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WO2019154420A1 - Il17 antibody and application thereof - Google Patents

Il17 antibody and application thereof Download PDF

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Publication number
WO2019154420A1
WO2019154420A1 PCT/CN2019/074805 CN2019074805W WO2019154420A1 WO 2019154420 A1 WO2019154420 A1 WO 2019154420A1 CN 2019074805 W CN2019074805 W CN 2019074805W WO 2019154420 A1 WO2019154420 A1 WO 2019154420A1
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seq
antibody
amino acid
acid sequence
antigen
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PCT/CN2019/074805
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French (fr)
Chinese (zh)
Inventor
王华菁
李博华
何晓文
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Shanghai OriginCell Medical Technology Co Ltd
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Shanghai OriginCell Medical Technology Co Ltd
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Priority to CN201980012724.9A priority Critical patent/CN111699006B/en
Priority to CN202111071115.6A priority patent/CN113603777B/en
Priority to CN202111069984.5A priority patent/CN113603776B/en
Publication of WO2019154420A1 publication Critical patent/WO2019154420A1/en
Anticipated expiration legal-status Critical
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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
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • 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
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/66—General methods for inserting a gene into a vector to form a recombinant vector using cleavage and ligation; Use of non-functional linkers or adaptors, e.g. linkers containing the sequence for a restriction endonuclease
    • 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
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—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]
    • 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

Definitions

  • the present application relates to the field of biomedicine, and in particular to an IL17 antibody and use thereof.
  • Interleukin-17 also known as CTLA-8, is a pro-inflammatory cytokine produced by T cells that stimulates various non-immune cells to secrete a variety of other cytokines.
  • IL17 is mainly produced by activated memory T cells and functions by binding to a cell surface receptor (IL17R) that is spread throughout (Yao et al, Cytokine, 9, 794-800 (1997)).
  • IL17R cell surface receptor
  • IL17 acts as a pro-inflammatory cytokine, and its inappropriate or excessive production can lead to a variety of diseases.
  • rheumatoid arthritis Woitowski et al, Cell Mol Life Sci, 61: 567-579 (2004)
  • osteoarthritis bone implant loosening
  • acute graft rejection Antonysamy et al, J Immunol 162, 577-584 ( 1999); van Kooten et al, J Am Soc Nephrol 9, 1526-1534 (1998)), sepsis, septic or endotoxic shock, allergy, asthma (Molet et al, J Allergy Clin Immunol 108, 430-438 (2001) ), bone loss, psoriasis (Teunissen et al, J. Invest Dermatol 111, 645-649 (1998)), ischemia, systemic sclerosis (Kurasawa et al, Arthritis Rheum 43, 2455-2463 (2000)), Stroke and other
  • antibodies targeting IL-17 can be used to prevent and/or treat psoriasis (eg, plaque psoriasis), psoriatic arthritis, ankylosing spondylitis A disease or condition associated with inappropriate or overproduction of IL17.
  • psoriasis eg, plaque psoriasis
  • psoriatic arthritis e.g, ankylosing spondylitis A disease or condition associated with inappropriate or overproduction of IL17.
  • novel anti-IL17 antibodies that specifically recognize and bind to the IL17 protein, inhibit the binding of the IL17 protein to the IL17 receptor, and/or inhibit the secretion of cytokines by immune cells.
  • the present application provides an IL17 antibody, an antigen-binding fragment thereof, which has one or more of the following properties: 1) capable of binding IL17 protein with high affinity and specificity; 2) inhibiting IL17 protein and IL17 receptor Binding, such as IL17A protein or IL17F protein; 3) inhibiting the expression of cytokines, especially chemokines (such as CXCL1); and 4) can be used to treat autoimmune diseases.
  • the present application also provides methods and uses for the preparation of the IL17 antibody, antigen-binding fragment thereof.
  • the present application provides an antibody or antigen-binding fragment thereof, which combine to 6 ⁇ 10 -9 M or less and a K D value of IL17 protein.
  • the antibody or antigen-binding fragment thereof inhibits binding of an IL17 protein to an IL17 receptor.
  • the antibody or antigen-binding fragment thereof which inhibits expression of a cytokine.
  • the antibody or antigen-binding fragment thereof, the cytokine comprising: an interleukin and a chemokine.
  • the antibody or antigen-binding fragment thereof, the chemokine comprising: CXCL1.
  • the antibody or antigen-binding fragment thereof which ameliorates or treats a disease or condition associated with inappropriate or overproduction of IL17.
  • the disease or condition comprises: ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, osteoarthritis, bone implant loosening, acute graft rejection, respiratory inflammation, inflammatory Enteropathy, sepsis, septic or endotoxic shock, bone loss, psoriasis, allergy, ischemia, systemic sclerosis, stroke and asthma.
  • the antibody or antigen-binding fragment thereof comprises: a monoclonal antibody, a single chain antibody, a chimeric antibody, a humanized antibody, and/or a fully human antibody.
  • the antibody or antigen-binding fragment thereof comprising: Fab, Fab', F(ab)2, Fv fragment, F(ab')2, scFv, di-scFv And / or VhH.
  • the antibody or antigen-binding fragment thereof which competes with a reference antibody for binding to the IL17 protein
  • the reference antibody comprises a light chain variable region and a heavy chain variable region
  • the light chain variable region of the reference antibody comprises LCDR1, LCDR2 and LCDR3, the LCDR1 comprising the amino acid sequence set forth in any one of the following: SEQ ID NO: 126, SEQ ID NO: 22, and SEQ ID NO: 40
  • the LCDR2 includes the amino acid sequence shown in any one of the following: SEQ ID NO: 5, SEQ ID NO: 23, and SEQ ID NO: 41
  • the LCDR3 comprises the amino acid sequence shown in any one of the following: SEQ ID NO: 6, SEQ ID NO: 24 and SEQ ID NO: 131
  • the heavy chain variable region of the reference antibody comprises HCDR1, HCDR2 and HCDR3, and the HCDR1 comprises an amino acid represented by any one of the following SEQ ID NO: 123, SEQ ID NO: 19 and SEQ ID NO: 37;
  • the LCDR1 of the reference antibody comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 4 and SEQ ID NO: 96.
  • the LCDR3 of the reference antibody comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 42 and SEQ ID NO: 102.
  • the HCDR1 of the reference antibody comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 1, SEQ ID NO: 91, and SEQ ID NO: 92.
  • the HCDR2 of the reference antibody comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 2 and SEQ ID NO: 93; in certain embodiments, the reference antibody The HCDR3 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO:3, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:39, SEQ ID NO:100, and SEQ ID NO:101.
  • the light chain variable region of the reference antibody comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 16, SEQ ID NO: 134, SEQ ID NO: 34, SEQ ID And the SEQ ID NO: 52 and : 135, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 51 and SEQ ID NO: 133.
  • the light chain variable region of the reference antibody comprises the amino acid sequence set forth in any one of the following: SEQ ID NO:54, SEQ ID NO:103, SEQ ID NO:18, and SEQ ID NO: 109.
  • SEQ ID NO: 105 NO: 17 SEQ ID NO: 111, SEQ ID NO: 114, SEQ ID NO: 117, and SEQ ID NO: 120.
  • the light chain of the reference antibody comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 64, SEQ ID NO: 68, SEQ ID NO: 72, SEQ ID NO: 138 SEQ ID NO: 84 and SEQ ID NO: 136; and the heavy chain of the reference antibody comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 62, SEQ ID NO: 66, SEQ ID NO :70, SEQ ID NO: 139, SEQ ID NO: 82 and SEQ ID NO: 137.
  • the light chain of the reference antibody comprises the amino acid sequence set forth in any one of the following: SEQ ID NO:90, SEQ ID NO:104, SEQ ID NO:78, and SEQ ID NO:110 .
  • the heavy chain of the reference antibody comprises the amino acid sequence set forth in any one of the following: SEQ ID NO:88, SEQ ID NO:106, SEQ ID NO:108, SEQ ID NO:76 SEQ ID NO: 112, SEQ ID NO: 115, SEQ ID NO: 118, and SEQ ID NO: 121.
  • the antibody comprises an antibody light chain or a fragment thereof comprising LCDR1, and the LCDR1 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO:126, SEQ ID NO:22, and SEQ ID NO: 40.
  • the amino acid sequence of the LCDR1 in the antibody or antigen-binding fragment thereof comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 4 and SEQ ID NO: 96.
  • the antibody light chain or fragment thereof comprises LCDR2, and the LCDR2 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 5, SEQ ID NO: 23, and SEQ ID NO: 41.
  • the antibody light chain or fragment thereof comprises LCDR3, and the LCDR3 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 6, SEQ ID NO: 24, and SEQ ID NO: 131.
  • the LCDR3 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 42 and SEQ ID NO: 102.
  • the antibody light chain or fragment thereof further comprises framework regions L-FR1, L-FR2, L-FR3, and L-FR4.
  • the framework regions L-FR1, L-FR2, L-FR3, and L-FR4 are selected from any of the group consisting of human consensus framework sequences and human germline sequences.
  • the C-terminus of the L-FR1 is directly or indirectly linked to the N-terminus of the LCDR1, the L-FR1 comprising the amino acid sequence set forth in any one of the following: SEQ ID NO:127, SEQ ID NO:29 and SEQ ID NO:47.
  • the L-FR1 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 11 and SEQ ID NO: 97.
  • the L-FR2 is located between the LCDR1 and the LCDR2, and the L-FR2 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 128, SEQ ID NO: 30 and SEQ ID NO:48.
  • the L-FR2 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 12 and SEQ ID NO: 98.
  • the L-FR3 is located between the LCDR2 and the LCDR3, and the L-FR3 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 13, SEQ ID NO: 31 and SEQ ID NO:49.
  • the N-terminus of the L-FR4 is directly or indirectly linked to the C-terminus of the LCDR3, and the L-FR4 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 14. SEQ ID NO:32 and SEQ ID NO:50.
  • the antibody light chain or fragment thereof comprises a light chain variable region VL
  • the light chain variable region VL comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: SEQ ID NO: 134, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 52, and SEQ ID NO: 132.
  • the light chain variable region comprises the amino acid sequence set forth in any one of the following: SEQ ID NO:54, SEQ ID NO:103, SEQ ID NO:18, and SEQ ID NO:109.
  • the antibody light chain or fragment thereof further comprises a human constant region or a murine constant region.
  • the antibody light chain or fragment thereof comprises a human constant region
  • the human constant region comprises a human Ig kappa or Ig lambda constant region.
  • the antibody light chain or fragment thereof comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 64, SEQ ID NO: 68, SEQ ID NO: 72, SEQ ID NO: 138 SEQ ID NO: 84 and SEQ ID NO: 136.
  • the antibody light chain or fragment thereof comprises the amino acid sequence set forth in any one of the following: SEQ ID NO:90, SEQ ID NO:104, SEQ ID NO:78, and SEQ ID NO:110 .
  • the antibody comprises an antibody heavy chain or a fragment thereof.
  • the antibody heavy chain or fragment thereof comprises HCDR1
  • the HCDR1 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 123, SEQ ID NO: 19, and SEQ ID NO: 37.
  • the HCDR1 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 1, SEQ ID NO: 91, and SEQ ID NO: 92.
  • the antibody heavy chain or fragment thereof comprises HCDR2, and the HCDR2 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 124, SEQ ID NO: 20, and SEQ ID NO: 38.
  • the HCDR2 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 2 and SEQ ID NO: 93.
  • the antibody heavy chain or fragment thereof comprises HCDR3, and the HCDR3 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 125, SEQ ID NO: 21, and SEQ ID NO: 130.
  • the HCDR3 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO:3, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:39, SEQ ID NO: 100 and SEQ ID NO:101.
  • the antibody heavy chain or fragment thereof further comprises framework regions H-FR1, H-FR2, H-FR2, and H-FR4.
  • the framework regions are selected from any of the group consisting of human consensus framework sequences and human germline sequences.
  • the C-terminus of H-FR1 is directly or indirectly linked to the N-terminus of said HCDR1, said H-FR1 comprising the amino acid sequence set forth in any one of the following: SEQ ID NO: SEQ ID NO: 25 and SEQ ID NO: 43.
  • the H-FR2 is between the HCDR1 and the HCDR2, and the H-FR2 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO:8, SEQ ID NO: 26 and SEQ ID NO:44.
  • the H-FR3 is between the HCDR2 and the HCDR3, and the H-FR3 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 129, SEQ ID NO: 27 and SEQ ID NO:45.
  • the H-FR3 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO:9 and SEQ ID NO:99.
  • the N-terminus of the H-FR4 is directly or indirectly linked to the C-terminus of the HCDR3, and the H-FR4 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: SEQ ID NO:28 and SEQ ID NO:46.
  • the antibody heavy chain or fragment thereof comprises a heavy chain variable region VH
  • the heavy chain variable region VH comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: SEQ ID NO: 135, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 51 and SEQ ID NO: 133.
  • SEQ ID NO: 105 SEQ ID NO: 107, 17.
  • the antibody heavy chain or fragment thereof further comprises a human constant region or a murine constant region.
  • the antibody heavy chain or fragment thereof comprises a human constant region
  • the human constant region comprises a human IgG constant region
  • the IgG constant region comprises a human IgGl constant region.
  • the antibody heavy chain or fragment thereof comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 62, SEQ ID NO: 66, SEQ ID NO: 70, SEQ ID NO: 139 SEQ ID NO: 82 and SEQ ID NO: 137.
  • the IL7 protein is a human IL17 protein. In certain embodiments, the IL7 protein comprises an IL17A protein and/or an IL17F protein.
  • the application provides an isolated nucleic acid molecule or molecules encoding an antibody or antigen-binding fragment thereof as described herein.
  • the application provides a vector comprising a nucleic acid molecule as described herein.
  • the application provides a host cell comprising a nucleic acid molecule described herein or a vector described herein.
  • the application provides a method of making the antibody or antigen-binding fragment thereof, the method comprising culturing the method described in the present application under conditions such that the antibody or antigen-binding fragment thereof of the present application is expressed Host cell. In certain embodiments, it optionally comprises harvesting the antibody or antigen-binding fragment thereof.
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof described herein, a nucleic acid molecule described herein, a vector described herein, and/or described herein Host cells, and optionally pharmaceutically acceptable adjuvants.
  • the application provides the use of the antibody or antigen-binding fragment thereof for the preparation of a medicament for preventing or treating a disease or condition.
  • the disease or condition comprises: ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, osteoarthritis, bone implant loosening, acute graft rejection, respiratory inflammation, inflammatory Enteropathy, sepsis, septic or endotoxic shock, bone loss, psoriasis, allergy, ischemia, systemic sclerosis, stroke and asthma.
  • the disease or condition comprises: ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, osteoarthritis, bone implant loosening, acute graft rejection, respiratory inflammation, inflammatory Enteropathy, sepsis, septic or endotoxic shock, bone loss, psoriasis, allergy, ischemia, systemic sclerosis, stroke and asthma.
  • the application provides a method of preventing or treating a disease comprising administering an antibody or antigen-binding fragment thereof as described herein, a nucleic acid molecule described herein, a vector described herein, the present application Host cells and/or pharmaceutical compositions described herein.
  • the disease or condition comprises: ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, osteoarthritis, bone implant loosening, acute graft rejection, respiratory inflammation, inflammatory Enteropathy, sepsis, septic or endotoxic shock, bone loss, psoriasis, allergy, ischemia, systemic sclerosis, stroke and asthma.
  • the application provides a method of inhibiting binding of an IL17 protein and an IL17 ligand, comprising administering an antibody or antigen-binding fragment thereof, a nucleic acid molecule described herein, a vector described herein, The host cells described herein and/or the pharmaceutical compositions described herein.
  • the application provides a method of inhibiting the biological activity of an IL17 protein comprising administering an antibody or antigen-binding fragment thereof as described herein, a nucleic acid molecule described herein, a vector described herein, and The host cells and/or pharmaceutical compositions described herein are claimed.
  • the application provides a method of inhibiting expression of a chemokine comprising an antibody or antigen-binding fragment thereof described herein, a nucleic acid molecule described herein, a vector described herein, and a Host cells and/or pharmaceutical compositions described herein.
  • a chemokine comprising an antibody or antigen-binding fragment thereof described herein, a nucleic acid molecule described herein, a vector described herein, and a Host cells and/or pharmaceutical compositions described herein.
  • the chemokine comprises CXCL1.
  • 1A-1C show amino acid sequence alignments of the heavy chain variable region and the light chain variable region of the IL17 antibody of the present application and related germline sequences.
  • 2A-2C show that the IL17 antibody of the present application inhibits the binding of the IL17A protein to the IL17 receptor.
  • Figure 3 shows that IL17 antibody in the present application inhibits IL17A protein-induced chemokine CXCL1 production by HT-29 cells.
  • Figure 4 shows the binding activity of the IL17 antibody of the present application to the IL17F protein.
  • Figure 5 shows that the IL17 antibody of the present application inhibits the binding of the IL17A protein to the IL17 protein receptor.
  • Figures 6A-6C show that IL17 antibodies in the present application inhibit IL17A protein-induced CXCL1 production by HT-29 cells.
  • Figures 7A-7C show that IL17 antibodies in the present application inhibit IL17A protein-induced IL-8 production by HS-27 cells.
  • an antibody generally refers to a polypeptide molecule capable of specifically recognizing and/or neutralizing a particular antigen.
  • an antibody may comprise an immunoglobulin consisting of at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, and includes any molecule comprising an antigen-binding portion thereof.
  • the term “antibody” includes monoclonal antibodies, antibody fragments or antibody derivatives including, but not limited to, human antibodies, humanized antibodies, chimeric antibodies, single chain antibodies (eg, scFv), and antibody fragments that bind to an antigen (eg, , Fab, Fab' and (Fab) 2 fragments).
  • antibody also includes all recombinant forms of the antibody, such as antibodies expressed in prokaryotic cells, unglycosylated antibodies, and any antigen-binding antibody fragments and derivatives thereof described herein.
  • Each heavy chain can be composed of a heavy chain variable region (VH) and a heavy chain constant region.
  • Each light chain can be composed of a light chain variable region (VL) and a light chain constant region.
  • VH heavy chain variable region
  • VL light chain variable region
  • variable region or “variable domain” refers to the amino terminal domain of the heavy or light chain of an antibody.
  • the variable domains of the heavy and light chains can be referred to as "VH" and "VL", respectively.
  • VH and VL regions can be further distinguished as hypervariable regions termed complementarity determining regions (CDRs), which are interspersed in more conserved regions called framework regions (FR).
  • CDRs complementarity determining regions
  • FR framework regions
  • Each VH and VL can be composed of three CDRs and four FR regions, which can be arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.
  • the variable regions of the heavy and light chains contain a binding domain that interacts with the antigen.
  • the constant region of the antibody can mediate binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (eg, effector cells) and the first component (Clq) of the classical complement system.
  • the terms “immunoglobulin” (Ig) and “antibody” are used interchangeably herein.
  • the basic four-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light chains (L) and two identical heavy chains (H).
  • the IgM antibody consists of 5 basic heterotetramer units together with an additional polypeptide called the J chain and contains 10 antigen binding sites, while the IgA antibody comprises 2-5 basic four chain units, which are polymerizable. A multivalent assembly in combination with the J chain is formed. In the case of IgG, the four chain unit is typically about 150,000 daltons.
  • Each L chain is linked to the H chain by a covalent disulfide bond, and the two H chains are linked to each other by one or more disulfide bonds, the number of disulfide bonds depending on the isoform of the H chain.
  • Each H and L chain also has regularly spaced intrachain disulfide bonds.
  • Each H chain has a variable domain (VH) at the N-terminus, followed by three (for each alpha and gamma chain) or four (for the ⁇ and epsilon isoforms) constant domain (CH).
  • VH variable domain
  • CH constant domain
  • Human IgG has four subtypes: IgG1, IgG2, IgG3, and IgG4.
  • the term "monoclonal antibody” generally refers to an antibody obtained from a population of substantially homologous antibodies, ie, the individual antibodies comprising the population are identical except for the naturally occurring mutations that may be present in minor amounts.
  • Monoclonal antibodies are highly specific and target a single antigenic site. Each monoclonal antibody is directed against a single determinant on the antigen as compared to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes).
  • monoclonal antibodies have the advantage that they are synthesized by hybridoma culture and are not contaminated by other immunoglobulins.
  • monoclonal antibodies for use in accordance with the present invention can be made by a variety of techniques including, for example, hybridoma methods (see, for example, Kohler and Milstein, Nature, 256:495-97 (1975); Hongo et al, Hybridoma, 14 (3): 253-260 (1995), Harlow et al, Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, Second Edition 1988); Hammerling et al, Monoclonal Antibodies and T-Cell Hybridomas, 563-681, (Elsevier , NY, 1981)), recombinant DNA methods (see, for example, U.S.
  • Patent No. 4,816,567) phage display technology (see, for example, Clackson et al, Nature, 352:624-628 (1991); Marks et al, J . Mol. Biol., 222: 581-597 (1992); Sidhu et al, J. Mol. Biol. 338 (2): 299-310 (2004); Lee et al, J. Mol. Biol. 340 (5): 1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101 (34): 12467-12472 (2004); and Lee et al. J. Immunol.
  • framework region generally refers to those variable domain residues other than CDR residues.
  • human consensus framework generally refers to the most frequently occurring amino acid residues in human immunoglobulin VL or VH framework sequences.
  • the selection of human immunoglobulin VL or VH sequences is selected from subtypes of variable domain sequences.
  • the subtype of the sequence is as described in Kabat et al. (see Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991)).
  • Subtype examples include, for VL, the subtype may be a subtype kappa I, kappa II, kappa III or kappa IV as described by Kabat et al.
  • the subtype may be subtype I, subtype II or subtype III as described by Kabat et al.
  • a human consensus framework can be obtained as described above, wherein a particular residue, such as a human framework residue, is selected based on its homology to the donor framework by placing the donor framework with a plurality of human framework sequences The comparison of the collections is made.
  • the acceptor human framework "derived from" a human immunoglobulin framework or human consensus framework may comprise the same amino acid sequence, or it may comprise a change in a pre-existing amino acid sequence.
  • the number of pre-existing amino acid changes may be 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less (for example, one).
  • a change in the amino acid sequence can include substitution or deletion of a specified residue, or insertion of at least one amino acid residue in the vicinity of a specified residue. Insertion in the vicinity of a specified residue means insertion within one or two residues adjacent thereto. The insertion can be at the N-terminus or C-terminus of the specified residue.
  • the amino acid modification may be a substitution.
  • single-chain antibody generally refers to a molecule which is formed by linking an antibody heavy chain variable region and a light chain variable region through a short peptide linker.
  • chimeric antibody generally refers to an antibody in which a portion of each heavy or light chain amino acid sequence is homologous to the corresponding amino acid sequence in an antibody from a particular species, or belongs to a particular class, and The remaining segments of the strand are homologous to the corresponding sequences in another species.
  • the variable regions of both the light and heavy chains are derived from the variable regions of antibodies of one animal species (eg, mice, rats, etc.), while the constant portions are homologous to antibody sequences from another species (eg, humans).
  • a non-human B cell or hybridoma cell can be utilized to generate a variable region, and the constant region combined therewith is derived from a human.
  • variable region has the advantage of being easy to prepare, and its specificity is not affected by the source of the constant region with which it is combined.
  • the constant region of the chimeric antibody can be derived from humans, the probability of an antibody eliciting an immune response at the time of injection is lower than that of a non-human source using a constant region.
  • humanized antibody generally refers to the use of genetic engineering techniques to reduce the immunogenicity of antibodies, immunoglobulin binding proteins and polypeptides derived from non-human species (eg, mice or rats) to humans. Engineered antibodies that retain the antigen binding properties of the original antibody while still retaining.
  • CDR grafting can be used (Jones et al., Nature 321:522 (1986)); including “reshaping", (Verhoeyen, et al., 1988 Science 239: 1534-1536; Riechmann, et al., 1988 Nature 332: 323-337; Tempest, et al., Bio/Technol 1991 9: 266-271), "hyperchimerization", (Queen, et al., 1989 Proc Natl Acad Sci USA 86: 10029- 10033; Co, et al., 1991 Proc Natl Acad Sci USA 88: 2869-2873; Co, et al., 1992 J Immunol 148: 1149-1154) and "veneering", (Mark, et al.
  • the term "fully human antibody” generally means that all of the antibody (including the constant region portion of the antibody, the CH and CL regions) are encoded by genes of human origin. Fully human antibodies can greatly reduce the immune side effects caused by heterologous antibodies.
  • the term "antigen-binding fragment” generally refers to a portion of an intact antibody, eg, an antigen binding region and/or a variable region of an intact antibody.
  • the antigen binding fragment can comprise a Fab, Fab', F(ab)2, Fv fragment, F(ab')2, scFv, di-scFv and/or VhH.
  • antibodies described herein can include diabodies, linear antibodies, single chain antibody molecules, and multispecific antibodies formed from antibody fragments. After digestion of an antibody with intact structure by papain (eg, removal of the Fc region and hinge region), two identical antigen-binding fragments, termed "Fab" fragments, are produced.
  • the Fab fragment consists of the entire light chain, the heavy chain variable region (VH) and the first constant domain (CH1) of the heavy chain. Each Fab fragment is monovalent relative to antigen binding, ie it has a single antigen binding site.
  • the F(ab) 2 antibody fragment was originally produced as a pair of Fab fragments with a cysteine linkage between them. The digestion of an antibody with an intact structure by pepsin produces a single large F(ab') 2 fragment roughly equivalent to two Fab fragments having different antigen binding activities linked by disulfide bonds and still capable of cross-linking antigen.
  • Fab' fragments differ from Fab fragments by having several additional residues at the carboxy terminus of the CH1 domain, including one or more cysteines from the antibody hinge region.
  • the Fv fragment consists of the VL and VH domains of one arm of the antibody.
  • IL17 protein generally refers to interleukin 17.
  • IL17A is the prototype of the IL17 family
  • IL17F has the highest homology (about 50%) with IL17A, and its coding gene is located in the same segment of chromosome 6p12.
  • GenBank accession number of human IL17A can be NP_002181.
  • the IL17 protein can comprise the amino acid sequence shown in accession number Accession No. Q16552 in the UniProtKB database.
  • the IL17F protein can comprise the amino acid sequence set forth in Accession No. NP_443104.1 in the NCBI database.
  • Members of the IL17 family function in the form of homodimers or heterodimers.
  • IL17A is a pro-inflammatory factor similar to IL-1Rs and TLRs receptors.
  • IL17A also induces downstream genes by activating NF- ⁇ B and MAPK.
  • IL17 can mediate a phosphorylation cascade to inactivate C/EBPb.
  • the IL17 protein activates Erk via the SEFIR-TILL domain of IL17RA.
  • IL17 protein is associated with autoimmune diseases such as multiple/systemic sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), psoriasis, bone and joint Inflammation, loose bone implants, ankylosing spondylitis.
  • IL17 protein is also associated with host defense, especially in mucosal sites such as lung, intestine, and oral cavity (eg, stroke, asthma, acute graft rejection, respiratory inflammation, inflammatory bowel disease, sepsis, septicemia, allergies, ischemia, and Endotoxic shock, etc.).
  • IL-17 protein can induce pro-inflammatory factors such as IL-6, IL-1b, TNF ⁇ , which mediate defense responses.
  • IL-17 protein also induces cytokines (G-CSF) and chemokines (CXCL1, CXCL2, CXCL5) that promote polymorphonuclear leukocyte proliferation and survival to regulate neutrophils.
  • G-CSF cytokines
  • CXCL1, CXCL2, CXCL5 chemokines
  • IL-17 proteins can target these cells to the mucosal surface by inducing chemotactic proteins (CXCL9, CXCL10, CCL20) on lymphocytes, dendritic cells and other immune cells; by inducing recruitment of CCL2 and CCL7 Monocytes.
  • IL17 receptor generally refers to a member of the IL17 receptor family, including IL17RA to IL17RE.
  • GenBank accession number of human IL17R can be CAJ86450.1. All family members are single-type transmembrane proteins with conserved structural motifs, including an extracellular fibronectin III-like domain and an intracellular SEF/IL17R (SEFIR) structure. area.
  • SEFIR SEF/IL17R
  • Members of the IL17 receptor family can be combined into different receptor complexes, of which IL17RA, by far the largest molecule in this family, is a universal subunit that transmits signals to at least four ligands. Recent studies have shown that blocking the PI3K pathway upregulates IL17RA, which may enhance IL17 signaling.
  • the term "cytokine” generally refers to immune cells (eg, mononuclear, macrophage, T cells, B cells, NK cells, etc.) and certain non-immune cells (endothelial cells, epidermal cells, fibroblasts).
  • the cytokine may have various functions such as regulation of innate immunity and adaptive immunity, hematopoiesis, cell growth, APSC pluripotent cells, and repair of damaged tissues.
  • the cytokine may include interleukins and chemokines.
  • the cytokine is a chemokine.
  • CXCL generally refers to a CXC chemokine family ligand. It includes CXCL1, CXCL2, CXCL3, CXCL12, CXCL14 and the like. Among them, CXCL1 (chemokine (CXC motif) ligand 1) is expressed by macrophages, neutrophils and epithelial cells and has neutrophil chemotactic activity. CXCL1 inhibits the migration of oligodendrocyte precursors in spinal cord development. Acts and participates in angiogenesis, arteriogenesis, inflammation, wound healing and tumorigenesis.
  • CXCL1 chemokine (CXC motif) ligand 1
  • CXCL1 chemokine (CXC motif) ligand 1
  • CXCL1 inhibits the migration of oligodendrocyte precursors in spinal cord development. Acts and participates in angiogenesis, arteriogenesis, inflammation, wound healing and tumorigenesis.
  • K D with “KD” are used interchangeably, generally refers to a particular antibody - antigen interaction dissociation equilibrium constant, in units of M (mol / L).
  • isolated nucleic acid molecule generally refers to an isolated form of nucleotide, deoxyribonucleotide or ribonucleotide or analogue thereof of any length isolated or artificially synthesized from its natural environment. .
  • the term "vector” generally refers to a nucleic acid molecule capable of self-replication in a suitable host, which transfers the inserted nucleic acid molecule into and/or between host cells.
  • the vector may include a vector mainly for inserting DNA or RNA into a cell, a vector mainly for replicating DNA or RNA, and a vector mainly for expression of transcription and/or translation of DNA or RNA.
  • the carrier also includes a carrier having a plurality of the above functions.
  • the vector may be a polynucleotide that is capable of being transcribed and translated into a polypeptide when introduced into a suitable host cell. Typically, the vector will produce the desired expression product by culturing a suitable host cell comprising the vector.
  • the term "host cell” generally refers to a plasmid or vector which may or already contains a nucleic acid molecule as described herein, or an individual cell, cell line capable of expressing an antibody or antigen-binding fragment thereof as described herein. Or cell culture.
  • the host cell can comprise a progeny of a single host cell. Due to natural, accidental or deliberate mutations, the progeny cells may not necessarily be identical in morphology or genomic to the original parental cell, but may be capable of expressing an antibody or antigen-binding fragment thereof as described herein.
  • the host cell can be obtained by transfecting cells in vitro using a vector described herein.
  • the host cell may be a prokaryotic cell (such as E.
  • the host cell is a mammalian cell.
  • the mammalian cell can be a CHO-K1 cell.
  • the term "recombinant host cell” generally refers to a cell into which a recombinant expression vector has been introduced. The recombinant host cell includes not only a specific cell but also the progeny of these cells.
  • tumor generally refers to a neoplasm formed by the proliferation of local tissue cells by a body (eg, a cell or a component thereof) in a mammal under the action of various tumorigenic factors.
  • the tumor can include rectal adenocarcinoma.
  • the term "between” generally means that the C-terminus of an amino acid fragment is directly or indirectly linked to the N-terminus of the first amino acid fragment, and its N-terminus is directly or C-terminally to the second amino acid fragment. Indirect connection.
  • the N-terminus of the L-FR2 is directly or indirectly connected to the C-terminus of the LCDR1
  • the C-terminus of the L-FR2 is directly or indirectly connected to the N-terminus of the LCDR2.
  • the N-terminus of the L-FR3 is directly or indirectly connected to the C-terminus of the LCDR2
  • the C-terminus of the L-FR3 is directly or indirectly connected to the N-terminus of the LCDR3.
  • the N-terminus of the H-FR2 is directly or indirectly linked to the C-terminus of the HCDR1
  • the C-terminus of the H-FR2 is directly or indirectly linked to the N-terminus of the HCDR2.
  • the N-terminus of the H-FR3 is directly or indirectly linked to the C-terminus of the HCDR2
  • the C-terminus of the H-FR3 is directly or indirectly linked to the N-terminus of the HCDR3.
  • the expression "XnY” generally means that the residue X of the n-th position in the sequence is substituted by the residue Y.
  • the amino acid substitution "R175L” means that the residue R at position 175 in the sequence is substituted by the residue L.
  • the term "about” generally means a range of 0.5% to 10% above or below a specified value, such as 0.5%, 1%, 1.5%, 2%, 2.5% above or below a specified value, Variations within the range of 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10%.
  • Antibody antigen-binding fragment thereof
  • an antibody, antigen-binding fragment thereof, of the present application can compete with a reference antibody for binding to the IL17 protein, wherein the reference antibody can comprise a light chain variable region and a heavy chain variable region,
  • the light chain variable region of the reference antibody can comprise LCDR1, LCDR2 and LCDR3.
  • the LCDR1 may comprise the amino acid sequence shown in any one of the following: SEQ ID NO: 126, SEQ ID NO: 22, and SEQ ID NO: 40; the LCDR2 may comprise any one of the following The amino acid sequences shown are: SEQ ID NO: 5, SEQ ID NO: 23 and SEQ ID NO: 41; and the LCDR3 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 6, SEQ ID NO And SEQ ID NO: 131; and the heavy chain variable region of the reference antibody may comprise HCDR1, HCDR2 and HCDR3, and the HCDR1 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: SEQ ID NO: 19 and SEQ ID NO: 37; The HCDR3 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 125, SEQ ID NO: 21, and SEQ ID NO: 130.
  • the LCDR1 of the reference antibody may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 4 and SEQ ID NO: 96.
  • the LCDR3 of the reference antibody may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 42 and SEQ ID NO: 102.
  • the HCDR1 of the reference antibody may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 1, SEQ ID NO: 91, and SEQ ID NO: 92.
  • the HCDR2 of the reference antibody may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 2 and SEQ ID NO: 93.
  • the HCDR3 of the reference antibody may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 3, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 39, SEQ ID NO: 100 and SEQ ID NO:101.
  • the light chain variable region of the reference antibody can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 16, SEQ ID NO: 134, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 52 and SEQ ID NO: 132; and the heavy chain variable region of the reference antibody may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 15, SEQ ID NO: 135, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 51 and SEQ ID NO: 133.
  • the light chain variable region of the reference antibody can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 54, SEQ ID NO: 103, SEQ ID NO: 18, and SEQ ID NO: 109.
  • the heavy chain variable region of the reference antibody may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO:53, SEQ ID NO:105, SEQ ID NO:107, SEQ ID NO:17, SEQ ID NO: 111, SEQ ID NO: 114, SEQ ID NO: 117, and SEQ ID NO: 120.
  • the light chain of the reference antibody can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 64, SEQ ID NO: 68, SEQ ID NO: 72, SEQ ID NO: 138, SEQ ID NO And SEQ ID NO: 136; and the heavy chain of the reference antibody may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 62, SEQ ID NO: 66, SEQ ID NO: 70, SEQ ID NO: 139, SEQ ID NO: 82 and SEQ ID NO: 137.
  • the light chain of the reference antibody can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO:90, SEQ ID NO:104, SEQ ID NO:78, and SEQ ID NO:110.
  • the heavy chain of the reference antibody may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO:88, SEQ ID NO:106, SEQ ID NO:108, SEQ ID NO:76, SEQ ID NO : 112, SEQ ID NO: 115, SEQ ID NO: 118 and SEQ ID NO: 121.
  • an antibody, antigen-binding fragment thereof, as described herein can compete with a reference antibody for binding to an IL17 protein (eg, a human IL17 protein).
  • the reference antibody may comprise LCDR1-3 and HCDR1-3, and the amino acid sequence of LCDR1 may comprise SEQ ID NO: 4; the amino acid sequence of LCDR2 may comprise SEQ ID NO: 5; the amino acid sequence of LCDR3 may comprise SEQ ID NO
  • the amino acid sequence of HCDR1 may comprise SEQ ID NO: 1; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 2; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 3.
  • the reference antibody can include antibody YN-008 or an antibody having the same LCDR1-3 and HCDR1-3.
  • the reference antibody can comprise a light chain variable region and a heavy chain variable region, the amino acid sequence of the light chain variable region can comprise SEQ ID NO: 16; and the amino acid sequence of the heavy chain variable region SEQ ID NO: 15 can be included.
  • the reference antibody can include antibody YN-008 or an antibody having the same light chain variable region and heavy chain variable region.
  • the reference antibody can comprise a light chain and a heavy chain, the amino acid sequence of the light chain can be as set forth in SEQ ID NO: 64 and the amino acid sequence of the heavy chain can be as set forth in SEQ ID NO:62.
  • the reference antibody can comprise or have the same light and heavy chains as antibody YN-008.
  • an antibody, antigen-binding fragment thereof, as described herein can compete with a reference antibody for binding to an IL17 protein (eg, a human IL17 protein).
  • the reference antibody may comprise LCDR1-3 and HCDR1-3, and the amino acid sequence of LCDR1 may include SEQ ID NO: 22; the amino acid sequence of LCDR2 may include SEQ ID NO: 23, and the amino acid sequence of LCDR3 may include SEQ ID NO
  • the amino acid sequence of HCDR1 may comprise SEQ ID NO: 19; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 20; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 21.
  • the reference antibody can include antibody YN-009 or an antibody having the same LCDR1-3 and HCDR1-3.
  • the reference antibody can comprise a light chain variable region and a heavy chain variable region, the amino acid sequence of the light chain variable region can comprise SEQ ID NO: 34; and the amino acid sequence of the heavy chain variable region SEQ ID NO: 33 can be included.
  • the reference antibody can include antibody YN-009 or an antibody having the same light chain variable region and heavy chain variable region.
  • the reference antibody can comprise a light chain and a heavy chain, the amino acid sequence of the light chain can be as set forth in SEQ ID NO: 68 and the amino acid sequence of the heavy chain can be as set forth in SEQ ID NO:66.
  • the reference antibody can include antibody YN-009 or an antibody having the same light and heavy chains thereto.
  • an antibody, antigen-binding fragment thereof, as described herein can compete with a reference antibody for binding to an IL17 protein (eg, a human IL17 protein).
  • the reference antibody may comprise LCDR1-3 and HCDR1-3, and the amino acid sequence of LCDR1 may comprise SEQ ID NO: 40; the amino acid sequence of LCDR2 may comprise SEQ ID NO: 41; the amino acid sequence of LCDR3 may comprise SEQ ID NO
  • the amino acid sequence of HCDR1 may comprise SEQ ID NO: 37; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 38; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 39.
  • the reference antibody can include antibody YN-010 or an antibody having the same LCDR1-3 and HCDR1-3.
  • the reference antibody can comprise a light chain variable region and a heavy chain variable region, the amino acid sequence of the light chain variable region can comprise SEQ ID NO: 52; and the amino acid sequence of the heavy chain variable region SEQ ID NO: 51 can be included.
  • the reference antibody can include antibody YN-010 or an antibody having the same light chain variable region and heavy chain variable region.
  • the reference antibody can comprise a light chain and a heavy chain, the amino acid sequence of the light chain can be as set forth in SEQ ID NO: 72 and the amino acid sequence of the heavy chain can be as set forth in SEQ ID NO:70.
  • the reference antibody can include antibody YN-010 or an antibody having the same light and heavy chains thereto.
  • an antibody, antigen-binding fragment thereof, as described herein can compete with a reference antibody for binding to an IL17 protein (eg, a human IL17 protein).
  • the reference antibody may comprise LCDR1-3 and HCDR1-3, and the amino acid sequence of LCDR1 may comprise SEQ ID NO: 4; the amino acid sequence of LCDR2 may comprise SEQ ID NO: 5; the amino acid sequence of LCDR3 may comprise SEQ ID NO
  • the amino acid sequence of HCDR1 may comprise SEQ ID NO: 1; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 2; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 3.
  • the reference antibody can include antibody YN-011 or an antibody having the same LCDR1-3 and HCDR1-3.
  • the reference antibody comprises L-FR1-4 and H-FR1-4
  • the amino acid sequence of L-FR1 may comprise SEQ ID NO: 11
  • the amino acid sequence of L-FR2 may comprise SEQ ID NO: 12
  • the amino acid sequence of -FR3 may comprise SEQ ID NO: 13
  • the amino acid sequence of L-FR4 may comprise SEQ ID NO: 14
  • the amino acid sequence of H-FR1 may comprise SEQ ID NO: 7
  • the amino acid sequence of H-FR2 may comprise SEQ ID NO:8
  • the amino acid sequence of H-FR3 may comprise SEQ ID NO:9
  • the amino acid sequence of H-FR4 may comprise SEQ ID NO:10.
  • the antibody or antigen-binding fragment thereof may include antibody YN-011 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4.
  • the reference antibody can comprise a light chain variable region and a heavy chain variable region, the amino acid sequence of the light chain variable region can comprise SEQ ID NO: 18; and the amino acid sequence of the heavy chain variable region SEQ ID NO: 17 can be included.
  • the reference antibody can include antibody YN-011 or an antibody having the same light chain variable region and heavy chain variable region.
  • the reference antibody can comprise a light chain and a heavy chain, the amino acid sequence of the light chain can be as set forth in SEQ ID NO: 78 and the heavy chain amino acid sequence can be as set forth in SEQ ID NO:76.
  • the reference antibody can include antibody YN-011 or an antibody having the same light and heavy chains thereto.
  • an antibody, antigen-binding fragment thereof, as described herein can compete with a reference antibody for binding to an IL17 protein (e.g., human IL17 protein).
  • the reference antibody may comprise LCDR1-3 and HCDR1-3, and the amino acid sequence of LCDR1 may comprise SEQ ID NO: 22; the amino acid sequence of LCDR2 may comprise SEQ ID NO: 23; the amino acid sequence of LCDR3 may comprise SEQ ID NO
  • the amino acid sequence of HCDR1 may comprise SEQ ID NO: 19; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 20; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 21.
  • the reference antibody can include antibody YN-012 or an antibody having the same LCDR1-3 and HCDR1-3.
  • the reference antibody can comprise a light chain variable region and a heavy chain variable region, the amino acid sequence of the light chain variable region can comprise SEQ ID NO: 36; and the amino acid sequence of the heavy chain variable region SEQ ID NO: 35 can be included.
  • the reference antibody can include antibody YN-012 or an antibody having the same light chain variable region and heavy chain variable region.
  • the reference antibody can comprise a light chain and a heavy chain, the amino acid sequence of the light chain can be as set forth in SEQ ID NO: 84 and the heavy chain amino acid sequence can be as set forth in SEQ ID NO:82.
  • the reference antibody can include antibody YN-012 or an antibody having the same light and heavy chains thereto.
  • an antibody, antigen-binding fragment thereof, as described herein can compete with a reference antibody for binding to an IL17 protein (eg, a human IL17 protein).
  • the reference antibody may comprise LCDR1-3 and HCDR1-3, and the amino acid sequence of LCDR1 may comprise SEQ ID NO: 40; the amino acid sequence of LCDR2 may comprise SEQ ID NO: 41; the amino acid sequence of LCDR3 may comprise SEQ ID NO
  • the amino acid sequence of HCDR1 may comprise SEQ ID NO: 37; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 38; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 39.
  • the reference antibody can include antibody YN-013 or an antibody having the same LCDR1-3 and HCDR1-3.
  • the reference antibody may comprise L-FR1-4 and H-FR1-4, and the amino acid sequence of L-FR1 may comprise SEQ ID NO: 47; the amino acid sequence of L-FR2 may comprise SEQ ID NO: 48; The amino acid sequence of L-FR3 may comprise SEQ ID NO: 49; the amino acid sequence of L-FR4 may comprise SEQ ID NO: 50; and the amino acid sequence of H-FR1 may comprise SEQ ID NO: 43; the amino acid sequence of H-FR2 may The amino acid sequence comprising SEQ ID NO: 44; H-FR3 may comprise SEQ ID NO: 45; the amino acid sequence of H-FR4 may comprise SEQ ID NO: 46.
  • the reference antibody may comprise antibody YN-013 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4 and H-FR1-4.
  • the reference antibody can comprise a light chain variable region and a heavy chain variable region, the amino acid sequence of the light chain variable region can comprise SEQ ID NO: 54; and the amino acid sequence of the heavy chain variable region SEQ ID NO: 53 can be included.
  • the reference antibody can include antibody YN-013 or an antibody having the same light chain variable region and heavy chain variable region.
  • the reference antibody can comprise a light chain and a heavy chain, the amino acid sequence of the light chain can be as set forth in SEQ ID NO: 90 and the amino acid sequence of the heavy chain can be as set forth in SEQ ID NO:88.
  • the reference antibody can include antibody YN-013 or an antibody having the same light and heavy chains thereto.
  • an antibody, antigen-binding fragment thereof, as described herein can compete with a reference antibody for binding to an IL17 protein (eg, a human IL17 protein).
  • the reference antibody may comprise LCDR1-3 and HCDR1-3, and the amino acid sequence of LCDR1 may comprise SEQ ID NO: 40; the amino acid sequence of LCDR2 may comprise SEQ ID NO: 41; the amino acid sequence of LCDR3 may comprise SEQ ID NO
  • the amino acid sequence of HCDR1 may comprise SEQ ID NO: 37; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 38; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 100.
  • the reference antibody can include antibody YN-065 or an antibody having the same LCDR1-3 and HCDR1-3.
  • the reference antibody may comprise L-FR1-4 and H-FR1-4, and the amino acid sequence of L-FR1 may comprise SEQ ID NO: 47; the amino acid sequence of L-FR2 may comprise SEQ ID NO: 48; The amino acid sequence of L-FR3 may comprise SEQ ID NO: 49; the amino acid sequence of L-FR4 may comprise SEQ ID NO: 50; and the amino acid sequence of H-FR1 may comprise SEQ ID NO: 43; the amino acid sequence of H-FR2 may The amino acid sequence comprising SEQ ID NO: 44; H-FR3 may comprise SEQ ID NO: 45; the amino acid sequence of H-FR4 may comprise SEQ ID NO: 46.
  • the reference antibody can include antibody YN-065 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4.
  • the reference antibody can comprise a light chain variable region and a heavy chain variable region, the amino acid sequence of the light chain variable region can comprise SEQ ID NO: 103; and the amino acid sequence of the heavy chain variable region SEQ ID NO: 105 can be included.
  • the reference antibody can include antibody YN-065 or an antibody having the same light chain variable region and heavy chain variable region.
  • the reference antibody can comprise a light chain and a heavy chain, the amino acid sequence of the light chain can be as set forth in SEQ ID NO: 104 and the amino acid sequence of the heavy chain can be as set forth in SEQ ID NO:106.
  • the reference antibody can include antibody YN-065 or an antibody having the same light and heavy chains thereto.
  • an antibody, antigen-binding fragment thereof, as described herein can compete with a reference antibody for binding to an IL17 protein (eg, a human IL17 protein).
  • the reference antibody may comprise LCDR1-3 and HCDR1-3, and the amino acid sequence of LCDR1 may comprise SEQ ID NO: 40; the amino acid sequence of LCDR2 may comprise SEQ ID NO: 41; the amino acid sequence of LCDR3 may comprise SEQ ID NO
  • the amino acid sequence of HCDR1 may comprise SEQ ID NO: 37; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 38; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 101.
  • the reference antibody can include antibody YN-066 or an antibody having the same LCDR1-3 and HCDR1-3.
  • the reference antibody may comprise L-FR1-4 and H-FR1-4, and the amino acid sequence of L-FR1 may comprise SEQ ID NO: 47; the amino acid sequence of L-FR2 may comprise SEQ ID NO: 48; The amino acid sequence of L-FR3 may comprise SEQ ID NO: 49; the amino acid sequence of L-FR4 may comprise SEQ ID NO: 50; and the amino acid sequence of H-FR1 may comprise SEQ ID NO: 43; the amino acid sequence of H-FR2 may The amino acid sequence comprising SEQ ID NO: 44; H-FR3 may comprise SEQ ID NO: 45; the amino acid sequence of H-FR4 may comprise SEQ ID NO: 46.
  • the reference antibody can include antibody YN-066 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4.
  • the reference antibody can comprise a light chain variable region and a heavy chain variable region, the amino acid sequence of the light chain variable region can comprise SEQ ID NO: 103; and the amino acid sequence of the heavy chain variable region SEQ ID NO: 107 can be included.
  • the reference antibody can include antibody YN-066 or an antibody having the same light chain variable region and heavy chain variable region.
  • the reference antibody can comprise a light chain and a heavy chain, the amino acid sequence of the light chain can be as set forth in SEQ ID NO: 104 and the amino acid sequence of the heavy chain can be as set forth in SEQ ID NO:108.
  • the reference antibody can include antibody YN-066 or an antibody having the same light and heavy chains thereto.
  • an antibody, antigen-binding fragment thereof, as described herein can compete with a reference antibody for binding to an IL17 protein (eg, a human IL17 protein).
  • the reference antibody may comprise LCDR1-3 and HCDR1-3, and the amino acid sequence of LCDR1 may include SEQ ID NO: 96; the amino acid sequence of LCDR2 may include SEQ ID NO: 5; the amino acid sequence of LCDR3 may include SEQ ID NO
  • the amino acid sequence of HCDR1 may comprise SEQ ID NO: 91; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 2; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 94.
  • the reference antibody can include antibody YN-067 or an antibody having the same LCDR1-3 and HCDR1-3.
  • the reference antibody may comprise L-FR1-4 and H-FR1-4, and the amino acid sequence of L-FR1 may comprise SEQ ID NO:97; the amino acid sequence of L-FR2 may comprise SEQ ID NO:98;
  • the amino acid sequence of L-FR3 may comprise SEQ ID NO: 13; the amino acid sequence of L-FR4 may comprise SEQ ID NO: 14; and the amino acid sequence of H-FR1 may comprise SEQ ID NO: 7; the amino acid sequence of H-FR2 may The amino acid sequence comprising SEQ ID NO: 8; H-FR3 may comprise SEQ ID NO: 9; the amino acid sequence of H-FR4 may comprise SEQ ID NO: 10.
  • the reference antibody can include antibody YN-067 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4.
  • the reference antibody can comprise a light chain variable region and a heavy chain variable region, the amino acid sequence of the light chain variable region can comprise SEQ ID NO: 109; and the amino acid sequence of the heavy chain variable region SEQ ID NO: 111 can be included.
  • the reference antibody can include antibody YN-067 or an antibody having the same light chain variable region and heavy chain variable region.
  • the reference antibody can comprise a light chain and a heavy chain, the amino acid sequence of the light chain can be as set forth in SEQ ID NO: 110 and the amino acid sequence of the heavy chain can be as set forth in SEQ ID NO: 112.
  • the reference antibody can include antibody YN-067 or an antibody having the same light and heavy chains thereto.
  • an antibody, antigen-binding fragment thereof, as described herein can compete with a reference antibody for binding to an IL17 protein (eg, a human IL17 protein).
  • the reference antibody may comprise LCDR1-3 and HCDR1-3, and the amino acid sequence of LCDR1 may include SEQ ID NO: 96; the amino acid sequence of LCDR2 may include SEQ ID NO: 5; the amino acid sequence of LCDR3 may include SEQ ID NO
  • the amino acid sequence of HCDR1 may comprise SEQ ID NO: 1; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 2; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 95.
  • the reference antibody can include antibody YN-068 or an antibody having the same LCDR1-3 and HCDR1-3.
  • the reference antibody may comprise L-FR1-4 and H-FR1-4, and the amino acid sequence of L-FR1 may comprise SEQ ID NO:97; the amino acid sequence of L-FR2 may comprise SEQ ID NO:98;
  • the amino acid sequence of L-FR3 may comprise SEQ ID NO: 13; the amino acid sequence of L-FR4 may comprise SEQ ID NO: 14; and the amino acid sequence of H-FR1 may comprise SEQ ID NO: 7; the amino acid sequence of H-FR2 may The amino acid sequence comprising SEQ ID NO: 8; H-FR3 may comprise SEQ ID NO: 9; the amino acid sequence of H-FR4 may comprise SEQ ID NO: 10.
  • the reference antibody can include antibody YN-068 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4.
  • the reference antibody can comprise a light chain variable region and a heavy chain variable region, the amino acid sequence of the light chain variable region can comprise SEQ ID NO: 109; and the amino acid sequence of the heavy chain variable region SEQ ID NO: 114 can be included.
  • the reference antibody can include antibody YN-068 or an antibody having the same light chain variable region and heavy chain variable region.
  • the reference antibody can comprise a light chain and a heavy chain, the amino acid sequence of the light chain can be as set forth in SEQ ID NO: 110 and the amino acid sequence of the heavy chain can be as set forth in SEQ ID NO: 115.
  • the reference antibody can include antibody YN-068 or an antibody having the same light and heavy chains thereto.
  • an antibody, antigen-binding fragment thereof, as described herein can compete with a reference antibody for binding to an IL17 protein (eg, a human IL17 protein).
  • the reference antibody may comprise LCDR1-3 and HCDR1-3, and the amino acid sequence of LCDR1 may include SEQ ID NO: 96; the amino acid sequence of LCDR2 may include SEQ ID NO: 5; the amino acid sequence of LCDR3 may include SEQ ID NO
  • the amino acid sequence of HCDR1 may comprise SEQ ID NO: 92; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 2; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 94.
  • the reference antibody can include antibody YN-069 or an antibody having the same LCDR1-3 and HCDR1-3.
  • the reference antibody may comprise L-FR1-4 and H-FR1-4, and the amino acid sequence of L-FR1 may comprise SEQ ID NO:97; the amino acid sequence of L-FR2 may comprise SEQ ID NO:98;
  • the amino acid sequence of L-FR3 may comprise SEQ ID NO: 13; the amino acid sequence of L-FR4 may comprise SEQ ID NO: 14; and the amino acid sequence of H-FR1 may comprise SEQ ID NO: 7; the amino acid sequence of H-FR2 may The amino acid sequence comprising SEQ ID NO: 8; H-FR3 may comprise SEQ ID NO: 9; the amino acid sequence of H-FR4 may comprise SEQ ID NO: 10.
  • the reference antibody can include antibody YN-069 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4.
  • the reference antibody can comprise a light chain variable region and a heavy chain variable region, the amino acid sequence of the light chain variable region can comprise SEQ ID NO: 109; and the amino acid sequence of the heavy chain variable region SEQ ID NO: 117 can be included.
  • the reference antibody can include antibody YN-069 or an antibody having the same light chain variable region and heavy chain variable region.
  • the reference antibody can comprise a light chain and a heavy chain, the amino acid sequence of the light chain can be as set forth in SEQ ID NO: 110 and the amino acid sequence of the heavy chain can be as set forth in SEQ ID NO: 118.
  • the reference antibody can include antibody YN-069 or an antibody having the same light and heavy chains thereto.
  • an antibody, antigen-binding fragment thereof, as described herein can compete with a reference antibody for binding to an IL17 protein (eg, a human IL17 protein).
  • the reference antibody may comprise LCDR1-3 and HCDR1-3, and the amino acid sequence of LCDR1 may include SEQ ID NO: 96; the amino acid sequence of LCDR2 may include SEQ ID NO: 5; the amino acid sequence of LCDR3 may include SEQ ID NO
  • the amino acid sequence of HCDR1 may comprise SEQ ID NO: 91; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 93; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 94.
  • the reference antibody can include antibody YN-070 or an antibody having the same LCDR1-3 and HCDR1-3.
  • the reference antibody may comprise L-FR1-4 and H-FR1-4, and the amino acid sequence of L-FR1 may comprise SEQ ID NO:97; the amino acid sequence of L-FR2 may comprise SEQ ID NO:98;
  • the amino acid sequence of L-FR3 may comprise SEQ ID NO: 13; the amino acid sequence of L-FR4 may comprise SEQ ID NO: 14; and the amino acid sequence of H-FR1 may comprise SEQ ID NO: 7; the amino acid sequence of H-FR2 may The amino acid sequence comprising SEQ ID NO: 8; H-FR3 may comprise SEQ ID NO: 99; the amino acid sequence of H-FR4 may comprise SEQ ID NO: 10.
  • the reference antibody may include antibody YN-070 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4.
  • the reference antibody can comprise a light chain variable region and a heavy chain variable region, the amino acid sequence of the light chain variable region can comprise SEQ ID NO: 109; and the amino acid sequence of the heavy chain variable region SEQ ID NO: 120 can be included.
  • the reference antibody can include antibody YN-069 or an antibody having the same light chain variable region and heavy chain variable region.
  • the reference antibody can comprise a light chain and a heavy chain, the amino acid sequence of the light chain can be as set forth in SEQ ID NO: 110 and the amino acid sequence of the heavy chain can be as set forth in SEQ ID NO:121.
  • the reference antibody can include antibody YN-070 or an antibody having the same light and heavy chains thereto.
  • Antibody antigen-binding fragment thereof
  • the application provides an antibody, antigen-binding fragment thereof, which is 6 ⁇ 10 -9 M or less (for example, the value of K D may be not higher than about 6 ⁇ 10 -9 M, not high About 1 ⁇ 10 -9 M, not higher than about 9 ⁇ 10 ⁇ 10 M, not higher than about 8 ⁇ 10 ⁇ 10 M, not higher than about 7 ⁇ 10 ⁇ 10 M, not higher than about 6 ⁇ 10 ⁇ 10 M, not higher than about 5 ⁇ 10 -10 M, not higher than about 4 ⁇ 10 -10 M, not higher than about 3 ⁇ 10 -10 M, not higher than about 2 ⁇ 10 -10 M, not higher than about 1 ⁇ 10 -10 M, or no greater than about 1 ⁇ 10 -11 M or less) of K D values of IL17 protein combination.
  • the value of K D may be not higher than about 6 ⁇ 10 -9 M, not high About 1 ⁇ 10 -9 M, not higher than about 9 ⁇ 10 ⁇ 10 M, not higher than about 8 ⁇ 10 ⁇ 10 M, not higher than about 7 ⁇ 10 ⁇ 10
  • an antibody, antigen-binding fragment thereof, as described herein competes with an IL17 ligand for binding to an IL17 protein.
  • the antibodies, antigen-binding fragments thereof, of the present application inhibit the expression of cytokines.
  • the cytokine can be selected from the group consisting of interleukins and chemokines.
  • the chemokine can comprise CXCL1.
  • the antibodies, antigen-binding fragments thereof described herein can alleviate or treat diseases or conditions associated with inappropriate or overproduction of IL17.
  • the disease or condition may be selected from the group consisting of ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, osteoarthritis, bone implant loosening, acute graft rejection, respiratory inflammation, inflammatory bowel Disease, sepsis, septic or endotoxic shock, bone loss, psoriasis, allergy, ischemia, systemic sclerosis, stroke and asthma.
  • the IL17 protein described herein can include the human IL17A protein.
  • the IL17 protein can comprise the amino acid sequence shown in accession number Accession No. Q16552 in the UniProtKB database.
  • an IL17 protein described herein can include an IL17F protein (eg, a human IL17F protein).
  • the IL17F protein can comprise the amino acid sequence shown in Accession No. NP_443104.1 in the NCBI database.
  • the antigen-binding fragments described herein may be selected from the group consisting of Fab, Fab', F(ab)2, Fv fragments, F(ab')2, scFv, di-scfv and/or VhH.
  • an antibody, antigen-binding fragment thereof, as described herein, can comprise an antibody light chain or a fragment thereof.
  • the antibody comprises: a monoclonal antibody, a single chain antibody, a chimeric antibody, a humanized antibody, and/or a fully human antibody.
  • the antibody light chain or fragment thereof can comprise a human constant region, which can comprise a human Ig kappa or Ig lambda constant region.
  • An antibody, antigen-binding fragment thereof, as described herein, may comprise an antibody light chain or a fragment thereof, and the antibody light chain or fragment thereof may further comprise LCDR1-3.
  • the antibody light chain or a fragment thereof may comprise LCDR1, and the LCDR1 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 126, SEQ ID NO: 22, and SEQ ID NO: 40.
  • the LCDR1 may comprise the amino acid sequence set forth in SEQ ID NO: 126:
  • the LCDR1 comprises at least an amino acid substitution selected from the group consisting of an amino acid substitution at X 16 as compared to LCDR1 of the antibody of SEQ ID NO: 4.
  • the antibody LCDR1 comprises at least an amino acid substitution at least at X 16 as compared to LCDR1 of the antibody of SEQ ID NO: 4, wherein the amino acid at X 16 can be substituted with D Or E.
  • the LCDR1 may comprise the amino acid sequences shown below: SEQ ID NO: 4 and SEQ ID NO: 96.
  • the antibody light chain or a fragment thereof may comprise LCDR2, and the LCDR2 may comprise an amino acid sequence selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 23, and SEQ ID NO: 41.
  • the antibody light chain or a fragment thereof may comprise LCDR3, which may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 6, SEQ ID NO: 24, and SEQ ID NO: 131 .
  • the LCDR3 may comprise the amino acid sequence set forth in SEQ ID NO: 131:
  • the SEQ ID NO: LCDR3 amino acid as compared to the antibody as shown in 42 comprises at least a substituent selected from the following: In the amino acid substitution at X 5 and / or X 6.
  • the LCDR3 comprises an amino acid substitution at least at X 5 and/or X 6 compared to LCDR3 of the antibody set forth in SEQ ID NO:42, wherein the amino acid at X 5 is Substituted as H or Y, the amino acid at X 6 can be substituted with G or W.
  • the LCDR3 can comprise the amino acid sequences shown below: SEQ ID NO: 42 and SEQ ID NO: 102.
  • the antibody light chain or a fragment thereof may further comprise a framework region L-FR1-4.
  • the framework region L-FR1-4 may be selected from the group consisting of a human consensus framework sequence and a human germline sequence.
  • the C-terminus of the L-FR1 may be directly or indirectly linked to the N-terminus of the LCDR1, and the L-FR1 comprises the amino acid sequence shown in any one of the following: SEQ ID NO: 127, SEQ ID NO:29 and SEQ ID NO:47.
  • the L-FR1 may comprise the amino acid sequence set forth in SEQ ID NO: 127:
  • the L-FR1 comprises at least an amino acid substitution selected from the group consisting of amino acid substitutions at X 12 as compared to L-FR1 of the antibody set forth in SEQ ID NO: 11.
  • the L-FR1 comprises at least an amino acid substitution at least at X 12 as compared to L-FR1 of the antibody of SEQ ID NO: 11, wherein the amino acid at X 12 is Replaced with P or H.
  • the L-FR1 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 11 and SEQ ID NO: 97.
  • the L-FR2 may be located between the LCDR1 and the LCDR2, and the L-FR2 may comprise the amino acid sequence shown in any one of the following: SEQ ID NO: 128, SEQ ID NO: 30 and SEQ ID NO:48.
  • the L-FR2 may comprise the amino acid sequence set forth in SEQ ID NO: 128:
  • the L-FR2 comprises at least an amino acid substitution selected from the group consisting of an amino acid substitution at X 12 as compared to L-FR2 of the antibody set forth in SEQ ID NO: 12.
  • the L-FR2 comprises at least an amino acid substitution at least at X 12 as compared to L-FR2 of the antibody of SEQ ID NO: 12, wherein the amino acid at X 12 is Replaced with L or P.
  • the L-FR2 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 12 and SEQ ID NO: 98.
  • the L-FR3 may be located between the LCDR2 and the LCDR3, and the L-FR3 may comprise the amino acid sequence shown in any one of the following: SEQ ID NO: 13, SEQ ID NO: 31 and SEQ ID NO:49.
  • the N-terminus of the L-FR4 may be directly or indirectly linked to the C-terminus of the LCDR3, and the L-FR4 may comprise an amino acid sequence selected from the group consisting of SEQ ID NO: 14, SEQ ID NO. :32 and SEQ ID NO:50.
  • the antibody light chain or the fragment thereof in the antigen-binding fragment thereof may comprise a light chain variable region VL, and the light chain variable region VL may comprise an amino acid represented by any one of the following Sequence: SEQ ID NO: 16, SEQ ID NO: 134, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 52, and SEQ ID NO: 132.
  • the light chain variable region can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO:54, SEQ ID NO:103, SEQ ID NO:18, and SEQ ID NO:109 .
  • the antibody light chain variable region may comprise the amino acid sequence set forth in SEQ ID NO: 132:
  • the antibody light chain variable region or fragment thereof comprises at least one amino acid substitution selected from the group consisting of: Amino acid substitution at 92 and/or X 93 .
  • the antibody light chain variable region or fragment thereof comprises at least an amino acid substitution at X 92 and/or X 93 as compared to the light chain variable region of the antibody set forth in SEQ ID NO:54.
  • the amino acid at X 92 may be substituted with H or Y; the amino acid at X 93 may be substituted with G or W.
  • the antibody light chain variable region can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 54 and SEQ ID NO: 103.
  • the antibody light chain variable region may comprise the amino acid sequence set forth in SEQ ID NO: 134:
  • DIVMTQSPLSLX 12 VTPGEPASISCRSSQSLLHSNGYNYLX 39 WYLQKPGQSPQX 51 LIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPTFGGGTKLEIKR;
  • the antibody light chain variable region or fragment thereof can comprise at least one amino acid substitution selected from the group consisting of: Amino acid substitution at X 12 , X 39 and/or X 51 .
  • the antibody light chain or fragment thereof can comprise at least amino acid substitutions at X 12 , X 39 and/or X 51 compared to the light chain variable region of the antibody set forth in SEQ ID NO:18
  • the amino acid at X 12 may be substituted with P or H
  • the amino acid at X 39 may be substituted with D or E
  • the amino acid at X 51 may be substituted with L or P.
  • the antibody light chain variable region can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 18 and SEQ ID NO: 109.
  • the antibody light chain or fragment thereof may further comprise a human constant region or a murine constant region.
  • the human constant region may comprise a human Ig ⁇ or Ig ⁇ constant region.
  • the antibody light chain or a fragment thereof may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 64, SEQ ID NO: 68, SEQ ID NO: 72, SEQ ID NO: 138, SEQ ID NO: 84 and SEQ ID NO: 136.
  • the antibody light chain or fragment thereof can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO:90, SEQ ID NO:104, SEQ ID NO:78, and SEQ ID NO: 110.
  • the antibody light chain binding fragment eg, the antigen binding fragment can be a Fab
  • the antibody light chain or fragment thereof may comprise the amino acid sequence set forth in SEQ ID NO: 136:
  • the antibody light chain or fragment thereof comprises at least an amino acid substitution at any one selected from the group consisting of: the X 92 and/or the X 93 , compared to the light chain of the antibody of SEQ ID NO:90. Substitution of amino acids.
  • the SEQ ID NO: 90 compared to FIG antibody light chain said antibody or fragment thereof comprises a light chain amino acid and at least X 92 / X 93 at or substituted, wherein the, X 92 is The amino acid may be substituted with H or Y; the amino acid at X 93 may be substituted with G or W.
  • the antibody light chain or fragment thereof can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 90 and SEQ ID NO: 104.
  • the antibody light chain or fragment thereof may comprise the amino acid sequence set forth in SEQ ID NO: 138:
  • DIVMTQSPLSLX 12 VTPGEPASISCRSSQSLLHSNGYNYLX 39 WYLQKPGQSPQX 51 LIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 138).
  • the antibody light chain or fragment thereof comprises at least an amino acid substitution at any one of the group consisting of: X 12 , X 39 , and / or a light chain of the antibody of SEQ ID NO: 78 Or substitution of an amino acid at X 51 .
  • the antibody light chain or fragment thereof comprises at least an amino acid substitution at X 12 , X 39 and/or X 51 compared to the light chain of the antibody of SEQ ID NO: 78, wherein X
  • the amino acid at 12 may be substituted with P or H; the amino acid at X 39 may be substituted with D or E; the amino acid at X 51 may be substituted with L or P.
  • the antibody light chain or fragment thereof can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO:78 and SEQ ID NO:110.
  • an antibody, antigen-binding fragment thereof, as described herein may comprise an antibody heavy chain or a fragment thereof, and the heavy chain or fragment thereof may comprise HCDR1-3.
  • the antibody heavy chain or fragment thereof may comprise HCDR1 comprising the amino acid sequence set forth in any one of the following: SEQ ID NO: 123, SEQ ID NO: 19 and SEQ ID NO: 37.
  • the HCDR1 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 1, SEQ ID NO: 91, and SEQ ID NO: 92.
  • the HCDR1 may comprise the amino acid sequence set forth in SEQ ID NO: 123:
  • the HCDR1 comprises at least an amino acid substitution at a group selected from the group consisting of the HCDR1 of the antibody of SEQ ID NO:
  • the SEQ ID NO: 1 shown in HCDR1 antibody compared to the HCDR1 comprises at least the amino acid substitution at X 5, wherein amino acids at X 92 may be replaced by M or I.
  • the HCDR1 comprises at least an amino acid substitution at X 4 and/or X 5 compared to HCDR1 of the antibody of SEQ ID NO: 1, wherein the amino acid at X 92 can be substituted with M Or the amino acid at I, X 5 can be substituted with S or N.
  • the HCDR1 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 1, SEQ ID NO: 91, and SEQ ID NO: 92.
  • the antibody heavy chain or a fragment thereof may comprise an HCDR2 comprising the amino acid sequence set forth in any one of the following: SEQ ID NO: 124, SEQ ID NO: 20, and SEQ ID NO: 38.
  • the HCDR2 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 2 and SEQ ID NO: 93.
  • the antibody heavy chain or fragment thereof may comprise the amino acid sequence set forth in SEQ ID NO: 124:
  • the HCDR2 comprises at least an amino acid substitution at any one of the group consisting of: a substitution of an amino acid at X 15 as compared to the HCDR2 of the antibody of SEQ ID NO: 2.
  • the SEQ ID NO: 2 as compared to FIG antibody HCDR2, HCDR2 comprising the amino acid substitutions in at least 15 of the X, wherein the amino acid at 15 X may be substituted is T or A.
  • the HCDR2 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 2 and SEQ ID NO: 93.
  • the antibody heavy chain or fragment thereof comprises HCDR3, and the HCDR3 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 125, SEQ ID NO: 21, and SEQ ID NO: 130 .
  • the HCDR3 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 3, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 39, SEQ ID NO: 100 And SEQ ID NO:101.
  • the HCDR3 may comprise the amino acid sequence set forth in SEQ ID NO: 125:
  • the HCDR3 can comprise at least an amino acid substitution at any one selected from the group consisting of the HCDR3 of the antibody of SEQ ID NO: 3:
  • the SEQ ID NO: 3 as compared to an antibody HCDR3 shown, the HCDR3 may comprise at least the amino acid substitution at X 5, wherein X 5 amino acids may be substituted at G or E.
  • the HCDR3 may comprise at least an amino acid substitution at X 5 and/or X 9 compared to the HCDR3 of the antibody of SEQ ID NO: 3, wherein the amino acid at X 5 may be substituted
  • the amino acid at G or E, X 9 can be substituted with F or L.
  • the HCDR3 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO:3, SEQ ID NO:94, and SEQ ID NO:95.
  • the HCDR3 may comprise the amino acid sequence set forth in SEQ ID NO: 130:
  • X 2 R or G
  • X 3 Y or N
  • X 5 G or D
  • X 6 W or F
  • X 7 Y or N.
  • the HCDR3 can comprise at least an amino acid substitution at any one selected from the group consisting of the heavy chain of the antibody set forth in SEQ ID NO:39:
  • the HCDR3 may comprise at least an amino acid substitution at X 5 compared to the HCDR3 of the antibody of SEQ ID NO: 39, wherein the amino acid at X 2 may be substituted with R or G, X The amino acid at 3 may be substituted with Y or N, the amino acid at X 5 may be substituted with G or D, and the amino acid at X 7 may be substituted with Y or N.
  • the SEQ ID NO: 39 shown in HCDR3 antibody as compared to the antibody HCDR3 amino acid may comprise at least X / X 7 or at 3, X 6 and substituted, wherein, at the amino acid X 3 It may be substituted with Y or N, the amino acid at X 6 may be substituted with W or F, and the amino acid at X 7 may be substituted with Y or N.
  • the HCDR3 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 39, SEQ ID NO: 100, SEQ ID NO: 101.
  • the antibody heavy chain or fragment thereof in the antibody, antigen-binding fragment thereof described herein may further comprise a framework region H-FR1-4.
  • the framework regions may be selected from the group consisting of human consensus framework sequences and human germline sequences.
  • the C-terminus of the H-FR1 can be directly or indirectly linked to the N-terminus of the HCDR1, and the H-FR1 can comprise an amino acid sequence selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 25 and SEQ ID NO: 43.
  • the H-FR2 can be between the HCDR1 and the HCDR2, and the H-FR2 can comprise an amino acid sequence selected from the group consisting of SEQ ID NO:8, SEQ ID NO:26 And SEQ ID NO:44.
  • the H-FR3 can be between the HCDR2 and the HCDR3, and the H-FR3 can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 129, SEQ ID NO: 27 and SEQ ID NO: 45.
  • the H-FR3 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 9 and SEQ ID NO: 99.
  • the H-FR3 may comprise the amino acid sequence set forth in SEQ ID NO: 129:
  • the SEQ ID NO: 9 amino acids of the antibody compared to H-FR3, H-FR3 comprising the at least a substituent selected from: the amino acid substitution at X 23 in.
  • the H-FR3 comprises at least an amino acid substitution at X 5 compared to H-FR3 of the antibody of SEQ ID NO: 9, wherein the amino acid at X 23 can be substituted with E or Q.
  • the H-FR3 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 9 and SEQ ID NO: 99.
  • the N-terminus of the H-FR4 can be directly or indirectly linked to the C-terminus of the HCDR3, and the H-FR4 can comprise an amino acid sequence selected from the group consisting of SEQ ID NO: SEQ ID NO:28 and SEQ ID NO:46.
  • the antibody heavy chain or a fragment thereof may comprise a heavy chain variable region VH
  • the heavy chain variable region VH may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: SEQ ID NO: 135, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 51 and SEQ ID NO: 133.
  • the heavy chain variable region VH can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO:53, SEQ ID NO:105, SEQ ID NO:107, SEQ ID NO: 17.
  • the antibody heavy chain variable region may comprise the amino acid sequence set forth in SEQ ID NO: 133:
  • the heavy chain variable region can comprise at least one amino acid substitution at least one selected from the group consisting of the heavy chain variable region of the antibody of SEQ ID NO: 53:
  • the heavy chain variable region can comprise at least at X 99 , X 100 , X 102 and/or X 104 as compared to the heavy chain variable region of the antibody set forth in SEQ ID NO:53 Amino acid substitution, wherein the amino acid at X 99 can be substituted with R or G, the amino acid at X 100 can be substituted with Y or N, the amino acid at X 102 can be substituted with G or D, and the amino acid at X 103 can be Substituted as W or F, the amino acid at X 104 can be substituted with Y or N.
  • the heavy chain variable region can comprise at least an amino acid substitution at X 100 , X 103 and/or X 104 as compared to the heavy chain variable region of the antibody set forth in SEQ ID NO:53.
  • the amino acid at X 100 can be substituted with Y or N
  • the amino acid at X 103 can be substituted with W or F
  • the amino acid at X 104 can be substituted with Y or S.
  • the antibody heavy chain variable region can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 53, SEQ ID NO: 105, and SEQ ID NO: 107.
  • the antibody heavy chain variable region may comprise the amino acid sequence set forth in SEQ ID NO: 135:
  • the heavy chain variable region comprises at least one amino acid substitution at least one selected from the group consisting of the heavy chain variable region of the antibody of SEQ ID NO:17:
  • the heavy chain variable region can comprise at least an amino acid substitution at X35 and/or X105 , wherein X is compared to the heavy chain variable region of the antibody of SEQ ID NO:17
  • the amino acid at 35 can be substituted with S or N
  • the amino acid at X 105 can be substituted with G or E.
  • the heavy chain variable region can comprise at least an amino acid substitution at X 105 and/or X 109 compared to the heavy chain variable region of the antibody set forth in SEQ ID NO:17, wherein X
  • the amino acid at 105 can be substituted with G or E
  • the amino acid at X 109 can be substituted with F or L.
  • the SEQ ID NO: antibody heavy chain variable region as compared to the FIG. 17, the heavy chain variable region may comprise at least 34 amino acid X, X 35, and / or substituted at X 105, wherein the amino acid at X 34 may be substituted with M or I, the amino acid at X 35 may be substituted with S or N, and the amino acid at X 105 may be substituted with G or E.
  • the SEQ ID NO: antibody heavy chain variable region as compared to the FIG. 17, the heavy chain variable region may comprise at least 34 amino acid X, X 35, and / or substituted at X 105, wherein the amino acid at X 35 may be substituted with S or N, the amino acid at X 91 may be substituted with E or Q, and the amino acid at X 105 may be substituted with G or E.
  • the antibody heavy chain variable region may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 17, SEQ ID NO: 111, SEQ ID NO: 114, SEQ ID NO: 117, and SEQ ID NO : 120.
  • the antibody heavy chain or a fragment thereof may further comprise a human constant region, and the human constant region may comprise a human IgG constant region.
  • the human IgG constant region can comprise a human IgGl constant region.
  • the antibody heavy chain or a fragment thereof may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 62, SEQ ID NO: 66, SEQ ID NO: 70, SEQ ID NO: 139, SEQ ID NO: 82 and SEQ ID NO: 137.
  • the antigen-binding fragment of the antibody heavy chain can comprise an amino acid sequence selected from the group consisting of SEQ ID NO: 113, SEQ ID NO: 116, SEQ ID NO: 119 and SEQ ID NO: 122.
  • the antibody heavy chain or fragment thereof may comprise the amino acid sequence set forth in SEQ ID NO: 137:
  • the antibody heavy chain or fragment thereof can comprise at least one amino acid substitution at least one selected from the group consisting of the heavy chain of the antibody of SEQ ID NO: 88:
  • the antibody heavy chain or fragment thereof can comprise at least amino acid substitutions at X 99 , X 100 , X 102 and/or X 104 as compared to the heavy chain of the antibody set forth in SEQ ID NO:88
  • the amino acid at X 99 may be substituted with R or G
  • the amino acid at X 100 may be substituted with Y or N
  • the amino acid at X 102 may be substituted with G or D
  • the amino acid at X 103 may be substituted
  • W or F the amino acid at X 104 can be substituted with Y or N.
  • the antibody heavy chain or fragment thereof can comprise at least an amino acid substitution at X 100 , X 103 and/or X 104 as compared to the heavy chain of the antibody of SEQ ID NO: 88, wherein
  • the amino acid at X 100 can be substituted with Y or N
  • the amino acid at X 103 can be substituted with W or F
  • the amino acid at X 104 can be substituted with Y or S.
  • the antibody heavy chain or fragment thereof can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO:88, SEQ ID NO:106, and SEQ ID NO:108.
  • the antibody heavy chain or fragment thereof may comprise the amino acid sequence set forth in SEQ ID NO: 139:
  • the antibody heavy chain or fragment thereof can comprise at least one amino acid substitution at least one selected from the group consisting of the heavy chain of the antibody of SEQ ID NO: 76:
  • the antibody heavy chain or fragment thereof can comprise at least an amino acid substitution at X35 and/or X105 , wherein X 35 is at least as compared to the heavy chain of the antibody set forth in SEQ ID NO:76
  • the amino acid can be substituted with S or N, and the amino acid at X 105 can be substituted with G or E.
  • the antibody heavy chain or fragment thereof can comprise at least an amino acid substitution at X 105 and/or X 109 , wherein X 105 is at a temperature to the heavy chain of the antibody set forth in SEQ ID NO:76
  • the amino acid can be substituted with G or E, and the amino acid at X 109 can be substituted with F or L.
  • the SEQ ID NO: Compared antibody heavy chain shown in FIG 76, the antibody heavy chain or fragment thereof may comprise at least X 34, X 35 amino acid substitutions and / or at X 105, wherein, The amino acid at X 34 may be substituted with M or I, the amino acid at X 35 may be substituted with S or N, and the amino acid at X 105 may be substituted with G or E.
  • the SEQ ID NO: Compared antibody heavy chain shown in FIG 76, the antibody heavy chain or fragment thereof may comprise at least X 34, X 35 amino acid substitutions and / or at X 105, wherein, The amino acid at X 35 may be substituted with S or N, the amino acid at X 91 may be substituted with E or Q, and the amino acid at X 105 may be substituted with G or E.
  • the antibody heavy chain or fragment thereof can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO:76, SEQ ID NO:112, SEQ ID NO:115, SEQ ID NO:118, and SEQ ID NO :121.
  • the amino acid sequence of LCDR1 in the antibody, antigen-binding fragment thereof of the present application may include SEQ ID NO: 4; the amino acid sequence of LCDR2 may include SEQ ID NO: 5; the amino acid sequence of LCDR3 may include SEQ ID NO: 6; and the amino acid sequence of HCDR1 may comprise SEQ ID NO: 1; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 2; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 3.
  • the antibody, antigen-binding fragment thereof can include antibody YN-008 or an antibody having the same LCDR1-3 and HCDR1-3.
  • the amino acid sequence of the light chain variable region of an antibody, antigen-binding fragment thereof, of the present application may comprise SEQ ID NO: 16; and the amino acid sequence of the heavy chain variable region thereof may comprise SEQ ID NO :15.
  • the antibody, antigen-binding fragment thereof can include antibody YN-008 or an antibody having the same light chain variable region and heavy chain variable region.
  • an antibody, antigen-binding fragment thereof, as described herein can comprise a light chain and a heavy chain, the amino acid sequence of the light chain can be set forth in SEQ ID NO: 64 and the heavy chain amino acid sequence can be As shown in SEQ ID NO:62.
  • the antibody, antigen-binding fragment thereof can include antibody YN-008 or an antibody having the same light and heavy chains therewith.
  • the amino acid sequence of LCDR1 in the antibody, antigen-binding fragment thereof of the present application may include SEQ ID NO: 22; the amino acid sequence of LCDR2 may include SEQ ID NO: 23; the amino acid sequence of LCDR3 may include SEQ ID NO: 24; and the amino acid sequence of HCDR1 may comprise SEQ ID NO: 19; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 20; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 21.
  • the antibody, antigen-binding fragment thereof can include antibody YN-009 or an antibody having the same LCDR1-3 and HCDR1-3.
  • the amino acid sequence of the light chain variable region of an antibody, antigen-binding fragment thereof, of the present application may comprise SEQ ID NO: 34; and the amino acid sequence of the heavy chain variable region thereof may comprise SEQ ID NO :33.
  • the antibody, antigen-binding fragment thereof can include antibody YN-009 or an antibody having the same light chain variable region and heavy chain variable region.
  • an antibody, antigen-binding fragment thereof, as described herein can comprise a light chain and a heavy chain, the amino acid sequence of which is set forth in SEQ ID NO: 68 and the amino acid sequence of the heavy chain is as SEQ ID NO: 66.
  • the antibody, antigen-binding fragment thereof can include antibody YN-009 or an antibody having the same light and heavy chains thereto.
  • the amino acid sequence of LCDR1 in the antibody, antigen-binding fragment thereof of the present application may include SEQ ID NO: 40; the amino acid sequence of LCDR2 may include SEQ ID NO: 41; the amino acid sequence of LCDR3 may include SEQ ID NO: 42; and the amino acid sequence of HCDR1 may comprise SEQ ID NO: 37; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 38; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 39.
  • the antibody, antigen-binding fragment thereof can include antibody YN-010 or an antibody having the same LCDR1-3 and HCDR1-3.
  • an antibody, antigen-binding fragment thereof, as described herein can comprise a light chain variable region, the amino acid sequence of the light chain variable region can comprise SEQ ID NO: 52; and can comprise a heavy chain The variable region, the amino acid sequence of the heavy chain variable region can include SEQ ID NO:51.
  • the antibody, antigen-binding fragment thereof can include antibody YN-010 or an antibody having the same light chain variable region and heavy chain variable region.
  • an antibody, antigen-binding fragment thereof, as described herein can comprise a light chain and a heavy chain, the amino acid sequence of which is set forth in SEQ ID NO: 72 and the amino acid sequence of the heavy chain is as SEQ ID NO:70.
  • the antibody, antigen-binding fragment thereof can include antibody YN-010 or an antibody having the same light and heavy chains thereto.
  • the amino acid sequence of LCDR1 in the antibody, antigen-binding fragment thereof of the present application may include SEQ ID NO: 4; the amino acid sequence of LCDR2 may include SEQ ID NO: 5; the amino acid sequence of LCDR3 may include SEQ ID NO: 6; and the amino acid sequence of HCDR1 may comprise SEQ ID NO: 1; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 2; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 3.
  • the antibody, antigen-binding fragment thereof can include antibody YN-011 or an antibody having the same LCDR1-3 and HCDR1-3.
  • the amino acid sequence of L-FR1 in the antibody, antigen-binding fragment thereof can include SEQ ID NO: 11; the amino acid sequence of L-FR2 can include SEQ ID NO: 12; the amino acid sequence of L-FR3 can The amino acid sequence comprising SEQ ID NO: 13; L-FR4 may comprise SEQ ID NO: 14; and the amino acid sequence of H-FR1 may comprise SEQ ID NO: 7; the amino acid sequence of H-FR2 may comprise SEQ ID NO: 8; The amino acid sequence of H-FR3 may comprise SEQ ID NO: 9; and the amino acid sequence of H-FR4 may comprise SEQ ID NO: 10.
  • the antibody, antigen-binding fragment thereof may include antibody YN-011 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4.
  • the light chain of an antibody, antigen-binding fragment thereof, of the present application may comprise a light chain variable region, the amino acid sequence of the light chain variable region comprising SEQ ID NO: 18;
  • the chain may comprise a heavy chain variable region, and the amino acid sequence of the heavy chain variable region may comprise SEQ ID NO: 17.
  • the antibody, antigen-binding fragment thereof can include antibody YN-011 or an antibody having the same light chain variable region and heavy chain variable region.
  • an antibody, antigen-binding fragment thereof, as described herein can comprise a light chain and a heavy chain, the amino acid sequence of which is set forth in SEQ ID NO: 78 and the amino acid sequence of the heavy chain is as SEQ ID NO:76.
  • the antibody, antigen-binding fragment thereof can include antibody YN-011 or an antibody having the same light and heavy chains therewith.
  • the amino acid sequence of LCDR1 in the antibody, antigen-binding fragment thereof of the present application may include SEQ ID NO: 22; the amino acid sequence of LCDR2 may include SEQ ID NO: 23; the amino acid sequence of LCDR3 may include SEQ ID NO: 24; and the amino acid sequence of HCDR1 may comprise SEQ ID NO: 19; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 20; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 21.
  • the antibody, antigen-binding fragment thereof can include antibody YN-012 or an antibody having the same LCDR1-3 and HCDR1-3.
  • the amino acid sequence of L-FR1 in the antibody, antigen-binding fragment thereof described in the present application may include SEQ ID NO: 29; the amino acid sequence of L-FR2 may include SEQ ID NO: 30; the amino acid sequence of L-FR3 may include SEQ ID NO: 31; the amino acid sequence of L-FR4 may include SEQ ID NO: 32; and the amino acid sequence of H-FR1 may include SEQ ID NO: 25; the amino acid sequence of H-FR2 may include SEQ ID NO: 26; H-FR3
  • the amino acid sequence can include SEQ ID NO:27; the amino acid sequence of H-FR4 can include SEQ ID NO:28.
  • the antibody, antigen-binding fragment thereof may include antibody YN-012 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4.
  • the light chain of an antibody, antigen-binding fragment thereof, of the present application may comprise a light chain variable region, the amino acid sequence of the light chain variable region comprising SEQ ID NO: 36;
  • the chain may comprise a heavy chain variable region, and the amino acid sequence of the heavy chain variable region may comprise SEQ ID NO:35.
  • the antibody, antigen-binding fragment thereof can include antibody YN-012 or an antibody having the same light chain variable region and heavy chain variable region.
  • an antibody, antigen-binding fragment thereof, as described herein can comprise a light chain and a heavy chain, the amino acid sequence of which is set forth in SEQ ID NO: 84 and the amino acid sequence of the heavy chain is as SEQ ID NO: 82.
  • the antibody, antigen-binding fragment thereof can include antibody YN-012 or an antibody having the same light and heavy chains thereto.
  • the amino acid sequence of LCDR1 in the antibody, antigen-binding fragment thereof of the present application may include SEQ ID NO: 40; the amino acid sequence of LCDR2 may include SEQ ID NO: 41; the amino acid sequence of LCDR3 may include SEQ ID NO: 42; and the amino acid sequence of HCDR1 may comprise SEQ ID NO: 37; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 38; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 39.
  • the antibody, antigen-binding fragment thereof can include antibody YN-013 or an antibody having the same LCDR1-3 and HCDR1-3.
  • the amino acid sequence of L-FR1 in the antibody, antigen-binding fragment thereof described in the present application may include SEQ ID NO: 47; the amino acid sequence of L-FR2 may include SEQ ID NO: 48; the amino acid sequence of L-FR3 may include SEQ ID NO: 49; the amino acid sequence of L-FR4 may include SEQ ID NO: 50; and the amino acid sequence of H-FR1 may include SEQ ID NO: 43; the amino acid sequence of H-FR2 may include SEQ ID NO: 44; H-FR3
  • the amino acid sequence may comprise SEQ ID NO: 45; the amino acid sequence of H-FR4 may comprise SEQ ID NO: 46.
  • the antibody, antigen-binding fragment thereof may include antibody YN-013 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4.
  • the light chain of an antibody, antigen-binding fragment thereof, of the present application may comprise a light chain variable region, the amino acid sequence of the light chain variable region comprising SEQ ID NO: 54;
  • the chain may comprise a heavy chain variable region, and the amino acid sequence of the heavy chain variable region may comprise SEQ ID NO:53.
  • the antibody, antigen-binding fragment thereof can include antibody YN-013 or an antibody having the same light chain variable region and heavy chain variable region.
  • an antibody, antigen-binding fragment thereof, as described herein can comprise a light chain and a heavy chain, the amino acid sequence of which is set forth in SEQ ID NO: 90 and the amino acid sequence of the heavy chain is as SEQ ID NO:88.
  • the antibody, antigen-binding fragment thereof can include antibody YN-013 or an antibody having the same light and heavy chains thereto.
  • the amino acid sequence of LCDR1 in the antibody, antigen-binding fragment thereof of the present application may include SEQ ID NO: 40; the amino acid sequence of LCDR2 may include SEQ ID NO: 41; the amino acid sequence of LCDR3 may include SEQ ID NO: 102; and the amino acid sequence of HCDR1 may comprise SEQ ID NO: 37; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 38; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 100.
  • the antibody, antigen-binding fragment thereof can include antibody YN-065 or an antibody having the same LCDR1-3 and HCDR1-3.
  • the amino acid sequence of L-FR1 in the antibody, antigen-binding fragment thereof described in the present application may include SEQ ID NO: 47; the amino acid sequence of L-FR2 may include SEQ ID NO: 48; the amino acid sequence of L-FR3 may include SEQ ID NO: 49; the amino acid sequence of L-FR4 may include SEQ ID NO: 50; and the amino acid sequence of H-FR1 may include SEQ ID NO: 43; the amino acid sequence of H-FR2 may include SEQ ID NO: 44; H-FR3
  • the amino acid sequence may comprise SEQ ID NO: 45; the amino acid sequence of H-FR4 may comprise SEQ ID NO: 46.
  • the antibody, antigen-binding fragment thereof may include antibody YN-065 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4.
  • the light chain of an antibody, antigen-binding fragment thereof, of the present application may comprise a light chain variable region, the amino acid sequence of the light chain variable region comprising SEQ ID NO: 103;
  • the chain may comprise a heavy chain variable region, and the amino acid sequence of the heavy chain variable region may comprise SEQ ID NO:105.
  • the antibody, antigen-binding fragment thereof can include antibody YN-065 or an antibody having the same light chain variable region and heavy chain variable region.
  • an antibody, antigen-binding fragment thereof, as described herein can comprise a light chain and a heavy chain, the amino acid sequence of which is set forth in SEQ ID NO: 104 and the amino acid sequence of the heavy chain is as SEQ ID NO:106.
  • the antibody, antigen-binding fragment thereof can include antibody YN-065 or an antibody having the same light and heavy chains thereto.
  • the amino acid sequence of LCDR1 in the antibody, antigen-binding fragment thereof of the present application may include SEQ ID NO: 40; the amino acid sequence of LCDR2 may include SEQ ID NO: 41; the amino acid sequence of LCDR3 may include SEQ ID NO: 102; and the amino acid sequence of HCDR1 may comprise SEQ ID NO: 37; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 38; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 101.
  • the antibody, antigen-binding fragment thereof can include antibody YN-066 or an antibody having the same LCDR1-3 and HCDR1-3.
  • the amino acid sequence of L-FR1 in the antibody, antigen-binding fragment thereof described in the present application may include SEQ ID NO: 47; the amino acid sequence of L-FR2 may include SEQ ID NO: 48; the amino acid sequence of L-FR3 may include SEQ ID NO: 49; the amino acid sequence of L-FR4 may include SEQ ID NO: 50; and the amino acid sequence of H-FR1 may include SEQ ID NO: 43; the amino acid sequence of H-FR2 may include SEQ ID NO: 44; H-FR3
  • the amino acid sequence may comprise SEQ ID NO: 45; the amino acid sequence of H-FR4 may comprise SEQ ID NO: 46.
  • the antibody, antigen-binding fragment thereof can include antibody YN-066 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4.
  • the light chain of an antibody, antigen-binding fragment thereof, of the present application may comprise a light chain variable region, the amino acid sequence of the light chain variable region comprising SEQ ID NO: 103;
  • the chain may comprise a heavy chain variable region, and the amino acid sequence of the heavy chain variable region may comprise SEQ ID NO:107.
  • the antibody, antigen-binding fragment thereof can include antibody YN-066 or an antibody having the same light chain variable region and heavy chain variable region.
  • an antibody, antigen-binding fragment thereof, as described herein can comprise a light chain and a heavy chain, the amino acid sequence of which is set forth in SEQ ID NO: 104 and the amino acid sequence of the heavy chain is as SEQ ID NO:108.
  • the antibody, antigen-binding fragment thereof can include antibody YN-066 or an antibody having the same light and heavy chains thereto.
  • the amino acid sequence of LCDR1 in the antibody, antigen-binding fragment thereof of the present application may include SEQ ID NO: 96; the amino acid sequence of LCDR2 may include SEQ ID NO: 5; the amino acid sequence of LCDR3 may include SEQ ID NO:6; and the amino acid sequence of HCDR1 may comprise SEQ ID NO:91; the amino acid sequence of HCDR2 may comprise SEQ ID NO:2; the amino acid sequence of HCDR3 may comprise SEQ ID NO:94.
  • the antibody, antigen-binding fragment thereof can include antibody YN-067 or an antibody having the same LCDR1-3 and HCDR1-3.
  • the amino acid sequence of L-FR1 in the antibody, antigen-binding fragment thereof described in the present application may include SEQ ID NO: 97; the amino acid sequence of L-FR2 may include SEQ ID NO: 98; the amino acid sequence of L-FR3 may include SEQ ID NO: 13; the amino acid sequence of L-FR4 may include SEQ ID NO: 14; and the amino acid sequence of H-FR1 may include SEQ ID NO: 7; the amino acid sequence of H-FR2 may include SEQ ID NO: 8; H-FR3
  • the amino acid sequence can include SEQ ID NO: 9; the amino acid sequence of H-FR4 can include SEQ ID NO: 10.
  • the antibody, antigen-binding fragment thereof may include antibody YN-067 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4.
  • the light chain of an antibody, antigen-binding fragment thereof, of the present application may comprise a light chain variable region, the amino acid sequence of the light chain variable region comprising SEQ ID NO: 109;
  • the chain may comprise a heavy chain variable region, and the amino acid sequence of the heavy chain variable region may comprise SEQ ID NO: 111.
  • the antibody, antigen-binding fragment thereof can include antibody YN-067 or an antibody having the same light chain variable region and heavy chain variable region.
  • an antibody, antigen-binding fragment thereof, as described herein can comprise a light chain and a heavy chain, the amino acid sequence of which is set forth in SEQ ID NO: 110 and the amino acid sequence of the heavy chain is as SEQ ID NO: 112.
  • the antibody, antigen-binding fragment thereof can include antibody YN-067 or an antibody having the same light and heavy chains thereto.
  • the amino acid sequence of LCDR1 in the antibody, antigen-binding fragment thereof of the present application may include SEQ ID NO: 96; the amino acid sequence of LCDR2 may include SEQ ID NO: 5; the amino acid sequence of LCDR3 may include SEQ ID NO: 6; and the amino acid sequence of HCDR1 may comprise SEQ ID NO: 1; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 2; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 95.
  • the antibody, antigen-binding fragment thereof can include antibody YN-068 or an antibody having the same LCDR1-3 and HCDR1-3.
  • the amino acid sequence of L-FR1 in the antibody, antigen-binding fragment thereof described in the present application may include SEQ ID NO: 97; the amino acid sequence of L-FR2 may include SEQ ID NO: 98; the amino acid sequence of L-FR3 may include SEQ ID NO: 13; the amino acid sequence of L-FR4 may include SEQ ID NO: 14; and the amino acid sequence of H-FR1 may include SEQ ID NO: 7; the amino acid sequence of H-FR2 may include SEQ ID NO: 8; H-FR3
  • the amino acid sequence can include SEQ ID NO: 9; the amino acid sequence of H-FR4 can include SEQ ID NO: 10.
  • the antibody, antigen-binding fragment thereof can include antibody YN-068 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4.
  • the light chain of an antibody, antigen-binding fragment thereof, of the present application may comprise a light chain variable region, the amino acid sequence of the light chain variable region comprising SEQ ID NO: 109;
  • the chain may comprise a heavy chain variable region, and the amino acid sequence of the heavy chain variable region may comprise SEQ ID NO: 114.
  • the antibody, antigen-binding fragment thereof can include antibody YN-068 or an antibody having the same light chain variable region and heavy chain variable region.
  • an antibody, antigen-binding fragment thereof, as described herein can comprise a light chain and a heavy chain, the amino acid sequence of which is set forth in SEQ ID NO: 110 and the amino acid sequence of the heavy chain is as SEQ ID NO: 115.
  • the antibody, antigen-binding fragment thereof can include antibody YN-068 or an antibody having the same light and heavy chains thereto.
  • the amino acid sequence of LCDR1 in the antibody, antigen-binding fragment thereof of the present application may include SEQ ID NO: 96; the amino acid sequence of LCDR2 may include SEQ ID NO: 5; the amino acid sequence of LCDR3 may include SEQ ID NO: 6; and the amino acid sequence of HCDR1 may comprise SEQ ID NO: 92; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 2; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 94.
  • the antibody, antigen-binding fragment thereof can include antibody YN-069 or an antibody having the same LCDR1-3 and HCDR1-3.
  • the amino acid sequence of L-FR1 in the antibody, antigen-binding fragment thereof described in the present application may include SEQ ID NO: 97; the amino acid sequence of L-FR2 may include SEQ ID NO: 98; the amino acid sequence of L-FR3 may include SEQ ID NO: 13; the amino acid sequence of L-FR4 may include SEQ ID NO: 14; and the amino acid sequence of H-FR1 may include SEQ ID NO: 7; the amino acid sequence of H-FR2 may include SEQ ID NO: 8; H-FR3
  • the amino acid sequence can include SEQ ID NO: 9; the amino acid sequence of H-FR4 can include SEQ ID NO: 10.
  • the antibody, antigen-binding fragment thereof can include antibody YN-069 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4.
  • the light chain of an antibody, antigen-binding fragment thereof, of the present application may comprise a light chain variable region, the amino acid sequence of the light chain variable region comprising SEQ ID NO: 109;
  • the chain may comprise a heavy chain variable region, and the amino acid sequence of the heavy chain variable region may comprise SEQ ID NO:117.
  • the antibody, antigen-binding fragment thereof can include antibody YN-069 or an antibody having the same light chain variable region and heavy chain variable region.
  • an antibody, antigen-binding fragment thereof, as described herein can comprise a light chain and a heavy chain, the amino acid sequence of which is set forth in SEQ ID NO: 110 and the amino acid sequence of the heavy chain is as SEQ ID NO: 118.
  • the antibody, antigen-binding fragment thereof can include antibody YN-069 or an antibody having the same light and heavy chains thereto.
  • the amino acid sequence of LCDR1 in the antibody, antigen-binding fragment thereof of the present application may include SEQ ID NO: 96; the amino acid sequence of LCDR2 may include SEQ ID NO: 5; the amino acid sequence of LCDR3 may include SEQ ID NO:6; and the amino acid sequence of HCDR1 may comprise SEQ ID NO:91; the amino acid sequence of HCDR2 may comprise SEQ ID NO:93; the amino acid sequence of HCDR3 may comprise SEQ ID NO:94.
  • the antibody, antigen-binding fragment thereof can include antibody YN-070 or an antibody having the same LCDR1-3 and HCDR1-3.
  • the amino acid sequence of L-FR1 in the antibody, antigen-binding fragment thereof described in the present application may include SEQ ID NO: 97; the amino acid sequence of L-FR2 may include SEQ ID NO: 98; the amino acid sequence of L-FR3 may include SEQ ID NO: 13; the amino acid sequence of L-FR4 may include SEQ ID NO: 14; and the amino acid sequence of H-FR1 may include SEQ ID NO: 7; the amino acid sequence of H-FR2 may include SEQ ID NO: 8; H-FR3
  • the amino acid sequence can include SEQ ID NO: 99; the amino acid sequence of H-FR4 can include SEQ ID NO: 10.
  • the antibody, antigen-binding fragment thereof may include antibody YN-070 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4.
  • the light chain of an antibody, antigen-binding fragment thereof, of the present application may comprise a light chain variable region, the amino acid sequence of the light chain variable region comprising SEQ ID NO: 109;
  • the chain may comprise a heavy chain variable region, and the amino acid sequence of the heavy chain variable region may comprise SEQ ID NO:120.
  • the antibody, antigen-binding fragment thereof can include antibody YN-070 or an antibody having the same light chain variable region and heavy chain variable region.
  • an antibody, antigen-binding fragment thereof, as described herein can comprise a light chain and a heavy chain, the amino acid sequence of which is set forth in SEQ ID NO: 110 and the amino acid sequence of the heavy chain is as SEQ ID NO: 121.
  • the antibody, antigen-binding fragment thereof can include antibody YN-070 or an antibody having the same light and heavy chains thereto.
  • a protein, polypeptide and/or amino acid sequence referred to in this application is also understood to include at least the following range: a variant or homologue having the same or similar function as the protein or polypeptide.
  • the variant may be one or more substituted, deleted or added to the amino acid sequence of the protein and/or the polypeptide (eg, an antibody or fragment thereof that specifically binds to a CD38 protein) A protein or polypeptide of an amino acid.
  • the functional variant may comprise having been substituted by at least 1, for example 1-30, 1-20 or 1-10, for example 1 , 2, 3, 4 or 5 amino acids.
  • the functional variant may substantially retain the biological properties of the protein or the polypeptide prior to alteration (eg, substitution, deletion or addition).
  • the functional variant can retain at least 60%, 70%, 80%, 90%, or 100% of the biological activity (eg, antigen binding capacity) of the protein or the polypeptide prior to the alteration.
  • the substitution can be a conservative substitution.
  • the homolog may be at least about 85% of the amino acid sequence of the protein and/or the polypeptide (eg, an antibody or fragment thereof that specifically binds to a CD38 protein) (eg, having at least Approximately 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or more) A protein or polypeptide derived from a source.
  • the polypeptide eg, an antibody or fragment thereof that specifically binds to a CD38 protein
  • the homology generally refers to the similarity, similarity or association between two or more sequences.
  • the "percentage of sequence homology” can be calculated by comparing two sequences to be aligned in a comparison window to determine the presence of the same nucleic acid base in both sequences (eg, A, T, C, G, I) Or the same amino acid residues (eg, Ala, Pro, Ser, Thr, Gly, Val, Leu, Ile, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gln, Cys, and Met)
  • the number of positions is obtained to obtain the number of matching positions, the number of matching positions is divided by the total number of positions in the comparison window (ie, the window size), and the result is multiplied by 100 to generate a sequence homology percentage.
  • Alignment to determine percent sequence homology can be accomplished in a variety of ways known in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software.
  • BLAST BLAST-2
  • ALIGN ALIGN
  • Megalign DNASTAR
  • One of skill in the art can determine suitable parameters for aligning the sequences, including any algorithms needed to achieve maximum alignment within the full length sequence being compared or within the target sequence region.
  • the homology can also be determined by the following methods: FASTA and BLAST. A description of the FASTA algorithm can be found in WRPearson and DJ Lipman, "Improved Tools for Biological Sequence Comparison," Proc. Natl. Acad.
  • the application also provides an isolated nucleic acid molecule or molecules encoding an antibody, antigen-binding fragment thereof, as described herein.
  • each of the one or more nucleic acid molecules can encode the entire antibody, its antigen-binding fragment, or a portion thereof (eg, HCDR1-3, LCDR1-3, VL, VH) , one or more of a light chain or a heavy chain).
  • the nucleic acid molecules described herein can be isolated. For example, it may be produced or synthesized by (i) amplification in vitro, such as by polymerase chain reaction (PCR) amplification, (ii) production by clonal recombination, (iii) purification. , for example, by fractionation by gel digestion and gel electrophoresis, or (iv) synthetic, for example by chemical synthesis.
  • the isolated nucleic acid is a nucleic acid molecule produced by recombinant DNA techniques.
  • nucleic acids encoding the antibodies, antigen-binding fragments thereof can be prepared by a variety of methods known in the art including, but not limited to, restriction fragment manipulation or the use of synthetic oligonucleotides.
  • Overlap extension PCR see Sambrook et al, Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989; and Ausube et al. Current Protocols in Molecular Biology, Greene Publishing and Wiley-Interscience, for specific procedures. New York NY, 1993.
  • the application provides one or more vectors comprising one or more nucleic acid molecules described herein.
  • One or more of the nucleic acid molecules can be included in each vector.
  • other genes may be included in the vector, such as a marker gene that allows selection of the vector in a suitable host cell and under appropriate conditions.
  • the vector may further comprise an expression control element that allows the coding region to be correctly expressed in a suitable host.
  • control elements are well known to those skilled in the art and may include, for example, promoters, ribosome binding sites, enhancers, and other control elements that regulate gene transcription or mRNA translation.
  • the expression control sequence is a tunable element.
  • the specific structure of the expression control sequence may vary depending on the function of the species or cell type, but typically comprises 5' non-transcribed sequences and 5' and 3' untranslated sequences, respectively, involved in transcriptional and translational initiation, such as TATA boxes, plus Cap sequence, CAAT sequence, and the like.
  • a 5' non-transcribed expression control sequence can comprise a promoter region, and the promoter region can comprise a promoter sequence for transcriptional control of a functionally linked nucleic acid.
  • the expression control sequence may also include an enhancer sequence or an upstream activator sequence.
  • suitable promoters may include, for example, promoters for SP6, T3 and T7 polymerase, human U6 RNA promoter, CMV promoter and artificial hybrid promoters thereof (such as CMV), wherein the promoter A portion may be fused to a portion of a promoter of another cellular protein (eg, human GAPDH, glyceraldehyde-3-phosphate dehydrogenase) gene, which may or may not contain additional introns.
  • a promoter of another cellular protein eg, human GAPDH, glyceraldehyde-3-phosphate dehydrogenase
  • One or more nucleic acid molecules described herein can be operably linked to the expression control element.
  • Such vectors may include, for example, plasmids, cosmids, viruses, bacteriophages or other vectors commonly used, for example, in genetic engineering.
  • the vector is an expression vector.
  • the application provides a host cell, which can comprise one or more nucleic acid molecules described herein and/or one or more vectors described herein.
  • each or each host cell can comprise one or one of the nucleic acid molecules or vectors described herein.
  • each or each host cell can comprise multiple (eg, two or more) or multiple (eg, two or more) nucleic acid molecules or vectors described herein.
  • a vector described herein can be introduced into the host cell, such as a prokaryotic cell (eg, a bacterial cell), a CHO cell, an NS/0 cell, a HEK293T cell, or a HEK293A cell, or other eukaryotic cell, such as from a plant. Cell, fungus or yeast cells, etc.
  • Vectors described herein can be introduced into the host cell by methods known in the art, such as electroporation, lipofectine transfection, lipofectamin transfection, and the like.
  • the host cell can be COS, CHO, NSO, sf9, sf21, DH5a, BL21 (DE3) or TG1.
  • the application provides a method of making an antibody, antigen-binding fragment thereof, as described herein.
  • the method can comprise culturing a host cell as described herein under conditions such that the antibody, its antigen-binding fragment is expressed.
  • such methods can be understood by those of ordinary skill in the art by using appropriate media, appropriate temperatures and incubation times, and the like.
  • the methods can also include the step of harvesting (eg, isolating and/or purifying) the antibodies, antigen-binding fragments thereof described herein.
  • affinity chromatography can be carried out using protein G-Sepharose or Protein A-Sepharose, and the antibody and antigen-binding fragment thereof described in the present application can also be purified and isolated by gel electrophoresis and/or high performance liquid chromatography or the like.
  • the fusion protein polypeptide bound to the affinity column can also be eluted by using a high salt buffer, changing the pH, and the like.
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising an antibody, antigen-binding fragment thereof, and, optionally, a pharmaceutically acceptable carrier, as described herein.
  • the pharmaceutically acceptable carrier can include buffers, antioxidants, preservatives, low molecular weight polypeptides, proteins, hydrophilic polymers, amino acids, sugars, chelating agents, counterions, metal complexes, and/or nonionic surface active agents. Agents, etc.
  • the pharmaceutical composition can be formulated for oral administration, intravenous administration, intramuscular administration, in situ administration at the tumor site, inhalation, rectal administration, vaginal administration, transdermal Administration or administration via a subcutaneous reservoir.
  • the pharmaceutical composition can be used to inhibit or delay the progression or progression of a disease or condition, and/or can alleviate and/or stabilize the condition of the disease or condition.
  • compositions described herein may comprise a prophylactically and/or therapeutically effective amount of the antibody, antigen-binding fragment thereof.
  • the prophylactically and/or therapeutically effective amount is a dose that is capable of preventing and/or treating (at least partially treating) a disease or condition in a subject having or at risk of development and/or any complications thereof.
  • the application provides the use of the antibody, antigen-binding fragment thereof, for the manufacture of a medicament for preventing or treating a disease or condition.
  • the antibodies, antigen-binding fragments thereof, provided herein are useful for preventing or treating a disease or condition.
  • the application provides a method of preventing or treating a disease or condition, comprising administering (eg, administering to a subject in need thereof) an antibody, antigen-binding fragment thereof, nucleic acid molecule, Said vector, said host cell and / or said pharmaceutical composition.
  • the disease or condition may be selected from the group consisting of ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, osteoarthritis, bone implant loosening, acute graft rejection, respiratory inflammation, Inflammatory bowel disease, sepsis, septic or endotoxic shock, bone loss, psoriasis, allergy, ischemia, systemic sclerosis, stroke and asthma.
  • the application provides a method of inhibiting binding of an IL17 protein to an IL17 ligand, comprising administering an antibody, an antigen-binding fragment thereof, the nucleic acid molecule, the vector, the host cell, and a host cell, And/or the pharmaceutical composition described.
  • the method can be an in vitro or ex vivo method.
  • the application provides a method of inhibiting the biological activity of an IL17 protein comprising administering an antibody, an antigen-binding fragment thereof, the nucleic acid molecule, the vector, the host cell, and/or Or the pharmaceutical composition described.
  • the method can be an in vitro or ex vivo method.
  • the application provides a method of inhibiting expression of a chemokine comprising administering the antibody, antigen-binding fragment thereof, the nucleic acid molecule, the vector, the host cell, and/or the Pharmaceutical composition.
  • the chemokine can include CXCL1.
  • the method can be an in vitro or ex vivo method.
  • Recombinant human IL17A protein (Beijing Yiqiao Shenzhou Biotechnology Co., Ltd.) was used as an antigen for sorting by phage natural human antibody library (Primary Energy Cell Technology Co., Ltd.).
  • 1 ml of the antigen IL17A protein was coated with CBS buffer, and the concentration of IL17A protein was 20 ⁇ g/ml (first and second round) or 10 ⁇ g/ml (third and fourth round), overnight at 4 ° C; 2 ml of PBS buffer containing 10% skim milk powder was used to block the immunotube; 1 ml of the blocked phage was added to the immunotube, incubated for 1 h at room temperature; PBST was washed 10 times (first, second round) or 15 times (third, Four rounds); add 800 ⁇ L of Gly-HCl buffer at pH 2.2, immediately add 400 ⁇ L of Tris-HCl buffer at pH 8.0, and add to 20 ml of E.
  • coli SS320 with a logarithmic growth phase OD of about 0.8.
  • the OD was equal to 0.2, and when the OD reached 0.8, the 160 ⁇ L of helper phage was added, and then mixed at 37 ° C for 1 h; IPTG, kanamycin, 250 rpm, 30 ° C, Incubate overnight with shaking; collect the supernatant, pellet the phage with PEG/NaCl solution, resuspend in 1.5 ml of PBS buffer; resuspend Enrichment of cells for the next round of screening, after four panning, significant enrichment was observed.
  • the phage antibody clones obtained by panning were identified by ELISA: human IL17A protein (Beijing Yishen Shenzhou Biotechnology Co., Ltd., 12047-HNAS) was coated on a 96-well ELISA plate at a concentration of 1 ⁇ g/ml overnight at 4 °C. The non-specific binding sites were then blocked with 10% skim milk powder. After thorough washing, the monoclonal phage supernatant was added to a 96-well plate and incubated at 37 ° C for 2 hours.
  • human IL17A protein Beijing Yishen Shenzhou Biotechnology Co., Ltd., 12047-HNAS
  • Three phage antibody clones 1F10, 1B6, and 1F3 capable of specifically binding to human IL17A were obtained by ELISA.
  • the phage antibody clone 1F10 was redesigned into a complete IgG1, kappa antibody: the primers were designed to PCR-amplify the VH of the phage antibody, and the PCR product was recombinantly cloned into the pCMV-IgG1 NEM vector digested with AgeI and SalI; the primer pair phage was designed.
  • the VL of the antibody was subjected to PCR amplification, and the PCR product was recombinantly cloned into the pCMV- ⁇ vector double-digested with AgeI and BsiWI.
  • the heavy and light chain expression vectors were co-transfected into 293F cells for transient expression, and purified by ProteinA column.
  • the intact IgG1, ⁇ antibody of 1F10 was named YN-008.
  • the phage antibodies 1B6 and 1F3 were redesigned into intact IgG1, kappa antibodies, respectively, and expressed and purified.
  • the method of expression and purification was the same as that of 1F10.
  • the intact IgG1, kappa antibody of 1B6 was named YN-009; the intact IgG1, kappa antibody of 1F3 was named YN-010.
  • VH and VL sequences of YN-008, YN-009 and YN-010 were analyzed using the Kabat system for determining CDR regions to determine H-CDR1, H-CDR2 and H-CDR3 and L-CDR1, L-CDR2 and L- The amino acid sequence of CDR3.
  • amino acid sequences of LCDR1-3 of anti-IL17A fully human antibody YN-008 are shown in SEQ ID NO. 4, SEQ ID NO. 5 and SEQ ID NO. 6, respectively; the amino acid sequence of VL is SEQ ID NO.
  • the corresponding nucleotide sequence is shown in SEQ ID NO. 56; the amino acid sequence of the light chain is shown in SEQ ID NO. 64; the corresponding nucleotide sequence is shown in SEQ ID NO. 63;
  • the amino acid sequences of HCDR1-3 of YN-008 are shown in SEQ ID NO. 1, SEQ ID NO. 2 and SEQ ID NO. 3, respectively; the amino acid sequence of VH is shown in SEQ ID NO. 15; the corresponding nucleotide The sequence is set forth in SEQ ID NO. 55; the amino acid sequence of the heavy chain is set forth in SEQ ID NO. 62; the corresponding nucleotide sequence is set forth in SEQ ID NO.
  • the amino acid sequence of LCDR1-3 of anti-IL17A fully human antibody YN-009 is shown in SEQ ID NO. 22, SEQ ID NO. 23 and SEQ ID NO. 24, respectively; the amino acid sequence of VL is shown in SEQ ID NO.
  • the corresponding nucleotide sequence is shown in SEQ ID NO. 58; the amino acid sequence of the light chain is shown in SEQ ID NO. 68; the corresponding nucleotide sequence is shown in SEQ ID NO. 67; the antibody YN-009
  • the amino acid sequences of HCDR1-3 are shown in SEQ ID NO. 19, SEQ ID NO. 20 and SEQ ID NO. 21, respectively; the amino acid sequence of VH is shown in SEQ ID NO. 33; the corresponding nucleotide sequence is SEQ ID.
  • the amino acid sequence of the heavy chain is shown in SEQ ID NO. 66; the corresponding nucleotide sequence is shown in SEQ ID NO.
  • the amino acid sequence of LCDR1-3 of the anti-IL17A fully human antibody YN-010 is shown in SEQ ID NO. 40, SEQ ID NO. 41 and SEQ ID NO. 42, respectively; the amino acid sequence of VL is shown in SEQ ID NO.
  • the corresponding nucleotide sequence is shown in SEQ ID NO. 60; the amino acid sequence of the light chain is shown in SEQ ID NO. 72; the corresponding nucleotide sequence is shown in SEQ ID NO. 71; and the antibody YN-010
  • the amino acid sequences of HCDR1-3 are shown in SEQ ID NO. 37, SEQ ID NO. 38 and SEQ ID NO. 39, respectively; the amino acid sequence of VH is shown in SEQ ID NO. 51; the corresponding nucleotide sequence is SEQ ID.
  • the amino acid sequence of the heavy chain is shown in SEQ ID NO. 70; the corresponding nucleotide sequence is shown in SEQ ID NO.
  • Example 3 Germlined version of anti-IL17A full human antibody YN-008, YN-009, YN-010
  • YN-011 is a germlined version of YN-008 that returns three amino acids in the FR1 region of the YN-008 heavy chain variable region to a germline sequence, and the YN-008 light chain is The amino acid in the FR1 region of the variable region is restored to the germline sequence (see Fig. 1A).
  • the heavy chain expression vector of the anti-IL17A full human antibody YN-011 was obtained by site-directed mutagenesis using the mutation kit (Day Root Point Mutagenesis Kit, KM101) based on the heavy chain expression plasmid of YN-008 constructed above.
  • the YN-011 light chain expression vector was obtained by site-directed mutagenesis using a mutation kit (Day Root Point Mutagenesis Kit, KM101) based on the YN-008 light chain expression plasmid.
  • the nucleotide sequence is shown in SEQ ID NO. 77; the amino acid sequence of VH of YN-011 is shown in SEQ ID NO. 17; the corresponding nucleotide sequence is shown in SEQ ID NO. 73; the amino acid of heavy chain
  • the sequence is set forth in SEQ ID NO. 76; the corresponding nucleotide sequence is set forth in SEQ ID NO.
  • the method of expression and purification of the YN-011 antibody is referred to the YN-008 antibody.
  • YN-012 is a germlined version of YN-009, which returns two amino acids in the FR1 region of the YN-009 heavy chain variable region to a germline sequence, and the YN-009 light chain can be The amino acid in the FR2 region of the variable region was restored to the germline sequence (see Fig. 1B).
  • the heavy chain expression vector of the anti-IL17A fully human antibody YN-012 was obtained by site-directed mutagenesis using the mutation kit (Day Root Point Mutagenesis Kit, KM101) based on the heavy chain expression plasmid of YN-009 constructed above.
  • the YN-012 light chain expression vector was obtained by site-directed mutagenesis using a mutation kit (Day Root Point Mutagenesis Kit, KM101) based on the YN-009 light chain expression plasmid.
  • the method of expression and purification of the YN-012 antibody is referred to the YN-008 antibody.
  • YN-013 is a germlined version of YN-010 which returns a sequence of 1 amino acid in the FR1 region of the YN-010 heavy chain variable region and 1 amino acid in the FR3 region to a germline sequence. And preparing one amino acid in the FR1 region of the YN-010 light chain variable region, three amino acids in the FR2 region, and one amino acid in the FR3 region are returned to the germline sequence (see FIG. 1C).
  • the heavy chain expression vector of the anti-IL17A fully human antibody YN-013 was obtained by site-directed mutagenesis using the mutation kit (Day Root Point Mutagenesis Kit, KM101) based on the heavy chain expression plasmid of YN-010 constructed above.
  • the YN-013 light chain expression vector was obtained by site-directed mutagenesis using a mutation kit (Day Root Point Mutagenesis Kit, KM101) based on the YN-010 light chain expression plasmid.
  • the nucleotide sequence is shown in SEQ ID NO. 89; the amino acid sequence of VH of YN-013 is shown in SEQ ID NO. 53; the corresponding nucleotide sequence is shown in SEQ ID NO. 85; the amino acid of heavy chain
  • the sequence is set forth in SEQ ID NO. 88; the corresponding nucleotide sequence is set forth in SEQ ID NO.
  • the method of expression and purification of the YN-013 antibody is referred to the YN-008 antibody.
  • the binding affinities of the IL17 antibodies YN-008, YN-009, YN-010, YN-01, YN-012 and YN-013 against the recombinant human IL17A protein were measured by using an Octet RED384 instrument (Pall ForteBio). First, human IL17A protein was labeled with biotin (EZ-Link S ⁇ Lfo-NHS-LC-Biotin, Pierce, 21327).
  • the forebio octet RED384 instrument (PALL) molecular interaction analyzer was used to perform binding kinetic analysis between antigen and antibody by biofilm interference (BLI) technique (antigen and antibody dilution were both 0.1% BSA and 0.02% tween20 PBS). Buffer).
  • the biotin-conjugated antigen was incubated with a SA sensor at a concentration of 50 nM, 1500 rpm/min for 10 minutes; then combined with a double-diluted antibody solution (100 nM-0 nM) for 10 min, 1500 rpm/min. Finally, dissociation was carried out for 10 minutes at 1500 rpm/min. Residual antibodies will be regenerated by glycine pulse.
  • the obtained results will be analyzed by octet Data Analysis 9.0 software (fortebio) to calculate the binding strength of the antigen to the antibody, and obtain K D value, Ka (1/Ms) value and Kd (1/s) value (R2 value). >0.95 is a credible result).
  • Example 5 IL17 antibody inhibits binding between human IL17A protein and human IL17R
  • IL17 antibodies YN-008, YN-009, YN-010, YN-011, YN-02, YN-013 were evaluated using an Octet RED384 instrument (Pall ForteBio).
  • human IL17RA/Fc protein (Beijing Baipusis Biotechnology Co., Ltd., H5257) was labeled with biotin (EZ-Link S ⁇ Lfo-NHS-LC-Biotin, Pierce, 21327).
  • the binding kinetics of IL17 antibody inhibition between human IL17A protein and human IL17 receptor was performed by biofilm interference (BLI) technique using the fortebio octet RED384 instrument (PALL) molecular interaction analyzer (antigen and antibody dilution were used). 0.1% BSA and 0.02% tween20 in PBS buffer).
  • Biotin-conjugated recombinant human IL17RA was incubated with SA sensor at a concentration of 100 nM, 1500 rpm/min for 10 min; human IL17A protein at a final concentration of 100 nM was mixed with a three-fold diluted antibody solution (2000 nM-0 nM), incubating 60 After a minute, the machine was combined for 10 minutes at 1500 rpm/min. Finally, dissociation was carried out for 10 minutes at 1500 rpm/min. The residual antigen-antibody complex will be regenerated by pulsed glycine. The results obtained will be analyzed by octet Data Analysis 9.0 software (fortebio) to calculate the inhibitory intensity of the antibody against the antigen and ligand.
  • Fig. 2A-2C sequentially shows the results of IL17 antibody YN-011, YN-012, YN-013 inhibiting the binding of human IL17A protein and human IL17 receptor, and the abscissa is the concentration of the antibody (unit Log nM). The ordinate is the RU value.
  • the results in Figure 2 show that the IL17 antibodies YN-011, YN-012 and YN-013 are effective in inhibiting the binding of the human IL17A protein to the human IL17 receptor.
  • Example 6 IL17 antibody inhibits IL17A protein-induced chemokine CXCL1 production in HT-29 cells
  • HT-29 cells are human colorectal adenocarcinoma epithelial cells (Chinese Academy of Sciences Shanghai Cell Bank), which naturally express IL17 receptor. Incubation of HT-29 cells with human IL17A protein results in the production of the chemokine CXCL1, which can be detected using ELISA.
  • the abscissa is the concentration of the antibody and the ordinate is the concentration of CXCL1.
  • the results in Figure 3 show that IL17 antibodies YN-011, YN-012, and YN-013 are effective in inhibiting the production of the chemokine CXCL1 by HT-29 cells.
  • the IL-17F protein (product of ACRObiosystems) was diluted with PBS buffer (pH 7.2) to 2 ⁇ g/ml, 50 ⁇ L/well, and coated at 4 ° C overnight. After 5% skim milk was blocked at room temperature for 2 hours, different concentrations of each IL-17 antibody were added, 50 ⁇ L/well, and incubated for 2 hours at room temperature. The supernatant was discarded, washed 3 times with PBST, and HRP-labeled goat anti-human IgG monoclonal antibody (product of KPL) diluted with titer was added, 50 ⁇ L/well, and incubated at room temperature for 45 min.
  • PBS buffer pH 7.2
  • Example 8 Affinity maturation of IL-17 antibody YN013
  • the single-chain antibody (scFv) gene of IL-17 antibody YN-013 was constructed by overlapping PCR and cloned into pDF phagemid vector, which was designated as pDF-YN-013 scFv.
  • the degenerate primers were designed using pDF-YN-013scFv as a template.
  • the six CDR regions of antibody YN-013 (Fig. 1C) were randomized by overlapping PCR, respectively.
  • the scFv gene fragment randomized by the CDR region obtained by overlapping PCR was digested with BssHII and NheI, and ligated with the pDF phagemid vector digested with BssHII and NheI, and electroporated 1 ⁇ g of the ligation product into TG1 electroporation.
  • the mixture was diluted and coated with 2YT+AG plate. The next day, the lawn was scraped from the plate, expanded to 300ml 2YT+Amp medium, and cultured at 37°C until about OD 0.8. After mixing with helper phage, it was allowed to stand.
  • kanamycin at a final concentration of 1 mM IPTG, 50 ⁇ g/ml was added and shaken overnight at 30 °C. The next day, the supernatant was centrifuged, 0.45 filter membrane was sterilized, 1/5 volume of PEG-NaCl was added to precipitate phage, the pellet was centrifuged, and the pellet was resuspended in 1/10 volume of PBS.
  • the phage pfu was calculated by OD260 and stored at 4 ° C.
  • the phage antibody library can be directly used for post-panning.
  • the recombinant human IL17A protein (Beijing Yiqiao Shenzhou Biotechnology Co., Ltd.) was used as an antigen for sorting the above phage antibody library.
  • 1 ml of antigen was coated with CBS buffer, the antigen concentration was 100 nM (first round, second round) or 5 nM (third round), overnight at 4 ° C; the next day with 10% skim milk powder in PBS buffer 2 ml closed immunotube; 1 ml of blocked phage was added to the immunotube, incubated for 1 h at room temperature; washed 20 times (first round), 50 times (second round) or 100 times (third round) with PBST; .2 Gly-HCl buffer 800 ⁇ l elution, immediately add 400 ⁇ l of pH 8.0 Tris-HCl buffer to neutralize; add to 20 ml of logarithmic growth phase OD about 0.8 E.coli TG1, mix 37 ° C static Set 1h; take 500 ⁇ l to
  • the phage antibody clones obtained by panning were identified by ELISA: human IL17A protein was coated on a 96-well ELISA plate at a concentration of 1 ⁇ g/ml overnight at 4 °C. The non-specific binding sites were then blocked with 10% skim milk powder. After thorough washing, the monoclonal phage supernatant was added to a 96-well plate and incubated at 37 ° C for 2 hours. After sufficient washing, HRP-labeled anti-M13 antibody (GE healtcare, 27-9421-01) was added, and the reaction was carried out at 37 ° C for 45 min. After thorough washing, TMB was added for color development.
  • HRP-labeled anti-M13 antibody GE healtcare, 27-9421-01
  • each phage antibody was redesigned into a full-length IgG1, kappa antibody: designed primers to PCR-amplify the VH of each phage antibody clone, and the PCR product was cloned by recombinant
  • the pCMV-IgG1 NDL antibody heavy chain expression vector was digested with AgeI and SalI; the primers were designed to PCR-amplify the VL of each phage antibody clone, and the PCR product was recombinantly cloned into pCMV-digested with AgeI and BsiWI.
  • ⁇ antibody light chain expression vector After sequencing, the heavy and light chain expression vectors of each antibody were co-transfected into 293F cells for transient expression. After 7 days of culture in serum-free medium, the cell culture supernatant was collected and purified by ProteinA column to obtain antibody protein. The purified antibody was purified by PBS. Dialysis was performed and finally quantified using the BCA Protein Assay Kit (Pierce, 23225).
  • the binding affinity of the IL17 antibody to the recombinant human IL17A protein was measured by using an Octet RED384 instrument (Pall ForteBio).
  • human IL17A-Fc protein (Shanghai Yuanneng Cell Medical Technology Co., Ltd.) was labeled with biotin (EZ-Link S ⁇ Lfo-NHS-LC-Biotin, Pierce, 21327).
  • the forebio octet RED384 instrument (PALL) molecular interaction analyzer was used to perform binding kinetic analysis between antigen and antibody by biofilm interference (BLI) technique (antigen and antibody dilutions were both 0.1% BSA and 0.02% tween20 in PBS). Buffer).
  • the biotin-conjugated antigen was fixed at 50 nM with a SA sensor, 1500 rpm/min for 5 minutes; then combined with a double-diluted antibody solution (100, 50, 25, 12.5, 6.25, 3.125, 1.56 nM) for 5 min. , 1500 rpm / min. Finally, dissociation was carried out for 10 minutes at 1500 rpm/min. The results obtained were analyzed by Octet Data Analysis 9.0 software (Pall ForteBio) to obtain K D values, K on (1/Ms) values and K off (1/s) values. After multiple rounds of screening and combination, the two YN-013 antibody mutant clones with the highest affinity were named YN-065 antibody and YN-066 antibody, respectively.
  • the affinities obtained by the above two methods by the above methods are shown in Table 2. Affinity data showed that the affinities of YN-065 and YN-066 were 14 and 12 times, respectively, of secukinumab.
  • amino acid sequence of the VL of the YN-065 antibody is shown in SEQ ID NO. 103
  • amino acid sequence of the light chain is shown in SEQ ID NO. 104
  • amino acid sequence of the VH of the YN-065 antibody is shown in SEQ ID NO.
  • amino acid sequence of the heavy chain is set forth in SEQ ID NO. 106;
  • amino acid sequence of the VL of the YN-066 antibody is shown in SEQ ID NO. 103
  • amino acid sequence of the light chain is shown in SEQ ID NO. 104
  • amino acid sequence of the VH of the YN-066 antibody is shown in SEQ ID NO.
  • amino acid sequence of the heavy chain is set forth in SEQ ID NO.
  • the single-chain antibody (scFv) gene of IL-17 antibody YN-011 was constructed by overlapping PCR and cloned into pDF phagemid vector, which was designated as pDF-YN-011 scFv. Primers were designed using pDF-YN-011 scFv as a template. The scFv sequences were randomized by a random mutagenesis kit (Agilent, Cat. 200552).
  • the randomized scFv gene fragment was digested with BssHII and NheI, and ligated with the pDF phagemid vector digested with BssHII and NheI, and electroporated 1 ⁇ g of the ligation product into TG1 electroporation competent cells. After dilution, apply 2YT+AG plate, scrape the lawn from the plate the next day, expand to 300ml 2YT+Amp medium, incubate to OD 0.8 at 37°C, mix with helper phage, let stand for 1 hour, add final concentration. For 1 mM IPTG, 50 ⁇ g/ml kanamycin was shaken overnight at 30 °C.
  • phage antibody library can be directly used for post-panning.
  • the recombinant human IL17A protein (Beijing Yiqiao Shenzhou Biotechnology Co., Ltd.) was used as an antigen for sorting the above phage antibody library.
  • 1 ml of antigen was coated with CBS buffer, the antigen concentration was 100 nM (first round, second round) or 5 nM (third round), overnight at 4 ° C; the next day with 10% skim milk powder in PBS buffer 2 ml closed immunotube; 1 ml of blocked phage was added to the immunotube, incubated for 1 h at room temperature; washed 20 times (first round), 50 times (second round) or 100 times (third round) with PBST; .2 Gly-HCl buffer 800 ⁇ l elution, immediately add 400 ⁇ l of pH 8.0 Tris-HCl buffer to neutralize; add to 20 ml of logarithmic growth phase OD about 0.8 E.coli TG1, mix 37 ° C static Set 1h; take 500 ⁇ l to
  • the phage antibody clones obtained by panning were identified by ELISA: human IL17A protein was coated on a 96-well ELISA plate at a concentration of 1 ⁇ g/ml overnight at 4 °C. The non-specific binding sites were then blocked with 10% skim milk powder. After thorough washing, the monoclonal phage supernatant was added to a 96-well plate and incubated at 37 ° C for 2 hours. After sufficient washing, HRP-labeled anti-M13 antibody (GE healtcare, 27-9421-01) was added, and the reaction was carried out at 37 ° C for 45 min. After thorough washing, TMB was added for color development. After 5-10 min at room temperature, the reaction was terminated with sulfuric acid.
  • HRP-labeled anti-M13 antibody GE healtcare, 27-9421-01
  • each well was measured at 450 nm, and a phage antibody clone having a high OD450 value was selected for sequencing.
  • a phage antibody clone having a high OD450 value was selected for sequencing.
  • we redesigned each phage antibody into a Fab fragment designed primers for PCR amplification of VH of phage antibody clones and anti-weight chain expression vector pCMV-IgG1NDL
  • the first antibody heavy chain constant region was subjected to PCR amplification, and the VHCH1 gene fragment was constructed by overlapping PCR and cloned into the pCMV-IgG1 NDL antibody heavy chain expression vector by double digestion with AgeI and BamH1; primers were designed for each phage.
  • the VL of the antibody clone was subjected to PCR amplification, and the PCR product was recombinantly cloned into the pCMV- ⁇ antibody light chain expression vector double-digested with AgeI and BsiWI. After sequencing, the heavy and light chain expression vectors of each Fab fragment were co-transfected into 293F cells for transient expression. After 7 days of culture in serum-free medium, the cell culture supernatant was collected and purified by Protein G column to obtain antibody protein. Dialysis was performed in PBS and finally quantified using the BCA Protein Assay Kit (Pierce, 23225).
  • the binding affinity of the IL17 antibody Fab fragment to the recombinant human IL17A protein was measured by an Octet RED384 instrument (Pall ForteBio).
  • human IL17A-Fc protein (Shanghai Yuanneng Cell Medical Technology Co., Ltd.) was labeled with biotin (EZ-Link S ⁇ Lfo-NHS-LC-Biotin, Pierce, 21327).
  • biotin EZ-Link S ⁇ Lfo-NHS-LC-Biotin, Pierce, 21327.
  • the forebio octet RED384 instrument (PALL) molecular interaction analyzer was used to perform binding kinetic analysis between antigen and antibody by biofilm interference (BLI) technique (antigen and antibody dilution were both 0.1% BSA and 0.02% tween20 PBS). Buffer).
  • the biotin-conjugated antigen was fixed at 50 nM with a SA sensor, 1500 rpm/min for 5 minutes; then combined with a double-diluted antibody solution (100, 50, 25, 12.5, 6.25, 3.125, 1.56 nM) for 5 min. , 1500 rpm / min. Finally, dissociation was carried out for 10 minutes at 1500 rpm/min. The obtained results were analyzed by octet Data Analysis 9.0 software (fortebio) to calculate the binding strength of the antigen to the antibody, and the K D value, the Ka (1/Ms) value, and the Kd (1/s) value were obtained.
  • the four YN-011 antibody mutant Fabs with the highest affinity were named YN-067Fab, YN-068Fab, YN-069Fab, and YN-070Fab, respectively.
  • the affinity values of the four Fab fragments determined by the above method are shown in Table 3.
  • the light chain amino acid sequence of YN-067 Fab is set forth in SEQ ID NO. 110; the heavy chain amino acid sequence of the YN-067 Fab antibody is set forth in SEQ ID NO.
  • the light chain amino acid sequence of YN-068 Fab is set forth in SEQ ID NO. 110; the heavy chain amino acid sequence of the YN-068 Fab antibody is set forth in SEQ ID NO.
  • the light chain amino acid sequence of YN-069 Fab is set forth in SEQ ID NO. 110; the heavy chain amino acid sequence of the YN-069 Fab antibody is set forth in SEQ ID NO.
  • the light chain amino acid sequence of YN-070 Fab is set forth in SEQ ID NO. 110; the heavy chain amino acid sequence of the YN-070 Fab antibody is set forth in SEQ ID NO.
  • the method of redesigning phage antibody into full-length IgG1, ⁇ antibody is as follows: Primer is designed to PCR-amplify VH of each phage antibody clone, and the PCR product is recombinantly cloned into pCMV-IgG1NDL antibody heavy chain double-digested with AgeI and SalI. Expression vector; primers were designed for PCR amplification of VL of each phage antibody clone, and the PCR product was recombinantly cloned into the pCMV- ⁇ antibody light chain expression vector double-digested with AgeI and BsiWI.
  • the heavy and light chain expression vectors of each antibody were co-transfected into 293F cells for transient expression. After 7 days of culture in serum-free medium, the cell culture supernatant was collected and purified by Protein A column to obtain antibody protein. The purified antibody was used in PBS. Dialysis was performed and finally quantified using the BCA Protein Assay Kit (Pierce, 23225).
  • the full-length IgG1 and ⁇ antibodies corresponding to YN-067-Fab, YN-068-Fab, YN-069-Fab, and YN-070-Fab were named YN-067, YN-068, YN-069, and YN-070, respectively. .
  • amino acid sequence of the VL of the YN-067 antibody is shown in SEQ ID NO. 109
  • amino acid sequence of the light chain is shown in SEQ ID NO. 110
  • amino acid sequence of the VH of the YN-067 antibody is shown in SEQ ID NO.
  • amino acid sequence of the heavy chain is set forth in SEQ ID NO.
  • the amino acid sequence of VL of YN-068 antibody is shown in SEQ ID NO. 109
  • the amino acid sequence of light chain is shown in SEQ ID NO. 110
  • the amino acid sequence of VH of YN-068 antibody is shown in SEQ ID NO.
  • the amino acid sequence of the heavy chain is set forth in SEQ ID NO.
  • amino acid sequence of the VL of the YN-069 antibody is shown in SEQ ID NO. 109
  • amino acid sequence of the light chain is shown in SEQ ID NO. 110
  • amino acid sequence of the VH of the YN-069 antibody is shown in SEQ ID NO.
  • amino acid sequence of the heavy chain is set forth in SEQ ID NO.
  • amino acid sequence of the VL of the YN-070 antibody is shown in SEQ ID NO. 109
  • amino acid sequence of the light chain is shown in SEQ ID NO. 110
  • amino acid sequence of the VH of the YN-070 antibody is shown in SEQ ID NO.
  • amino acid sequence of the heavy chain is set forth in SEQ ID NO.
  • Example 10 IL17 antibody inhibits binding between human IL17A protein and human IL17R
  • IL17 antibodies YN-065, YN-066, YN-067, YN-068, YN-069, YN-070 were assessed using an Octet RED384 instrument (Pall ForteBio).
  • human IL17RA/Fc protein (Beijing Baipusis Biotechnology Co., Ltd., H5257) was labeled with biotin (EZ-Link S ⁇ Lfo-NHS-LC-Biotin, Pierce, 21327).
  • Biotin-conjugated recombinant human IL17RA was incubated with a SA sensor at a concentration of 100 nM, 1500 rpm/min for 10 min; a final concentration of 50 nM human IL17A protein and a four-fold diluted antibody solution (1000, 250, 62.5, 15.625, Mix 3.9, 0.97, 0 nM), incubate for 60 minutes and then combine with the machine for 10 minutes at 1500 rpm/min. Finally, dissociation was carried out for 1 minute at 1500 rpm/min. The results obtained will be analyzed by octet Data Analysis 9.0 software (fortebio) to calculate the inhibitory intensity of the antibody against the antigen and ligand.
  • Figure 5 shows the results of IL17 antibody YN-065, YN-066, YN-067, YN-068, YN-069, YN070 inhibiting the binding of human IL17A protein and human IL17 receptor.
  • the abscissa is the concentration of the antibody, and the ordinate is RU value.
  • the results in Figure 5 show that the IL17 antibodies YN-065, YN-066, YN-067, YN-068, YN-069, and YN070 are effective in inhibiting the binding of the human IL17A protein to the human IL17 receptor.
  • Example 11 IL17 antibody inhibits IL17A protein-induced chemokine CXCL1 production in HT-29 cells
  • HT-29 cells are human colorectal adenocarcinoma epithelial cells (Chinese Academy of Sciences Shanghai Cell Bank), which naturally express IL17 receptor. Incubation of HT-29 cells with human IL17A protein results in the production of the chemokine CXCL1, which can be detected using ELISA.
  • the abscissa is the concentration of the antibody and the ordinate is the concentration of CXCL1.
  • the results of Fig. 6A and Fig. 6B show that the IL17 antibodies YN-065, YN-066, YN-067, and YN-068 can effectively inhibit the production of the chemokine CXCL1 by HT-29 cells, and their inhibitory ability is significantly stronger than that of Secukinumab.
  • the results in Figure 6C show that YN069 and YN070 inhibit HT-29 cells from producing CXCL1 with a similar ability to YN068.
  • Example 12 IL17 antibody inhibits IL17A protein-induced IL-27 production of interleukin-8 (IL-8)
  • IL-17 induces secretion of IL-8 by human HS-27 cells (ATCC #CRL-1634), which can be detected using ELISA.
  • the abscissa is the concentration of the antibody and the ordinate is the concentration of IL-8.
  • the results of Fig. 7A and Fig. 7B show that the IL17 antibodies YN-065, YN-066, YN-067, and YN-068 can effectively inhibit the production of IL-8 by HS-27 cells, and their inhibitory ability is significantly stronger than that of Secukinumab, Fig. 7C.
  • the results showed that YN069 and YN070 inhibited the production of IL-8 by HS-27 cells similarly to YN068.

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Abstract

The present application provides an antibody and an antigen-binding fragment thereof. The antibody is bound to an IL17 protein in a K D value less than 6×10 -9M. The antibody and the antigen-binding fragment thereof have a strong binding ability to specific identification of the IL17 protein, and can inhibit binding of the IL17 protein and an IL17 receptor and/or inhibits immune cells from secreting cytokines. The present application further provides use of the antibody and the antigen-binding fragment thereof in treating or preventing diseases related to improper or excessive production of IL17.

Description

IL17抗体及其应用IL17 antibody and its application 技术领域Technical field

本申请涉及生物医药领域，具体涉及一种IL17抗体及其应用。The present application relates to the field of biomedicine, and in particular to an IL17 antibody and use thereof.

背景技术Background technique

白介素17(IL17)，亦称CTLA-8，是由T细胞产生的促炎细胞因子，可刺激各种非免疫细胞分泌各种各样的其他细胞因子。IL17主要由活化记忆T细胞产生并通过与遍布的细胞表面受体(IL17R)结合而发挥作用(Yao等，Cytokine，9，794-800(1997))。Interleukin-17 (IL17), also known as CTLA-8, is a pro-inflammatory cytokine produced by T cells that stimulates various non-immune cells to secrete a variety of other cytokines. IL17 is mainly produced by activated memory T cells and functions by binding to a cell surface receptor (IL17R) that is spread throughout (Yao et al, Cytokine, 9, 794-800 (1997)).

IL17作为促炎细胞因子，其不当或过度的产生会导致多种疾病。例如，类风湿性关节炎(Witowski等，Cell Mol Life Sci，61：567-579(2004))、骨关节炎、骨植入物松动、急性移植排斥(Antonysamy等，J Immunol162，577-584(1999)；van Kooten等，J Am Soc Nephrol 9，1526-1534(1998))、败血症、败血症性或内毒素性休克、变态反应、哮喘(Molet等，JAllergy Clin Immunol 108，430-438(2001))、骨丢失、银屑病(Teunissen等，J.Invest Dermatol 111，645-649(1998))、局部缺血、系统性硬化症(Kurasawa等，Arthritis Rheum 43，2455-2463(2000))、中风和其他炎性病症。IL17 acts as a pro-inflammatory cytokine, and its inappropriate or excessive production can lead to a variety of diseases. For example, rheumatoid arthritis (Witowski et al, Cell Mol Life Sci, 61: 567-579 (2004)), osteoarthritis, bone implant loosening, acute graft rejection (Antonysamy et al, J Immunol 162, 577-584 ( 1999); van Kooten et al, J Am Soc Nephrol 9, 1526-1534 (1998)), sepsis, septic or endotoxic shock, allergy, asthma (Molet et al, J Allergy Clin Immunol 108, 430-438 (2001) ), bone loss, psoriasis (Teunissen et al, J. Invest Dermatol 111, 645-649 (1998)), ischemia, systemic sclerosis (Kurasawa et al, Arthritis Rheum 43, 2455-2463 (2000)), Stroke and other inflammatory conditions.

已有研究显示，靶向IL-17的抗体(例如，secukinumab、Ixekizumab)可用于预防和/或治疗银屑病(例如，斑块状银屑病)、银屑病关节炎、强直性脊柱炎等与IL17的不当或过度产生相关的疾病或病症。然而，仍然需要对IL17蛋白特异性识别结合能力强、可抑制IL17蛋白与IL17受体的结合和/或抑制免疫细胞分泌细胞因子的新型抗IL17抗体。Studies have shown that antibodies targeting IL-17 (eg, secukinumab, Ixekizumab) can be used to prevent and/or treat psoriasis (eg, plaque psoriasis), psoriatic arthritis, ankylosing spondylitis A disease or condition associated with inappropriate or overproduction of IL17. However, there is still a need for novel anti-IL17 antibodies that specifically recognize and bind to the IL17 protein, inhibit the binding of the IL17 protein to the IL17 receptor, and/or inhibit the secretion of cytokines by immune cells.

发明内容Summary of the invention

本申请提供了一种IL17抗体、其抗原结合片段，其具有下列性质中的一种或多种：1)能够以较高的亲和力和特异性结合IL17蛋白；2)能够抑制IL17蛋白与IL17受体的结合，如IL17A蛋白或IL17F蛋白；3)能够抑制细胞因子，尤其是趋化因子(例如CXCL1)的表达；和4)能够用于治疗自身免疫疾病。本申请还提供所述IL17抗体、其抗原结合片段的制备方法和应用。The present application provides an IL17 antibody, an antigen-binding fragment thereof, which has one or more of the following properties: 1) capable of binding IL17 protein with high affinity and specificity; 2) inhibiting IL17 protein and IL17 receptor Binding, such as IL17A protein or IL17F protein; 3) inhibiting the expression of cytokines, especially chemokines (such as CXCL1); and 4) can be used to treat autoimmune diseases. The present application also provides methods and uses for the preparation of the IL17 antibody, antigen-binding fragment thereof.

一方面，本申请提供了一种抗体或其抗原结合片段，其以6×10 -9M或更低的K D值与IL17蛋白相结合。 In one aspect, the present application provides an antibody or antigen-binding fragment thereof, which combine to 6 × 10 -9 M or less and a K D value of IL17 protein.

在某些实施方式中，所述的抗体或其抗原结合片段其抑制IL17蛋白与IL17受体的结合。In certain embodiments, the antibody or antigen-binding fragment thereof inhibits binding of an IL17 protein to an IL17 receptor.

在某些实施方式中，所述的抗体或其抗原结合片段，其抑制细胞因子的表达。In certain embodiments, the antibody or antigen-binding fragment thereof, which inhibits expression of a cytokine.

在某些实施方式中，所述的抗体或其抗原结合片段，所述细胞因子包括：白介素和趋化因子。In certain embodiments, the antibody or antigen-binding fragment thereof, the cytokine comprising: an interleukin and a chemokine.

在某些实施方式中，所述的抗体或其抗原结合片段，所述趋化因子包括：CXCL1。In certain embodiments, the antibody or antigen-binding fragment thereof, the chemokine comprising: CXCL1.

在某些实施方式中，所述的抗体或其抗原结合片段，其可缓解或治疗与IL17的不当或过度产生相关的疾病或病症。在某些实施方式中，所述疾病或病症包括：强直性脊柱炎、银屑病关节炎、类风湿性关节炎、骨关节炎、骨植入物松动、急性移植排斥、呼吸道炎症、炎性肠病、败血症、败血症性或内毒素性休克、骨丢失、银屑病、变态反应、局部缺血、系统性硬化症、中风和哮喘。In certain embodiments, the antibody or antigen-binding fragment thereof, which ameliorates or treats a disease or condition associated with inappropriate or overproduction of IL17. In certain embodiments, the disease or condition comprises: ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, osteoarthritis, bone implant loosening, acute graft rejection, respiratory inflammation, inflammatory Enteropathy, sepsis, septic or endotoxic shock, bone loss, psoriasis, allergy, ischemia, systemic sclerosis, stroke and asthma.

在某些实施方式中，所述的抗体或其抗原结合片段，所述抗体包括：单克隆抗体、单链抗体、嵌合抗体、人源化抗体和/或全人源抗体。In certain embodiments, the antibody or antigen-binding fragment thereof, the antibody comprises: a monoclonal antibody, a single chain antibody, a chimeric antibody, a humanized antibody, and/or a fully human antibody.

在某些实施方式中，所述的抗体或其抗原结合片段，所述抗原结合片段包括：Fab，Fab’，F(ab)2、Fv片段、F(ab’)2，scFv，di-scFv和/或VhH。In certain embodiments, the antibody or antigen-binding fragment thereof, comprising: Fab, Fab', F(ab)2, Fv fragment, F(ab')2, scFv, di-scFv And / or VhH.

在某些实施方式中，所述的抗体或其抗原结合片段，其与参比抗体竞争结合所述IL17蛋白，其中所述参比抗体包含轻链可变区和重链可变区，所述参比抗体的轻链可变区包含LCDR1、LCDR2和LCDR3，所述LCDR1包含下述任一项所示的氨基酸序列：SEQ ID NO:126、SEQ ID NO:22和SEQ ID NO:40；所述LCDR2包含下述任一项所示的氨基酸序列：SEQ ID NO:5、SEQ ID NO:23和SEQ ID NO:41；以及，所述LCDR3包含下述任一项所示的氨基酸序列：SEQ ID NO:6、SEQ ID NO:24和SEQ ID NO:131；且，所述参比抗体的重链可变区包含HCDR1、HCDR2和HCDR3，所述HCDR1包含下述任一项所示的氨基酸序列：SEQ ID NO:123、SEQ ID NO:19和SEQ ID NO:37；所述HCDR2包含下述任一项所示的氨基酸序列：SEQ ID NO:124、SEQ ID NO:20和SEQ ID NO:38；以及，所述HCDR3包含下述任一项所示的氨基酸序列：SEQ ID NO:125、SEQ ID NO:21和SEQ ID NO:130。In certain embodiments, the antibody or antigen-binding fragment thereof, which competes with a reference antibody for binding to the IL17 protein, wherein the reference antibody comprises a light chain variable region and a heavy chain variable region, The light chain variable region of the reference antibody comprises LCDR1, LCDR2 and LCDR3, the LCDR1 comprising the amino acid sequence set forth in any one of the following: SEQ ID NO: 126, SEQ ID NO: 22, and SEQ ID NO: 40; The LCDR2 includes the amino acid sequence shown in any one of the following: SEQ ID NO: 5, SEQ ID NO: 23, and SEQ ID NO: 41; and the LCDR3 comprises the amino acid sequence shown in any one of the following: SEQ ID NO: 6, SEQ ID NO: 24 and SEQ ID NO: 131; and the heavy chain variable region of the reference antibody comprises HCDR1, HCDR2 and HCDR3, and the HCDR1 comprises an amino acid represented by any one of the following SEQ ID NO: 123, SEQ ID NO: 19 and SEQ ID NO: 37; the HCDR2 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 124, SEQ ID NO: 20 and SEQ ID NO And the HCDR3 comprises the amino acid sequence shown in any one of the following: SEQ ID NO: 125, SEQ ID NO: 21, and SEQ ID NO: 13. 0.

在某些实施方式中，所述参比抗体的LCDR1包含下述任一项所示的氨基酸序列：SEQ ID NO:4和SEQ ID NO:96。在某些实施方式中，所述参比抗体的LCDR3包含下述任一项所示的氨基酸序列：SEQ ID NO:42和SEQ ID NO:102。In certain embodiments, the LCDR1 of the reference antibody comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 4 and SEQ ID NO: 96. In certain embodiments, the LCDR3 of the reference antibody comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 42 and SEQ ID NO: 102.

在某些实施方式中，所述参比抗体的HCDR1包含下述任一项所示的氨基酸序列：SEQ ID NO:1、SEQ ID NO:91和SEQ ID NO:92。在某些实施方式中，所述参比抗体的HCDR2包含下述任一项所示的氨基酸序列：SEQ ID NO:2和SEQ ID NO:93；在某些实施方式中，所述参比抗体的HCDR3包含下述任一项所示的氨基酸序列：SEQ ID NO:3、SEQ ID NO:94、SEQ ID NO:95、SEQ ID NO:39、SEQ ID NO:100和SEQ ID NO:101。In certain embodiments, the HCDR1 of the reference antibody comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 1, SEQ ID NO: 91, and SEQ ID NO: 92. In certain embodiments, the HCDR2 of the reference antibody comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 2 and SEQ ID NO: 93; in certain embodiments, the reference antibody The HCDR3 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO:3, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:39, SEQ ID NO:100, and SEQ ID NO:101.

在某些实施方式中，所述参比抗体的轻链可变区包含下述任一项所示的氨基酸序列：SEQ ID NO:16、SEQ ID NO:134、SEQ ID NO:34、SEQ ID NO:36、SEQ ID NO:52和SEQ ID NO:132；且，所述参比抗体的重链可变区包含下述任一项所示的氨基酸序列：SEQ ID NO:15、SEQ ID NO:135、SEQ ID NO:33、SEQ ID NO:35、SEQ ID NO:51和SEQ ID NO:133。In certain embodiments, the light chain variable region of the reference antibody comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 16, SEQ ID NO: 134, SEQ ID NO: 34, SEQ ID And the SEQ ID NO: 52 and : 135, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 51 and SEQ ID NO: 133.

在某些实施方式中，所述参比抗体的轻链可变区包含下述任一项所示的氨基酸序列：SEQ ID NO:54、SEQ ID NO:103、SEQ ID NO:18和SEQ ID NO:109。In certain embodiments, the light chain variable region of the reference antibody comprises the amino acid sequence set forth in any one of the following: SEQ ID NO:54, SEQ ID NO:103, SEQ ID NO:18, and SEQ ID NO: 109.

在某些实施方式中，所述参比抗体的重链可变区包含下述任一项所示的氨基酸序列：SEQ ID NO:53、SEQ ID NO:105、SEQ ID NO:107、SEQ ID NO:17、SEQ ID NO:111、SEQ ID NO:114、SEQ ID NO:117和SEQ ID NO:120。And a SEQ ID NO: 105 NO: 17, SEQ ID NO: 111, SEQ ID NO: 114, SEQ ID NO: 117, and SEQ ID NO: 120.

在某些实施方式中，所述参比抗体的轻链包含下述任一项所示的氨基酸序列：SEQ ID NO:64、SEQ ID NO:68、SEQ ID NO:72、SEQ ID NO:138、SEQ ID NO:84和SEQ ID NO:136；且，所述参比抗体的重链包含下述任一项所示的氨基酸序列：SEQ ID NO:62、SEQ ID NO:66、SEQ ID NO:70、SEQ ID NO:139、SEQ ID NO:82和SEQ ID NO:137。In certain embodiments, the light chain of the reference antibody comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 64, SEQ ID NO: 68, SEQ ID NO: 72, SEQ ID NO: 138 SEQ ID NO: 84 and SEQ ID NO: 136; and the heavy chain of the reference antibody comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 62, SEQ ID NO: 66, SEQ ID NO :70, SEQ ID NO: 139, SEQ ID NO: 82 and SEQ ID NO: 137.

在某些实施方式中，所述参比抗体的轻链包含下述任一项所示的氨基酸序列：SEQ ID NO:90、SEQ ID NO:104、SEQ ID NO:78和SEQ ID NO:110。在某些实施方式中，所述参比抗体的重链包含下述任一项所示的氨基酸序列：SEQ ID NO:88、SEQ ID NO:106、SEQ ID NO:108、SEQ ID NO:76、SEQ ID NO:112、SEQ ID NO:115、SEQ ID NO:118和SEQ ID NO:121。In certain embodiments, the light chain of the reference antibody comprises the amino acid sequence set forth in any one of the following: SEQ ID NO:90, SEQ ID NO:104, SEQ ID NO:78, and SEQ ID NO:110 . In certain embodiments, the heavy chain of the reference antibody comprises the amino acid sequence set forth in any one of the following: SEQ ID NO:88, SEQ ID NO:106, SEQ ID NO:108, SEQ ID NO:76 SEQ ID NO: 112, SEQ ID NO: 115, SEQ ID NO: 118, and SEQ ID NO: 121.

在某些实施方式中，所述抗体包含抗体轻链或其片段包含LCDR1，且所述LCDR1包含下述任一项所示的氨基酸序列：SEQ ID NO:126、SEQ ID NO:22和SEQ ID NO:40。In certain embodiments, the antibody comprises an antibody light chain or a fragment thereof comprising LCDR1, and the LCDR1 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO:126, SEQ ID NO:22, and SEQ ID NO: 40.

在某些实施方式中，所述的抗体或其抗原结合片段中所述LCDR1的氨基酸序列包含下述任一项所示的氨基酸序列：SEQ ID NO:4和SEQ ID NO:96。在某些实施方式中，所述抗体轻链或其片段包含LCDR2，且所述LCDR2包含下述任一项所示的氨基酸序列：SEQ ID NO:5、SEQ ID NO:23和SEQ ID NO:41。在某些实施方式中，所述抗体轻链或其片段包含LCDR3，且所述LCDR3包含下述任一项所示的氨基酸序列：SEQ ID NO:6、SEQ ID NO:24和SEQ ID NO:131。In certain embodiments, the amino acid sequence of the LCDR1 in the antibody or antigen-binding fragment thereof comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 4 and SEQ ID NO: 96. In certain embodiments, the antibody light chain or fragment thereof comprises LCDR2, and the LCDR2 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 5, SEQ ID NO: 23, and SEQ ID NO: 41. In certain embodiments, the antibody light chain or fragment thereof comprises LCDR3, and the LCDR3 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 6, SEQ ID NO: 24, and SEQ ID NO: 131.

在某些实施方式中，所述LCDR3包含下述任一项所示的氨基酸序列：SEQ ID NO:42和SEQ ID NO:102。In certain embodiments, the LCDR3 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 42 and SEQ ID NO: 102.

在某些实施方式中，所述抗体轻链或其片段还包括框架区L-FR1、L-FR2、L-FR3和L-FR4。在某些实施方式中，所述框架区L-FR1、L-FR2、L-FR3和L-FR4选自以下组中任一项：人共有框架序列和人种系序列。In certain embodiments, the antibody light chain or fragment thereof further comprises framework regions L-FR1, L-FR2, L-FR3, and L-FR4. In certain embodiments, the framework regions L-FR1, L-FR2, L-FR3, and L-FR4 are selected from any of the group consisting of human consensus framework sequences and human germline sequences.

在某些实施方式中，所述L-FR1的C末端与所述LCDR1的N末端直接或间接相连，所述L-FR1包含下述任一项所示的氨基酸序列：SEQ ID NO:127、SEQ ID NO:29和SEQ ID NO:47。In certain embodiments, the C-terminus of the L-FR1 is directly or indirectly linked to the N-terminus of the LCDR1, the L-FR1 comprising the amino acid sequence set forth in any one of the following: SEQ ID NO:127, SEQ ID NO:29 and SEQ ID NO:47.

在某些实施方式中，所述L-FR1包含下述任一项所示的氨基酸序列：SEQ ID NO:11和SEQ ID NO:97。在某些实施方式中，所述L-FR2位于所述LCDR1与所述LCDR2之间，所述L-FR2包含下述任一项所示的氨基酸序列：SEQ ID NO:128、SEQ ID NO:30和SEQ ID NO:48。在某些实施方式中，所述L-FR2包含下述任一项所示的氨基酸序列：SEQ ID NO:12和SEQ ID NO:98。在某些实施方式中，所述L-FR3位于所述LCDR2与所述LCDR3之间，所述L-FR3包含下述任一项所示的氨基酸序列：SEQ ID NO:13、SEQ ID NO:31和SEQ ID NO:49。在某些实施方式中，所述L-FR4的N末端与所述LCDR3的C末端直接或间接相连，所述L-FR4包含下述任一项所示的氨基酸序列：SEQ ID NO:14、SEQ ID NO:32和SEQ ID NO:50。In certain embodiments, the L-FR1 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 11 and SEQ ID NO: 97. In certain embodiments, the L-FR2 is located between the LCDR1 and the LCDR2, and the L-FR2 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 128, SEQ ID NO: 30 and SEQ ID NO:48. In certain embodiments, the L-FR2 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 12 and SEQ ID NO: 98. In certain embodiments, the L-FR3 is located between the LCDR2 and the LCDR3, and the L-FR3 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 13, SEQ ID NO: 31 and SEQ ID NO:49. In certain embodiments, the N-terminus of the L-FR4 is directly or indirectly linked to the C-terminus of the LCDR3, and the L-FR4 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 14. SEQ ID NO:32 and SEQ ID NO:50.

在某些实施方式中，所述抗体轻链或其片段包含轻链可变区VL，且所述轻链可变区VL包含下述任一项所示的氨基酸序列：SEQ ID NO:16、SEQ ID NO:134、SEQ ID NO:34、SEQ ID NO:36、SEQ ID NO:52和SEQ ID NO:132。In certain embodiments, the antibody light chain or fragment thereof comprises a light chain variable region VL, and the light chain variable region VL comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: SEQ ID NO: 134, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 52, and SEQ ID NO: 132.

在某些实施方式中，所述轻链可变区包含下述任一项所示的氨基酸序列：SEQ ID NO:54、SEQ ID NO:103、SEQ ID NO:18和SEQ ID NO:109。In certain embodiments, the light chain variable region comprises the amino acid sequence set forth in any one of the following: SEQ ID NO:54, SEQ ID NO:103, SEQ ID NO:18, and SEQ ID NO:109.

在某些实施方式中，所述抗体轻链或其片段还包含人恒定区或鼠恒定区。在某些实施方式中，所述抗体轻链或其片段包含人恒定区，且所述人恒定区包括人Igκ或Igλ恒定区。在某些实施方式中，所述抗体轻链或其片段包含下述任一项所示的氨基酸序列：SEQ ID NO:64、SEQ ID NO:68、SEQ ID NO:72、SEQ ID NO:138、SEQ ID NO:84和SEQ ID NO:136。在某些实施方式中，所述抗体轻链或其片段包含下述任一项所示的氨基酸序列：SEQ ID NO:90、SEQ ID NO:104、SEQ ID NO:78和SEQ ID NO:110。In certain embodiments, the antibody light chain or fragment thereof further comprises a human constant region or a murine constant region. In certain embodiments, the antibody light chain or fragment thereof comprises a human constant region, and the human constant region comprises a human Ig kappa or Ig lambda constant region. In certain embodiments, the antibody light chain or fragment thereof comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 64, SEQ ID NO: 68, SEQ ID NO: 72, SEQ ID NO: 138 SEQ ID NO: 84 and SEQ ID NO: 136. In certain embodiments, the antibody light chain or fragment thereof comprises the amino acid sequence set forth in any one of the following: SEQ ID NO:90, SEQ ID NO:104, SEQ ID NO:78, and SEQ ID NO:110 .

在某些实施方式中，所述抗体包含抗体重链或其片段。在某些实施方式中，所述抗体重链或其片段包含HCDR1，且所述HCDR1包含下述任一项所示的氨基酸序列：SEQ ID NO:123、SEQ ID NO:19和SEQ ID NO:37。在某些实施方式中，所述HCDR1包含下述任一项所示的氨基酸序列：SEQ ID NO:1、SEQ ID NO:91和SEQ ID NO:92。在某些实施方式中，所述抗体重链或其片段包含HCDR2，且所述HCDR2包含下述任一项所示的氨基酸序列：SEQ ID NO:124、SEQ ID NO:20和SEQ ID NO:38。在某些实施方式中，所述HCDR2包含下述任一项所示的氨基酸序列：SEQ ID NO:2和SEQ ID NO:93。In certain embodiments, the antibody comprises an antibody heavy chain or a fragment thereof. In certain embodiments, the antibody heavy chain or fragment thereof comprises HCDR1, and the HCDR1 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 123, SEQ ID NO: 19, and SEQ ID NO: 37. In certain embodiments, the HCDR1 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 1, SEQ ID NO: 91, and SEQ ID NO: 92. In certain embodiments, the antibody heavy chain or fragment thereof comprises HCDR2, and the HCDR2 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 124, SEQ ID NO: 20, and SEQ ID NO: 38. In certain embodiments, the HCDR2 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 2 and SEQ ID NO: 93.

在某些实施方式中，所述抗体重链或其片段包含HCDR3，且所述HCDR3包含下述任一项所示的氨基酸序列：SEQ ID NO:125、SEQ ID NO:21和SEQ ID NO:130。In certain embodiments, the antibody heavy chain or fragment thereof comprises HCDR3, and the HCDR3 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 125, SEQ ID NO: 21, and SEQ ID NO: 130.

在某些实施方式中，所述HCDR3包含下述任一项所示的氨基酸序列：SEQ ID NO:3、SEQ ID NO:94、SEQ ID NO:95、SEQ ID NO:39、SEQ ID NO:100和SEQ ID NO:101。In certain embodiments, the HCDR3 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO:3, SEQ ID NO:94, SEQ ID NO:95, SEQ ID NO:39, SEQ ID NO: 100 and SEQ ID NO:101.

在某些实施方式中，所述抗体重链或其片段还包括框架区H-FR1、H-FR2、H-FR2和H-FR4。在某些实施方式中，所述框架区选自以下组中任一项：人共有框架序列和人种系序列。在某些实施方式中，所述H-FR1的C末端与所述HCDR1的N末端直接或间接相连，所述H-FR1包含下述任一项所示的氨基酸序列：SEQ ID NO:7、SEQ ID NO:25和SEQ ID NO:43。在某些实施方式中，所述H-FR2位于所述HCDR1与所述HCDR2之间，所述H-FR2包含下述任一项所示的氨基酸序列：SEQ ID NO:8、SEQ ID NO:26和SEQ ID NO:44。在某些实施方式中，所述H-FR3位于所述HCDR2与所述HCDR3之间，所述H-FR3包含下述任一项所示的氨基酸序列：SEQ ID NO:129、SEQ ID NO:27和SEQ ID NO:45。在某些实施方式中，所述H-FR3包含下述任一项所示的氨基酸序列：SEQ ID NO:9和SEQ ID NO:99。在某些实施方式中，所述H-FR4的N末端与所述HCDR3的C末端直接或间接相连，所述H-FR4包含下述任一项所示的氨基酸序列：SEQ ID NO:10、SEQ ID NO:28和SEQ ID NO:46。In certain embodiments, the antibody heavy chain or fragment thereof further comprises framework regions H-FR1, H-FR2, H-FR2, and H-FR4. In certain embodiments, the framework regions are selected from any of the group consisting of human consensus framework sequences and human germline sequences. In certain embodiments, the C-terminus of H-FR1 is directly or indirectly linked to the N-terminus of said HCDR1, said H-FR1 comprising the amino acid sequence set forth in any one of the following: SEQ ID NO: SEQ ID NO: 25 and SEQ ID NO: 43. In certain embodiments, the H-FR2 is between the HCDR1 and the HCDR2, and the H-FR2 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO:8, SEQ ID NO: 26 and SEQ ID NO:44. In certain embodiments, the H-FR3 is between the HCDR2 and the HCDR3, and the H-FR3 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 129, SEQ ID NO: 27 and SEQ ID NO:45. In certain embodiments, the H-FR3 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO:9 and SEQ ID NO:99. In certain embodiments, the N-terminus of the H-FR4 is directly or indirectly linked to the C-terminus of the HCDR3, and the H-FR4 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: SEQ ID NO:28 and SEQ ID NO:46.

在某些实施方式中，所述抗体重链或其片段包含重链可变区VH，且所述重链可变区VH包含下述任一项所示的氨基酸序列：SEQ ID NO:15、SEQ ID NO:135、SEQ ID NO:33、SEQ ID NO:35、SEQ ID NO:51和SEQ ID NO:133。In certain embodiments, the antibody heavy chain or fragment thereof comprises a heavy chain variable region VH, and the heavy chain variable region VH comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: SEQ ID NO: 135, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 51 and SEQ ID NO: 133.

在某些实施方式中，其中所述重链可变区VH包含下述任一项所示的氨基酸序列：SEQ ID NO:53、SEQ ID NO:105、SEQ ID NO:107、SEQ ID NO:17、SEQ ID NO:111、SEQ ID NO:114、SEQ ID NO:117和SEQ ID NO:120。And a SEQ ID NO: 105, SEQ ID NO: 107, 17. SEQ ID NO: 111, SEQ ID NO: 114, SEQ ID NO: 117, and SEQ ID NO: 120.

在某些实施方式中，所述抗体重链或其片段还包含人恒定区或鼠恒定区。In certain embodiments, the antibody heavy chain or fragment thereof further comprises a human constant region or a murine constant region.

在某些实施方式中，所述抗体重链或其片段包含人恒定区，且所述人恒定区包括人IgG恒定区。在某些实施方式中，IgG恒定区包含人IgG1恒定区。In certain embodiments, the antibody heavy chain or fragment thereof comprises a human constant region, and the human constant region comprises a human IgG constant region. In certain embodiments, the IgG constant region comprises a human IgGl constant region.

在某些实施方式中，所述抗体重链或其片段包含下述任一项所示的氨基酸序列：SEQ ID NO:62、SEQ ID NO:66、SEQ ID NO:70、SEQ ID NO:139、SEQ ID NO:82和SEQ ID NO:137。In certain embodiments, the antibody heavy chain or fragment thereof comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 62, SEQ ID NO: 66, SEQ ID NO: 70, SEQ ID NO: 139 SEQ ID NO: 82 and SEQ ID NO: 137.

在某些实施方式中，所述重链包含下述任一项所示的氨基酸序列：SEQ ID NO:88、SEQ ID NO:106、SEQ ID NO:108、SEQ ID NO:76、SEQ ID NO:112、SEQ ID NO:115、SEQ ID NO:118和SEQ ID NO:121。And a SEQ ID NO: 108 : 112, SEQ ID NO: 115, SEQ ID NO: 118 and SEQ ID NO: 121.

在某些实施方式中，所述IL7蛋白为人IL17蛋白。在某些实施方式中，所述IL7蛋白包 括IL17A蛋白和/或IL17F蛋白。In certain embodiments, the IL7 protein is a human IL17 protein. In certain embodiments, the IL7 protein comprises an IL17A protein and/or an IL17F protein.

另一方面，本申请提供了分离的一种或多种核酸分子，其编码本申请所述的抗体或其抗原结合片段。In another aspect, the application provides an isolated nucleic acid molecule or molecules encoding an antibody or antigen-binding fragment thereof as described herein.

另一方面，本申请提供了一种载体，其包含本申请所述的核酸分子。In another aspect, the application provides a vector comprising a nucleic acid molecule as described herein.

另一方面，本申请提供了一种宿主细胞，其包含本申请所述的核酸分子或本申请所述的载体。In another aspect, the application provides a host cell comprising a nucleic acid molecule described herein or a vector described herein.

另一方面，本申请提供了一种制备所述的抗体或其抗原结合片段的方法，所述方法包括在使得本申请所述抗体或其抗原结合片段表达的条件下，培养本申请所述的宿主细胞。在某些实施方式中，其任选地包含收获所述抗体或其抗原结合片段。In another aspect, the application provides a method of making the antibody or antigen-binding fragment thereof, the method comprising culturing the method described in the present application under conditions such that the antibody or antigen-binding fragment thereof of the present application is expressed Host cell. In certain embodiments, it optionally comprises harvesting the antibody or antigen-binding fragment thereof.

另一方面，本申请提供了一种药物组合物，其包含本申请所述的抗体或其抗原结合片段、本申请所述的核酸分子、本申请所述的载体和/或本申请所述的宿主细胞，以及任选地药学上可接受的佐剂。In another aspect, the application provides a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof described herein, a nucleic acid molecule described herein, a vector described herein, and/or described herein Host cells, and optionally pharmaceutically acceptable adjuvants.

另一方面，本申请提供了所述的抗体或其抗原结合片段在制备预防或治疗疾病或病症的药物中的用途。在某些实施方式中，所述疾病或病症包括：强直性脊柱炎、银屑病关节炎、类风湿性关节炎、骨关节炎、骨植入物松动、急性移植排斥、呼吸道炎症、炎性肠病、败血症、败血症性或内毒素性休克、骨丢失、银屑病、变态反应、局部缺血、系统性硬化症、中风和哮喘。In another aspect, the application provides the use of the antibody or antigen-binding fragment thereof for the preparation of a medicament for preventing or treating a disease or condition. In certain embodiments, the disease or condition comprises: ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, osteoarthritis, bone implant loosening, acute graft rejection, respiratory inflammation, inflammatory Enteropathy, sepsis, septic or endotoxic shock, bone loss, psoriasis, allergy, ischemia, systemic sclerosis, stroke and asthma.

在某些实施方式中，其用于预防或治疗疾病或病症。在某些实施方式中，所述疾病或病症包括：强直性脊柱炎、银屑病关节炎、类风湿性关节炎、骨关节炎、骨植入物松动、急性移植排斥、呼吸道炎症、炎性肠病、败血症、败血症性或内毒素性休克、骨丢失、银屑病、变态反应、局部缺血、系统性硬化症、中风和哮喘。In certain embodiments, it is used to prevent or treat a disease or condition. In certain embodiments, the disease or condition comprises: ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, osteoarthritis, bone implant loosening, acute graft rejection, respiratory inflammation, inflammatory Enteropathy, sepsis, septic or endotoxic shock, bone loss, psoriasis, allergy, ischemia, systemic sclerosis, stroke and asthma.

另一方面，本申请提供了一种预防或治疗疾病的方法，其包括施用本申请所述的抗体或其抗原结合片段、本申请所述的核酸分子、本申请所述的载体、本申请所述的宿主细胞和/或本申请所述的药物组合物。In another aspect, the application provides a method of preventing or treating a disease comprising administering an antibody or antigen-binding fragment thereof as described herein, a nucleic acid molecule described herein, a vector described herein, the present application Host cells and/or pharmaceutical compositions described herein.

在某些实施方式中，所述疾病或病症包括：强直性脊柱炎、银屑病关节炎、类风湿性关节炎、骨关节炎、骨植入物松动、急性移植排斥、呼吸道炎症、炎性肠病、败血症、败血症性或内毒素性休克、骨丢失、银屑病、变态反应、局部缺血、系统性硬化症、中风和哮喘。In certain embodiments, the disease or condition comprises: ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, osteoarthritis, bone implant loosening, acute graft rejection, respiratory inflammation, inflammatory Enteropathy, sepsis, septic or endotoxic shock, bone loss, psoriasis, allergy, ischemia, systemic sclerosis, stroke and asthma.

另一方面，本申请提供了一种抑制IL17蛋白和IL17配体结合的方法，其包括施用本申请所述的抗体或其抗原结合片段、本申请所述的核酸分子、本申请所述的载体、本申请所述的宿主细胞和/或本申请所述的药物组合物。In another aspect, the application provides a method of inhibiting binding of an IL17 protein and an IL17 ligand, comprising administering an antibody or antigen-binding fragment thereof, a nucleic acid molecule described herein, a vector described herein, The host cells described herein and/or the pharmaceutical compositions described herein.

另一方面，本申请提供了一种抑制IL17蛋白生物学活性的方法，其包括施用本申请所述的抗体或其抗原结合片段、本申请所述的核酸分子、本申请所述的载体、本申请所述的宿主细胞和/或本申请所述的药物组合物。In another aspect, the application provides a method of inhibiting the biological activity of an IL17 protein comprising administering an antibody or antigen-binding fragment thereof as described herein, a nucleic acid molecule described herein, a vector described herein, and The host cells and/or pharmaceutical compositions described herein are claimed.

另一方面，本申请提供了抑制趋化因子表达的方法，其包括本申请所述的抗体或其抗原结合片段、本申请所述的核酸分子、本申请所述的载体、本申请所述的宿主细胞和/或本申请所述的药物组合物。在某些实施方式中，所述趋化因子包括CXCL1。In another aspect, the application provides a method of inhibiting expression of a chemokine comprising an antibody or antigen-binding fragment thereof described herein, a nucleic acid molecule described herein, a vector described herein, and a Host cells and/or pharmaceutical compositions described herein. In certain embodiments, the chemokine comprises CXCL1.

本领域技术人员能够从下文的详细描述中容易地洞察到本公开的其它方面和优势。下文的详细描述中仅显示和描述了本公开的示例性实施方式。如本领域技术人员将认识到的，本公开的内容使得本领域技术人员能够对所公开的具体实施方式进行改动而不脱离本申请所涉及发明的精神和范围。相应地，本申请的附图和说明书中的描述仅仅是示例性的，而非为限制性的。Other aspects and advantages of the present disclosure will be readily apparent to those skilled in the art from the following detailed description. Only the exemplary embodiments of the present disclosure are shown and described in the following detailed description. As will be recognized by those skilled in the art, the present disclosure will be able to make modifications to the disclosed embodiments without departing from the spirit and scope of the invention. The drawings in the present specification and the description in the specification are merely illustrative and not restrictive.

附图说明DRAWINGS

本申请所涉及的发明的具体特征如所附权利要求书所显示。通过参考下文中详细描述的示例性实施方式和附图能够更好地理解本申请所涉及发明的特点和优势。对附图简要说明书如下：Specific features of the inventions referred to in this application are set forth in the appended claims. The features and advantages of the inventions of the present application can be better understood by referring to the exemplary embodiments and the accompanying drawings. A brief description of the drawing is as follows:

图1A-1C显示的是本申请中的IL17抗体的重链可变区和轻链可变区与相关种系序列的氨基酸序列对比。1A-1C show amino acid sequence alignments of the heavy chain variable region and the light chain variable region of the IL17 antibody of the present application and related germline sequences.

图2A-2C显示的是本申请中的IL17抗体抑制IL17A蛋白与IL17受体的结合。2A-2C show that the IL17 antibody of the present application inhibits the binding of the IL17A protein to the IL17 receptor.

图3显示的是本申请中的IL17抗体抑制IL17A蛋白诱导HT-29细胞产生趋化因子CXCL1。Figure 3 shows that IL17 antibody in the present application inhibits IL17A protein-induced chemokine CXCL1 production by HT-29 cells.

图4显示的是本申请中的IL17抗体与IL17F蛋白的结合活性。Figure 4 shows the binding activity of the IL17 antibody of the present application to the IL17F protein.

图5显示的是本申请中的IL17抗体抑制IL17A蛋白与IL17蛋白受体的结合。Figure 5 shows that the IL17 antibody of the present application inhibits the binding of the IL17A protein to the IL17 protein receptor.

图6A-6C显示的是本申请中的IL17抗体抑制IL17A蛋白诱导HT-29细胞产生CXCL1。Figures 6A-6C show that IL17 antibodies in the present application inhibit IL17A protein-induced CXCL1 production by HT-29 cells.

图7A-7C显示的是本申请中的IL17抗体抑制IL17A蛋白诱导HS-27细胞产生IL-8。Figures 7A-7C show that IL17 antibodies in the present application inhibit IL17A protein-induced IL-8 production by HS-27 cells.

具体实施方式Detailed ways

以下由特定的具体实施例说明本申请发明的实施方式，熟悉此技术的人士可由本说明书所公开的内容容易地了解本申请发明的其他优点及效果。The embodiments of the present invention are described below by way of specific embodiments, and those skilled in the art can readily appreciate other advantages and effects of the present invention from the disclosure of the present specification.

在本申请中，术语“抗体”通常是指能够特异性识别和/或中和特定抗原的多肽分子。例如，抗体可包含通过二硫键相互连接的至少两条重(H)链和两条轻(L)链组成的免疫球蛋白，并且包括任何包含其抗原结合部分的分子。术语“抗体”包括单克隆抗体、抗体片段或抗 体衍生物，包括但不限于人抗体、人源化抗体、嵌合抗体、单链抗体(例如，scFv)，以及与抗原结合的抗体片段(例如，Fab、Fab’和(Fab) 2片段)。术语“抗体”还包括抗体的所有重组体形式，例如在原核细胞中表达的抗体、未糖基化的抗体以及本文所述的任何与抗原结合的抗体片段及其衍生物。每条重链可由重链可变区(VH)和重链恒定区构成。每条轻链可由轻链可变区(VL)和轻链恒定区构成。术语“可变区”或“可变结构域”是指抗体的重链或轻链的氨基末端结构域。重链和轻链的可变结构域可分别称为“VH”和“VL”。这些结构域通常是抗体的最可变的部分(相对于相同类型的其它抗体)并含有抗原结合位点。VH和VL区可进一步被区分为称为互补决定区(CDR)的高变区，它们散布在称为框架区(FR)的更保守的区域中。每个VH和VL可由三个CDR和四个FR区构成，它们从氨基端至羧基端可按以下顺序排列：FR1、CDR1、FR2、CDR2、FR3、CDR3和FR4。重链和轻链的可变区含有与抗原相互作用的结合结构域。抗体的恒定区可介导该免疫球蛋白与宿主组织或因子的结合，所述宿主组织或因子包括免疫系统的多种细胞(例如，效应细胞)和经典补体系统的第一成分(Clq)。 In the present application, the term "antibody" generally refers to a polypeptide molecule capable of specifically recognizing and/or neutralizing a particular antigen. For example, an antibody may comprise an immunoglobulin consisting of at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, and includes any molecule comprising an antigen-binding portion thereof. The term "antibody" includes monoclonal antibodies, antibody fragments or antibody derivatives including, but not limited to, human antibodies, humanized antibodies, chimeric antibodies, single chain antibodies (eg, scFv), and antibody fragments that bind to an antigen (eg, , Fab, Fab' and (Fab) 2 fragments). The term "antibody" also includes all recombinant forms of the antibody, such as antibodies expressed in prokaryotic cells, unglycosylated antibodies, and any antigen-binding antibody fragments and derivatives thereof described herein. Each heavy chain can be composed of a heavy chain variable region (VH) and a heavy chain constant region. Each light chain can be composed of a light chain variable region (VL) and a light chain constant region. The term "variable region" or "variable domain" refers to the amino terminal domain of the heavy or light chain of an antibody. The variable domains of the heavy and light chains can be referred to as "VH" and "VL", respectively. These domains are typically the most variable part of the antibody (relative to other antibodies of the same type) and contain antigen binding sites. The VH and VL regions can be further distinguished as hypervariable regions termed complementarity determining regions (CDRs), which are interspersed in more conserved regions called framework regions (FR). Each VH and VL can be composed of three CDRs and four FR regions, which can be arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with the antigen. The constant region of the antibody can mediate binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (eg, effector cells) and the first component (Clq) of the classical complement system.

术语“免疫球蛋白”(Ig)与“抗体”在本文中可互换使用。基本的四链抗体单元是异四聚体糖蛋白，其由两条相同的轻链(L)和两条相同的重链(H)构成。IgM抗体由5个基本的异四聚体单元连同额外的被称为J链的多肽组成，并包含10个抗原结合位点，而IgA抗体包括2-5个基本的四链单元，其可聚合形成与J链组合的多价装配物。在IgG的情况中，四链单元通常是约150，000道尔顿。每个L链通过一个共价二硫键连接到H链，而两条H链通过一个或多个二硫键彼此相连，二硫键的数目取决于H链的同种型。每个H和L链还具有规律间隔的链内二硫键。每条H链在N-末端具有可变结构域(VH)，接着是三个(对于每条α和γ链)或四个(对于μ和ε同种型)恒定结构域(CH)。人IgG有四个亚型：IgG1、IgG2、IgG3和IgG4。The terms "immunoglobulin" (Ig) and "antibody" are used interchangeably herein. The basic four-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light chains (L) and two identical heavy chains (H). The IgM antibody consists of 5 basic heterotetramer units together with an additional polypeptide called the J chain and contains 10 antigen binding sites, while the IgA antibody comprises 2-5 basic four chain units, which are polymerizable. A multivalent assembly in combination with the J chain is formed. In the case of IgG, the four chain unit is typically about 150,000 daltons. Each L chain is linked to the H chain by a covalent disulfide bond, and the two H chains are linked to each other by one or more disulfide bonds, the number of disulfide bonds depending on the isoform of the H chain. Each H and L chain also has regularly spaced intrachain disulfide bonds. Each H chain has a variable domain (VH) at the N-terminus, followed by three (for each alpha and gamma chain) or four (for the μ and epsilon isoforms) constant domain (CH). Human IgG has four subtypes: IgG1, IgG2, IgG3, and IgG4.

在本申请中，术语“单克隆抗体”通常是指得自一群基本同源的抗体的抗体，即包含该群的各个抗体除了可能的以微量存在的天然发生的突变之外是相同的。单克隆抗体是高度特异性的，直接针对单个抗原性位点。与多克隆抗体制剂(其通常包括针对不同决定簇(表位)的不同抗体)相比，每个单克隆抗体针对抗原上的单个决定簇。除它们的特异性外，单克隆抗体的优势在于它们通过杂交瘤培养合成，未受到其它免疫球蛋白的污染。修饰语“单克隆”表明该抗体的特征为从抗体的基本上同质的群中获得，不应解释为要求通过任何特定方法来生产抗体。例如，根据本发明使用的单克隆抗体可通过多种技术来制成，包括例如杂交瘤法(例如，可参见Kohler和Milstein，Nature，256：495-97(1975)；Hongo等，Hybridoma， 14(3)：253-260(1995)，Harlow等，Antibodies：A Laboratory Manual，(Cold Spring Harbor Laboratory Press，第二版1988)；Hammerling等，Monoclonal Antibodies and T-Cell Hybridomas，563-681，(Elsevier，N.Y.，1981))、重组DNA法(例如，可参见美国专利US4，816，567)、噬菌体展示技术(例如，可参见Clackson等，Nature，352：624-628(1991)；Marks等，J.Mol.Biol.，222：581-597(1992)；Sidhu等，J.Mol.Biol.338(2)：299-310(2004)；Lee等，J.Mol.Biol.340(5)：1073-1093(2004)；Fellouse，Proc.Natl.Acad.Sci.USA101(34)：12467-12472(2004)；和Lee等J.Immunol.Methods284(1-2)：119-132(2004))、及用于从具有部分或整个人免疫球蛋白基因座或编码人免疫球蛋白序列的基因的动物生成人或人样抗体的技术(例如，可参见WO 1998/24893；WO 1996/34096；WO1996/33735；WO 1991/10741；Jakobovits等，Proc.Natl.Acad.Sci.USA，90：2551(1993)；Jakobovits等，Nature，362：255-258(1993)；Bruggemann等，Year in Immunol，7：33(1993)；美国专利US5，545，807；US5，545，806；US5，569，825；US5，625，126；US5，633，425和US5，661，016，Marks等，Bio/Technology，10：779-783(1992)；Lonberg等，Nature，368：856-859(1994)；Morrison，Nature，368：812-813(1994)；Fishwild等，Nature Biotechnol.，14：845-851(1996)；Neuberger，Nature Biotechnol，14：826(1996)；和Lonberg和Huszar，Intern.Rev Immunol，13：65-93(1995))。In the present application, the term "monoclonal antibody" generally refers to an antibody obtained from a population of substantially homologous antibodies, ie, the individual antibodies comprising the population are identical except for the naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific and target a single antigenic site. Each monoclonal antibody is directed against a single determinant on the antigen as compared to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes). In addition to their specificity, monoclonal antibodies have the advantage that they are synthesized by hybridoma culture and are not contaminated by other immunoglobulins. The modifier "monoclonal" indicates that the antibody is characterized as being obtained from a substantially homogeneous population of antibodies and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies for use in accordance with the present invention can be made by a variety of techniques including, for example, hybridoma methods (see, for example, Kohler and Milstein, Nature, 256:495-97 (1975); Hongo et al, Hybridoma, 14 (3): 253-260 (1995), Harlow et al, Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, Second Edition 1988); Hammerling et al, Monoclonal Antibodies and T-Cell Hybridomas, 563-681, (Elsevier , NY, 1981)), recombinant DNA methods (see, for example, U.S. Patent No. 4,816,567), phage display technology (see, for example, Clackson et al, Nature, 352:624-628 (1991); Marks et al, J . Mol. Biol., 222: 581-597 (1992); Sidhu et al, J. Mol. Biol. 338 (2): 299-310 (2004); Lee et al, J. Mol. Biol. 340 (5): 1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101 (34): 12467-12472 (2004); and Lee et al. J. Immunol. Methods 284 (1-2): 119-132 (2004)) And techniques for generating human or human-like antibodies from animals having partial or entire human immunoglobulin loci or genes encoding human immunoglobulin sequences (eg, See WO 1998/24893; WO 1996/34096; WO 1996/33735; WO 1991/10741; Jakobovits et al, Proc. Natl. Acad. Sci. USA, 90:2551 (1993); Jakobovits et al, Nature, 362: 255-258 (1993); Bruggemann et al, Year in Immunol, 7:33 (1993); US Patent 5,545,807; US 5,545,806; US 5,569,825; US 5,625,126; US 5,633,425 and US 5,661,016, Marks et al, Bio/Technology, 10:779-783 (1992); Lonberg et al, Nature, 368: 856-859 (1994); Morrison, Nature, 368: 812-813 (1994); Fishwild Etc., Nature Biotechnol., 14: 845-851 (1996); Neuberger, Nature Biotechnol, 14: 826 (1996); and Lonberg and Huszar, Intern. Rev Immunol, 13: 65-93 (1995)).

在本申请中，术语“框架区”(FR)通常是指CDR残基之外的那些可变结构域残基。In the present application, the term "framework region" (FR) generally refers to those variable domain residues other than CDR residues.

在本申请中，术语“人共有框架”通常是指人免疫球蛋白VL或VH框架序列中，最常出现的氨基酸残基。一般而言，对人免疫球蛋白VL或VH序列的选择是从可变结构域序列的亚型中选择。一般而言，该序列的亚型是如Kabat等指出的免疫目的蛋白序列(参见Sequences of Proteins of Immunological Interest，第5版，Public HealthService，国家健康研究所，Bethesda，MD(1991))中记载的亚型。实例包括，对于VL，该亚型可以是如Kabat等记载的亚型κI，κII，κIII或κIV。另外，对于VH，该亚型可以是如Kabat等记载的亚型I、亚型II或亚型III。备选地，可如上所述获得人共有框架，其中特定残基，如人框架残基基于其与供体框架的同源性进行选择，该选择通过将供体框架与多种人框架序列的集合的比对来进行。接纳体人框架“衍生自”人免疫球蛋白框架或人共有框架可以包含其相同的氨基酸序列，或其可以包含预先存在的氨基酸序列的变化。在一些实施方案中，预先存在的氨基酸变化的数目可以是10以下，9以下，8以下，7以下，6以下，5以下，4以下，3以下或2以下(例如，1个)。在某些实施方式中，所述的氨基酸序列的变化可以包括置换或删除指定残基，或在指定残基附近插入至少一个氨基酸残基。在指定残基“附近”插入的意思是在其 邻近的一至两个残基内插入。插入可以在指定残基的N末端或C末端。在本申请中，所述氨基酸修饰可以是置换。In the present application, the term "human consensus framework" generally refers to the most frequently occurring amino acid residues in human immunoglobulin VL or VH framework sequences. In general, the selection of human immunoglobulin VL or VH sequences is selected from subtypes of variable domain sequences. In general, the subtype of the sequence is as described in Kabat et al. (see Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991)). Subtype. Examples include, for VL, the subtype may be a subtype kappa I, kappa II, kappa III or kappa IV as described by Kabat et al. Further, for VH, the subtype may be subtype I, subtype II or subtype III as described by Kabat et al. Alternatively, a human consensus framework can be obtained as described above, wherein a particular residue, such as a human framework residue, is selected based on its homology to the donor framework by placing the donor framework with a plurality of human framework sequences The comparison of the collections is made. The acceptor human framework "derived from" a human immunoglobulin framework or human consensus framework may comprise the same amino acid sequence, or it may comprise a change in a pre-existing amino acid sequence. In some embodiments, the number of pre-existing amino acid changes may be 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less (for example, one). In certain embodiments, a change in the amino acid sequence can include substitution or deletion of a specified residue, or insertion of at least one amino acid residue in the vicinity of a specified residue. Insertion in the vicinity of a specified residue means insertion within one or two residues adjacent thereto. The insertion can be at the N-terminus or C-terminus of the specified residue. In the present application, the amino acid modification may be a substitution.

在本申请中，术语“单链抗体”(scFv)通常是指是由抗体重链可变区和轻链可变区通过短肽连接子(linker)连接而成的分子。In the present application, the term "single-chain antibody" (scFv) generally refers to a molecule which is formed by linking an antibody heavy chain variable region and a light chain variable region through a short peptide linker.

在本申请中，术语“嵌合抗体”通常是指这样的抗体，其中每个重链或轻链氨基酸序列的一部分与来自特定物种的抗体中相应氨基酸序列同源，或者属于特定的类别，而该链的其余区段则与另一物种中的相应序列同源。例如，轻链和重链的可变区均来自一个动物物种(如小鼠、大鼠等)的抗体的可变区，而恒定部分则与来自另一物种(如人)的抗体序列同源。例如，为获得嵌合抗体，可利用非人源的B细胞或杂交瘤细胞产生可变区，而与其组合的恒定区则来自人。所述可变区具有易于制备的优点，并且其特异性不受与其组合的恒定区的来源的影响。同时，由于嵌合抗体的恒定区可来源于人类，因此嵌合在注射时抗体引发免疫应答的可能性会低于使用恒定区为非人来源的抗体。In the present application, the term "chimeric antibody" generally refers to an antibody in which a portion of each heavy or light chain amino acid sequence is homologous to the corresponding amino acid sequence in an antibody from a particular species, or belongs to a particular class, and The remaining segments of the strand are homologous to the corresponding sequences in another species. For example, the variable regions of both the light and heavy chains are derived from the variable regions of antibodies of one animal species (eg, mice, rats, etc.), while the constant portions are homologous to antibody sequences from another species (eg, humans). . For example, to obtain a chimeric antibody, a non-human B cell or hybridoma cell can be utilized to generate a variable region, and the constant region combined therewith is derived from a human. The variable region has the advantage of being easy to prepare, and its specificity is not affected by the source of the constant region with which it is combined. At the same time, since the constant region of the chimeric antibody can be derived from humans, the probability of an antibody eliciting an immune response at the time of injection is lower than that of a non-human source using a constant region.

在本申请中，术语“人源化抗体”通常是指使用遗传工程技术将衍生自非人物种(例如小鼠或大鼠)的抗体、免疫球蛋白结合蛋白和多肽对人体的免疫原性降低，同时仍保留原始抗体的抗原结合特性的改造抗体。例如，可以使用CDR移植(Jones et al.，Nature 321:522(1986))；包括“重塑”(reshaping)，(Verhoeyen，et al.，1988Science 239:1534-1536；Riechmann，et al.，1988Nature 332:323-337；Tempest，et al.，Bio/Technol 1991 9:266-271)，“高度加成”(hyperchimerization)，(Queen，et al.，1989 Proc Natl Acad Sci USA 86:10029-10033；Co，et al.，1991 Proc Natl Acad Sci USA 88:2869-2873；Co，et al.，1992 J Immunol 148:1149-1154)和“贴面”(veneering)，(Mark，et al.，“Derivation of therapeutically active humanized and veneered anti-CD18 antibodies.”In:Metcalf B W，Dalton B J，eds.Cellular adhesion:molecular definition to therapeutic potential.New York:Plenum Press，1994:291-312)等技术手段，对非人源的结合域进行人源化。如果其他区域，例如铰链区和恒定区结构域也源自非人来源，则这些区域也可以被人源化。In the present application, the term "humanized antibody" generally refers to the use of genetic engineering techniques to reduce the immunogenicity of antibodies, immunoglobulin binding proteins and polypeptides derived from non-human species (eg, mice or rats) to humans. Engineered antibodies that retain the antigen binding properties of the original antibody while still retaining. For example, CDR grafting can be used (Jones et al., Nature 321:522 (1986)); including "reshaping", (Verhoeyen, et al., 1988 Science 239: 1534-1536; Riechmann, et al., 1988 Nature 332: 323-337; Tempest, et al., Bio/Technol 1991 9: 266-271), "hyperchimerization", (Queen, et al., 1989 Proc Natl Acad Sci USA 86: 10029- 10033; Co, et al., 1991 Proc Natl Acad Sci USA 88: 2869-2873; Co, et al., 1992 J Immunol 148: 1149-1154) and "veneering", (Mark, et al. , "Derivation of therapeutically active humanized and veneered anti-CD18 antibodies." In: Metcalf B W, Dalton B J, eds. Cellular adhesion: molecular definition to therapeutic potential. New York: Plenum Press, 1994: 291-312) Means to humanize the binding domain of non-human sources. If other regions, such as the hinge region and the constant region domain, are also derived from non-human sources, these regions can also be humanized.

在本申请中，术语“全人源抗体”通常是指抗体所有全部(包括抗体的恒定区部分，CH和CL区)均由人类来源的基因所编码。全人源抗体可以大大减少异源抗体对人体造成的免疫副反应。In the present application, the term "fully human antibody" generally means that all of the antibody (including the constant region portion of the antibody, the CH and CL regions) are encoded by genes of human origin. Fully human antibodies can greatly reduce the immune side effects caused by heterologous antibodies.

在本申请中，术语“抗原结合片段”通常是指完整抗体的一部分，例如，完整抗体的抗原结合区和/或可变区。在某些实施方式中，所述抗原结合片段可包括Fab，Fab’，F(ab)2、Fv片段、F(ab’)2，scFv，di-scFv和/或VhH。在某些实施方式中，本申请所述的抗体可包括 双链抗体、线性抗体、单链抗体分子和由抗体片段形成的多特异性抗体。由木瓜蛋白酶消化具有完整结构的抗体后(例如，去除了Fc区和铰链区)而产生两个相同的抗原结合片段，称为“Fab”片段。Fab片段由完整的轻链、重链可变区(VH)和重链的第一恒定结构域(CH1)组成。每个Fab片段相对于抗原结合是单价的，即它具有单一的抗原结合位点。F(ab) 2抗体片段最初作为成对的Fab片段产生，在它们之间有半胱氨酸相连接。由胃蛋白酶消化具有完整结构的抗体后产生单一的大的F(ab') 2片段，其粗略地相当于两个通过二硫键相连具有不同的抗原结合活性的Fab片段，且仍能够交联抗原。Fab'片段与Fab片段不同之处在于在CH1结构域的羧基末端具有几个额外的残基，包括来自抗体铰链区的一个或多个半胱氨酸。Fv片段由抗体单臂的VL和VH结构域组成。 In the present application, the term "antigen-binding fragment" generally refers to a portion of an intact antibody, eg, an antigen binding region and/or a variable region of an intact antibody. In certain embodiments, the antigen binding fragment can comprise a Fab, Fab', F(ab)2, Fv fragment, F(ab')2, scFv, di-scFv and/or VhH. In certain embodiments, antibodies described herein can include diabodies, linear antibodies, single chain antibody molecules, and multispecific antibodies formed from antibody fragments. After digestion of an antibody with intact structure by papain (eg, removal of the Fc region and hinge region), two identical antigen-binding fragments, termed "Fab" fragments, are produced. The Fab fragment consists of the entire light chain, the heavy chain variable region (VH) and the first constant domain (CH1) of the heavy chain. Each Fab fragment is monovalent relative to antigen binding, ie it has a single antigen binding site. The F(ab) 2 antibody fragment was originally produced as a pair of Fab fragments with a cysteine linkage between them. The digestion of an antibody with an intact structure by pepsin produces a single large F(ab') 2 fragment roughly equivalent to two Fab fragments having different antigen binding activities linked by disulfide bonds and still capable of cross-linking antigen. Fab' fragments differ from Fab fragments by having several additional residues at the carboxy terminus of the CH1 domain, including one or more cysteines from the antibody hinge region. The Fv fragment consists of the VL and VH domains of one arm of the antibody.

在本申请中，术语“IL17蛋白”通常是指白细胞介素17。迄今为止，已有六个IL17家族成员被发现:IL17A、IL17B、IL17C、IL17D、IL17E(亦命名为IL-25)和IL17F。IL17A是IL17家族的原型，IL17F与IL17A有最高的同源性(约50％)，而且其编码基因定位于染色体的同一区段6p12。例如，人IL17A的GenBank登记号可以为NP_002181。例如，所述IL17蛋白可包含参见UniProtKB数据库中登录号Accession No.Q16552所示的氨基酸序列。又例如，所述IL17F蛋白可包含参见NCBI数据库中登录号NP_443104.1所示的氨基酸序列。IL17家族成员以同源二聚体或异源二聚体的形式行使功能。IL17A是一个促炎症因子，跟IL-1Rs与TLRs受体类似，IL17A也通过激活NF-κB、MAPK诱导下游基因。IL17可以介导磷酸化级联反应来使C/EBPb失活。IL17蛋白可通过IL17RA的SEFIR-TILL结构域激活Erk。IL17蛋白与自身免疫疾病相关，如多发性/系统性硬化症(MS)、风湿性关节炎(RA)、系统性红斑狼疮(SLE)、炎症性肠病(IBD)、银屑病、骨关节炎、骨植入物松动、强直性脊柱炎。IL17蛋白也与宿主防御相关，尤其在肺、肠、口腔等粘膜的位置(例如，中风、哮喘、急性移植排斥、呼吸道炎症、炎性肠病、败血症、败血症性、变态反应、局部缺血和内毒素性休克等)。IL-17蛋白能够诱导介导防御反应的IL-6、IL-1b、TNFα等促炎症因子。IL-17蛋白还能诱导促进多形核白细胞增殖与存活的细胞因子(G-CSF)及趋化因子(CXCL1、CXCL2、CXCL5)来调节嗜中性粒细胞。此外，IL-17蛋白还能通过诱导对淋巴细胞、树突状细胞及其它免疫细胞有趋化活性的蛋白(CXCL9、CXCL10、CCL20)将这些细胞靶向到粘膜表面；通过诱导CCL2与CCL7招募单核细胞。In the present application, the term "IL17 protein" generally refers to interleukin 17. To date, six IL17 family members have been identified: IL17A, IL17B, IL17C, IL17D, IL17E (also named IL-25) and IL17F. IL17A is the prototype of the IL17 family, IL17F has the highest homology (about 50%) with IL17A, and its coding gene is located in the same segment of chromosome 6p12. For example, the GenBank accession number of human IL17A can be NP_002181. For example, the IL17 protein can comprise the amino acid sequence shown in accession number Accession No. Q16552 in the UniProtKB database. As another example, the IL17F protein can comprise the amino acid sequence set forth in Accession No. NP_443104.1 in the NCBI database. Members of the IL17 family function in the form of homodimers or heterodimers. IL17A is a pro-inflammatory factor similar to IL-1Rs and TLRs receptors. IL17A also induces downstream genes by activating NF-κB and MAPK. IL17 can mediate a phosphorylation cascade to inactivate C/EBPb. The IL17 protein activates Erk via the SEFIR-TILL domain of IL17RA. IL17 protein is associated with autoimmune diseases such as multiple/systemic sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), psoriasis, bone and joint Inflammation, loose bone implants, ankylosing spondylitis. IL17 protein is also associated with host defense, especially in mucosal sites such as lung, intestine, and oral cavity (eg, stroke, asthma, acute graft rejection, respiratory inflammation, inflammatory bowel disease, sepsis, septicemia, allergies, ischemia, and Endotoxic shock, etc.). IL-17 protein can induce pro-inflammatory factors such as IL-6, IL-1b, TNFα, which mediate defense responses. IL-17 protein also induces cytokines (G-CSF) and chemokines (CXCL1, CXCL2, CXCL5) that promote polymorphonuclear leukocyte proliferation and survival to regulate neutrophils. In addition, IL-17 proteins can target these cells to the mucosal surface by inducing chemotactic proteins (CXCL9, CXCL10, CCL20) on lymphocytes, dendritic cells and other immune cells; by inducing recruitment of CCL2 and CCL7 Monocytes.

在本申请中，术语“IL17受体”(IL17R)通常是指IL17受体家族的成员，包括IL17RA至IL17RE。例如，人IL17R的GenBank登记号可以为CAJ86450.1。所有的家族成员都是一型单次跨膜蛋白，具有保守结构基序，包括一个胞外的类纤维结合素III(fibronectin III-like) 结构域和一个胞内的SEF/IL17R(SEFIR)结构域。IL17受体家族成员之间可组合为不同的受体复合物，其中IL17RA作为这个家族里迄今为止最大的分子，是至少四个配体的传递信号的通用亚基。近来研究表明，阻断PI3K通路能够上调IL17RA，这有可能增强IL17信号。In the present application, the term "IL17 receptor" (IL17R) generally refers to a member of the IL17 receptor family, including IL17RA to IL17RE. For example, the GenBank accession number of human IL17R can be CAJ86450.1. All family members are single-type transmembrane proteins with conserved structural motifs, including an extracellular fibronectin III-like domain and an intracellular SEF/IL17R (SEFIR) structure. area. Members of the IL17 receptor family can be combined into different receptor complexes, of which IL17RA, by far the largest molecule in this family, is a universal subunit that transmits signals to at least four ligands. Recent studies have shown that blocking the PI3K pathway upregulates IL17RA, which may enhance IL17 signaling.

在本申请中，术语“细胞因子”通常是指由免疫细胞(如单核、巨噬细胞、T细胞、B细胞、NK细胞等)和某些非免疫细胞(内皮细胞、表皮细胞、纤维母细胞等)经刺激而合成、分泌的一类具有广泛生物学活性的小分子蛋白质。所述细胞因子可具有调节固有免疫和适应性免疫、血细胞生成、细胞生长、APSC多能细胞以及损伤组织修复等多种功能。在本申请中，所述细胞因子可包括白细胞介素和趋化因子。例如，所述细胞因子为趋化因子。In the present application, the term "cytokine" generally refers to immune cells (eg, mononuclear, macrophage, T cells, B cells, NK cells, etc.) and certain non-immune cells (endothelial cells, epidermal cells, fibroblasts). A group of small molecular proteins with broad biological activity that are synthesized and secreted by stimulation. The cytokine may have various functions such as regulation of innate immunity and adaptive immunity, hematopoiesis, cell growth, APSC pluripotent cells, and repair of damaged tissues. In the present application, the cytokine may include interleukins and chemokines. For example, the cytokine is a chemokine.

在本申请中，术语“CXCL”通常是指CXC趋化因子家族配体。其包括CXCL1、CXCL2、CXCL3、CXCL12、CXCL14等。其中CXCL1(chemokine(C-X-C motif)ligand 1)由巨噬细胞、中性粒细胞和上皮细胞表达，具有中性粒细胞趋化活性，CXCL1通过抑制少突胶质细胞前体的迁移在脊髓发育中起作用，并参与血管生成、动脉生成、炎症、伤口愈合和肿瘤发生过程。In the present application, the term "CXCL" generally refers to a CXC chemokine family ligand. It includes CXCL1, CXCL2, CXCL3, CXCL12, CXCL14 and the like. Among them, CXCL1 (chemokine (CXC motif) ligand 1) is expressed by macrophages, neutrophils and epithelial cells and has neutrophil chemotactic activity. CXCL1 inhibits the migration of oligodendrocyte precursors in spinal cord development. Acts and participates in angiogenesis, arteriogenesis, inflammation, wound healing and tumorigenesis.

在本申请中，术语“K D”可与“KD”互换使用，通常是指特定的抗体-抗原相互作用的解离平衡常数，单位为M(mol/L)。K D可通过物质AB和其解离得到的物质A和物质B的浓度来计算：K D＝c(A)*c(B)/c(AB)。由该公式可知，K D值越大，说明解离越多，代表物质A、B之间的亲和力越弱；反之，K D值越小，说明解离越少，代表物质A、B之间的亲和力越强。 In the present application, the term "K D" with "KD" are used interchangeably, generally refers to a particular antibody - antigen interaction dissociation equilibrium constant, in units of M (mol / L). K D can be calculated from the concentration of substance A and substance B obtained by dissociation of substance AB: K D =c(A)*c(B)/c(AB). It can be seen from the formula that the larger the K D value, the more dissociation, the weaker the affinity between the representative substances A and B; conversely, the smaller the K D value, the less the dissociation is, representing the between substances A and B. The stronger the affinity.

在本申请中，术语“分离的核酸分子”通常是指从其天然环境中分离的或人工合成的任何长度的分离形式的核苷酸、脱氧核糖核苷酸或核糖核苷酸或其类似物。In the present application, the term "isolated nucleic acid molecule" generally refers to an isolated form of nucleotide, deoxyribonucleotide or ribonucleotide or analogue thereof of any length isolated or artificially synthesized from its natural environment. .

在本申请中，术语“载体”通常是指能够在合适的宿主中自我复制的核酸分子，其将插入的核酸分子转移到宿主细胞中和/或宿主细胞之间。所述载体可包括主要用于将DNA或RNA插入细胞中的载体、主要用于复制DNA或RNA的载体，以及主要用于DNA或RNA的转录和/或翻译的表达的载体。所述载体还包括具有多种上述功能的载体。所述载体可以是当引入合适的宿主细胞时能够转录并翻译成多肽的多核苷酸。通常，通过培养包含所述载体的合适的宿主细胞，所述载体可以产生期望的表达产物。In the present application, the term "vector" generally refers to a nucleic acid molecule capable of self-replication in a suitable host, which transfers the inserted nucleic acid molecule into and/or between host cells. The vector may include a vector mainly for inserting DNA or RNA into a cell, a vector mainly for replicating DNA or RNA, and a vector mainly for expression of transcription and/or translation of DNA or RNA. The carrier also includes a carrier having a plurality of the above functions. The vector may be a polynucleotide that is capable of being transcribed and translated into a polypeptide when introduced into a suitable host cell. Typically, the vector will produce the desired expression product by culturing a suitable host cell comprising the vector.

在本申请中，术语“宿主细胞”通常是指可以或已经含有包括本申请所述的核酸分子的质粒或载体，或者能够表达本申请所述的抗体或其抗原结合片段的个体细胞，细胞系或细胞培养物。所述宿主细胞可以包括单个宿主细胞的子代。由于天然的，意外的或故意的突变，子代细胞与原始亲本细胞在形态上或在基因组上可能不一定完全相同，但能够表达本申请所 述的抗体或其抗原结合片段即可。所述宿主细胞可以通过使用本申请所述的载体体外转染细胞而得到。所述宿主细胞可以是原核细胞(例如大肠杆菌)，也可以是真核细胞(例如酵母细胞，例如COS细胞，中国仓鼠卵巢(CHO)细胞，HeLa细胞，HEK293细胞，COS-1细胞，NS0细胞或骨髓瘤细胞)。在一些实施方案中，所述宿主细胞是哺乳动物细胞。例如，所述哺乳动物细胞可以是CHO-K1细胞。在本申请中，术语“重组宿主细胞”通常指在其中引入了重组表达载体的细胞。所述重组宿主细胞不仅包括某种特定的细胞，还包括这些细胞的后代。In the present application, the term "host cell" generally refers to a plasmid or vector which may or already contains a nucleic acid molecule as described herein, or an individual cell, cell line capable of expressing an antibody or antigen-binding fragment thereof as described herein. Or cell culture. The host cell can comprise a progeny of a single host cell. Due to natural, accidental or deliberate mutations, the progeny cells may not necessarily be identical in morphology or genomic to the original parental cell, but may be capable of expressing an antibody or antigen-binding fragment thereof as described herein. The host cell can be obtained by transfecting cells in vitro using a vector described herein. The host cell may be a prokaryotic cell (such as E. coli) or a eukaryotic cell (such as a yeast cell, such as COS cells, Chinese hamster ovary (CHO) cells, HeLa cells, HEK293 cells, COS-1 cells, NSO cells). Or myeloma cells). In some embodiments, the host cell is a mammalian cell. For example, the mammalian cell can be a CHO-K1 cell. In the present application, the term "recombinant host cell" generally refers to a cell into which a recombinant expression vector has been introduced. The recombinant host cell includes not only a specific cell but also the progeny of these cells.

在本申请中，术语“肿瘤”通常是指哺乳动物中的机体(例如，细胞或其组成部分)在各种致瘤因子作用下，局部组织细胞增生所形成的赘生物。在本申请中，肿瘤可以包括直肠腺癌。In the present application, the term "tumor" generally refers to a neoplasm formed by the proliferation of local tissue cells by a body (eg, a cell or a component thereof) in a mammal under the action of various tumorigenic factors. In the present application, the tumor can include rectal adenocarcinoma.

在本申请中，术语“在……之间”通常是指某种氨基酸片段的C端与第一氨基酸片段的N端直接或间接连接，并且其N端与第二氨基酸片段的C端直接或间接连接。在轻链中，例如，所述L-FR2的N末端与所述LCDR1的C末端直接或间接相连，且所述L-FR2的C末端与所述LCDR2的N末端直接或间接相连。又例如，所述L-FR3的N末端与所述LCDR2的C末端直接或间接相连，且所述L-FR3的C末端与所述LCDR3的N末端直接或间接相连。在重链中，例如，所述H-FR2的N末端与所述HCDR1的C末端直接或间接相连，且所述H-FR2的C末端与所述HCDR2的N末端直接或间接相连。又例如，所述H-FR3的N末端与所述HCDR2的C末端直接或间接相连，且所述H-FR3的C末端与所述HCDR3的N末端直接或间接相连。In the present application, the term "between" generally means that the C-terminus of an amino acid fragment is directly or indirectly linked to the N-terminus of the first amino acid fragment, and its N-terminus is directly or C-terminally to the second amino acid fragment. Indirect connection. In the light chain, for example, the N-terminus of the L-FR2 is directly or indirectly connected to the C-terminus of the LCDR1, and the C-terminus of the L-FR2 is directly or indirectly connected to the N-terminus of the LCDR2. For another example, the N-terminus of the L-FR3 is directly or indirectly connected to the C-terminus of the LCDR2, and the C-terminus of the L-FR3 is directly or indirectly connected to the N-terminus of the LCDR3. In the heavy chain, for example, the N-terminus of the H-FR2 is directly or indirectly linked to the C-terminus of the HCDR1, and the C-terminus of the H-FR2 is directly or indirectly linked to the N-terminus of the HCDR2. In another example, the N-terminus of the H-FR3 is directly or indirectly linked to the C-terminus of the HCDR2, and the C-terminus of the H-FR3 is directly or indirectly linked to the N-terminus of the HCDR3.

在本申请中，当描述序列中氨基酸残基的取代时，表述“XnY”通常表示序列中第n位的残基X被残基Y取代。例如，氨基酸取代“R175L”表示，序列中第175位的残基R被残基L取代。In the present application, when describing the substitution of an amino acid residue in a sequence, the expression "XnY" generally means that the residue X of the n-th position in the sequence is substituted by the residue Y. For example, the amino acid substitution "R175L" means that the residue R at position 175 in the sequence is substituted by the residue L.

在本申请中，术语“包括”通常是指包含、总括、含有或包涵的含义。在某些情况下，也表示“为”、“由……组成”的含义。In the present application, the term "comprising" generally means the meaning of inclusion, inclusion, inclusion or inclusion. In some cases, it also means the meaning of "for" and "consisting of."

在本申请中，术语“约”通常是指在指定数值以上或以下0.5％-10％的范围内变动，例如在指定数值以上或以下0.5％、1％、1.5％、2％、2.5％、3％、3.5％、4％、4.5％、5％、5.5％、6％、6.5％、7％、7.5％、8％、8.5％、9％、9.5％、或10％的范围内变动。In the present application, the term "about" generally means a range of 0.5% to 10% above or below a specified value, such as 0.5%, 1%, 1.5%, 2%, 2.5% above or below a specified value, Variations within the range of 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10%.

抗体、其抗原结合片段Antibody, antigen-binding fragment thereof

与参比抗体竞争结合Competing with reference antibodies

在某些实施方式中，本申请所述抗体、其抗原结合片段可与参比抗体竞争结合所述IL17蛋白，其中所述参比抗体可包含轻链可变区和重链可变区，所述参比抗体的轻链可变区可包含LCDR1、LCDR2和LCDR3。In certain embodiments, an antibody, antigen-binding fragment thereof, of the present application can compete with a reference antibody for binding to the IL17 protein, wherein the reference antibody can comprise a light chain variable region and a heavy chain variable region, The light chain variable region of the reference antibody can comprise LCDR1, LCDR2 and LCDR3.

在本申请中，所述LCDR1可包含下述任一项所示的氨基酸序列：SEQ ID NO:126、SEQ ID NO:22和SEQ ID NO:40；所述LCDR2可包含下述任一项所示的氨基酸序列：SEQ ID NO:5、SEQ ID NO:23和SEQ ID NO:41；以及，所述LCDR3可包含下述任一项所示的氨基酸序列：SEQ ID NO:6、SEQ ID NO:24和SEQ ID NO:131；且，所述参比抗体的重链可变区可包含HCDR1、HCDR2和HCDR3，所述HCDR1可包含下述任一项所示的氨基酸序列：SEQ ID NO:123、SEQ ID NO:19和SEQ ID NO:37；所述HCDR2可包含下述任一项所示的氨基酸序列：SEQ ID NO:124、SEQ ID NO:20和SEQ ID NO:38；以及，所述HCDR3可包含下述任一项所示的氨基酸序列：SEQ ID NO:125、SEQ ID NO:21和SEQ ID NO:130。In the present application, the LCDR1 may comprise the amino acid sequence shown in any one of the following: SEQ ID NO: 126, SEQ ID NO: 22, and SEQ ID NO: 40; the LCDR2 may comprise any one of the following The amino acid sequences shown are: SEQ ID NO: 5, SEQ ID NO: 23 and SEQ ID NO: 41; and the LCDR3 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 6, SEQ ID NO And SEQ ID NO: 131; and the heavy chain variable region of the reference antibody may comprise HCDR1, HCDR2 and HCDR3, and the HCDR1 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: SEQ ID NO: 19 and SEQ ID NO: 37; The HCDR3 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 125, SEQ ID NO: 21, and SEQ ID NO: 130.

例如，所述参比抗体的LCDR1可包含下述任一项所示的氨基酸序列：SEQ ID NO:4和SEQ ID NO:96。For example, the LCDR1 of the reference antibody may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 4 and SEQ ID NO: 96.

例如，所述参比抗体的LCDR3可包含下述任一项所示的氨基酸序列：SEQ ID NO:42和SEQ ID NO:102。For example, the LCDR3 of the reference antibody may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 42 and SEQ ID NO: 102.

例如，所述参比抗体的HCDR1可包含下述任一项所示的氨基酸序列：SEQ ID NO:1、SEQ ID NO:91和SEQ ID NO:92。For example, the HCDR1 of the reference antibody may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 1, SEQ ID NO: 91, and SEQ ID NO: 92.

例如，所述参比抗体的HCDR2可包含下述任一项所示的氨基酸序列：SEQ ID NO:2和SEQ ID NO:93。For example, the HCDR2 of the reference antibody may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 2 and SEQ ID NO: 93.

例如，所述参比抗体的HCDR3可包含下述任一项所示的氨基酸序列：SEQ ID NO:3、SEQ ID NO:94、SEQ ID NO:95、SEQ ID NO:39、SEQ ID NO:100和SEQ ID NO:101。For example, the HCDR3 of the reference antibody may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 3, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 39, SEQ ID NO: 100 and SEQ ID NO:101.

例如，所述参比抗体的轻链可变区可包含下述任一项所示的氨基酸序列：SEQ ID NO:16、SEQ ID NO:134、SEQ ID NO:34、SEQ ID NO:36、SEQ ID NO:52和SEQ ID NO:132；且，所述参比抗体的重链可变区可包含下述任一项所示的氨基酸序列：SEQ ID NO:15、SEQ ID NO:135、SEQ ID NO:33、SEQ ID NO:35、SEQ ID NO:51和SEQ ID NO:133。For example, the light chain variable region of the reference antibody can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 16, SEQ ID NO: 134, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 52 and SEQ ID NO: 132; and the heavy chain variable region of the reference antibody may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 15, SEQ ID NO: 135, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 51 and SEQ ID NO: 133.

例如，所述参比抗体的轻链可变区可包含下述任一项所示的氨基酸序列：SEQ ID NO:54、SEQ ID NO:103、SEQ ID NO:18和SEQ ID NO:109。For example, the light chain variable region of the reference antibody can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 54, SEQ ID NO: 103, SEQ ID NO: 18, and SEQ ID NO: 109.

例如，所述参比抗体的重链可变区可包含下述任一项所示的氨基酸序列：SEQ ID NO:53、SEQ ID NO:105、SEQ ID NO:107、SEQ ID NO:17、SEQ ID NO:111、SEQ ID NO:114、SEQ ID NO:117和SEQ ID NO:120。For example, the heavy chain variable region of the reference antibody may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO:53, SEQ ID NO:105, SEQ ID NO:107, SEQ ID NO:17, SEQ ID NO: 111, SEQ ID NO: 114, SEQ ID NO: 117, and SEQ ID NO: 120.

例如，所述参比抗体的轻链可包含下述任一项所示的氨基酸序列：SEQ ID NO:64、SEQ ID NO:68、SEQ ID NO:72、SEQ ID NO:138、SEQ ID NO:84和SEQ ID NO:136；且，所述参比抗体的重链可包含下述任一项所示的氨基酸序列：SEQ ID NO:62、SEQ ID NO:66、SEQ ID NO:70、SEQ ID NO:139、SEQ ID NO:82和SEQ ID NO:137。For example, the light chain of the reference antibody can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 64, SEQ ID NO: 68, SEQ ID NO: 72, SEQ ID NO: 138, SEQ ID NO And SEQ ID NO: 136; and the heavy chain of the reference antibody may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 62, SEQ ID NO: 66, SEQ ID NO: 70, SEQ ID NO: 139, SEQ ID NO: 82 and SEQ ID NO: 137.

例如，所述参比抗体的轻链可包含下述任一项所示的氨基酸序列：SEQ ID NO:90、SEQ ID NO:104、SEQ ID NO:78和SEQ ID NO:110。For example, the light chain of the reference antibody can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO:90, SEQ ID NO:104, SEQ ID NO:78, and SEQ ID NO:110.

例如，所述参比抗体的重链可包含下述任一项所示的氨基酸序列：SEQ ID NO:88、SEQ ID NO:106、SEQ ID NO:108、SEQ ID NO:76、SEQ ID NO:112、SEQ ID NO:115、SEQ ID NO:118和SEQ ID NO:121。For example, the heavy chain of the reference antibody may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO:88, SEQ ID NO:106, SEQ ID NO:108, SEQ ID NO:76, SEQ ID NO : 112, SEQ ID NO: 115, SEQ ID NO: 118 and SEQ ID NO: 121.

例如，本申请所述的抗体、其抗原结合片段可与参比抗体竞争结合IL17蛋白(例如，人IL17蛋白)。所述参比抗体可包含LCDR1-3和HCDR1-3，且其LCDR1的氨基酸序列可包括SEQ ID NO:4；LCDR2的氨基酸序列可包括SEQ ID NO:5；LCDR3的氨基酸序列可包括SEQ ID NO:6；其HCDR1的氨基酸序列可包括SEQ ID NO:1；HCDR2的氨基酸序列可包括SEQ ID NO:2；HCDR3的氨基酸序列可包括SEQ ID NO:3。例如，所述参比抗体可包括抗体YN-008或与其具有相同的LCDR1-3及HCDR1-3的抗体。例如，所述参比抗体可包含轻链可变区和重链可变区，所述轻链可变区的氨基酸序列可包括SEQ ID NO:16；且所述重链可变区的氨基酸序列可包括SEQ ID NO:15。例如，该参比抗体可包括抗体YN-008或与其具有相同的轻链可变区及重链可变区的抗体。例如，所述参比抗体可包含轻链和重链，所述轻链的氨基酸序列可如SEQ ID NO:64所示且所述重链的氨基酸序列可如SEQ ID NO:62所示。例如，该参比抗体可包括抗体YN-008或与其具有相同的轻链及重链。For example, an antibody, antigen-binding fragment thereof, as described herein, can compete with a reference antibody for binding to an IL17 protein (eg, a human IL17 protein). The reference antibody may comprise LCDR1-3 and HCDR1-3, and the amino acid sequence of LCDR1 may comprise SEQ ID NO: 4; the amino acid sequence of LCDR2 may comprise SEQ ID NO: 5; the amino acid sequence of LCDR3 may comprise SEQ ID NO The amino acid sequence of HCDR1 may comprise SEQ ID NO: 1; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 2; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 3. For example, the reference antibody can include antibody YN-008 or an antibody having the same LCDR1-3 and HCDR1-3. For example, the reference antibody can comprise a light chain variable region and a heavy chain variable region, the amino acid sequence of the light chain variable region can comprise SEQ ID NO: 16; and the amino acid sequence of the heavy chain variable region SEQ ID NO: 15 can be included. For example, the reference antibody can include antibody YN-008 or an antibody having the same light chain variable region and heavy chain variable region. For example, the reference antibody can comprise a light chain and a heavy chain, the amino acid sequence of the light chain can be as set forth in SEQ ID NO: 64 and the amino acid sequence of the heavy chain can be as set forth in SEQ ID NO:62. For example, the reference antibody can comprise or have the same light and heavy chains as antibody YN-008.

例如，本申请所述的抗体、其抗原结合片段可与参比抗体竞争结合IL17蛋白(例如，人IL17蛋白)。所述参比抗体可包含LCDR1-3和HCDR1-3，且其LCDR1的氨基酸序列可包括SEQ ID NO:22；LCDR2的氨基酸序列可包括SEQ ID NO:23，LCDR3的氨基酸序列可包括SEQ ID NO:24；其HCDR1的氨基酸序列可包括SEQ ID NO:19；HCDR2的氨基酸序列可包括SEQ ID NO:20；HCDR3的氨基酸序列可包括SEQ ID NO:21。例如，该参比抗体可包括抗体YN-009或与其具有相同LCDR1-3和HCDR1-3的抗体。例如，所述参比抗体可包含轻链可变区和重链可变区，所述轻链可变区的氨基酸序列可包括SEQ ID NO:34；且所述重链可变区的氨基酸序列可包括SEQ ID NO:33。例如，该参比抗体可包括抗体YN-009或与其具有相同的轻链可变区及重链可变区的抗体。例如，所述参比抗体可包含轻链和重链，所述轻链的氨基酸序列可如SEQ ID NO:68所示且所述重链的氨基酸序列可如SEQ ID NO:66所示。 例如，该参比抗体可包括抗体YN-009或与其具有相同的轻链及重链的抗体。For example, an antibody, antigen-binding fragment thereof, as described herein, can compete with a reference antibody for binding to an IL17 protein (eg, a human IL17 protein). The reference antibody may comprise LCDR1-3 and HCDR1-3, and the amino acid sequence of LCDR1 may include SEQ ID NO: 22; the amino acid sequence of LCDR2 may include SEQ ID NO: 23, and the amino acid sequence of LCDR3 may include SEQ ID NO The amino acid sequence of HCDR1 may comprise SEQ ID NO: 19; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 20; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 21. For example, the reference antibody can include antibody YN-009 or an antibody having the same LCDR1-3 and HCDR1-3. For example, the reference antibody can comprise a light chain variable region and a heavy chain variable region, the amino acid sequence of the light chain variable region can comprise SEQ ID NO: 34; and the amino acid sequence of the heavy chain variable region SEQ ID NO: 33 can be included. For example, the reference antibody can include antibody YN-009 or an antibody having the same light chain variable region and heavy chain variable region. For example, the reference antibody can comprise a light chain and a heavy chain, the amino acid sequence of the light chain can be as set forth in SEQ ID NO: 68 and the amino acid sequence of the heavy chain can be as set forth in SEQ ID NO:66. For example, the reference antibody can include antibody YN-009 or an antibody having the same light and heavy chains thereto.

例如，本申请所述的抗体、其抗原结合片段可与参比抗体竞争结合IL17蛋白(例如，人IL17蛋白)。所述参比抗体可包含LCDR1-3和HCDR1-3，且其LCDR1的氨基酸序列可包括SEQ ID NO:40；LCDR2的氨基酸序列可包括SEQ ID NO:41；LCDR3的氨基酸序列可包括SEQ ID NO:42；其HCDR1的氨基酸序列可包括SEQ ID NO:37；HCDR2的氨基酸序列可包括SEQ ID NO:38；HCDR3的氨基酸序列可包括SEQ ID NO:39。例如，所述参比抗体可包括抗体YN-010或与其具有相同的LCDR1-3及HCDR1-3的抗体。例如，所述参比抗体可包含轻链可变区和重链可变区，所述轻链可变区的氨基酸序列可包括SEQ ID NO:52；且所述重链可变区的氨基酸序列可包括SEQ ID NO:51。例如，该参比抗体可包括抗体YN-010或与其具有相同的轻链可变区及重链可变区的抗体。例如，所述参比抗体可包含轻链和重链，所述轻链的氨基酸序列可如SEQ ID NO:72所示且所述重链的氨基酸序列可如SEQ ID NO:70所示。例如，该参比抗体可包括抗体YN-010或与其具有相同的轻链及重链的抗体。For example, an antibody, antigen-binding fragment thereof, as described herein, can compete with a reference antibody for binding to an IL17 protein (eg, a human IL17 protein). The reference antibody may comprise LCDR1-3 and HCDR1-3, and the amino acid sequence of LCDR1 may comprise SEQ ID NO: 40; the amino acid sequence of LCDR2 may comprise SEQ ID NO: 41; the amino acid sequence of LCDR3 may comprise SEQ ID NO The amino acid sequence of HCDR1 may comprise SEQ ID NO: 37; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 38; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 39. For example, the reference antibody can include antibody YN-010 or an antibody having the same LCDR1-3 and HCDR1-3. For example, the reference antibody can comprise a light chain variable region and a heavy chain variable region, the amino acid sequence of the light chain variable region can comprise SEQ ID NO: 52; and the amino acid sequence of the heavy chain variable region SEQ ID NO: 51 can be included. For example, the reference antibody can include antibody YN-010 or an antibody having the same light chain variable region and heavy chain variable region. For example, the reference antibody can comprise a light chain and a heavy chain, the amino acid sequence of the light chain can be as set forth in SEQ ID NO: 72 and the amino acid sequence of the heavy chain can be as set forth in SEQ ID NO:70. For example, the reference antibody can include antibody YN-010 or an antibody having the same light and heavy chains thereto.

例如，本申请所述的抗体、其抗原结合片段可与参比抗体竞争结合IL17蛋白(例如，人IL17蛋白)。所述参比抗体可包含LCDR1-3和HCDR1-3，且其LCDR1的氨基酸序列可包括SEQ ID NO:4；LCDR2的氨基酸序列可包括SEQ ID NO:5；LCDR3的氨基酸序列可包括SEQ ID NO:6；其HCDR1的氨基酸序列可包括SEQ ID NO:1；HCDR2的氨基酸序列可包括SEQ ID NO:2；HCDR3的氨基酸序列可包括SEQ ID NO:3。例如，所述参比抗体可包括抗体YN-011或与其具有相同的LCDR1-3及HCDR1-3的抗体。例如，所述参比抗体包含L-FR1-4及H-FR1-4，且L-FR1的氨基酸序列可包括SEQ ID NO:11；L-FR2的氨基酸序列可包括SEQ ID NO:12；L-FR3的氨基酸序列可包括SEQ ID NO:13；L-FR4的氨基酸序列可包括SEQ ID NO:14；且H-FR1的氨基酸序列可包括SEQ ID NO:7；H-FR2的氨基酸序列可包括SEQ ID NO:8；H-FR3的氨基酸序列可包括SEQ ID NO:9；H-FR4的氨基酸序列可包括SEQ ID NO:10。例如，该抗体或其抗原结合片段可包括抗体YN-011或与其具有相同的LCDR1-3、HCDR1-3、L-FR1-4及H-FR1-4的抗体。例如，所述参比抗体可包含轻链可变区和重链可变区，所述轻链可变区的氨基酸序列可包括SEQ ID NO:18；且所述重链可变区的氨基酸序列可包括SEQ ID NO:17。例如，该参比抗体可包括抗体YN-011或与其具有相同的轻链可变区及重链可变区的抗体。例如，所述参比抗体可包含轻链和重链，所述轻链的氨基酸序列可如SEQ ID NO:78所示且所述重链氨基酸序列可如SEQ ID NO:76所示。例如，该参比抗体可包括抗体YN-011或与其具有相同的轻链及重链的抗体。For example, an antibody, antigen-binding fragment thereof, as described herein, can compete with a reference antibody for binding to an IL17 protein (eg, a human IL17 protein). The reference antibody may comprise LCDR1-3 and HCDR1-3, and the amino acid sequence of LCDR1 may comprise SEQ ID NO: 4; the amino acid sequence of LCDR2 may comprise SEQ ID NO: 5; the amino acid sequence of LCDR3 may comprise SEQ ID NO The amino acid sequence of HCDR1 may comprise SEQ ID NO: 1; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 2; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 3. For example, the reference antibody can include antibody YN-011 or an antibody having the same LCDR1-3 and HCDR1-3. For example, the reference antibody comprises L-FR1-4 and H-FR1-4, and the amino acid sequence of L-FR1 may comprise SEQ ID NO: 11; the amino acid sequence of L-FR2 may comprise SEQ ID NO: 12; The amino acid sequence of -FR3 may comprise SEQ ID NO: 13; the amino acid sequence of L-FR4 may comprise SEQ ID NO: 14; and the amino acid sequence of H-FR1 may comprise SEQ ID NO: 7; the amino acid sequence of H-FR2 may comprise SEQ ID NO:8; the amino acid sequence of H-FR3 may comprise SEQ ID NO:9; the amino acid sequence of H-FR4 may comprise SEQ ID NO:10. For example, the antibody or antigen-binding fragment thereof may include antibody YN-011 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4. For example, the reference antibody can comprise a light chain variable region and a heavy chain variable region, the amino acid sequence of the light chain variable region can comprise SEQ ID NO: 18; and the amino acid sequence of the heavy chain variable region SEQ ID NO: 17 can be included. For example, the reference antibody can include antibody YN-011 or an antibody having the same light chain variable region and heavy chain variable region. For example, the reference antibody can comprise a light chain and a heavy chain, the amino acid sequence of the light chain can be as set forth in SEQ ID NO: 78 and the heavy chain amino acid sequence can be as set forth in SEQ ID NO:76. For example, the reference antibody can include antibody YN-011 or an antibody having the same light and heavy chains thereto.

例如，本申请所述的抗体、其抗原结合片段可与参比抗体竞争结合IL17蛋白(例如，人 IL17蛋白)。所述参比抗体可包含LCDR1-3和HCDR1-3，且其LCDR1的氨基酸序列可包括SEQ ID NO:22；LCDR2的氨基酸序列可包括SEQ ID NO:23；LCDR3的氨基酸序列可包括SEQ ID NO:24；其HCDR1的氨基酸序列可包括SEQ ID NO:19；HCDR2的氨基酸序列可包括SEQ ID NO:20；HCDR3的氨基酸序列可包括SEQ ID NO:21。例如，所述参比抗体可包括抗体YN-012或与其具有相同的LCDR1-3及HCDR1-3的抗体。例如，所述参比抗体可包含轻链可变区和重链可变区，所述轻链可变区的氨基酸序列可包括SEQ ID NO:36；且所述重链可变区的氨基酸序列可包括SEQ ID NO:35。例如，该参比抗体可包括抗体YN-012或与其具有相同的轻链可变区及重链可变区的抗体。例如，所述参比抗体可包含轻链和重链，所述轻链的氨基酸序列可如SEQ ID NO:84所示且所述重链氨基酸序列可如SEQ ID NO:82所示。例如，该参比抗体可包括抗体YN-012或与其具有相同的轻链及重链的抗体。For example, an antibody, antigen-binding fragment thereof, as described herein, can compete with a reference antibody for binding to an IL17 protein (e.g., human IL17 protein). The reference antibody may comprise LCDR1-3 and HCDR1-3, and the amino acid sequence of LCDR1 may comprise SEQ ID NO: 22; the amino acid sequence of LCDR2 may comprise SEQ ID NO: 23; the amino acid sequence of LCDR3 may comprise SEQ ID NO The amino acid sequence of HCDR1 may comprise SEQ ID NO: 19; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 20; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 21. For example, the reference antibody can include antibody YN-012 or an antibody having the same LCDR1-3 and HCDR1-3. For example, the reference antibody can comprise a light chain variable region and a heavy chain variable region, the amino acid sequence of the light chain variable region can comprise SEQ ID NO: 36; and the amino acid sequence of the heavy chain variable region SEQ ID NO: 35 can be included. For example, the reference antibody can include antibody YN-012 or an antibody having the same light chain variable region and heavy chain variable region. For example, the reference antibody can comprise a light chain and a heavy chain, the amino acid sequence of the light chain can be as set forth in SEQ ID NO: 84 and the heavy chain amino acid sequence can be as set forth in SEQ ID NO:82. For example, the reference antibody can include antibody YN-012 or an antibody having the same light and heavy chains thereto.

例如，本申请所述的抗体、其抗原结合片段可与参比抗体竞争结合IL17蛋白(例如，人IL17蛋白)。所述参比抗体可包含LCDR1-3和HCDR1-3，且其LCDR1的氨基酸序列可包括SEQ ID NO:40；LCDR2的氨基酸序列可包括SEQ ID NO:41；LCDR3的氨基酸序列可包括SEQ ID NO:42；其HCDR1的氨基酸序列可包括SEQ ID NO:37；HCDR2的氨基酸序列可包括SEQ ID NO:38；HCDR3的氨基酸序列可包括SEQ ID NO:39。例如，所述参比抗体可包括抗体YN-013或与其具有相同的LCDR1-3及HCDR1-3的抗体。例如，所述参比抗体可包含L-FR1-4及H-FR1-4，且L-FR1的氨基酸序列可包括SEQ ID NO:47；L-FR2的氨基酸序列可包括SEQ ID NO:48；L-FR3的氨基酸序列可包括SEQ ID NO:49；L-FR4的氨基酸序列可包括SEQ ID NO:50；且H-FR1的氨基酸序列可包括SEQ ID NO:43；H-FR2的氨基酸序列可包括SEQ ID NO:44；H-FR3的氨基酸序列可包括SEQ ID NO:45；H-FR4的氨基酸序列可包括SEQ ID NO:46。例如，该参比抗体可包括抗体YN-013或与其具有相同的LCDR1-3、HCDR1-3、L-FR1-4及H-FR1-4的抗体。例如，所述参比抗体可包含轻链可变区和重链可变区，所述轻链可变区的氨基酸序列可包括SEQ ID NO:54；且所述重链可变区的氨基酸序列可包括SEQ ID NO:53。例如，该参比抗体可包括抗体YN-013或与其具有相同的轻链可变区及重链可变区的抗体。例如，所述参比抗体可包含轻链和重链，所述轻链的氨基酸序列可如SEQ ID NO:90所示且所述重链的氨基酸序列可如SEQ ID NO:88所示。例如，该参比抗体可包括抗体YN-013或与其具有相同的轻链及重链的抗体。For example, an antibody, antigen-binding fragment thereof, as described herein, can compete with a reference antibody for binding to an IL17 protein (eg, a human IL17 protein). The reference antibody may comprise LCDR1-3 and HCDR1-3, and the amino acid sequence of LCDR1 may comprise SEQ ID NO: 40; the amino acid sequence of LCDR2 may comprise SEQ ID NO: 41; the amino acid sequence of LCDR3 may comprise SEQ ID NO The amino acid sequence of HCDR1 may comprise SEQ ID NO: 37; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 38; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 39. For example, the reference antibody can include antibody YN-013 or an antibody having the same LCDR1-3 and HCDR1-3. For example, the reference antibody may comprise L-FR1-4 and H-FR1-4, and the amino acid sequence of L-FR1 may comprise SEQ ID NO: 47; the amino acid sequence of L-FR2 may comprise SEQ ID NO: 48; The amino acid sequence of L-FR3 may comprise SEQ ID NO: 49; the amino acid sequence of L-FR4 may comprise SEQ ID NO: 50; and the amino acid sequence of H-FR1 may comprise SEQ ID NO: 43; the amino acid sequence of H-FR2 may The amino acid sequence comprising SEQ ID NO: 44; H-FR3 may comprise SEQ ID NO: 45; the amino acid sequence of H-FR4 may comprise SEQ ID NO: 46. For example, the reference antibody may comprise antibody YN-013 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4 and H-FR1-4. For example, the reference antibody can comprise a light chain variable region and a heavy chain variable region, the amino acid sequence of the light chain variable region can comprise SEQ ID NO: 54; and the amino acid sequence of the heavy chain variable region SEQ ID NO: 53 can be included. For example, the reference antibody can include antibody YN-013 or an antibody having the same light chain variable region and heavy chain variable region. For example, the reference antibody can comprise a light chain and a heavy chain, the amino acid sequence of the light chain can be as set forth in SEQ ID NO: 90 and the amino acid sequence of the heavy chain can be as set forth in SEQ ID NO:88. For example, the reference antibody can include antibody YN-013 or an antibody having the same light and heavy chains thereto.

例如，本申请所述的抗体、其抗原结合片段可与参比抗体竞争结合IL17蛋白(例如，人IL17蛋白)。所述参比抗体可包含LCDR1-3和HCDR1-3，且其LCDR1的氨基酸序列可包括SEQ ID NO:40；LCDR2的氨基酸序列可包括SEQ ID NO:41；LCDR3的氨基酸序列可包 括SEQ ID NO:102；其HCDR1的氨基酸序列可包括SEQ ID NO:37；HCDR2的氨基酸序列可包括SEQ ID NO:38；HCDR3的氨基酸序列可包括SEQ ID NO:100。例如，所述参比抗体可包括抗体YN-065或与其具有相同的LCDR1-3及HCDR1-3的抗体。例如，所述参比抗体可包含L-FR1-4及H-FR1-4，且L-FR1的氨基酸序列可包括SEQ ID NO:47；L-FR2的氨基酸序列可包括SEQ ID NO:48；L-FR3的氨基酸序列可包括SEQ ID NO:49；L-FR4的氨基酸序列可包括SEQ ID NO:50；且H-FR1的氨基酸序列可包括SEQ ID NO:43；H-FR2的氨基酸序列可包括SEQ ID NO:44；H-FR3的氨基酸序列可包括SEQ ID NO:45；H-FR4的氨基酸序列可包括SEQ ID NO:46。例如，该参比抗体可包括抗体YN-065或与其具有相同的LCDR1-3、HCDR1-3、L-FR1-4及H-FR1-4的抗体。例如，所述参比抗体可包含轻链可变区和重链可变区，所述轻链可变区的氨基酸序列可包括SEQ ID NO:103；且所述重链可变区的氨基酸序列可包括SEQ ID NO:105。例如，该参比抗体可包括抗体YN-065或与其具有相同的轻链可变区及重链可变区的抗体。例如，所述参比抗体可包含轻链和重链，所述轻链的氨基酸序列可如SEQ ID NO:104所示且所述重链的氨基酸序列可如SEQ ID NO:106所示。例如，该参比抗体可包括抗体YN-065或与其具有相同的轻链及重链的抗体。For example, an antibody, antigen-binding fragment thereof, as described herein, can compete with a reference antibody for binding to an IL17 protein (eg, a human IL17 protein). The reference antibody may comprise LCDR1-3 and HCDR1-3, and the amino acid sequence of LCDR1 may comprise SEQ ID NO: 40; the amino acid sequence of LCDR2 may comprise SEQ ID NO: 41; the amino acid sequence of LCDR3 may comprise SEQ ID NO The amino acid sequence of HCDR1 may comprise SEQ ID NO: 37; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 38; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 100. For example, the reference antibody can include antibody YN-065 or an antibody having the same LCDR1-3 and HCDR1-3. For example, the reference antibody may comprise L-FR1-4 and H-FR1-4, and the amino acid sequence of L-FR1 may comprise SEQ ID NO: 47; the amino acid sequence of L-FR2 may comprise SEQ ID NO: 48; The amino acid sequence of L-FR3 may comprise SEQ ID NO: 49; the amino acid sequence of L-FR4 may comprise SEQ ID NO: 50; and the amino acid sequence of H-FR1 may comprise SEQ ID NO: 43; the amino acid sequence of H-FR2 may The amino acid sequence comprising SEQ ID NO: 44; H-FR3 may comprise SEQ ID NO: 45; the amino acid sequence of H-FR4 may comprise SEQ ID NO: 46. For example, the reference antibody can include antibody YN-065 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4. For example, the reference antibody can comprise a light chain variable region and a heavy chain variable region, the amino acid sequence of the light chain variable region can comprise SEQ ID NO: 103; and the amino acid sequence of the heavy chain variable region SEQ ID NO: 105 can be included. For example, the reference antibody can include antibody YN-065 or an antibody having the same light chain variable region and heavy chain variable region. For example, the reference antibody can comprise a light chain and a heavy chain, the amino acid sequence of the light chain can be as set forth in SEQ ID NO: 104 and the amino acid sequence of the heavy chain can be as set forth in SEQ ID NO:106. For example, the reference antibody can include antibody YN-065 or an antibody having the same light and heavy chains thereto.

例如，本申请所述的抗体、其抗原结合片段可与参比抗体竞争结合IL17蛋白(例如，人IL17蛋白)。所述参比抗体可包含LCDR1-3和HCDR1-3，且其LCDR1的氨基酸序列可包括SEQ ID NO:40；LCDR2的氨基酸序列可包括SEQ ID NO:41；LCDR3的氨基酸序列可包括SEQ ID NO:102；其HCDR1的氨基酸序列可包括SEQ ID NO:37；HCDR2的氨基酸序列可包括SEQ ID NO:38；HCDR3的氨基酸序列可包括SEQ ID NO:101。例如，所述参比抗体可包括抗体YN-066或与其具有相同的LCDR1-3及HCDR1-3的抗体。例如，所述参比抗体可包含L-FR1-4及H-FR1-4，且L-FR1的氨基酸序列可包括SEQ ID NO:47；L-FR2的氨基酸序列可包括SEQ ID NO:48；L-FR3的氨基酸序列可包括SEQ ID NO:49；L-FR4的氨基酸序列可包括SEQ ID NO:50；且H-FR1的氨基酸序列可包括SEQ ID NO:43；H-FR2的氨基酸序列可包括SEQ ID NO:44；H-FR3的氨基酸序列可包括SEQ ID NO:45；H-FR4的氨基酸序列可包括SEQ ID NO:46。例如，该参比抗体可包括抗体YN-066或与其具有相同的LCDR1-3、HCDR1-3、L-FR1-4及H-FR1-4的抗体。例如，所述参比抗体可包含轻链可变区和重链可变区，所述轻链可变区的氨基酸序列可包括SEQ ID NO:103；且所述重链可变区的氨基酸序列可包括SEQ ID NO:107。例如，该参比抗体可包括抗体YN-066或与其具有相同的轻链可变区及重链可变区的抗体。例如，所述参比抗体可包含轻链和重链，所述轻链的氨基酸序列可如SEQ ID NO:104所示且所述重链的氨基酸序列可如SEQ ID NO:108所示。例如，该参比 抗体可包括抗体YN-066或与其具有相同的轻链及重链的抗体。For example, an antibody, antigen-binding fragment thereof, as described herein, can compete with a reference antibody for binding to an IL17 protein (eg, a human IL17 protein). The reference antibody may comprise LCDR1-3 and HCDR1-3, and the amino acid sequence of LCDR1 may comprise SEQ ID NO: 40; the amino acid sequence of LCDR2 may comprise SEQ ID NO: 41; the amino acid sequence of LCDR3 may comprise SEQ ID NO The amino acid sequence of HCDR1 may comprise SEQ ID NO: 37; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 38; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 101. For example, the reference antibody can include antibody YN-066 or an antibody having the same LCDR1-3 and HCDR1-3. For example, the reference antibody may comprise L-FR1-4 and H-FR1-4, and the amino acid sequence of L-FR1 may comprise SEQ ID NO: 47; the amino acid sequence of L-FR2 may comprise SEQ ID NO: 48; The amino acid sequence of L-FR3 may comprise SEQ ID NO: 49; the amino acid sequence of L-FR4 may comprise SEQ ID NO: 50; and the amino acid sequence of H-FR1 may comprise SEQ ID NO: 43; the amino acid sequence of H-FR2 may The amino acid sequence comprising SEQ ID NO: 44; H-FR3 may comprise SEQ ID NO: 45; the amino acid sequence of H-FR4 may comprise SEQ ID NO: 46. For example, the reference antibody can include antibody YN-066 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4. For example, the reference antibody can comprise a light chain variable region and a heavy chain variable region, the amino acid sequence of the light chain variable region can comprise SEQ ID NO: 103; and the amino acid sequence of the heavy chain variable region SEQ ID NO: 107 can be included. For example, the reference antibody can include antibody YN-066 or an antibody having the same light chain variable region and heavy chain variable region. For example, the reference antibody can comprise a light chain and a heavy chain, the amino acid sequence of the light chain can be as set forth in SEQ ID NO: 104 and the amino acid sequence of the heavy chain can be as set forth in SEQ ID NO:108. For example, the reference antibody can include antibody YN-066 or an antibody having the same light and heavy chains thereto.

例如，本申请所述的抗体、其抗原结合片段可与参比抗体竞争结合IL17蛋白(例如，人IL17蛋白)。所述参比抗体可包含LCDR1-3和HCDR1-3，且其LCDR1的氨基酸序列可包括SEQ ID NO:96；LCDR2的氨基酸序列可包括SEQ ID NO:5；LCDR3的氨基酸序列可包括SEQ ID NO:6；其HCDR1的氨基酸序列可包括SEQ ID NO:91；HCDR2的氨基酸序列可包括SEQ ID NO:2；HCDR3的氨基酸序列可包括SEQ ID NO:94。例如，所述参比抗体可包括抗体YN-067或与其具有相同的LCDR1-3及HCDR1-3的抗体。例如，所述参比抗体可包含L-FR1-4及H-FR1-4，且L-FR1的氨基酸序列可包括SEQ ID NO:97；L-FR2的氨基酸序列可包括SEQ ID NO:98；L-FR3的氨基酸序列可包括SEQ ID NO:13；L-FR4的氨基酸序列可包括SEQ ID NO:14；且H-FR1的氨基酸序列可包括SEQ ID NO:7；H-FR2的氨基酸序列可包括SEQ ID NO:8；H-FR3的氨基酸序列可包括SEQ ID NO:9；H-FR4的氨基酸序列可包括SEQ ID NO:10。例如，该参比抗体可包括抗体YN-067或与其具有相同的LCDR1-3、HCDR1-3、L-FR1-4及H-FR1-4的抗体。例如，所述参比抗体可包含轻链可变区和重链可变区，所述轻链可变区的氨基酸序列可包括SEQ ID NO:109；且所述重链可变区的氨基酸序列可包括SEQ ID NO:111。例如，该参比抗体可包括抗体YN-067或与其具有相同的轻链可变区及重链可变区的抗体。例如，所述参比抗体可包含轻链和重链，所述轻链的氨基酸序列可如SEQ ID NO:110所示且所述重链的氨基酸序列可如SEQ ID NO:112所示。例如，该参比抗体可包括抗体YN-067或与其具有相同的轻链及重链的抗体。For example, an antibody, antigen-binding fragment thereof, as described herein, can compete with a reference antibody for binding to an IL17 protein (eg, a human IL17 protein). The reference antibody may comprise LCDR1-3 and HCDR1-3, and the amino acid sequence of LCDR1 may include SEQ ID NO: 96; the amino acid sequence of LCDR2 may include SEQ ID NO: 5; the amino acid sequence of LCDR3 may include SEQ ID NO The amino acid sequence of HCDR1 may comprise SEQ ID NO: 91; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 2; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 94. For example, the reference antibody can include antibody YN-067 or an antibody having the same LCDR1-3 and HCDR1-3. For example, the reference antibody may comprise L-FR1-4 and H-FR1-4, and the amino acid sequence of L-FR1 may comprise SEQ ID NO:97; the amino acid sequence of L-FR2 may comprise SEQ ID NO:98; The amino acid sequence of L-FR3 may comprise SEQ ID NO: 13; the amino acid sequence of L-FR4 may comprise SEQ ID NO: 14; and the amino acid sequence of H-FR1 may comprise SEQ ID NO: 7; the amino acid sequence of H-FR2 may The amino acid sequence comprising SEQ ID NO: 8; H-FR3 may comprise SEQ ID NO: 9; the amino acid sequence of H-FR4 may comprise SEQ ID NO: 10. For example, the reference antibody can include antibody YN-067 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4. For example, the reference antibody can comprise a light chain variable region and a heavy chain variable region, the amino acid sequence of the light chain variable region can comprise SEQ ID NO: 109; and the amino acid sequence of the heavy chain variable region SEQ ID NO: 111 can be included. For example, the reference antibody can include antibody YN-067 or an antibody having the same light chain variable region and heavy chain variable region. For example, the reference antibody can comprise a light chain and a heavy chain, the amino acid sequence of the light chain can be as set forth in SEQ ID NO: 110 and the amino acid sequence of the heavy chain can be as set forth in SEQ ID NO: 112. For example, the reference antibody can include antibody YN-067 or an antibody having the same light and heavy chains thereto.

例如，本申请所述的抗体、其抗原结合片段可与参比抗体竞争结合IL17蛋白(例如，人IL17蛋白)。所述参比抗体可包含LCDR1-3和HCDR1-3，且其LCDR1的氨基酸序列可包括SEQ ID NO:96；LCDR2的氨基酸序列可包括SEQ ID NO:5；LCDR3的氨基酸序列可包括SEQ ID NO:6；其HCDR1的氨基酸序列可包括SEQ ID NO:1；HCDR2的氨基酸序列可包括SEQ ID NO:2；HCDR3的氨基酸序列可包括SEQ ID NO:95。例如，所述参比抗体可包括抗体YN-068或与其具有相同的LCDR1-3及HCDR1-3的抗体。例如，所述参比抗体可包含L-FR1-4及H-FR1-4，且L-FR1的氨基酸序列可包括SEQ ID NO:97；L-FR2的氨基酸序列可包括SEQ ID NO:98；L-FR3的氨基酸序列可包括SEQ ID NO:13；L-FR4的氨基酸序列可包括SEQ ID NO:14；且H-FR1的氨基酸序列可包括SEQ ID NO:7；H-FR2的氨基酸序列可包括SEQ ID NO:8；H-FR3的氨基酸序列可包括SEQ ID NO:9；H-FR4的氨基酸序列可包括SEQ ID NO:10。例如，该参比抗体可包括抗体YN-068或与其具有相同的LCDR1-3、HCDR1-3、L-FR1-4及H-FR1-4的抗体。例如，所述参比抗体可包含轻链可变区和重链可变区，所述轻 链可变区的氨基酸序列可包括SEQ ID NO:109；且所述重链可变区的氨基酸序列可包括SEQ ID NO:114。例如，该参比抗体可包括抗体YN-068或与其具有相同的轻链可变区及重链可变区的抗体。例如，所述参比抗体可包含轻链和重链，所述轻链的氨基酸序列可如SEQ ID NO:110所示且所述重链的氨基酸序列可如SEQ ID NO:115所示。例如，该参比抗体可包括抗体YN-068或与其具有相同的轻链及重链的抗体。For example, an antibody, antigen-binding fragment thereof, as described herein, can compete with a reference antibody for binding to an IL17 protein (eg, a human IL17 protein). The reference antibody may comprise LCDR1-3 and HCDR1-3, and the amino acid sequence of LCDR1 may include SEQ ID NO: 96; the amino acid sequence of LCDR2 may include SEQ ID NO: 5; the amino acid sequence of LCDR3 may include SEQ ID NO The amino acid sequence of HCDR1 may comprise SEQ ID NO: 1; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 2; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 95. For example, the reference antibody can include antibody YN-068 or an antibody having the same LCDR1-3 and HCDR1-3. For example, the reference antibody may comprise L-FR1-4 and H-FR1-4, and the amino acid sequence of L-FR1 may comprise SEQ ID NO:97; the amino acid sequence of L-FR2 may comprise SEQ ID NO:98; The amino acid sequence of L-FR3 may comprise SEQ ID NO: 13; the amino acid sequence of L-FR4 may comprise SEQ ID NO: 14; and the amino acid sequence of H-FR1 may comprise SEQ ID NO: 7; the amino acid sequence of H-FR2 may The amino acid sequence comprising SEQ ID NO: 8; H-FR3 may comprise SEQ ID NO: 9; the amino acid sequence of H-FR4 may comprise SEQ ID NO: 10. For example, the reference antibody can include antibody YN-068 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4. For example, the reference antibody can comprise a light chain variable region and a heavy chain variable region, the amino acid sequence of the light chain variable region can comprise SEQ ID NO: 109; and the amino acid sequence of the heavy chain variable region SEQ ID NO: 114 can be included. For example, the reference antibody can include antibody YN-068 or an antibody having the same light chain variable region and heavy chain variable region. For example, the reference antibody can comprise a light chain and a heavy chain, the amino acid sequence of the light chain can be as set forth in SEQ ID NO: 110 and the amino acid sequence of the heavy chain can be as set forth in SEQ ID NO: 115. For example, the reference antibody can include antibody YN-068 or an antibody having the same light and heavy chains thereto.

例如，本申请所述的抗体、其抗原结合片段可与参比抗体竞争结合IL17蛋白(例如，人IL17蛋白)。所述参比抗体可包含LCDR1-3和HCDR1-3，且其LCDR1的氨基酸序列可包括SEQ ID NO:96；LCDR2的氨基酸序列可包括SEQ ID NO:5；LCDR3的氨基酸序列可包括SEQ ID NO:6；其HCDR1的氨基酸序列可包括SEQ ID NO:92；HCDR2的氨基酸序列可包括SEQ ID NO:2；HCDR3的氨基酸序列可包括SEQ ID NO:94。例如，所述参比抗体可包括抗体YN-069或与其具有相同的LCDR1-3及HCDR1-3的抗体。例如，所述参比抗体可包含L-FR1-4及H-FR1-4，且L-FR1的氨基酸序列可包括SEQ ID NO:97；L-FR2的氨基酸序列可包括SEQ ID NO:98；L-FR3的氨基酸序列可包括SEQ ID NO:13；L-FR4的氨基酸序列可包括SEQ ID NO:14；且H-FR1的氨基酸序列可包括SEQ ID NO:7；H-FR2的氨基酸序列可包括SEQ ID NO:8；H-FR3的氨基酸序列可包括SEQ ID NO:9；H-FR4的氨基酸序列可包括SEQ ID NO:10。例如，该参比抗体可包括抗体YN-069或与其具有相同的LCDR1-3、HCDR1-3、L-FR1-4及H-FR1-4的抗体。例如，所述参比抗体可包含轻链可变区和重链可变区，所述轻链可变区的氨基酸序列可包括SEQ ID NO:109；且所述重链可变区的氨基酸序列可包括SEQ ID NO:117。例如，该参比抗体可包括抗体YN-069或与其具有相同的轻链可变区及重链可变区的抗体。例如，所述参比抗体可包含轻链和重链，所述轻链的氨基酸序列可如SEQ ID NO:110所示且所述重链的氨基酸序列可如SEQ ID NO:118所示。例如，该参比抗体可包括抗体YN-069或与其具有相同的轻链及重链的抗体。For example, an antibody, antigen-binding fragment thereof, as described herein, can compete with a reference antibody for binding to an IL17 protein (eg, a human IL17 protein). The reference antibody may comprise LCDR1-3 and HCDR1-3, and the amino acid sequence of LCDR1 may include SEQ ID NO: 96; the amino acid sequence of LCDR2 may include SEQ ID NO: 5; the amino acid sequence of LCDR3 may include SEQ ID NO The amino acid sequence of HCDR1 may comprise SEQ ID NO: 92; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 2; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 94. For example, the reference antibody can include antibody YN-069 or an antibody having the same LCDR1-3 and HCDR1-3. For example, the reference antibody may comprise L-FR1-4 and H-FR1-4, and the amino acid sequence of L-FR1 may comprise SEQ ID NO:97; the amino acid sequence of L-FR2 may comprise SEQ ID NO:98; The amino acid sequence of L-FR3 may comprise SEQ ID NO: 13; the amino acid sequence of L-FR4 may comprise SEQ ID NO: 14; and the amino acid sequence of H-FR1 may comprise SEQ ID NO: 7; the amino acid sequence of H-FR2 may The amino acid sequence comprising SEQ ID NO: 8; H-FR3 may comprise SEQ ID NO: 9; the amino acid sequence of H-FR4 may comprise SEQ ID NO: 10. For example, the reference antibody can include antibody YN-069 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4. For example, the reference antibody can comprise a light chain variable region and a heavy chain variable region, the amino acid sequence of the light chain variable region can comprise SEQ ID NO: 109; and the amino acid sequence of the heavy chain variable region SEQ ID NO: 117 can be included. For example, the reference antibody can include antibody YN-069 or an antibody having the same light chain variable region and heavy chain variable region. For example, the reference antibody can comprise a light chain and a heavy chain, the amino acid sequence of the light chain can be as set forth in SEQ ID NO: 110 and the amino acid sequence of the heavy chain can be as set forth in SEQ ID NO: 118. For example, the reference antibody can include antibody YN-069 or an antibody having the same light and heavy chains thereto.

例如，本申请所述的抗体、其抗原结合片段可与参比抗体竞争结合IL17蛋白(例如，人IL17蛋白)。所述参比抗体可包含LCDR1-3和HCDR1-3，且其LCDR1的氨基酸序列可包括SEQ ID NO:96；LCDR2的氨基酸序列可包括SEQ ID NO:5；LCDR3的氨基酸序列可包括SEQ ID NO:6；其HCDR1的氨基酸序列可包括SEQ ID NO:91；HCDR2的氨基酸序列可包括SEQ ID NO:93；HCDR3的氨基酸序列可包括SEQ ID NO:94。例如，所述参比抗体可包括抗体YN-070或与其具有相同的LCDR1-3及HCDR1-3的抗体。例如，所述参比抗体可包含L-FR1-4及H-FR1-4，且L-FR1的氨基酸序列可包括SEQ ID NO:97；L-FR2的氨基酸序列可包括SEQ ID NO:98；L-FR3的氨基酸序列可包括SEQ ID NO:13；L-FR4的氨基酸序列 可包括SEQ ID NO:14；且H-FR1的氨基酸序列可包括SEQ ID NO:7；H-FR2的氨基酸序列可包括SEQ ID NO:8；H-FR3的氨基酸序列可包括SEQ ID NO:99；H-FR4的氨基酸序列可包括SEQ ID NO:10。例如，该参比抗体可包括抗体YN-070或与其具有相同的LCDR1-3、HCDR1-3、L-FR1-4及H-FR1-4的抗体。例如，所述参比抗体可包含轻链可变区和重链可变区，所述轻链可变区的氨基酸序列可包括SEQ ID NO:109；且所述重链可变区的氨基酸序列可包括SEQ ID NO:120。例如，该参比抗体可包括抗体YN-069或与其具有相同的轻链可变区及重链可变区的抗体。例如，所述参比抗体可包含轻链和重链，所述轻链的氨基酸序列可如SEQ ID NO:110所示且所述重链的氨基酸序列可如SEQ ID NO:121所示。例如，该参比抗体可包括抗体YN-070或与其具有相同的轻链及重链的抗体。For example, an antibody, antigen-binding fragment thereof, as described herein, can compete with a reference antibody for binding to an IL17 protein (eg, a human IL17 protein). The reference antibody may comprise LCDR1-3 and HCDR1-3, and the amino acid sequence of LCDR1 may include SEQ ID NO: 96; the amino acid sequence of LCDR2 may include SEQ ID NO: 5; the amino acid sequence of LCDR3 may include SEQ ID NO The amino acid sequence of HCDR1 may comprise SEQ ID NO: 91; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 93; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 94. For example, the reference antibody can include antibody YN-070 or an antibody having the same LCDR1-3 and HCDR1-3. For example, the reference antibody may comprise L-FR1-4 and H-FR1-4, and the amino acid sequence of L-FR1 may comprise SEQ ID NO:97; the amino acid sequence of L-FR2 may comprise SEQ ID NO:98; The amino acid sequence of L-FR3 may comprise SEQ ID NO: 13; the amino acid sequence of L-FR4 may comprise SEQ ID NO: 14; and the amino acid sequence of H-FR1 may comprise SEQ ID NO: 7; the amino acid sequence of H-FR2 may The amino acid sequence comprising SEQ ID NO: 8; H-FR3 may comprise SEQ ID NO: 99; the amino acid sequence of H-FR4 may comprise SEQ ID NO: 10. For example, the reference antibody may include antibody YN-070 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4. For example, the reference antibody can comprise a light chain variable region and a heavy chain variable region, the amino acid sequence of the light chain variable region can comprise SEQ ID NO: 109; and the amino acid sequence of the heavy chain variable region SEQ ID NO: 120 can be included. For example, the reference antibody can include antibody YN-069 or an antibody having the same light chain variable region and heavy chain variable region. For example, the reference antibody can comprise a light chain and a heavy chain, the amino acid sequence of the light chain can be as set forth in SEQ ID NO: 110 and the amino acid sequence of the heavy chain can be as set forth in SEQ ID NO:121. For example, the reference antibody can include antibody YN-070 or an antibody having the same light and heavy chains thereto.

本申请所述抗体、其抗原结合片段Antibody, antigen-binding fragment thereof

在一个方面，本申请提供了一种抗体、其抗原结合片段，其以6×10 -9M以下(例如，所述K D的值可为不高于约6×10 -9M、不高于约1×10 -9M、不高于约9×10 -10M、不高于约8×10 -10M、不高于约7×10 -10M、不高于约6×10 -10M、不高于约5×10 -10M、不高于约4×10 -10M、不高于约3×10 -10M、不高于约2×10 -10M、不高于约1×10 -10M或不高于约1×10 -11M或以下)的K D值与IL17蛋白相结合。 In one aspect, the application provides an antibody, antigen-binding fragment thereof, which is 6×10 -9 M or less (for example, the value of K D may be not higher than about 6×10 -9 M, not high About 1×10 -9 M, not higher than about 9×10 −10 M, not higher than about 8×10 −10 M, not higher than about 7×10 −10 M, not higher than about 6×10 − 10 M, not higher than about 5 × 10 -10 M, not higher than about 4 × 10 -10 M, not higher than about 3 × 10 -10 M, not higher than about 2 × 10 -10 M, not higher than about 1 × 10 -10 M, or no greater than about 1 × 10 -11 M or less) of K D values of IL17 protein combination.

在某些实施方式中，本申请所述的抗体、其抗原结合片段可与IL17配体竞争对IL17蛋白的结合。在某些情形中，本申请所述的抗体、其抗原结合片段可抑制细胞因子的表达。例如，所述细胞因子可选自以下组：白介素和趋化因子。例如，所述趋化因子可以包含CXCL1。In certain embodiments, an antibody, antigen-binding fragment thereof, as described herein, competes with an IL17 ligand for binding to an IL17 protein. In certain instances, the antibodies, antigen-binding fragments thereof, of the present application inhibit the expression of cytokines. For example, the cytokine can be selected from the group consisting of interleukins and chemokines. For example, the chemokine can comprise CXCL1.

本申请所述的抗体、其抗原结合片段可缓解或治疗与IL17的不当或过度产生相关的疾病或病症。例如，所述疾病或病症可以选自以下组：强直性脊柱炎、银屑病关节炎、类风湿性关节炎、骨关节炎、骨植入物松动、急性移植排斥、呼吸道炎症、炎性肠病、败血症、败血症性或内毒素性休克、骨丢失、银屑病、变态反应、局部缺血、系统性硬化症、中风和哮喘。The antibodies, antigen-binding fragments thereof described herein, can alleviate or treat diseases or conditions associated with inappropriate or overproduction of IL17. For example, the disease or condition may be selected from the group consisting of ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, osteoarthritis, bone implant loosening, acute graft rejection, respiratory inflammation, inflammatory bowel Disease, sepsis, septic or endotoxic shock, bone loss, psoriasis, allergy, ischemia, systemic sclerosis, stroke and asthma.

本申请所述的IL17蛋白可包括人IL17A蛋白。例如，所述IL17蛋白可包含参见UniProtKB数据库中登录号Accession No.Q16552所示的氨基酸序列。The IL17 protein described herein can include the human IL17A protein. For example, the IL17 protein can comprise the amino acid sequence shown in accession number Accession No. Q16552 in the UniProtKB database.

在某些实施方式中，本申请所述的IL17蛋白可包括IL17F蛋白(例如，人IL17F蛋白)。例如，所述IL17F蛋白可包含参见NCBI数据库中登录号NP_443104.1所示的氨基酸序列。In certain embodiments, an IL17 protein described herein can include an IL17F protein (eg, a human IL17F protein). For example, the IL17F protein can comprise the amino acid sequence shown in Accession No. NP_443104.1 in the NCBI database.

本申请所述的抗原结合片段可选自下组：Fab，Fab’，F(ab)2、Fv片段、F(ab’)2，scFv，di-scfv和/或VhH。The antigen-binding fragments described herein may be selected from the group consisting of Fab, Fab', F(ab)2, Fv fragments, F(ab')2, scFv, di-scfv and/or VhH.

本申请所述的抗体、其抗原结合片段可包含抗体轻链或其片段。在某些实施方式中，所述抗体包括：单克隆抗体、单链抗体、嵌合抗体、人源化抗体和/或全人源抗体。例如，所述 抗体轻链或其片段可以包含人恒定区，所述人恒定区可包含人Igκ或Igλ恒定区。An antibody, antigen-binding fragment thereof, as described herein, can comprise an antibody light chain or a fragment thereof. In certain embodiments, the antibody comprises: a monoclonal antibody, a single chain antibody, a chimeric antibody, a humanized antibody, and/or a fully human antibody. For example, the antibody light chain or fragment thereof can comprise a human constant region, which can comprise a human Ig kappa or Ig lambda constant region.

本申请所述的抗体、其抗原结合片段可包含抗体轻链或其片段，所述抗体轻链或其片段还可包括LCDR1-3。An antibody, antigen-binding fragment thereof, as described herein, may comprise an antibody light chain or a fragment thereof, and the antibody light chain or fragment thereof may further comprise LCDR1-3.

在本申请中，所述抗体轻链或其片段可包含LCDR1，且所述LCDR1可包含下述任一项所示的氨基酸序列：SEQ ID NO:126、SEQ ID NO:22和SEQ ID NO:40。In the present application, the antibody light chain or a fragment thereof may comprise LCDR1, and the LCDR1 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 126, SEQ ID NO: 22, and SEQ ID NO: 40.

在本申请中，所述LCDR1可包含SEQ ID NO:126所示的氨基酸序列：In the present application, the LCDR1 may comprise the amino acid sequence set forth in SEQ ID NO: 126:

RSSQSLLHSNGYNYLX 16(SEQ ID NO:126)；其中，X 16＝D或E。 RSSQSLLHSNGYNYLX 16 (SEQ ID NO: 126); wherein X 16 = D or E.

在某些实施方式中，与SEQ ID NO:4所示抗体的LCDR1相比，所述LCDR1至少包含在选自以下的氨基酸取代：在X 16处的氨基酸取代。 In certain embodiments, the LCDR1 comprises at least an amino acid substitution selected from the group consisting of an amino acid substitution at X 16 as compared to LCDR1 of the antibody of SEQ ID NO: 4.

在某些实施方式中，与SEQ ID NO:4所示抗体的LCDR1相比，所述抗体LCDR1至少包含在至少包含在X 16处的氨基酸取代，其中，X 16处的氨基酸可被取代为D或E。 In certain embodiments, the antibody LCDR1 comprises at least an amino acid substitution at least at X 16 as compared to LCDR1 of the antibody of SEQ ID NO: 4, wherein the amino acid at X 16 can be substituted with D Or E.

例如，所述LCDR1可包含下述所示的氨基酸序列：SEQ ID NO:4和SEQ ID NO:96。For example, the LCDR1 may comprise the amino acid sequences shown below: SEQ ID NO: 4 and SEQ ID NO: 96.

在本申请中，所述抗体轻链或其片段可包含LCDR2，且所述LCDR2可包含选自下组的氨基酸序列：SEQ ID NO:5、SEQ ID NO:23和SEQ ID NO:41。In the present application, the antibody light chain or a fragment thereof may comprise LCDR2, and the LCDR2 may comprise an amino acid sequence selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 23, and SEQ ID NO: 41.

在本申请中，所述抗体轻链或其片段可包含LCDR3，所述LCDR3可包含下述任一项所示的氨基酸序列：SEQ ID NO:6、SEQ ID NO:24和SEQ ID NO:131。In the present application, the antibody light chain or a fragment thereof may comprise LCDR3, which may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 6, SEQ ID NO: 24, and SEQ ID NO: 131 .

在本申请中，所述LCDR3可包含SEQ ID NO:131所示的氨基酸序列：In the present application, the LCDR3 may comprise the amino acid sequence set forth in SEQ ID NO: 131:

QTWDX 5X 6TSKYV(SEQ ID NO:131)；其中，X 5＝H或Y；X 6＝G或W。 QTWDX 5 X 6 TSKYV (SEQ ID NO: 131); wherein X 5 = H or Y; X 6 = G or W.

在某些实施方式中，与SEQ ID NO:42所示的抗体的LCDR3相比，所述LCDR3至少包含在选自以下的氨基酸取代：在X 5和/或X 6处的氨基酸取代。 In certain embodiments, the SEQ ID NO: LCDR3 amino acid as compared to the antibody as shown in 42, the LCDR3 comprises at least a substituent selected from the following: In the amino acid substitution at X 5 and / or X 6.

在某些实施方式中，与SEQ ID NO:42所示的抗体的LCDR3相比，所述LCDR3包含在至少包含在X 5和/或X 6处的氨基酸取代，其中，X 5处的氨基酸可被取代为H或Y，X 6处的氨基酸可被取代为G或W。 In certain embodiments, the LCDR3 comprises an amino acid substitution at least at X 5 and/or X 6 compared to LCDR3 of the antibody set forth in SEQ ID NO:42, wherein the amino acid at X 5 is Substituted as H or Y, the amino acid at X 6 can be substituted with G or W.

例如，所述LCDR3可包含下述所示的氨基酸序列：SEQ ID NO:42和SEQ ID NO:102。For example, the LCDR3 can comprise the amino acid sequences shown below: SEQ ID NO: 42 and SEQ ID NO: 102.

在本申请所述的抗体、其抗原结合片段中，抗体轻链或其片段还可包括框架区L-FR1-4。在本申请中，所述框架区L-FR1-4可以选自以下组：人共有框架序列和人种系序列。In the antibodies, antigen-binding fragments thereof, of the present application, the antibody light chain or a fragment thereof may further comprise a framework region L-FR1-4. In the present application, the framework region L-FR1-4 may be selected from the group consisting of a human consensus framework sequence and a human germline sequence.

在本申请中，所述L-FR1的C末端可与所述LCDR1的N末端可直接或间接相连，所述L-FR1包含下述任一项所示的氨基酸序列：SEQ ID NO:127、SEQ ID NO:29和SEQ ID NO:47。In the present application, the C-terminus of the L-FR1 may be directly or indirectly linked to the N-terminus of the LCDR1, and the L-FR1 comprises the amino acid sequence shown in any one of the following: SEQ ID NO: 127, SEQ ID NO:29 and SEQ ID NO:47.

在本申请中，所述L-FR1可包含SEQ ID NO:127所示的氨基酸序列：In the present application, the L-FR1 may comprise the amino acid sequence set forth in SEQ ID NO: 127:

DIVMTQSPLSLX 12VTPGEPASISC(SEQ ID NO:127)；其中，X 12＝P或H。 DIVMTQSPLSLX 12 VTPGEPASISC (SEQ ID NO: 127); wherein X 12 = P or H.

在某些实施方式中，与SEQ ID NO:11所示的抗体的L-FR1相比，所述L-FR1至少包含在选自以下的氨基酸取代：在X 12处的氨基酸取代。 In certain embodiments, the L-FR1 comprises at least an amino acid substitution selected from the group consisting of amino acid substitutions at X 12 as compared to L-FR1 of the antibody set forth in SEQ ID NO: 11.

在某些实施方式中，与SEQ ID NO:11所示的抗体的L-FR1相比，所述L-FR1至少包含在至少包含在X 12处的氨基酸取代，其中，X 12处的氨基酸可被取代为P或H。 In certain embodiments, the L-FR1 comprises at least an amino acid substitution at least at X 12 as compared to L-FR1 of the antibody of SEQ ID NO: 11, wherein the amino acid at X 12 is Replaced with P or H.

例如，所述L-FR1可包含下述任一项所示的氨基酸序列：SEQ ID NO:11和SEQ ID NO:97。For example, the L-FR1 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 11 and SEQ ID NO: 97.

在本申请中，所述L-FR2可位于所述LCDR1与所述LCDR2之间，所述L-FR2可包含下述任一项所示的氨基酸序列：SEQ ID NO:128、SEQ ID NO:30和SEQ ID NO:48。In the present application, the L-FR2 may be located between the LCDR1 and the LCDR2, and the L-FR2 may comprise the amino acid sequence shown in any one of the following: SEQ ID NO: 128, SEQ ID NO: 30 and SEQ ID NO:48.

在本申请中，所述L-FR2可包含SEQ ID NO:128所示的氨基酸序列：In the present application, the L-FR2 may comprise the amino acid sequence set forth in SEQ ID NO: 128:

WYLQKPGQSPQX 12LIY(SEQ ID NO:128)；其中，X 12＝L或P。 WYLQKPGQSPQX 12 LIY (SEQ ID NO: 128); wherein X 12 = L or P.

在某些实施方式中，与SEQ ID NO:12所示的抗体的L-FR2相比，所述L-FR2至少包含在选自以下的氨基酸取代：在X 12处的氨基酸取代。 In certain embodiments, the L-FR2 comprises at least an amino acid substitution selected from the group consisting of an amino acid substitution at X 12 as compared to L-FR2 of the antibody set forth in SEQ ID NO: 12.

在某些实施方式中，与SEQ ID NO:12所示的抗体的L-FR2相比，所述L-FR2至少包含在至少包含在X 12处的氨基酸取代，其中，X 12处的氨基酸可被取代为L或P。 In certain embodiments, the L-FR2 comprises at least an amino acid substitution at least at X 12 as compared to L-FR2 of the antibody of SEQ ID NO: 12, wherein the amino acid at X 12 is Replaced with L or P.

例如，所述L-FR2可包含下述任一项所示的氨基酸序列：SEQ ID NO:12和SEQ ID NO:98。For example, the L-FR2 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 12 and SEQ ID NO: 98.

在本申请中，所述L-FR3可位于所述LCDR2与所述LCDR3之间，所述L-FR3可包含下述任一项所示的氨基酸序列：SEQ ID NO:13、SEQ ID NO:31和SEQ ID NO:49。In the present application, the L-FR3 may be located between the LCDR2 and the LCDR3, and the L-FR3 may comprise the amino acid sequence shown in any one of the following: SEQ ID NO: 13, SEQ ID NO: 31 and SEQ ID NO:49.

在本申请中，所述L-FR4的N末端可与所述LCDR3的C末端直接或间接相连，所述L-FR4可以包含选自下组的氨基酸序列：SEQ ID NO:14、SEQ ID NO:32和SEQ ID NO:50。In the present application, the N-terminus of the L-FR4 may be directly or indirectly linked to the C-terminus of the LCDR3, and the L-FR4 may comprise an amino acid sequence selected from the group consisting of SEQ ID NO: 14, SEQ ID NO. :32 and SEQ ID NO:50.

本申请中，所述的抗体、其抗原结合片段中的抗体轻链或其片段可包含轻链可变区VL，且所述轻链可变区VL可包含下述任一项所示的氨基酸序列：SEQ ID NO:16、SEQ ID NO:134、SEQ ID NO:34、SEQ ID NO:36、SEQ ID NO:52和SEQ ID NO:132。In the present application, the antibody light chain or the fragment thereof in the antigen-binding fragment thereof may comprise a light chain variable region VL, and the light chain variable region VL may comprise an amino acid represented by any one of the following Sequence: SEQ ID NO: 16, SEQ ID NO: 134, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 52, and SEQ ID NO: 132.

在某些实施方式中，所述轻链可变区可包含下述任一项所示的氨基酸序列：SEQ ID NO:54、SEQ ID NO:103、SEQ ID NO:18和SEQ ID NO:109。In certain embodiments, the light chain variable region can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO:54, SEQ ID NO:103, SEQ ID NO:18, and SEQ ID NO:109 .

在本申请中，所述抗体轻链可变区可包含SEQ ID NO:132所示的氨基酸序列：In the present application, the antibody light chain variable region may comprise the amino acid sequence set forth in SEQ ID NO: 132:

SYELTQPPSVSVSPGQTASITCSGDDLGSKYASWYQQKPGQSPVLVIYQDDQRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCQTWDX 92X 93TSKYVFGPGTKLTVLG(SEQ ID NO:132)；其中，X 92＝H或Y；X 93＝G或W。 SYELTQPPSVSVSPGQTASITCSGDDLGSKYASWYQQKPGQSPVLVIYQDDQRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCQTWDX 92 X 93 TSKYVFGPGTKLTVLG (SEQ ID NO: 132); wherein X 92 = H or Y; X 93 = G or W.

在一些实施方式中，与SEQ ID NO:54所示抗体的轻链可变区相比，所述抗体轻链可变区或其片段至少包含在选自以下任一组的氨基酸取代：在X 92和/或X 93处的氨基酸取代。 In some embodiments, the antibody light chain variable region or fragment thereof comprises at least one amino acid substitution selected from the group consisting of: Amino acid substitution at 92 and/or X 93 .

在一些实施方式中，与SEQ ID NO:54所示抗体的轻链可变区相比，所述抗体轻链可变 区或其片段至少包含在X 92和/或X 93处的氨基酸取代，其中，X 92处的氨基酸可被取代为H或Y；X 93处的氨基酸可被取代为G或W。 In some embodiments, the antibody light chain variable region or fragment thereof comprises at least an amino acid substitution at X 92 and/or X 93 as compared to the light chain variable region of the antibody set forth in SEQ ID NO:54. Among them, the amino acid at X 92 may be substituted with H or Y; the amino acid at X 93 may be substituted with G or W.

例如，所述抗体轻链可变区可包含下述任一项所示的氨基酸序列：SEQ ID NO:54和SEQ ID NO:103。For example, the antibody light chain variable region can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 54 and SEQ ID NO: 103.

在本申请中，所述抗体轻链可变区可包含SEQ ID NO:134所示的氨基酸序列：In the present application, the antibody light chain variable region may comprise the amino acid sequence set forth in SEQ ID NO: 134:

DIVMTQSPLSLX 12VTPGEPASISCRSSQSLLHSNGYNYLX 39WYLQKPGQSPQX 51LIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPTFGGGTKLEIKR； DIVMTQSPLSLX 12 VTPGEPASISCRSSQSLLHSNGYNYLX 39 WYLQKPGQSPQX 51 LIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPTFGGGTKLEIKR;

其中，X 12＝P或H；X 39＝D或E；X 51＝L或P。 Where X 12 = P or H; X 39 = D or E; X 51 = L or P.

在一些实施方式中，与SEQ ID NO:18所示抗体的轻链可变区相比，所述抗体轻链可变区或其片段可至少包含在选自以下任一组的氨基酸取代：在X 12、X 39和/或X 51处的氨基酸取代。 In some embodiments, the antibody light chain variable region or fragment thereof can comprise at least one amino acid substitution selected from the group consisting of: Amino acid substitution at X 12 , X 39 and/or X 51 .

在一些实施方式中，与SEQ ID NO:18所示抗体的轻链可变区相比，所述抗体轻链或其片段可至少包含在X 12、X 39和/或X 51处的氨基酸取代，其中，X 12处的氨基酸可被取代为P或H；X 39处的氨基酸可被取代为D或E；X 51处的氨基酸可被取代为L或P。 In some embodiments, the antibody light chain or fragment thereof can comprise at least amino acid substitutions at X 12 , X 39 and/or X 51 compared to the light chain variable region of the antibody set forth in SEQ ID NO:18 Wherein the amino acid at X 12 may be substituted with P or H; the amino acid at X 39 may be substituted with D or E; the amino acid at X 51 may be substituted with L or P.

例如，所述抗体轻链可变区可包含下述任一项所示的氨基酸序列：SEQ ID NO:18和SEQ ID NO:109。For example, the antibody light chain variable region can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 18 and SEQ ID NO: 109.

在本申请中，所述抗体轻链或其片段还可包含人恒定区或鼠恒定区。在本申请中，所述人恒定区可包括人Igκ或Igλ恒定区。In the present application, the antibody light chain or fragment thereof may further comprise a human constant region or a murine constant region. In the present application, the human constant region may comprise a human Igκ or Igλ constant region.

在本申请中，所述抗体轻链或其片段可包含下述任一项所示的氨基酸序列：SEQ ID NO:64、SEQ ID NO:68、SEQ ID NO:72、SEQ ID NO:138、SEQ ID NO:84和SEQ ID NO:136。在某些实施方式中，所述抗体轻链或其片段可包含下述任一项所示的氨基酸序列：SEQ ID NO:90、SEQ ID NO:104、SEQ ID NO:78和SEQ ID NO:110。在某些实施方式中，所述抗体轻链结合片段(例如，所述抗原结合片段可为Fab)可包含选自下组的氨基酸序列：SEQ ID NO:110。In the present application, the antibody light chain or a fragment thereof may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 64, SEQ ID NO: 68, SEQ ID NO: 72, SEQ ID NO: 138, SEQ ID NO: 84 and SEQ ID NO: 136. In certain embodiments, the antibody light chain or fragment thereof can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO:90, SEQ ID NO:104, SEQ ID NO:78, and SEQ ID NO: 110. In certain embodiments, the antibody light chain binding fragment (eg, the antigen binding fragment can be a Fab) can comprise an amino acid sequence selected from the group consisting of SEQ ID NO:110.

在本申请中，所述抗体轻链或其片段可包含SEQ ID NO:136所示的氨基酸序列：In the present application, the antibody light chain or fragment thereof may comprise the amino acid sequence set forth in SEQ ID NO: 136:

SYELTQPPSVSVSPGQTASITCSGDDLGSKYASWYQQKPGQSPVLVIYQDDQRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCQTWDX 92X 93TSKYVFGPGTKLTVLGTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:136)。 SYELTQPPSVSVSPGQTASITCSGDDLGSKYASWYQQKPGQSPVLVIYQDDQRPSGIPERFSGSNSGNTATLTISGTQAMDEADYYCQTWDX 92 X 93 TSKYVFGPGTKLTVLGTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 136).

其中，X 92＝H或Y；X 93＝G或W。 Where X 92 = H or Y; X 93 = G or W.

在一些实施方式中，与SEQ ID NO:90所示抗体的轻链相比，所述抗体轻链或其片段至少包含在选自以下任一组的氨基酸取代：在X 92和/或X 93处的氨基酸的取代。 In some embodiments, the antibody light chain or fragment thereof comprises at least an amino acid substitution at any one selected from the group consisting of: the X 92 and/or the X 93 , compared to the light chain of the antibody of SEQ ID NO:90. Substitution of amino acids.

在一些实施方式中，与SEQ ID NO:90所示抗体的轻链相比，所述抗体轻链或其片段至少包含在X 92和/或X 93处的氨基酸取代，其中，X 92处的氨基酸可被取代为H或Y；X 93处的氨基酸可被取代为G或W。 In some embodiments, the SEQ ID NO: 90 compared to FIG antibody light chain, said antibody or fragment thereof comprises a light chain amino acid and at least X 92 / X 93 at or substituted, wherein the, X 92 is The amino acid may be substituted with H or Y; the amino acid at X 93 may be substituted with G or W.

例如，所述抗体轻链或其片段可包含下述任一项所示的氨基酸序列：SEQ ID NO:90和SEQ ID NO:104。For example, the antibody light chain or fragment thereof can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 90 and SEQ ID NO: 104.

在本申请中，所述抗体轻链或其片段可包含SEQ ID NO:138所示的氨基酸序列：In the present application, the antibody light chain or fragment thereof may comprise the amino acid sequence set forth in SEQ ID NO: 138:

DIVMTQSPLSLX 12VTPGEPASISCRSSQSLLHSNGYNYLX 39WYLQKPGQSPQX 51LIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:138)。 DIVMTQSPLSLX 12 VTPGEPASISCRSSQSLLHSNGYNYLX 39 WYLQKPGQSPQX 51 LIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 138).

其中，X 12＝P或H；X 39＝D或E；X 51＝L或P。 Where X 12 = P or H; X 39 = D or E; X 51 = L or P.

在一些实施方式中，与SEQ ID NO:78所示抗体的轻链相比，所述抗体轻链或其片段至少包含在选自以下任一组的氨基酸取代：在X 12、X 39和/或X 51处的氨基酸的取代。 In some embodiments, the antibody light chain or fragment thereof comprises at least an amino acid substitution at any one of the group consisting of: X 12 , X 39 , and / or a light chain of the antibody of SEQ ID NO: 78 Or substitution of an amino acid at X 51 .

在一些实施方式中，与SEQ ID NO:78所示抗体的轻链相比，所述抗体轻链或其片段至少包含在X 12、X 39和/或X 51处的氨基酸取代，其中，X 12处的氨基酸可被取代为P或H；X 39处的氨基酸可被取代为D或E；X 51处的氨基酸可被取代为L或P。 In some embodiments, the antibody light chain or fragment thereof comprises at least an amino acid substitution at X 12 , X 39 and/or X 51 compared to the light chain of the antibody of SEQ ID NO: 78, wherein X The amino acid at 12 may be substituted with P or H; the amino acid at X 39 may be substituted with D or E; the amino acid at X 51 may be substituted with L or P.

例如，所述抗体轻链或其片段可包含下述任一项所示的氨基酸序列：SEQ ID NO:78和SEQ ID NO:110。For example, the antibody light chain or fragment thereof can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO:78 and SEQ ID NO:110.

在本申请中，本申请所述的抗体、其抗原结合片段可包含抗体重链或其片段，所述重链或其片段可包括HCDR1-3。In the present application, an antibody, antigen-binding fragment thereof, as described herein, may comprise an antibody heavy chain or a fragment thereof, and the heavy chain or fragment thereof may comprise HCDR1-3.

在本申请中，所述抗体重链或其片段可包含HCDR1，所述HCDR1包含下述任一项所示的氨基酸序列：SEQ ID NO:123、SEQ ID NO:19和SEQ ID NO:37。在某些实施方式中，所述HCDR1包含下述任一项所示的氨基酸序列：SEQ ID NO:1、SEQ ID NO:91和SEQ ID NO:92。In the present application, the antibody heavy chain or fragment thereof may comprise HCDR1 comprising the amino acid sequence set forth in any one of the following: SEQ ID NO: 123, SEQ ID NO: 19 and SEQ ID NO: 37. In certain embodiments, the HCDR1 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 1, SEQ ID NO: 91, and SEQ ID NO: 92.

在本申请中，所述HCDR1可包含SEQ ID NO:123所示的氨基酸序列：In the present application, the HCDR1 may comprise the amino acid sequence set forth in SEQ ID NO: 123:

DYAX 4X 5(SEQ ID NO:123)；其中，X 4＝M或I；X 5＝S或N。 DYAX 4 X 5 (SEQ ID NO: 123); wherein X 4 = M or I; X 5 = S or N.

在一些实施方式中，与SEQ ID NO:1所示抗体的HCDR1相比，所述HCDR1至少包含在选自以下任一组的氨基酸取代：In some embodiments, the HCDR1 comprises at least an amino acid substitution at a group selected from the group consisting of the HCDR1 of the antibody of SEQ ID NO:

(1)在X 5处的氨基酸的取代； (1) substitution of an amino acid at X 5 ;

(2)在X 4和/或X 5处的氨基酸的取代。 (2) Substitution of an amino acid at X 4 and/or X 5 .

在一些实施方式中，与SEQ ID NO:1所示抗体的HCDR1相比，所述HCDR1至少包含在X 5处的氨基酸取代，其中，X 92处的氨基酸可被取代为M或I。 In some embodiments, the SEQ ID NO: 1 shown in HCDR1 antibody compared to the HCDR1 comprises at least the amino acid substitution at X 5, wherein amino acids at X 92 may be replaced by M or I.

在一些实施方式中，与SEQ ID NO:1所示抗体的HCDR1相比，所述HCDR1至少包含在X 4和/或X 5处的氨基酸取代，其中，X 92处的氨基酸可被取代为M或I，X 5处的氨基酸可被取代为S或N。 In some embodiments, the HCDR1 comprises at least an amino acid substitution at X 4 and/or X 5 compared to HCDR1 of the antibody of SEQ ID NO: 1, wherein the amino acid at X 92 can be substituted with M Or the amino acid at I, X 5 can be substituted with S or N.

例如，所述HCDR1可包含下述任一项所示的氨基酸序列：SEQ ID NO:1、SEQ ID NO:91和SEQ ID NO:92。For example, the HCDR1 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 1, SEQ ID NO: 91, and SEQ ID NO: 92.

在本申请中，所述抗体重链或其片段可包含HCDR2，所述HCDR2包含下述任一项所示的氨基酸序列：SEQ ID NO:124、SEQ ID NO:20和SEQ ID NO:38。在某些实施方式中，所述HCDR2包含下述任一项所示的氨基酸序列：SEQ ID NO:2和SEQ ID NO:93。In the present application, the antibody heavy chain or a fragment thereof may comprise an HCDR2 comprising the amino acid sequence set forth in any one of the following: SEQ ID NO: 124, SEQ ID NO: 20, and SEQ ID NO: 38. In certain embodiments, the HCDR2 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 2 and SEQ ID NO: 93.

在本申请中，所述抗体重链或其片段可包含SEQ ID NO:124所示的氨基酸序列：In the present application, the antibody heavy chain or fragment thereof may comprise the amino acid sequence set forth in SEQ ID NO: 124:

FIRSKAYGGTTEYAX 15SVKG(SEQ ID NO:124)；其中，X 15＝T或A。 FIRSKAYGGTTEYAX 15 SVKG (SEQ ID NO: 124); wherein X 15 = T or A.

在一些实施方式中，与SEQ ID NO:2所示抗体的HCDR2相比，所述HCDR2至少包含在选自以下任一组的氨基酸取代：在X 15处的氨基酸的取代。 In some embodiments, the HCDR2 comprises at least an amino acid substitution at any one of the group consisting of: a substitution of an amino acid at X 15 as compared to the HCDR2 of the antibody of SEQ ID NO: 2.

在一些实施方式中，与SEQ ID NO:2所示抗体的HCDR2相比，所述HCDR2至少包含在X 15处的氨基酸取代，其中，X 15处的氨基酸可被取代为T或A。 In some embodiments, the SEQ ID NO: 2 as compared to FIG antibody HCDR2, HCDR2 comprising the amino acid substitutions in at least 15 of the X, wherein the amino acid at 15 X may be substituted is T or A.

例如，所述HCDR2可包含下述任一项所示的氨基酸序列：SEQ ID NO:2和SEQ ID NO:93。For example, the HCDR2 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 2 and SEQ ID NO: 93.

在本申请中，所述抗体重链或其片段包含HCDR3，且所述HCDR3可包含下述任一项所示的氨基酸序列：SEQ ID NO:125、SEQ ID NO:21和SEQ ID NO:130。在本申请中，所述HCDR3可包含下述任一项所示的氨基酸序列：SEQ ID NO:3、SEQ ID NO:94、SEQ ID NO:95、SEQ ID NO:39、SEQ ID NO:100和SEQ ID NO:101。In the present application, the antibody heavy chain or fragment thereof comprises HCDR3, and the HCDR3 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 125, SEQ ID NO: 21, and SEQ ID NO: 130 . In the present application, the HCDR3 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 3, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 39, SEQ ID NO: 100 And SEQ ID NO:101.

在本申请中，所述HCDR3可包含SEQ ID NO:125所示的氨基酸序列：In the present application, the HCDR3 may comprise the amino acid sequence set forth in SEQ ID NO: 125:

DGSDX 5IRYX 9DWLFNYWYFDL(SEQ ID NO:125)；其中，X 5＝G或E，X 9＝F或L。 DGSDX 5 IRYX 9 DWLFNYWYFDL (SEQ ID NO: 125); wherein X 5 = G or E, X 9 = F or L.

在一些实施方式中，与SEQ ID NO:3所示抗体的HCDR3相比，所述HCDR3可至少包含在选自以下任一组的氨基酸取代：In some embodiments, the HCDR3 can comprise at least an amino acid substitution at any one selected from the group consisting of the HCDR3 of the antibody of SEQ ID NO: 3:

(1)在X 5处的氨基酸的取代； (1) substitution of an amino acid at X 5 ;

(2)在X 5和/或X 9处的氨基酸的取代。 (2) Substitution of amino acids at X 5 and/or X 9 .

在一些实施方式中，与SEQ ID NO:3所示抗体的HCDR3相比，所述HCDR3可至少包含在X 5处的氨基酸取代，其中，X 5处的氨基酸可被取代为G或E。 In some embodiments, the SEQ ID NO: 3 as compared to an antibody HCDR3 shown, the HCDR3 may comprise at least the amino acid substitution at X 5, wherein X 5 amino acids may be substituted at G or E.

在一些实施方式中，与SEQ ID NO:3所示抗体的HCDR3相比，所述HCDR3可至少包含在X 5和/或X 9处的氨基酸取代，其中，X 5处的氨基酸可被取代为G或E，X 9处的氨基酸可被取代为F或L。 In some embodiments, the HCDR3 may comprise at least an amino acid substitution at X 5 and/or X 9 compared to the HCDR3 of the antibody of SEQ ID NO: 3, wherein the amino acid at X 5 may be substituted The amino acid at G or E, X 9 can be substituted with F or L.

例如，所述HCDR3可包含下述任一项所示的氨基酸序列：SEQ ID NO:3、SEQ ID NO:94和SEQ ID NO:95。For example, the HCDR3 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO:3, SEQ ID NO:94, and SEQ ID NO:95.

在本申请中，所述HCDR3可包含SEQ ID NO:130所示的氨基酸序列：In the present application, the HCDR3 may comprise the amino acid sequence set forth in SEQ ID NO: 130:

GX 2X 3SX 5X 6X 7FDY(SEQ ID NO:130)。 GX 2 X 3 SX 5 X 6 X 7 FDY (SEQ ID NO: 130).

其中X 2＝R或G；X 3＝Y或N；X 5＝G或D；X 6＝W或F；X 7＝Y或N。 Wherein X 2 = R or G; X 3 = Y or N; X 5 = G or D; X 6 = W or F; X 7 = Y or N.

在一些实施方式中，与SEQ ID NO:39所示抗体的重链相比，所述HCDR3可至少包含在选自以下任一组的氨基酸取代：In some embodiments, the HCDR3 can comprise at least an amino acid substitution at any one selected from the group consisting of the heavy chain of the antibody set forth in SEQ ID NO:39:

(1)在X 2、X 3、X 5和/或X 7处的氨基酸的取代； (1) substitution of an amino acid at X 2 , X 3 , X 5 and/or X 7 ;

(2)在X 3、X 6和/或X 7处的氨基酸的取代。 (2) Substitution of amino acids at X 3 , X 6 and/or X 7 .

在一些实施方式中，与SEQ ID NO:39所示抗体的HCDR3相比，所述HCDR3可至少包含在X 5处的氨基酸取代，其中，X 2处的氨基酸可被取代为R或G，X 3处的氨基酸可被取代为Y或N，X 5处的氨基酸可被取代为G或D，X 7处的氨基酸可被取代为Y或N。 In some embodiments, the HCDR3 may comprise at least an amino acid substitution at X 5 compared to the HCDR3 of the antibody of SEQ ID NO: 39, wherein the amino acid at X 2 may be substituted with R or G, X The amino acid at 3 may be substituted with Y or N, the amino acid at X 5 may be substituted with G or D, and the amino acid at X 7 may be substituted with Y or N.

在一些实施方式中，与SEQ ID NO:39所示抗体的HCDR3相比，所述抗体HCDR3可至少包含在X 3、X 6和/或X 7处的氨基酸取代，其中，X 3处的氨基酸可被取代为Y或N，X 6处的氨基酸可被取代为W或F，X 7处的氨基酸可被取代为Y或N。 In some embodiments, the SEQ ID NO: 39 shown in HCDR3 antibody as compared to the antibody HCDR3 amino acid may comprise at least X / X 7 or at 3, X 6 and substituted, wherein, at the amino acid X 3 It may be substituted with Y or N, the amino acid at X 6 may be substituted with W or F, and the amino acid at X 7 may be substituted with Y or N.

例如，所述HCDR3可包含下述任一项所示的氨基酸序列：SEQ ID NO:39、SEQ ID NO:100、SEQ ID NO:101。For example, the HCDR3 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 39, SEQ ID NO: 100, SEQ ID NO: 101.

本申请所述的抗体、其抗原结合片段中的抗体重链或其片段还可以包括框架区H-FR1-4。在本申请中，所述框架区可以选自以下组：人共有框架序列和人种系序列。The antibody heavy chain or fragment thereof in the antibody, antigen-binding fragment thereof described herein may further comprise a framework region H-FR1-4. In the present application, the framework regions may be selected from the group consisting of human consensus framework sequences and human germline sequences.

在某些实施方式中，所述H-FR1的C末端可与所述HCDR1的N末端直接或间接相连，所述H-FR1可以包含选自下组的氨基酸序列：SEQ ID NO:7、SEQ ID NO:25和SEQ ID NO:43。In certain embodiments, the C-terminus of the H-FR1 can be directly or indirectly linked to the N-terminus of the HCDR1, and the H-FR1 can comprise an amino acid sequence selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 25 and SEQ ID NO: 43.

在某些实施方式中，所述H-FR2可位于所述HCDR1与所述HCDR2之间，所述H-FR2可以包含选自下组的氨基酸序列：SEQ ID NO:8、SEQ ID NO:26和SEQ ID NO:44。In certain embodiments, the H-FR2 can be between the HCDR1 and the HCDR2, and the H-FR2 can comprise an amino acid sequence selected from the group consisting of SEQ ID NO:8, SEQ ID NO:26 And SEQ ID NO:44.

在某些实施方式中，所述H-FR3可位于所述HCDR2与所述HCDR3之间，且所述H-FR3可以包含下述任一项所示的氨基酸序列：SEQ ID NO:129、SEQ ID NO:27和SEQ ID NO:45。例如，所述H-FR3可包含下述任一项所示的氨基酸序列：SEQ ID NO:9和SEQ ID NO:99。In certain embodiments, the H-FR3 can be between the HCDR2 and the HCDR3, and the H-FR3 can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 129, SEQ ID NO: 27 and SEQ ID NO: 45. For example, the H-FR3 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 9 and SEQ ID NO: 99.

在本申请中，所述H-FR3可包含SEQ ID NO:129所示的氨基酸序列：In the present application, the H-FR3 may comprise the amino acid sequence set forth in SEQ ID NO: 129:

RFTISRDDSKSIAYLQMNSLKTX 23DTAVYYCAR(SEQ ID NO:129)；其中X 23＝E或Q。 RFTISRDDSKSIAYLQMNSLKTX 23 DTAVYYCAR (SEQ ID NO: 129); wherein X 23 = E or Q.

在一些实施方式中，与SEQ ID NO:9所示抗体的H-FR3相比，所述H-FR3至少包含在选自以下的氨基酸取代：在X 23处的氨基酸的取代。 In some embodiments, the SEQ ID NO: 9 amino acids of the antibody compared to H-FR3, H-FR3 comprising the at least a substituent selected from: the amino acid substitution at X 23 in.

在一些实施方式中，与SEQ ID NO:9所示抗体的H-FR3相比，所述H-FR3至少包含在X 5处的氨基酸取代，其中，X 23处的氨基酸可被取代为E或Q。 In some embodiments, the H-FR3 comprises at least an amino acid substitution at X 5 compared to H-FR3 of the antibody of SEQ ID NO: 9, wherein the amino acid at X 23 can be substituted with E or Q.

例如，所述H-FR3可包含下述任一项所示的氨基酸序列：SEQ ID NO:9和SEQ ID NO:99。For example, the H-FR3 may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 9 and SEQ ID NO: 99.

在某些实施方式中，所述H-FR4的N末端可与所述HCDR3的C末端直接或间接相连，且所述H-FR4可包含选自下组的氨基酸序列：SEQ ID NO:10、SEQ ID NO:28和SEQ ID NO:46。In certain embodiments, the N-terminus of the H-FR4 can be directly or indirectly linked to the C-terminus of the HCDR3, and the H-FR4 can comprise an amino acid sequence selected from the group consisting of SEQ ID NO: SEQ ID NO:28 and SEQ ID NO:46.

在本申请中，所述抗体重链或其片段可包含重链可变区VH，且所述重链可变区VH可包含下述任一项所示的氨基酸序列：SEQ ID NO:15、SEQ ID NO:135、SEQ ID NO:33、SEQ ID NO:35、SEQ ID NO:51和SEQ ID NO:133。在某些实施方式中，所述重链可变区VH可包含下述任一项所示的氨基酸序列：SEQ ID NO:53、SEQ ID NO:105、SEQ ID NO:107、SEQ ID NO:17、SEQ ID NO:111、SEQ ID NO:114、SEQ ID NO:117和SEQ ID NO:120。In the present application, the antibody heavy chain or a fragment thereof may comprise a heavy chain variable region VH, and the heavy chain variable region VH may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: SEQ ID NO: 135, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 51 and SEQ ID NO: 133. In certain embodiments, the heavy chain variable region VH can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO:53, SEQ ID NO:105, SEQ ID NO:107, SEQ ID NO: 17. SEQ ID NO: 111, SEQ ID NO: 114, SEQ ID NO: 117, and SEQ ID NO: 120.

在本申请中，所述抗体重链可变区可包含SEQ ID NO:133所示的氨基酸序列：In the present application, the antibody heavy chain variable region may comprise the amino acid sequence set forth in SEQ ID NO: 133:

QVTLKESGGGLIQPGGSLRLSCAASGFTVSSNHMSWVRQAPGKGLEWVSIIYSDGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGX 99X 100SX 102X 103X 104FDYWGQGTLVTVSS(SEQ ID NO:133)；其中X 99＝R或G；X 100＝Y或N；X 102＝G或D；X 103＝W或F；X 104＝Y、N或S。 QVTLKESGGGLIQPGGSLRLSCAASGFTVSSNHMSWVRQAPGKGLEWVSIIYSDGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGX 99 X 100 SX 102 X 103 X 104 FDYWGQGTLVTVSS (SEQ ID NO: 133); wherein X 99 = R or G; X 100 = Y or N; X 102 = G or D; X 103 = W or F; X 104 =Y, N or S.

在一些实施方式中，与SEQ ID NO:53所示抗体的重链可变区相比，所述重链可变区可至少包含在选自以下至少一种的氨基酸取代：In some embodiments, the heavy chain variable region can comprise at least one amino acid substitution at least one selected from the group consisting of the heavy chain variable region of the antibody of SEQ ID NO: 53:

(1)在X 99，X 100，X 102和/或X 104处的氨基酸的取代； (1) substitution of an amino acid at X 99 , X 100 , X 102 and/or X 104 ;

(2)在X 100，X 103和/或X 104处的氨基酸的取代。 (2) Substitution of amino acids at X 100 , X 103 and/or X 104 .

在一些实施方式中，与SEQ ID NO:53所示抗体的重链可变区相比，所述重链可变区可至少包含在X 99，X 100，X 102和/或X 104处的氨基酸取代，其中，X 99处的氨基酸可被取代为R或G，X 100处的氨基酸可被取代为Y或N，X 102处的氨基酸可被取代为G或D，X 103处的氨基酸可被取代为W或F，X 104处的氨基酸可被取代为Y或N。 In some embodiments, the heavy chain variable region can comprise at least at X 99 , X 100 , X 102 and/or X 104 as compared to the heavy chain variable region of the antibody set forth in SEQ ID NO:53 Amino acid substitution, wherein the amino acid at X 99 can be substituted with R or G, the amino acid at X 100 can be substituted with Y or N, the amino acid at X 102 can be substituted with G or D, and the amino acid at X 103 can be Substituted as W or F, the amino acid at X 104 can be substituted with Y or N.

在一些实施方式中，与SEQ ID NO:53所示抗体的重链可变区相比，所述重链可变区可至少包含在X 100，X 103和/或X 104处的氨基酸取代，其中，X 100处的氨基酸可被取代为Y或N，X 103处的氨基酸可被取代为W或F，X 104处的氨基酸可被取代为Y或S。 In some embodiments, the heavy chain variable region can comprise at least an amino acid substitution at X 100 , X 103 and/or X 104 as compared to the heavy chain variable region of the antibody set forth in SEQ ID NO:53. Wherein, the amino acid at X 100 can be substituted with Y or N, the amino acid at X 103 can be substituted with W or F, and the amino acid at X 104 can be substituted with Y or S.

例如，所述抗体重链可变区可包含下述任一项所示的氨基酸序列：SEQ ID NO:53、SEQ ID  NO:105和SEQ ID NO:107。For example, the antibody heavy chain variable region can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 53, SEQ ID NO: 105, and SEQ ID NO: 107.

在本申请中，所述抗体重链可变区可包含SEQ ID NO:135所示的氨基酸序列：In the present application, the antibody heavy chain variable region may comprise the amino acid sequence set forth in SEQ ID NO: 135:

QVQLVESGGGLVQPGRSLRLSCTASGFTFGDYAX 34X 35WFRQAPGKGLEWVGFIRSKAYGGTTEYAX 54SVKGRFTISRDDSKSIAYLQMNSLKTX 91DTAVYYCARDGSDX 105IRYX 109DWLFNYWYFDLWGRGTLVTVSS(SEQ ID NO:135)，其中X34＝M或I；X35＝S或N；X54＝A或T；X91＝E或Q；X105＝G或E；X109＝F或L。 QVQLVESGGGLVQPGRSLRLSCTASGFTFGDYAX 34 X 35 WFRQAPGKGLEWVGFIRSKAYGGTTEYAX 54 SVKGRFTISRDDSKSIAYLQMNSLKTX 91 DTAVYYCARDGSDX 105 IRYX 109 DWLFNYWYFDLWGRGTLVTVSS (SEQ ID NO: 135), where X34=M or I; X35=S or N; X54=A or T; X91=E or Q; X105=G or E; X109 = F or L.

在一些实施方式中，与SEQ ID NO:17所示抗体的重链可变区相比，所述重链可变区至少包含在选自以下至少一种的氨基酸取代：In some embodiments, the heavy chain variable region comprises at least one amino acid substitution at least one selected from the group consisting of the heavy chain variable region of the antibody of SEQ ID NO:17:

(1)在X 35和/或X 105处的氨基酸的取代； (1) substitution of an amino acid at X 35 and/or X 105 ;

(2)在X 105和/或X 109处的氨基酸的取代； (2) substitution of an amino acid at X 105 and/or X 109 ;

(3)在X 34、X 35和/或X 105处的氨基酸的取代； (3) substitution of an amino acid at X 34 , X 35 and/or X 105 ;

(4)在X 35、X 91和/或X 105处的氨基酸的取代。 (4) Substitution of amino acids at X 35 , X 91 and/or X 105 .

在一些实施方式中，与SEQ ID NO:17所示抗体的重链可变区相比，所述重链可变区可至少包含在X 35和/或X 105处的氨基酸取代，其中，X 35处的氨基酸可被取代为S或N，X 105处的氨基酸可被取代为G或E。 In some embodiments, the heavy chain variable region can comprise at least an amino acid substitution at X35 and/or X105 , wherein X is compared to the heavy chain variable region of the antibody of SEQ ID NO:17 The amino acid at 35 can be substituted with S or N, and the amino acid at X 105 can be substituted with G or E.

在一些实施方式中，与SEQ ID NO:17所示抗体的重链可变区相比，所述重链可变区可至少包含在X 105和/或X 109处的氨基酸取代，其中，X 105处的氨基酸可被取代为G或E，X 109处的氨基酸可被取代为F或L。 In some embodiments, the heavy chain variable region can comprise at least an amino acid substitution at X 105 and/or X 109 compared to the heavy chain variable region of the antibody set forth in SEQ ID NO:17, wherein X The amino acid at 105 can be substituted with G or E, and the amino acid at X 109 can be substituted with F or L.

在一些实施方式中，与SEQ ID NO:17所示抗体的重链可变区相比，所述重链可变区可至少包含在X 34、X 35和/或X 105处的氨基酸取代，其中，X 34处的氨基酸可被取代为M或I，X 35处的氨基酸可被取代为S或N，X 105处的氨基酸可被取代为G或E。 In some embodiments, the SEQ ID NO: antibody heavy chain variable region as compared to the FIG. 17, the heavy chain variable region may comprise at least 34 amino acid X, X 35, and / or substituted at X 105, Wherein the amino acid at X 34 may be substituted with M or I, the amino acid at X 35 may be substituted with S or N, and the amino acid at X 105 may be substituted with G or E.

在一些实施方式中，与SEQ ID NO:17所示抗体的重链可变区相比，所述重链可变区可至少包含在X 34、X 35和/或X 105处的氨基酸取代，其中，X 35处的氨基酸可被取代为S或N，X 91处的氨基酸可被取代为E或Q，X 105处的氨基酸可被取代为G或E。 In some embodiments, the SEQ ID NO: antibody heavy chain variable region as compared to the FIG. 17, the heavy chain variable region may comprise at least 34 amino acid X, X 35, and / or substituted at X 105, Wherein the amino acid at X 35 may be substituted with S or N, the amino acid at X 91 may be substituted with E or Q, and the amino acid at X 105 may be substituted with G or E.

例如，所述抗体重链可变区可包含下述任一项所示的氨基酸序列：SEQ ID NO:17、SEQ ID NO:111、SEQ ID NO:114、SEQ ID NO:117和SEQ ID NO:120。For example, the antibody heavy chain variable region may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 17, SEQ ID NO: 111, SEQ ID NO: 114, SEQ ID NO: 117, and SEQ ID NO : 120.

在本申请所述的抗体、其抗原结合片段中，所述抗体重链或其片段还可以包含人恒定区，且所述人恒定区可以包括人IgG恒定区。例如，所述人IgG恒定区可包含人IgG1恒定区。In the antibodies, antigen-binding fragments thereof, of the present application, the antibody heavy chain or a fragment thereof may further comprise a human constant region, and the human constant region may comprise a human IgG constant region. For example, the human IgG constant region can comprise a human IgGl constant region.

在本申请中，所述抗体重链或其片段可包含下述任一项所示的氨基酸序列：SEQ ID NO:62、SEQ ID NO:66、SEQ ID NO:70、SEQ ID NO:139、SEQ ID NO:82和SEQ ID NO:137。In the present application, the antibody heavy chain or a fragment thereof may comprise the amino acid sequence set forth in any one of the following: SEQ ID NO: 62, SEQ ID NO: 66, SEQ ID NO: 70, SEQ ID NO: 139, SEQ ID NO: 82 and SEQ ID NO: 137.

在某些实施方式中，所述重链可包含下述任一项所示的氨基酸序列：SEQ ID NO:88、SEQ ID NO:106、SEQ ID NO:108、SEQ ID NO:76、SEQ ID NO:112、SEQ ID NO:115、SEQ ID NO:118和SEQ ID NO:121。在某些实施方式中，所述抗体重链的抗原结合片段(例如，所述抗原结合片段可为Fab)可包含选自下组的氨基酸序列：SEQ ID NO:113、SEQ ID NO:116、SEQ ID NO:119和SEQ ID NO:122。And SEQ ID NO: 108 NO: 112, SEQ ID NO: 115, SEQ ID NO: 118, and SEQ ID NO: 121. In certain embodiments, the antigen-binding fragment of the antibody heavy chain (eg, the antigen-binding fragment can be a Fab) can comprise an amino acid sequence selected from the group consisting of SEQ ID NO: 113, SEQ ID NO: 116, SEQ ID NO: 119 and SEQ ID NO: 122.

在本申请中，所述抗体重链或其片段可包含SEQ ID NO:137所示的氨基酸序列：In the present application, the antibody heavy chain or fragment thereof may comprise the amino acid sequence set forth in SEQ ID NO: 137:

QVTLKESGGGLIQPGGSLRLSCAASGFTVSSNHMSWVRQAPGKGLEWVSIIYSDGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGX 99X 100SX 102X 103X 104FDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:137)。 QVTLKESGGGLIQPGGSLRLSCAASGFTVSSNHMSWVRQAPGKGLEWVSIIYSDGTTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGX 99 X 100 SX 102 X 103 X 104 FDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 137).

其中X 99＝R或G；X 100＝Y或N；X 102＝G或D；X 103＝W或F；X 104＝Y、N或S。在一些实施方式中，与SEQ ID NO:88所示抗体的重链相比，所述抗体重链或其片段可至少包含在选自以下至少一种的氨基酸取代： Wherein X 99 =R or G; X 100 =Y or N; X 102 =G or D; X 103 =W or F; X 104 =Y, N or S. In some embodiments, the antibody heavy chain or fragment thereof can comprise at least one amino acid substitution at least one selected from the group consisting of the heavy chain of the antibody of SEQ ID NO: 88:

(1)在X 99，X 100，X 102和/或X 104处的氨基酸的取代； (1) substitution of an amino acid at X 99 , X 100 , X 102 and/or X 104 ;

(2)在X 100，X 103和/或X 104处的氨基酸的取代。 (2) Substitution of amino acids at X 100 , X 103 and/or X 104 .

在一些实施方式中，与SEQ ID NO:88所示抗体的重链相比，所述抗体重链或其片段可至少包含在X 99，X 100，X 102和/或X 104处的氨基酸取代，其中，X 99处的氨基酸可被取代为R或G，X 100处的氨基酸可被取代为Y或N，X 102处的氨基酸可被取代为G或D，X 103处的氨基酸可被取代为W或F，X 104处的氨基酸可被取代为Y或N。 In some embodiments, the antibody heavy chain or fragment thereof can comprise at least amino acid substitutions at X 99 , X 100 , X 102 and/or X 104 as compared to the heavy chain of the antibody set forth in SEQ ID NO:88 Wherein the amino acid at X 99 may be substituted with R or G, the amino acid at X 100 may be substituted with Y or N, the amino acid at X 102 may be substituted with G or D, and the amino acid at X 103 may be substituted For W or F, the amino acid at X 104 can be substituted with Y or N.

在一些实施方式中，与SEQ ID NO:88所示抗体的重链相比，所述抗体重链或其片段可至少包含在X 100，X 103和/或X 104处的氨基酸取代，其中，X 100处的氨基酸可被取代为Y或N，X 103处的氨基酸可被取代为W或F，X 104处的氨基酸可被取代为Y或S。 In some embodiments, the antibody heavy chain or fragment thereof can comprise at least an amino acid substitution at X 100 , X 103 and/or X 104 as compared to the heavy chain of the antibody of SEQ ID NO: 88, wherein The amino acid at X 100 can be substituted with Y or N, the amino acid at X 103 can be substituted with W or F, and the amino acid at X 104 can be substituted with Y or S.

例如，所述抗体重链或其片段可包含下述任一项所示的氨基酸序列：SEQ ID NO:88、SEQ ID NO:106和SEQ ID NO:108。For example, the antibody heavy chain or fragment thereof can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO:88, SEQ ID NO:106, and SEQ ID NO:108.

在本申请中，所述抗体重链或其片段可包含SEQ ID NO:139所示的氨基酸序列：In the present application, the antibody heavy chain or fragment thereof may comprise the amino acid sequence set forth in SEQ ID NO: 139:

QVQLVESGGGLVQPGRSLRLSCTASGFTFGDYAX 34X 35WFRQAPGKGLEWVGFIRSKA YGGTTEYAX 54SVKGRFTISRDDSKSIAYLQMNSLKTX 91DTAVYYCARDGSDX 105IRYX 109DWLFNYWYFDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:139)。 QVQLVESGGGLVQPGRSLRLSCTASGFTFGDYAX 34 X 35 WFRQAPGKGLEWVGFIRSKA YGGTTEYAX 54 SVKGRFTISRDDSKSIAYLQMNSLKTX 91 DTAVYYCARDGSDX 105 IRYX 109 DWLFNYWYFDLWGRGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 139).

其中X 34＝M或I；X 35＝S或N；X 54＝A或T；X 91＝E或Q；X 105＝G或E；X 109＝F或L。在一些实施方式中，与SEQ ID NO:76所示抗体的重链相比，所述抗体重链或其片段可至少包含在选自以下至少一种的氨基酸取代： Wherein X 34 = M or I; X 35 = S or N; X 54 = A or T; X 91 = E or Q; X 105 = G or E; X 109 = F or L. In some embodiments, the antibody heavy chain or fragment thereof can comprise at least one amino acid substitution at least one selected from the group consisting of the heavy chain of the antibody of SEQ ID NO: 76:

(1)在X 35和/或X 105处的氨基酸的取代； (1) substitution of an amino acid at X 35 and/or X 105 ;

(2)在X 105和/或X 109处的氨基酸的取代； (2) substitution of an amino acid at X 105 and/or X 109 ;

(3)在X 34、X 35和/或X 105处的氨基酸的取代； (3) substitution of an amino acid at X 34 , X 35 and/or X 105 ;

(4)在X 35、X 91和/或X 105处的氨基酸的取代。 (4) Substitution of amino acids at X 35 , X 91 and/or X 105 .

在一些实施方式中，与SEQ ID NO:76所示抗体的重链相比，所述抗体重链或其片段可至少包含在X 35和/或X 105处的氨基酸取代，其中，X 35处的氨基酸可被取代为S或N，X 105处的氨基酸可被取代为G或E。 In some embodiments, the antibody heavy chain or fragment thereof can comprise at least an amino acid substitution at X35 and/or X105 , wherein X 35 is at least as compared to the heavy chain of the antibody set forth in SEQ ID NO:76 The amino acid can be substituted with S or N, and the amino acid at X 105 can be substituted with G or E.

在一些实施方式中，与SEQ ID NO:76所示抗体的重链相比，所述抗体重链或其片段可至少包含在X 105和/或X 109处的氨基酸取代，其中，X 105处的氨基酸可被取代为G或E，X 109处的氨基酸可被取代为F或L。 In some embodiments, the antibody heavy chain or fragment thereof can comprise at least an amino acid substitution at X 105 and/or X 109 , wherein X 105 is at a temperature to the heavy chain of the antibody set forth in SEQ ID NO:76 The amino acid can be substituted with G or E, and the amino acid at X 109 can be substituted with F or L.

在一些实施方式中，与SEQ ID NO:76所示抗体的重链相比，所述抗体重链或其片段可至少包含在X 34、X 35和/或X 105处的氨基酸取代，其中，X 34处的氨基酸可被取代为M或I，X 35处的氨基酸可被取代为S或N，X 105处的氨基酸可被取代为G或E。 In some embodiments, the SEQ ID NO: Compared antibody heavy chain shown in FIG 76, the antibody heavy chain or fragment thereof may comprise at least X 34, X 35 amino acid substitutions and / or at X 105, wherein, The amino acid at X 34 may be substituted with M or I, the amino acid at X 35 may be substituted with S or N, and the amino acid at X 105 may be substituted with G or E.

在一些实施方式中，与SEQ ID NO:76所示抗体的重链相比，所述抗体重链或其片段可至少包含在X 34、X 35和/或X 105处的氨基酸取代，其中，X 35处的氨基酸可被取代为S或N，X 91处的氨基酸可被取代为E或Q，X 105处的氨基酸可被取代为G或E。 In some embodiments, the SEQ ID NO: Compared antibody heavy chain shown in FIG 76, the antibody heavy chain or fragment thereof may comprise at least X 34, X 35 amino acid substitutions and / or at X 105, wherein, The amino acid at X 35 may be substituted with S or N, the amino acid at X 91 may be substituted with E or Q, and the amino acid at X 105 may be substituted with G or E.

例如，所述抗体重链或其片段可包含下述任一项所示的氨基酸序列：SEQ ID NO:76、SEQ ID NO:112、SEQ ID NO:115、SEQ ID NO:118和SEQ ID NO:121。For example, the antibody heavy chain or fragment thereof can comprise the amino acid sequence set forth in any one of the following: SEQ ID NO:76, SEQ ID NO:112, SEQ ID NO:115, SEQ ID NO:118, and SEQ ID NO :121.

在某些实施方式中，本申请所述的抗体、其抗原结合片段中LCDR1的氨基酸序列可包括SEQ ID NO:4；LCDR2的氨基酸序列可包括SEQ ID NO:5；LCDR3的氨基酸序列可包括 SEQ ID NO:6；且HCDR1的氨基酸序列可包括SEQ ID NO:1；HCDR2的氨基酸序列可包括SEQ ID NO:2；HCDR3的氨基酸序列可包括SEQ ID NO:3。例如，所述抗体、其抗原结合片段可包括抗体YN-008或与其具有相同的LCDR1-3及HCDR1-3的抗体。在某些实施方式中，本申请所述的抗体、其抗原结合片段的轻链可变区的氨基酸序列可包括SEQ ID NO:16；且其重链可变区的氨基酸序列可包括SEQ ID NO:15。例如，该抗体、其抗原结合片段可包括抗体YN-008或与其具有相同的轻链可变区及重链可变区的抗体。在某些实施方式中，本申请所述的抗体、其抗原结合片段可包含轻链和重链，所述轻链的氨基酸序列可如SEQ ID NO:64所示且所述重链氨基酸序列可如SEQ ID NO:62所示。例如，该抗体、其抗原结合片段可包括抗体YN-008或与其具有相同的轻链及重链的抗体。In certain embodiments, the amino acid sequence of LCDR1 in the antibody, antigen-binding fragment thereof of the present application may include SEQ ID NO: 4; the amino acid sequence of LCDR2 may include SEQ ID NO: 5; the amino acid sequence of LCDR3 may include SEQ ID NO: 6; and the amino acid sequence of HCDR1 may comprise SEQ ID NO: 1; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 2; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 3. For example, the antibody, antigen-binding fragment thereof can include antibody YN-008 or an antibody having the same LCDR1-3 and HCDR1-3. In certain embodiments, the amino acid sequence of the light chain variable region of an antibody, antigen-binding fragment thereof, of the present application may comprise SEQ ID NO: 16; and the amino acid sequence of the heavy chain variable region thereof may comprise SEQ ID NO :15. For example, the antibody, antigen-binding fragment thereof can include antibody YN-008 or an antibody having the same light chain variable region and heavy chain variable region. In certain embodiments, an antibody, antigen-binding fragment thereof, as described herein, can comprise a light chain and a heavy chain, the amino acid sequence of the light chain can be set forth in SEQ ID NO: 64 and the heavy chain amino acid sequence can be As shown in SEQ ID NO:62. For example, the antibody, antigen-binding fragment thereof can include antibody YN-008 or an antibody having the same light and heavy chains therewith.

在某些实施方式中，本申请所述的抗体、其抗原结合片段中LCDR1的氨基酸序列可包括SEQ ID NO:22；LCDR2的氨基酸序列可包括SEQ ID NO:23；LCDR3的氨基酸序列可包括SEQ ID NO:24；且HCDR1的氨基酸序列可包括SEQ ID NO:19；HCDR2的氨基酸序列可包括SEQ ID NO:20；HCDR3的氨基酸序列可包括SEQ ID NO:21。例如，该抗体、其抗原结合片段可包括抗体YN-009或与其具有相同的LCDR1-3及HCDR1-3的抗体。在某些实施方式中，本申请所述的抗体、其抗原结合片段的轻链可变区的氨基酸序列可包括SEQ ID NO:34；且其重链可变区的氨基酸序列可包括SEQ ID NO:33。例如，该抗体、其抗原结合片段可包括抗体YN-009或与其具有相同的轻链可变区及重链可变区的抗体。在某些实施方式中，本申请所述的抗体、其抗原结合片段可包含轻链和重链，所述轻链的氨基酸序列如SEQ ID NO:68所示且所述重链的氨基酸序列如SEQ ID NO:66所示。例如，该抗体、其抗原结合片段可包括抗体YN-009或与其具有相同的轻链及重链的抗体。In certain embodiments, the amino acid sequence of LCDR1 in the antibody, antigen-binding fragment thereof of the present application may include SEQ ID NO: 22; the amino acid sequence of LCDR2 may include SEQ ID NO: 23; the amino acid sequence of LCDR3 may include SEQ ID NO: 24; and the amino acid sequence of HCDR1 may comprise SEQ ID NO: 19; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 20; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 21. For example, the antibody, antigen-binding fragment thereof can include antibody YN-009 or an antibody having the same LCDR1-3 and HCDR1-3. In certain embodiments, the amino acid sequence of the light chain variable region of an antibody, antigen-binding fragment thereof, of the present application may comprise SEQ ID NO: 34; and the amino acid sequence of the heavy chain variable region thereof may comprise SEQ ID NO :33. For example, the antibody, antigen-binding fragment thereof can include antibody YN-009 or an antibody having the same light chain variable region and heavy chain variable region. In certain embodiments, an antibody, antigen-binding fragment thereof, as described herein, can comprise a light chain and a heavy chain, the amino acid sequence of which is set forth in SEQ ID NO: 68 and the amino acid sequence of the heavy chain is as SEQ ID NO: 66. For example, the antibody, antigen-binding fragment thereof can include antibody YN-009 or an antibody having the same light and heavy chains thereto.

在某些实施方式中，本申请所述的抗体、其抗原结合片段中LCDR1的氨基酸序列可包括SEQ ID NO:40；LCDR2的氨基酸序列可包括SEQ ID NO:41；LCDR3的氨基酸序列可包括SEQ ID NO:42；且HCDR1的氨基酸序列可包括SEQ ID NO:37；HCDR2的氨基酸序列可包括SEQ ID NO:38；HCDR3的氨基酸序列可包括SEQ ID NO:39。例如，该抗体、其抗原结合片段可包括抗体YN-010或与其具有相同的LCDR1-3及HCDR1-3的抗体。在某些实施方式中，本申请所述的抗体、其抗原结合片段可包含轻链可变区，所述轻链可变区的氨基酸序列可包括SEQ ID NO:52；且其可包含重链可变区，所述重链可变区的氨基酸序列可包括SEQ ID NO:51。例如，该抗体、其抗原结合片段可包括抗体YN-010或与其具有相同的轻链可变区及重链可变区的抗体。在某些实施方式中，本申请所述的抗体、其抗原结合片段可包含轻链和重链，所述轻链的氨基酸序列如SEQ ID NO:72所示且所述重链的氨基酸序列如SEQ  ID NO:70所示。例如，该抗体、其抗原结合片段可包括抗体YN-010或与其具有相同的轻链及重链的抗体。In certain embodiments, the amino acid sequence of LCDR1 in the antibody, antigen-binding fragment thereof of the present application may include SEQ ID NO: 40; the amino acid sequence of LCDR2 may include SEQ ID NO: 41; the amino acid sequence of LCDR3 may include SEQ ID NO: 42; and the amino acid sequence of HCDR1 may comprise SEQ ID NO: 37; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 38; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 39. For example, the antibody, antigen-binding fragment thereof can include antibody YN-010 or an antibody having the same LCDR1-3 and HCDR1-3. In certain embodiments, an antibody, antigen-binding fragment thereof, as described herein, can comprise a light chain variable region, the amino acid sequence of the light chain variable region can comprise SEQ ID NO: 52; and can comprise a heavy chain The variable region, the amino acid sequence of the heavy chain variable region can include SEQ ID NO:51. For example, the antibody, antigen-binding fragment thereof can include antibody YN-010 or an antibody having the same light chain variable region and heavy chain variable region. In certain embodiments, an antibody, antigen-binding fragment thereof, as described herein, can comprise a light chain and a heavy chain, the amino acid sequence of which is set forth in SEQ ID NO: 72 and the amino acid sequence of the heavy chain is as SEQ ID NO:70. For example, the antibody, antigen-binding fragment thereof can include antibody YN-010 or an antibody having the same light and heavy chains thereto.

在某些实施方式中，本申请所述的抗体、其抗原结合片段中LCDR1的氨基酸序列可包括SEQ ID NO:4；LCDR2的氨基酸序列可包括SEQ ID NO:5；LCDR3的氨基酸序列可包括SEQ ID NO:6；且HCDR1的氨基酸序列可包括SEQ ID NO:1；HCDR2的氨基酸序列可包括SEQ ID NO:2；HCDR3的氨基酸序列可包括SEQ ID NO:3。例如，该抗体、其抗原结合片段可包括抗体YN-011或与其具有相同的LCDR1-3及HCDR1-3的抗体。在某些情形中，所述抗体、其抗原结合片段中L-FR1的氨基酸序列可包括SEQ ID NO:11；L-FR2的氨基酸序列可包括SEQ ID NO:12；L-FR3的氨基酸序列可包括SEQ ID NO:13；L-FR4的氨基酸序列可包括SEQ ID NO:14；且H-FR1的氨基酸序列可包括SEQ ID NO:7；H-FR2的氨基酸序列可包括SEQ ID NO:8；H-FR3的氨基酸序列可包括SEQ ID NO:9；且H-FR4的氨基酸序列可包括SEQ ID NO:10。例如，该抗体、其抗原结合片段可包括抗体YN-011或与其具有相同的LCDR1-3、HCDR1-3、L-FR1-4及H-FR1-4的抗体。在某些实施方式中，本申请所述的抗体、其抗原结合片段的轻链可包含轻链可变区，所述轻链可变区的氨基酸序列可包括SEQ ID NO:18；且其中重链可包含重链可变区，所述重链可变区的氨基酸序列可包括SEQ ID NO:17。例如，该抗体、其抗原结合片段可包括抗体YN-011或与其具有相同的轻链可变区及重链可变区的抗体。在某些实施方式中，本申请所述的抗体、其抗原结合片段可包含轻链和重链，所述轻链的氨基酸序列如SEQ ID NO:78所示且所述重链的氨基酸序列如SEQ ID NO:76所示。例如，该抗体、其抗原结合片段可包括抗体YN-011或与其具有相同的轻链及重链的抗体。In certain embodiments, the amino acid sequence of LCDR1 in the antibody, antigen-binding fragment thereof of the present application may include SEQ ID NO: 4; the amino acid sequence of LCDR2 may include SEQ ID NO: 5; the amino acid sequence of LCDR3 may include SEQ ID NO: 6; and the amino acid sequence of HCDR1 may comprise SEQ ID NO: 1; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 2; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 3. For example, the antibody, antigen-binding fragment thereof can include antibody YN-011 or an antibody having the same LCDR1-3 and HCDR1-3. In certain instances, the amino acid sequence of L-FR1 in the antibody, antigen-binding fragment thereof can include SEQ ID NO: 11; the amino acid sequence of L-FR2 can include SEQ ID NO: 12; the amino acid sequence of L-FR3 can The amino acid sequence comprising SEQ ID NO: 13; L-FR4 may comprise SEQ ID NO: 14; and the amino acid sequence of H-FR1 may comprise SEQ ID NO: 7; the amino acid sequence of H-FR2 may comprise SEQ ID NO: 8; The amino acid sequence of H-FR3 may comprise SEQ ID NO: 9; and the amino acid sequence of H-FR4 may comprise SEQ ID NO: 10. For example, the antibody, antigen-binding fragment thereof may include antibody YN-011 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4. In certain embodiments, the light chain of an antibody, antigen-binding fragment thereof, of the present application may comprise a light chain variable region, the amino acid sequence of the light chain variable region comprising SEQ ID NO: 18; The chain may comprise a heavy chain variable region, and the amino acid sequence of the heavy chain variable region may comprise SEQ ID NO: 17. For example, the antibody, antigen-binding fragment thereof can include antibody YN-011 or an antibody having the same light chain variable region and heavy chain variable region. In certain embodiments, an antibody, antigen-binding fragment thereof, as described herein, can comprise a light chain and a heavy chain, the amino acid sequence of which is set forth in SEQ ID NO: 78 and the amino acid sequence of the heavy chain is as SEQ ID NO:76. For example, the antibody, antigen-binding fragment thereof can include antibody YN-011 or an antibody having the same light and heavy chains therewith.

在某些实施方式中，本申请所述的抗体、其抗原结合片段中LCDR1的氨基酸序列可包括SEQ ID NO:22；LCDR2的氨基酸序列可包括SEQ ID NO:23；LCDR3的氨基酸序列可包括SEQ ID NO:24；且HCDR1的氨基酸序列可包括SEQ ID NO:19；HCDR2的氨基酸序列可包括SEQ ID NO:20；HCDR3的氨基酸序列可包括SEQ ID NO:21。例如，该抗体、其抗原结合片段可包括抗体YN-012或与其具有相同的LCDR1-3及HCDR1-3的抗体。本申请所述的抗体、其抗原结合片段中L-FR1的氨基酸序列可包括SEQ ID NO:29；L-FR2的氨基酸序列可包括SEQ ID NO:30；L-FR3的氨基酸序列可包括SEQ ID NO:31；L-FR4的氨基酸序列可包括SEQ ID NO:32；且H-FR1的氨基酸序列可包括SEQ ID NO:25；H-FR2的氨基酸序列可包括SEQ ID NO:26；H-FR3的氨基酸序列可包括SEQ ID NO:27；H-FR4的氨基酸序列可包括SEQ ID NO:28。例如，该抗体、其抗原结合片段可包括抗体YN-012或与其具有相同的LCDR1-3、HCDR1-3、L-FR1-4及H-FR1-4的抗体。在某些实施方式中，本申请所述的抗体、 其抗原结合片段的轻链可包含轻链可变区，所述轻链可变区的氨基酸序列可包括SEQ ID NO:36；且其中重链可包含重链可变区，所述重链可变区的氨基酸序列可包括SEQ ID NO:35。例如，该抗体、其抗原结合片段可包括抗体YN-012或与其具有相同的轻链可变区及重链可变区的抗体。在某些实施方式中，本申请所述的抗体、其抗原结合片段可包含轻链和重链，所述轻链的氨基酸序列如SEQ ID NO:84所示且所述重链的氨基酸序列如SEQ ID NO:82所示。例如，该抗体、其抗原结合片段可包括抗体YN-012或与其具有相同的轻链及重链的抗体。In certain embodiments, the amino acid sequence of LCDR1 in the antibody, antigen-binding fragment thereof of the present application may include SEQ ID NO: 22; the amino acid sequence of LCDR2 may include SEQ ID NO: 23; the amino acid sequence of LCDR3 may include SEQ ID NO: 24; and the amino acid sequence of HCDR1 may comprise SEQ ID NO: 19; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 20; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 21. For example, the antibody, antigen-binding fragment thereof can include antibody YN-012 or an antibody having the same LCDR1-3 and HCDR1-3. The amino acid sequence of L-FR1 in the antibody, antigen-binding fragment thereof described in the present application may include SEQ ID NO: 29; the amino acid sequence of L-FR2 may include SEQ ID NO: 30; the amino acid sequence of L-FR3 may include SEQ ID NO: 31; the amino acid sequence of L-FR4 may include SEQ ID NO: 32; and the amino acid sequence of H-FR1 may include SEQ ID NO: 25; the amino acid sequence of H-FR2 may include SEQ ID NO: 26; H-FR3 The amino acid sequence can include SEQ ID NO:27; the amino acid sequence of H-FR4 can include SEQ ID NO:28. For example, the antibody, antigen-binding fragment thereof may include antibody YN-012 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4. In certain embodiments, the light chain of an antibody, antigen-binding fragment thereof, of the present application may comprise a light chain variable region, the amino acid sequence of the light chain variable region comprising SEQ ID NO: 36; The chain may comprise a heavy chain variable region, and the amino acid sequence of the heavy chain variable region may comprise SEQ ID NO:35. For example, the antibody, antigen-binding fragment thereof can include antibody YN-012 or an antibody having the same light chain variable region and heavy chain variable region. In certain embodiments, an antibody, antigen-binding fragment thereof, as described herein, can comprise a light chain and a heavy chain, the amino acid sequence of which is set forth in SEQ ID NO: 84 and the amino acid sequence of the heavy chain is as SEQ ID NO: 82. For example, the antibody, antigen-binding fragment thereof can include antibody YN-012 or an antibody having the same light and heavy chains thereto.

在某些实施方式中，本申请所述的抗体、其抗原结合片段中LCDR1的氨基酸序列可包括SEQ ID NO:40；LCDR2的氨基酸序列可包括SEQ ID NO:41；LCDR3的氨基酸序列可包括SEQ ID NO:42；且HCDR1的氨基酸序列可包括SEQ ID NO:37；HCDR2的氨基酸序列可包括SEQ ID NO:38；HCDR3的氨基酸序列可包括SEQ ID NO:39。例如，该抗体、其抗原结合片段可包括抗体YN-013或与其具有相同的LCDR1-3及HCDR1-3的抗体。本申请所述的抗体、其抗原结合片段中L-FR1的氨基酸序列可包括SEQ ID NO:47；L-FR2的氨基酸序列可包括SEQ ID NO:48；L-FR3的氨基酸序列可包括SEQ ID NO:49；L-FR4的氨基酸序列可包括SEQ ID NO:50；且H-FR1的氨基酸序列可包括SEQ ID NO:43；H-FR2的氨基酸序列可包括SEQ ID NO:44；H-FR3的氨基酸序列可包括SEQ ID NO:45；H-FR4的氨基酸序列可包括SEQ ID NO:46。例如，该抗体、其抗原结合片段可包括抗体YN-013或与其具有相同的LCDR1-3、HCDR1-3、L-FR1-4及H-FR1-4的抗体。在某些实施方式中，本申请所述的抗体、其抗原结合片段的轻链可包含轻链可变区，所述轻链可变区的氨基酸序列可包括SEQ ID NO:54；且其中重链可包含重链可变区，所述重链可变区的氨基酸序列可包括SEQ ID NO:53。例如，该抗体、其抗原结合片段可包括抗体YN-013或与其具有相同的轻链可变区及重链可变区的抗体。在某些实施方式中，本申请所述的抗体、其抗原结合片段可包含轻链和重链，所述轻链的氨基酸序列如SEQ ID NO:90所示且所述重链的氨基酸序列如SEQ ID NO:88所示。例如，该抗体、其抗原结合片段可包括抗体YN-013或与其具有相同的轻链及重链的抗体。In certain embodiments, the amino acid sequence of LCDR1 in the antibody, antigen-binding fragment thereof of the present application may include SEQ ID NO: 40; the amino acid sequence of LCDR2 may include SEQ ID NO: 41; the amino acid sequence of LCDR3 may include SEQ ID NO: 42; and the amino acid sequence of HCDR1 may comprise SEQ ID NO: 37; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 38; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 39. For example, the antibody, antigen-binding fragment thereof can include antibody YN-013 or an antibody having the same LCDR1-3 and HCDR1-3. The amino acid sequence of L-FR1 in the antibody, antigen-binding fragment thereof described in the present application may include SEQ ID NO: 47; the amino acid sequence of L-FR2 may include SEQ ID NO: 48; the amino acid sequence of L-FR3 may include SEQ ID NO: 49; the amino acid sequence of L-FR4 may include SEQ ID NO: 50; and the amino acid sequence of H-FR1 may include SEQ ID NO: 43; the amino acid sequence of H-FR2 may include SEQ ID NO: 44; H-FR3 The amino acid sequence may comprise SEQ ID NO: 45; the amino acid sequence of H-FR4 may comprise SEQ ID NO: 46. For example, the antibody, antigen-binding fragment thereof may include antibody YN-013 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4. In certain embodiments, the light chain of an antibody, antigen-binding fragment thereof, of the present application may comprise a light chain variable region, the amino acid sequence of the light chain variable region comprising SEQ ID NO: 54; The chain may comprise a heavy chain variable region, and the amino acid sequence of the heavy chain variable region may comprise SEQ ID NO:53. For example, the antibody, antigen-binding fragment thereof can include antibody YN-013 or an antibody having the same light chain variable region and heavy chain variable region. In certain embodiments, an antibody, antigen-binding fragment thereof, as described herein, can comprise a light chain and a heavy chain, the amino acid sequence of which is set forth in SEQ ID NO: 90 and the amino acid sequence of the heavy chain is as SEQ ID NO:88. For example, the antibody, antigen-binding fragment thereof can include antibody YN-013 or an antibody having the same light and heavy chains thereto.

在某些实施方式中，本申请所述的抗体、其抗原结合片段中LCDR1的氨基酸序列可包括SEQ ID NO:40；LCDR2的氨基酸序列可包括SEQ ID NO:41；LCDR3的氨基酸序列可包括SEQ ID NO:102；且HCDR1的氨基酸序列可包括SEQ ID NO:37；HCDR2的氨基酸序列可包括SEQ ID NO:38；HCDR3的氨基酸序列可包括SEQ ID NO:100。例如，该抗体、其抗原结合片段可包括抗体YN-065或与其具有相同的LCDR1-3及HCDR1-3的抗体。本申请所述的抗体、其抗原结合片段中L-FR1的氨基酸序列可包括SEQ ID NO:47；L-FR2的氨基酸序列可包括SEQ ID NO:48；L-FR3的氨基酸序列可包括SEQ ID NO:49；L-FR4的氨基酸序 列可包括SEQ ID NO:50；且H-FR1的氨基酸序列可包括SEQ ID NO:43；H-FR2的氨基酸序列可包括SEQ ID NO:44；H-FR3的氨基酸序列可包括SEQ ID NO:45；H-FR4的氨基酸序列可包括SEQ ID NO:46。例如，该抗体、其抗原结合片段可包括抗体YN-065或与其具有相同的LCDR1-3、HCDR1-3、L-FR1-4及H-FR1-4的抗体。在某些实施方式中，本申请所述的抗体、其抗原结合片段的轻链可包含轻链可变区，所述轻链可变区的氨基酸序列可包括SEQ ID NO:103；且其中重链可包含重链可变区，所述重链可变区的氨基酸序列可包括SEQ ID NO:105。例如，该抗体、其抗原结合片段可包括抗体YN-065或与其具有相同的轻链可变区及重链可变区的抗体。在某些实施方式中，本申请所述的抗体、其抗原结合片段可包含轻链和重链，所述轻链的氨基酸序列如SEQ ID NO:104所示且所述重链的氨基酸序列如SEQ ID NO:106所示。例如，该抗体、其抗原结合片段可包括抗体YN-065或与其具有相同的轻链及重链的抗体。In certain embodiments, the amino acid sequence of LCDR1 in the antibody, antigen-binding fragment thereof of the present application may include SEQ ID NO: 40; the amino acid sequence of LCDR2 may include SEQ ID NO: 41; the amino acid sequence of LCDR3 may include SEQ ID NO: 102; and the amino acid sequence of HCDR1 may comprise SEQ ID NO: 37; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 38; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 100. For example, the antibody, antigen-binding fragment thereof can include antibody YN-065 or an antibody having the same LCDR1-3 and HCDR1-3. The amino acid sequence of L-FR1 in the antibody, antigen-binding fragment thereof described in the present application may include SEQ ID NO: 47; the amino acid sequence of L-FR2 may include SEQ ID NO: 48; the amino acid sequence of L-FR3 may include SEQ ID NO: 49; the amino acid sequence of L-FR4 may include SEQ ID NO: 50; and the amino acid sequence of H-FR1 may include SEQ ID NO: 43; the amino acid sequence of H-FR2 may include SEQ ID NO: 44; H-FR3 The amino acid sequence may comprise SEQ ID NO: 45; the amino acid sequence of H-FR4 may comprise SEQ ID NO: 46. For example, the antibody, antigen-binding fragment thereof may include antibody YN-065 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4. In certain embodiments, the light chain of an antibody, antigen-binding fragment thereof, of the present application may comprise a light chain variable region, the amino acid sequence of the light chain variable region comprising SEQ ID NO: 103; The chain may comprise a heavy chain variable region, and the amino acid sequence of the heavy chain variable region may comprise SEQ ID NO:105. For example, the antibody, antigen-binding fragment thereof can include antibody YN-065 or an antibody having the same light chain variable region and heavy chain variable region. In certain embodiments, an antibody, antigen-binding fragment thereof, as described herein, can comprise a light chain and a heavy chain, the amino acid sequence of which is set forth in SEQ ID NO: 104 and the amino acid sequence of the heavy chain is as SEQ ID NO:106. For example, the antibody, antigen-binding fragment thereof can include antibody YN-065 or an antibody having the same light and heavy chains thereto.

在某些实施方式中，本申请所述的抗体、其抗原结合片段中LCDR1的氨基酸序列可包括SEQ ID NO:40；LCDR2的氨基酸序列可包括SEQ ID NO:41；LCDR3的氨基酸序列可包括SEQ ID NO:102；且HCDR1的氨基酸序列可包括SEQ ID NO:37；HCDR2的氨基酸序列可包括SEQ ID NO:38；HCDR3的氨基酸序列可包括SEQ ID NO:101。例如，该抗体、其抗原结合片段可包括抗体YN-066或与其具有相同的LCDR1-3及HCDR1-3的抗体。本申请所述的抗体、其抗原结合片段中L-FR1的氨基酸序列可包括SEQ ID NO:47；L-FR2的氨基酸序列可包括SEQ ID NO:48；L-FR3的氨基酸序列可包括SEQ ID NO:49；L-FR4的氨基酸序列可包括SEQ ID NO:50；且H-FR1的氨基酸序列可包括SEQ ID NO:43；H-FR2的氨基酸序列可包括SEQ ID NO:44；H-FR3的氨基酸序列可包括SEQ ID NO:45；H-FR4的氨基酸序列可包括SEQ ID NO:46。例如，该抗体、其抗原结合片段可包括抗体YN-066或与其具有相同的LCDR1-3、HCDR1-3、L-FR1-4及H-FR1-4的抗体。在某些实施方式中，本申请所述的抗体、其抗原结合片段的轻链可包含轻链可变区，所述轻链可变区的氨基酸序列可包括SEQ ID NO:103；且其中重链可包含重链可变区，所述重链可变区的氨基酸序列可包括SEQ ID NO:107。例如，该抗体、其抗原结合片段可包括抗体YN-066或与其具有相同的轻链可变区及重链可变区的抗体。在某些实施方式中，本申请所述的抗体、其抗原结合片段可包含轻链和重链，所述轻链的氨基酸序列如SEQ ID NO:104所示且所述重链的氨基酸序列如SEQ ID NO:108所示。例如，该抗体、其抗原结合片段可包括抗体YN-066或与其具有相同的轻链及重链的抗体。In certain embodiments, the amino acid sequence of LCDR1 in the antibody, antigen-binding fragment thereof of the present application may include SEQ ID NO: 40; the amino acid sequence of LCDR2 may include SEQ ID NO: 41; the amino acid sequence of LCDR3 may include SEQ ID NO: 102; and the amino acid sequence of HCDR1 may comprise SEQ ID NO: 37; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 38; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 101. For example, the antibody, antigen-binding fragment thereof can include antibody YN-066 or an antibody having the same LCDR1-3 and HCDR1-3. The amino acid sequence of L-FR1 in the antibody, antigen-binding fragment thereof described in the present application may include SEQ ID NO: 47; the amino acid sequence of L-FR2 may include SEQ ID NO: 48; the amino acid sequence of L-FR3 may include SEQ ID NO: 49; the amino acid sequence of L-FR4 may include SEQ ID NO: 50; and the amino acid sequence of H-FR1 may include SEQ ID NO: 43; the amino acid sequence of H-FR2 may include SEQ ID NO: 44; H-FR3 The amino acid sequence may comprise SEQ ID NO: 45; the amino acid sequence of H-FR4 may comprise SEQ ID NO: 46. For example, the antibody, antigen-binding fragment thereof can include antibody YN-066 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4. In certain embodiments, the light chain of an antibody, antigen-binding fragment thereof, of the present application may comprise a light chain variable region, the amino acid sequence of the light chain variable region comprising SEQ ID NO: 103; The chain may comprise a heavy chain variable region, and the amino acid sequence of the heavy chain variable region may comprise SEQ ID NO:107. For example, the antibody, antigen-binding fragment thereof can include antibody YN-066 or an antibody having the same light chain variable region and heavy chain variable region. In certain embodiments, an antibody, antigen-binding fragment thereof, as described herein, can comprise a light chain and a heavy chain, the amino acid sequence of which is set forth in SEQ ID NO: 104 and the amino acid sequence of the heavy chain is as SEQ ID NO:108. For example, the antibody, antigen-binding fragment thereof can include antibody YN-066 or an antibody having the same light and heavy chains thereto.

在某些实施方式中，本申请所述的抗体、其抗原结合片段中LCDR1的氨基酸序列可包 括SEQ ID NO:96；LCDR2的氨基酸序列可包括SEQ ID NO:5；LCDR3的氨基酸序列可包括SEQ ID NO:6；且HCDR1的氨基酸序列可包括SEQ ID NO:91；HCDR2的氨基酸序列可包括SEQ ID NO:2；HCDR3的氨基酸序列可包括SEQ ID NO:94。例如，该抗体、其抗原结合片段可包括抗体YN-067或与其具有相同的LCDR1-3及HCDR1-3的抗体。本申请所述的抗体、其抗原结合片段中L-FR1的氨基酸序列可包括SEQ ID NO:97；L-FR2的氨基酸序列可包括SEQ ID NO:98；L-FR3的氨基酸序列可包括SEQ ID NO:13；L-FR4的氨基酸序列可包括SEQ ID NO:14；且H-FR1的氨基酸序列可包括SEQ ID NO:7；H-FR2的氨基酸序列可包括SEQ ID NO:8；H-FR3的氨基酸序列可包括SEQ ID NO:9；H-FR4的氨基酸序列可包括SEQ ID NO:10。例如，该抗体、其抗原结合片段可包括抗体YN-067或与其具有相同的LCDR1-3、HCDR1-3、L-FR1-4及H-FR1-4的抗体。在某些实施方式中，本申请所述的抗体、其抗原结合片段的轻链可包含轻链可变区，所述轻链可变区的氨基酸序列可包括SEQ ID NO:109；且其中重链可包含重链可变区，所述重链可变区的氨基酸序列可包括SEQ ID NO:111。例如，该抗体、其抗原结合片段可包括抗体YN-067或与其具有相同的轻链可变区及重链可变区的抗体。在某些实施方式中，本申请所述的抗体、其抗原结合片段可包含轻链和重链，所述轻链的氨基酸序列如SEQ ID NO:110所示且所述重链的氨基酸序列如SEQ ID NO:112所示。例如，该抗体、其抗原结合片段可包括抗体YN-067或与其具有相同的轻链及重链的抗体。In certain embodiments, the amino acid sequence of LCDR1 in the antibody, antigen-binding fragment thereof of the present application may include SEQ ID NO: 96; the amino acid sequence of LCDR2 may include SEQ ID NO: 5; the amino acid sequence of LCDR3 may include SEQ ID NO:6; and the amino acid sequence of HCDR1 may comprise SEQ ID NO:91; the amino acid sequence of HCDR2 may comprise SEQ ID NO:2; the amino acid sequence of HCDR3 may comprise SEQ ID NO:94. For example, the antibody, antigen-binding fragment thereof can include antibody YN-067 or an antibody having the same LCDR1-3 and HCDR1-3. The amino acid sequence of L-FR1 in the antibody, antigen-binding fragment thereof described in the present application may include SEQ ID NO: 97; the amino acid sequence of L-FR2 may include SEQ ID NO: 98; the amino acid sequence of L-FR3 may include SEQ ID NO: 13; the amino acid sequence of L-FR4 may include SEQ ID NO: 14; and the amino acid sequence of H-FR1 may include SEQ ID NO: 7; the amino acid sequence of H-FR2 may include SEQ ID NO: 8; H-FR3 The amino acid sequence can include SEQ ID NO: 9; the amino acid sequence of H-FR4 can include SEQ ID NO: 10. For example, the antibody, antigen-binding fragment thereof may include antibody YN-067 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4. In certain embodiments, the light chain of an antibody, antigen-binding fragment thereof, of the present application may comprise a light chain variable region, the amino acid sequence of the light chain variable region comprising SEQ ID NO: 109; The chain may comprise a heavy chain variable region, and the amino acid sequence of the heavy chain variable region may comprise SEQ ID NO: 111. For example, the antibody, antigen-binding fragment thereof can include antibody YN-067 or an antibody having the same light chain variable region and heavy chain variable region. In certain embodiments, an antibody, antigen-binding fragment thereof, as described herein, can comprise a light chain and a heavy chain, the amino acid sequence of which is set forth in SEQ ID NO: 110 and the amino acid sequence of the heavy chain is as SEQ ID NO: 112. For example, the antibody, antigen-binding fragment thereof, can include antibody YN-067 or an antibody having the same light and heavy chains thereto.

在某些实施方式中，本申请所述的抗体、其抗原结合片段中LCDR1的氨基酸序列可包括SEQ ID NO:96；LCDR2的氨基酸序列可包括SEQ ID NO:5；LCDR3的氨基酸序列可包括SEQ ID NO:6；且HCDR1的氨基酸序列可包括SEQ ID NO:1；HCDR2的氨基酸序列可包括SEQ ID NO:2；HCDR3的氨基酸序列可包括SEQ ID NO:95。例如，该抗体、其抗原结合片段可包括抗体YN-068或与其具有相同的LCDR1-3及HCDR1-3的抗体。本申请所述的抗体、其抗原结合片段中L-FR1的氨基酸序列可包括SEQ ID NO:97；L-FR2的氨基酸序列可包括SEQ ID NO:98；L-FR3的氨基酸序列可包括SEQ ID NO:13；L-FR4的氨基酸序列可包括SEQ ID NO:14；且H-FR1的氨基酸序列可包括SEQ ID NO:7；H-FR2的氨基酸序列可包括SEQ ID NO:8；H-FR3的氨基酸序列可包括SEQ ID NO:9；H-FR4的氨基酸序列可包括SEQ ID NO:10。例如，该抗体、其抗原结合片段可包括抗体YN-068或与其具有相同的LCDR1-3、HCDR1-3、L-FR1-4及H-FR1-4的抗体。在某些实施方式中，本申请所述的抗体、其抗原结合片段的轻链可包含轻链可变区，所述轻链可变区的氨基酸序列可包括SEQ ID NO:109；且其中重链可包含重链可变区，所述重链可变区的氨基酸序列可包括SEQ ID  NO:114。例如，该抗体、其抗原结合片段可包括抗体YN-068或与其具有相同的轻链可变区及重链可变区的抗体。在某些实施方式中，本申请所述的抗体、其抗原结合片段可包含轻链和重链，所述轻链的氨基酸序列如SEQ ID NO:110所示且所述重链的氨基酸序列如SEQ ID NO:115所示。例如，该抗体、其抗原结合片段可包括抗体YN-068或与其具有相同的轻链及重链的抗体。In certain embodiments, the amino acid sequence of LCDR1 in the antibody, antigen-binding fragment thereof of the present application may include SEQ ID NO: 96; the amino acid sequence of LCDR2 may include SEQ ID NO: 5; the amino acid sequence of LCDR3 may include SEQ ID NO: 6; and the amino acid sequence of HCDR1 may comprise SEQ ID NO: 1; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 2; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 95. For example, the antibody, antigen-binding fragment thereof can include antibody YN-068 or an antibody having the same LCDR1-3 and HCDR1-3. The amino acid sequence of L-FR1 in the antibody, antigen-binding fragment thereof described in the present application may include SEQ ID NO: 97; the amino acid sequence of L-FR2 may include SEQ ID NO: 98; the amino acid sequence of L-FR3 may include SEQ ID NO: 13; the amino acid sequence of L-FR4 may include SEQ ID NO: 14; and the amino acid sequence of H-FR1 may include SEQ ID NO: 7; the amino acid sequence of H-FR2 may include SEQ ID NO: 8; H-FR3 The amino acid sequence can include SEQ ID NO: 9; the amino acid sequence of H-FR4 can include SEQ ID NO: 10. For example, the antibody, antigen-binding fragment thereof can include antibody YN-068 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4. In certain embodiments, the light chain of an antibody, antigen-binding fragment thereof, of the present application may comprise a light chain variable region, the amino acid sequence of the light chain variable region comprising SEQ ID NO: 109; The chain may comprise a heavy chain variable region, and the amino acid sequence of the heavy chain variable region may comprise SEQ ID NO: 114. For example, the antibody, antigen-binding fragment thereof can include antibody YN-068 or an antibody having the same light chain variable region and heavy chain variable region. In certain embodiments, an antibody, antigen-binding fragment thereof, as described herein, can comprise a light chain and a heavy chain, the amino acid sequence of which is set forth in SEQ ID NO: 110 and the amino acid sequence of the heavy chain is as SEQ ID NO: 115. For example, the antibody, antigen-binding fragment thereof can include antibody YN-068 or an antibody having the same light and heavy chains thereto.

在某些实施方式中，本申请所述的抗体、其抗原结合片段中LCDR1的氨基酸序列可包括SEQ ID NO:96；LCDR2的氨基酸序列可包括SEQ ID NO:5；LCDR3的氨基酸序列可包括SEQ ID NO:6；且HCDR1的氨基酸序列可包括SEQ ID NO:92；HCDR2的氨基酸序列可包括SEQ ID NO:2；HCDR3的氨基酸序列可包括SEQ ID NO:94。例如，该抗体、其抗原结合片段可包括抗体YN-069或与其具有相同的LCDR1-3及HCDR1-3的抗体。本申请所述的抗体、其抗原结合片段中L-FR1的氨基酸序列可包括SEQ ID NO:97；L-FR2的氨基酸序列可包括SEQ ID NO:98；L-FR3的氨基酸序列可包括SEQ ID NO:13；L-FR4的氨基酸序列可包括SEQ ID NO:14；且H-FR1的氨基酸序列可包括SEQ ID NO:7；H-FR2的氨基酸序列可包括SEQ ID NO:8；H-FR3的氨基酸序列可包括SEQ ID NO:9；H-FR4的氨基酸序列可包括SEQ ID NO:10。例如，该抗体、其抗原结合片段可包括抗体YN-069或与其具有相同的LCDR1-3、HCDR1-3、L-FR1-4及H-FR1-4的抗体。在某些实施方式中，本申请所述的抗体、其抗原结合片段的轻链可包含轻链可变区，所述轻链可变区的氨基酸序列可包括SEQ ID NO:109；且其中重链可包含重链可变区，所述重链可变区的氨基酸序列可包括SEQ ID NO:117。例如，该抗体、其抗原结合片段可包括抗体YN-069或与其具有相同的轻链可变区及重链可变区的抗体。在某些实施方式中，本申请所述的抗体、其抗原结合片段可包含轻链和重链，所述轻链的氨基酸序列如SEQ ID NO:110所示且所述重链的氨基酸序列如SEQ ID NO:118所示。例如，该抗体、其抗原结合片段可包括抗体YN-069或与其具有相同的轻链及重链的抗体。In certain embodiments, the amino acid sequence of LCDR1 in the antibody, antigen-binding fragment thereof of the present application may include SEQ ID NO: 96; the amino acid sequence of LCDR2 may include SEQ ID NO: 5; the amino acid sequence of LCDR3 may include SEQ ID NO: 6; and the amino acid sequence of HCDR1 may comprise SEQ ID NO: 92; the amino acid sequence of HCDR2 may comprise SEQ ID NO: 2; the amino acid sequence of HCDR3 may comprise SEQ ID NO: 94. For example, the antibody, antigen-binding fragment thereof can include antibody YN-069 or an antibody having the same LCDR1-3 and HCDR1-3. The amino acid sequence of L-FR1 in the antibody, antigen-binding fragment thereof described in the present application may include SEQ ID NO: 97; the amino acid sequence of L-FR2 may include SEQ ID NO: 98; the amino acid sequence of L-FR3 may include SEQ ID NO: 13; the amino acid sequence of L-FR4 may include SEQ ID NO: 14; and the amino acid sequence of H-FR1 may include SEQ ID NO: 7; the amino acid sequence of H-FR2 may include SEQ ID NO: 8; H-FR3 The amino acid sequence can include SEQ ID NO: 9; the amino acid sequence of H-FR4 can include SEQ ID NO: 10. For example, the antibody, antigen-binding fragment thereof can include antibody YN-069 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4. In certain embodiments, the light chain of an antibody, antigen-binding fragment thereof, of the present application may comprise a light chain variable region, the amino acid sequence of the light chain variable region comprising SEQ ID NO: 109; The chain may comprise a heavy chain variable region, and the amino acid sequence of the heavy chain variable region may comprise SEQ ID NO:117. For example, the antibody, antigen-binding fragment thereof can include antibody YN-069 or an antibody having the same light chain variable region and heavy chain variable region. In certain embodiments, an antibody, antigen-binding fragment thereof, as described herein, can comprise a light chain and a heavy chain, the amino acid sequence of which is set forth in SEQ ID NO: 110 and the amino acid sequence of the heavy chain is as SEQ ID NO: 118. For example, the antibody, antigen-binding fragment thereof can include antibody YN-069 or an antibody having the same light and heavy chains thereto.

在某些实施方式中，本申请所述的抗体、其抗原结合片段中LCDR1的氨基酸序列可包括SEQ ID NO:96；LCDR2的氨基酸序列可包括SEQ ID NO:5；LCDR3的氨基酸序列可包括SEQ ID NO:6；且HCDR1的氨基酸序列可包括SEQ ID NO:91；HCDR2的氨基酸序列可包括SEQ ID NO:93；HCDR3的氨基酸序列可包括SEQ ID NO:94。例如，该抗体、其抗原结合片段可包括抗体YN-070或与其具有相同的LCDR1-3及HCDR1-3的抗体。本申请所述的抗体、其抗原结合片段中L-FR1的氨基酸序列可包括SEQ ID NO:97；L-FR2的氨基酸序列可包括SEQ ID NO:98；L-FR3的氨基酸序列可包括SEQ ID NO:13；L-FR4的氨基酸序列 可包括SEQ ID NO:14；且H-FR1的氨基酸序列可包括SEQ ID NO:7；H-FR2的氨基酸序列可包括SEQ ID NO:8；H-FR3的氨基酸序列可包括SEQ ID NO:99；H-FR4的氨基酸序列可包括SEQ ID NO:10。例如，该抗体、其抗原结合片段可包括抗体YN-070或与其具有相同的LCDR1-3、HCDR1-3、L-FR1-4及H-FR1-4的抗体。在某些实施方式中，本申请所述的抗体、其抗原结合片段的轻链可包含轻链可变区，所述轻链可变区的氨基酸序列可包括SEQ ID NO:109；且其中重链可包含重链可变区，所述重链可变区的氨基酸序列可包括SEQ ID NO:120。例如，该抗体、其抗原结合片段可包括抗体YN-070或与其具有相同的轻链可变区及重链可变区的抗体。在某些实施方式中，本申请所述的抗体、其抗原结合片段可包含轻链和重链，所述轻链的氨基酸序列如SEQ ID NO:110所示且所述重链的氨基酸序列如SEQ ID NO:121所示。例如，该抗体、其抗原结合片段可包括抗体YN-070或与其具有相同的轻链及重链的抗体。In certain embodiments, the amino acid sequence of LCDR1 in the antibody, antigen-binding fragment thereof of the present application may include SEQ ID NO: 96; the amino acid sequence of LCDR2 may include SEQ ID NO: 5; the amino acid sequence of LCDR3 may include SEQ ID NO:6; and the amino acid sequence of HCDR1 may comprise SEQ ID NO:91; the amino acid sequence of HCDR2 may comprise SEQ ID NO:93; the amino acid sequence of HCDR3 may comprise SEQ ID NO:94. For example, the antibody, antigen-binding fragment thereof can include antibody YN-070 or an antibody having the same LCDR1-3 and HCDR1-3. The amino acid sequence of L-FR1 in the antibody, antigen-binding fragment thereof described in the present application may include SEQ ID NO: 97; the amino acid sequence of L-FR2 may include SEQ ID NO: 98; the amino acid sequence of L-FR3 may include SEQ ID NO: 13; the amino acid sequence of L-FR4 may include SEQ ID NO: 14; and the amino acid sequence of H-FR1 may include SEQ ID NO: 7; the amino acid sequence of H-FR2 may include SEQ ID NO: 8; H-FR3 The amino acid sequence can include SEQ ID NO: 99; the amino acid sequence of H-FR4 can include SEQ ID NO: 10. For example, the antibody, antigen-binding fragment thereof may include antibody YN-070 or an antibody having the same LCDR1-3, HCDR1-3, L-FR1-4, and H-FR1-4. In certain embodiments, the light chain of an antibody, antigen-binding fragment thereof, of the present application may comprise a light chain variable region, the amino acid sequence of the light chain variable region comprising SEQ ID NO: 109; The chain may comprise a heavy chain variable region, and the amino acid sequence of the heavy chain variable region may comprise SEQ ID NO:120. For example, the antibody, antigen-binding fragment thereof can include antibody YN-070 or an antibody having the same light chain variable region and heavy chain variable region. In certain embodiments, an antibody, antigen-binding fragment thereof, as described herein, can comprise a light chain and a heavy chain, the amino acid sequence of which is set forth in SEQ ID NO: 110 and the amino acid sequence of the heavy chain is as SEQ ID NO: 121. For example, the antibody, antigen-binding fragment thereof can include antibody YN-070 or an antibody having the same light and heavy chains thereto.

在本申请中涉及的蛋白质、多肽和/或氨基酸序列，还应理解为至少包含以下的范围：与该所述蛋白质或多肽具备相同或类似功能的变体或同源物。A protein, polypeptide and/or amino acid sequence referred to in this application is also understood to include at least the following range: a variant or homologue having the same or similar function as the protein or polypeptide.

在本申请中，所述变体可以为，在所述蛋白质和/或所述多肽(例如，特异性结合CD38蛋白的抗体或其片段)的氨基酸序列中经过取代、缺失或添加一个或多个氨基酸的蛋白质或多肽。例如，所述功能性变体可包含已经通过至少1个，例如1-30个、1-20个或1-10个，又例如1个、2个、3个、4个或5个氨基酸取代、缺失和/或插入而具有氨基酸改变的蛋白质或多肽。所述功能性变体可基本上保持改变(例如取代、缺失或添加)之前的所述蛋白质或所述多肽的生物学特性。例如，所述功能性变体可保持改变之前的所述蛋白质或所述多肽的至少60％，70％，80％，90％，或100％的生物学活性(例如抗原结合能力)。例如，所述取代可以为保守取代。In the present application, the variant may be one or more substituted, deleted or added to the amino acid sequence of the protein and/or the polypeptide (eg, an antibody or fragment thereof that specifically binds to a CD38 protein) A protein or polypeptide of an amino acid. For example, the functional variant may comprise having been substituted by at least 1, for example 1-30, 1-20 or 1-10, for example 1 , 2, 3, 4 or 5 amino acids. A protein or polypeptide having an amino acid change, deleted and/or inserted. The functional variant may substantially retain the biological properties of the protein or the polypeptide prior to alteration (eg, substitution, deletion or addition). For example, the functional variant can retain at least 60%, 70%, 80%, 90%, or 100% of the biological activity (eg, antigen binding capacity) of the protein or the polypeptide prior to the alteration. For example, the substitution can be a conservative substitution.

在本申请中，所述同源物可以为，与所述蛋白质和/或所述多肽(例如，特异性结合CD38蛋白的抗体或其片段)的氨基酸序列具有至少约85％(例如，具有至少约85％、约90％、约91％、约92％、约93％、约94％、约95％、约96％、约97％、约98％、约99％或更高的)序列同源性的蛋白质或多肽。In the present application, the homolog may be at least about 85% of the amino acid sequence of the protein and/or the polypeptide (eg, an antibody or fragment thereof that specifically binds to a CD38 protein) (eg, having at least Approximately 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or more) A protein or polypeptide derived from a source.

在本申请中，所述同源性通常是指两个或多个序列之间的相似性、类似或关联。可以通过以下方式计算“序列同源性百分比”：将两条待比对的序列在比较窗中进行比较，确定两条序列中存在相同核酸碱基(例如，A、T、C、G、I)或相同氨基酸残基(例如，Ala、Pro、Ser、Thr、Gly、Val、Leu、Ile、Phe、Tyr、Trp、Lys、Arg、His、Asp、Glu、Asn、Gln、Cys和Met)的位置的数目以得到匹配位置的数目，将匹配位置的数目除以比较窗中的总位置数 (即，窗大小)，并且将结果乘以100，以产生序列同源性百分比。为了确定序列同源性百分数而进行的比对，可以按本领域已知的多种方式实现，例如，使用可公开获得的计算机软件如BLAST、BLAST-2、ALIGN或Megalign(DNASTAR)软件。本领域技术人员可以确定用于比对序列的适宜参数，包括为实现正在比较的全长序列范围内或目标序列区域内最大比对所需要的任何算法。所述同源性也可以通过以下的方法测定：FASTA和BLAST。对FASTA算法的描述可以参见W.R.Pearson和D.J.Lipman的“用于生物学序列比较的改进的工具”，美国国家科学院院刊(Proc.Natl.Acad.Sci.)，85：2444-2448，1988；和D.J.Lipman和W.R.Pearson的“快速灵敏的蛋白质相似性搜索”，Science，227：1435-1441，1989。对BLAST算法的描述可参见S.Altschul、W.Gish、W.Miller、E.W.Myers和D.Lipman的“一种基本的局部对比(alignment)搜索工具”，分子生物学杂志，215：403-410，1990。In the present application, the homology generally refers to the similarity, similarity or association between two or more sequences. The "percentage of sequence homology" can be calculated by comparing two sequences to be aligned in a comparison window to determine the presence of the same nucleic acid base in both sequences (eg, A, T, C, G, I) Or the same amino acid residues (eg, Ala, Pro, Ser, Thr, Gly, Val, Leu, Ile, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gln, Cys, and Met) The number of positions is obtained to obtain the number of matching positions, the number of matching positions is divided by the total number of positions in the comparison window (ie, the window size), and the result is multiplied by 100 to generate a sequence homology percentage. Alignment to determine percent sequence homology can be accomplished in a variety of ways known in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. One of skill in the art can determine suitable parameters for aligning the sequences, including any algorithms needed to achieve maximum alignment within the full length sequence being compared or within the target sequence region. The homology can also be determined by the following methods: FASTA and BLAST. A description of the FASTA algorithm can be found in WRPearson and DJ Lipman, "Improved Tools for Biological Sequence Comparison," Proc. Natl. Acad. Sci., 85: 2444-2448, 1988; And "Difficult and Sensitive Protein Similarity Search" by DJ Lipman and WRPearson, Science, 227: 1435-1441, 1989. A description of the BLAST algorithm can be found in "A Basic Local Alignment Search Tool" by S. Altschul, W. Gish, W. Miller, EW Myers, and D. Lipman, Journal of Molecular Biology, 215: 403-410 , 1990.

核酸、载体、宿主细胞和制备方法Nucleic acid, vector, host cell and preparation method

在另一个方面，本申请还提供了分离的一种或多种核酸分子，所述一种或多种核酸分子可编码本申请所述的抗体、其抗原结合片段。例如，所述一种或多种核酸分子中的每一个核酸分子可以编码完整的所述抗体、其抗原结合片段，也可以编码其中的一部分(例如，HCDR1-3、LCDR1-3、VL、VH、轻链或重链中的一种或多种)。In another aspect, the application also provides an isolated nucleic acid molecule or molecules encoding an antibody, antigen-binding fragment thereof, as described herein. For example, each of the one or more nucleic acid molecules can encode the entire antibody, its antigen-binding fragment, or a portion thereof (eg, HCDR1-3, LCDR1-3, VL, VH) , one or more of a light chain or a heavy chain).

本申请所述的核酸分子可以为分离的。例如，其可以是通过以下方法产生或合成的：(i)在体外扩增的，例如通过聚合酶链式反应(PCR)扩增产生的，(ii)通过克隆重组产生的，(iii)纯化的，例如通过酶切和凝胶电泳分级分离，或者(iv)合成的，例如通过化学合成。在某些实施方式中，所述分离的核酸是通过重组DNA技术制备的核酸分子。The nucleic acid molecules described herein can be isolated. For example, it may be produced or synthesized by (i) amplification in vitro, such as by polymerase chain reaction (PCR) amplification, (ii) production by clonal recombination, (iii) purification. , for example, by fractionation by gel digestion and gel electrophoresis, or (iv) synthetic, for example by chemical synthesis. In certain embodiments, the isolated nucleic acid is a nucleic acid molecule produced by recombinant DNA techniques.

在本申请中，可以通过本领域已知的多种方法来制备编码所述抗体、其抗原结合片段的核酸，这些方法包括但不限于，采用限制性片段操作或采用合成性寡核苷酸的重叠延伸PCR，具体操作可参见Sambrook等人，Molecular Cloning，A Laboratory Manual，Cold Spring Harbor Laboratory Press，Cold Spring Harbor，N.Y.，1989；和Ausube等人Current Protocols in Molecular Biology，Greene Publishing and Wiley-Interscience，New York N.Y.，1993。In the present application, nucleic acids encoding the antibodies, antigen-binding fragments thereof can be prepared by a variety of methods known in the art including, but not limited to, restriction fragment manipulation or the use of synthetic oligonucleotides. Overlap extension PCR, see Sambrook et al, Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989; and Ausube et al. Current Protocols in Molecular Biology, Greene Publishing and Wiley-Interscience, for specific procedures. New York NY, 1993.

在另一个方面，本申请提供了一种或多种载体，其包含本申请所述的一种或多种核酸分子。每种载体中可包含一种或多种所述核酸分子。此外，所述载体中还可包含其他基因，例如允许在适当的宿主细胞中和在适当的条件下选择该载体的标记基因。此外，所述载体还可包含允许编码区在适当宿主中正确表达的表达控制元件。这样的控制元件为本领域技术人员所熟知的，例如，可包括启动子、核糖体结合位点、增强子和调节基因转录或mRNA翻译的 其他控制元件等。在某些实施方式中，所述表达控制序列为可调的元件。所述表达控制序列的具体结构可根据物种或细胞类型的功能而变化，但通常包含分别参与转录和翻译起始的5’非转录序列和5’及3’非翻译序列，例如TATA盒、加帽序列、CAAT序列等。例如，5’非转录表达控制序列可包含启动子区，启动子区可包含用于转录控制功能性连接核酸的启动子序列。所述表达控制序列还可包括增强子序列或上游活化子序列。在本申请中，适当的启动子可包括，例如用于SP6、T3和T7聚合酶的启动子、人U6RNA启动子、CMV启动子及其人工杂合启动子(如CMV)，其中启动子的某部分可与其他细胞蛋白(如人GAPDH，甘油醛-3-磷酸脱氢酶)基因启动子的某部分融合，其可包含或不包含另外的内含子。本申请所述的一种或多种核酸分子可以与所述表达控制元件可操作地连接。In another aspect, the application provides one or more vectors comprising one or more nucleic acid molecules described herein. One or more of the nucleic acid molecules can be included in each vector. Furthermore, other genes may be included in the vector, such as a marker gene that allows selection of the vector in a suitable host cell and under appropriate conditions. Furthermore, the vector may further comprise an expression control element that allows the coding region to be correctly expressed in a suitable host. Such control elements are well known to those skilled in the art and may include, for example, promoters, ribosome binding sites, enhancers, and other control elements that regulate gene transcription or mRNA translation. In certain embodiments, the expression control sequence is a tunable element. The specific structure of the expression control sequence may vary depending on the function of the species or cell type, but typically comprises 5' non-transcribed sequences and 5' and 3' untranslated sequences, respectively, involved in transcriptional and translational initiation, such as TATA boxes, plus Cap sequence, CAAT sequence, and the like. For example, a 5' non-transcribed expression control sequence can comprise a promoter region, and the promoter region can comprise a promoter sequence for transcriptional control of a functionally linked nucleic acid. The expression control sequence may also include an enhancer sequence or an upstream activator sequence. In the present application, suitable promoters may include, for example, promoters for SP6, T3 and T7 polymerase, human U6 RNA promoter, CMV promoter and artificial hybrid promoters thereof (such as CMV), wherein the promoter A portion may be fused to a portion of a promoter of another cellular protein (eg, human GAPDH, glyceraldehyde-3-phosphate dehydrogenase) gene, which may or may not contain additional introns. One or more nucleic acid molecules described herein can be operably linked to the expression control element.

所述载体可以包括，例如质粒、粘粒、病毒、噬菌体或者在例如遗传工程中通常使用的其他载体。例如，所述载体为表达载体。Such vectors may include, for example, plasmids, cosmids, viruses, bacteriophages or other vectors commonly used, for example, in genetic engineering. For example, the vector is an expression vector.

在另一方面，本申请提供了宿主细胞，所述宿主细胞可包含本申请所述的一种或多种核酸分子和/或本申请所述的一种或多种载体。在某些实施方式中，每种或每个宿主细胞可包含一个或一种本申请所述的核酸分子或载体。在某些实施方式中，每种或每个宿主细胞可包含多个(例如，2个或以上)或多种(例如，2种或以上)本申请所述的核酸分子或载体。例如，可将本申请所述的载体引入所述宿主细胞中，例如原核细胞(例如，细菌细胞)、CHO细胞、NS/0细胞、HEK293T细胞或HEK293A细胞，或者其他真核细胞，如来自植物的细胞、真菌或酵母细胞等。可通过本领域已知的方法将本申请所述的载体引入所述宿主细胞中，例如电穿孔、lipofectine转染、lipofectamin转染等。例如，所述宿主细胞可以为COS、CHO、NSO、sf9、sf21、DH5a、BL21(DE3)或TG1。In another aspect, the application provides a host cell, which can comprise one or more nucleic acid molecules described herein and/or one or more vectors described herein. In certain embodiments, each or each host cell can comprise one or one of the nucleic acid molecules or vectors described herein. In certain embodiments, each or each host cell can comprise multiple (eg, two or more) or multiple (eg, two or more) nucleic acid molecules or vectors described herein. For example, a vector described herein can be introduced into the host cell, such as a prokaryotic cell (eg, a bacterial cell), a CHO cell, an NS/0 cell, a HEK293T cell, or a HEK293A cell, or other eukaryotic cell, such as from a plant. Cell, fungus or yeast cells, etc. Vectors described herein can be introduced into the host cell by methods known in the art, such as electroporation, lipofectine transfection, lipofectamin transfection, and the like. For example, the host cell can be COS, CHO, NSO, sf9, sf21, DH5a, BL21 (DE3) or TG1.

在另一个方面，本申请提供了制备本申请所述的抗体、其抗原结合片段的方法。所述方法可包括，在使得所述抗体、其抗原结合片段表达的条件下，培养本申请所述的宿主细胞。例如，可通过使用适当的培养基、适当的温度和培养时间等，这些方法是本领域普通技术人员所了解的。In another aspect, the application provides a method of making an antibody, antigen-binding fragment thereof, as described herein. The method can comprise culturing a host cell as described herein under conditions such that the antibody, its antigen-binding fragment is expressed. For example, such methods can be understood by those of ordinary skill in the art by using appropriate media, appropriate temperatures and incubation times, and the like.

在某些情形中，所述方法还可包括收获(例如分离和/或纯化)，本申请所述的抗体、其抗原结合片段的步骤。例如，可以采用蛋白G-琼脂糖或蛋白A-琼脂糖进行亲和层析，还可通过凝胶电泳和/或高效液相色谱等来纯化和分离本申请所述的抗体、其抗原结合片段。例如，还可以通过使用高盐缓冲液、改变pH等方法洗脱结合在亲和柱上的融合蛋白多肽。In certain instances, the methods can also include the step of harvesting (eg, isolating and/or purifying) the antibodies, antigen-binding fragments thereof described herein. For example, affinity chromatography can be carried out using protein G-Sepharose or Protein A-Sepharose, and the antibody and antigen-binding fragment thereof described in the present application can also be purified and isolated by gel electrophoresis and/or high performance liquid chromatography or the like. . For example, the fusion protein polypeptide bound to the affinity column can also be eluted by using a high salt buffer, changing the pH, and the like.

药物组合物、应用Pharmaceutical composition, application

在另一个方面，本申请提供了一种药物组合物，其可包含本申请所述的抗体、其抗原结合片段，以及任选地药学上可接受的载体。In another aspect, the application provides a pharmaceutical composition comprising an antibody, antigen-binding fragment thereof, and, optionally, a pharmaceutically acceptable carrier, as described herein.

所述药学上可接受的载体可以包括缓冲剂、抗氧化剂、防腐剂、低分子量多肽、蛋白质、亲水聚合物、氨基酸、糖、螯合剂、反离子、金属复合物和/或非离子表面活性剂等。The pharmaceutically acceptable carrier can include buffers, antioxidants, preservatives, low molecular weight polypeptides, proteins, hydrophilic polymers, amino acids, sugars, chelating agents, counterions, metal complexes, and/or nonionic surface active agents. Agents, etc.

在本申请中，所述药物组合物可被配制用于口服给药，静脉内给药，肌肉内给药，在肿瘤部位的原位给药，吸入，直肠给药，阴道给药，经皮给药或通过皮下储存库给药。In the present application, the pharmaceutical composition can be formulated for oral administration, intravenous administration, intramuscular administration, in situ administration at the tumor site, inhalation, rectal administration, vaginal administration, transdermal Administration or administration via a subcutaneous reservoir.

所述药物组合物可以用于抑制或延缓疾病或病症的发展或进展，和/或可以减轻和/或稳定疾病或病症的状态。The pharmaceutical composition can be used to inhibit or delay the progression or progression of a disease or condition, and/or can alleviate and/or stabilize the condition of the disease or condition.

本申请所述的药物组合物可以包含预防和/或治疗有效量的所述抗体、其抗原结合片段。所述预防和/或治疗有效量是能够预防和/或治疗(至少部分治疗)患有或具有发展风险的受试者中的疾病或病症和/或其任何并发症而所需的剂量。The pharmaceutical compositions described herein may comprise a prophylactically and/or therapeutically effective amount of the antibody, antigen-binding fragment thereof. The prophylactically and/or therapeutically effective amount is a dose that is capable of preventing and/or treating (at least partially treating) a disease or condition in a subject having or at risk of development and/or any complications thereof.

另一方面，本申请提供了所述抗体、其抗原结合片段在制备预防或治疗疾病或病症的药物中的用途。In another aspect, the application provides the use of the antibody, antigen-binding fragment thereof, for the manufacture of a medicament for preventing or treating a disease or condition.

另一方面，本申请提供的所述抗体、其抗原结合片段，可用于预防或治疗疾病或病症。另一方面，本申请提供了预防或治疗疾病或病症的方法，其包括施用(例如，向有需要的受试者施用)本申请所述的抗体、其抗原结合片段、所述的核酸分子、所述的载体、所述的宿主细胞和/或所述的药物组合物。In another aspect, the antibodies, antigen-binding fragments thereof, provided herein, are useful for preventing or treating a disease or condition. In another aspect, the application provides a method of preventing or treating a disease or condition, comprising administering (eg, administering to a subject in need thereof) an antibody, antigen-binding fragment thereof, nucleic acid molecule, Said vector, said host cell and / or said pharmaceutical composition.

在本申请中，所述疾病或病症可选自以下组：强直性脊柱炎、银屑病关节炎、类风湿性关节炎、骨关节炎、骨植入物松动、急性移植排斥、呼吸道炎症、炎性肠病、败血症、败血症性或内毒素性休克、骨丢失、银屑病、变态反应、局部缺血、系统性硬化症、中风和哮喘。In the present application, the disease or condition may be selected from the group consisting of ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, osteoarthritis, bone implant loosening, acute graft rejection, respiratory inflammation, Inflammatory bowel disease, sepsis, septic or endotoxic shock, bone loss, psoriasis, allergy, ischemia, systemic sclerosis, stroke and asthma.

另一方面，本申请提供了抑制IL17蛋白与IL17配体结合的方法，其包括施用本申请所述的抗体、其抗原结合片段、所述的核酸分子、所述的载体、所述的宿主细胞和/或所述的药物组合物。例如，所述方法可以为体外或离体方法。In another aspect, the application provides a method of inhibiting binding of an IL17 protein to an IL17 ligand, comprising administering an antibody, an antigen-binding fragment thereof, the nucleic acid molecule, the vector, the host cell, and a host cell, And/or the pharmaceutical composition described. For example, the method can be an in vitro or ex vivo method.

另一方面，本申请提供了抑制IL17蛋白生物学活性的方法，其包括施用本申请所述的抗体、其抗原结合片段、所述的核酸分子、所述的载体、所述的宿主细胞和/或所述的药物组合物。例如，所述方法可以为体外或离体方法。In another aspect, the application provides a method of inhibiting the biological activity of an IL17 protein comprising administering an antibody, an antigen-binding fragment thereof, the nucleic acid molecule, the vector, the host cell, and/or Or the pharmaceutical composition described. For example, the method can be an in vitro or ex vivo method.

另一方面，本申请提供了抑制趋化因子表达的方法，其包括施用所述的抗体、其抗原结合片段、所述的核酸分子、所述的载体、所述的宿主细胞和/或所述的药物组合物。例如，所述的趋化因子可以包括CXCL1。例如，所述方法可以为体外或离体方法。In another aspect, the application provides a method of inhibiting expression of a chemokine comprising administering the antibody, antigen-binding fragment thereof, the nucleic acid molecule, the vector, the host cell, and/or the Pharmaceutical composition. For example, the chemokine can include CXCL1. For example, the method can be an in vitro or ex vivo method.

不欲被任何理论所限，下文中的实施例仅仅是为了阐释本申请的装置、方法和系统的工 作方式，而不用于限制本申请发明的范围。Without being limited to any theory, the following examples are merely illustrative of the operation of the apparatus, methods and systems of the present application and are not intended to limit the scope of the invention.

实施例Example

下面显示的实施例意在说明本发明的具体实施方案，并且不意在以任何方式限制本说明书或权利要求书的范围。实施例不包括对传统方法的详细描述，如那些用于构建载体和质粒的方法，将编码蛋白的基因插入到这样的载体和质粒的方法或将质粒引入宿主细胞的方法.这样的方法对于本领域中具有普通技术的人员是众所周知的，并且在许多出版物中都有所描述，包括Sambrook，J.，Fritsch，E.F.and Maniais，T.(1989)MolecμLar Cloning：A Laboratory Manual，2nd edition，Cold spring Harbor Laboratory Press。The examples shown below are intended to illustrate the specific embodiments of the invention and are not intended to limit the scope of the invention or the claims. The examples do not include a detailed description of conventional methods, such as those used to construct vectors and plasmids, methods for inserting genes encoding proteins into such vectors and plasmids, or methods for introducing plasmids into host cells. Those of ordinary skill in the art are well known and described in many publications, including Sambrook, J., Fritsch, EF and Maniais, T. (1989) Molec μLar Cloning: A Laboratory Manual, 2nd edition, Cold Spring Harbor Laboratory Press.

实施例1利用噬菌体抗体文库筛选抗IL17抗体Example 1 Screening of anti-IL17 antibodies using phage antibody libraries

利用重组人IL17A蛋白(北京义翘神州生物技术有限公司)为抗原用于噬菌体天然人源性抗体文库(原能细胞医学技术有限公司)分选。酶联免疫管中使用CBS缓冲液包被抗原IL17A蛋白1ml，IL17A蛋白的浓度为20μg/ml(第一、二轮)或10μg/ml(第三、四轮)，4℃过夜；次日用含10％的脱脂奶粉的PBS缓冲液2ml封闭免疫管；将1ml的封闭过的噬菌体加入到免疫管中，室温孵育1h；PBST洗涤10次(第一、二轮)或15次(第三、四轮)；加入pH2.2的Gly-HCl缓冲液800μL洗脱，立即加400μL的pH8.0的Tris-HCl缓冲液中和；加入到20ml对数生长期OD约0.8的E.coli SS320中，混匀37℃静置1h；取出500μL用来测定噬菌体滴度及甘油保菌；剩余菌液涂平板，培养箱中37℃过夜培养；第二天刮下平板的菌，按一定比例接入80ml的2YT-Amp培养基中，使OD等于0.2，培养数小时以OD达到0.8时，加入160μL的helper噬菌体，然后混匀37℃静置1h；加入IPTG、卡那霉素，250rpm，30℃，振荡培养过夜；收集上清，用PEG/NaCl溶液沉淀噬菌体，重悬于1.5ml的PBS缓冲液中；重悬的噬菌体用于下一轮的富集筛选，4轮淘洗之后，观察到显著的富集。利用ELISA对淘选得到的噬菌体抗体克隆进行鉴定：在96孔ELISA板上包被人IL17A蛋白(北京义翘神州生物技术有限公司，12047-HNAS)，浓度1μg/ml，4℃过夜。然后用10％脱脂奶粉封闭非特异性结合位点，充分洗涤后，取单克隆的噬菌体上清加入96孔板，37℃孵育2小时。充分洗涤后，加入(GE healtcare，27-9421-01)，37℃作用45min，充分洗涤后加入TMB显色，室温下作用5-10min后，最后用硫酸终止反应，于450nm处测定各孔OD值。Recombinant human IL17A protein (Beijing Yiqiao Shenzhou Biotechnology Co., Ltd.) was used as an antigen for sorting by phage natural human antibody library (Primary Energy Cell Technology Co., Ltd.). In the enzyme-linked immunotube, 1 ml of the antigen IL17A protein was coated with CBS buffer, and the concentration of IL17A protein was 20 μg/ml (first and second round) or 10 μg/ml (third and fourth round), overnight at 4 ° C; 2 ml of PBS buffer containing 10% skim milk powder was used to block the immunotube; 1 ml of the blocked phage was added to the immunotube, incubated for 1 h at room temperature; PBST was washed 10 times (first, second round) or 15 times (third, Four rounds); add 800 μL of Gly-HCl buffer at pH 2.2, immediately add 400 μL of Tris-HCl buffer at pH 8.0, and add to 20 ml of E. coli SS320 with a logarithmic growth phase OD of about 0.8. Mix well at 37 ° C for 1 h; remove 500 μL for determination of phage titer and glycerol preservation; the remaining bacterial solution is plated, and cultured at 37 ° C overnight in the incubator; the next day, the plate is scraped off, and 80 ml is added according to a certain ratio. In the 2YT-Amp medium, the OD was equal to 0.2, and when the OD reached 0.8, the 160 μL of helper phage was added, and then mixed at 37 ° C for 1 h; IPTG, kanamycin, 250 rpm, 30 ° C, Incubate overnight with shaking; collect the supernatant, pellet the phage with PEG/NaCl solution, resuspend in 1.5 ml of PBS buffer; resuspend Enrichment of cells for the next round of screening, after four panning, significant enrichment was observed. The phage antibody clones obtained by panning were identified by ELISA: human IL17A protein (Beijing Yishen Shenzhou Biotechnology Co., Ltd., 12047-HNAS) was coated on a 96-well ELISA plate at a concentration of 1 μg/ml overnight at 4 °C. The non-specific binding sites were then blocked with 10% skim milk powder. After thorough washing, the monoclonal phage supernatant was added to a 96-well plate and incubated at 37 ° C for 2 hours. After sufficient washing, add (GE healtcare, 27-9421-01), act at 37 ° C for 45 min, fully wash, add TMB color, after 5-10 min at room temperature, finally terminate the reaction with sulfuric acid, determine the OD of each well at 450 nm value.

通过ELISA鉴定获得了3株能特异性结合人IL17A的噬菌体抗体克隆1F10、1B6、1F3。Three phage antibody clones 1F10, 1B6, and 1F3 capable of specifically binding to human IL17A were obtained by ELISA.

实施例2抗IL17A全人源完整抗体的表达和纯化Example 2 Expression and purification of anti-IL17A fully human intact antibody

将噬菌体抗体克隆1F10重新设计成完整IgG1，κ抗体：设计引物对噬菌体抗体的VH进行PCR扩增，将PCR产物通过重组克隆至经AgeI和SalI双酶切的pCMV-IgG1NEM载体；设计引物对噬菌体抗体的VL进行PCR扩增，将PCR产物通过重组克隆至经AgeI和BsiWI双酶切的pCMV-κ载体。测序正确后将重、轻链表达载体共转染293F细胞进行瞬时表达，并通过ProteinA柱纯化，将1F10的完整IgG1，κ抗体命名为YN-008。The phage antibody clone 1F10 was redesigned into a complete IgG1, kappa antibody: the primers were designed to PCR-amplify the VH of the phage antibody, and the PCR product was recombinantly cloned into the pCMV-IgG1 NEM vector digested with AgeI and SalI; the primer pair phage was designed. The VL of the antibody was subjected to PCR amplification, and the PCR product was recombinantly cloned into the pCMV-κ vector double-digested with AgeI and BsiWI. After sequencing, the heavy and light chain expression vectors were co-transfected into 293F cells for transient expression, and purified by ProteinA column. The intact IgG1, κ antibody of 1F10 was named YN-008.

将噬菌体抗体1B6、1F3分别重新设计成完整IgG1，κ抗体，并进行表达纯化，表达纯化的方法与1F10相同。将1B6的完整IgG1，κ抗体命名为YN-009；将1F3的完整IgG1，κ抗体命名为YN-010。The phage antibodies 1B6 and 1F3 were redesigned into intact IgG1, kappa antibodies, respectively, and expressed and purified. The method of expression and purification was the same as that of 1F10. The intact IgG1, kappa antibody of 1B6 was named YN-009; the intact IgG1, kappa antibody of 1F3 was named YN-010.

使用确定CDR区的Kabat系统分析YN-008、YN-009和YN-010的VH序列和VL序列，从而确定H-CDR1、H-CDR2和H-CDR3以及L-CDR1、L-CDR2和L-CDR3的氨基酸序列。The VH and VL sequences of YN-008, YN-009 and YN-010 were analyzed using the Kabat system for determining CDR regions to determine H-CDR1, H-CDR2 and H-CDR3 and L-CDR1, L-CDR2 and L- The amino acid sequence of CDR3.

测序结果显示，抗IL17A全人源抗体YN-008的LCDR1-3的氨基酸序列分别如SEQ ID NO.4、SEQ ID NO.5和SEQ ID NO.6所示；VL的氨基酸序列如SEQ ID NO.16所示；对应的核苷酸序列如SEQ ID NO.56所示；轻链的氨基酸序列如SEQ ID NO.64所示；对应的核苷酸序列如SEQ ID NO.63所示；抗体YN-008的HCDR1-3的氨基酸序列分别如SEQ ID NO.1、SEQ ID NO.2和SEQ ID NO.3所示；VH的氨基酸序列如SEQ ID NO.15所示；对应的核苷酸序列如SEQ ID NO.55所示；重链的氨基酸序列如SEQ ID NO.62所示；对应的核苷酸序列如SEQ ID NO.61所示。The sequencing results showed that the amino acid sequences of LCDR1-3 of anti-IL17A fully human antibody YN-008 are shown in SEQ ID NO. 4, SEQ ID NO. 5 and SEQ ID NO. 6, respectively; the amino acid sequence of VL is SEQ ID NO. The corresponding nucleotide sequence is shown in SEQ ID NO. 56; the amino acid sequence of the light chain is shown in SEQ ID NO. 64; the corresponding nucleotide sequence is shown in SEQ ID NO. 63; The amino acid sequences of HCDR1-3 of YN-008 are shown in SEQ ID NO. 1, SEQ ID NO. 2 and SEQ ID NO. 3, respectively; the amino acid sequence of VH is shown in SEQ ID NO. 15; the corresponding nucleotide The sequence is set forth in SEQ ID NO. 55; the amino acid sequence of the heavy chain is set forth in SEQ ID NO. 62; the corresponding nucleotide sequence is set forth in SEQ ID NO.

抗IL17A全人源抗体YN-009的LCDR1-3的氨基酸序列分别如SEQ ID NO.22、SEQ ID NO.23和SEQ ID NO.24所示；VL的氨基酸序列如SEQ ID NO.34所示；对应的核苷酸序列如SEQ ID NO.58所示；轻链的氨基酸序列如SEQ ID NO.68所示；对应的核苷酸序列如SEQ ID NO.67所示；抗体YN-009的HCDR1-3的氨基酸序列分别如SEQ ID NO.19、SEQ ID NO.20和SEQ ID NO.21所示；VH的氨基酸序列如SEQ ID NO.33所示；对应的核苷酸序列如SEQ ID NO.57所示；重链的氨基酸序列如SEQ ID NO.66所示；对应的核苷酸序列如SEQ ID NO.65所示。The amino acid sequence of LCDR1-3 of anti-IL17A fully human antibody YN-009 is shown in SEQ ID NO. 22, SEQ ID NO. 23 and SEQ ID NO. 24, respectively; the amino acid sequence of VL is shown in SEQ ID NO. The corresponding nucleotide sequence is shown in SEQ ID NO. 58; the amino acid sequence of the light chain is shown in SEQ ID NO. 68; the corresponding nucleotide sequence is shown in SEQ ID NO. 67; the antibody YN-009 The amino acid sequences of HCDR1-3 are shown in SEQ ID NO. 19, SEQ ID NO. 20 and SEQ ID NO. 21, respectively; the amino acid sequence of VH is shown in SEQ ID NO. 33; the corresponding nucleotide sequence is SEQ ID. The amino acid sequence of the heavy chain is shown in SEQ ID NO. 66; the corresponding nucleotide sequence is shown in SEQ ID NO.

抗IL17A全人源抗体YN-010的LCDR1-3的氨基酸序列分别如SEQ ID NO.40、SEQ ID NO.41和SEQ ID NO.42所示；VL的氨基酸序列如SEQ ID NO.52所示；对应的核苷酸序列如SEQ ID NO.60所示；轻链的氨基酸序列如SEQ ID NO.72所示；对应的核苷酸序列如SEQ ID NO.71所示；抗体YN-010的HCDR1-3的氨基酸序列分别如SEQ ID NO.37、SEQ ID NO.38和SEQ ID NO.39所示；VH的氨基酸序列如SEQ ID NO.51所示；对应的核苷酸序列如 SEQ ID NO.59所示；重链的氨基酸序列如SEQ ID NO.70所示；对应的核苷酸序列如SEQ ID NO.69所示。The amino acid sequence of LCDR1-3 of the anti-IL17A fully human antibody YN-010 is shown in SEQ ID NO. 40, SEQ ID NO. 41 and SEQ ID NO. 42, respectively; the amino acid sequence of VL is shown in SEQ ID NO. The corresponding nucleotide sequence is shown in SEQ ID NO. 60; the amino acid sequence of the light chain is shown in SEQ ID NO. 72; the corresponding nucleotide sequence is shown in SEQ ID NO. 71; and the antibody YN-010 The amino acid sequences of HCDR1-3 are shown in SEQ ID NO. 37, SEQ ID NO. 38 and SEQ ID NO. 39, respectively; the amino acid sequence of VH is shown in SEQ ID NO. 51; the corresponding nucleotide sequence is SEQ ID. The amino acid sequence of the heavy chain is shown in SEQ ID NO. 70; the corresponding nucleotide sequence is shown in SEQ ID NO.

实施例3：抗IL17A全人源抗体YN-008、YN-009、YN-010的种系形式(germlined version)Example 3: Germlined version of anti-IL17A full human antibody YN-008, YN-009, YN-010

将抗IL17A全人源抗体YN-008重链免疫球蛋白序列与已知人种系免疫球蛋白重链序列对比，证实YN-008的重链利用来自人种系IGHV3-49*03的VH节段、来自人种系IGHD3-9*01的D节段以及来自人种系IGHJ2*01的JH节段。Comparison of the anti-IL17A full human antibody YN-008 heavy chain immunoglobulin sequence with the known human germline immunoglobulin heavy chain sequence, confirming that the heavy chain of YN-008 utilizes the VH segment from the human germline IGHV3-49*03 From the D segment of the human germline IGHD3-9*01 and the JH segment from the human germline IGHJ2*01.

将YN-008轻链免疫球蛋白序列与已知人种系免疫球蛋白轻链序列对比，证实YN-008轻链利用来自人种系IGKV2-28*01的VL节段，来自人种系IGKJ4*01的JL节段。Comparison of the YN-008 light chain immunoglobulin sequence with the known human germline immunoglobulin light chain sequence confirmed that the YN-008 light chain utilizes the VL segment from human germline IGKV2-28*01 from human germline IGKJ4* JL section of 01.

将抗IL17A全人源抗体YN-009重链免疫球蛋白序列与已知人种系免疫球蛋白重链序列对比，证实YN-009重链利用来自人种系IGHV1-46*01的VH节段、来自人种系IGHD3-22*01的D节段及来自人种系IGHJ3*02的JH节段。Comparison of the anti-IL17A full human antibody YN-009 heavy chain immunoglobulin sequence with the known human germline immunoglobulin heavy chain sequence, confirming that the YN-009 heavy chain utilizes the VH segment from the human germline IGHV1-46*01, Segment D from human germline IGHD3-22*01 and JH segment from human germline IGHJ3*02.

将YN-009轻链免疫球蛋白序列与已知人种系免疫球蛋白轻链序列对比，证实YN-009轻链利用来自人种系IGKV3-1*01的VL节段，来自人种系IGLJ1*01的JL节段。Comparison of the YN-009 light chain immunoglobulin sequence with the known human germline immunoglobulin light chain sequence confirmed that the YN-009 light chain utilizes the VL segment from the human germline IGKV3-1*01 from the human germline IGLJ1* JL section of 01.

将抗IL17A全人源抗体YN-010重链免疫球蛋白序列与已知人种系免疫球蛋白重链序列对比，证实YN-010重链利用来自人种系IGHV3-53*01的VH节段、来自人种系IGHD6-19*01的D节段及来自人种系IGHJ4*02的JH节段。Comparison of the anti-IL17A full human antibody YN-010 heavy chain immunoglobulin sequence with the known human germline immunoglobulin heavy chain sequence, confirming that the YN-010 heavy chain utilizes the VH segment from the human germline IGHV3-53*01, Segment D from human germline IGHD6-19*01 and JH segment from human germline IGHJ4*02.

将YN-010轻链免疫球蛋白序列与已知人种系免疫球蛋白轻链序列对比，证实YN-010轻链利用来自人种系IGLV3-1*01的VL节段，来自人种系IGLJ1*01的JL节段。Comparison of the YN-010 light chain immunoglobulin sequence with the known human germline immunoglobulin light chain sequence confirmed that the YN-010 light chain utilizes the VL segment from the human germline IGLV3-1*01 from the human germline IGLJ1* JL section of 01.

(1)为了使YN-008的免疫原性最小化，可将一些氨基酸残基突变回到种系序列。YN-011是YN-008的一种种系形式(germlined version)，其通过将YN-008重链可变区的FR1区中的3个氨基酸返回为种系序列，并且将YN-008轻链可变区中FR1区中1个氨基酸回复为种系序列而制备(参见图1A)。抗IL17A全人源抗体YN-011的重链表达载体在上述构建的YN-008的重链表达质粒的基础上利用突变试剂盒(天根点突变试剂盒，KM101)定点突变获得。YN-011轻链表达载体是在YN-008轻链表达质粒的基础上利用突变试剂盒(天根点突变试剂盒，KM101)定点突变获得。(1) In order to minimize the immunogenicity of YN-008, some amino acid residues can be mutated back to the germline sequence. YN-011 is a germlined version of YN-008 that returns three amino acids in the FR1 region of the YN-008 heavy chain variable region to a germline sequence, and the YN-008 light chain is The amino acid in the FR1 region of the variable region is restored to the germline sequence (see Fig. 1A). The heavy chain expression vector of the anti-IL17A full human antibody YN-011 was obtained by site-directed mutagenesis using the mutation kit (Day Root Point Mutagenesis Kit, KM101) based on the heavy chain expression plasmid of YN-008 constructed above. The YN-011 light chain expression vector was obtained by site-directed mutagenesis using a mutation kit (Day Root Point Mutagenesis Kit, KM101) based on the YN-008 light chain expression plasmid.

结果显示，YN-011的VL的氨基酸序列如SEQ ID NO.18所示；对应的核苷酸序列如SEQ ID NO.74所示；轻链的氨基酸序列如SEQ ID NO.78所示；对应的核苷酸序列如SEQ ID NO.77所示；YN-011的VH的氨基酸序列如SEQ ID NO.17所示；对应的核苷酸序列如SEQ ID NO.73所示；重链的氨基酸序列如SEQ ID NO.76所示；对应的核苷酸序列如SEQ ID NO.75所示。The results show that the amino acid sequence of VL of YN-011 is shown in SEQ ID NO. 18; the corresponding nucleotide sequence is shown in SEQ ID NO. 74; the amino acid sequence of light chain is shown in SEQ ID NO. The nucleotide sequence is shown in SEQ ID NO. 77; the amino acid sequence of VH of YN-011 is shown in SEQ ID NO. 17; the corresponding nucleotide sequence is shown in SEQ ID NO. 73; the amino acid of heavy chain The sequence is set forth in SEQ ID NO. 76; the corresponding nucleotide sequence is set forth in SEQ ID NO.

YN-011抗体的表达、纯化的方法步骤参照YN-008抗体。The method of expression and purification of the YN-011 antibody is referred to the YN-008 antibody.

(2)为了使YN-009的免疫原性最小化，可将一些氨基酸残基突变回到种系序列。YN-012是YN-009的一种种系形式(germlined version)，其通过将YN-009重链可变区的FR1区中的2个氨基酸返回为种系序列，并且将YN-009轻链可变区中FR2区中1个氨基酸恢复为种系序列而制备(参见图1B)。抗IL17A全人源抗体YN-012的重链表达载体在上述构建的YN-009的重链表达质粒的基础上利用突变试剂盒(天根点突变试剂盒，KM101)定点突变获得。YN-012轻链表达载体是在YN-009轻链表达质粒的基础上利用突变试剂盒(天根点突变试剂盒，KM101)定点突变获得。(2) In order to minimize the immunogenicity of YN-009, some amino acid residues can be mutated back to the germline sequence. YN-012 is a germlined version of YN-009, which returns two amino acids in the FR1 region of the YN-009 heavy chain variable region to a germline sequence, and the YN-009 light chain can be The amino acid in the FR2 region of the variable region was restored to the germline sequence (see Fig. 1B). The heavy chain expression vector of the anti-IL17A fully human antibody YN-012 was obtained by site-directed mutagenesis using the mutation kit (Day Root Point Mutagenesis Kit, KM101) based on the heavy chain expression plasmid of YN-009 constructed above. The YN-012 light chain expression vector was obtained by site-directed mutagenesis using a mutation kit (Day Root Point Mutagenesis Kit, KM101) based on the YN-009 light chain expression plasmid.

结果显示，YN-012的VL的氨基酸序列如SEQ ID NO.36所示；对应的核苷酸序列如SEQ ID NO.80所示；轻链的氨基酸序列如SEQ ID NO.84所示；对应的核苷酸序列如SEQ ID NO.83所示；YN-012的VH的氨基酸序列如SEQ ID NO.35所示；对应的核苷酸序列如SEQ ID NO.79所示；重链的氨基酸序列如SEQ ID NO.82所示；对应的核苷酸序列如SEQ ID NO.81所示。The results show that the amino acid sequence of VL of YN-012 is shown in SEQ ID NO. 36; the corresponding nucleotide sequence is shown in SEQ ID NO. 80; the amino acid sequence of light chain is shown in SEQ ID NO. 84; The nucleotide sequence is shown in SEQ ID NO. 83; the amino acid sequence of VH of YN-012 is shown in SEQ ID NO. 35; the corresponding nucleotide sequence is shown in SEQ ID NO. 79; the amino acid of heavy chain The sequence is set forth in SEQ ID NO. 82; the corresponding nucleotide sequence is set forth in SEQ ID NO.

YN-012抗体的表达、纯化的方法步骤参照YN-008抗体。The method of expression and purification of the YN-012 antibody is referred to the YN-008 antibody.

(3)为了使YN-010的免疫原性最小化，可将一些氨基酸残基突变回到种系序列。YN-013是YN-010的一种种系形式(germlined version)，其通过将YN-010重链可变区的FR1区中的1个氨基酸和FR3区中的1个氨基酸返回为种系序列，以及将YN-010轻链可变区中FR1区中1个氨基酸、FR2区中3个氨基酸、FR3区中1个氨基酸返回为种系序列而制备(参见图1C)。抗IL17A全人源抗体YN-013的重链表达载体在上述构建的YN-010的重链表达质粒的基础上利用突变试剂盒(天根点突变试剂盒，KM101)定点突变获得。YN-013轻链表达载体是在YN-010轻链表达质粒的基础上利用突变试剂盒(天根点突变试剂盒，KM101)定点突变获得。(3) In order to minimize the immunogenicity of YN-010, some amino acid residues can be mutated back to the germline sequence. YN-013 is a germlined version of YN-010 which returns a sequence of 1 amino acid in the FR1 region of the YN-010 heavy chain variable region and 1 amino acid in the FR3 region to a germline sequence. And preparing one amino acid in the FR1 region of the YN-010 light chain variable region, three amino acids in the FR2 region, and one amino acid in the FR3 region are returned to the germline sequence (see FIG. 1C). The heavy chain expression vector of the anti-IL17A fully human antibody YN-013 was obtained by site-directed mutagenesis using the mutation kit (Day Root Point Mutagenesis Kit, KM101) based on the heavy chain expression plasmid of YN-010 constructed above. The YN-013 light chain expression vector was obtained by site-directed mutagenesis using a mutation kit (Day Root Point Mutagenesis Kit, KM101) based on the YN-010 light chain expression plasmid.

结果显示，YN-013的VL的氨基酸序列如SEQ ID NO.54所示；对应的核苷酸序列如SEQ ID NO.86所示；轻链的氨基酸序列如SEQ ID NO.90所示；对应的核苷酸序列如SEQ ID NO.89所示；YN-013的VH的氨基酸序列如SEQ ID NO.53所示；对应的核苷酸序列如SEQ ID NO.85所示；重链的氨基酸序列如SEQ ID NO.88所示；对应的核苷酸序列如SEQ ID NO.87所示；The results show that the amino acid sequence of VL of YN-013 is shown in SEQ ID NO. 54; the corresponding nucleotide sequence is shown in SEQ ID NO. 86; the amino acid sequence of light chain is shown in SEQ ID NO. The nucleotide sequence is shown in SEQ ID NO. 89; the amino acid sequence of VH of YN-013 is shown in SEQ ID NO. 53; the corresponding nucleotide sequence is shown in SEQ ID NO. 85; the amino acid of heavy chain The sequence is set forth in SEQ ID NO. 88; the corresponding nucleotide sequence is set forth in SEQ ID NO.

YN-013抗体的表达、纯化的方法步骤参照YN-008抗体。The method of expression and purification of the YN-013 antibody is referred to the YN-008 antibody.

实施例4：IL17抗体的结合亲和力检测Example 4: Detection of binding affinity of IL17 antibody

通过使用Octet RED384仪器(Pall ForteBio公司)测量IL17抗体YN-008、YN-009、YN-010、YN-011、YN-012和YN-013针对重组人IL17A蛋白的结合亲和力。首先，用生物素(EZ-Link SμLfo-NHS-LC-Biotin，Pierce，21327)标记人IL17A蛋白。通过生物膜干涉(BLI)技术，使用fortebio octet RED384仪器(PALL)分子相互作用分析仪，来进行抗原抗体之间的结合 动力学分析(抗原、抗体稀释均使用0.1％BSA及0.02％tween20的PBS缓冲液)。使用浓度为50nM经过biotin偶联的抗原与SA传感器固定，1500rpm/min，结合10分钟；然后再与对倍稀释的抗体溶液(100nM-0nM)结合10min，1500rpm/min。最后进行解离10分钟，1500rpm/min。残留的抗体将通过甘氨酸脉冲再生。得到的结果将通过octet Data Analysis 9.0软件(fortebio)进行数据分析，来计算出抗原与抗体的结合强度，得到K D值、Ka(1/Ms)值和Kd(1/s)值(R2值>0.95为可信结果)。 The binding affinities of the IL17 antibodies YN-008, YN-009, YN-010, YN-01, YN-012 and YN-013 against the recombinant human IL17A protein were measured by using an Octet RED384 instrument (Pall ForteBio). First, human IL17A protein was labeled with biotin (EZ-Link SμLfo-NHS-LC-Biotin, Pierce, 21327). The forebio octet RED384 instrument (PALL) molecular interaction analyzer was used to perform binding kinetic analysis between antigen and antibody by biofilm interference (BLI) technique (antigen and antibody dilution were both 0.1% BSA and 0.02% tween20 PBS). Buffer). The biotin-conjugated antigen was incubated with a SA sensor at a concentration of 50 nM, 1500 rpm/min for 10 minutes; then combined with a double-diluted antibody solution (100 nM-0 nM) for 10 min, 1500 rpm/min. Finally, dissociation was carried out for 10 minutes at 1500 rpm/min. Residual antibodies will be regenerated by glycine pulse. The obtained results will be analyzed by octet Data Analysis 9.0 software (fortebio) to calculate the binding strength of the antigen to the antibody, and obtain K D value, Ka (1/Ms) value and Kd (1/s) value (R2 value). >0.95 is a credible result).

测得的结果参见表1。The measured results are shown in Table 1.

表1 IL17抗体与人IL17A的亲和力Table 1 Affinity of IL17 antibody and human IL17A

Figure PCTCN2019074805-appb-000001
Figure PCTCN2019074805-appb-000001

实施例5：IL17抗体抑制人IL17A蛋白和人IL17R之间的结合Example 5: IL17 antibody inhibits binding between human IL17A protein and human IL17R

使用Octet RED384仪器(Pall ForteBio公司)评估IL17抗体YN-008、YN-009、YN-010、YN-011、YN-012、YN-013阻断人IL17A和人IL17受体结合的能力。首先，用生物素(EZ-Link SμLfo-NHS-LC-Biotin，Pierce，21327)标记人IL17RA/Fc蛋白(北京百普赛斯生物科技有限公司，H5257)。通过生物膜干涉(BLI)技术，使用fortebio octet RED384仪器(PALL)分子相互作用分析仪，来进行IL17抗体抑制人IL17A蛋白和人IL17受体之间的结合动力学分析(抗原、抗体稀释均使用0.1％BSA及0.02％tween20的PBS缓冲液)。使用浓度为100nM经过生物素偶联的重组的人IL17RA与SA传感器固定，1500rpm/min，结合10min；终浓度100nM的人IL17A蛋白与三倍比稀释的抗体溶液(2000nM-0nM)混合，孵育60分钟后上机结合10分钟，1500rpm/min。最后进行解离10分钟，1500rpm/min。残留的抗原抗体复合物将通过甘氨酸脉冲再生。得到的结果将通过octet Data Analysis 9.0软件(fortebio)进行数据分析，来计算出抗体对抗原与配体的抑制强度。结果参见图2，其中图2A-2C依次显示IL17抗体YN-011、YN-012、YN-013抑制人IL17A蛋白和人IL17受体结合的结果，横坐标为该抗体的浓度(单位Log nM)，纵坐标为RU值。图2的结果显示，IL17抗体YN-011、YN-012和YN-013可有效抑制人IL17A蛋白与人IL17受体结合。The ability of the IL17 antibodies YN-008, YN-009, YN-010, YN-011, YN-02, YN-013 to block the binding of human IL17A and human IL17 receptor was evaluated using an Octet RED384 instrument (Pall ForteBio). First, human IL17RA/Fc protein (Beijing Baipusis Biotechnology Co., Ltd., H5257) was labeled with biotin (EZ-Link SμLfo-NHS-LC-Biotin, Pierce, 21327). The binding kinetics of IL17 antibody inhibition between human IL17A protein and human IL17 receptor was performed by biofilm interference (BLI) technique using the fortebio octet RED384 instrument (PALL) molecular interaction analyzer (antigen and antibody dilution were used). 0.1% BSA and 0.02% tween20 in PBS buffer). Biotin-conjugated recombinant human IL17RA was incubated with SA sensor at a concentration of 100 nM, 1500 rpm/min for 10 min; human IL17A protein at a final concentration of 100 nM was mixed with a three-fold diluted antibody solution (2000 nM-0 nM), incubating 60 After a minute, the machine was combined for 10 minutes at 1500 rpm/min. Finally, dissociation was carried out for 10 minutes at 1500 rpm/min. The residual antigen-antibody complex will be regenerated by pulsed glycine. The results obtained will be analyzed by octet Data Analysis 9.0 software (fortebio) to calculate the inhibitory intensity of the antibody against the antigen and ligand. The results are shown in Fig. 2, wherein Fig. 2A-2C sequentially shows the results of IL17 antibody YN-011, YN-012, YN-013 inhibiting the binding of human IL17A protein and human IL17 receptor, and the abscissa is the concentration of the antibody (unit Log nM). The ordinate is the RU value. The results in Figure 2 show that the IL17 antibodies YN-011, YN-012 and YN-013 are effective in inhibiting the binding of the human IL17A protein to the human IL17 receptor.

实施例6：IL17抗体抑制IL17A蛋白诱导HT-29细胞产生趋化因子CXCL1Example 6: IL17 antibody inhibits IL17A protein-induced chemokine CXCL1 production in HT-29 cells

HT-29细胞是人结直肠腺癌上皮细胞(中科院上海细胞库)，其天然表达IL17受体。HT-29细胞与人IL17A蛋白一起温育会导致趋化因子CXCL1的产生，所述CXCL1可以使用ELISA进行检测。HT-29 cells are human colorectal adenocarcinoma epithelial cells (Chinese Academy of Sciences Shanghai Cell Bank), which naturally express IL17 receptor. Incubation of HT-29 cells with human IL17A protein results in the production of the chemokine CXCL1, which can be detected using ELISA.

2×10 5个/ml的HT-29细胞加入96孔板中，在37℃培养12小时。将2nM的IL17A与梯度浓度的IL17抗体(YN-011、YN-012或YN-013)或对照抗体(IgG Fc)的混合物在37℃温育1小时后加入到以上96孔板中，与HT-29细胞在37℃共温育48小时，然后用CXCL1的ELISA试剂盒(R&D公司)检测细胞培养上清中的CXCL1的水平。结果参见图3，横坐标为抗体的浓度，纵坐标则为CXCL1的浓度。图3的结果显示，IL17抗体YN-011、YN-012、YN-013可有效抑制HT-29细胞产生趋化因子CXCL1。 2 × 10 5 /ml of HT-29 cells were added to a 96-well plate and cultured at 37 ° C for 12 hours. A mixture of 2nM IL17A and a gradient concentration of IL17 antibody (YN-011, YN-012 or YN-013) or a control antibody (IgG Fc) was incubated at 37 ° C for 1 hour and then added to the above 96-well plate with HT The -29 cells were incubated at 37 ° C for 48 hours, and then the level of CXCL1 in the cell culture supernatant was measured using a CXCL1 ELISA kit (R&D). The results are shown in Figure 3. The abscissa is the concentration of the antibody and the ordinate is the concentration of CXCL1. The results in Figure 3 show that IL17 antibodies YN-011, YN-012, and YN-013 are effective in inhibiting the production of the chemokine CXCL1 by HT-29 cells.

实施例7：与IL-17F蛋白的交叉结合活性Example 7: Cross-binding activity with IL-17F protein

将IL-17F蛋白(ACRObiosystems公司产品)用PBS缓冲液(pH 7.2)稀释成2μg/ml，50μL/孔，4℃包被过夜。5％脱脂奶室温封闭2小时后，分别加入不同浓度的各IL-17抗体，50μL/孔，室温孵育2小时。弃上清液，PBST洗涤3次，加入按效价稀释好的HRP标记的羊抗人IgG单抗(KPL公司产品)，50μL/孔，室温孵育45min。PBST充分洗涤后，TMD显色后，置酶标仪(Elx型自动酶标比色仪，美国BIO-TEK公司)中测定450nm吸光度(OD450)值。实验结果如图4所示，结果表明抗体YN008和YN011能交叉结合IL17F蛋白。The IL-17F protein (product of ACRObiosystems) was diluted with PBS buffer (pH 7.2) to 2 μg/ml, 50 μL/well, and coated at 4 ° C overnight. After 5% skim milk was blocked at room temperature for 2 hours, different concentrations of each IL-17 antibody were added, 50 μL/well, and incubated for 2 hours at room temperature. The supernatant was discarded, washed 3 times with PBST, and HRP-labeled goat anti-human IgG monoclonal antibody (product of KPL) diluted with titer was added, 50 μL/well, and incubated at room temperature for 45 min. After PBST was sufficiently washed, TMD was developed, and the 450 nm absorbance (OD450) value was measured in a microplate reader (Elx type automatic enzyme standard colorimeter, BIO-TEK, USA). The experimental results are shown in Figure 4. The results indicate that the antibodies YN008 and YN011 can cross-binding the IL17F protein.

实施例8：IL-17抗体YN013的亲和力成熟Example 8: Affinity maturation of IL-17 antibody YN013

设计引物利用重叠PCR构建IL-17抗体YN-013的单链抗体(scFv)基因，并将其克隆到pDF噬菌粒载体，记作pDF-YN-013scFv。以pDF-YN-013scFv为模板设计简并引物利用重叠PCR对抗体YN-013的六个CDR区(图1C)分别进行随机化。Design primers The single-chain antibody (scFv) gene of IL-17 antibody YN-013 was constructed by overlapping PCR and cloned into pDF phagemid vector, which was designated as pDF-YN-013 scFv. The degenerate primers were designed using pDF-YN-013scFv as a template. The six CDR regions of antibody YN-013 (Fig. 1C) were randomized by overlapping PCR, respectively.

将重叠PCR获得的CDR区随机化后的scFv基因片段用BssHII和NheI双酶切后，与经BssHII和NheI双酶切的pDF噬菌粒载体连接，将1μg连接产物电穿孔转入TG1电转感受态细胞中，倍比稀释后凃2YT+AG平板，次日将菌苔从平板上刮下，扩大至300ml 2YT+Amp培养基，37℃培养至OD 0.8左右，加入helper phage混匀后静置1小时，加入终浓度为1mM IPTG，50μg/ml的卡那霉素，30℃振摇过夜。次日离心收上清，0.45滤膜过滤除菌，加入1/5 体积的PEG-NaCl沉淀phage，离心取沉淀，1/10体积的PBS重悬沉淀，测OD260计算噬菌体pfu，4℃保存，该噬菌体抗体库可直接用于后期淘选。The scFv gene fragment randomized by the CDR region obtained by overlapping PCR was digested with BssHII and NheI, and ligated with the pDF phagemid vector digested with BssHII and NheI, and electroporated 1 μg of the ligation product into TG1 electroporation. In the cells, the mixture was diluted and coated with 2YT+AG plate. The next day, the lawn was scraped from the plate, expanded to 300ml 2YT+Amp medium, and cultured at 37°C until about OD 0.8. After mixing with helper phage, it was allowed to stand. For 1 hour, kanamycin at a final concentration of 1 mM IPTG, 50 μg/ml was added and shaken overnight at 30 °C. The next day, the supernatant was centrifuged, 0.45 filter membrane was sterilized, 1/5 volume of PEG-NaCl was added to precipitate phage, the pellet was centrifuged, and the pellet was resuspended in 1/10 volume of PBS. The phage pfu was calculated by OD260 and stored at 4 ° C. The phage antibody library can be directly used for post-panning.

利用重组人IL17A蛋白(北京义翘神州生物技术有限公司)为抗原用于以上噬菌体抗体库分选。酶联免疫管中使用CBS缓冲液包被抗原1ml，抗原浓度为100nM(第一、二轮)或5nM(第三轮)，4℃过夜；次日用含10％的脱脂奶粉的PBS缓冲液2ml封闭免疫管；将1ml的封闭过的phage加入到免疫管中，室温孵育1h；PBST洗涤20次(第一轮)、50次(第二轮)或100次(第三轮)；加入pH2.2的Gly-HCl缓冲液800μl洗脱，立即加400μl的pH8.0的Tris-HCl缓冲液中和；加入到20ml对数生长期OD约0.8的E.coli TG1中，混匀37℃静置1h；取出500μl用来测定噬菌体滴度及甘油保菌；剩余菌液涂平板，培养箱中37℃过夜培养；第二天刮下平板的菌，按一定比例接入80ml的2YT-Amp培养基中，使OD等于0.2，培养数小时以OD达到0.8时，加入160μl的helper phage，然后混匀37℃静置1h；加入IPTG、Kan抗生素，250rpm，30℃，振荡培养过夜；收集上清，用PEG/NaCl溶液沉淀噬菌体，重悬于1.5ml的PBS缓冲液中；重悬的噬菌体用于下一轮的富集筛选，3轮淘选之后，观察到显著的富集。利用ELISA对淘选得到的噬菌体抗体克隆进行鉴定：在96孔ELISA板上包被人IL17A蛋白，浓度1μg/ml，4℃过夜。然后用10％脱脂奶粉封闭非特异性结合位点，充分洗涤后，取单克隆的噬菌体上清加入96孔板，37℃孵育2小时。充分洗涤后，加入HRP标记的抗M13抗体(GE healtcare，27-9421-01)，37℃作用45min，充分洗涤后加入TMB显色，室温下作用5-10min后，最后用硫酸终止反应，于450nm处测定各孔OD值，选择OD450值高的噬菌体抗体克隆进行测序。获得各噬菌体抗体克隆的重、轻链可变区基因序列后，将各噬菌体抗体重新设计成全长IgG1，κ抗体：设计引物对各噬菌体抗体克隆的VH进行PCR扩增，将PCR产物通过重组克隆至经AgeI和SalI双酶切的pCMV-IgG1NDL抗体重链表达载体；设计引物对各噬菌体抗体克隆的的VL进行PCR扩增，将PCR产物通过重组克隆至经AgeI和BsiWI双酶切的pCMV-κ抗体轻链表达载体。测序正确后分别将各抗体的重、轻链表达载体共转染293F细胞进行瞬时表达，用无血清培养基培养7天后收集细胞培养上清通过ProteinA柱纯化获得抗体蛋白，将纯化抗体用PBS进行透析，最后用BCA Protein Assay Kit定量(Pierce，23225)。The recombinant human IL17A protein (Beijing Yiqiao Shenzhou Biotechnology Co., Ltd.) was used as an antigen for sorting the above phage antibody library. In the enzyme-linked immunotube, 1 ml of antigen was coated with CBS buffer, the antigen concentration was 100 nM (first round, second round) or 5 nM (third round), overnight at 4 ° C; the next day with 10% skim milk powder in PBS buffer 2 ml closed immunotube; 1 ml of blocked phage was added to the immunotube, incubated for 1 h at room temperature; washed 20 times (first round), 50 times (second round) or 100 times (third round) with PBST; .2 Gly-HCl buffer 800 μl elution, immediately add 400 μl of pH 8.0 Tris-HCl buffer to neutralize; add to 20 ml of logarithmic growth phase OD about 0.8 E.coli TG1, mix 37 ° C static Set 1h; take 500μl to determine phage titer and glycerol preservation; the remaining bacterial solution is plated, cultured at 37 °C overnight; the next day scraping the plate of bacteria, a certain proportion of 80Y 2YT-Amp medium In the middle, the OD is equal to 0.2, and when the OD reaches 0.8, the 160 μl of helper phage is added, and then the mixture is allowed to stand at 37 ° C for 1 h; IPTG, Kan antibiotics, 250 rpm, 30 ° C, shaking culture overnight; The phage were precipitated with PEG/NaCl solution and resuspended in 1.5 ml of PBS buffer; the resuspended phage was used for the next round of enrichment. Election, after three rounds of panning, significant enrichment was observed. The phage antibody clones obtained by panning were identified by ELISA: human IL17A protein was coated on a 96-well ELISA plate at a concentration of 1 μg/ml overnight at 4 °C. The non-specific binding sites were then blocked with 10% skim milk powder. After thorough washing, the monoclonal phage supernatant was added to a 96-well plate and incubated at 37 ° C for 2 hours. After sufficient washing, HRP-labeled anti-M13 antibody (GE healtcare, 27-9421-01) was added, and the reaction was carried out at 37 ° C for 45 min. After thorough washing, TMB was added for color development. After 5-10 min at room temperature, the reaction was terminated with sulfuric acid. The OD value of each well was measured at 450 nm, and a phage antibody clone having a high OD450 value was selected for sequencing. After obtaining the heavy and light chain variable region gene sequences of each phage antibody clone, each phage antibody was redesigned into a full-length IgG1, kappa antibody: designed primers to PCR-amplify the VH of each phage antibody clone, and the PCR product was cloned by recombinant The pCMV-IgG1 NDL antibody heavy chain expression vector was digested with AgeI and SalI; the primers were designed to PCR-amplify the VL of each phage antibody clone, and the PCR product was recombinantly cloned into pCMV-digested with AgeI and BsiWI. κ antibody light chain expression vector. After sequencing, the heavy and light chain expression vectors of each antibody were co-transfected into 293F cells for transient expression. After 7 days of culture in serum-free medium, the cell culture supernatant was collected and purified by ProteinA column to obtain antibody protein. The purified antibody was purified by PBS. Dialysis was performed and finally quantified using the BCA Protein Assay Kit (Pierce, 23225).

通过使用Octet RED384仪器(Pall ForteBio公司)测量IL17抗体针对重组人IL17A蛋白的结合亲和力。首先，用生物素(EZ-Link SμLfo-NHS-LC-Biotin，Pierce，21327)标记人IL17A-Fc蛋白(上海原能细胞医学技术有限公司)。通过生物膜干涉(BLI)技术，使用fortebio octet RED384仪器(PALL)分子相互作用分析仪，来进行抗原抗体之间的结合动力学分析(抗原、 抗体稀释均使用0.1％BSA及0.02％tween20的PBS缓冲液)。使用浓度为50nM经过biotin偶联的抗原与SA传感器固定，1500rpm/min，结合5分钟；然后再与对倍稀释的抗体溶液(100,50，25，12.5，6.25，3.125，1.56nM)结合5min，1500rpm/min。最后进行解离10分钟，1500rpm/min。得到的结果将通过Octet Data Analysis 9.0软件(Pall ForteBio公司)进行数据分析，得到K D值，K on(1/Ms)值和K off(1/s)值。经过多轮筛选和组合，将亲和力最高的2个YN-013抗体突变体克隆分别命名为YN-065抗体、YN-066抗体。这2个抗体通过以上方法测定获得的亲和力数值参见表2。亲和力数据显示YN-065和YN-066的亲和力分别为secukinumab的14倍和12倍。 The binding affinity of the IL17 antibody to the recombinant human IL17A protein was measured by using an Octet RED384 instrument (Pall ForteBio). First, human IL17A-Fc protein (Shanghai Yuanneng Cell Medical Technology Co., Ltd.) was labeled with biotin (EZ-Link SμLfo-NHS-LC-Biotin, Pierce, 21327). The forebio octet RED384 instrument (PALL) molecular interaction analyzer was used to perform binding kinetic analysis between antigen and antibody by biofilm interference (BLI) technique (antigen and antibody dilutions were both 0.1% BSA and 0.02% tween20 in PBS). Buffer). The biotin-conjugated antigen was fixed at 50 nM with a SA sensor, 1500 rpm/min for 5 minutes; then combined with a double-diluted antibody solution (100, 50, 25, 12.5, 6.25, 3.125, 1.56 nM) for 5 min. , 1500 rpm / min. Finally, dissociation was carried out for 10 minutes at 1500 rpm/min. The results obtained were analyzed by Octet Data Analysis 9.0 software (Pall ForteBio) to obtain K D values, K on (1/Ms) values and K off (1/s) values. After multiple rounds of screening and combination, the two YN-013 antibody mutant clones with the highest affinity were named YN-065 antibody and YN-066 antibody, respectively. The affinities obtained by the above two methods by the above methods are shown in Table 2. Affinity data showed that the affinities of YN-065 and YN-066 were 14 and 12 times, respectively, of secukinumab.

表2 IL-17抗体与人IL-17A的亲和力Table 2 Affinity of IL-17 antibody to human IL-17A

Figure PCTCN2019074805-appb-000002
Figure PCTCN2019074805-appb-000002

YN-065抗体的VL的氨基酸序列如SEQ ID NO.103所示，轻链的氨基酸序列如SEQ ID NO.104所示；YN-065抗体的VH的氨基酸序列如SEQ ID NO.105所示，重链的氨基酸序列如SEQ ID NO.106所示；The amino acid sequence of the VL of the YN-065 antibody is shown in SEQ ID NO. 103, the amino acid sequence of the light chain is shown in SEQ ID NO. 104, and the amino acid sequence of the VH of the YN-065 antibody is shown in SEQ ID NO. The amino acid sequence of the heavy chain is set forth in SEQ ID NO. 106;

YN-066抗体的VL的氨基酸序列如SEQ ID NO.103所示，轻链的氨基酸序列如SEQ ID NO.104所示；YN-066抗体的VH的氨基酸序列如SEQ ID NO.107所示，重链的氨基酸序列如SEQ ID NO.108所示；The amino acid sequence of the VL of the YN-066 antibody is shown in SEQ ID NO. 103, the amino acid sequence of the light chain is shown in SEQ ID NO. 104, and the amino acid sequence of the VH of the YN-066 antibody is shown in SEQ ID NO. The amino acid sequence of the heavy chain is set forth in SEQ ID NO.

实施例9：IL-17抗体YN011的亲和力成熟Example 9: Affinity maturation of IL-17 antibody YN011

设计引物利用重叠PCR构建IL-17抗体YN-011的单链抗体(scFv)基因，并将其克隆到pDF噬菌粒载体，记作pDF-YN-011scFv。以pDF-YN-011scFv为模板设计引物通过随机突变试剂盒(Agilent，Cat.200552)对scFv序列进行随机化。Design primers The single-chain antibody (scFv) gene of IL-17 antibody YN-011 was constructed by overlapping PCR and cloned into pDF phagemid vector, which was designated as pDF-YN-011 scFv. Primers were designed using pDF-YN-011 scFv as a template. The scFv sequences were randomized by a random mutagenesis kit (Agilent, Cat. 200552).

将随机化后的scFv基因片段用BssHII和NheI双酶切后，与经BssHII和NheI双酶切的pDF噬菌粒载体连接，将1μg连接产物电穿孔转入TG1电转感受态细胞中，倍比稀释后凃2YT+AG平板，次日将菌苔从平板上刮下，扩大至300ml 2YT+Amp培养基，37℃培养至OD 0.8左右，加入helper phage混匀后静置1小时，加入终浓度为1mM IPTG，50μg/ml的卡那霉素，30℃振摇过夜。次日离心收上清，0.45滤膜过滤除菌，加入1/5体积的PEG-NaCl沉淀 phage，离心取沉淀，1/10体积的PBS重悬沉淀，测OD260计算噬菌体pfu，4℃保存，该噬菌体抗体库可直接用于后期淘选。The randomized scFv gene fragment was digested with BssHII and NheI, and ligated with the pDF phagemid vector digested with BssHII and NheI, and electroporated 1 μg of the ligation product into TG1 electroporation competent cells. After dilution, apply 2YT+AG plate, scrape the lawn from the plate the next day, expand to 300ml 2YT+Amp medium, incubate to OD 0.8 at 37°C, mix with helper phage, let stand for 1 hour, add final concentration. For 1 mM IPTG, 50 μg/ml kanamycin was shaken overnight at 30 °C. The next day, the supernatant was centrifuged, the filter was sterilized by 0.45 membrane filtration, phage was precipitated by adding 1/5 volume of PEG-NaCl, the precipitate was centrifuged, the pellet was resuspended in 1/10 volume of PBS, and the phage pfu was calculated by OD260, and stored at 4 ° C. The phage antibody library can be directly used for post-panning.

利用重组人IL17A蛋白(北京义翘神州生物技术有限公司)为抗原用于以上噬菌体抗体库分选。酶联免疫管中使用CBS缓冲液包被抗原1ml，抗原浓度为100nM(第一、二轮)或5nM(第三轮)，4℃过夜；次日用含10％的脱脂奶粉的PBS缓冲液2ml封闭免疫管；将1ml的封闭过的phage加入到免疫管中，室温孵育1h；PBST洗涤20次(第一轮)、50次(第二轮)或100次(第三轮)；加入pH2.2的Gly-HCl缓冲液800μl洗脱，立即加400μl的pH8.0的Tris-HCl缓冲液中和；加入到20ml对数生长期OD约0.8的E.coli TG1中，混匀37℃静置1h；取出500μl用来测定噬菌体滴度及甘油保菌；剩余菌液涂平板，培养箱中37℃过夜培养；第二天刮下平板的菌，按一定比例接入80ml的2YT-Amp培养基中，使OD等于0.2，培养数小时以OD达到0.8时，加入160μl的helper phage，然后混匀37℃静置1h；加入IPTG、Kan抗生素，250rpm，30℃，振荡培养过夜；收集上清，用PEG/NaCl溶液沉淀噬菌体，重悬于1.5ml的PBS缓冲液中；重悬的噬菌体用于下一轮的富集筛选，3轮淘选之后，观察到显著的富集。利用ELISA对淘选得到的噬菌体抗体克隆进行鉴定：在96孔ELISA板上包被人IL17A蛋白，浓度1μg/ml，4℃过夜。然后用10％脱脂奶粉封闭非特异性结合位点，充分洗涤后，取单克隆的噬菌体上清加入96孔板，37℃孵育2小时。充分洗涤后，加入HRP标记的抗M13抗体(GE healtcare，27-9421-01)，37℃作用45min，充分洗涤后加入TMB显色，室温下作用5-10min后，最后用硫酸终止反应，于450nm处测定各孔OD值，选择OD450值高的噬菌体抗体克隆进行测序。获得各噬菌体抗体克隆的重、轻链可变区基因序列后，我们将各噬菌体抗体重新设计成Fab片段：设计引物分别对噬菌体抗体克隆的VH进行PCR扩增和对抗体重链表达载体pCMV-IgG1NDL上第一个抗体重链恒定区进行PCR扩增，通过重叠PCR构建VHCH1基因片段并将其通过重组克隆至经AgeI和BamH1双酶切的pCMV-IgG1NDL抗体重链表达载体；设计引物对各噬菌体抗体克隆的的VL进行PCR扩增，将PCR产物通过重组克隆至经AgeI和BsiWI双酶切的pCMV-κ抗体轻链表达载体。测序正确后分别将各Fab片段的重、轻链表达载体共转染293F细胞进行瞬时表达，用无血清培养基培养7天后收集细胞培养上清通过Protein G柱纯化获得抗体蛋白，将纯化抗体用PBS进行透析，最后用BCA Protein Assay Kit定量(Pierce，23225)。通过Octet RED384仪器(Pall ForteBio公司)测量IL17抗体Fab片段针对重组人IL17A蛋白的结合亲和力。首先，用生物素(EZ-Link SμLfo-NHS-LC-Biotin，Pierce，21327)标记人IL17A-Fc蛋白(上海原能细胞医学技术有限公司)。通过生物膜干涉(BLI)技术，使用fortebio octet RED384仪器(PALL)分子相互 作用分析仪，来进行抗原抗体之间的结合动力学分析(抗原、抗体稀释均使用0.1％BSA及0.02％tween20的PBS缓冲液)。使用浓度为50nM经过biotin偶联的抗原与SA传感器固定，1500rpm/min，结合5分钟；然后再与对倍稀释的抗体溶液(100，50，25，12.5，6.25，3.125，1.56nM)结合5min，1500rpm/min。最后进行解离10分钟，1500rpm/min。得到的结果将通过octet Data Analysis 9.0软件(fortebio)进行数据分析，来计算出抗原与抗体的结合强度，得到K D值、Ka(1/Ms)值和Kd(1/s)值。经过多轮筛选和组合，将亲和力最高的4个YN-011抗体突变体Fab分别命名为YN-067Fab、YN-068Fab、YN-069Fab、YN-070Fab。这4个Fab片段通过以上方法测定获得的亲和力数值参见表3。 The recombinant human IL17A protein (Beijing Yiqiao Shenzhou Biotechnology Co., Ltd.) was used as an antigen for sorting the above phage antibody library. In the enzyme-linked immunotube, 1 ml of antigen was coated with CBS buffer, the antigen concentration was 100 nM (first round, second round) or 5 nM (third round), overnight at 4 ° C; the next day with 10% skim milk powder in PBS buffer 2 ml closed immunotube; 1 ml of blocked phage was added to the immunotube, incubated for 1 h at room temperature; washed 20 times (first round), 50 times (second round) or 100 times (third round) with PBST; .2 Gly-HCl buffer 800 μl elution, immediately add 400 μl of pH 8.0 Tris-HCl buffer to neutralize; add to 20 ml of logarithmic growth phase OD about 0.8 E.coli TG1, mix 37 ° C static Set 1h; take 500μl to determine phage titer and glycerol preservation; the remaining bacterial solution is plated, cultured at 37 °C overnight; the next day scraping the plate of bacteria, a certain proportion of 80Y 2YT-Amp medium In the middle, the OD is equal to 0.2, and when the OD reaches 0.8, the 160 μl of helper phage is added, and then the mixture is allowed to stand at 37 ° C for 1 h; IPTG, Kan antibiotics, 250 rpm, 30 ° C, shaking culture overnight; The phage were precipitated with PEG/NaCl solution, resuspended in 1.5 ml of PBS buffer; the resuspended phage was used in the next round of enrichment sieve After the 3 rounds of panning, significant enrichment was observed. The phage antibody clones obtained by panning were identified by ELISA: human IL17A protein was coated on a 96-well ELISA plate at a concentration of 1 μg/ml overnight at 4 °C. The non-specific binding sites were then blocked with 10% skim milk powder. After thorough washing, the monoclonal phage supernatant was added to a 96-well plate and incubated at 37 ° C for 2 hours. After sufficient washing, HRP-labeled anti-M13 antibody (GE healtcare, 27-9421-01) was added, and the reaction was carried out at 37 ° C for 45 min. After thorough washing, TMB was added for color development. After 5-10 min at room temperature, the reaction was terminated with sulfuric acid. The OD value of each well was measured at 450 nm, and a phage antibody clone having a high OD450 value was selected for sequencing. After obtaining the heavy and light chain variable region gene sequences of each phage antibody clone, we redesigned each phage antibody into a Fab fragment: designed primers for PCR amplification of VH of phage antibody clones and anti-weight chain expression vector pCMV-IgG1NDL The first antibody heavy chain constant region was subjected to PCR amplification, and the VHCH1 gene fragment was constructed by overlapping PCR and cloned into the pCMV-IgG1 NDL antibody heavy chain expression vector by double digestion with AgeI and BamH1; primers were designed for each phage. The VL of the antibody clone was subjected to PCR amplification, and the PCR product was recombinantly cloned into the pCMV-κ antibody light chain expression vector double-digested with AgeI and BsiWI. After sequencing, the heavy and light chain expression vectors of each Fab fragment were co-transfected into 293F cells for transient expression. After 7 days of culture in serum-free medium, the cell culture supernatant was collected and purified by Protein G column to obtain antibody protein. Dialysis was performed in PBS and finally quantified using the BCA Protein Assay Kit (Pierce, 23225). The binding affinity of the IL17 antibody Fab fragment to the recombinant human IL17A protein was measured by an Octet RED384 instrument (Pall ForteBio). First, human IL17A-Fc protein (Shanghai Yuanneng Cell Medical Technology Co., Ltd.) was labeled with biotin (EZ-Link SμLfo-NHS-LC-Biotin, Pierce, 21327). The forebio octet RED384 instrument (PALL) molecular interaction analyzer was used to perform binding kinetic analysis between antigen and antibody by biofilm interference (BLI) technique (antigen and antibody dilution were both 0.1% BSA and 0.02% tween20 PBS). Buffer). The biotin-conjugated antigen was fixed at 50 nM with a SA sensor, 1500 rpm/min for 5 minutes; then combined with a double-diluted antibody solution (100, 50, 25, 12.5, 6.25, 3.125, 1.56 nM) for 5 min. , 1500 rpm / min. Finally, dissociation was carried out for 10 minutes at 1500 rpm/min. The obtained results were analyzed by octet Data Analysis 9.0 software (fortebio) to calculate the binding strength of the antigen to the antibody, and the K D value, the Ka (1/Ms) value, and the Kd (1/s) value were obtained. After multiple rounds of screening and combination, the four YN-011 antibody mutant Fabs with the highest affinity were named YN-067Fab, YN-068Fab, YN-069Fab, and YN-070Fab, respectively. The affinity values of the four Fab fragments determined by the above method are shown in Table 3.

YN-067Fab的轻链氨基酸序列如SEQ ID NO.110所示；YN-067Fab抗体的重链氨基酸序列如SEQ ID NO.113所示。The light chain amino acid sequence of YN-067 Fab is set forth in SEQ ID NO. 110; the heavy chain amino acid sequence of the YN-067 Fab antibody is set forth in SEQ ID NO.

YN-068Fab的轻链氨基酸序列如SEQ ID NO.110所示；YN-068Fab抗体的重链氨基酸序列如SEQ ID NO.116所示。The light chain amino acid sequence of YN-068 Fab is set forth in SEQ ID NO. 110; the heavy chain amino acid sequence of the YN-068 Fab antibody is set forth in SEQ ID NO.

YN-069Fab的轻链氨基酸序列如SEQ ID NO.110所示；YN-069Fab抗体的重链氨基酸序列如SEQ ID NO.119所示。The light chain amino acid sequence of YN-069 Fab is set forth in SEQ ID NO. 110; the heavy chain amino acid sequence of the YN-069 Fab antibody is set forth in SEQ ID NO.

YN-070Fab的轻链氨基酸序列如SEQ ID NO.110所示；YN-070Fab抗体的重链氨基酸序列如SEQ ID NO.122所示。The light chain amino acid sequence of YN-070 Fab is set forth in SEQ ID NO. 110; the heavy chain amino acid sequence of the YN-070 Fab antibody is set forth in SEQ ID NO.

我们还参照以上方法构建、表达、纯化了IL-17抗体secukinumab的Fab片段，命名为secukinumab-Fab，并通过上述亲和力测定方法测定了secukinumab-Fab的亲和力，亲和力数值参见表3。亲和力数据表明YN-067Fab、YN-068Fab、YN-069Fab、YN-070Fab的亲和力分别为secukinumab-Fab的8.8、3.0、8.4、27倍。We also constructed, expressed and purified the Fab fragment of IL-17 antibody secukinumab, which was named secukinumab-Fab, and determined the affinity of secukinumab-Fab by the above affinity assay. The affinity values are shown in Table 3. Affinity data indicated that the affinities of YN-067 Fab, YN-068 Fab, YN-069 Fab, and YN-070 Fab were 8.8, 3.0, 8.4, and 27 fold, respectively, of secukinumab-Fab.

表3 IL-17抗体Fab片段与人IL-17A的亲和力Table 3 Affinity of IL-17 Antibody Fab Fragment to Human IL-17A

Figure PCTCN2019074805-appb-000003
Figure PCTCN2019074805-appb-000003

将噬菌体抗体重新设计成全长IgG1,κ抗体的方法如下：设计引物对各噬菌体抗体克隆的VH进行PCR扩增，将PCR产物通过重组克隆至经AgeI和SalI双酶切的pCMV-IgG1NDL抗体重链表达载体；设计引物对各噬菌体抗体克隆的的VL进行PCR扩增，将PCR产物通过 重组克隆至经AgeI和BsiWI双酶切的pCMV-κ抗体轻链表达载体。测序正确后分别将各抗体的重、轻链表达载体共转染293F细胞进行瞬时表达，用无血清培养基培养7天后收集细胞培养上清通过Protein A柱纯化获得抗体蛋白，将纯化抗体用PBS进行透析，最后用BCA Protein Assay Kit定量(Pierce，23225)。YN-067-Fab、YN-068-Fab、YN-069-Fab、YN-070-Fab各自对应的全长IgG1,κ抗体分别命名为YN-067、YN-068、YN-069、YN-070。The method of redesigning phage antibody into full-length IgG1, κ antibody is as follows: Primer is designed to PCR-amplify VH of each phage antibody clone, and the PCR product is recombinantly cloned into pCMV-IgG1NDL antibody heavy chain double-digested with AgeI and SalI. Expression vector; primers were designed for PCR amplification of VL of each phage antibody clone, and the PCR product was recombinantly cloned into the pCMV-κ antibody light chain expression vector double-digested with AgeI and BsiWI. After sequencing, the heavy and light chain expression vectors of each antibody were co-transfected into 293F cells for transient expression. After 7 days of culture in serum-free medium, the cell culture supernatant was collected and purified by Protein A column to obtain antibody protein. The purified antibody was used in PBS. Dialysis was performed and finally quantified using the BCA Protein Assay Kit (Pierce, 23225). The full-length IgG1 and κ antibodies corresponding to YN-067-Fab, YN-068-Fab, YN-069-Fab, and YN-070-Fab were named YN-067, YN-068, YN-069, and YN-070, respectively. .

YN-067抗体的VL的氨基酸序列如SEQ ID NO.109所示，轻链的氨基酸序列如SEQ ID NO.110所示；YN-067抗体的VH的氨基酸序列如SEQ ID NO.111所示，重链的氨基酸序列如SEQ ID NO.112所示。The amino acid sequence of the VL of the YN-067 antibody is shown in SEQ ID NO. 109, the amino acid sequence of the light chain is shown in SEQ ID NO. 110, and the amino acid sequence of the VH of the YN-067 antibody is shown in SEQ ID NO. The amino acid sequence of the heavy chain is set forth in SEQ ID NO.

YN-068抗体的VL的氨基酸序列如SEQ ID NO.109所示，轻链的氨基酸序列如SEQ ID NO.110所示；YN-068抗体的VH的氨基酸序列如SEQ ID NO.114所示，重链的氨基酸序列如SEQ ID NO.115所示。The amino acid sequence of VL of YN-068 antibody is shown in SEQ ID NO. 109, the amino acid sequence of light chain is shown in SEQ ID NO. 110, and the amino acid sequence of VH of YN-068 antibody is shown in SEQ ID NO. The amino acid sequence of the heavy chain is set forth in SEQ ID NO.

YN-069抗体的VL的氨基酸序列如SEQ ID NO.109所示，轻链的氨基酸序列如SEQ ID NO.110所示；YN-069抗体的VH的氨基酸序列如SEQ ID NO.117所示，重链的氨基酸序列如SEQ ID NO.118所示。The amino acid sequence of the VL of the YN-069 antibody is shown in SEQ ID NO. 109, the amino acid sequence of the light chain is shown in SEQ ID NO. 110, and the amino acid sequence of the VH of the YN-069 antibody is shown in SEQ ID NO. The amino acid sequence of the heavy chain is set forth in SEQ ID NO.

YN-070抗体的VL的氨基酸序列如SEQ ID NO.109所示，轻链的氨基酸序列如SEQ ID NO.110所示；YN-070抗体的VH的氨基酸序列如SEQ ID NO.120所示，重链的氨基酸序列如SEQ ID NO.121所示。The amino acid sequence of the VL of the YN-070 antibody is shown in SEQ ID NO. 109, the amino acid sequence of the light chain is shown in SEQ ID NO. 110, and the amino acid sequence of the VH of the YN-070 antibody is shown in SEQ ID NO. The amino acid sequence of the heavy chain is set forth in SEQ ID NO.

实施例10：IL17抗体抑制人IL17A蛋白和人IL17R之间的结合Example 10: IL17 antibody inhibits binding between human IL17A protein and human IL17R

使用Octet RED384仪器(Pall ForteBio公司)评估IL17抗体YN-065、YN-066、YN-067、YN-068、YN-069、YN-070阻断人IL17A和人IL17受体结合的能力。首先，用生物素(EZ-Link SμLfo-NHS-LC-Biotin，Pierce，21327)标记人IL17RA/Fc蛋白(北京百普赛斯生物科技有限公司，H5257)。通过生物膜干涉(BLI)技术，使用fortebio octet RED384仪器(PALL)分子相互作用分析仪，对IL17抗体抑制人IL17A蛋白和人IL17受体之间的结合进行分析(抗原、抗体稀释均使用0.1％BSA及0.02％Tween20的PBS缓冲液)。使用浓度为100nM经过生物素偶联的重组的人IL17RA与SA传感器固定，1500rpm/min，结合10min；终浓度50nM的人IL17A蛋白与四倍比稀释的抗体溶液(1000，250，62.5，15.625，3.9，0.97，0nM)混合，孵育60分钟后上机结合10分钟，1500rpm/min。最后进行解离1分钟，1500rpm/min。得到的结果将通过octet Data Analysis 9.0软件(fortebio)进行数据分析，来计算出抗体对抗原与配体的抑制强度。图5显示IL17抗体YN-065、YN-066、YN-067、YN-068、YN-069、 YN070抑制人IL17A蛋白和人IL17受体结合的结果，横坐标为该抗体的浓度，纵坐标为RU值。图5的结果显示，IL17抗体YN-065、YN-066、YN-067、YN-068、YN-069、YN070可有效抑制人IL17A蛋白与人IL17受体结合。The ability of the IL17 antibodies YN-065, YN-066, YN-067, YN-068, YN-069, YN-070 to block binding of human IL17A and human IL17 receptor was assessed using an Octet RED384 instrument (Pall ForteBio). First, human IL17RA/Fc protein (Beijing Baipusis Biotechnology Co., Ltd., H5257) was labeled with biotin (EZ-Link SμLfo-NHS-LC-Biotin, Pierce, 21327). The binding of IL17 antibody to human IL17A protein and human IL17 receptor was analyzed by biofilm interference (BLI) technique using the fortebio octet RED384 instrument (PALL) molecular interaction analyzer (0.1% for antigen and antibody dilution) BSA and 0.02% Tween20 in PBS buffer). Biotin-conjugated recombinant human IL17RA was incubated with a SA sensor at a concentration of 100 nM, 1500 rpm/min for 10 min; a final concentration of 50 nM human IL17A protein and a four-fold diluted antibody solution (1000, 250, 62.5, 15.625, Mix 3.9, 0.97, 0 nM), incubate for 60 minutes and then combine with the machine for 10 minutes at 1500 rpm/min. Finally, dissociation was carried out for 1 minute at 1500 rpm/min. The results obtained will be analyzed by octet Data Analysis 9.0 software (fortebio) to calculate the inhibitory intensity of the antibody against the antigen and ligand. Figure 5 shows the results of IL17 antibody YN-065, YN-066, YN-067, YN-068, YN-069, YN070 inhibiting the binding of human IL17A protein and human IL17 receptor. The abscissa is the concentration of the antibody, and the ordinate is RU value. The results in Figure 5 show that the IL17 antibodies YN-065, YN-066, YN-067, YN-068, YN-069, and YN070 are effective in inhibiting the binding of the human IL17A protein to the human IL17 receptor.

实施例11：IL17抗体抑制IL17A蛋白诱导HT-29细胞产生趋化因子CXCL1Example 11: IL17 antibody inhibits IL17A protein-induced chemokine CXCL1 production in HT-29 cells

HT-29细胞是人结直肠腺癌上皮细胞(中科院上海细胞库)，其天然表达IL17受体。HT-29细胞与人IL17A蛋白一起温育会导致趋化因子CXCL1的产生，所述CXCL1可以使用ELISA进行检测。HT-29 cells are human colorectal adenocarcinoma epithelial cells (Chinese Academy of Sciences Shanghai Cell Bank), which naturally express IL17 receptor. Incubation of HT-29 cells with human IL17A protein results in the production of the chemokine CXCL1, which can be detected using ELISA.

2×10 5个/ml的HT-29细胞加入96孔板中，在37℃培养12小时。将2nM的IL17A(北京义翘神州生物技术有限公司)与梯度浓度的IL17抗体或的对照抗体(IgG Fc)的混合物在37℃温育1小时后加入到以上96孔板中，与HT-29细胞在37℃共温育48小时，然后用CXCL1的ELISA试剂盒(R&D公司)检测细胞培养上清中的CXCL1的水平。结果参见图6，横坐标为抗体的浓度，纵坐标则为CXCL1的浓度。图6A和图6B的结果显示：IL17抗体YN-065、YN-066、YN-067、YN-068可有效抑制HT-29细胞产生趋化因子CXCL1，它们的抑制能力明显强于Secukinumab。图6C的结果显示YN069和YN070抑制HT-29细胞产生CXCL1的能力与YN068相似。 2 × 10 5 /ml of HT-29 cells were added to a 96-well plate and cultured at 37 ° C for 12 hours. A mixture of 2nM IL17A (Beijing Yishen Shenzhou Biotechnology Co., Ltd.) and a gradient concentration of IL17 antibody or a control antibody (IgG Fc) was incubated at 37 ° C for 1 hour and then added to the above 96-well plate with HT-29. The cells were incubated at 37 ° C for 48 hours, and then the level of CXCL1 in the cell culture supernatant was measured using a CXCL1 ELISA kit (R&D). The results are shown in Figure 6. The abscissa is the concentration of the antibody and the ordinate is the concentration of CXCL1. The results of Fig. 6A and Fig. 6B show that the IL17 antibodies YN-065, YN-066, YN-067, and YN-068 can effectively inhibit the production of the chemokine CXCL1 by HT-29 cells, and their inhibitory ability is significantly stronger than that of Secukinumab. The results in Figure 6C show that YN069 and YN070 inhibit HT-29 cells from producing CXCL1 with a similar ability to YN068.

实施例12：IL17抗体抑制IL17A蛋白诱导HS-27细胞产生白细胞介素8(IL-8)Example 12: IL17 antibody inhibits IL17A protein-induced IL-27 production of interleukin-8 (IL-8)

IL-17可诱导人HS-27细胞(ATCC#CRL-1634)分泌IL-8，所述IL-8可以使用ELISA进行检测。IL-17 induces secretion of IL-8 by human HS-27 cells (ATCC #CRL-1634), which can be detected using ELISA.

2×10 5个/ml的HS-27细胞加入96孔板中，在37℃培养12小时。将100ng/ml的IL17A(北京义翘神州生物技术有限公司)与梯度浓度的IL17抗体或相对照抗体(IgG Fc)的混合物在37℃温育1小时后加入到以上96孔板中，与HS-27细胞在37℃共温育48小时，然后用IL-8的ELISA试剂盒(R&D公司)检测细胞培养上清中的IL-8的水平。结果参见图7，横坐标为抗体的浓度，纵坐标则为IL-8的浓度。图7A和图7B的结果显示：IL17抗体YN-065、YN-066、YN-067、YN-068可有效抑制HS-27细胞产生IL-8，它们的抑制能力均显著强于Secukinumab，图7C的结果显示YN069和YN070抑制HS-27细胞产生IL-8的能力与YN068相似。 2 × 10 5 /ml of HS-27 cells were added to a 96-well plate and cultured at 37 ° C for 12 hours. A mixture of 100 ng/ml IL17A (Beijing Yishen Shenzhou Biotechnology Co., Ltd.) and a gradient concentration of IL17 antibody or phase control antibody (IgG Fc) was incubated at 37 ° C for 1 hour and then added to the above 96-well plate with HS. The -27 cells were incubated at 37 ° C for 48 hours, and then the IL-8 level in the cell culture supernatant was measured using an IL-8 ELISA kit (R&D). The results are shown in Figure 7. The abscissa is the concentration of the antibody and the ordinate is the concentration of IL-8. The results of Fig. 7A and Fig. 7B show that the IL17 antibodies YN-065, YN-066, YN-067, and YN-068 can effectively inhibit the production of IL-8 by HS-27 cells, and their inhibitory ability is significantly stronger than that of Secukinumab, Fig. 7C. The results showed that YN069 and YN070 inhibited the production of IL-8 by HS-27 cells similarly to YN068.

前述详细说明是以解释和举例的方式提供的，并非要限制所附权利要求的范围。目前本文所列举的实施方式的多种变化对本领域普通技术人员来说是显而易见的，且保留在所附的 权利要求和其等同方案的范围内。The foregoing detailed description has been presented by way of illustration Numerous variations of the embodiments of the present invention will be apparent to those of ordinary skill in the art and the scope of the appended claims.

Claims (80)

抗体或其抗原结合片段，其以6×10 -9M或更低的K D值与IL17蛋白相结合。 Antibody or antigen binding fragment thereof, which combine to 6 × 10 -9 M or less and a K D value of IL17 protein. 根据权利要求1所述的抗体或其抗原结合片段，其抑制IL17蛋白与IL17受体的结合。The antibody or antigen-binding fragment thereof according to claim 1, which inhibits binding of an IL17 protein to an IL17 receptor. 根据权利要求1-2中任一项所述的抗体或其抗原结合片段，其抑制细胞因子的表达。The antibody or antigen-binding fragment thereof according to any one of claims 1 to 2 which inhibits the expression of a cytokine. 根据权利要求3所述的抗体或其抗原结合片段，所述细胞因子包括：白介素和趋化因子。The antibody or antigen-binding fragment thereof according to claim 3, which comprises: an interleukin and a chemokine. 根据权利要求4所述的抗体或其抗原结合片段，所述趋化因子包括CXCL1。The antibody or antigen-binding fragment thereof according to claim 4, which comprises CXCL1. 根据权利要求1-5中任一项所述的抗体或其抗原结合片段，其可缓解或治疗与IL17的不当或过度产生相关的疾病或病症。The antibody or antigen-binding fragment thereof according to any one of claims 1 to 5 which ameliorates or treats a disease or condition associated with inappropriate or overproduction of IL17. 根据权利要求6所述的抗体或其抗原结合片段，所述疾病或病症包括：强直性脊柱炎、银屑病关节炎、类风湿性关节炎、骨关节炎、骨植入物松动、急性移植排斥、呼吸道炎症、炎性肠病、败血症、败血症性或内毒素性休克、骨丢失、银屑病、变态反应、局部缺血、系统性硬化症、中风和哮喘。The antibody or antigen-binding fragment thereof according to claim 6, comprising: ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, osteoarthritis, bone implant loosening, acute transplantation Rejection, respiratory inflammation, inflammatory bowel disease, sepsis, septic or endotoxic shock, bone loss, psoriasis, allergy, ischemia, systemic sclerosis, stroke and asthma. 根据权利要求1-7中任一项所述的抗体或其抗原结合片段，所述抗体包括：单克隆抗体、单链抗体、嵌合抗体、人源化抗体和/或全人源抗体。The antibody or antigen-binding fragment thereof according to any one of claims 1 to 7, which comprises: a monoclonal antibody, a single chain antibody, a chimeric antibody, a humanized antibody and/or a fully human antibody. 根据权利要求1-8中任一项所述的抗体或其抗原结合片段，所述抗原结合片段包括：Fab，Fab’，F(ab)2、Fv片段、F(ab’)2，scFv，di-scFv和/或VhH。The antibody or antigen-binding fragment thereof according to any one of claims 1 to 8, which comprises: Fab, Fab', F(ab)2, Fv fragment, F(ab')2, scFv, di-scFv and / or VhH. 根据权利要求1-9中任一项所述的抗体或其抗原结合片段，其与参比抗体竞争结合所述IL17蛋白，其中所述参比抗体包含轻链可变区和重链可变区，所述参比抗体的轻链可变区包含LCDR1、LCDR2和LCDR3，所述LCDR1包含下述任一项所示的氨基酸序列：SEQ ID NO:126、SEQ ID NO:22和SEQ ID NO:40；所述LCDR2包含下述任一项所示的氨基酸序列：SEQ ID NO:5、SEQ ID NO:23和SEQ ID NO:41；以及，The antibody or antigen-binding fragment thereof according to any one of claims 1 to 9 which competes with a reference antibody for binding to the IL17 protein, wherein the reference antibody comprises a light chain variable region and a heavy chain variable region The light chain variable region of the reference antibody comprises LCDR1, LCDR2, and LCDR3, the LCDR1 comprising the amino acid sequence set forth in any one of the following: SEQ ID NO: 126, SEQ ID NO: 22, and SEQ ID NO: 40: The LCDR2 comprises the amino acid sequence shown in any one of the following: SEQ ID NO: 5, SEQ ID NO: 23, and SEQ ID NO: 41; 所述LCDR3包含下述任一项所示的氨基酸序列：SEQ ID NO:6、SEQ ID NO:24和SEQ ID NO:131；且，The LCDR3 comprises the amino acid sequence shown in any one of the following: SEQ ID NO: 6, SEQ ID NO: 24, and SEQ ID NO: 131; 所述参比抗体的重链可变区包含HCDR1、HCDR2和HCDR3，所述HCDR1包含下述任一项所示的氨基酸序列：SEQ ID NO:123、SEQ ID NO:19和SEQ ID NO:37；所述HCDR2包含下述任一项所示的氨基酸序列：SEQ ID NO:124、SEQ ID NO:20和SEQ ID NO:38；以及，所述HCDR3包含下述任一项所示的氨基酸序列：SEQ ID NO:125、SEQ ID NO:21和SEQ ID NO:130。The heavy chain variable region of the reference antibody comprises HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence set forth in any one of the following: SEQ ID NO: 123, SEQ ID NO: 19 and SEQ ID NO: 37 The HCDR2 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 124, SEQ ID NO: 20, and SEQ ID NO: 38; and the HCDR3 comprises the amino acid sequence set forth in any one of the following SEQ ID NO: 125, SEQ ID NO: 21 and SEQ ID NO: 130. 根据权利要求10所述的抗体、其抗原结合片段，其中所述参比抗体的LCDR1包含下述任一项所示的氨基酸序列：SEQ ID NO:4和SEQ ID NO:96。The antibody, antigen-binding fragment thereof, according to claim 10, wherein the LCDR1 of the reference antibody comprises the amino acid sequence shown in any one of the following: SEQ ID NO: 4 and SEQ ID NO: 96. 根据权利要求10-11中任一项所述的抗体或其抗原结合片段，其中所述参比抗体的LCDR3包含下述任一项所示的氨基酸序列：SEQ ID NO:42和SEQ ID NO:102。The antibody or antigen-binding fragment thereof according to any one of claims 10 to 11, wherein the LCDR3 of the reference antibody comprises the amino acid sequence shown in any one of the following: SEQ ID NO: 42 and SEQ ID NO: 102. 根据权利要求10-12中任一项所述的抗体或其抗原结合片段，其中所述参比抗体的HCDR1包含下述任一项所示的氨基酸序列：SEQ ID NO:1、SEQ ID NO:91和SEQ ID NO:92。The antibody or antigen-binding fragment thereof according to any one of claims 10 to 12, wherein the HCDR1 of the reference antibody comprises the amino acid sequence shown in any one of the following: SEQ ID NO: 1, SEQ ID NO: 91 and SEQ ID NO:92. 根据权利要求10-13中任一项所述的抗体或其抗原结合片段，其中所述参比抗体的HCDR2包含下述任一项所示的氨基酸序列：SEQ ID NO:2和SEQ ID NO:93；The antibody or antigen-binding fragment thereof according to any one of claims 10 to 13, wherein the HCDR2 of the reference antibody comprises the amino acid sequence shown in any one of the following: SEQ ID NO: 2 and SEQ ID NO: 93; 根据权利要求10-14中任一项所述的抗体或其抗原结合片段，其中所述参比抗体的HCDR3包含下述任一项所示的氨基酸序列：SEQ ID NO:3、SEQ ID NO:94、SEQ ID NO:95、SEQ ID NO:39、SEQ ID NO:100和SEQ ID NO:101。The antibody or antigen-binding fragment thereof according to any one of claims 10 to 14, wherein the HCDR3 of the reference antibody comprises the amino acid sequence shown in any one of the following: SEQ ID NO: 3, SEQ ID NO: 94. SEQ ID NO: 95, SEQ ID NO: 39, SEQ ID NO: 100, and SEQ ID NO: 101. 根据权利要求10-15中任一项所述的抗体或其抗原结合片段，其中所述参比抗体的轻链可变区包含下述任一项所示的氨基酸序列：SEQ ID NO:16、SEQ ID NO:134、SEQ ID NO:34、SEQ ID NO:36、SEQ ID NO:52和SEQ ID NO:132；且，The antibody or antigen-binding fragment thereof according to any one of claims 10 to 15, wherein the light chain variable region of the reference antibody comprises the amino acid sequence shown in any one of the following: SEQ ID NO: SEQ ID NO: 134, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 52, and SEQ ID NO: 132; 所述参比抗体的重链可变区包含下述任一项所示的氨基酸序列：SEQ ID NO:15、SEQ ID NO:135、SEQ ID NO:33、SEQ ID NO:35、SEQ ID NO:51和SEQ ID NO:133。The heavy chain variable region of the reference antibody comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 15, SEQ ID NO: 135, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO : 51 and SEQ ID NO: 133. 根据权利要求16所述的抗体或其抗原结合片段，其中所述参比抗体的轻链可变区包含下述任一项所示的氨基酸序列：SEQ ID NO:54、SEQ ID NO:103、SEQ ID NO:18和SEQ ID NO:109。The antibody or antigen-binding fragment thereof according to claim 16, wherein the light chain variable region of the reference antibody comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 54, SEQ ID NO: 103, SEQ ID NO: 18 and SEQ ID NO: 109. 根据权利要求16-17中任一项所述的抗体或其抗原结合片段，其中所述参比抗体的重链可变区包含下述任一项所示的氨基酸序列：SEQ ID NO:53、SEQ ID NO:105、SEQ ID NO:107、SEQ ID NO:17、SEQ ID NO:111、SEQ ID NO:114、SEQ ID NO:117和SEQ ID NO:120。The antibody or antigen-binding fragment thereof according to any one of claims 16-17, wherein the heavy chain variable region of the reference antibody comprises the amino acid sequence set forth in any one of the following: SEQ ID NO:53, SEQ ID NO: 105, SEQ ID NO: 107, SEQ ID NO: 17, SEQ ID NO: 111, SEQ ID NO: 114, SEQ ID NO: 117, and SEQ ID NO: 120. 根据权利要求10-18中任一项所述的抗体或其抗原结合片段，其中所述参比抗体的轻链包含下述任一项所示的氨基酸序列：SEQ ID NO:64、SEQ ID NO:68、SEQ ID NO:72、SEQ ID NO:138、SEQ ID NO:84和SEQ ID NO:136；且，The antibody or antigen-binding fragment thereof according to any one of claims 10 to 18, wherein the light chain of the reference antibody comprises the amino acid sequence shown in any one of the following: SEQ ID NO: 64, SEQ ID NO :68, SEQ ID NO: 72, SEQ ID NO: 138, SEQ ID NO: 84, and SEQ ID NO: 136; 所述参比抗体的重链包含下述任一项所示的氨基酸序列：SEQ ID NO:62、SEQ ID NO:66、SEQ ID NO:70、SEQ ID NO:139、SEQ ID NO:82和SEQ ID NO:137。The heavy chain of the reference antibody comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 62, SEQ ID NO: 66, SEQ ID NO: 70, SEQ ID NO: 139, SEQ ID NO: 82 and SEQ ID NO:137. 根据权利要求19所述的抗体或其抗原结合片段，其中所述参比抗体的轻链包含下述任一项所示的氨基酸序列：SEQ ID NO:90、SEQ ID NO:104、SEQ ID NO:78和SEQ ID NO:110。The antibody or antigen-binding fragment thereof according to claim 19, wherein the light chain of the reference antibody comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 90, SEQ ID NO: 104, SEQ ID NO :78 and SEQ ID NO:110. 根据权利要求19-20中任一项所述的抗体或其抗原结合片段，其中所述参比抗体的重链包含下述任一项所示的氨基酸序列：SEQ ID NO:88、SEQ ID NO:106、SEQ ID NO:108、SEQ ID NO:76、SEQ ID NO:112、SEQ ID NO:115、SEQ ID NO:118和SEQ ID NO:121。The antibody or antigen-binding fragment thereof according to any one of claims 19 to 20, wherein the heavy chain of the reference antibody comprises the amino acid sequence shown in any one of the following: SEQ ID NO: 88, SEQ ID NO : 106, SEQ ID NO: 108, SEQ ID NO: 76, SEQ ID NO: 112, SEQ ID NO: 115, SEQ ID NO: 118, and SEQ ID NO: 121. 根据权利要求1-21中任一项所述的抗体或其抗原结合片段，其中所述抗体包含抗体轻链或其片段。The antibody or antigen-binding fragment thereof according to any one of claims 1 to 21, wherein the antibody comprises an antibody light chain or a fragment thereof. 根据权利要求22所述的抗体或其抗原结合片段，所述抗体轻链或其片段包含LCDR1，且所述LCDR1包含下述任一项所示的氨基酸序列：SEQ ID NO:126、SEQ ID NO:22和SEQ ID NO:40。The antibody or antigen-binding fragment thereof according to claim 22, wherein the antibody light chain or a fragment thereof comprises LCDR1, and the LCDR1 comprises the amino acid sequence shown in any one of the following: SEQ ID NO: 126, SEQ ID NO : 22 and SEQ ID NO:40. 根据权利要求23所述的抗体或其抗原结合片段，所述LCDR1的氨基酸序列包含下述任一项所示的氨基酸序列：SEQ ID NO:4和SEQ ID NO:96。The antibody or antigen-binding fragment thereof according to claim 23, wherein the amino acid sequence of LCDR1 comprises the amino acid sequence shown in any one of the following: SEQ ID NO: 4 and SEQ ID NO: 96. 根据权利要求22-24中任一项所述的抗体或其抗原结合片段，所述抗体轻链或其片段包含LCDR2，且所述LCDR2包含下述任一项所示的氨基酸序列：SEQ ID NO:5、SEQ ID NO:23和SEQ ID NO:41。The antibody or antigen-binding fragment thereof according to any one of claims 22 to 24, wherein the antibody light chain or fragment thereof comprises LCDR2, and the LCDR2 comprises the amino acid sequence shown in any one of the following: SEQ ID NO : 5, SEQ ID NO: 23 and SEQ ID NO: 41. 根据权利要求22-25中任一项所述的抗体或其抗原结合片段，所述抗体轻链或其片段包含LCDR3，且所述LCDR3包含下述任一项所示的氨基酸序列：SEQ ID NO:6、SEQ ID NO:24和SEQ ID NO:131。The antibody or antigen-binding fragment thereof according to any one of claims 22 to 25, wherein the antibody light chain or a fragment thereof comprises LCDR3, and the LCDR3 comprises the amino acid sequence shown in any one of the following: SEQ ID NO : 6, SEQ ID NO: 24 and SEQ ID NO: 131. 根据权利要求26所述的抗体或其抗原结合片段，所述LCDR3包含下述任一项所示的氨基酸序列：SEQ ID NO:42和SEQ ID NO:102。The antibody or antigen-binding fragment thereof according to claim 26, wherein the LCDR3 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 42 and SEQ ID NO: 102. 根据权利要求22-27中任一项所述的抗体或其抗原结合片段，所述抗体轻链或其片段还包括框架区L-FR1、L-FR2、L-FR3和L-FR4。The antibody or antigen-binding fragment thereof according to any one of claims 22 to 27, further comprising framework regions L-FR1, L-FR2, L-FR3 and L-FR4. 根据权利要求28所述的抗体或其抗原结合片段，所述框架区L-FR1、L-FR2、L-FR3和L-FR4选自以下组中任一项：人共有框架序列和人种系序列。The antibody or antigen-binding fragment thereof according to claim 28, wherein said framework regions L-FR1, L-FR2, L-FR3 and L-FR4 are selected from any one of the group consisting of human consensus framework sequences and human germline sequence. 根据权利要求28-29中任一项所述的抗体或其抗原结合片段，所述L-FR1的C末端与所述LCDR1的N末端直接或间接相连，所述L-FR1包含下述任一项所示的氨基酸序列：SEQ ID NO:127、SEQ ID NO:29和SEQ ID NO:47。The antibody or antigen-binding fragment thereof according to any one of claims 28 to 29, wherein the C-terminus of the L-FR1 is directly or indirectly linked to the N-terminus of the LCDR1, and the L-FR1 comprises any one of the following The amino acid sequences shown are: SEQ ID NO: 127, SEQ ID NO: 29 and SEQ ID NO: 47. 根据权利要求30所述的抗体或其抗原结合片段，所述L-FR1包含下述任一项所示的氨基酸序列：SEQ ID NO:11和SEQ ID NO:97。The antibody or antigen-binding fragment thereof according to claim 30, wherein the L-FR1 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 11 and SEQ ID NO: 97. 根据权利要求28-31中任一项所述的抗体或其抗原结合片段，所述L-FR2位于所述LCDR1与所述LCDR2之间，所述L-FR2包含下述任一项所示的氨基酸序列：SEQ ID  NO:128、SEQ ID NO:30和SEQ ID NO:48。The antibody or antigen-binding fragment thereof according to any one of claims 28 to 31, wherein the L-FR2 is located between the LCDR1 and the LCDR2, and the L-FR2 comprises any one of the following Amino acid sequences: SEQ ID NO: 128, SEQ ID NO: 30 and SEQ ID NO: 48. 根据权利要求32所述的抗体或其抗原结合片段，所述L-FR2包含下述任一项所示的氨基酸序列：SEQ ID NO:12和SEQ ID NO:98。The antibody or antigen-binding fragment thereof according to claim 32, wherein the L-FR2 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 12 and SEQ ID NO: 98. 根据权利要求28-33中任一项所述的抗体或其抗原结合片段，所述L-FR3位于所述LCDR2与所述LCDR3之间，所述L-FR3包含下述任一项所示的氨基酸序列：SEQ ID NO:13、SEQ ID NO:31和SEQ ID NO:49。The antibody or antigen-binding fragment thereof according to any one of claims 28 to 33, wherein the L-FR3 is located between the LCDR2 and the LCDR3, and the L-FR3 comprises any one of the following Amino acid sequences: SEQ ID NO: 13, SEQ ID NO: 31 and SEQ ID NO: 49. 根据权利要求28-34中任一项所述的抗体或其抗原结合片段，所述L-FR4的N末端与所述LCDR3的C末端直接或间接相连，所述L-FR4包含下述任一项所示的氨基酸序列：SEQ ID NO:14、SEQ ID NO:32和SEQ ID NO:50。The antibody or antigen-binding fragment thereof according to any one of claims 28 to 34, wherein the N-terminus of the L-FR4 is directly or indirectly linked to the C-terminus of the LCDR3, and the L-FR4 comprises any one of the following The amino acid sequences shown are: SEQ ID NO: 14, SEQ ID NO: 32 and SEQ ID NO: 50. 根据权利要求22-35中任一项所述的抗体或其抗原结合片段，所述抗体轻链或其片段包含轻链可变区VL，且所述轻链可变区VL包含下述任一项所示的氨基酸序列：SEQ ID NO:16、SEQ ID NO:134、SEQ ID NO:34、SEQ ID NO:36、SEQ ID NO:52和SEQ ID NO:132。The antibody or antigen-binding fragment thereof according to any one of claims 22 to 35, wherein the antibody light chain or fragment thereof comprises a light chain variable region VL, and the light chain variable region VL comprises any one of the following The amino acid sequences shown are: SEQ ID NO: 16, SEQ ID NO: 134, SEQ ID NO: 34, SEQ ID NO: 36, SEQ ID NO: 52, and SEQ ID NO: 132. 根据权利要求36所述的抗体或其抗原结合片段，其中所述轻链可变区包含下述任一项所示的氨基酸序列：SEQ ID NO:54、SEQ ID NO:103、SEQ ID NO:18和SEQ ID NO:109。The antibody or antigen-binding fragment thereof according to claim 36, wherein the light chain variable region comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 54, SEQ ID NO: 103, SEQ ID NO: 18 and SEQ ID NO: 109. 根据权利要求22-37中任一项所述的抗体或其抗原结合片段，所述抗体轻链或其片段还包含人恒定区或鼠恒定区。The antibody or antigen-binding fragment thereof according to any one of claims 22 to 37, further comprising a human constant region or a murine constant region. 根据权利要求38所述的抗体或其抗原结合片段，所述抗体轻链或其片段包含人恒定区，且所述人恒定区包括人Igκ或Igλ恒定区。The antibody or antigen-binding fragment thereof according to claim 38, wherein the antibody light chain or fragment thereof comprises a human constant region, and the human constant region comprises a human Ig kappa or Ig lambda constant region. 根据权利要求22-39中任一项所述的抗体或其抗原结合片段，所述抗体轻链或其片段包含下述任一项所示的氨基酸序列：SEQ ID NO:64、SEQ ID NO:68、SEQ ID NO:72、SEQ ID NO:138、SEQ ID NO:84和SEQ ID NO:136。The antibody or antigen-binding fragment thereof according to any one of claims 22 to 39, wherein the antibody light chain or fragment thereof comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 64, SEQ ID NO: 68. SEQ ID NO: 72, SEQ ID NO: 138, SEQ ID NO: 84, and SEQ ID NO: 136. 根据权利要求40所述的抗体或其抗原结合片段，所述抗体轻链或其片段包含下述任一项所示的氨基酸序列：SEQ ID NO:90、SEQ ID NO:104、SEQ ID NO:78和SEQ ID NO:110。The antibody or antigen-binding fragment thereof according to claim 40, wherein the antibody light chain or fragment thereof comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 90, SEQ ID NO: 104, SEQ ID NO: 78 and SEQ ID NO: 110. 根据权利要求1-41中任一项所述的抗体或其抗原结合片段，所述抗体包含抗体重链或其片段。The antibody or antigen-binding fragment thereof according to any one of claims 1 to 41, which antibody comprises an antibody heavy chain or a fragment thereof. 根据权利要求42所述的抗体或其抗原结合片段，所述抗体重链或其片段包含HCDR1，且所述HCDR1包含下述任一项所示的氨基酸序列：SEQ ID NO:123、SEQ ID NO:19 和SEQ ID NO:37。The antibody or antigen-binding fragment thereof according to claim 42, wherein the antibody heavy chain or a fragment thereof comprises HCDR1, and the HCDR1 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 123, SEQ ID NO :19 and SEQ ID NO:37. 根据权利要求43所述的抗体或其抗原结合片段，所述HCDR1包含下述任一项所示的氨基酸序列：SEQ ID NO:1、SEQ ID NO:91和SEQ ID NO:92。The antibody or antigen-binding fragment thereof according to claim 43, which comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 1, SEQ ID NO: 91 and SEQ ID NO: 92. 根据权利要求42-44中任一项所述的抗体或其抗原结合片段，所述抗体重链或其片段包含HCDR2，且所述HCDR2包含下述任一项所示的氨基酸序列：SEQ ID NO:124、SEQ ID NO:20和SEQ ID NO:38。The antibody or antigen-binding fragment thereof according to any one of claims 42-44, wherein the antibody heavy chain or fragment thereof comprises HCDR2, and the HCDR2 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO : 124, SEQ ID NO: 20 and SEQ ID NO: 38. 根据权利要求45所述的抗体或其抗原结合片段，所述HCDR2包含下述任一项所示的氨基酸序列：SEQ ID NO:2和SEQ ID NO:93。The antibody or antigen-binding fragment thereof according to claim 45, which comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 2 and SEQ ID NO: 93. 根据权利要求42-46中任一项所述的抗体或其抗原结合片段，所述抗体重链或其片段包含HCDR3，且所述HCDR3包含下述任一项所示的氨基酸序列：SEQ ID NO:125、SEQ ID NO:21和SEQ ID NO:130。The antibody or antigen-binding fragment thereof according to any one of claims 42-46, wherein the antibody heavy chain or fragment thereof comprises HCDR3, and the HCDR3 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO :125, SEQ ID NO: 21 and SEQ ID NO: 130. 根据权利要求47所述的抗体或其抗原结合片段，所述HCDR3包含下述任一项所示的氨基酸序列：SEQ ID NO:3、SEQ ID NO:94、SEQ ID NO:95、SEQ ID NO:39、SEQ ID NO:100和SEQ ID NO:101。The antibody or antigen-binding fragment thereof according to claim 47, which comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 3, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO 39, SEQ ID NO: 100 and SEQ ID NO: 101. 根据权利要求42-48中任一项所述的抗体或其抗原结合片段，所述抗体重链或其片段还包括框架区H-FR1、H-FR2、H-FR2和H-FR4。The antibody or antigen-binding fragment thereof according to any one of claims 42-48, further comprising framework regions H-FR1, H-FR2, H-FR2 and H-FR4. 根据权利要求49所述的抗体或其抗原结合片段，所述框架区选自以下组中任一项：人共有框架序列和人种系序列。The antibody or antigen-binding fragment thereof according to claim 49, wherein the framework region is selected from any one of the group consisting of a human consensus framework sequence and a human germline sequence. 根据权利要求49-50中任一项所述的抗体或其抗原结合片段，所述H-FR1的C末端与所述HCDR1的N末端直接或间接相连，所述H-FR1包含下述任一项所示的氨基酸序列：SEQ ID NO:7、SEQ ID NO:25和SEQ ID NO:43。The antibody or antigen-binding fragment thereof according to any one of claims 49 to 50, wherein the C-terminus of the H-FR1 is directly or indirectly linked to the N-terminus of the HCDR1, and the H-FR1 comprises any one of the following The amino acid sequences shown are: SEQ ID NO: 7, SEQ ID NO: 25 and SEQ ID NO: 43. 根据权利要求49-51中任一项所述的抗体或其抗原结合片段，所述H-FR2位于所述HCDR1与所述HCDR2之间，所述H-FR2包含下述任一项所示的氨基酸序列：SEQ ID NO:8、SEQ ID NO:26和SEQ ID NO:44。The antibody or antigen-binding fragment thereof according to any one of claims 49 to 51, wherein the H-FR2 is located between the HCDR1 and the HCDR2, and the H-FR2 comprises any one of the following Amino acid sequences: SEQ ID NO: 8, SEQ ID NO: 26 and SEQ ID NO: 44. 根据权利要求49-52中任一项所述的抗体或其抗原结合片段，所述H-FR3位于所述HCDR2与所述HCDR3之间，所述H-FR3包含下述任一项所示的氨基酸序列：SEQ ID NO:129、SEQ ID NO:27和SEQ ID NO:45。The antibody or antigen-binding fragment thereof according to any one of claims 49 to 52, wherein the H-FR3 is located between the HCDR2 and the HCDR3, and the H-FR3 comprises any one of the following Amino acid sequences: SEQ ID NO: 129, SEQ ID NO: 27 and SEQ ID NO: 45. 根据权利要求53所述的抗体或其抗原结合片段，所述H-FR3包含下述任一项所示的氨基酸序列：SEQ ID NO:9和SEQ ID NO:99。The antibody or antigen-binding fragment thereof according to claim 53, wherein the H-FR3 comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 9 and SEQ ID NO: 99. 根据权利要求49-54中任一项所述的抗体或其抗原结合片段，所述H-FR4的N末端 与所述HCDR3的C末端直接或间接相连，所述H-FR4包含下述任一项所示的氨基酸序列：SEQ ID NO:10、SEQ ID NO:28和SEQ ID NO:46。The antibody or antigen-binding fragment thereof according to any one of claims 49-54, wherein the N-terminus of H-FR4 is directly or indirectly linked to the C-terminus of said HCDR3, said H-FR4 comprising any of the following The amino acid sequences shown are: SEQ ID NO: 10, SEQ ID NO: 28 and SEQ ID NO: 46. 根据权利要求49-55中任一项所述的抗体或其抗原结合片段，所述抗体重链或其片段包含重链可变区VH，且所述重链可变区VH包含下述任一项所示的氨基酸序列：SEQ ID NO:15、SEQ ID NO:135、SEQ ID NO:33、SEQ ID NO:35、SEQ ID NO:51和SEQ ID NO:133。The antibody or antigen-binding fragment thereof according to any one of claims 49 to 55, wherein the antibody heavy chain or a fragment thereof comprises a heavy chain variable region VH, and the heavy chain variable region VH comprises any one of the following The amino acid sequences shown are: SEQ ID NO: 15, SEQ ID NO: 135, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 51, and SEQ ID NO: 133. 根据权利要求56所述的抗体或其抗原结合片段，其中所述重链可变区VH包含下述任一项所示的氨基酸序列：SEQ ID NO:53、SEQ ID NO:105、SEQ ID NO:107、SEQ ID NO:17、SEQ ID NO:111、SEQ ID NO:114、SEQ ID NO:117和SEQ ID NO:120。The antibody or antigen-binding fragment thereof according to claim 56, wherein the heavy chain variable region VH comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 53, SEQ ID NO: 105, SEQ ID NO : 107, SEQ ID NO: 17, SEQ ID NO: 111, SEQ ID NO: 114, SEQ ID NO: 117, and SEQ ID NO: 120. 根据权利要求42-57中任一项所述的抗体或其抗原结合片段，所述抗体重链或其片段还包含人恒定区或鼠恒定区。The antibody or antigen-binding fragment thereof according to any one of claims 42-57, further comprising a human constant region or a murine constant region. 根据权利要求58所述的抗体或其抗原结合片段，所述抗体重链或其片段包含人恒定区，且所述人恒定区包括人IgG恒定区。The antibody or antigen-binding fragment thereof according to claim 58, the antibody heavy chain or fragment thereof comprising a human constant region, and the human constant region comprises a human IgG constant region. 根据权利要求58-59中任一项所述的抗体或其抗原结合片段，IgG恒定区包含人IgG1恒定区。The antibody or antigen-binding fragment thereof according to any one of claims 58-59, wherein the IgG constant region comprises a human IgG1 constant region. 根据权利要求42-60中任一项所述的抗体或其抗原结合片段，所述抗体重链或其片段包含下述任一项所示的氨基酸序列：SEQ ID NO:62、SEQ ID NO:66、SEQ ID NO:70、SEQ ID NO:139、SEQ ID NO:82和SEQ ID NO:137。The antibody or antigen-binding fragment thereof according to any one of claims 42-60, wherein the antibody heavy chain or fragment thereof comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 62, SEQ ID NO: 66. SEQ ID NO: 70, SEQ ID NO: 139, SEQ ID NO: 82 and SEQ ID NO: 137. 根据权利要求61所述的抗体或其抗原结合片段，所述重链包含下述任一项所示的氨基酸序列：SEQ ID NO:88、SEQ ID NO:106、SEQ ID NO:108、SEQ ID NO:76、SEQ ID NO:112、SEQ ID NO:115、SEQ ID NO:118和SEQ ID NO:121。The antibody or antigen-binding fragment thereof according to claim 61, which comprises the amino acid sequence set forth in any one of the following: SEQ ID NO: 88, SEQ ID NO: 106, SEQ ID NO: 108, SEQ ID NO: 76, SEQ ID NO: 112, SEQ ID NO: 115, SEQ ID NO: 118, and SEQ ID NO: 121. 根据权利要求1-62中任一项所述的抗体或其抗原结合片段，所述IL7蛋白为人IL17蛋白。The antibody or antigen-binding fragment thereof according to any one of claims 1 to 62, which is a human IL17 protein. 根据权利要求1-62中任一项所述的抗体或其抗原结合片段，所述IL7蛋白包括IL17A蛋白和/或IL17F蛋白。The antibody or antigen-binding fragment thereof according to any one of claims 1 to 62, which comprises an IL17A protein and/or an IL17F protein. 分离的一种或多种核酸分子，其编码权利要求1-62中任一项所述的抗体或其抗原结合片段。An isolated nucleic acid molecule or an antigen-binding fragment thereof, according to any one of claims 1 to 6. 载体，其包含权利要求65所述的核酸分子。A vector comprising the nucleic acid molecule of claim 65. 宿主细胞，其包含权利要求65所述的核酸分子或权利要求66所述的载体。A host cell comprising the nucleic acid molecule of claim 65 or the vector of claim 66. 制备所述的抗体或其抗原结合片段的方法，所述方法包括在使得权利要求1-62中任 一项所述抗体或其抗原结合片段表达的条件下，培养权利要求67所述的宿主细胞。A method of producing the antibody or antigen-binding fragment thereof, which comprises culturing the host cell of claim 67 under conditions such that the antibody or antigen-binding fragment thereof of any one of claims 1-62 is expressed . 根据权利要求68所述的方法，其任选地包含收获所述抗体或其抗原结合片段。The method of claim 68, optionally comprising harvesting the antibody or antigen-binding fragment thereof. 药物组合物，其包含权利要求1-62中所述的抗体或其抗原结合片段、权利要求65所述的核酸分子、权利要求66所述的载体和/或权利要求67所述的宿主细胞，以及任选地药学上可接受的佐剂。A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof according to claims 1-62, the nucleic acid molecule of claim 65, the vector of claim 66 and/or the host cell of claim 67, And optionally a pharmaceutically acceptable adjuvant. 权利要求1-62中任一项所述的抗体或其抗原结合片段在制备预防或治疗疾病或病症的药物中的用途。Use of an antibody or antigen-binding fragment thereof according to any one of claims 1 to 62 for the preparation of a medicament for preventing or treating a disease or condition. 根据权利要求71所述的用途，所述疾病或病症包括：强直性脊柱炎、银屑病关节炎、类风湿性关节炎、骨关节炎、骨植入物松动、急性移植排斥、呼吸道炎症、炎性肠病、败血症、败血症性或内毒素性休克、骨丢失、银屑病、变态反应、局部缺血、系统性硬化症、中风和哮喘。The use according to claim 71, comprising: ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, osteoarthritis, bone implant loosening, acute graft rejection, respiratory inflammation, Inflammatory bowel disease, sepsis, septic or endotoxic shock, bone loss, psoriasis, allergy, ischemia, systemic sclerosis, stroke and asthma. 权利要求1-62中任一项抗体或其抗原结合片段，其用于预防或治疗疾病或病症。The antibody or antigen-binding fragment thereof according to any one of claims 1 to 62 for use in the prevention or treatment of a disease or condition. 根据权利要求73所述的抗体或其抗原结合片段，所述疾病或病症包括：强直性脊柱炎、银屑病关节炎、类风湿性关节炎、骨关节炎、骨植入物松动、急性移植排斥、呼吸道炎症、炎性肠病、败血症、败血症性或内毒素性休克、骨丢失、银屑病、变态反应、局部缺血、系统性硬化症、中风和哮喘。The antibody or antigen-binding fragment thereof according to claim 73, which comprises ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, osteoarthritis, bone implant loosening, acute transplantation Rejection, respiratory inflammation, inflammatory bowel disease, sepsis, septic or endotoxic shock, bone loss, psoriasis, allergy, ischemia, systemic sclerosis, stroke and asthma. 预防或治疗疾病的方法，其包括施用权利要求1-62中任一项所述的抗体或其抗原结合片段、权利要求65所述的核酸分子、权利要求66所述的载体、权利要求67所述的宿主细胞和/或权利要求70所述的药物组合物。A method for preventing or treating a disease, which comprises administering the antibody or antigen-binding fragment thereof according to any one of claims 1 to 62, the nucleic acid molecule of claim 65, the vector of claim 66, and the method of claim 67 The host cell and/or the pharmaceutical composition of claim 70. 根据权利要求75所述的方法，所述疾病或病症包括：强直性脊柱炎、银屑病关节炎、类风湿性关节炎、骨关节炎、骨植入物松动、急性移植排斥、呼吸道炎症、炎性肠病、败血症、败血症性或内毒素性休克、骨丢失、银屑病、变态反应、局部缺血、系统性硬化症、中风和哮喘。The method according to claim 75, wherein the disease or condition comprises ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, osteoarthritis, bone implant loosening, acute graft rejection, respiratory inflammation, Inflammatory bowel disease, sepsis, septic or endotoxic shock, bone loss, psoriasis, allergy, ischemia, systemic sclerosis, stroke and asthma. 抑制IL17蛋白和IL17配体结合的方法，其包括施用权利要求1-62中任一项所述的抗体或其抗原结合片段、权利要求65所述的核酸分子、权利要求66所述的载体、权利要求67所述的宿主细胞和/或权利要求70所述的药物组合物。A method of inhibiting the binding of an IL17 protein and an IL17 ligand, comprising administering the antibody or antigen-binding fragment thereof according to any one of claims 1 to 62, the nucleic acid molecule of claim 65, the vector of claim 66, The host cell of claim 67 and/or the pharmaceutical composition of claim 70. 抑制IL17蛋白生物学活性的方法，其包括施用权利要求1-62中任一项所述的抗体或其抗原结合片段、权利要求65所述的核酸分子、权利要求66所述的载体、权利要求67所述的宿主细胞和/或权利要求70所述的药物组合物。A method of inhibiting the biological activity of an IL17 protein, which comprises administering the antibody or antigen-binding fragment thereof according to any one of claims 1 to 62, the nucleic acid molecule of claim 65, the vector of claim 66, the claims 67. The host cell of claim 67 and/or the pharmaceutical composition of claim 70. 抑制趋化因子表达的方法，其包括权利要求1-62中任一项所述的抗体或其抗原结合 片段、权利要求65所述的核酸分子、权利要求66所述的载体、权利要求67所述的宿主细胞和/或权利要求70所述的药物组合物。A method of inhibiting expression of a chemokine, which comprises the antibody or antigen-binding fragment thereof according to any one of claims 1 to 62, the nucleic acid molecule of claim 65, the vector of claim 66, and the method of claim 67 The host cell and/or the pharmaceutical composition of claim 70. 根据权利要求79所述的方法，所述趋化因子包括CXCL1。The method of claim 79, wherein the chemokine comprises CXCL1.
PCT/CN2019/074805 2018-02-12 2019-02-11 Il17 antibody and application thereof Ceased WO2019154420A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CN201980012724.9A CN111699006B (en) 2018-02-12 2019-02-11 IL17 antibody and its application
CN202111071115.6A CN113603777B (en) 2018-02-12 2019-02-11 IL17 antibodies and uses thereof
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