or from Miltenyi Biotec (Bergisch Gladbach, Germany) such as CD3-VioGreen (clone REA613, #130-113-142, or from Biolegend (San Diego, CA, USA) such as anti-biotin a0TCR (clone IP26, #
  • the T-cells described herein may be primary cells, for example from a subject, such as described in the examples for a human subject.
  • the T-cells may be ap or ybT cells derived from a human subject.
  • the T-cells may be a T-cell line, such as SupT-1 or Jurkat cells or any other widely available cell line. Any cell type, being a primary cell or any cell line can suffice, as long as the cell population, or a substantial part thereof, expresses or is able to express a T-cell receptor, i.e., such as being positive for the a TCR or the ybTCR in a FACS sorting or the like as described above.
  • any cell or cell population may be contemplated that, when provided with a yPTCR according to the invention, is capable of forming a functional TCR complex and exerting e.g., a functional cytotoxic response and/or cytokine production as later defined herein.
  • the cell that is provided may also be a progenitor cell, preferably a blood progenitor cell such as a thymocyte or a blood stem cell, which, after it has been provided with the right stimuli, can develop into a T-cell.
  • T-cells provided herein express or are able to express a ybTCR.
  • T-cells may have been transduced (e.g., with a nucleic acid molecule, construct, or vector as described herein) to express a ybTCR or already express a yTCR and have been transduced to express a 6TCR (or respectively already express a 6TCR and have been transduced to express a yTCR).
  • a preferred bT-cell receptor chain is a 61T-cell receptor chain. Another preferred bT-cell receptor chain is a 63T-cell receptor chain. A preferred yT-cell receptor chain is a y2T-cell receptor chain. Another preferred yT-cell receptor chain is a y3T-cell receptor chain. Another preferred yT-cell receptor chain is a y5T-cell receptor chain. Another preferred yT-cell receptor chain is a y8T-cell receptor chain.
  • a ybT-cell receptor is a y261T-cell receptor. In some embodiments, a ybT-cell receptor is a y361T-cell receptor. In some embodiments, a ybT-cell receptor is a y263T-cell receptor. In some embodiments, a ybT-cell receptor is a y561T-cell receptor. In some embodiments, a ybT-cell receptor is a y861 T-cell receptor.
  • the biological relevance of a yT-cell receptor chain, a bT-cell receptor chain, a ybT-cell receptor, or a part thereof, may for example be assessed by assessing the anti-tumour and/or anti-infective activity/response of a T-cell expressing a defined nucleic acid molecule encoding an amino acid sequence as defined herein.
  • a biological relevance may, for example, be its ability to mediate an anti-tumour or anti-infective response as described herein.
  • the T-cell may already express a bT-cell- or a yT-cell receptor-chain, respectively, identified herein. Using such an approach, multiple combinations of y and bT-cell receptor chains or parts thereof may be assessed.
  • an anti-tumour and/or anti-infective activity/response mediated by a yT-cell receptor chain and/or a bT-cell receptor chain is assessed in an immunoresponsive cell, such asT-cell, that does not endogenously (naturally) express a y or 6 chain of the TCR on their cell surface.
  • an immunoresponsive cell such asT-cell
  • Such a cell may, for example, be an apT-cell or a NK-cell.
  • a nucleic acid molecule, construct, or vector encoding a bT-cell receptor chain or part thereof, preferably a 61 -, 63-T-cell receptor chain, or part thereof, may be introduced into T-cells to provide an engineered T- cell, for example as explained in the general part of the description dedicated to the definitions.
  • a nucleic acid molecule, construct, or vector encoding a yT-cell receptor chain or part thereof, preferably a y2-, y3-, y5-, y8-T-cell receptor chain, or part thereof, may be introduced into T-cells to provide an engineered T-cell, for example as explained in the general part of the description dedicated to the definitions.
  • a nucleic acid molecule, construct, or vector encoding a y6T-cell receptor or part thereof, preferably a y261 T-cell receptor, y361 T-cell receptor, y263T-cell receptor, y561 T-cell receptor, y861 T-cell receptor, or part thereof, may be introduced into T-cells to provide an engineered T-cell, for example as explained in the general part of the description dedicated to the definitions.
  • the cells in order to assess the biological relevance of a 6T-cell receptor chain the cells, such as T-cells, used should also express a yT-cell receptor chain.
  • a y6TCR is preferably expressed in said cells, the 6T-cell receptor chain being the one assesed.
  • the cells, such as T-cells used should also express a 6T-cell receptor chain.
  • a y6TCR is preferably expressed in said cells, the yT-cell receptor chain being the one assesed.
  • the nucleic acid molecule or construct encoding a yT-cell receptor chain, a 6T- cell receptor chain, a y6T-cell receptor, or a part thereof is provided in an vector, preferably a retroviral or lentiviral vector, in a T-cell. This has been extensively explained in the general part of the description dedicated to the definitions.
  • T-cells may optionally be expanded before or after the transfer of the nucleic acids encoding the polypeptides described herein. Preferably, the expansion is after the transfer, allowing the amount of nucleic acids that needs to be transferred to be as low as possible.
  • Expansion of T cells may optionally be performed by stimulation with anti-CD3/CD28 polymeric nanomatrix beads, in the presence of IL-7 and IL-15. Expansion may be performed using commercially available kits, such as T-cell TransActTM (Miltenyi Biotec, Bergisch Gladbach, Germany). A further example is provided in the experimental section herein.
  • the anti-tumour and/or anti-infective activity/response of the provided T-cell expressing a yT-cell receptor chain, a 6T-cell receptor chain, a y6T-cell receptor, or a part thereof, may be assessed using any technique known to the skilled person.
  • determining an anti-tumour and/or anti-infective response or reactivity or activity comprises contacting the T-cells with tumour cells, tumour cell lines, infected cells, or infectious agents such as e.g., fungal cells.
  • Determining an anti-tumour or anti-infective activity may include any assay in which an anti-tumour or anti-infective effect may be determined, such as having an effect on tumour cell or infected cell division rate, i.e., the speed with which the tumour or infected cells divide, cell death, cytolysis/cytotoxicity of the tumour or infected cell, binding to the tumour or infected cells, induction of the production of a cytokine such as IFN-y, IL-2, or TNFa.
  • a cytokine such as IFN-y, IL-2, or TNFa.
  • Tumour cells may be any kind of tumour cells. As a non-limiting example, they may be primary tumour cells from a patient.
  • the tumour cells may be tumour cells from cell lines, such as (but not limited to) the cell lines listed hereafter: HT-29, OVCAR-3, MDA-MB-231 , RKO, BT-549, and RPMI 8226, which are well known in the art.
  • Tumour cell lines may easily be obtained from the American Type Culture Collection (ATCC, Manassas, Virginia) and the like.
  • Infected cells may, for example, be cells that have been infected by a bacterium or a virus.
  • the infection may result in the infected cell displaying an antigen or epitope that is a target of a yT-cell receptor chain, a bT-cell receptor chain, a ybT-cell receptor, or a part thereof as described herein.
  • Non-limiting examples are Plasmodium falciparum, Mycobacterium (M.) tuberculosis and M. leprae.
  • Infectious agents may, for example be, bacteria or fungal cells.
  • determining an anti-tumour or anti-infective response includes contacting the T-cell expressing a defined nucleic acid molecule encoding a yT-cell receptor chain, a bT-cell receptor chain, a ybT-cell receptor, or a part thereof, as described herein, with a tumour or infected cell and measuring its ability to lyse the tumour or infected cell and/or to induce the production of a cytokine such as IFN-y, IL-2, and/or TNFa.
  • the contacting step may, for example, have a duration (incubation period) from 10 hours to 1 , 2, 3, 4, 5 days.
  • the measurement of the ability to lyse the tumour or infected cell may include initially providing a fixed number of tumour or infected cells with which the T-cell is contacted and, after an incubation period, counting the number of the viable tumour or infected cells.
  • An anti-tumour or anti-infective response may be considered to be present when the number of viable tumour or infected cells at the end of the incubation step is less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, or less than 10% of the initial number of tumour or infected cells at the onset of the incubation step.
  • an anti-tumour or anti-infective response may be considered to be present when the number of viable tumour or infected cells at the end of the incubation step with the T-cell is lower than the number of tumour or infected cells at the end of a similar incubation/contacting step with control (comparable) T- cells not comprising the yT-cell receptor chain, bT-cell receptor chain, ybT-cell receptor, or part thereof of the invention.
  • Lower in this context may mean at least 10% lower, at least 20% lower, at least 30% lower, at least 40% lower, at least 50% lower, at least 60% lower, at least 70% lower, at least 80% lower, at least 90% lower.
  • Such cells may be consided to exhibit an improved anti-tumour or anti-infective response compared to the control cells.
  • 51 Chromium-release assay which is known to the skilled person.
  • the amount of 51 Chromium release is a measure of the number of cells that have been lysed.
  • the incubation may have a duration of from 10 hours to 1 , 2, 3, 4, 5 days. In some embodiments, the duration is 1 or 2 days.
  • Control T-cells (not expressing the yT-cell receptor chain, bT-cell receptor chain, ybT-cell receptor, or part thereof of the invention) or control yT-cell receptor chains, bT-cell receptor chains, or yQT-cell receptors, may also be used.
  • Cytotoxicity may be measured using e.g., an xCELLigence assay (Agilent, CA, USA) and plotted as percentage of cytolysis relative to maximum cytolysis induced by treatment of the target cells with the detergent Triton-X-100.
  • the percentage of target cell cytolysis obtained by T-cells expressing the yT-cell receptor chain, bT-cell receptor chain, ybT-cell receptor, or part thereof is higher (preferably at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100% or more) than the percentage of cytolysis obtained when the same target cells are contacted with control (comparable) T-cells not expressing the yT-cell receptor chain, bT-cell receptor chain, ybT-cell receptor, or part thereof of the invention.
  • Such cells may be consided to exhibit an improved anti-tumour or anti-infective response compared to the control cells.
  • Cytotoxicity may be measured using e.g., an LDH release assay from target cells, by calculating the LDH release fold-change when the target cells are incubated with T-cells expressing the yT-cell receptor chain, bT-cell receptor chain, ybT-cell receptor, or part thereof of the invention relative to when the same target cells are incubated with control T-cells.
  • the LDH release when the target cells are incubated with T-cells expressing the yT-cell receptor chain, bT-cell receptor chain, ybT-cell receptor, or part thereof of the invention is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 100% (2-fold), at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, or at least 10-fold relative to when the same target cells are incubated with control T-cells.
  • cytotoxicity may be measured using e.g., a luciferase-based cytotoxicity assay, in which the target cells are pre-transduced to express luciferase and cytotoxicity is measured by measuring decreased luciferase activity relative to target cells cultured alone or with control T-cells.
  • assays may be performed according to commercial protocols, for example by adding D-luciferine substrate (e.g., from ThermoFisher Scientific, Waltham, MA, USA) to target cells incubated with the T-cells and reading the luminescence in culture endpoint mode using a Glomax luminometer according to the manufacturer’s instructions (Promega, Wl, USA).
  • the cytolysis of the target cells as measured in a luciferase-based cytotoxicity assay when the target cells are incubated with T-cells expressing the yT-cell receptor chain, bT-cell receptor chain, ybT-cell receptor, or part thereof of the invention relative to when the same target cells are incubated with control T-cells is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 100% (2-fold), at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8- fold, at least 9-fold, or at least 10-fold,
  • a cytokine such as IFN-y, IL-2 or TNFa
  • the secretion or the expression of activation markers may also be determined, e.g. via antibody staining, ELISA and/or quantitative PCR for the expressed mRNA.
  • Assays for determining the production of a cytokine such as IFN-y, IL-2 or TNFa are commercially widely available (for example from &D Systems, Minneapolis, MN, US).
  • the T-cell expressing a yT-cell receptor chain, a bT-cell receptor chain, a ybT-cell receptor, or a part thereof may be considered to exhibit an anti-tumour or anti-infective response.
  • the amount of IFN-y, IL-2 or TNFa produced at the end of the contacting step with said T-cell is higher (preferably at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100% or more) than the amount of IFN-y, IL-2 or TNFa produced when the tumour or infected cell is contacted with control (comparable) T- cells not expressing the yT-cell receptor chain, bT-cell receptor chain, ybT-cell receptor, or part thereof of the invention the cells may be consided to exhibit an improved anti-tumour or anti-infective response compared to the control cells.
  • An anti-tumour response may also be determined by assessing the binding of T-cells expressing a yT-cell receptor chain, a bT-cell receptor chain, a ybT-cell receptor, or a part thereof described herein to a tumour or infected cell after contacting both cells together.
  • Such a contacting step may have a duration of from 10 hours to 1 , 2, 3, 4, 5 days.
  • said T- cell may be considered to exhibit an anti-tumour or anti-infective response.
  • the binding of said T-cell to said tumour or infected cell at the end of the contacting step is higher (preferably at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100% or more) than the binding displayed by control (comparable) T-cells not expressing the yT-cell receptor chain, bT-cell receptor chain, ybT-cell receptor, or part thereof of the invention to the same tumour or infected cell.
  • Such cells may be consided to exhibit an improved anti-tumour or anti-infective response compared to the control cells.
  • the yT-cell receptor chain, bT-cell receptor chain, ybT-cell receptor, or part thereof mediates an anti-tumour or anti-infective response or activity.
  • tumour or infected cell division rate tumour or infected cell death, tumour or infected cell cytolysis/cytotoxicity, binding to the tumour or infected cell, induction of the production of a cytokine such as IFN-y, IL-2, or TNFa
  • a cytokine such as IFN-y, IL-2, or TNFa
  • the yT-cell receptor chain, bT-cell receptor chain, ybT-cell receptor, or part thereof may be considered to mediate an anti-tumour or anti-infective response.
  • control cells may, for example, be T-cells that are untransduced or that are transduced by an empty viral vector or that are transduced by a control yT-cell receptor chain, bT-cell receptor chain, ybT-cell receptor, or part thereof.
  • a control T-cell may express a ybT-cell receptor as described in WO2017/212072, incorporated herein by reference in its entirety.
  • the control T- cell is an apT-cell expressing a yT-cell receptorchain represented by SEQ ID NO: 218 and a bT-cell receptor chain represented by SEQ ID NO: 217.
  • control T-cell is an apT-cell expressing a yT-cell receptor chain comprising a yCDR3 region represented by SEQ ID NO: 220 and a bT-cell receptor chain comprising a 6CDR3 region represented by SEQ ID NO: 219.
  • expression of a yT-cell receptor chain, a bT-cell receptor chain, a ybT-cell receptor, or a part thereof, by a T-cell as described herein may result in increased expansion, fitness, and/or survival of the T-cell relative to an otherwise comparable T-cell not expressing the yT-cell receptor chain, bT-cell receptor chain, ybT-cell receptor, or part thereof of the invention.
  • the expansion (proliferative ability), fitness and/or survival (lifespan) of the provided T-cells may be assessed using any technique known to the skilled person.
  • T-cells may be optionally stimulated with anti- CD3/CD28 polymeric nanomatrix beads, in the presence of IL-7 and IL-15. This may be performed using commercially available kits as discussed earlier herein. The skilled person may measure the T-cell number prior to and post-stimulation and thus determine the proliferative ability of the cells. Alternatively, expansion may be monitored via e.g., cell trace violet (or any other suitable dye) dilution when T-cell are stained at the start of a proliferative assay.
  • cell trace violet or any other suitable dye
  • Fitness of T-cells may, for example, be monitored based on staining for various markers including, but not limited to CD4, CD8a, CD3, apTCR, ybTCR, 4-1 BB, 0X40, PD-1 , TIM-3, LAG-3, 4-1 BBL, OX40L, CD86, Fab2, CD107a and CD69, for example staining with fluorescent-labeled antibodies targeting these markers in combination with flow cytometry.
  • markers including, but not limited to CD4, CD8a, CD3, apTCR, ybTCR, 4-1 BB, 0X40, PD-1 , TIM-3, LAG-3, 4-1 BBL, OX40L, CD86, Fab2, CD107a and CD69, for example staining with fluorescent-labeled antibodies targeting these markers in combination with flow cytometry.
  • T-cells may, for example, be monitored based on any cell viability assay known to the skilled person, many of which are commercially available (see for example the assays offered by ThermoFisher Scientific, WA, MA, USA).
  • Non-limiting examples of cell viability assays involve the use of dyes such as calcein AM, ethidium-homodimer-1 , SYTOX Deep Red, DiOC 19(3), propidium iodide, SYBR 14, SYTO 10, green ethidium homodimer-2, SYTOX Green, C-12 resazurin, BOBO-3 iodide, DAPI, and others.
  • the skilled person may monitor their survival by measuring the number of viable cells over time.
  • expansion of a T-cell expressing a yT-cell receptor chain, a bT-cell receptor chain, a ybT-cell receptor, or a part thereof, as described herein is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 2- fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9- fold, at least 10-fold, or more, relative to an otherwise comparable T-cell not expressing the yT-cell receptor chain, bT-cell receptor chain, ybT-cell receptor, or part thereof.
  • fitness of a T-cell expressing a yT-cell receptor chain, a bT-cell receptor chain, a ybT-cell receptor, or a part thereof, as described herein is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, or more, relative to an otherwise comparable T-cell not expressing the yT-cell receptor chain, bT-cell receptor chain, ybT-cell receptor, or part thereof.
  • survival of a T-cell expressing a yT-cell receptor chain, a bT-cell receptor chain, a ybT-cell receptor, or a part thereof, as described herein is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, or more, relative to an otherwise comparable T-cell not expressing the yT-cell receptor chain, bT-cell receptor chain, ybT-cell receptor, or part thereof.
  • Survival may be measured over a defined period, for example over about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weks, about 7 weeks, about 8 weeks, about 9 weeks, or about 10 weeks.
  • a chimeric polypeptide comprising a yT-cell receptor chain, a bT-cell receptor chain, a ybT-cell receptor, or a part thereof (such as e.g., an extracellular domain or part thereof) and a T-cell- and/or NK-cell-binding domain (and optionally any other suitable domain discussed herein) may be provided together with T-cells in the assays described herein, and the anti-tumour or anti-infective response of the T-cells as mediated by the chimeric polypeptide may then be assessed using any of the assays described above. Control T-cells as described above may similarly be used for the comparisons.
  • a population of cells comprising the cell as defined earlier herein.
  • a cell expresses a yT-cell receptor chain, a bT-cell receptor chain, a ydT-cell receptor, or a part thereof as described herein.
  • such a cell comprises a nucleic acid molecule, construct, or vector encoding a yT-cell receptor chain, a bT-cell receptor chain, a ybT-cell receptor, or a part thereof, as described herein.
  • the cells within the cell population, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% of the cells are expressing a a yT-cell receptor chain, a bT-cell receptor chain, a ybT-cell receptor, a part thereof, or comprising a nucleic acid molecule, construct, or vector encoding a yT-cell receptor chain, a bT-cell receptor chain, a ybT-cell receptor, or a part thereof, as described herein.
  • the cells are T-cells, more preferably apT-cells or NK-cells, most preferably apT-cells.
  • the person skilled in the art is well capable of selecting and/or identifying cell populations, or cells within cell populations, characterized by expression of the yT-cell receptor chain, bT-cell receptor chain, ybT-cell receptor, part thereof using, e.g., flow cytometric methods such as FACS as explained earlier herein.
  • a T-cell preferably an apT-cell, that comprises: a) a nucleic acid molecule, construct, or vector encoding a yT-cell receptor chain, a bT-cell receptor chain, a ybT-cell receptor, or part thereof, and/or expresses a yT-cell receptor chain, a bT-cell receptor chain, a ybT-cell receptor, or part thereof, as described earlier herein, and b) a polynucleotide encoding a chimeric bidirectional signaling transmembrane protein able to transduce at least two intracellular signals, said protein comprising:
  • heterologous intracellular signaling domain transducing a first signal after binding of the extracellular ligand domain to its interaction partner.
  • chimeric bidirectional signaling transmembrane protein may be replaced by the expression “chimeric signaling protein’’ or "MIDIS”.
  • MIDIS chimeric signaling protein
  • bidirectional signal transducer proteins or chimeric signaling proteins that may be coexpressed in conjunction with the yT-cell receptor chains, bT-cell receptor chains, ybT-cell receptors, or parts thereof described herein, in T-cells, preferably apT-cells.
  • T-cells for example, difficulties in generating sufficient numbers of the desired cells, limited proliferative ability or lifespan of the cells, limited induction of effector function upon cell recognition of antigen, and cell exhaustion.
  • these chimeric signaling proteins can be used to improve the production and use of T-cells as identified herein.
  • the expression of such a chimeric signaling protein may have a positive effect on some properties exhibited by these T-cells, such as their immune effector function.
  • These chimeric signaling proteins are engineered fusion proteins that contain an extracellular ligand domain that binds to an interaction partner, a transmembrane domain, and a heterologous intracellular signaling domain (from or derived from a different protein than the extracellular ligand domain).
  • multi-directional signaling is induced that comprises at least one signal mediated by the heterologous intracellular signaling domain of said chimeric signaling protein, and at least one signal mediated by an intracellular signaling domain of the interaction partner.
  • the at least two signals may be induced in the same cell, or in different cells.
  • Fig. 13 demonstrates a schematic of the chimeric signaling protein described herein.
  • An extracellular ligand domain of a chimeric signaling protein may be be selected based on its ability to induce signaling mediated by a desired interaction partner. In some cases, an extracellular ligand domain of a chimeric signaling protein may be selected based on its ability to elicit signaling mediated by the heterologous intracellular signaling domain of the chimeric signaling protein upon binding to the interaction partner.
  • the “at least two intracellular signals’’ are inducible.
  • the chimeric bidirectional signaling transmembrane protein may be considered as having two configurations: one wherein no signal is induced and one wherein “at least two intracellular signals’’ are induced upon interaction of the extracellular ligand domain of the chimeric signaling protein with the extracellular ligand domain of its interaction partner. These “at least two intracellular signals’’ may occur simultaneously or sequentially.
  • the inducibility of these “at least two intracellular signals’’ is attractive as the chimeric signaling protein is controllable by the interaction partner and vice versa. This inducibility may be assessed using techniques known to the skilled person and depending on the identity of the heterologous intracellular signaling domain of the chimeric signaling protein and of the intracellular domain of the interaction partner.
  • one of these “at least two intracellular signals’’ may depend on the activation of an additional receptor, for example but not limited to a ybTCR.
  • An extracellular ligand domain can comprise an amino acid sequence that is from or derived from a protein that is expressed on a cell surface.
  • the protein expressed on a cell surface has agonist activity on a cognate receptor.
  • the extracellular ligand domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from a type I transmembrane protein. In some embodiments, the extracellular ligand domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from a type II transmembrane protein.
  • the extracellular ligand domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from a tumour necrosis factor superfamily member. In some cases, the extracellular ligand domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from an immune co-receptor ligand, for example, an immune co-stimulatory ligand. In some embodiments, the extracellular ligand domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from an immunoglobulin superfamily member. The extracellular ligand domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from 41 BBL, OX40L, CD86, RANK, or CD70.
  • the extracellular ligand domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from 41 BBL. In some embodiments, the extracellular ligand domain of a chimeric signaling protein is from or derived from 41 BBL which is a type II transmembrane protein. In some embodiments, the extracellular ligand domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from OX40L. In some embodiments, the extracellular ligand domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from CD86. In some embodiments, the extracellular ligand domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from RANK. In some embodiments, the extracellular ligand domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from CD70.
  • the extracellular ligand domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from a receptor, for example, an ion channel, GPCR, or receptor tyrosine kinase.
  • the extracellular ligand domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from a tumour necrosis factor receptor superfamily member.
  • the extracellular ligand domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from an immune co-receptor.
  • the extracellular ligand domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from a cytokine.
  • the extracellular ligand domain can comprise an amino acid sequence that is from or derived from a C-type lectin.
  • the extracellular ligand domain can comprise an amino acid sequence that is from or derived from a soluble protein, for example, a secreted or cytoplasmic protein.
  • An extracellular ligand domain of a chimeric signaling protein can comprise a peptide ligand of an interaction partner, for example, a naturally-occurring or a synthetic peptide ligand.
  • An extracellular ligand domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from an antigen-binding protein.
  • antigen-binding proteins include antibodies, variable regions (e.g., variable chain heavy region (VH) and/or variable chain light region (VL)), short chain variable fragments (scFv), single domain antibodies, Fab, Fab', F(ab') 2 , dimers and trimers of Fab conjugates, Fv, minibodies, diabodies, triabodies, tetrabodies, affibodies, ankyrin proteins, ankyrin repeats, DARPins, monobodies, nanobodies, avimers, adnectins, anticalins, Fynomers, Kunitz domains, knottins, or 0-hairpin mimetics.
  • an extracellular ligand domain comprises one or more single-chain variable fragments (scFvs).
  • scFv single-chain variable fragment
  • a scFv is a fusion protein that can comprise VH and VL domains connected by a peptide linker. Manipulation of the orientation of the VH and VL domains and the linker length can be used to create different forms of molecules that can be monomeric, dimeric (diabody), trimeric (triabody), or tetrameric (tetrabody).
  • Minibodies are scFv-CH3fusion proteins that assemble into bivalent dimers.
  • an extracellular ligand domain of a chimeric signaling protein comprises one or more DARPins.
  • an extracellular ligand domain of a chimeric signaling protein comprises one or more complementarity determining regions (CDRs) from an antibody or T cell receptor, for example, one, three or six CDRs.
  • CDRs complementarity determining regions
  • Antigen-binding fragments derived from monoclonal antibodies can be, for example, chimeric, humanized or fully human.
  • An extracellular ligand domain of a chimeric signaling protein can be selected based on its binding affinity for a desired interaction partner.
  • an extracellular ligand domain binds to an interaction partner with a KD of, for example, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 1 nM, less than about 900 pM, less than about 800 pM, less than about 700 pM, less than about 600 pM, less than about 500 pM, less than about 400 pM, less than about 300 pM, less than about 200 pM, less than about 100 pM, less than about
  • An extracellular ligand domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from a wild type protein amino acid sequence.
  • a wild type protein amino acid sequence can refer to a sequence that is naturally occurring and encoded by a germline genome.
  • a species can have one wild type sequence, or two or more wild type sequences (for example, with one canonical wild type sequence and one or more non-canonical wild type sequences).
  • a wild type protein amino acid sequence can be a mature form of a protein that has been processed to remove N-terminal and/or C-terminal residues, for example, to remove a signal peptide.
  • An extracellular ligand domain of a chimeric signaling protein can comprise an amino acid sequence that is modified compared to a wild type protein amino acid sequence or any other amino acid sequence disclosed herein, for example, to achieve a desirable level of expression, surface expression, stability, resistance to aggregation, resistance to degradation, affinity for an interaction partner, or level of signaling mediated by an interaction partner.
  • An extracellular ligand domain of a chimeric signaling protein can comprise an amino acid sequence that is modified compared to a wild type protein amino acid sequence or an amino acid sequence disclosed herein, for example, to promote folding of the chimeric signaling protein into a biologically active conformation.
  • part or all of an extracellular ligand domain of a chimeric signaling protein comprises an amino acid sequence that is inverted compared to a wild type amino acid sequence (i.e. expressed as a retro-protein).
  • An extracellular ligand domain of a chimeric signaling protein can comprise, consist essentially of, or consist of an amino acid sequence with at least a minimal level of sequence identity compared to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein.
  • such an extracellular ligand domain having at least a minimal level of sequence identity compared to a given amino acid sequence is functional and therefore encompassed by the invention as long as this extracellular ligand domain is able to bind or interact with the extracellular domain of its interaction partner.
  • the level of binding or interaction should be detectable using an assay known to the skilled person. Examples of suitable assays are western blotting or FACS, ELISA or SPR assays.
  • the extracellular ligand domain used, the skilled person will know which assay is the most appropriate. For example, for 0X40, NFKB signaling will be assessed, for 41 BBL the binding of 41 BB will be assessed. In some embodiments, the activity of the extracellular ligand domain is assessed when said extracellular ligand domain is still comprised within the full length transmembrane molecule it originates from.
  • an extracellular ligand domain of a chimeric signaling protein can comprise, consist essentially of, or consist of an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 98.5%, at least 99%, or at least 99.5% sequence identity to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 57-63 (see Table 2).
  • an extracellular ligand domain of a chimeric signaling protein comprises an amino acid sequence that is inverted compared to a wild type amino acid sequence (i.e. expressed as a retro-protein)
  • the wild type protein amino acid sequence can be inverted prior to calculating sequence identity.
  • an extracellular ligand domain of a chimeric signaling protein can comprise, consist essentially of, or consist of an amino acid sequence that is a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein,
  • An interaction partner may be a co-immune receptor.
  • Table 2 provides non-limiting examples of amino acid sequences that extracellular domains of of a chimeric signaling protein described herein can comprise, consist of, consist essentially of, or be derived from (EC: extracellular).
  • An extracellular ligand domain of a chimeric signaling protein can comprise an amino acid sequence with one or more amino acid insertions, deletions, or substitutions compared to a wild type protein amino acid sequence or any other amino acid sequence disclosed herein.
  • an extracellular ligand domain can comprise an amino acid sequence with at least 1 , at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11 , at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, or at least 50 amino acid insertions relative to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 57-63.
  • an extracellular ligand domain of a chimeric signaling protein comprises an amino acid sequence with at most 1 , at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 1 1 , at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 25, at most 30, at most 35, at most 40, at most 45, or at most 50 amino acid insertions relative to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 57-63.
  • an extracellular ligand domain of a chimeric signaling protein comprises an amino acid sequence with 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 amino acid insertions relative to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 57-63.
  • the one or more insertions can be at the N-terminus, C-terminus, within the amino acid sequence, or a combination thereof.
  • the one or more insertions can be contiguous, non-contiguous, or a combination thereof.
  • an extracellular ligand domain of a chimeric signaling protein comprises an amino acid sequence with at least 1 , at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11 , at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, or at least 50 amino acid deletions relative to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 57-63.
  • an extracellular ligand domain of a chimeric signaling protein comprises an amino acid sequence with at most 1 , at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11 , at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 25, at most 30, at most 35, at most 40, at most 45, or at most 50 amino acid deletions relative to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 57-63.
  • an extracellular ligand domain of a chimeric signaling protein comprises an amino acid sequence with 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 amino acid deletions relative to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 57-63.
  • the one or more deletions can be at the N-terminus, C-terminus, within the amino acid sequence, or a combination thereof.
  • the one or more deletions can be contiguous, non-contiguous, or a combination thereof.
  • an extracellular ligand domain of a chimeric signaling protein comprises an amino acid sequence with at least 1 , at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11 , at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, or at least 50 amino acid substitutions relative to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 57-63.
  • an extracellular ligand domain of a chimeric signaling protein comprises an amino acid sequence with at most 1 , at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11 , at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 25, at most 30, at most 35, at most 40, at most 45, or at most 50 amino acid substitutions relative to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 57-63.
  • an extracellular ligand domain of a chimeric signaling protein comprises an amino acid sequence with 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 amino acid substitutions relative to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 57-63.
  • the one or more substitutions can be at the N-terminus, C-terminus, within the amino acid sequence, or a combination thereof.
  • the one or more substitutions can be contiguous, non-contiguous, or a combination thereof.
  • the one or more substitutions can be conservative, non-conservative, or a combination thereof.
  • a chimeric signaling protein can have any suitable number of extracellular ligand domains. In some embodiments a chimeric signaling protein has one extracellular ligand domain. In some embodiments, a chimeric signaling protein has two extracellular ligand domains. In some embodiments, a chimeric signaling protein has 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 extracellular ligand domain(s). In some embodiments, a chimeric signaling protein has at least 1 , at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 extracellular ligand domain(s). In some embodiments, a chimeric signaling protein has at most 1 , at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, or at most 10 extracellular ligand domain(s).
  • An interaction partner of an extracellular ligand domain is present on the surface of a cell and upon binding of the extracellular ligand domain to the interaction partner, signaling via an intracellular domain of the interaction partner is induced. Induction of the signaling pathway can contribute to a range of target biological outcomes and biological functions disclosed herein, for example, enhanced cellular proliferation, survival, and greater magnitude and duration of immune effector functions.
  • An interaction partner may be a co-immune receptor.
  • a T-cell preferably apT-cell comprises, preferably expresses the chimeric bidirectional signaling transmembrane protein and the interaction partner, each as a transmembrane protein.
  • the interaction partner may be endogenously expressed on a cell and said cell may be transduced or transform with the chimeric bidirectional signaling transmembrane protein.
  • both the interaction partner and the chimeric bidirectional signaling transmembrane protein may be transduced into the same cell.
  • the interaction partner of the chimeric bidirectional signaling transmembrane protein comprises: an extracellular domain able to interact with the extracellular ligand domain of the chimeric signaling protein, a transmembrane domain, and an intracellular domain transducing a second signal after binding of the extracellular domain of the interaction partner to the extracellular ligand domain of the chimeric signaling protein.
  • binding of the extracellular ligand domain of the chimeric signaling protein to the interaction partner modulates a second signaling pathway, for example, induces, or increases or decreases activity of the second signaling pathway.
  • the interaction partner is present in a signaling complex and upon binding of the extracellular ligand domain of the chimeric signaling protein to the interaction partner, signaling mediated by the interaction partner is modulated, e.g., signaling mediated by the signaling complex is increased or decreased.
  • activity of a first signaling pathway is reduced and a different signaling pathway is induced.
  • An interaction partner can be selected based on its ability to modulate (e.g., induce) a signaling pathway that is associated with a desired biological outcome or biological function.
  • the chimeric signaling protein binds to the interaction partner as a monomer. In some embodiments, the chimeric signaling protein forms a dimer when bound to the interaction partner. In some embodiments, the chimeric signaling protein forms a trimer when bound to the interaction partner. In some embodiments, the chimeric signaling protein binds to the interaction partner as a tetramer, a pentamer, a hexamer, or a multimer.
  • the chimeric signaling protein When bound as a multimer (e.g., a dimer, trimer, tetramer, pentamer, hexamer, or higher order multimer), the chimeric signaling protein can form a homo-multimer (e.g., homodimer, homotrimer, homotetramer, homopentamer, homohexamer, or higher order homomultimer). In some cases, the chimeric signaling protein binds to the interaction partner as a hetero-multimer (e.g., a heterodimer, heterotrimer, heterotetramer, heteropentamer, heterohexamer, or higher order heteromultimer).
  • a hetero-multimer e.g., a heterodimer, heterotrimer, heterotetramer, heteropentamer, heterohexamer, or higher order heteromultimer.
  • the interaction partner that binds to the extracellular ligand domain of the chimeric signaling protein is expressed by an immune cell.
  • the interaction partner is expressed by a leukocyte, such as a lymphocyte, e.g., a T-cell.
  • the interaction partner is expressed by a cancer cell.
  • the interaction partner is expressed by a mammalian cell.
  • the interaction partner is expressed by a human cell.
  • the interaction partner is expressed by an apT-cell , a ybT-cell, CD4+ T- cell, CD8+ T-cell, a T effector cell, a lymphocyte, a B-cell, an NK-cell, an NKT-cell, a myeloid cell, a monocyte, a macrophage, a neutrophil, a basophil, a dendritic cell, an eosinophil, a granulocyte, a helper T-cell, a memory T-cell, a Langerhans cell, a lymphoid cell, an innate lymphoid cell (ILC), a mast cell, a megakaryocyte, a plasma cell, a regulatory T-cell, a thymocyte, a fibroblast, a keratinocyte, a mesenchymal stem cell, an endothelial cell, a stromal cell, or any mixture or combination of cells thereof.
  • the interaction partner is expressed by an ap
  • the interaction partner is expressed by a cell that is the same cell type as the cell that expresses the chimeric signaling protein (that is the T-cell as earlier defined herein). In some embodiments, the chimeric signaling protein and the interaction partner are both expressed by the same cell (that is the T-cell as earlier defined herein).
  • An interaction partner can be a receptor, for example, for example a tumour necrosis factor receptor superfamily member.
  • the interaction partner can be, for example, 41 BB, 0X40, RANKL, IL18RAP (IL18RB), or CD27.
  • the interaction partner is 41 BB.
  • the interaction partner is 0X40.
  • the interaction partner is RANKL.
  • the interaction partner is IL18RAP.
  • the intereaction partner is CD27.
  • an interaction partner is an immunoglobulin superfamily member, or an immune coreceptor, for example an activating immune co-receptor, such as CD86.
  • an interaction partner is a cytokine receptor.
  • an interaction partner is a C-type lectin receptor.
  • the interaction partner is an ion channel, GPCR, peptidase, integrin, tetraspanin, or receptor tyrosine kinase.
  • an interaction partner is a tumour necrosis factor superfamily member that comprises an intracellular domain that can mediate signaling.
  • the interaction partner is 41 BBL or OX40L.
  • the at least two inducible intracellular signals transduced by the chimeric bidirectional signaling transmembrane protein contribute to an improvement of a biological parameter and/or function of the T-cell as earlier defined herein expressing the chimeric signaling protein and the ybTCR and/or an improvement of a biological parameter and/or function induced by such a cell.
  • the function is an anti-tumour or anti-infective response or activity as earlier defined herein.
  • the antitumour or anti-infectice response or activity is stronger and more durable. The assessment of an anti-tumour or anti-infective response or reactivity or activity has been already explained herein.
  • the extracellular ligand domain of the chimeric signaling protein upon binding of the extracellular ligand domain of the chimeric signaling protein to the interaction partner, at least one, at least two, at least three, at least four, at least five, or at least six signaling pathways are induced that are mediated by the intracellular domain of the interaction partner. In some embodiments, upon binding of the extracellular ligand domain to the interaction partner, one, two, three, four, five, or six signaling pathways are induced that are mediated by the intracellular domain of the interaction partner. In some embodiments, upon binding of the extracellular ligand domain to the interaction partner, one signaling pathway is induced that is mediated by the intracellular domain of the interaction partner.
  • the extracellular part of the chimeric signaling protein can comprise one or more additional extracellular domains as well as the one or more extracellular ligand domains.
  • a chimeric signaling protein comprises one or more additional extracellular domains from the same protein as the extracellular ligand domain, e.g., stretches of amino acids that do not participate in binding to an interaction partner, or do not induce signaling mediated by an interaction partner that binds to the extracellular ligand domain.
  • an additional extracellulardomain does not participate in binding to the interaction partner but, increases or decreases a level of signaling mediated by the interaction partner.
  • a chimeric signaling protein comprises an additional extracellular domain that is from or derived from the same protein as the transmembrane domain, e.g., the same protein or a different protein than the heterologous intracellular signaling domain. In some embodiments, such an additional extracellular domain does not induce signaling mediated by an interaction partner.
  • a chimeric signaling protein comprises an additional extracellular domain that is from or derived from the same protein as the heterologous intracellular signaling domain. In some embodiments, such an additional extracellular domain does not induce signaling mediated by an interaction partner. In some cases, an additional extracellular domain can be selected based on its ability to elicit signaling in mediated by the heterologous intracellular signaling domain of the chimeric signaling protein upon binding of the extracellular ligand domain to the interaction partner.
  • An additional extracellular domain of a chimeric signaling protein can be or can comprise a cleavage site, for example, an ADAM family cleavage site or a metalloprotease family cleavage site.
  • An additional extracellular domain can be or can comprise a multimerization domain (e.g., a domain that facilitates formation of a homo- or hetero- dimer, trimer, tetramer, pentamer, hexamer, or higher order multimer, such as a tenascin-C oligomerization domain, a thrombospondin oligomerization domain, or a GCN4 oligomerization domain).
  • a multimerization domain e.g., a domain that facilitates formation of a homo- or hetero- dimer, trimer, tetramer, pentamer, hexamer, or higher order multimer, such as a tenascin-C oligomerization domain, a thrombospondin
  • An additional extracellular domain can be or can comprise a cellular localization motif, e.g., a lipid raft localization motif or a nuclear localization motif.
  • An additional extracellular domain can be or can comprise a target peptide, e.g., a signal peptide.
  • An additional extracellular domain can comprise a linker.
  • An additional extracellular domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from a wild type protein amino acid sequence.
  • An additional extracellular domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from any protein or type of protein disclosed elsewhere herein.
  • An additional extracellular domain of a chimeric signaling protein can comprise an amino acid sequence that is modified compared to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, to achieve a desirable level of expression, surface expression, stability, resistance to aggregation, resistance to shedding, or resistance to degradation.
  • An additional extracellular domain of a chimeric signaling protein can comprise an amino acid sequence that is modified compared to a wild type protein amino acid sequence or an amino acid sequence disclosed herein, for example, to promote folding of the chimeric signaling protein into a biologically active conformation.
  • part or all of an additional extracellular domain of a chimeric signaling protein comprises an amino acid sequence that is inverted compared to a wild type amino acid sequence (i.e. expressed as a retro-protein).
  • An additional extracellular domain of a chimeric signaling protein can comprise an amino acid sequence with one or more amino acid insertions, deletions, or substitutions compared to a wild type protein amino acid sequence or any other such amino acid sequence as disclosed elsewhere herein.
  • An additional extracellular domain of a chimeric signaling protein can comprise at least a minimal level of sequence identity compared to a wild type protein amino acid sequence or any other such amino acid sequence as disclosed elsewhere herein.
  • Chimeric signaling proteins described herein comprise at least one heterologous intracellular signaling domain.
  • “Heterologous” refers to the fact that the intracellular signaling domain is from or is derived from a different protein than the extracellular ligand domain.
  • a signaling pathway mediated by the heterologous intracellular signaling domain of a chimeric signaling protein is induced upon binding of the extracellular ligand domain to an interaction partner.
  • the induction of the signaling pathway can contribute to a range of target biological outcomes and biological functions disclosed herein, for example, enhanced cellular proliferation, survival, and greater magnitude and duration of immune effector functions such as anti-tumour or anti-infective activity.
  • a heterologous intracellular signaling domain of a chimeric signaling protein can be selected based on its ability to induce a signaling pathway that is associated with a desired biological outcome or biological function.
  • a heterologous intracellular signaling domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from a transmembrane protein, for example, a protein that is expressed on a cell surface.
  • the heterologous intracellular signaling domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from a type I transmembrane protein.
  • the heterologous intracellular signaling domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from a type II transmembrane protein.
  • the heterologous intracellular signaling domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from a tumour necrosis factor receptor superfamily member.
  • the heterologous intracellular signaling domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from an immunoglobulin superfamily member.
  • the heterologous intracellular signaling domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from a cytokine receptor.
  • the heterologous intracellular signaling domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from a C-lectin family member.
  • the heterologous intracellular signaling domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from 41 BB, 0X40, NKp80, or IL2RB. In some embodiments, the heterologous intracellular signaling domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from 41 BB. In some embodiments, the heterologous intracellular signaling domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from 0X40. In some embodiment, the heterologous intracellular signaling domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from 0X40 and is from or derived from a type I transmembrane 0X40 protein.
  • the heterologous intracellular signaling domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from NKp80. In some embodiments, the heterologous intracellular signaling domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from IL18RAP. In some embodiments, the heterologous intracellular signaling domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from IL2RB.
  • the heterologous intracellular signaling domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from a receptor, for example, an ion channel, GPCR, serine protease, an immunoglobulin superfamily member, complement receptor, TIR domain containing receptor, or receptor tyrosine kinase.
  • the heterologous intracellular signaling domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from a cytokine receptor.
  • the heterologous intracellular signaling domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from a C-type lectin receptor.
  • the heterologous intracellular signaling domain can comprise an amino acid sequence that is from or derived a cytoplasmic protein that participates in a signaling pathway.
  • the heterologous intracellular signaling domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived a nuclear protein that participates in a signaling pathway.
  • the heterologous intracellular signaling domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from an intracellular domain of a tumour necrosis factor superfamily member. In some embodiments, the heterologous intracellular signaling domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from an intracellular domain of an immune co-receptor. In some cases, the heterologous intracellular signaling domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from an intracellular domain of an immune co-receptor ligand that contains a signaling domain, for example, an intracellular signaling domain of an immune co-stimulatory ligand.
  • a truncated portion of the signaling domain can be used in the heterologous intracellular signaling domain of a chimeric signaling protein.
  • the heterologous intracellular signaling domain of a chimeric signaling protein can be structurally distinct from intracellular domains found in chimeric antigen receptors and similar chimeric signaling proteins.
  • the heterologous intracellular signaling domain of a chimeric signaling protein can lack one or more components associated with TCR complex signaling.
  • the heterologous intracellular signaling domain of a chimeric signaling protein does not contain an ITAM.
  • the heterologous intracellular signaling domain of a chimeric signaling protein contains a hemITAM but does not contain an ITAM. In some embodiments, the heterologous intracellular signaling domain of a chimeric signaling protein is not phosphorylated upon binding of the chimeric signaling protein to the interaction partner. In some embodiments, the heterologous intracellular signaling domain of a chimeric signaling protein does not contain an intracellular domain from a CD3 chain, for example does not contain an intracellular domain of a CD3 zeta chain. In some embodiments, the heterologous intracellular signaling domain of a chimeric signaling protein does not contain an intracellular domain from a TCR signaling complex.
  • the heterologous intracellular signaling domain of a chimeric signaling protein is phosphorylated upon binding of the chimeric signaling protein to the interaction partner.
  • a heterologous intracellular signaling domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from a wild type protein amino acid sequence.
  • a heterologous intracellular signaling domain of a chimeric signaling protein can comprise an amino acid sequence that is modified compared to a wild type protein amino acid sequence or any such other amino acid sequence disclosed herein, for example, to achieve a desirable level of expression, surface expression, stability, resistance to aggregation, resistance to degradation, signaling strength, or affinity for a protein that participates in downstream signaling, e.g., an adapter protein.
  • a heterologous intracellular signaling domain of a chimeric signaling protein can comprise an amino acid sequence that is modified compared to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, to promote folding of the chimeric signaling protein into a biologically active conformation.
  • part or all of a heterologous intracellular signaling domain of a chimeric signaling protein comprises an amino acid sequence that is inverted compared to a wild type amino acid sequence (i.e. expressed as a retro- protein).
  • a heterologous intracellular signaling domain of a chimeric signaling protein can comprise, consist essentially of, or consist of an amino acid sequence with at least a minimal level of sequence identity compared to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein.
  • a heterologous intracellular signaling domain of a chimeric signaling protein can comprise, consist essentially of, or consist of an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 98.5%, at least 99%, or at least 99.5% sequence identity to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs:64-77 (see Table 3).
  • such heterologous intracellular signaling domain having at least a minimal level of sequence identity compared to a given amino acid sequence is functional and therefore encompassed by the invention as long as this intracellular signaling domain is able to transduce a first signal after binding of the extracellular ligand domain to its interaction partner.
  • the first signal should be detectable using an assay known to the skilled person. Examples of suitable assays are western blotting or FACS, luminescence assays. Depending on the identity of the heterologous intracellu lar sig naling domain used, the skilled person will know which assay is appropriate to use.
  • a NfKB reporter assay may be used to assess the activity of said heterologous intracellular domain.
  • the activity of the heterologous intracellular signaling domain is assessed when said intracellular signaling domain is still comprised within the full length transmembrane molecule it originates from.
  • a heterologous intracellular signaling domain of a chimeric signaling protein comprises an amino acid sequence that is inverted compared to a wild type amino acid sequence (i.e. expressed as a retro-protein)
  • the wild type protein amino acid sequence can be inverted prior to calculating sequence identity.
  • a heterologous intracellular signaling domain of a chimeric signaling protein can comprise, consist essentially of, or consist of an amino acid sequence that is a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 64-77.
  • Table 3 provides non-limiting examples of amino acid sequences that intracellular domains and heterologous intracellular signaling domain of a chimeric signaling protein described herein can comprise, consist of, consist essentially of, or be derived from.
  • a heterologous intracellular signaling domain of a chimeric signaling protein can comprise an amino acid sequence with one or more amino acid insertions, deletions, or substitutions compared to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein.
  • a heterologous intracellular signaling domain of a chimeric signaling protein can comprise an amino acid sequence with at least 1 , at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11 , at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, or at least 50 amino acid insertions relative to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 64-77.
  • a heterologous intracellular signaling domain of a chimeric signaling protein comprises an amino acid sequence with at most 1 , at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11 , at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 25, at most 30, at most 35, at most 40, at most 45, or at most 50 amino acid insertions relative to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 64-77.
  • a heterologous intracellular signaling domain of a chimeric signaling protein comprises an amino acid sequence with 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 amino acid insertions relative to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 64-77.
  • the one or more insertions can be at the N-terminus, C-terminus, within the amino acid sequence, or a combination thereof.
  • the one or more insertions can be contiguous, non-contiguous, or a combination thereof.
  • a heterologous intracellular signaling domain of a chimeric signaling protein comprises an amino acid sequence with at least 1 , at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11 , at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, or at least 50 amino acid deletions relative to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 64-77.
  • a heterologous intracellular signaling domain of a chimeric signaling protein comprises an amino acid sequence with at most 1 , at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11 , at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 25, at most 30, at most 35, at most 40, at most 45, or at most 50 amino acid deletions relative to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 64-77.
  • a heterologous intracellular signaling domain of a chimeric signaling protein comprises an amino acid sequence with 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 amino acid deletions relative to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 64-77.
  • the one or more deletions can be at the N-terminus, C-terminus, within the amino acid sequence, or a combination thereof.
  • the one or more deletions can be contiguous, non-contiguous, or a combination thereof.
  • a heterologous intracellular signaling domain of a chimeric signaling protein comprises an amino acid sequence with at least 1 , at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11 , at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, or at least 50 amino acid substitutions relative to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 64-77.
  • a heterologous intracellular signaling domain of a chimeric signaling protein comprises an amino acid sequence with at most 1 , at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11 , at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 25, at most 30, at most 35, at most 40, at most 45, or at most 50 amino acid substitutions relative to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 64-77.
  • a heterologous intracellular signaling domain of a chimeric signaling protein comprises an amino acid sequence with 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 amino acid substitutions relative to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 64-77.
  • the one or more substitutions can be at the N-terminus, C-terminus, within the amino acid sequence, or a combination thereof.
  • the one or more substitutions can be contiguous, non-contiguous, or a combination thereof.
  • the one or more substitutions can be conservative, non-conservative, or a combination thereof.
  • the heterologous intracellular signaling domain of a chimeric signaling protein signals as a monomer. In some embodiments, the heterologous intracellular signaling domain of a chimeric signaling protein signals as a dimer. In some embodiments, the heterologous intracellular signaling domain of a chimeric signaling protein signals as a trimer. In some embodiments, the heterologous intracellular signaling domain of a chimeric signaling protein signals as a tetramer, a pentamer, a hexamer, or a multimer.
  • the heterologous intracellular signaling domain of a chimeric signaling protein can signal as a homo-multimer (e.g., homodimer, homotrimer, homotetramer, homopentamer, homohexamer, or higher order homomultimer).
  • the heterologous intracellular signaling domain of a chimeric signaling protein signals as a hetero-multimer (e.g., a heterodimer, heterotrimer, heterotetramer, heteropentamer, heterohexamer, or higher order heteromultimer).
  • the heterologous intracellular signaling domain of a chimeric signaling protein signals in a different conformation or as a different multimer than a full length wild type protein from which the heterologous intracellular signaling domain is from or derived from.
  • a chimeric signaling protein can have any suitable number of heterologous intracellular signaling domains. In some embodiments a chimeric signaling protein has one heterologous intracellular signaling domain. In some embodiments, a chimeric signaling protein has two heterologous intracellular signaling domains. In some embodiments, a chimeric signaling protein has 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 heterologous intracellular signaling domain(s). In some embodiments, a chimeric signaling protein has at least 1 , at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 heterologous intracellular signaling domain(s). In some embodiments, a chimeric signaling protein has at most 1 , at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, or at most 10 heterologous intracellular signaling domain(s).
  • a chimeric signaling protein comprises two heterologous intracellular signaling domains that are from or derived from 41 BB, 0X40, NKp80, IL18RAP, or IL2RB. In some embodiments, a chimeric signaling protein comprises a heterologous intracellular signaling domain that is from or derived from 0X40, and a heterologous domain that is from or derived from 41 BB, NKp80, IL18RAP, or IL2RB. In some embodiments, a chimeric signaling protein comprises a heterologous intracellular signaling domain that is from or derived from 0X40, and a heterologous intracellular signalling domain that is from or derived from IL2RB.
  • At least one, at least two, at least three, at least four, at least five, or at least six signaling pathways are induced that are mediated by the heterologous intracellular signaling domain of the chimeric signaling protein.
  • one, two, three, four, five, or six signaling pathways are induced that are mediated by the heterologous intracellular signaling domain of the chimeric signaling protein.
  • one signaling pathway is induced that is mediated by the heterologous intracellular signaling domain of the chimeric signaling protein.
  • a chimeric signaling protein can comprise one or more additional intracellular domains as well as the one or more heterologous intracellular signaling domains.
  • a chimeric signaling protein comprises one or more additional intracellular domains from or derived from the same protein as the heterologous intracellular signaling domain, e.g., stretches of amino acids that do not participate in signaling.
  • an additional intracellular domain of a chimeric signaling protein does not directly participate in signaling (e.g., does not bind a signaling pathway component or undergo a chemical or structural change as part of a signaling pathway), but increases or decreases a level of signaling mediated by the heterologous intracellular signaling domain.
  • a chimeric signaling protein comprises an additional intracellular domain that is from or derived from the same protein as the transmembrane domain, which can be e.g., the same protein or a different protein than the extracellular ligand domain.
  • Such an intracellular domain can comprise a signaling domain or can lack a signaling domain.
  • a chimeric signaling protein comprises an intracellular domain that is from or derived from the same protein as the extracellular ligand domain. Such an intracellular domain can lack a signaling domain or can comprise a different signaling domain to the heterologous intracellular signaling domain that is present in the chimeric signaling protein.
  • one or more amino acids are added to achieve sequence similarity and/or structural similarity to the protein that is the source of the extracellular ligand domain.
  • the amino acids MLG can be added to the intracellular N-terminus of a chimeric signaling protein that contains a 41 BBL extracellular ligand domain.
  • An additional intracellular domain of a chimeric signaling protein can be or can comprise a cleavage site, for example, an ADAM family cleavage site or a metalloprotease family cleavage site.
  • An additional intracellular domain of a chimeric signaling protein can be or can comprise a multimerization domain (e.g., a domain that facilitates formation of a homo- or hetero- dimer, trimer, tetramer, pentamer, hexamer, or higher order multimer, such as a tenascin-C oligomerization domain, a thrombospondin oligomerization domain, or a GCN4 oligomerization domain).
  • a multimerization domain e.g., a domain that facilitates formation of a homo- or hetero- dimer, trimer, tetramer, pentamer, hexamer, or higher order multimer, such as a tenascin-C oligomerization domain,
  • An additional intracellular domain of a chimeric signaling protein can be or can comprise a target peptide, e.g. a signal peptide.
  • An additional intracellular domain of a chimeric signaling protein can be or can comprise a cellular localization motif, e.g., a lipid raft localization motif or a nuclear localization motif.
  • An additional intracellular domain of a chimeric signaling protein can comprise a linker.
  • An additional intracellular domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from a wild type protein amino acid sequence.
  • An additional intracellular domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from any protein or type of protein disclosed elsewhere herein.
  • An additional intracellular domain of a chimeric signaling protein can comprise an amino acid sequence that is modified compared to a wild type protein amino acid sequence or any other amino acid sequence disclosed herein, for example, to achieve a desirable level of expression, surface expression, stability, resistance to aggregation, resistance to degradation, signaling strength, or affinity for a protein that participates in downstream signaling, e.g., an adapter protein.
  • An additional intracellular domain of a chimeric signaling protein can comprise an amino acid sequence that is modified compared to a wild type protein amino acid sequence or an amino acid sequence disclosed herein, for example, to promote folding of the chimeric protein into a biologically active conformation.
  • part or all of an additional intracellular domain of a chimeric signaling protein comprises an amino acid sequence that is inverted compared to a wild type amino acid sequence (i.e. expressed as a retro-protein).
  • An additional intracellular domain of a chimeric signaling protein can comprise an amino acid sequence with one or more amino acid insertions, deletions, or substitutions compared to a wild type protein amino acid sequence or any other amino acid sequence as disclosed elsewhere herein.
  • An additional intracellular domain of a chimeric signaling protein can comprise at least a minimal level of sequence identity compared to a wild type protein amino acid sequence or any other amino acid sequence as disclosed elsewhere herein.
  • the entire intracellular part of the chimeric signaling protein (containing the one or more heterologous intracellular signaling domain(s) and any additional intracellular domains) can be structurally distinct from intracellular domains found in chimeric antigen receptors and similar chimeric signaling proteins.
  • the entire intracellular part of the chimeric signaling protein can lack one or more components associated with TCR complex signaling.
  • the entire intracellular part of the chimeric signaling protein does not contain an ITAM (e.g., contains a hemITAM but not an ITAM, or does not contain a hemITAM or an ITAM).
  • the entire intracellular part of the chimeric signaling protein is not phosphorylated upon binding of the chimeric signaling protein to the interaction partner. In some embodiments, an intracellular part of a chimeric signaling protein is phosphorylated upon binding of the chimeric signaling protein to the interaction partner. In some embodiments, the entire intracellular part of a chimeric signaling protein does not contain an intracellular domain from a CD3 chain, for example does not contain an intracellular domain of a CD3 zeta chain, or does not contain an intracellular domain from any CD3 chain. In some embodiments, the entire intracellular part of a chimeric signaling protein does not contain an intracellular domain from a TCR signaling complex.
  • the chimeric signaling proteins described herein comprise a transmembrane domain that connects the extracellular ligand domain to the heterologous intracellular signaling domain.
  • part or all of the transmembrane domain of a chimeric signaling protein is from the same protein as the extracellular ligand domain.
  • the transmembrane domain and the extracellular ligand domain can be part of a contiguous amino acid sequence (e.g., that matches or corresponds to a wild type sequence), or can be separated by one or more amino acid insertions, deletions, and/or substitutions.
  • the transmembrane domain of a chimeric signaling protein or part thereof is from or derived from the same protein as the extracellular ligand domain.
  • part or all of the transmembrane domain of a chimeric signaling protein is from the same protein as the heterologous intracellular signaling domain.
  • the transmembrane domain and the heterologous intracellular signaling domain can be part of a contiguous amino acid sequence (e.g., that matches or corresponds to a wild type sequence), or can be separated by one or more amino acid insertions, deletions, and/or substitutions.
  • part or all of the transmembrane domain of a chimeric signaling protein is from or derived from a different protein than the extracellular ligand domain and the heterologous intracellular signaling domain.
  • a chimeric signaling protein described herein may comprise an extracellular ligand domain that comprises an amino acid sequence that is from or derived from CD70, a transmembrane domain that comprises an amino acid sequence that is from or derived from 41 BBL, and a heterologous intracellular signaling domain that comprises an amino acid sequence that is from or derived from 0X40.
  • a transmembrane domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from a transmembrane protein, for example, a protein that is expressed on a cell surface.
  • the transmembrane domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from a type I transmembrane protein.
  • the transmembrane domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from a type II transmembrane protein.
  • the transmembrane domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from a tumour necrosis factor receptor superfamily member.
  • the transmembrane domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from 41 BB, 0X40, NKp80, RANK, IL18RAP, or CD70.
  • the transmembrane domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from 41 BB.
  • the transmembrane domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from 0X40.
  • the transmembrane domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from NKp80. In some embodiments, the transmembrane domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from RANK. In some embodiments, the transmembrane domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from IL18RAP. In some embodiments, the transmembrane domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from CD70.
  • the transmembrane domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from a tumour necrosis factor superfamily member or an immunoglobulin superfamily.
  • the transmembrane domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from 41 BBL, OX40L, CD86, RANK, or CD70.
  • the transmembrane domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from 41 BBL.
  • the transmembrane domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from OX40L.
  • the transmembrane domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from CD86. In some embodiments, the transmembrane domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from RANK. In some embodiments, the transmembrane domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from CD70.
  • the transmembrane domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from a receptor, for example, an ion channel, GPCR, selectin family member, cytokine receptor, adhesion molecule, or receptor tyrosine kinase.
  • the transmembrane domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from a cytokine receptor.
  • the transmembrane domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from a C-type lectin or C type lectin receptor.
  • the transmembrane domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from an immune co-receptor. In some cases, the transmembrane domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from an immune co-receptor ligand, for example, an immune co-stimulatory ligand.
  • a transmembrane domain of a chimeric signaling protein is from an alpha chain of a T cell receptor (TCR), beta chain of a TCR, CD8, CD4, CD28, CD45, PD-1 and/or CD152.
  • TCR T cell receptor
  • a transmembrane domain of a chimeric signaling protein can comprise an amino acid sequence that is from or derived from a wild type protein amino acid sequence.
  • a transmembrane domain of a chimeric signaling protein can comprise an amino acid sequence that is modified compared to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, to achieve a desirable level of expression, surface expression, stability, resistance to aggregation, resistance to degradation, signaling strength, localization, or multimerization of the chimeric signaling protein.
  • a transmembrane domain of a chimeric signaling protein can comprise an amino acid sequence that is modified compared to a wild type protein amino acid sequence or an amino acid sequence disclosed herein, for example, to promote folding of the chimeric signaling protein into a biologically active conformation.
  • part or all of a transmembrane domain of a chimeric signaling protein comprises an amino acid sequence that is inverted compared to a wild type amino acid sequence (i.e. expressed as a retro- protein).
  • a transmembrane domain of a chimeric signaling protein can comprise an artificial hydrophobic sequence.
  • a transmembrane domain can comprise a cellular localization motif, e.g., a lipid raft localization motif or a nuclear localization motif.
  • a chimeric signaling protein can contain an extracellular ligand domain from RANK, and a transmembrane domain from IL18RAP.
  • inclusion of the transmembrane domain from IL18RAP induces formation of the chimeric signaling protein into a dimeric state, unlike wild type RANK, which can function as a trimer.
  • transmembrane domains described herein can induce formation of the chimeric signaling protein into a monomeric or multimeric state that is different than the state adopted by the full length wild type version of the protein the extracellular ligand domain is from or derived from, and/or that is different than the full length wild type version of the protein the heterologous intracellular domain is from or derived from.
  • a transmembrane domain of a chimeric signaling protein can comprise, consist essentially of, or consist of an amino acid sequence with at least a minimal level of sequence identity compared to a wild type protein amino acid sequence or any other amino acid sequence disclosed herein.
  • a transmembrane domain of a chimeric signaling protein can comprise, consist essentially of, or consist of an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 98.5%, at least 99%, or at least 99.5% sequence identity to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 78-86 (see Table 4).
  • such a transmembrane domain of a chimeric signaling protein having at least a minimal level of sequence identity compared to a given amino acid sequence is functional and therefore encompassed by the invention as long as this transmembrane domain is able to induce a multimerisation of the chimeric bidirectional signaling transmembrane protein comprising it upon binding of the extracellular domain of its interaction partner.
  • the level of binding or interaction should be detectable using an assay known to the skilled person. Examples of suitable assays are western blotting or FACS, single photon microscopy assays.
  • a transmembrane domain of a chimeric signaling protein comprises an amino acid sequence that is inverted compared to a wild type amino acid sequence (i.e. expressed as a retro- protein)
  • the wild type protein amino acid sequence can be inverted prior to calculating sequence identity.
  • a transmembrane domain of a chimeric signaling protein can comprise, consist essentially of, or consist of an amino acid sequence that is a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 78-86.
  • Table 4 provides non-limiting examples of amino acid sequences that a transmembrane domain of a chimeric signaling protein described herein can comprise, consist of, consist essentially of, or be derived from.
  • a transmembrane domain of a chimeric signaling protein can comprise an amino acid sequence with one or more amino acid insertions, deletions, or substitutions compared to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein.
  • a transmembrane domain of a chimeric signaling protein can comprise an amino acid sequence with at least 1 , at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 amino acid insertions relative to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 78-86.
  • a transmembrane domain of a chimeric signaling protein comprises an amino acid sequence with at most 1 , at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, or at most 10 amino acid insertions relative to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 78-86.
  • a transmembrane domain of a chimeric signaling protein comprises an amino acid sequence with 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid insertions relative to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 78-86.
  • the one or more insertions can be at the N-terminus, C-terminus, within the amino acid sequence, or a combination thereof.
  • the one or more insertions can be contiguous, non-contiguous, or a combination thereof.
  • a transmembrane domain a chimeric signaling protein comprises an amino acid sequence with at least 1 , at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 amino acid deletions relative to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 78-86.
  • a transmembrane domain a chimeric signaling protein comprises an amino acid sequence with at most 1 , at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, or at most 10 amino acid deletions relative to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 78-86.
  • a transmembrane domain a chimeric signaling protein comprises an amino acid sequence with 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid deletions relative to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 78-86.
  • the one or more deletions can be at the N-terminus, C-terminus, within the amino acid sequence, or a combination thereof.
  • the one or more deletions can be contiguous, non-contiguous, or a combination thereof.
  • a transmembrane domain a chimeric signaling protein comprises an amino acid sequence with at least 1 , at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10, amino acid substitutions relative to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 78-86.
  • a transmembrane domain a chimeric signaling protein comprises an amino acid sequence with at most 1 , at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, or at most 10 amino acid substitutions relative to a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 78-86.
  • a transmembrane domain a chimeric signaling protein comprises an amino acid sequence with 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 78-86.
  • the one or more substitutions can be at the N-terminus, C-terminus, within the amino acid sequence, or a combination thereof.
  • the one or more substitutions can be contiguous, non-contiguous, or a combination thereof.
  • the one or more substitutions can be conservative, non-conservative, or a combination thereof.
  • Chimeric signaling proteins can comprise one or more linkers that connect amino acid sequences, for example, amino acid sequences from or derived from different proteins.
  • a linker can connect, for example, an extracellular ligand domain to a transmembrane domain, a heterologous intracellular signaling domain to a transmembrane domain, one extracellular ligand domain to a second extracellular ligand domain or an additional extracellular domain, one heterologous intracellular signaling domain to another heterologous intracellular signaling domain or an additional intracellular domain, or any domain disclosed herein to another amino acid sequence.
  • a linkeror can allow forseparation and flexibility of the domains it separates, for example, a transmembrane domain and an extracellular ligand domain.
  • the length of a linker can be adjusted to alter the ability of a domain to bind to, for example, an interaction partner (for the extracellular ligand domain), or a factor that participates in a signaling pathway (e.g., forthe heterologous intracellular signaling domain).
  • a linker sequence can be, for example, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, or 50 amino acid residues in length.
  • a linker is at least 1 , at least 3, at least 5, at least 7, at least 9, at least 11 , or at least 15 amino acids in length.
  • a linker is at most
  • a flexible linker can have a sequence containing stretches of glycine and serine residues. The small size of the glycine and serine residues provides flexibility and allows for mobility of the connected functional domains. The incorporation of serine orthreonine can maintain the stability of the linker in aqueous solutions by forming hydrogen bonds with the water molecules, thereby reducing unfavorable interactions between the linker and protein moieties. Flexible linkers can also contain additional amino acids such as threonine and alanine to maintain flexibility, as well as polar amino acids such as lysine and glutamine to improve solubility.
  • a rigid linker can have, for example, an alpha helix-structure. An alpha-helical rigid linker can act as a spacer between protein domains.
  • a linker may, for example, comprise any of the sequences in Table 5, or repeats thereof (e.g., 2, 3, 4, 5,
  • a linker may comprise the amino acid sequence GG or GGS, or repeats thereof (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 repeats thereof).
  • a chimeric signaling protein comprises a linker with at least 1 , at least 2, at least 3, at least 4, or at least 5 amino acid insertions, deletions, or substitutions relative to any of SEQ ID NOs: 87- 89, 91-98, 100-103, or to the amino acid sequence GG or GGS.
  • the insertions, deletions, or substitutions can be at the N-terminus, the C-terminus, within the sequence, or a combination thereof.
  • the insertions, deletions, or substitutions can be contiguous or non-contiguous. In some cases, the substitutions are conservative. In some cases, the substitutions are non-conservative.
  • a chimeric signaling protein does not contain any linkers, for example, the chimeric signaling protein is a direct fusion of amino acid sequences from other proteins with no intervening amino acid sequence.
  • linkers described above as suitable for the chimeric signaling protein may also be suitable for the soluble polypeptides comprising a yT-cell receptor chain, a bT-cell receptor chain, a ybT-cell receptor, or parts thereof (such as e.g., an extracellular domain thereof) described earlier herein.
  • the chimeric bidirectional signaling transmembrane protein able to transduce at least two inducible intracellular signals comprises: an extracellular ligand domain, able to interact with the extracellular domain of its interaction partner a transmembrane domain, and a heterologous intracellular signaling domain transducing a first signal after binding of the extracellular ligand domain to its interaction partner, wherein the second intracellular signal is transduced via the intracellular domain of the interaction partner.
  • the chimeric bidirectional signaling transmembrane protein able to transduce at least two inducible intracellular signals comprises: an extracellular ligand domain, able to interact with the extracellular domain of its interaction partner wherein the extracellular ligand domain is represented by a sequence having at least 80% identity with one of SEQ ID NO: 57-63 as identified in Table 2, a transmembrane domain represented by a sequence having at least 80% identity with one of SEQ ID NO: 78-86 as identified in Table 4, and a heterologous intracellular signaling domain transducing a first signal after binding of the extracellular ligand domain to its interaction partner, wherein the heterologous intracellular signaling domain is represented by a sequence having at least 80% identity with one of SEQ ID NO: 64-77 as identified in Table 3, wherein the second intracellular signal is transduced via the intracellular domain of the interaction partner.
  • sequence identity may be at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%.
  • the transmembrane domain and the extracellular ligand domain are from the same proteins. Examples are CD86-OX40, 41 BBL-OX40, OX40L-41 BB.
  • the chimeric bidirectional signaling transmembrane protein able to transduce at least two inducible intracellular signals comprises:
  • Such chimeric signaling proteins comprising part of a type I and part of a type II transmembrane protein may exhibit surprising and unexpected effects, as type I and type II transmembrane proteins cannot be readily combined into a functional protein.
  • the chimeric bidirectional signaling transmembrane protein comprises:
  • an extracellular ligand domain comprising an amino acid sequence from a tumour necrosis factor superfamily member, a cytokine, a C-type lectin, an immunoglobulin superfamily member, or an antibody or antigen-binding fragment thereof;
  • heterologous intracellular signaling domain comprising an amino acid sequence from a tumour necrosis factor receptor superfamily member, a cytokine receptor, or a C-type lectin receptor.
  • the chimeric bidirectional signaling transmembrane protein comprises: an extracellular ligand domain comprising an amino acid sequence from 41 BBL, OX40L, CD86, RANK, or CD70, and a heterologous intracellular signaling domain comprising an amino acid sequence from 0X40, 41 BB, NKp80, IL18RAP, or IL2RB.
  • the chimeric bidirectional signaling transmembrane protein comprises:
  • the extracellular ligand domain comprises an amino acid sequence from 41 BBL and the heterologous intracellular signaling domain comprises an amino acid sequence from 0X40, preferably wherein the extracellular ligand domain is from or is derived from a type II transmembrane protein 41 BBL and the heterologous intracellular signaling domain is from or is derived from a type I transmembrane protein 0X40,
  • the extracellular ligand domain comprises an amino acid sequence from CD86 and the heterologous intracellular signaling domain comprises an amino acid sequence from 0X40,
  • the extracellular ligand domain comprises an amino acid sequence from 41 BBL and the heterologous intracellular signaling domain comprises an amino acid sequence from NKp80,
  • the extracellular ligand domain comprises an amino acid sequence from RANK and the heterologous intracellular signaling domain comprises an amino acid sequence from IL18RAP,
  • the extracellular ligand domain comprises an amino acid sequence from RANK and the heterologous intracellular signaling domain comprises an amino acid sequence from 0X40,
  • the extracellular ligand domain comprises an amino acid sequence from RANK and the heterologous intracellular signaling domain comprises an amino acid sequence from 41 BB,
  • the extracellular ligand domain comprises an amino acid sequence from OX40L and the heterologous intracellular signaling domain comprises an amino acid sequence from 41 BB,or
  • the extracellular ligand domain comprises an amino acid sequence from CD86 and the heterologous intracellular signaling domain comprises an amino acid sequence from IL18RAP.
  • the extracellular ligand domain comprises an amino acid sequence from CD70 and the heterologous intracellular signaling domain comprises an amino acid sequence from 0X40, or (j) the extracellular ligand domain comprises an amino acid sequence from 41 BBL and the heterologous intracellular signaling domain comprises an amino acid sequence from 0X40 and an amino acid sequence from IL2RB.
  • the chimeric bidirectional signaling transmembrane protein identified under a) is represented by an amino acid sequence having at least 80% identity or similarity with SEQ ID NO: 104, 105, 106, 117, 118, 119, 120, 121 , 122, 123, 124, 142, or 143 as identified in Table 6.
  • the chimeric bidirectional signaling transmembrane protein identified under b) is represented by an amino acid sequence having at least 80% identity or similarity with SEQ ID NO 112, 113, or 133 as identified in Table 6.
  • the chimeric bidirectional signaling transmembrane protein identified under c) is represented by an amino acid sequence having at least 80% identity or similarity with SEQ ID NO: 107 or 108 as identified in Table 6.
  • the chimeric bidirectional signaling transmembrane protein identified under d) is represented by an amino acid sequence having at least 80% identity or similarity with SEQ ID NO: 138 as identified in Table 6.
  • the chimeric bidirectional signaling transmembrane protein identified under e) is represented by an amino acid sequence having at least 80% identity or similarity with SEQ ID NO: 136 as identified in Table 6.
  • the chimeric bidirectional signaling transmembrane protein identified under f) is represented by an amino acid sequence having at least 80% identity or similarity with SEQ ID NO: 137 as identified in Table 6.
  • the chimeric bidirectional signaling transmembrane protein identified under g) is represented by an amino acid sequence having at least 80% identity or similarity with SEQ ID NO: 109, 110, 111 , or 125 as identified in Table 6.
  • the chimeric bidirectional signaling transmembrane protein identified under h) is represented by an amino acid sequence having at least 80% identity or similarity with SEQ ID NO: 131 or 132 as identified in Table 6.
  • the chimeric bidirectional signaling transmembrane protein identified under i) is represented by an amino acid sequence having at least 80% identity or similarity with SEQ ID NO: 146 or 147 as identified in Table 6.
  • the chimeric bidirectional signaling transmembrane protein identified under j) is represented by an amino acid sequence having at least 80% identity or similarity with SEQ ID NO: 143 as identified in Table 6.
  • sequence identity or similarity may be at least 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%.
  • the chimeric bidirectional signaling transmembrane protein does not contain an ITAM or an intracellular domain from a TOR signaling complex.
  • an ITAM motif is “YxxL/l- x6-8- YxxL/l” wherein x stands for any amino acid.
  • X6-8 means any stretch of 6, 7 or 8 amino acids
  • Y is Tyrosine
  • L is Leucine
  • I is Isoleucine (PFAM source or see Lanier 2006, Trends Biotechnol 16(8): 388- 390, incorporated herein by reference in its entirety).
  • Non-limiting examples of chimeric signaling protein sequences, and sequences that can be included in the chimeric signaling proteins, are provided in Table 6.
  • a chimeric signaling protein can comprise, consist essentially of, or consist of an amino acid sequence with at least a minimal level of sequence identity compared to an amino acid sequence disclosed herein.
  • a chimeric signaling protein can comprise, consist essentially of, or consist of an amino acid sequence with at least 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 98.5%, at least 99%, or at least 99.5% sequence identity to an amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 104- 113, 117-125, 127, 131-133, 136-138, 142-143, or 146-147.
  • the chimeric bidirectional signaling transmembrane protein identified under a) is represented by an amino acid sequence having at least 80% identity or similarity with SEQ ID NO: 105 as identified in Table 6.
  • sequence identity or similarity may be at least 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%.
  • a chimeric bidirectional signaling transmembrane protein having at least a minimal level of sequence identity compared to a given amino acid sequence is functional and therefore encompassed by the invention as long as this chimeric signaling protein is able to transduce at least two inducible intracellular signals and/or is able to induce an improvement of a biological parameter and/or function in a T-cell expressing it as earlier defined herein and/or is able to induce an improvement of a biological parameter and/or function induced by such a cell especially when such cell is used as exemplified herein.
  • the transduction of these at least two inducible intracellular signals should be detectable using an assay known to the skilled person.
  • Such biological parameter and/or function in a T-cell of the invention may be the enhanced cellular proliferation, enhanced cellular survival, and greater magnitude and persistence of immune effector functions, such as anti-tumour or anti-infective response.
  • the anti-tumour or anti-infective response may be assessed as earlier defined herein.
  • the cytotoxicity and production of inflammatory mediators may be assessed.
  • the wording “target biological outcome’’ or “biological outcome’’ may be replaced by “biological parameter’’.
  • One or multiple biological functions and/or parameters of the cell may be modulated/improved. Multiple biological functions and/or parameters may be modulated, for example, any combination of induced or reduced biological functions and/or parameters that contributes to a target biological outcome such as an anti-tumour or anti-infective response.
  • a target biological outcome may be the treatment, or cure of a cancer or an infection.
  • multiple biological functions can be induced in the T-cell and/or a biological function can be induced and another one can be reduced.
  • suitable assays are western blotting, luminescence reporter or FACS assays.
  • the improvement of a biological parameter and/or function should also be detectable using an assay known to the skilled person. Depending on the parameter and/or function, the skilled person would know which assay may be used.
  • a chimeric signaling protein can comprise, consist essentially of, or consist of an amino acid sequence that is a wild type protein amino acid sequence or any other such amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 104-113, 117-125, 127, 131-133, 136- 138, 142-143, or 146-147.
  • a chimeric signaling protein can comprise an amino acid sequence with one or more amino acid insertions, deletions, or substitutions compared to an amino acid sequence disclosed herein.
  • a chimeric signaling protein can comprise an amino acid sequence with at least 1 , at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11 , at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, or at least 50 amino acid insertions relative to an amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 104-113, 117-125, 127, 131-133, 136-138, 142-143, or 146-147.
  • a chimeric signaling protein comprises an amino acid sequence with at most 1 , at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11 , at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 25, at most 30, at most 35, at most 40, at most 45, or at most 50 amino acid insertions relative to an amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 104-113, 117-125, 127, 131-133, 136-138, 142-143, or 146-147.
  • a chimeric signaling protein comprises an amino acid sequence with 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 amino acid insertions relative to an amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 104-113, 117-125, 127, 131-133, 136-138, 142-143, or 146-147.
  • the one or more insertions can be at the N-terminus, C-terminus, within the amino acid sequence, or a combination thereof.
  • the one or more insertions can be contiguous, non-contiguous, or a combination thereof.
  • a chimeric signaling protein comprises an amino acid sequence with at least 1 , at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11 , at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, or at least 50 amino acid deletions relative to an amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 104-113, 117-125, 127, 131- 133, 136-138, 142-143, or 146-147.
  • a chimeric signaling protein comprises an amino acid sequence with at most 1 , at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11 , at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 25, at most 30, at most 35, at most 40, at most 45, or at most 50 amino acid deletions relative to an amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 104-113, 117-125, 127, 131- 133, 136-138, 142-143, or 146-147.
  • a chimeric signaling protein comprises an amino acid sequence with 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 amino acid deletions relative to an amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 104-113, 117-125, 127, 131-133, 136-138, 142-143, or 146-147.
  • the one or more deletions can be at the N-terminus, C-terminus, within the amino acid sequence, or a combination thereof.
  • the one or more deletions can be contiguous, non-contiguous, or a combination thereof.
  • a chimeric signaling protein comprises an amino acid sequence with at least 1 , at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11 , at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, or at least 50 amino acid substitutions relative to an amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 104-113, 117-125, 127, 131-133, 136-138, 142-143, or 146-147.
  • a chimeric signaling protein comprises an amino acid sequence with at most 1 , at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, at most 10, at most 11 , at most 12, at most 13, at most 14, at most 15, at most 16, at most 17, at most 18, at most 19, at most 20, at most 25, at most 30, at most 35, at most 40, at most 45, or at most 50 amino acid substitutions relative to an amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 104-113, 117-125, 127, 131-133, 136-138, 142-143, or 146-147.
  • a chimeric signaling protein comprises an amino acid sequence with 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 amino acid substitutions relative to an amino acid sequence disclosed herein, for example, any one of SEQ ID NOs: 104-113, 117-125, 127, 131-133, 136-138, 142-143, or 146-147.
  • the one or more substitutions can be at the N-terminus, C-terminus, within the amino acid sequence, or a combination thereof.
  • the one or more substitutions can be contiguous, non-contiguous, or a combination thereof.
  • the one or more substitutions can be conservative, non-conservative, or a combination thereof.
  • Certain chimeric bidirectional signaling transmembrane proteins disclosed herein combine an amino acid sequence from a type I transmembrane protein with an amino acid sequence from a type II transmembrane protein.
  • such chimeric signaling proteins exhibit surprising and unexpected effects, as type I and type II transmembrane proteins cannot be readily combined into a functional protein.
  • the extracellular ligand domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from a type I transmembrane protein
  • the heterologous intracellular signaling domain comprises an amino acid sequence that is from or derived from a type II transmembrane protein.
  • the extracellular ligand domain of a chimeric signaling protein comprises an amino acid sequence that is from or derived from a type II transmembrane protein
  • the heterologous intracellular signaling domain comprises an amino acid sequence that is from or derived from a type I transmembrane protein (for example, an extracellular ligand domain from 41 BBL, and an intracellular signaling domain from 0X40).
  • part or all of an extracellular ligand domain and/or a heterologous intracellular signaling domain of a chimeric bidirectional signaling transmembrane protein comprises an amino acid sequence that is inverted compared to a wild type amino acid sequence (i.e. expressed as a retro-protein).
  • a chimeric bidirectional signaling transmembrane protein exhibit surprising and unexpected effects, as in many cases retro-proteins do not retain the functionality ofthe parent protein, e.g., due to a failure to adopt a functional conformation and/or tertiary structure.
  • a chimeric bidirectional signaling transmembrane protein combines an amino acid sequence from a type I transmembrane protein with an amino acid sequence from a type II transmembrane protein, and contains at least one amino acid sequence that is inverted compared to a wild type amino acid sequence. Functionality of such a chimeric signaling protein can be surprising and unexpected based on a lack of expectation of success combining sequences from type I and type II transmembrane proteins into a functioning fusion protein, and a lack of expectation of success in obtaining a functional retro-protein domain.
  • an extracellular ligand domain of a chimeric signaling protein is a tumour necrosis factor superfamily member or a molecule derived thereof and is derived from a type II transmembrane protein and is therefore a type II molecule.
  • an extracellular ligand domain of a chimeric signaling protein is an immunoglobulin superfamily member or is derived thereof and is derived from a type I transmembrane protein and is therefore a type I molecule
  • the T-cell preferably apT-cell, comprises (preferably expresses) a chimeric signaling protein as described herein and a ybT-cell receptor or part thereof comprising:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 1 or 4, preferably relative to SEQ ID NO: 1 , and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 5 or 8, preferably relative to SEQ ID NO: 5.
  • the ybT-cell receptor or part thereof further comprises:
  • -a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 209,
  • -a 6CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 195, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 202.
  • the T-cell preferably apT-cell, comprises (preferably expresses) a chimeric signaling protein as described herein and a ybT-cell receptor or part thereof comprising:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 9 or 12, preferably relative to SEQ ID NO: 9, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 13 or 16, preferably relative to SEQ ID NO: 13.
  • the ybT-cell receptor or part thereof further comprises: -a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 213,
  • -a 5CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 199, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 206.
  • the T-cell preferably apT-cell, comprises (preferably expresses) a chimeric signaling protein as described herein and a ybT-cell receptor or part thereof comprising:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 17 or 20, preferably relative to SEQ ID NO: 17, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 21 or 24, preferably relative to SEQ ID NO: 21 .
  • the ybT-cell receptor or part thereof further comprises:
  • -a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 210,
  • -a 6CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 216,
  • -a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 196, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 203.
  • the T-cell preferably apT-cell, comprises (preferably expresses) a chimeric signaling protein as described herein and a ybT-cell receptor or part thereof comprising:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 25 or 28, preferably relative to SEQ ID NO: 25, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 29 or 32, preferably relative to SEQ ID NO: 29.
  • the ybT-cell receptor or part thereof further comprises:
  • -a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 211 ,
  • -a 6CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 197, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 204.
  • the T-cell preferably apT-cell, comprises (preferably expresses) a chimeric signaling protein as described herein and a ybT-cell receptor or part thereof comprising:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 33 or 36, preferably relative to SEQ ID NO: 33, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 37 or 40, preferably relative to SEQ ID NO: 37.
  • the ybT-cell receptor or part thereof further comprises:
  • -a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 212,
  • -a 6CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 198, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 205.
  • the T-cell preferably apT-cell, comprises (preferably expresses) a chimeric signaling protein as described herein and a ybT-cell receptor or part thereof comprising:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 41 or 44, preferably relative to SEQ ID NO: 41 , and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 45 or 48, preferably relative to SEQ ID NO: 45.
  • the ybT-cell receptor or part thereof further comprises:
  • -a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 214,
  • -a 6CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 200, and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 207.
  • the T-cell preferably apT-cell, comprises (preferably expresses) a chimeric signaling protein as described herein and a ydT-cell receptor or part thereof comprising:
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 49 or 52, preferably relative to SEQ ID NO: 49, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, or no amino acid modifications relative to SEQ ID NO: 53 or 56, preferably relative to SEQ ID NO: 53.
  • the y6T-cell receptor or part thereof further comprises:
  • -a 6CDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 215,
  • -a 6CDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to the amino acid sequence QGS,
  • -a yCDR1 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 201 , and/or;
  • -a yCDR2 region represented by an amino acid sequence comprising from 0 to 3, from 0 to 2, from 0 to 1 , or no amino acid modifications relative to SEQ ID NO: 208.
  • the T-cell preferably a
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 5 or 8, preferably of SEQ ID NO: 5,
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 13 or 16, preferably of SEQ ID NO: 13,
  • bT-cell receptor chain or a part thereof comprising a CDR3 region
  • said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 17 or 20, preferably of SEQ ID NO: 17, and/or;
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 21 or 24, preferably of SEQ ID NO: 21 ,
  • yT-cell receptor chain or a part thereof comprising a CDR3 region
  • said yT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 29 or 32, preferably of SEQ ID NO: 29,
  • bT-cell receptor chain or a part thereof comprising a CDR3 region, wherein said bT-cell receptor chain or part thereof comprises an amino acid sequence, said amino acid sequence comprising at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100%, preferably at least 80%, sequence identity or similarity with the amino acid sequence of SEQ ID NO: 33 or 36, preferably of SEQ ID NO: 33, and/or;

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Abstract

L'invention concerne plusieurs nouvelles chaînes de récepteurs de cellules Tδ et de cellules Tγ, ou des fragments de celles-ci, qui médient des réponses antitumorales ou des réponses anti-infectieuses.
PCT/EP2023/063776 2022-05-24 2023-05-23 Nouvelles chaînes de récepteurs de cellules t delta et chaînes de récepteurs de cellules t gamma ou parties de celles-ci Ceased WO2023227594A1 (fr)

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