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WO2025229158A1 - Anticorps et constructions d'anticorps dirigés contre cd38 - Google Patents

Anticorps et constructions d'anticorps dirigés contre cd38

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Publication number
WO2025229158A1
WO2025229158A1 PCT/EP2025/062027 EP2025062027W WO2025229158A1 WO 2025229158 A1 WO2025229158 A1 WO 2025229158A1 EP 2025062027 W EP2025062027 W EP 2025062027W WO 2025229158 A1 WO2025229158 A1 WO 2025229158A1
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WIPO (PCT)
Prior art keywords
seq
antibody
polypeptide construct
antibodies
complement factor
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Pending
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PCT/EP2025/062027
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English (en)
Inventor
Mikael Becher Lykkegaard WINKLER
Nick Stub Laursen
Heidi Gytz OLESEN
Dennis Vestergaard Pedersen
Laust BAVNHØJ
Nina DYBDAL
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Commit Biologics Aps
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Commit Biologics Aps
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Priority claimed from GBGB2417959.0A external-priority patent/GB202417959D0/en
Priority claimed from GBGB2417958.2A external-priority patent/GB202417958D0/en
Application filed by Commit Biologics Aps filed Critical Commit Biologics Aps
Publication of WO2025229158A1 publication Critical patent/WO2025229158A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
    • 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
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/62—DNA sequences coding for fusion proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/35—Valency
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies

Definitions

  • the antibodies and antibody constructs against CD38 that are provided by the invention are also referred to herein as “antibodies of the invention”.
  • the invention also relates to uses of such antibodies, antibody constructs and compositions in the prevention and treatment of diseases and disorders in human beings, and in particular in the prevention and treatment of diseases and disorders in human beings that can be prevented or treated by suitably administering, to a subject in need thereof, an antibody, antibody construct or composition as described herein (i.e. in one or more suitable amounts and according to a suitable dose regimen).
  • diseases and disorders will be clear to the skilled person based on the disclosures herein and will also be referred to herein as “CD38- related diseases and disorders”.
  • CD38-related diseases and disorders may in particular include: (i) diseases and disorders that can be prevented and/or treated by suitably administering, to a subject in need thereof, one or more suitable amounts (i.e. according to a suitable dose regimen) of one of the known antibodies against CD38 referred to herein; and/or (ii) diseases and disorders that can be prevented and/or treated by suitably increasing, in the body of the subject to be treated, the activation of complement towards a cell that expresses CD38 on its surface (and in particular such that this may lead to an increase in the complement-dependent cytotoxicity that is exerted by the body of the subject to be treated towards a CD38 expressing cell).
  • diseases and disorders may in particular include multiple myeloma (MM) and other forms of cancer as well as other diseases or disorders for which known antibodies against CD38 are being applied or developed.
  • the invention further relates to nucleic acids encoding the antibodies of the invention, (also referred to herein as “nucleic acids of the invention” or “nucleotide sequences of the invention”); to methods for preparing the antibodies of the invention; and to host cells expressing or capable of expressing the antibodies of the invention.
  • WO2019/238674 describes single domain antibodies for complement regulation which are capable of specifically binding to an epitope of a human complement factor selected from the group consisting of C1q, C3, C4 and/or the proteolytic derivatives C3b and C4b.
  • WO2019/238674 also describes bi- and multispecific constructs comprising such a single domain antibody and at least one other antigen binding region (such as a second single domain antibody), in which said second antigen-binding domain binds to another target (such as a marker that is differentially expressed in cancer cells compared to non-malignant cells, a pathogenic marker a tissue-specific marker, an organ-specific marker, such as a marker specific for lung, eye, brain or kidney).
  • a target such as a marker that is differentially expressed in cancer cells compared to non-malignant cells, a pathogenic marker a tissue-specific marker, an organ-specific marker, such as a marker specific for lung, eye, brain or kidney.
  • WO2019/238674 also describes the use of such constructs in the treatment of diseases and disorders (depending, inter alia, on the target(s) of the antigen-binding regions that are present in said constructs next to the complement-binding single domain antibody or antibodies).
  • the international application WO2019/238674 also describes a number of specific Nanobodies against C1q, including the Nanobodies called “IF75” (SEQ ID NO: 13 in WO2019/238674) and “IF78” (SEQ ID NO:17 in WO2019/238674). [Note: IF75 is also referred to herein as Nb75 and IF78 is also referred to herein as Nb78].
  • WO2019/238674 also describes that the Nanobodies described in this application may be humanized.
  • the international application WO2020/167919 describes bispecific antigen-binding molecules comprising an antigen-binding domain that binds to a target antigen and an antigen- binding domain that binds to a complement component (such as C1q, C1r, C1s, C2, C3, C4, C5, C6, C7, C8 or C9).
  • WO2020/167919 also describes the use of such bispecific antigen- binding molecules in the treatment of diseases and disorders (again depending, inter alia, on the target to which the target-binding antigen-binding domain in the molecule can bind).
  • Some preferred C1q binders according to this International application may have a binding affinity to the C1q complement factor of from about 10 nanoMolar (nM) to about 2 microMolar ( ⁇ M), as determined by biolayer interferometry, and/or may bind to the C1q complement factor with a KD from about 10 nM to about 1.5 ⁇ M, from about 50 nM to about 1.4 ⁇ M, from about 100 nM to about 1.3 ⁇ M, from about 150 nM to about 1.2 ⁇ M or from about 200 nM to about 1 ⁇ M.
  • This International application also describes constructs comprising such C1q binders and at least one other antigen-binding moiety that binds to a target antigen, as well as uses of such constructs in the treatment of diseases and disorders (depending, inter alia, on the target antigen(s) to which said other antigen-binding moiety/moieties can bind).
  • Said C1q binders may also be humanized.
  • said International application describes that such C1q binders can be generated by suitably introducing one or more alanine mutations into the CDRs of a naturally occurring single domain antibody (or into the CDRs of a suitable humanized variant of a naturally occurring single domain antibody).
  • said International application describes such C1q binders that are variants of Nb75 or Nb78 (or of humanized variants of Nb75 or Nb78).
  • the non-prepublished International application entitled “Engineered proteins that engage complement factor and a protein antigen, methods, and uses thereof” in the name of applicant and filed on the same date as the present application describes polypeptide constructs comprising: (a) a first complement factor-engaging domain that binds to C1q; (b) an antigen- binding moiety that binds to a target protein; and (c) a second complement factor-engaging domain, wherein the first complement factor-engaging domain and the second complement factor-engaging domain are linked to the antigen-binding moiety.
  • said International application describes antibodies or antibody-based constructs that comprise two antibody heavy chains and two antibody light chains, which antibodies comprise a first C1q binder that is linked or fused to one or the antibody heavy or light chains and second C1q binder that is linked or fused to another of the antibody heavy or light chains.
  • first C1q binder is linked or fused to one of the antibody heavy chains and the second C1q binder is linked or fused to the other antibody heavy chain or alternatively the first C1q binder is linked or fused to one of the antibody light chains and the second C1q binder is linked or fused to the other antibody light chain.
  • the C1q binders may be linked to the N-terminus or the C-terminus of the antibody heavy chain or light chain, or may be linked to the N-terminus or the C-terminus of the antibody heavy chain or light chain (and, according to a specific but non-limiting aspect, when they are linked to the heavy chain, preferably linked to the N-terminus of the heavy chain; and when they are linked to the light chain, preferably linked to the C-terminus of the light chain).
  • such antibodies or antibody-based constructs comprise two antibody heavy chains and two antibody light chains and two C1q binders, in which one of said C1q binders is linked or fused to the C- terminus of one or the antibody light chains and the second C1q binder is linked or fused to the C-terminus of the other antibody light chain.
  • polypeptide constructs wherein the polypeptide constructs comprise: at least one heavy chain and at least one light chain, wherein the at least one heavy chain and the at least one light chain bind to a cluster of differentiation 38 (CD38); and at least one complement factor-engaging domain that binds to a C1q complement factor, wherein an affinity of the at least one complement factor-engaging domain for the C1q complement factor is between 10 nanoMolar (nM) to about 2 microMolar ( ⁇ M) as determined by biolayer inferometry.
  • polypeptide constructs comprises two complement factor-engaging domains that bind to the C1q complement factor.
  • polypeptide constructs wherein the at least one complement factor-engaging domain comprise an affinity for the C1q complement factor that is about 0.1 ⁇ M up to about 2 ⁇ M as determined by biolayer inferometry. Further provided herein are polypeptide constructs, wherein the polypeptide construct comprises two heavy chains that bind to the CD38. Further provided herein are polypeptide constructs, wherein the polypeptide construct comprises two light chains that bind to the CD38. Further provided herein are polypeptide constructs, wherein the at least one heavy chain comprises an amino acid sequence of SEQ ID NO: 1 or a variant thereof, wherein the variant comprises at least one amino acid substitution relative to SEQ ID NO: 1.
  • polypeptide constructs wherein the at least one light chain comprises an amino acid sequence of SEQ ID NO: 2 or a variant thereof, wherein the variant comprises at least one amino acid substitution relative to SEQ ID NO: 2.
  • polypeptide constructs wherein the at least one heavy chain comprises an amino acid sequence of SEQ ID NO: 1; and the at least one light chain comprises an amino acid sequence of SEQ ID NO: 2.
  • polypeptide constructs wherein the two heavy chains each comprise two heavy chain variable regions (VH).
  • polypeptide constructs, wherein the two light chains each comprise two light chain variable regions (VL).
  • polypeptide constructs wherein the polypeptide constructs comprise a first heavy chain comprising SEQ ID NO: 1; a second heavy chain comprising SEQ ID NO: 1; a first light chain comprising SEQ ID NO: 2; a second light chain comprising: SEQ ID NO: 2; a first complement factor-engaging domain; and a second complement factor- engaging domain.
  • pharmaceutical compositions wherein the pharmaceutical composition comprises a polypeptide construct provided herein.
  • FIG.1 shows a schematic of Dara-BiCE, HexaBody-CD38, daratumumab, and a BiCE negative control antibody.
  • FIG. 2 shows a graph of the cell lysis of various cell lines treated with the Dara-IgG- BiCE. The y-axis depicts percent maximum lysis, and the x-axis depicts cell lines grouped by activity as indicated.
  • FIG.3 shows a graph of the cytotoxicity of WSU-DLCL2 cells treated with Dara-BiCE, HexaBody-CD38, daratumumab, and a BiCE negative control antibody.
  • the y-axis depicts percent cytotoxicity, and the x-axis depicts concentration (nM).
  • FIG.4 shows a graph of the cytotoxicity of RAMOS cells (B cell Lymphoma) and LP- 1 cells (Multiple Myeloma) treated with Dara-BiCE, HexaBody-CD38, daratumumab, and a BiCE negative control antibody.
  • the y-axis depicts percent cytotoxicity, and the x-axis depicts concentration (nM).
  • FIG. 5 shows a heat map of protein levels and max cell lysis of cell lines treated with Dara-IgG BiCE, Daratumumab, or the CD38 hexabody.
  • FIG. 6 shows a graph of cytotoxicity of DOHH2 cells treated with CM91-751; CM1253-1255 (Felzartamab); CM1267-1269 (mezagitamab); CM1781-1782 (CM313); CM1781-1783 (CM313 + C1q binder); daratumumamb; CM220-221 (CD38 Hexabody); or isatuximab.
  • FIG. 7 shows a graph of cytotoxicity of WSU cells treated with CM1232-1234 (daratumumamb 005); CM1233-1234; CM1232-1235; CM1232-1236; CM1232-1237; CM1239-1241; CM1240-1241; CM1239-1242; CM1239-1243; CM1239-1244; CM1246- 1248; CM1247-1248.
  • the y-axis depicts percent cytotoxicity, and the x-axis depicts concentration (nM).
  • FIG.8 shows a graph of the cytotoxic effects of additional CD38-targeting polypeptide constructs.
  • FIG.9 shows a graphs of the cytotoxic effects of C1q and CD38-targeting polypeptide constructs (BiCE constructs) on WSU cells relative to their parental monoclonal antibody.
  • the y-axis depicts percent cytotoxicity, and the x-axis depicts concentration (nM).
  • FIG.10 shows graphs of the level of plasmablast and NK cell depletion in healthy bone marrow from donor treated with Dara-BiCE.
  • the y-axis depicts percent cells from live, and the x-axis depicts concentration (nM).
  • FIG. 11 shows a graph of plasma cell killing in human bone marrow samples treated with Dara-BiCE. Samples were from bone marrow samples from newly diagnosed multiple myeloma (MM) patients, a relapsing patient, and a patient with progressive MM The y-axis depicts percent plasma cell killing, and the x-axis depicts the construct.
  • FIG. 12A-FIG.12D show graphs of an ADCC bioassay of cells treated with CD38- targeting constructs provided herein. The y-axis depicts percent lysis, and the x-axis depicts the concentration.
  • FIG. 12A-FIG.12D show graphs of an ADCC bioassay of cells treated with CD38- targeting constructs provided herein. The y-axis depicts percent lysis, and the x-axis depicts the concentration.
  • FIG. 12A-FIG.12D show graphs of an ADCC bioassay of cells treated with CD38- targeting constructs provided herein. The
  • FIG. 13 shows a graph of C4a concentration in response to 003 Bice; MORO3080 BiCEs; meza BiCEs; and 024 BiCEs relative to controls.
  • the y-axis depicts C4a concentration (micrograms per milliliter), and the x-axis depicts the construct.
  • FIG.14 shows a graph of SRG rat tumor size over time in rats treated with palivizumab (20mg/kg) or varying concentrations of Dara-BiCE.
  • DETAILED DESCRIPTION CD38 is a transmembrane protein that is expressed on the surface of B lymphocytes. It is a well-known target for antibody-based therapies, in particular in multiple myeloma.
  • Some of the known antibodies against CD38 that have been approved or that are in various stages of research or development include daratumumab, isatuximab, the anti-CD38 antibodies known as Clone 003 and Clone 024 (GenMab; see also WO2006/099875), the anti- CD38 antibodies known as Moro3080, Moro 3087 and Moro 3088 (Morphosys), CM313, mezagitamab, felzartamab and the single domain antibody against CD38 known as MU1053.
  • Other antibodies against CD38 and the indications for which they are being used and/or developed will be clear to the skilled person.
  • CD38-related diseases and disorders can be used in the prevention and/or treatment of CD38-related diseases and disorders (as defined herein).
  • CD38-related diseases and disorders may in particular but without limitation be one of the following diseases or disorders: Multiple myeloma;
  • CLL Chronic Lymphocytic Leukemia
  • kidney diseases see for example Chen et al., Front. Immunol., 10 May 2024, Vol.15
  • autoimmune and inflammatory diseases see for example Ye et al., Autoimmunity Reviews, Volume 22, Issue 4, April 2023, 103289
  • Hemophilia Antibody-mediated organ rejection, Platelet Transfusion Primary Antiphospholipid Syndrome, Hemolytic Anemia, Immune Thrombocytopenia, Systemic Lupus Erythematosus, Lupus Nephritis, Immunoglobulin A (IgA) Nephropathy, Nephrotic Syndrome, Membranoproliferative Glomerulonephritis, Proliferative Glomerulonephritis With Monoclonal IgG Deposits, Neuromyelitis Optica Spectrum Disorder
  • the invention in its broadest sense is not limited to any particular explanation, hypothesis or mechanism-of-action.
  • the antibodies of the invention may exert their beneficial influence upon the body of a subject treated with an antibody of the invention via any suitable mechanism-of-action, including but not limited to any mechanism-of-action known per se for one or more of the known antibodies against CD38 referred to herein.
  • any suitable mechanism-of-action including but not limited to any mechanism-of-action known per se for one or more of the known antibodies against CD38 referred to herein.
  • a number of the known antibodies against CD38 have been successfully applied to the prevention and treatment of diseases and disorders in human subject, clinical practice has shown there is a continuous need for new antibodies and antibody constructs against CD38 (and in particular improved antibodies against CD38) that can be used in the prevention and treatment of diseases and disorders in human subjects.
  • the present invention provides such antibodies and antibody constructs.
  • the invention provides an antibody or antibody construct comprising two antibody heavy chains and two antibody light chains (which antibody heavy chains and antibody light chains form an antibody that is directed against CD38), which antibody or antibody construct suitably comprises two single domain antibodies that are directed against C1q (in accordance with the co-pending International applications referred to herein, such single domain antibodies against C1q are also referred to herein as “C1q binders”).
  • the invention in particular provides such an antibody or antibody construct in which the antibody heavy chains and antibody light chains form an antibody that is directed against the same epitope on CD38 as daratumumab.
  • the invention provides such an antibody or antibody construct in which the two V H domains that are present in the heavy chains contain the same CDRs as the V H domain that is present in daratumumab and in which the two V L domains that are present in the light chains contain the same CDRs as the V L domain that is present in daratumumab (in which said CDRs are the CDRs according to Kabat).
  • the invention provides such an antibody or antibody construct in which the two V H domains that are present in the heavy chains have the same amino acid sequence as the V H domain that is present in daratumumab and in which the two V L domains that are present in the light chains have the same amino acid sequence as the V L domain that is present in daratumumab.
  • the antibodies of the invention are as described in the co-pending International applications referred to herein.
  • the two heavy chains will have the same amino acid sequence and the two light chains will have the same amino acid sequence;
  • the two C1q binders that are present in the antibodies of the invention will have the same amino acid sequence; when one of the C1q binders is fused or linked to one of the heavy chains, then the other C1q binder will be fused or linked to the other heavy chain; when one of the C1q binders is fused or linked to one of the light chains, then the other C1q binder will be fused or linked to the other light chain; when one of the C1q binders is fused or linked to the N-terminus of a heavy or light chain, respectively, then the other C1q binder will also be fused or linked to N-terminus of the other heavy or light chain, respectively; when one of the C1q binders is fused or linked to the C-terminus of a heavy or light chain, respectively, then the other C
  • the invention relates to an antibody of the invention in which the one of the C1q binders is linked to the C-terminus of one of the light chains, and the other C1q binder is linked to the C-terminus of the other light chain.
  • the C1q binder is preferably a humanized variant of Nb78 with an affinity for C1q of between 10 nanoMolar (nM) to about 2 microMolar ( ⁇ M), as determined by biolayer interferometry, in particular of about 0.1 ⁇ M to about 2 ⁇ M, as determined by biolayer interferometry.
  • the invention relates to an antibody of the invention in which the two heavy chains both (essentially) comprise the amino acid sequence of SEQ ID NO:1 (not taking into account any C1q binders that maybe fused or linked to said heavy chains).
  • SEQ ID NO:1 is the amino acid sequence of the heavy chain of daratumumab.
  • Such mutations may also be used in a suitable combination, as will be clear to the skilled person (who on the basis of the disclosure herein will also be able to make essentially the same or similar mutations in another naturally occurring Fc region such as the Fc region that is present in the sequence of SEQ ID NO:1).
  • mutations or suitable combination of mutations may (i) alter (i.e. increase or decrease) the half-life of the antibody of the invention; (ii) alter (i.e. increase or decrease) the binding/affinity of the antibody to Fc gamma receptors; and/or (iii) alter (i.e.
  • the invention relates to an antibody of the invention (as further described herein) that contains a non-naturally occurring Fc region, which non-naturally occurring Fc region contains at least one mutation that alter (i.e. increase or decrease, but in particular decrease or essentially removed) the binding/affinity of the antibody to Fc gamma receptors.
  • the invention relates to an antibody of the invention (as further described herein) that contains a non-naturally occurring Fc region, which non-naturally occurring Fc region contains at least one mutation that alter (i.e. increase or decrease, but in particular decrease or essentially removed) the binding/affinity of the antibody to Fc gamma receptors, where such mutations essentially do not affect the affinity of the antibody of the invention for C1q.
  • suitable mutations or combinations of mutations will be clear to the skilled person based on the disclosure herein or can easily be determined (optionally after a limited degree of testing) by the skilled person, and for example include K320E, Q386R) deletion of G236 and/or K326W, E333S.
  • the invention relates to an antibody of the invention in which the two heavy chains both (essentially) comprise the amino acid sequence of SEQ ID NO: 1 (and are not fused or linked to a C1q binder) and in which the two light chains both (essentially) comprise the amino acid sequence of SEQ ID NO: 3 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASN RATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GECGGGGSGGGGSQVQLVESGGGSVQPGGSLRLSCTASGWTFRDSAYNLGW FRQA
  • the antibodies may in addition have one or more of the following advantages (again, compared to the same antibody without the C1q binder), depending on the Fc portion that is present in the specific antibody and in particular on the Fc mutation(s) that may be present in such Fc portion: the ability to activate complement on a cell that expresses CD38 (i.e.
  • the invention relates to a nucleic acid that encodes an antibody of the invention (as mentioned, also referred to herein as a “nucleic acid of the invention”).
  • Such a nucleic acid of the invention may for example be in the form of a genetic construct, as will be clear to the person skilled in the art and as described on pages 131-134 of WO 08/020079 (incorporated herein by reference).
  • Such genetic constructs generally comprise at least one nucleic acid of the invention that is optionally linked to one or more elements of genetic constructs known per se, such as for example one or more suitable regulatory elements (such as a suitable promoter(s), enhancer(s), terminator(s), etc.) and the further elements of genetic constructs known per se.
  • such a genetic construct may be in a form known per se for the expression or production of the known antibodies against CD38 referred to herein and/or in a suitable form as described in WO2019/238674, in WO2020/167919 or in the co- pending International applications.
  • the invention relates to a host or host cell that expresses and/or produces (or that under suitable circumstances is capable of expressing and/or producing) an antibody of the invention; and/or that contains a nucleic acid of the invention.
  • Suitable host cells and cell lines will be clear to the skilled person and may, for example and without limitation, include the cells and cell lines known per se that are used for the expression or production of the known antibodies against CD38 referred to herein, and in particular be mammalian cells (or a mammalian cell line) that are suitable for expressing/producing the antibodies of the invention and/or suitable host cells or cell lines as described in WO2019/238674, in WO2020/167919 or in the co-pending International applications.
  • the invention also relates to a method of expressing or producing an antibody of the invention, which method at least comprises the step of maintaining a host or host cell that expresses and/or produces (or that under suitable circumstances is capable of expressing and/or producing) an antibody of the invention (and/or that contains a nucleic acid of the invention) under conditions such that said host cell expresses/produces said antibody of the invention.
  • Suitable conditions will be clear to the skilled person based on the disclosure herein and may depend on the particular host cell or cell line used. Reference is again for example made to WO2019/238674, WO2020/167919 and the co-pending International applications.
  • the invention further relates to a product or composition containing or comprising at least one antibody of the invention and/or at least one nucleic acid of the invention, and optionally one or more further components of such compositions known per se, i.e. depending on the intended use of the composition.
  • a product or composition may for example be a pharmaceutical composition (as described herein), a veterinary composition or a product or composition for diagnostic use (as also described herein).
  • Some preferred but non-limiting examples of such products or compositions will become clear from the further description herein.
  • the antibodies of the invention can also be administered using gene therapy methods of delivery (including suitable vaccination methods such as mRNA or DNA vaccination methods) such that, upon such administration, an antibody of the invention is suitably expressed/formed in the body of the subject to be treated.
  • Suitable gene therapy vectors, mRNA vaccines and DNA vaccines and suitable methods of administering the same will be clear to the skilled person.
  • primary cells transfected with the gene encoding an antibody of the invention can additionally be transfected with tissue specific promoters to target specific organs, tissue, grafts, tumors, or cells and can additionally be transfected with signal and stabilization sequences for subcellularly localized expression.
  • the antibodies of the invention may be formulated as a pharmaceutical preparation or compositions comprising at least one antibody of the invention and at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and optionally one or more further pharmaceutically active polypeptides and/or compounds.
  • a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration, for administration by inhalation, by a skin patch, by an implant, by a suppository, etc.
  • Such suitable administration forms which may be solid, semi-solid or liquid, depending on the manner of administration - as well as methods and carriers for use in the preparation thereof, will be clear to the skilled person based on the disclosure herein, and may for example and without limitation, include formulations (and components and constituents of formulations) known per se that can be used for formulating the known antibodies against CD38 referred to herein and/or the formulations described in WO2019/238674, WO2020/167919 or in the co-pending International applications.
  • the invention relates to a pharmaceutical composition that contains at least one antibody of the invention and at least one suitable carrier, diluent or excipient (i.e. suitable for pharmaceutical use), and optionally one or more further active substances.
  • the antibodies of the invention can be formulated and administered in any suitable manner known per se, for which reference is for example made to the general background art cited above (and in particular to WO 04/041862, WO 04/041863, WO 04/041865, WO 04/041867 and WO 08/020079) as well as to the standard handbooks, such as Remington’s Pharmaceutical Sciences, 18 th Ed., Mack Publishing Company, USA (1990), Remington, the Science and Practice of Pharmacy, 21th Edition, Lippincott Williams and Wilkins (2005); or the Handbook of Therapeutic Antibodies (S. Dubel, Ed.), Wiley, Weinheim, 2007 (see for example pages 252-255).
  • the antibodies may be formulated and administered in any manner known per se for conventional antibodies (including the known anti-CD38 antibodies mentioned herein).
  • Such formulations and methods for preparing the same will be clear to the skilled person, and for example include preparations suitable for parenteral administration (for example intravenous, intraperitoneal, subcutaneous, intramuscular, intraluminal, intra-arterial or intrathecal administration) or for topical (i.e. transdermal or intradermal) administration.
  • Preparations for parenteral administration may for example be sterile solutions, suspensions, dispersions or emulsions that are suitable for infusion or injection.
  • Suitable carriers or diluents for such preparations for example include, without limitation, those mentioned in WO2019/238674, WO2020/167919 and the co-pending International applications.
  • aqueous solutions or suspensions will be preferred.
  • the amount(s) of the antibodies of the invention required for use in treatment i.e.
  • the dose(s) and dose regimen applied in such treatment will vary not only with the particular antibody of the invention used, but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician, who will be able to choose an appropriate dose regimen taking into account the considerations referred to herein.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
  • An administration regimen could include long-term, daily treatment.
  • long-term is meant at least two weeks and preferably, several weeks, months, or years of duration. Necessary modifications in this dosage range may be determined by one of ordinary skill in the art using only routine experimentation given the teachings herein. See Remington’s Pharmaceutical Sciences (Martin, E.W., ed.4), Mack Publishing Co., Easton, PA. The dosage can also be adjusted by the individual physician in the event of any complication.
  • the invention relates to a method for the prevention and/or treatment of at least CD38-related disease or disorder (as defined herein), said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of an antibody of the invention and/or of a pharmaceutical composition comprising the same (i.e. in one or more suitable doses and according to a suitable dosage regimen, as further described herein).
  • the invention relates to a method for increasing the complement- dependent cytotoxicity towards a CD38 expressing cell that is exerted by the body of a subject that is in need thereof, which method comprises administering, to said subject, a pharmaceutically active amount of an antibody of the invention or a pharmaceutical composition comprising the same.
  • prevention and/or treatment not only comprises preventing and/or treating the disease, but also generally comprises preventing the onset of the disease, slowing or reversing the progress of disease, preventing or slowing the onset of one or more symptoms associated with the disease, reducing and/or alleviating one or more symptoms associated with the disease, reducing the severity and/or the duration of the disease and/or of any symptoms associated therewith and/or preventing a further increase in the severity of the disease and/or of any symptoms associated therewith, preventing, reducing or reversing any physiological damage caused by the disease, and generally any pharmacological action that is beneficial to the patient being treated.
  • the subject to be treated may be any warm-blooded animal, but is in particular a mammal, and more in particular a human being.
  • the subject to be treated will in particular be a person suffering from, or at risk of, the diseases and disorders mentioned herein.
  • the invention relates to a method for immunotherapy, which method comprises administering, to a subject suffering from or at risk of a CD38-related disease or disorder, a pharmaceutically active amount of an antibody of the invention or a pharmaceutical composition comprising the same.
  • the antibody or composition of the invention will generally be administered to the subject to be treated according to a regime of treatment that is suitable for preventing and/or treating the disease or disorder to be prevented or treated.
  • the clinician will generally be able to determine a suitable treatment regimen, depending on factors such as the disease or disorder to be prevented or treated, the severity of the disease to be treated and/or the severity of the symptoms thereof, the specific antibody of the invention used, the specific route of administration and pharmaceutical formulation or composition to be used, the age, gender, weight, diet, general condition of the patient, and similar factors well known to the clinician.
  • the treatment regimen will comprise the administration of one or more antibodies of the invention, or of one or more compositions comprising the same, in one or more pharmaceutically effective amounts or doses.
  • the specific amount(s) or doses to administered can be determined by the clinician, again based on the factors cited herein.
  • the antibodies of the invention will generally be administered in an amount between 1 gram and 0.01 microgram per kg body weight per day, preferably between 0.1 gram and 0.1 microgram per kg body weight per day, such as about 1, 10, 100 or 1000 microgram per kg body weight per day, either continuously (e.g. by infusion), as a single daily dose or as multiple divided doses during the day.
  • the clinician will generally be able to determine a suitable daily dose, depending on the factors mentioned herein.
  • the clinician may choose to deviate from these amounts, for example on the basis of the factors cited above and his expert judgment.
  • some guidance on the amounts to be administered can be obtained from the amounts usually administered for comparable conventional antibodies or antibody fragments against the same target administered via essentially the same route, taking into account however differences in affinity/avidity, efficacy, biodistribution, half-life and similar factors well known to the skilled person.
  • a single antibody of the invention will be used. It is however within the scope of the invention to use two or more antibodies of the invention in combination.
  • the antibodies of the invention may also be used in combination with one or more further pharmaceutically active compounds or principles, i.e.
  • the antibodies of the invention may be used in combination with other pharmaceutically active compounds or principles that are or can be used for the prevention and/or treatment of the diseases and disorders cited herein, as a result of which a synergistic effect may or may not be obtained.
  • examples of such compounds and principles, as well as routes, methods and pharmaceutical formulations or compositions for administering them will be clear to the clinician, and for example include the active compounds or principles that are or can be used in combination with one of the known antibodies against CD38 referred to herein (e.g.
  • a suitable combined treatment regimen as will be able to be determined by the treating clinician).
  • two or more substances or principles are to be used as part of a combined treatment regimen, they can be administered via the same route of administration or via different routes of administration, at essentially the same time or at different times (e.g. essentially simultaneously, consecutively, or according to an alternating regime).
  • the substances or principles are to be administered simultaneously via the same route of administration, they may be administered as different pharmaceutical formulations or compositions or part of a combined pharmaceutical formulation or composition, as will be clear to the skilled person.
  • each of the substances or principles may be administered in the same amount and according to the same regimen as used when the compound or principle is used on its own, and such combined use may or may not lead to a synergistic effect.
  • the effectiveness of the treatment regimen used according to the invention may be determined and/or followed in any manner known per se for the disease or disorder involved, as will be clear to the clinician. Suitable methods and techniques will be clear to the skilled person and will often generally comprise a step of determining the level(s) of the relevant CD38 expressing cell(s) in the body of the subject to be treated (or in a suitable biological sample obtained from such subject). and/or determining any changes in such levels. Such methods and techniques may for example include the methods and techniques commonly used for determining the effectiveness and/or course of a treatment with one of the known antibodies against CD38 referred to herein.
  • the clinician will also be able, where appropriate and on a case-by-case basis, to change or modify a particular treatment regimen, so as to achieve the desired therapeutic effect, to avoid, limit or reduce unwanted side-effects, and/or to achieve an appropriate balance between achieving the desired therapeutic effect on the one hand and avoiding, limiting or reducing undesired side effects on the other hand.
  • the treatment regimen will be followed until the desired therapeutic effect is achieved and/or for as long as the desired therapeutic effect is to be maintained. Again, this can be determined by the clinician.
  • the invention relates to the use of an antibody of the invention in the preparation of a pharmaceutical composition for prevention and/or treatment of at least one CD38-related disease or disorder (as defined herein); and/or for use in one or more of the methods of treatment mentioned herein.
  • the invention further relates to an antibody of the invention (or a pharmaceutical composition comprising the same) for the prevention and/or treatment of at least one CD38-related disease or disorder (as defined herein).
  • the invention also relates to a method of preventing and/or treating a CD38-related disease or disorder (as defined herein), which method comprises administering, to a subject in need thereof, of an antibody of the invention or a pharmaceutical composition comprising the same (again, according to a suitable route of administration and a suitable dosage regimen, as further described herein).
  • a suitable route of administration and a suitable dosage regimen as further described herein.
  • the antibodies of the invention can be linked to a suitable detectable label and used as markers to detect or determine (qualitatively or quantitatively) the presence of CD38 or CD38 expressing cells, either in vitro, ex vivo or in vivo; and/or to determine whether the antibodies of the invention are capable of bringing together CD38-expressing cells and C1q (i.e. in order to initiate complement-dependent cytotoxicity by the complement system ).
  • a suitable detectable label and used as markers to detect or determine (qualitatively or quantitatively) the presence of CD38 or CD38 expressing cells, either in vitro, ex vivo or in vivo; and/or to determine whether the antibodies of the invention are capable of bringing together CD38-expressing cells and C1q (i.e. in order to initiate complement-dependent cytotoxicity by the complement system ).
  • a polypeptide construct with a complement factor-engaging domain at the C-terminus of an antibody light chain was designed in silico together with a corresponding heavy chain gene.
  • affinity variants of the polypeptide constructs comprising C1q complement factor- engaging domains as disclosed herein were designed and tested in this format.
  • Expi293 cells were transfected by mixing OPTI-MEM, DNA and PEI Max which was added to cells. 18h post transfection, each of the transfections were added Valproic acid, sodium propionate, and glucose to enhance the transfection efficacy.
  • CD38 mAbs and CD38 BiCE versions listed in Table 3 below were evaluated in a CDC Assay of DOHH2 cells, a human B cell lymphoma cell line. CytoToxGloTM (Promega, Madison, WI, USA) was used to evaluate cell cytotoxicity according to manufacturer’s instructions using 100,000 cells/well and 10% NHS. TABLE 3. CD38-targeting polypeptide and antibody constructs.
  • the C1q binder is hNb78 [M33A, T102A] having a sequence of: QVQLVESGGGSVQPGGSLRLSCTASGWTFRDSAYNLGWFRQAPGQEREAVAAISWR GGSTYYADSVKGRFTISRDNAKNTVTLQMNNLKPEDTAIYYCAADASARAALYSTG YEYDHWGQGTQVTVSS (SEQ ID NO: 21); or Nb75 [T53G] QVQLVETGGGLVQAGGSLRLSCAASGRTFNNDVMAWFRQAPGTEREFVALIGAGG GTHYADSVKGRFVISRDNDKNMAYLQMNSLKSEDTAIYYCGADENPPGWPSRWSS AYDYWGQGTQVTVSS (SEQ ID NO: 22)
  • the clone 003 sequence comprises the following heavy and light chain sequences below.
  • N ame Composition SEQ ID NO: C M1232-1234 Daratumumab (Dara 005) Hc and Lc SEQ ID NO: 1 and SEQ ID NO: 2 Nb75 (T53G)-10GS- Dara 005 Hc + Dara SEQ ID NO: 22; SEQ ID NO: 6 and CM1233-1234 005 Lc SEQ ID NO: 2 Dara (005) Hc + Dara modified Lc - 4G - SEQ ID NO: 1; SEQ ID NO: 7; and CM1232-1235 hNb78(M33A,T102A) SEQ ID NO: 21 Dara 005 Hc + Dara modified Lc - 5G - SEQ ID NO: 1; SEQ ID NO: 8 and CM1232-1236 hNb78(M33A,T102A) SEQ ID NO: 21 Dara 005 Hc + Nb75(T53G)-10GS- Dara SEQ ID NO: 22; SEQ ID NO: 6 and CM123
  • Nb75 T53G
  • hNb78 M33A, T102A
  • EXAMPLE 3 DEPLETION OF CD38 BONE MARROW CELLS
  • Dara-BiCE was evaluated for killing of CD38 positive cells in a bone marrow from healthy human donors in the presence of complement (FIG.10).
  • Dara-BiCE shows efficient complement mediated killing of plasmablasts and NK cells.
  • Activity of Dara-BiCE and Daratumumab was evaluated on bone marrow samples obtained from newly diagnosed multiple myeloma (MM) patients, a relapsing patient, and a patient with progressive MM.
  • Dara-BiCE shows superior ex vivo killing of MM cells compared to Daratumumab (FIG.11).
  • ADCC ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITY
  • KILR Raji cells
  • ADCC Antibody-dependent cellular cytotoxicity
  • MORO3080 binds strongly to cynomolgus monkey, marmoset, and rhesus monkey CD38 proteins.
  • EXAMPLE 6 EPITOPE BINNING REVEALS COMBINATIONS FOR BIPARATOPIC CD38 IGG BICES.
  • Epitope overlap of CD38 mAbs was evaluated using BLI and recombinant human CD38. BLI epitope binning was performed with CD38 clones: CM1232-1234, CM1239-1241, CM1246-1248, CM1253-1255, CM1260-1262, CM1267-1269, and CM1274-1275 on HIS sensors with hCD38-his.
  • CM1239-1241 (003) binds a different epitope on CD38 than all the other tested CD38 antibodies.
  • CM1274-1275 (024) binds another epitope on CD38 than the other tested CD38 antibodies.
  • the epitopes of CM1232-1234 (005), CM1246-1248 (MORO3080), CM1253-1255 (MORO3087), and CM1267-1269 (Mezagitamab) seem to overlap on CD38.
  • EXAMPLE 7 FLUID PHASE ACTIVATION AND SAFETY BiCE polypeptide constructs were evaluated for complement activation in a fluid phase assay measuring C4a generation.
  • the CD38-BiCEs exhibited specific complement activation in the present of CD38-expressing cells (FIG.
  • CD38 IgG BiCE constructs do not lead to complement activation in the absence of target cells.
  • a mixture of Dara-BiCE and soluble CD38 was combined in normal human serum.
  • CD38 BiCE shows no fluid phase in the presence of soluble CD38 and does not lead to complement activation (measured with C4a ELISA) further confirming that CD38 IgG BiCE constructs do not lead to complement activation in the absence of target cells.
  • EXAMPLE 8 PHARMACOKINETIC EVALUATION OF DARA-BiCE IN A RAT MODEL. The pharmacokinetic properties of Dara-BiCE was evaluated relative to daratumumab.
  • Daratumumab and Dara-BICE were dosed IV at 5 mg/kg and 6 mg/kg (equimolar) in SRG rats. Serum levels were detected using a generic IgG PK ELISA. Half-life, volume of distribution (Vd), clearance (CL), and area under the curve (AUC) were quantified as shown in Table 8 below. TABLE 8. Pharmacokinetic properties of Dara-Bice as compared to daratumumab.
  • EXAMPLE 9 EVALUATION OF DARA-BICE TREATMENT OF CANCER IN AN SRG RAT MODEL Dara-BiCE with a C1q-binding moiety that was optimized for rat C1q (Dara-BiCE surrogate); daratumumab; and palivizumab (negative control) were administered to Sprague Dawley Rag2 -/- Il2rg -/- (SRG) rats with human B cell lymphoma (Daudi cell line) according to the schedule in FIG. 14. SRG rats have no T cells, B cells, or NK cells but have a fully active complement system.

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Abstract

L'invention concerne des constructions polypeptidiques qui se lient à un facteur du complément (tels que C1q) et CD38). L'invention concerne également diverses configurations des constructions polypeptidiques et des modifications d'acides aminés pour une efficacité améliorée. Les constructions polypeptidiques peuvent être utilisées dans le traitement d'une maladie, par exemple, le cancer, les maladies auto-immunes, l'obésité, les maladies neurodégénératives, les maladies cardiovasculaires et les maladies métaboliques, entre autres.
PCT/EP2025/062027 2024-05-01 2025-05-01 Anticorps et constructions d'anticorps dirigés contre cd38 Pending WO2025229158A1 (fr)

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