WO2023232110A1 - Anticorps anti-cd24 humain et son utilisation - Google Patents

Anticorps anti-cd24 humain et son utilisation Download PDF

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WO2023232110A1
WO2023232110A1 PCT/CN2023/097784 CN2023097784W WO2023232110A1 WO 2023232110 A1 WO2023232110 A1 WO 2023232110A1 CN 2023097784 W CN2023097784 W CN 2023097784W WO 2023232110 A1 WO2023232110 A1 WO 2023232110A1
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amino acid
acid sequence
sequence shown
antibody
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Chinese (zh)
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任红媛
徐晓红
吴建
桂勋
朱戬
林鉴
邓小芳
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迈威(上海)生物科技股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07—ORGANIC CHEMISTRY
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    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
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    • G01N33/57407—Specifically defined cancers
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    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57423—Specifically defined cancers of lung
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    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
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    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
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    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
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    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
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    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/577—Immunoassay; Biospecific binding assay; Materials therefor involving monoclonal antibodies binding reaction mechanisms characterised by the use of monoclonal antibodies; monoclonal antibodies per se are classified with their corresponding antigens
    • 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
    • C07K2317/50—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
    • 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
    • C07K2317/565—Complementarity determining region [CDR]
    • G—PHYSICS
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    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70596—Molecules with a "CD"-designation not provided for elsewhere in G01N2333/705

Definitions

  • the present invention relates to the field of antibody drugs. Specifically, the invention relates to antibodies against human CD24 and their use for preparing drugs.
  • the CD24 molecule is a sialic acid glycoprotein, which consists of a core skeleton structure of 33 amino acid residues and has 16 potential O- or N-glycosylation sites.
  • the surface is highly glycosylated and the molecular weight ranges from 30 to 70kDa. between.
  • the CD24 molecule can be anchored to the surface of the cell membrane through glycosyl-phosphatidyl-inositol (GPI) at the carboxyl terminus. Under physiological conditions, CD24 molecules are only expressed at low levels on immature B cells, mature granulocytes, and a small number of epithelial cells and nerve cells.
  • GPI glycosyl-phosphatidyl-inositol
  • TNBC triple-negative breast cancer
  • CD24 inhibits inflammatory responses by interacting with Siglec-10 molecules on immune cells and transmitting immunosuppressive signals.
  • CD24-Siglec-10 as an innate immune checkpoint, can regulate macrophage-mediated anti-tumor immune responses. Therefore, CD24 may become an ideal target for tumor immunotherapy, especially for breast cancer or ovarian cancer.
  • the technical problem to be solved by the present invention is to obtain mouse antibodies through hybridoma technology, obtain better antibodies through mouse anti-activity analysis and screening, carry out humanized design and further activity analysis of the antibodies, and finally screen to obtain specific binding to human CD24 and Therapeutics with high affinity, selectivity and biological activity Antibody.
  • the object of the present invention is to provide an antibody or fragment thereof that specifically binds to human CD24 and provide its use.
  • the antibody fragments described in the present invention include various functional fragments of antibodies, such as their antigen-binding portions, such as Fab, F(ab') 2 or scFv fragments.
  • the invention provides an antibody or fragment thereof capable of specifically binding to CD24, in particular human CD24.
  • the antibody of the present invention is a murine antibody obtained by using human CD24 as an immunogen, as well as chimeric antibodies and humanized antibodies obtained based on the murine antibody.
  • the present invention provides an antibody or fragment thereof, said antibody or fragment thereof comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein:
  • the heavy chain variable region includes heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), heavy chain CDR3 (HCDR3) contained in the following amino acid sequences: SEQ ID NO.1, 3, 5, 7, The amino acid sequence shown in 9, 11, 13 or 15; and
  • the light chain variable region includes light chain CDR1 (LCDR1), light chain CDR2 (LCDR2), light chain CDR3 (LCDR3) contained in the following amino acid sequences: SEQ ID NO.2, 4, 6, 8, The amino acid sequence shown in 10, 12, 14 or 16.
  • the antibody or fragment thereof provided by the present invention is an anti-CD24, especially an antibody or fragment thereof against human CD24, which can bind to the CD24 with high affinity and specificity.
  • the combination of heavy and light chain CDRs comprised by the antibody or fragment thereof is derived from the specific antibodies of the invention (see the Examples section). Based on the heavy and light chain amino acid sequences comprised by these specific antibodies, those skilled in the art can routinely determine where CDRs included. According to the specific embodiment of the present invention, the heavy and light chain CDRs contained in any of the above amino acid sequences can be obtained using Chothia, AbM, Kabat, Contact, IMGT and comprehensive analysis. For details, please refer to the Examples section. Heavy and light chain CDRs divided by other methods known in the art and combinations thereof are also encompassed within the scope of the present invention.
  • fragment encompasses various functional fragments of the anti-CD24 antibody that retain the antigen-binding ability of the antibody and the corresponding biological activity. It is well known in the art that the binding ability of antibodies to antigens and the corresponding biological activities can be achieved by fragments of intact antibodies, which can be obtained using conventional techniques known to those skilled in the art and in the same manner as for intact antibodies. The way to filter is based on functionality.
  • antigen-binding fragments of the antibody can be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of the intact antibody.
  • the fragment may be a Fab, F(ab')2 or scFv fragment, etc.
  • the antibody or fragment thereof provided by the invention includes heavy chain CDR1 (HCDR1), heavy chain CDR2 (HCDR2), heavy chain CDR3 (HCDR3), light chain CDR1 (LCDR1), light chain CDR2 (LCDR2) and light chain CDR3 (LCDR3) are derived from the following amino acid sequence combinations:
  • the anti-CD24 antibody or fragment thereof provided by the invention includes a combination of heavy chain CDRs and light chain CDRs (HCDR1, HCDR2 and HCDR3; and LCDR1, LCDR2 and LCDR3) selected from the following:
  • the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO.20, SEQ ID NO.21 and SEQ ID NO.22; and, the LCDR1, LCDR2 and LCDR3 respectively comprise SEQ ID NO.23 , the amino acid sequence shown in SEQ ID NO.24 and SEQ ID NO.25;
  • the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO.26, SEQ ID NO.27 and SEQ ID NO.22; and the LCDR1, LCDR2 and LCDR3 respectively comprise SEQ ID NO.23 , ammonia shown in SEQ ID NO.24 and SEQ ID NO.25 amino acid sequence;
  • the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO.28, SEQ ID NO.29 and SEQ ID NO.22; and the LCDR1, LCDR2 and LCDR3 respectively comprise SEQ ID NO.23 , the amino acid sequence shown in SEQ ID NO.24 and SEQ ID NO.25;
  • the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO.30, SEQ ID NO.31 and SEQ ID NO.32; and the LCDR1, LCDR2 and LCDR3 respectively comprise SEQ ID NO.33 , the amino acid sequence shown in SEQ ID NO.34 and SEQ ID NO.35;
  • the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO.36, SEQ ID NO.37 and SEQ ID NO.38; and the LCDR1, LCDR2 and LCDR3 respectively comprise SEQ ID NO.39 , the amino acid sequence shown in SEQ ID NO.40 and SEQ ID NO.25;
  • the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO.26, SEQ ID NO.29 and SEQ ID NO.22; and the LCDR1, LCDR2 and LCDR3 respectively comprise SEQ ID NO.23 , the amino acid sequence shown in SEQ ID NO.24 and SEQ ID NO.25;
  • the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO.20, SEQ ID NO.41 and SEQ ID NO.42; and the LCDR1, LCDR2 and LCDR3 respectively comprise SEQ ID NO.43 , the amino acid sequence shown in SEQ ID NO.44 and SEQ ID NO.45;
  • the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO.26, SEQ ID NO.46 and SEQ ID NO.42; and the LCDR1, LCDR2 and LCDR3 respectively comprise SEQ ID NO.43 , the amino acid sequence shown in SEQ ID NO.44 and SEQ ID NO.45;
  • the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO.28, SEQ ID NO.47 and SEQ ID NO.42; and the LCDR1, LCDR2 and LCDR3 respectively comprise SEQ ID NO.43 , the amino acid sequence shown in SEQ ID NO.44 and SEQ ID NO.45;
  • the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO.30, SEQ ID NO.48 and SEQ ID NO.49; and, the LCDR1, LCDR2 and LCDR3 contains the amino acid sequences shown in SEQ ID NO.50, SEQ ID NO.51 and SEQ ID NO.52 respectively;
  • the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO.36, SEQ ID NO.84 and SEQ ID NO.85; and the LCDR1, LCDR2 and LCDR3 respectively comprise SEQ ID NO.86 , the amino acid sequence shown in SEQ ID NO.40 and SEQ ID NO.45;
  • the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO.26, SEQ ID NO.47 and SEQ ID NO.42; and the LCDR1, LCDR2 and LCDR3 respectively comprise SEQ ID NO.43 , the amino acid sequence shown in SEQ ID NO.44 and SEQ ID NO.45;
  • the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO.20, SEQ ID NO.21 and SEQ ID NO.53; and the LCDR1, LCDR2 and LCDR3 respectively comprise SEQ ID NO.23 , the amino acid sequence shown in SEQ ID NO.54 and SEQ ID NO.55;
  • the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO.26, SEQ ID NO.56 and SEQ ID NO.53; and the LCDR1, LCDR2 and LCDR3 respectively comprise SEQ ID NO.23 , the amino acid sequence shown in SEQ ID NO.54 and SEQ ID NO.55;
  • the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO.28, SEQ ID NO.57 and SEQ ID NO.53; and the LCDR1, LCDR2 and LCDR3 respectively comprise SEQ ID NO.23 , the amino acid sequence shown in SEQ ID NO.54 and SEQ ID NO.55;
  • the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO.30, SEQ ID NO.58 and SEQ ID NO.59; and the LCDR1, LCDR2 and LCDR3 respectively comprise SEQ ID NO.33 , the amino acid sequence shown in SEQ ID NO.60 and SEQ ID NO.61;
  • the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO.36, SEQ ID NO.37 and SEQ ID NO.62; and the LCDR1, LCDR2 and LCDR3 respectively comprise SEQ ID NO.39 , the amino acid sequence shown in SEQ ID NO.40 and SEQ ID NO.55;
  • the HCDR1, HCDR2 and HCDR3 respectively contain SEQ ID NO.26, SEQ ID The amino acid sequences shown in NO.57 and SEQ ID NO.53; and, the LCDR1, LCDR2 and LCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO.23, SEQ ID NO.54 and SEQ ID NO.55;
  • the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO.63, SEQ ID NO.64 and SEQ ID NO.65; and the LCDR1, LCDR2 and LCDR3 respectively comprise SEQ ID NO.66 , the amino acid sequence shown in SEQ ID NO.67 and SEQ ID NO.68;
  • the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO.69, SEQ ID NO.70 and SEQ ID NO.65; and the LCDR1, LCDR2 and LCDR3 respectively comprise SEQ ID NO.66 , the amino acid sequence shown in SEQ ID NO.67 and SEQ ID NO.68;
  • the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO.71, SEQ ID NO.72 and SEQ ID NO.65; and the LCDR1, LCDR2 and LCDR3 respectively comprise SEQ ID NO.66 , the amino acid sequence shown in SEQ ID NO.67 and SEQ ID NO.68;
  • the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO.73, SEQ ID NO.74 and SEQ ID NO.75; and the LCDR1, LCDR2 and LCDR3 respectively comprise SEQ ID NO.76 , the amino acid sequence shown in SEQ ID NO.77 and SEQ ID NO.78;
  • the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO.79, SEQ ID NO.80 and SEQ ID NO.81; and the LCDR1, LCDR2 and LCDR3 respectively comprise SEQ ID NO.82 , the amino acid sequence shown in SEQ ID NO.83 and SEQ ID NO.68;
  • the HCDR1, HCDR2 and HCDR3 respectively comprise the amino acid sequences shown in SEQ ID NO.69, SEQ ID NO.72 and SEQ ID NO.65; and the LCDR1, LCDR2 and LCDR3 respectively comprise SEQ ID NO.66 , SEQ ID NO.67 and the amino acid sequence shown in SEQ ID NO.68.
  • the heavy chain variable region may comprise the following amino acid sequence or an amino acid sequence having at least 75% identity with the amino acid sequence: SEQ ID NO. 1, 3, 5, 7, 9, 11, 13 or 15; and, the light chain variable region may comprise the following amino acid sequence or an amino acid sequence having at least 75% identity with the amino acid sequence Acid sequence: the amino acid sequence shown in SEQ ID NO. 2, 4, 6, 8, 10, 12, 14 or 16.
  • At least 75% identity used in the context of the present invention with respect to a sequence is, for example, at least 80%, preferably at least 85%, more preferably at least 90%, further preferably at least 91%, 92%, 93%, 94%, 95%, Any percentage of identity ⁇ 75% such as 96%, 97%, 98% or even 99% identity.
  • the antibody or fragment thereof of the present invention includes at least a heavy chain variable region and a light chain variable region, both of which include the CDRs described above and an intervening framework region, which includes a structural domain The arrangement is: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.
  • the "at least 75% identity" resulting in up to 25% difference in amino acid sequence may be present in any framework region of the heavy chain variable region or the light chain variable region, or may be present in the present invention. Any domain or sequence in the antibody or its antigen-binding fragment other than the heavy chain variable region and the light chain variable region. The differences may result from amino acid deletions, additions or substitutions at any position.
  • the heavy chain variable region and the light chain variable region comprise a sequence combination selected from the following:
  • the heavy chain variable region includes an amino acid sequence having at least 75% identity with the amino acid sequence shown in SEQ ID NO.1; and the light chain variable region includes an amino acid sequence shown in SEQ ID NO.2 Amino acid sequences with at least 75% identity;
  • the heavy chain variable region includes an amino acid sequence that is at least 75% identical to the amino acid sequence shown in SEQ ID NO.3; and the light chain variable region includes an amino acid sequence shown in SEQ ID NO.4 Amino acid sequences with at least 75% identity;
  • the heavy chain variable region includes an amino acid sequence having at least 75% identity with the amino acid sequence shown in SEQ ID NO.5; and the light chain variable region includes an amino acid sequence shown in SEQ ID NO.6 Amino acid sequences with at least 75% identity;
  • the heavy chain variable region includes an amino acid sequence having at least 75% identity with the amino acid sequence shown in SEQ ID NO.7; and the light chain variable region includes an amino acid sequence shown in SEQ ID NO.8 Amino acid sequences with at least 75% identity;
  • the heavy chain variable region includes an amino acid sequence having at least 75% identity with the amino acid sequence shown in SEQ ID NO.9; and the light chain variable region includes an amino acid sequence shown in SEQ ID NO.10 Amino acid sequences with at least 75% identity;
  • the heavy chain variable region includes an amino acid sequence that is at least 75% identical to the amino acid sequence shown in SEQ ID NO. 11; and the light chain variable region includes an amino acid sequence shown in SEQ ID NO. 12 Amino acid sequences with at least 75% identity;
  • the heavy chain variable region includes an amino acid sequence having at least 75% identity with the amino acid sequence shown in SEQ ID NO.13; and the light chain variable region includes an amino acid sequence shown in SEQ ID NO.14 Amino acid sequences with at least 75% identity;
  • the heavy chain variable region includes an amino acid sequence having at least 75% identity with the amino acid sequence shown in SEQ ID NO.15; and the light chain variable region includes an amino acid sequence shown in SEQ ID NO.16 Amino acid sequences with at least 75% identity.
  • the antibody provided by the invention is a mouse anti-, chimeric antibody or a fully or partially humanized antibody that binds to CD24, especially human CD24 (UniProt: P25063); the fragment is a half-antibody or an antigen-binding fragment of the antibody, Includes scFv, dsFv, (dsFv) 2 , Fab, Fab', F(ab') 2 or Fv fragment.
  • the antibody is a monoclonal antibody or a single chain antibody.
  • the antibody or fragment thereof also contains a human or murine constant region, preferably a human or murine heavy chain constant region (CH) and/or a light chain constant region (CL); preferably, the The antibody or fragment thereof comprises a heavy chain and a light chain; more preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region and/or a kappa or lambda light chain selected from the group consisting of IgG, IgA, IgM, IgD or IgE. constant region.
  • the antibody is a monoclonal antibody, preferably a murine, chimeric or humanized monoclonal antibody.
  • the monoclonal antibody is an IgG, in particular an IgG1 (eg human IgG1).
  • the antibody or fragment thereof provided by the present invention includes a heavy chain constant region, and the heavy chain constant region includes the amino acid sequence shown in SEQ ID NO. 17 or SEQ ID NO. 18 or is at least 75% identical to the amino acid sequence. % identical amino acid sequence; and/or comprising a light chain constant region, the light chain constant region comprising the amino acid sequence shown in SEQ ID NO. 19 or an amino acid sequence having at least 75% identity with the amino acid sequence.
  • the antibody provided by the present invention can be a monoclonal antibody, including two identical heavy chains and two identical light chains.
  • the present invention also provides a nucleic acid molecule comprising a nucleotide sequence encoding the antibody of the present invention or a fragment thereof, or a heavy chain CDR or a light chain CDR encoding the antibody or fragment thereof. , a light chain variable region, a heavy chain variable region, a nucleotide sequence of a heavy chain or a light chain.
  • the antibodies or fragments thereof provided by the invention can be obtained using any method known in the art.
  • the host cell provided by the invention is allowed to express the heavy chain variable region and/or light chain variable region of the antibody or the heavy chain and/or light chain of the antibody to assemble into the antibody
  • the host cells are cultured.
  • the method further includes the step of recovering the produced antibodies.
  • the present invention provides the use of the above-mentioned antibodies or fragments thereof, nucleic acid molecules, vectors, host cells and/or compositions in the preparation of medicaments for the treatment of diseases associated with CD24 expression or mediated by CD24.
  • the disease is a tumor or cancer; more preferably, the disease is colorectal cancer, ovarian cancer, breast cancer, liver cancer, bladder cancer, prostate cancer, non-small cell lung cancer, rectal cancer, pancreatic cancer or nasopharyngeal cancer cancer.
  • the present invention also provides a method for detecting or diagnosing diseases related to CD24 expression or mediated by CD24, which method includes making the antibody or fragment thereof, nucleic acid molecule, vector, host cell and/or The composition is contacted with a sample from the subject.
  • the disease is a tumor or cancer; more preferably, the disease is colorectal cancer, ovarian cancer, breast cancer, liver cancer, bladder cancer, prostate cancer, non-small cell lung cancer, rectal cancer, pancreatic cancer or nasopharyngeal cancer cancer.
  • the subject is a mammal; more preferably, the subject is a human.
  • Figure 1 shows the binding of anti-human CD24 chimeric antibodies to human CD24 expressed on the cell surface.
  • Figure 2 shows the detection results of the regulatory effect of anti-human CD24 chimeric antibodies on macrophage phagocytosis of SKOV-3 cells; among the results of each antibody in the figure, the left side is the 10 ⁇ g/mL concentration result, and the right side is the 1 ⁇ g/mL concentration result. .
  • Figure 3 shows the ADCC activity detection results of anti-human CD24 chimeric antibodies.
  • Figure 4 shows the antigen binding specificity detection results of anti-human CD24 chimeric antibodies, wherein 4A: MCF7 cell line; 4B: MCF7-CD24KO cell line.
  • Figure 5 shows the detection results of the regulatory effect of anti-human CD24 humanized antibodies on macrophage phagocytosis of SKOV-3 cells.
  • Figure 6 shows the ADCC activity detection results of anti-human CD24 humanized antibodies.
  • Figure 7 shows the ADCP activity detection results of anti-human CD24 humanized antibodies.
  • Figure 8 shows the detection results of the blocking activity of anti-human CD24 humanized antibodies on Siglec-10 binding to huCD24.
  • Figure 9 shows the test results of the stability of the anti-human CD24 humanized antibody binding to the antigen; wherein 9A, 9C: C55 Hz43; 9B, 9D: B17 Hz10.
  • Figure 10 shows the concentration versus time curve of the anti-human CD24 humanized antibody; 10B shows the half-life T 1/2 ⁇ of the anti-human CD24 humanized antibody obtained by compartmental analysis.
  • Figures 11 to 13 respectively show the detection results of the therapeutic effect of anti-human CD24 humanized antibodies on colorectal cancer.
  • SN3muIgG anti-human CD24 mouse monoclonal antibody from Abcam, Cat.No.ab134375;
  • Hu5F9 Anti-CD47 antibody from Forty Seven Company, take the V region sequence and splice it into the huIgG1 constant region sequence to obtain Hu5F9huIgG1;
  • the huIgG1 heavy chain constant region and light chain constant region or the LALA heavy chain constant region are used, and the sequences are as follows:
  • the hybridoma cells secreting anti-human CD24 antibodies were expanded and cultured, and the total RNA of the cells was extracted according to the instructions of the RNAfast200 kit (Shanghai Feijie Biotechnology Co., Ltd.); the total RNA of the hybridoma cells was reacted with 5 ⁇ PrimeScript RT Master Mix (Takara).
  • PCR amplification product was purified using extraction kit (Macherey-Nagel); according to the instructions of pClone007 Simple Vector Kit (Beijing Qingke Biotechnology Co., Ltd.), the amplified PCR product was connected to the T vector and transformed into E. coli competent cells. The strain was expanded After the plasmid is amplified and extracted, DNA sequencing is performed to obtain the monoclonal antibody variable region sequence.
  • the mouse monoclonal antibody variable region sequence is shown below.
  • the anti-human CD24 chimeric antibody of the present invention, Hu5F9, and unrelated negative antibodies were diluted 2-fold starting from a starting concentration of 10 nM, with a total of 7 concentration points. 10 ⁇ l of the antibody at each concentration point was added to a 384-well plate.
  • HCDR2 SEQ ID NO.57
  • Humanized antibodies are as follows:
  • VH is C01_VH_hz1 (SEQ ID NO.11);
  • VL is C01_VL_hz0 (SEQ ID NO.12);
  • VH is C55_VH_hz4 (SEQ ID NO.13);
  • VL is C55_VL_hz3 (SEQ ID NO.14);
  • VH is C60_VH_hz4 (SEQ ID NO.15);
  • VL is C60_VL_hz8 (SEQ ID NO.16);
  • VH is B17_VH_hz1 (SEQ ID NO.9)
  • VL is B17_VL_hz0 (SEQ ID NO.10).
  • MCF7 and CD24-knocked-out MCF7 were used as experimental cells respectively. Prepare a cell suspension of 5 ⁇ 10 6 cells/mL and add 80 ⁇ L/well into a 96-well plate. The cell wells are grouped as follows: blank control group (without adding antibodies or secondary antibodies); secondary antibody control group (without adding antibodies, Add secondary antibody); experimental group (add antibody and secondary antibody).
  • PE-labeled secondary antibody PE anti-human IgG Fc antibody
  • results show that the humanized antibodies and tool antibody SN3 provided by the present invention have binding activity to MCF7 normal cell lines, but have no binding signal to MCF7-CD24KO cells, proving that these antibodies can specifically bind to CD24.
  • Example 5 The experimental procedure described in 5.1 in Example 5 was followed, except that the anti-CD24 antibody was diluted to 1, 0.1, and 0.01 ⁇ g/mL.
  • the experimental process described in 5.2 in Example 5 was carried out, except that the dilution concentration of the anti-CD24 antibody was 100 ⁇ g/mL to 5 ng/mL.
  • the experimental process described in 5.2 in Example 5 was carried out, except that the dilution concentration of the anti-CD24 antibody was 100 ⁇ g/mL to 5 ng/mL.
  • a cell suspension of 1 ⁇ 10 5 cells/mL of HEK293-hCD24 cells (Acros, Cat: CHEK-ATP032) was prepared.
  • the antibody to be tested was diluted with 2% BSA, with a starting concentration of 100 ⁇ g/mL, and diluted 3 times to obtain 8 concentration dilutions.
  • E-Labeled Human Siglec-10 (Acros, Cat: S10-HP2E5) was diluted to 3 ⁇ g/mL with 2% BSA, added to the above cell suspension at 50 ⁇ L/well, and incubated on ice for 1 hour. After washing the cells with PBS, use a flow cytometer to analyze the MFI data obtained and perform a 4-parameter fitting to calculate the IC50.
  • the antigenic protein Human CD24-mFc and anti-IgG Fab monoclonal antibody (Sigma, I5260-1ML) were coated with PBS at 0.2 ⁇ g/ml, 100ul/well in a 96-well enzyme-linked plate, incubated at 4°C overnight, and then Wash three times with PBS at 300 ⁇ l/well, then add blocking solution (5% BSA+PBS) at 200 ⁇ l/well, block at 37°C for 1 h, and then remove the blocking solution.
  • the sample to be tested was diluted to 2 ⁇ g/ml using diluent (5% BSA+PBS+50% FBS), and diluted 3 times to obtain a total of 8 concentration sample dilutions.
  • diluent 5% BSA+PBS+50% FBS
  • Dilute HRP-labeled goat anti-human IgG secondary antibody Jackson, Cat. No. 109-035-098
  • mice Female Balb/C mice, 3/group, were administered with 200 ⁇ g of the antibody to be tested/animal in the tail vein. Blood was collected from the tail vein at different time points after administration, and the serum was collected by centrifugation and stored at -20°C for testing (the last serum collected was frozen at -20°C for at least 24 hours).
  • the antigen protein Human CD24-mFc was coated in a 96-well enzyme-linked plate with PBS at 0.2 ⁇ g/ml, 100 ⁇ l/well, incubated at 4°C overnight, and then washed three times with PBS at 300 ⁇ l/well. 200 ⁇ l/well Add blocking solution (5% BSA+PBS), block at 37°C for 1 hour, and then remove the blocking solution.
  • mice Female hSiglec-10 humanized mice aged 6-8 weeks (purchased from Southern Model Biology Company) were subcutaneously inoculated with MC38-hCD24 cells at 1 ⁇ 10 6 cells/mouse, and the survival status and subcutaneous tumor formation of the mice were observed the next day. situation, establishing the MC38-hCD24 colorectal cancer model. On the 8th day after inoculation, the average tumor volume was approximately 132mm 3 . The tumor-bearing mice were randomly divided into the following 6 groups, with 6 mice in each group:
  • Group 1 Isotype control, hIgG1;
  • Group 2 C01 hz10 huIgG1;
  • Group 3 C55 hz43 huIgG1;
  • Intraperitoneal administration was started on the day of grouping.
  • the administration volume of each group was 10 mL/kg, and the administration dose was 10 mg/kg.
  • Each group was administered continuously for 3 weeks, twice a week, for a total of 6 administrations.
  • mice were monitored throughout the treatment period, and there was no significant difference in the body weight of mice in each group, indicating that the mice had strong resistance to C01 hz10 huIgG1, C55 hz43 huIgG1, C55 hz43 LALA-huIgG1, C60 Hz48 huIgG1 and B17 hz10 huIgG1 antibodies. Well tolerated, these antibodies have minimal toxic side effects.
  • C55 hz43 huIgG1 (Group 2) and B17 hz10 huIgG1 (Group 6) have good inhibitory activity on tumor growth in mice, with TGIs of 57.40% and 91.42% respectively, while The remaining three groups of drugs had no inhibitory effect on tumors.
  • Day 24 the animals were euthanized, and the tumors were removed and weighed. The specific results are shown in the table above. They are consistent with the tumor volume results. The tumor weights of Group 2 and Group 6 are smaller, and the average tumor weights are 0.9g respectively. and 0.43g.
  • the establishment process of the MC38-hCD24 colorectal cancer model was the same as the drug efficacy experiment one. On the 7th day after inoculation, the average tumor volume was approximately 91mm 3 .
  • the tumor-bearing mice were randomly divided into the following 5 groups, with 6 mice in each group:
  • Group 1 B17 hz10 huIgG1;
  • Group 2 B17 hz10 LALA-huIgG1;
  • Intraperitoneal administration was started on the day of grouping.
  • the administration volume of each group was 10 mL/kg, and the administration dose was 10 mg/kg.
  • Each group was administered continuously for 2 weeks, twice a week, for a total of 4 times.
  • mice were tolerant to B17 hz10 huIgG1, B17 hz10 LALA-huIgG1, C55 hz43 huIgG1 and C55 hz43 LALA-huIgG1 antibodies.
  • the properties are good and these antibodies have little side effects.
  • B17 hz10 huIgG1 (Group 1) and C55 hz43 huIgG1 (Group 4) have good inhibitory activity on tumor growth in mice, and the tumor volume has a very significant difference (P ⁇ 0.01 ), TGI are 102.94% and 113.72% respectively.
  • TGI are 102.94% and 113.72% respectively.
  • the animals were euthanized and the tumors were removed and weighed. Among them, the tumors of Group 4 disappeared on the 11th day of administration and no tumors were collected, while the average tumor weight of Group 1 was only 0.16g, less than 1/6 of the control group (Group3).
  • the anti-tumor effects of B17 and C55 chimeric with different constant regions are also quite different.
  • the huIgG1 form of antibodies (Group 1 and 4) has a more significant inhibitory effect compared to the LALA-huIgG1 form of antibodies (Group 2 and 5).
  • tumor activity indicating that the ADCC function mediated by antibody Fc plays a very important role in inhibiting tumor growth.
  • the average tumor volume was approximately 94 mm 3 .
  • the tumor-bearing mice were randomly divided into 7 groups, with 6 rats in each group. Intraperitoneal administration began on the day of grouping. The administration volume of each group was 10 mL/kg, and each group was administered continuously. The drug was administered for 2 weeks, twice a week, for a total of 4 times.
  • the dosages of B17 hz10 huIgG1 and C55 hz43 huIgG1 are 0.5 mg/kg, 2 mg/kg and 10 mg/kg respectively.
  • the results showed that after 18 days of observation, the body weight of the mice was monitored throughout the treatment period. There was little difference in the body weight of the mice in each group, and there was no significant difference, indicating that the mice were tolerant to each dose of B17 hz10 huIgG1 and C55 hz43 huIgG1 antibody drugs. Good, indicating that these antibodies have little toxic side effects.
  • the medium and high-dose groups of B17 hz10 huIgG1 and C55 hz43 huIgG1 had good inhibitory activity on tumor growth in mice, and there was a significant difference in tumor volume (P ⁇ 0.05).
  • B17 The mid-dose group of hz10 huIgG1 (2mg/kg) and the high-dose group of C55 hz43 huIgG1 (10mg/kg) had better anti-tumor activity, with extremely significant differences (P ⁇ 0.01), with TGIs of 98.14% and 93.61% respectively.
  • the animals were euthanized, and the tumors were removed and weighed.
  • the average tumor weights of Group 3 and Group 7 were 0.26g and 0.29g respectively, with extremely significant differences (P ⁇ 0.01).

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Abstract

La présente invention concerne un anticorps anti-CD24 humain ou un fragment de celui-ci et son utilisation. L'anticorps anti-CD24 humain de la présente invention se lie spécifiquement au CD24 humain, a une activité cytotoxique dépendante du complément (CDC) et une activité cytotoxique dépendante des anticorps (ADCC) significatives sur la cellule exprimant la cible, peut réguler et contrôler la réponse immunitaire antitumorale médiée par les macrophages, et peut être utilisé pour l'immunothérapie antitumorale.
PCT/CN2023/097784 2022-06-01 2023-06-01 Anticorps anti-cd24 humain et son utilisation WO2023232110A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103819561A (zh) * 2014-01-22 2014-05-28 中国药科大学 抗cd24单克隆抗体、其可变区序列及其应用
CN105646712A (zh) * 2014-01-22 2016-06-08 中国药科大学 单克隆抗体及其应用
CN105646713A (zh) * 2014-01-22 2016-06-08 中国药科大学 一种单克隆抗体及其应用
CN106279421A (zh) * 2016-08-31 2017-01-04 上海美吉生物医药科技有限公司 一种cd133、cd24、cd44多重抗体免疫磁珠及其制备方法
CN106589126A (zh) * 2016-12-07 2017-04-26 中国药科大学 一种抗人cd24抗体突变体的设计及其应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103819561A (zh) * 2014-01-22 2014-05-28 中国药科大学 抗cd24单克隆抗体、其可变区序列及其应用
CN105646712A (zh) * 2014-01-22 2016-06-08 中国药科大学 单克隆抗体及其应用
CN105646713A (zh) * 2014-01-22 2016-06-08 中国药科大学 一种单克隆抗体及其应用
CN106279421A (zh) * 2016-08-31 2017-01-04 上海美吉生物医药科技有限公司 一种cd133、cd24、cd44多重抗体免疫磁珠及其制备方法
CN106589126A (zh) * 2016-12-07 2017-04-26 中国药科大学 一种抗人cd24抗体突变体的设计及其应用

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