WO2023143547A1 - Anticorps anti-cd28 et son utilisation - Google Patents

Anticorps anti-cd28 et son utilisation Download PDF

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WO2023143547A1
WO2023143547A1 PCT/CN2023/073643 CN2023073643W WO2023143547A1 WO 2023143547 A1 WO2023143547 A1 WO 2023143547A1 CN 2023073643 W CN2023073643 W CN 2023073643W WO 2023143547 A1 WO2023143547 A1 WO 2023143547A1
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seq
sequence
antibody
sequence shown
polypeptide
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PCT/CN2023/073643
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Chinese (zh)
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黄俊杰
徐振前
张慧
吴精博
汪志炜
陈俊有
张少榆
黄贤明
李胜峰
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百奥泰生物制药股份有限公司
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Publication of WO2023143547A1 publication Critical patent/WO2023143547A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • 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
    • 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
    • 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
    • A61P19/02—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
    • 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
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • 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
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids

Definitions

  • the present invention belongs to the field of immunology. Specifically, the present invention relates to an anti-CD28 antibody and its application.
  • CD28 is a co-stimulatory molecule expressed on the surface of T lymphocytes and plays an important role in the activation of T cells. It binds to B7 molecules on APCs (antigen presenting cells), mediates co-stimulation of T cells and promotes their survival, proliferation and cytokine production.
  • APCs antigen presenting cells
  • the complete activation of naive T cells usually requires three signals, the first signal is the combination of antigen and antigen receptor, the second signal is co-stimulatory signal, and the third signal is cytokine signal.
  • CD28 is involved in the reception of the second signal.
  • TCR peptide-major histocompatibility complex
  • helper T cells helper T cells
  • Tc cells cytotoxic T cells
  • T cell receptor T cell receptor
  • TCR and pMHC will lead to the phosphorylation of ITAM on the CD3 chain immediately adjacent to TCR by Lck kinase.
  • Other intracellular signal transduction-related enzymes are then recruited here, making contacts with the CD4 or CD8 co-receptors and the cytoplasmic tail of the CD3 chain. Together, these enzymes mediate an enzymatic cascade of chemical reactions that lead to the activation of multiple other enzymes. When this activation cascade occurs across multiple TCRs, T cells receive the first signal (Mak, Saunders et al. 2013, Primer to the immune response, Newnes.).
  • the combination of TCR and pMHC is not sufficient to fully activate a naive Th cell or Tc cell, and a second signal in the form of co-stimulatory signaling is required.
  • Th cells after receiving the first signal, the expression of CD28, an important co-stimulatory molecule on the surface of Th cells, is up-regulated.
  • CD28 in order for CD28 to transmit the second signal to the Th cell nucleus, it must combine with the ligand B7 molecule on the surface of DC presenting activated pMHC.
  • the activation of T cells is the basis for the continued proliferation and differentiation of T cells, and the complete activation of T cells requires the joint participation of the first signal and the second signal.
  • T cells are recognized by the TCR, which is the first signal for T cell activation.
  • TCR and CD3 molecule form a TCR-CD3 complex, and the function of CD3 molecule is to transduce the activation signal generated by TCR recognition antigen.
  • the second signal (or co-stimulatory signal) is generated by the interaction between co-stimulatory molecules on the surface of APC or target cells and corresponding co-stimulatory molecules on the surface of T cells, and CD28 is an extremely important co-stimulatory molecule in T cell activation.
  • the first CD28 super agonistic antibody Theralizumab (TGN1412, TAB08) was designed for the treatment of autoimmune-related diseases (Attarwala 2010, J Young Pharm 2(3):332-336.), and began to be used for the first time in 2006. clinical trial.
  • Theralizumab is currently used in Phase II clinical trials for the treatment of Merkel cell carcinoma, rheumatoid arthritis, systemic lupus erythematosus, and psoriasis.
  • the CD28 target lies more in the development of antagonist drugs.
  • FR-104 (JNJ-3133) of OSE Immunotherapeutics is a PEGylated monovalent anti-CD28 Fab antibody, which is used for the treatment of rheumatoid arthritis, organ transplant rejection, and postoperative complications.
  • Bristol-Myers Squibb's Lulizumab is also an antagonist antibody against the CD28 domain and is used to treat systemic lupus erythematosus and Sjogren-Larsson syndrome.
  • Other CD28-related drugs, such as oncolytic virus products, gene therapy products, and fusion protein products are also in the clinical research stage for indications such as tumors, transplant complications, and autoimmune diseases.
  • the present invention relates to anti-CD28 antibody and its application. Specifically, the present invention relates to the following:
  • an anti-CD28 antibody or antigen-binding fragment wherein the anti-CD28 antibody or antigen-binding fragment comprises one or more of the following HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 or variants thereof:
  • the sequence of HCDR1 comprises or consists of the sequence shown in SEQ ID NO:10,
  • the sequence of HCDR2 comprises or consists of the sequence shown in SEQ ID NO:11,
  • the sequence of HCDR3 comprises or consists of any one of the sequences shown in SEQ ID NO:12-17,
  • the sequence of LCDR1 comprises the sequence shown in SEQ ID NO:18 or consists of it,
  • the sequence of LCDR2 comprises or consists of the sequence shown in SEQ ID NO:19,
  • the sequence of LCDR3 comprises or consists of the sequence shown in SEQ ID NO:20;
  • the sequence of HCDR1 comprises or consists of the sequence shown in SEQ ID NO:10
  • the sequence of HCDR2 comprises or consists of the sequence shown in SEQ ID NO:11
  • the sequence of HCDR3 comprises SEQ ID NO:
  • the sequence of LCDR1 comprises or consists of the sequence shown in SEQ ID NO:18
  • the sequence of LCDR2 comprises or consists of the sequence shown in SEQ ID NO:19
  • the sequence of LCDR3 comprises The sequence shown in SEQ ID NO:20 or consisting of it;
  • the sequence of HCDR1 comprises or consists of the sequence shown in SEQ ID NO: 10
  • the sequence of HCDR2 comprises or consists of the sequence shown in SEQ ID NO: 11
  • the sequence of HCDR3 comprises Contains the sequence shown in SEQ ID NO:13 or consists of it
  • the sequence of LCDR1 contains the sequence shown in SEQ ID NO:18 or consists of it
  • the sequence of LCDR2 contains the sequence shown in SEQ ID NO:19 or consists of it
  • the sequence of LCDR3 comprises or consists of the sequence shown in SEQ ID NO:20;
  • HCDR1, HCDR2 and HCDR3 contained in the heavy chain variable region shown in SEQ ID NO:3, LCDR1, LCDR2 and LCDR3 contained in the light chain variable region shown in SEQ ID NO:7;
  • the sequence of HCDR1 comprises or consists of the sequence shown in SEQ ID NO:10
  • the sequence of HCDR2 comprises or consists of the sequence shown in SEQ ID NO:11
  • the sequence of HCDR3 comprises SEQ ID NO:
  • the sequence of LCDR1 comprises or consists of the sequence shown in SEQ ID NO:18
  • the sequence of LCDR2 comprises or consists of the sequence shown in SEQ ID NO:19
  • the sequence of LCDR3 comprises The sequence shown in SEQ ID NO:20 or consisting of it;
  • HCDR1, HCDR2 and HCDR3 contained in the heavy chain variable region shown in SEQ ID NO:4, LCDR1, LCDR2 and LCDR3 contained in the light chain variable region shown in SEQ ID NO:7;
  • the sequence of HCDR1 comprises or consists of the sequence shown in SEQ ID NO:10
  • the sequence of HCDR2 comprises or consists of the sequence shown in SEQ ID NO:11
  • the sequence of HCDR3 comprises SEQ ID NO: The sequence shown in 15 or consists of it
  • the sequence of LCDR1 comprises or consists of the sequence shown in SEQ ID NO:18
  • the sequence of LCDR2 comprises or consists of the sequence shown in SEQ ID NO:19
  • the sequence of LCDR3 comprises The sequence shown in SEQ ID NO:20 or consisting of it;
  • HCDR1, HCDR2 and HCDR3 contained in the heavy chain variable region shown in SEQ ID NO:5, LCDR1, LCDR2 and LCDR3 contained in the light chain variable region shown in SEQ ID NO:7;
  • the sequence of HCDR1 comprises or consists of the sequence shown in SEQ ID NO:10
  • the sequence of HCDR2 comprises or consists of the sequence shown in SEQ ID NO:11
  • the sequence of HCDR3 comprises SEQ ID NO:
  • the sequence of LCDR1 comprises or consists of the sequence shown in SEQ ID NO:18
  • the sequence of LCDR2 comprises or consists of the sequence shown in SEQ ID NO:19
  • the sequence of LCDR3 comprises or consisting of the sequence shown in SEQ ID NO: 20; or
  • HCDR1, HCDR2 and HCDR3 contained in the heavy chain variable region shown in SEQ ID NO:6, LCDR1, LCDR2 and LCDR3 contained in the light chain variable region shown in SEQ ID NO:7;
  • the sequence of HCDR1 comprises or consists of the sequence shown in SEQ ID NO:10
  • the sequence of HCDR2 comprises or consists of the sequence shown in SEQ ID NO:11
  • the sequence of HCDR3 comprises SEQ ID NO:
  • the sequence of LCDR1 comprises or consists of the sequence shown in SEQ ID NO:18
  • the sequence of LCDR2 comprises or consists of the sequence shown in SEQ ID NO:19
  • LCDR3 The sequence comprises or consists of the sequence shown in SEQ ID NO:20
  • said variant has 3, 2 or 1 amino acid difference (preferably conservative amino acid substitutions) or at least 80%, 85%, 90%, 91%, 92%, 93%, respectively, from said corresponding CDR sequence, respectively. 94%, 95%, 96%, 97%, 98%, 99% identity and the variants retain binding affinity to CD28.
  • the anti-CD28 antibody or antigen-binding fragment comprises one or more of HCDR1, HCDR2, and HCDR3 described above. In some embodiments, the anti-CD28 antibody or antigen-binding fragment comprises HCDR1, HCDR2, and HCDR3 described above. In some embodiments, the anti-CD28 antibody or antigen-binding fragment further comprises one or more of LCDR1, LCDR2, and LCDR3 described above.
  • the anti-CD28 antibody or antigen-binding fragment comprises one or more of the above-described LCDR1, LCDR2, and LCDR3, it further comprises one of the above-described HCDR1, HCDR2, and HCDR3 or more.
  • the anti-CD28 antibody or antigen-binding fragment comprises the following HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 or variants thereof:
  • the sequence of HCDR1 comprises or consists of the sequence shown in SEQ ID NO:10,
  • the sequence of HCDR2 comprises or consists of the sequence shown in SEQ ID NO:11,
  • the sequence of HCDR3 comprises or consists of any one of the sequences shown in SEQ ID NO:12-17,
  • the sequence of LCDR1 comprises the sequence shown in SEQ ID NO:18 or consists of it,
  • the sequence of LCDR2 comprises or consists of the sequence shown in SEQ ID NO:19,
  • the sequence of LCDR3 comprises or consists of the sequence shown in SEQ ID NO:20.
  • the anti-CD28 antibody or antigen-binding fragment wherein the anti-CD28 antibody or antigen-binding fragment comprises the heavy chain variable region of the sequence shown in SEQ ID NO: 1 or a variant thereof.
  • the anti-CD28 antibody or antigen-binding fragment wherein the anti-CD28 antibody or antigen-binding fragment comprises the light chain variable region of the sequence shown in SEQ ID NO: 7 or a variant thereof.
  • the anti-CD28 antibody or antigen-binding fragment wherein the anti-CD28 antibody or antigen-binding fragment comprises the heavy chain variable region of the sequence shown in SEQ ID NO: 1 or a variant thereof and the sequence shown in SEQ ID NO: 7 The light chain variable regions of the indicated sequences or variants thereof.
  • the variant has 3, 2 or 1 amino acid difference (preferably conservative amino acid substitutions) or at least 80%, 85%, 90%, 91%, 92% difference from the corresponding sequence, respectively. %, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity, and the variants retain binding affinity to CD28.
  • the anti-CD28 antibody or antigen-binding fragment thereof, wherein the anti-CD28 antibody or Antigen-binding fragments comprise the following CDRs or variants thereof:
  • HCDR1, HCDR2 and HCDR3 contained in the heavy chain variable region shown in SEQ ID NO:1, LCDR1, LCDR2 and LCDR3 contained in the light chain variable region shown in SEQ ID NO:7;
  • the sequence of HCDR1 comprises the sequence shown in SEQ ID NO:10 or consists of it
  • the sequence of HCDR2 comprises the sequence shown in SEQ ID NO:11 or consists of it
  • the sequence of HCDR3 comprises the sequence shown in SEQ ID NO:12 or Consisting of it
  • the sequence of LCDR1 comprises or consists of the sequence shown in SEQ ID NO:18
  • the sequence of LCDR2 comprises or consists of the sequence shown in SEQ ID NO:19
  • the sequence of LCDR3 comprises the sequence shown in SEQ ID NO:20 or consisting of the sequence shown;
  • the sequence of HCDR1 comprises the sequence shown in SEQ ID NO:10 or consists of it
  • the sequence of HCDR2 comprises the sequence shown in SEQ ID NO:11 or consists of it
  • the sequence of HCDR3 comprises the sequence shown in SEQ ID NO:13 or Consisting of it
  • the sequence of LCDR1 comprises or consists of the sequence shown in SEQ ID NO:18
  • the sequence of LCDR2 comprises or consists of the sequence shown in SEQ ID NO:19
  • the sequence of LCDR3 comprises the sequence shown in SEQ ID NO:20 or consisting of the sequence shown;
  • the sequence of HCDR1 comprises the sequence shown in SEQ ID NO:10 or consists of it
  • the sequence of HCDR2 comprises the sequence shown in SEQ ID NO:11 or consists of it
  • the sequence of HCDR3 comprises the sequence shown in SEQ ID NO:14 or Consisting of it
  • the sequence of LCDR1 comprises or consists of the sequence shown in SEQ ID NO:18
  • the sequence of LCDR2 comprises or consists of the sequence shown in SEQ ID NO:19
  • the sequence of LCDR3 comprises the sequence shown in SEQ ID NO:20 or consisting of the sequence shown;
  • HCDR1, HCDR2 and HCDR3 contained in the heavy chain variable region shown in SEQ ID NO:4, and LCDR1, LCDR2 and LCDR3 contained in the light chain variable region shown in SEQ ID NO:7;
  • the sequence of HCDR1 comprises the sequence shown in SEQ ID NO:10 or consists of it
  • the sequence of HCDR2 comprises the sequence shown in SEQ ID NO:11 or consists of it
  • the sequence of HCDR3 comprises the sequence shown in SEQ ID NO:15 or Consisting of it
  • the sequence of LCDR1 comprises or consists of the sequence shown in SEQ ID NO:18
  • the sequence of LCDR2 comprises or consists of the sequence shown in SEQ ID NO:19
  • the sequence of LCDR3 comprises the sequence shown in SEQ ID NO:20 or consisting of the sequence shown;
  • HCDR1, HCDR2 and HCDR3 contained in the heavy chain variable region shown in SEQ ID NO: 5, SEQ ID LCDR1, LCDR2 and LCDR3 contained in the light chain variable region shown in NO:7;
  • the sequence of HCDR1 comprises the sequence shown in SEQ ID NO:10 or consists of it
  • the sequence of HCDR2 comprises the sequence shown in SEQ ID NO:11 or consists of it
  • the sequence of HCDR3 comprises the sequence shown in SEQ ID NO:16 or Consisting of it
  • the sequence of LCDR1 comprises or consists of the sequence shown in SEQ ID NO:18
  • the sequence of LCDR2 comprises or consists of the sequence shown in SEQ ID NO:19
  • the sequence of LCDR3 comprises the sequence shown in SEQ ID NO:20 or consisting of the sequence shown; or
  • HCDR1, HCDR2 and HCDR3 contained in the heavy chain variable region shown in SEQ ID NO:6, LCDR1, LCDR2 and LCDR3 contained in the light chain variable region shown in SEQ ID NO:7;
  • the sequence of HCDR1 comprises the sequence shown in SEQ ID NO:10 or consists of it
  • the sequence of HCDR2 comprises the sequence shown in SEQ ID NO:11 or consists of it
  • the sequence of HCDR3 comprises the sequence shown in SEQ ID NO:17 or Consisting of it
  • the sequence of LCDR1 comprises or consists of the sequence shown in SEQ ID NO:18
  • the sequence of LCDR2 comprises or consists of the sequence shown in SEQ ID NO:19
  • the sequence of LCDR3 comprises the sequence shown in SEQ ID NO:20 or consisting of the sequence shown
  • said variant has 3, 2 or 1 amino acid difference (preferably conservative amino acid substitutions) or at least 80%, 85%, 90%, 91%, 92%, 93%, respectively, from said corresponding CDR sequence, respectively. 94%, 95%, 96%, 97%, 98%, 99% identity and the variants retain binding affinity to CD28.
  • the CDRs are according to the Kabat numbering system.
  • anti-CD28 antibody or antigen-binding fragment according to item 1, wherein the anti-CD28 antibody comprises a sequence shown in any one of SEQ ID NO: 1-6 or a heavy chain variable region consisting of it or a variant thereof.
  • the antibody comprises a heavy chain variable region and a light chain variable region selected from the group consisting of:
  • a heavy chain variable region comprising the sequence shown in SEQ ID NO: 1 or consisting of it, and a light chain variable region comprising the sequence shown in SEQ ID NO: 7 or consisting of it;
  • a heavy chain variable region comprising the sequence shown in SEQ ID NO: 2 or consisting of it, and a light chain variable region comprising the sequence shown in SEQ ID NO: 7 or consisting of it;
  • a heavy chain variable region comprising the sequence shown in SEQ ID NO: 3 or consisting of it, and a light chain variable region comprising the sequence shown in SEQ ID NO: 7 or consisting of it;
  • a heavy chain variable region comprising the sequence shown in SEQ ID NO: 4 or consisting of it, and a light chain variable region comprising the sequence shown in SEQ ID NO: 7 or consisting of it;
  • a heavy chain variable region comprising or consisting of the sequence shown in SEQ ID NO:5, a light chain variable region comprising or consisting of the sequence shown in SEQ ID NO:7; or
  • a heavy chain variable region comprising the sequence shown in SEQ ID NO: 6 or consisting of it, and a light chain variable region comprising the sequence shown in SEQ ID NO: 7 or consisting of it.
  • the variant has 3, 2 or 1 amino acid difference (preferably conservative amino acid substitutions) or at least 80%, 85%, 90%, 91%, respectively, from the corresponding variable region, respectively. 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity and the variants retain binding affinity to CD28.
  • the anti-CD28 antibody or antigen-binding fragment further comprises a light chain constant region and/or a heavy chain constant region.
  • the light chain constant region of the antibody or antigen-binding fragment is a kappa or lambda chain constant region.
  • the antibody or antigen-binding fragment is of an isotype of IgG, IgM, IgA, IgE, or IgD.
  • the antibody or antigen-binding fragment is IgGl, IgG2, IgG3, or IgG4.
  • the antibody or antigen-binding fragment is an IgG1 antibody.
  • the light chain constant region comprises or consists of the sequence shown in SEQ ID NO:8, and the heavy chain constant region comprises or consists of the sequence shown in SEQ ID NO:9.
  • the antibody or antigen-binding fragment is a monoclonal antibody.
  • the antibody or antigen-binding fragment is a humanized antibody.
  • the anti-CD28 antibody or antigen-binding fragment thereof according to item 1 or 2, wherein the antigen-binding fragment is selected from Fab, Fab', F(ab') 2 , F(ab) 2 , Fd, Fv, Fab/ c, scFv, scFv multimer, disulfide bond-stabilized Fv (dsFv), (dsFv) 2 , bispecific dsFv (dsFv-dsFv'), diabody, disulfide-stabilized diabody (ds-Diabody), a multispecific antibody formed from a portion of an antibody comprising one or more CDRs, a single domain antibody (sdAb), a nanobody, a domain antibody (dAb) or a bivalent domain antibody.
  • the antigen-binding fragment is selected from Fab, Fab', F(ab') 2 , F(ab) 2 , Fd, Fv, Fab/ c, scFv,
  • polypeptide selected from the group consisting of:
  • Polypeptides comprising the sequences shown in SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:12 or variants thereof, wherein the polypeptides are part of an anti-CD28 antibody specifically binding to CD28, the Said antibody also comprises the sequences shown in SEQ ID NO:18, SEQ ID NO:19 and SEQ ID NO:20;
  • polypeptide comprising the sequence shown in SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20 or variants thereof, wherein the polypeptide is part of an anti-CD28 antibody specifically binding to CD28, the Said antibody also comprises the sequences shown in SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:12;
  • polypeptide comprising the sequences shown in SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 13 or variants thereof, wherein the polypeptide is part of an anti-CD28 antibody specifically binding to CD28, the The antibodies also contain the sequences shown in SEQ ID NO:18, SEQ ID NO:19 and SEQ ID NO:20;
  • a polypeptide comprising the sequence shown in SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20 or a variant thereof, wherein the polypeptide is a part of an anti-CD28 antibody that specifically binds CD28, specifically sexually binding to CD28, the antibody also comprises the sequences shown in SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:13;
  • a polypeptide comprising the sequences shown in SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 14 or variants thereof, wherein the polypeptide is a part of an anti-CD28 antibody that specifically binds CD28, specifically sexually binding to CD28, the antibody also comprises the sequences shown in SEQ ID NO:18, SEQ ID NO:19 and SEQ ID NO:20;
  • a polypeptide comprising the sequence shown in SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20 or variants thereof, wherein the polypeptide is a part of an anti-CD28 antibody that specifically binds CD28, specifically sexually binding to CD28, the antibody should also comprise the sequences shown in SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:14;
  • a polypeptide comprising the sequences shown in SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 15 or variants thereof, wherein the polypeptide is a part of an anti-CD28 antibody that specifically binds CD28, specifically sexually binding to CD28, the antibody should also comprise the sequences shown in SEQ ID NO:18, SEQ ID NO:19 and SEQ ID NO:20;
  • Polypeptides comprising the sequences shown in SEQ ID NO:18, SEQ ID NO:19 and SEQ ID NO:20 or variants thereof, wherein the polypeptides are part of an anti-CD28 antibody that specifically binds CD28, specifically sexually binding to CD28, the antibody should also comprise the sequences shown in SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:15;
  • a polypeptide comprising the sequences shown in SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 16 or variants thereof, wherein the polypeptide is a part of an anti-CD28 antibody that specifically binds CD28, specifically sexually binding to CD28, the antibody should also comprise the sequences shown in SEQ ID NO:18, SEQ ID NO:19 and SEQ ID NO:20;
  • a polypeptide comprising the sequence shown in SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20 or a variant thereof, wherein the polypeptide is a part of an anti-CD28 antibody that specifically binds CD28, specifically sexually binding to CD28, the antibody should also comprise the sequences shown in SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:16;
  • a polypeptide comprising sequences shown in SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 17 or variants thereof, wherein the polypeptide is a part of an anti-CD28 antibody that specifically binds to CD28, so Said antibody should also comprise the sequence shown in SEQ ID NO:18, SEQ ID NO:19 and SEQ ID NO:20;
  • a polypeptide comprising the sequence shown in SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20 or a variant thereof, wherein the polypeptide is a part of an anti-CD28 antibody that specifically binds CD28, specifically sexually binding to CD28, the antibody should also comprise the sequences shown in SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:17;
  • a polypeptide comprising the sequence shown in SEQ ID NO: 1 or a variant thereof, wherein the polypeptide specifically binds CD28 as part of an anti-CD28 antibody that specifically binds CD28, and the antibody further comprises SEQ ID NO :7 the sequence shown;
  • a polypeptide comprising the sequence shown in SEQ ID NO: 7 or a variant thereof, wherein the polypeptide specifically binds CD28 as part of an anti-CD28 antibody that specifically binds CD28, and the antibody further comprises SEQ ID NO : the sequence shown in 1;
  • a polypeptide comprising the sequence shown in SEQ ID NO: 2 or a variant thereof, wherein the polypeptide specifically binds to CD28 as part of an anti-CD28 antibody that specifically binds to CD28, and the antibody further comprises SEQ ID NO : the sequence shown in 7;
  • a polypeptide comprising the sequence shown in SEQ ID NO: 7 or a variant thereof, wherein the polypeptide specifically binds to CD28 as part of an anti-CD28 antibody specifically binding to CD28, and the antibody further comprises SEQ ID NO : the sequence shown in 2;
  • a polypeptide comprising the sequence shown in SEQ ID NO: 3 or a variant thereof, wherein the polypeptide specifically binds CD28 as part of an anti-CD28 antibody specifically binding to CD28, and the antibody further comprises SEQ ID NO : the sequence shown in 7;
  • a polypeptide comprising the sequence shown in SEQ ID NO: 7 or a variant thereof, wherein the polypeptide specifically binds CD28 as part of an anti-CD28 antibody specifically binding to CD28, and the antibody further comprises SEQ ID NO : the sequence shown in 3;
  • a polypeptide comprising the sequence shown in SEQ ID NO: 4 or a variant thereof, wherein the polypeptide is a part of an anti-CD28 antibody that specifically binds to CD28, and the antibody further comprises the sequence shown in SEQ ID NO: 7 sequence;
  • a polypeptide comprising the sequence shown in SEQ ID NO: 7 or a variant thereof, wherein the polypeptide specifically binds CD28 as part of an anti-CD28 antibody specifically binding to CD28, and the antibody further comprises SEQ ID NO : the sequence shown in 4;
  • a polypeptide comprising the sequence shown in SEQ ID NO: 5 or a variant thereof, wherein the polypeptide specifically binds CD28 as part of an anti-CD28 antibody specifically binding to CD28, and the antibody further comprises SEQ ID NO : the sequence shown in 7;
  • a polypeptide comprising the sequence shown in SEQ ID NO: 7 or a variant thereof, wherein the polypeptide specifically binds CD28 as part of an anti-CD28 antibody specifically binding to CD28, and the antibody further comprises SEQ ID NO : the sequence shown in 5;
  • a polypeptide comprising the sequence shown in SEQ ID NO: 6 or a variant thereof, wherein the polypeptide specifically binds CD28 as part of an anti-CD28 antibody that specifically binds CD28, and the antibody further comprises SEQ ID NO : the sequence shown in 7; or
  • a polypeptide comprising the sequence shown in SEQ ID NO: 7 or a variant thereof, wherein the polypeptide, as a part of an anti-CD28 antibody, specifically binds to CD28, and the antibody further comprises the sequence shown in SEQ ID NO: 6 sequence;
  • the variant sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90% of the corresponding sequence shown in the sequence number, Preferably at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity and retains binding affinity to CD28, or the corresponding sequence as indicated by the sequence number Than a sequence having one or more (preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) and retaining binding affinity to CD28.
  • polypeptide that is part of an anti-CD28 antibody is selected from the group consisting of:
  • polypeptide comprising the sequences shown in SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:12 or variants thereof;
  • polypeptide comprising the sequences shown in SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:16 or variants thereof;
  • a polypeptide comprising the sequences shown in SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 17 or variants thereof.
  • the anti-CD28 antibody further comprises the sequences shown in SEQ ID NO: 18, SEQ ID NO: 19 and SEQ ID NO: 20 or variants thereof.
  • the polypeptide that is part of an anti-CD28 antibody that specifically binds CD28 comprises the sequences set forth in SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20, or variants thereof.
  • the anti-CD28 antibody specifically binding to CD28 further comprises SEQ ID NO: 10, SEQ ID NO: 11 and a sequence selected from SEQ ID NO: 12-17 or a variant thereof.
  • polypeptide that is part of an anti-CD28 antibody is selected from the group consisting of:
  • polypeptide comprising the sequence shown in SEQ ID NO: 1 or a variant thereof;
  • polypeptide it comprises the sequence shown in SEQ ID NO:4 or its variant
  • a polypeptide comprising the sequence shown in SEQ ID NO: 6 or a variant thereof.
  • the anti-CD28 antibody further comprises the sequence shown in SEQ ID NO: 7 or a variant thereof.
  • the polypeptide that is part of an anti-CD28 antibody that specifically binds CD28 comprises the sequence shown in SEQ ID NO: 7 or a variant thereof.
  • the anti-CD28 antibody further comprises a sequence selected from SEQ ID NO: 1-6 or variants thereof.
  • the variant sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% %, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity and retain binding affinity to CD28, or as indicated by the sequence number One or more (such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) conservative amino acid mutations (preferably substitutions, insertions or deletions) compared with the corresponding sequence and retain the binding affinity with CD28 sequence.
  • the anti-CD28 antibody or antigen-binding fragment is an isolated antibody or antigen-binding fragment or polypeptide.
  • nucleic acid molecule encoding the anti-CD28 antibody or antigen-binding fragment thereof of any one of items 1-3, or the polypeptide of item 4;
  • a host cell comprising a nucleic acid molecule encoding the anti-CD28 antibody or antigen-binding fragment thereof according to any one of items 1-3, or the polypeptide according to item 4.
  • the host cell is selected from CHO cells, HEK cells (such as HEK293F cells), BHK cells, Cos1 cells, Cos7 cells, CV1 cells or murine L cells.
  • the present invention also provides a method for preparing the anti-CD28 antibody or antigen-binding fragment of the present invention, comprising: culturing the above-mentioned host cells to express the antibody or antigen-binding fragment, and isolating the antibody or antigen-binding fragment thereof.
  • Conjugates comprising the anti-CD28 antibody or antigen-binding fragment thereof and a coupling portion according to any one of items 1-3, wherein the coupling portion is a purification tag (such as a His tag), a detectable Markers, drugs, toxins, cytokines, enzymes, or combinations thereof.
  • a purification tag such as a His tag
  • detectable Markers drugs, toxins, cytokines, enzymes, or combinations thereof.
  • the coupling moiety is a radioisotope, a fluorescent substance, a chemiluminescent substance, an organic Chromogenic substances, chemotherapeutic agents, biotoxins, polyethylene glycols, or enzymes.
  • kits comprising the anti-CD28 antibody or antigen-binding fragment thereof according to any one of items 1-3, and the conjugate according to item 6.
  • the kit also includes a second antibody that specifically recognizes the anti-CD28 antibody; optionally, the second antibody also includes a detectable label, such as a radioisotope, a fluorescent substance, a chemical Luminescent substances, colored substances or enzymes.
  • a detectable label such as a radioisotope, a fluorescent substance, a chemical Luminescent substances, colored substances or enzymes.
  • the kit is used to detect the presence or level of CD28 in a sample.
  • a pharmaceutical composition comprising the anti-CD28 antibody or antigen-binding fragment thereof according to any one of items 1-3, and the conjugate according to item 6.
  • the pharmaceutical composition further includes pharmaceutically acceptable carriers and/or excipients.
  • the pharmaceutical composition is in a form suitable for administration by subcutaneous injection, intradermal injection, intravenous injection, intramuscular injection, or intralesional injection.
  • the anti-CD28 antibody or its antigen-binding fragment described in any one of items 1-3, and the conjugate described in item 6 are used in the treatment and/or prevention of diseases or in the preparation of medicaments for treatment and/or prevention of diseases use.
  • a kit comprising (1) the anti-CD28 antibody or antigen-binding fragment thereof according to any one of items 1-3, the conjugate described in item 6, and (2) antibodies against other antigens or their antigens A binding fragment, and/or a cytotoxic agent, and optionally, instructions for use.
  • a method for treating or preventing a disease comprising administering a therapeutically effective amount of the anti-CD28 antibody or antigen-binding fragment thereof according to any one of items 1-3, or the conjugate described in item 6, to a subject.
  • the disease is a tumor, an autoimmune disease, or an inflammatory disease, such as a disease selected from the group consisting of Merkel cell carcinoma, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, Organ transplant rejection, postoperative complications, Sjogren-Larsson syndrome.
  • a disease selected from the group consisting of Merkel cell carcinoma, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, Organ transplant rejection, postoperative complications, Sjogren-Larsson syndrome.
  • Antibody refers to a polypeptide or polypeptide complex that specifically recognizes and binds an antigen. Antibodies can be whole antibodies and any antigen-binding fragments thereof or single chains thereof. The term “antibody” therefore includes molecules containing Any protein or peptide that is at least part of a biologically active immunoglobulin molecule. Examples of antibodies include, but are not limited to, heavy chains, light chains, complementarity determining regions (CDRs) of ligand binding portions thereof, heavy chain variable regions (VH), light chain variable regions (VL), heavy chain constant regions (CH), light chain constant region (CL), framework region (FR) or any part thereof or at least a part of a binding protein. The CDR regions include the CDR regions of the light chain (LCDR1-3) and the CDR regions of the heavy chain (HCDR1-3).
  • the CDR regions of an antibody are responsible for the binding specificity of the antibody to an antigen.
  • the known antibody heavy and light chain variable region sequences there are currently several methods for determining antibody CDR regions, including the Kabat, IMGT, Chothia, and AbM numbering systems.
  • each application of the definition to the CDRs of an antibody or variant thereof will be within the scope of the terms as defined and used herein.
  • the variable region amino acid sequence of the antibody one of skill in the art can generally determine which residues are contained in a particular CDR, without reliance on any experimental data outside of the sequence itself.
  • polypeptide is intended to encompass the singular as well as the plural “polypeptides” and refers to a molecule composed of amino acid monomers linked linearly by amide bonds (also known as peptide bonds).
  • polypeptide refers to any chain or chains of two or more amino acids, and does not refer to a specific length of the product.
  • peptide, dipeptide, tripeptide, oligopeptide, "protein”, “amino acid chain” or any other term used to refer to a chain of two or more amino acids is included in the definition of "polypeptide", and “polypeptide” may be defined by in place of, or interchangeably with, any of the above terms.
  • polypeptide is also intended to refer to the products of post-expression modifications of the polypeptide, including but not limited to glycosylation, acetylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, or non-natural Amino acid modifications that occur.
  • a polypeptide may be derived from a natural biological source or produced by recombinant techniques, but it need not be translated from a specified nucleic acid sequence, it may be produced by any means including chemical synthesis.
  • amino acid refers to an organic compound containing both amino and carboxyl groups, such as an ⁇ -amino acid, which can be encoded by a nucleic acid directly or in the form of a precursor.
  • a single amino acid is encoded by a nucleic acid consisting of three nucleotides (so-called codons or base triplets). Each amino acid is encoded by at least one codon. The fact that the same amino acid is encoded by different codons is called “degeneracy of the genetic code”.
  • Amino acids include natural amino acids and unnatural amino acids.
  • Natural amino acids include alanine (three-letter code: ala, one-letter code: A), arginine (arg, R), asparagine (asn, N), aspartic acid (asp, D), cysteine amino acid (cys, C), glutamine (gln, Q), glutamic acid (glu, E), glycine (gly, G), histidine (his, H), isoleucine (ile, I ), leucine (leu, L), lysine (lys, K), methionine (met, M), phenylalanine (phe, F), proline (pro, P), serine (ser, S), threonine (thr, T), tryptophan (trp, W), tyrosine (tyr, Y) and valine (val, V).
  • substitutions with amino acids with similar or similar properties usually do not change the function of the protein.
  • adding one or several amino acids at the C-terminus and/or N-terminus usually does not change the function of the protein.
  • the percentage "sequence homology" also referred to herein as "amino acid identity"
  • amino acid sequence having the greatest number of amino acid residues is considered the "first" amino acid sequence for the purposes of determining the percentage "sequence identity" between two amino acid sequences according to the calculation method set out above, And another amino acid sequence is considered a "second" amino acid sequence.
  • a “conservative amino acid substitution” is one in which an amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues with similar side chains have been defined in the art and include basic side chains (e.g. lysine, arginine, histidine), acidic side chains (e.g.
  • aspartic acid glutamic acid
  • uncharged polar side chains e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine
  • nonpolar side chains e.g., alanine , valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan
  • side chains of ⁇ -branches for example, threonine, valine, isoleucine amino acids
  • aromatic side chains e.g. tyrosine, phenylalanine, tryptophan, histidine
  • nonessential amino acid residues of an immunoglobulin polypeptide are preferably replaced with other amino acid residues from the same side chain family.
  • a string of amino acids may be replaced by a structurally similar string of amino acids that differ in sequence and/or composition of side chain families.
  • Non-limiting examples of conservative amino acid substitutions are provided in the table below, where a similarity score of 0 or higher indicates a conservative substitution between these two amino acids.
  • the conservative substitution is preferably a substitution wherein one amino acid residue within the following groups (a)-(e) is replaced by another amino acid residue within the same group: (a) small Aliphatic, non-polar or weakly polar residues: Ala, Ser, Thr, Pro and Gly; (b) polar, negatively charged residues and their (uncharged) amides: Asp, Asn, Glu and Gln; (c) polar, positively charged residues: His, Arg, and Lys; (d) large aliphatic, nonpolar residues: Met, Leu, Ile, Val, and Cys; and (e ) Aromatic residues: Phe, Tyr and Trp.
  • Particularly preferred conservative substitutions are as follows: Ala by Gly or by Ser; Arg by Lys; Asn by Gln or His; Asp by Glu; Cys by Ser; Gln by Asn; Glu by Asp; Gly replaced by Ala or replaced by Pro; His replaced by Asn or replaced by Gln; Ile replaced by Leu or replaced by Val; Leu replaced by Ile or replaced by Val; Lys replaced by Arg, replaced by Gln or replaced by Glu; Met Substitution of Leu, substitution of Tyr or substitution of Ile; substitution of Phe by Met, substitution of Leu or substitution of Tyr; substitution of Ser by Thr; substitution of Thr by Ser; substitution of Trp by Tyr; substitution of Tyr by Trp; and/or substitution of Phe To Val, to Ile or to Leu.
  • antibody fragment or "antigen-binding fragment” includes, but is not limited to, F(ab') 2 , F(ab) 2 , Fab', Fab, Fv, Fd, Fab/c, complementarity determining region (CDR) fragments, Single-chain Fvs (scFv), disulfide-stabilized Fv fragment (dsFv), (dsFv) 2 , bispecific dsFv (dsFv-dsFv'), diabody, disulfide-stabilized Diabodies (ds-Diabody), scFv multimers (such as scFv dimers, scFv trimers), multispecific antibodies formed from a part of antibodies containing one or more CDRs, nanobodies, single domains antibody (sdAb), domain antibody (dAb), bivalent domain antibody, or any other antibody that binds to an antigen but does not contain a complete antibody structure body fragment.
  • CDR complementarity determining region
  • an antigen-binding fragment includes any polypeptide or polypeptide complex capable of binding to the same antigen as the parent antibody or parent antibody fragment.
  • dsFv disulfide stabilized Fv Fragments
  • Progress in Biochemistry and Biophysics, 1998, 25(6):525-526 introduced the structure of dsFv.
  • Holt et al. "Domain antibodies: proteins for therapy”
  • Trends in Biotechnology (2003): Vol.21, No.11:484-490 reviewed antigen-binding fragments called "domain antibodies” or dAbs, which contain only the VH of the antibody or VL domains and thus smaller than eg Fab and scFv.
  • dAbs are the smallest known antigen-binding fragments of antibodies, ranging from 11 kDa to 15 kDa.
  • the Fab/c fragment contains the Fc and Fab determinants, wherein the "Fc" region contains two heavy chain fragments comprising the CH2 and CH3 domains of the antibody. The two heavy chain fragments are held together by two or more disulfide bonds and by hydrophobic interactions of the CH3 domain.
  • the term “antibody fragment” includes aptamers, aptamer aptamer aptamer aptamer aptamer aptamer aptamer aptamer aptamer aptamer aptamer aptamer aptamer aptamer aptamer aptamer aptamer aptamer aptamer aptamer aptamer aptamer aptamer aptamer aptamer aptamer aptamer aptamer aptamer aptamer aptamer apts and
  • the antibodies, antigen-binding fragments disclosed herein include derivatives that are modified, that is, modified by covalent linkage of any type of molecule to the antibody or antigen-binding fragment, wherein the covalent linkage does not prevent the antibody or antigen-binding fragment from binding to the epitope combined.
  • Antibodies or antigen-binding fragments can be glycosylated, acetylated, pegylated, phosphorylated, amidated, derivatized by known protecting/blocking groups, proteolytically cleaved, linked to cellular ligands or other proteins, etc. wait. Any of the numerous chemical modifications can be performed by existing techniques, including but not limited to specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, etc.
  • an antibody or antigen-binding fragment can be conjugated to a therapeutic agent, prodrug, peptide, protein, enzyme, virus, lipid, biological response modifier, pharmaceutical agent, or PEG.
  • the CD28 antigen can be from mammals, such as humans, rats, mice, and monkeys.
  • Antibodies described herein can be derived from any animal, including birds and mammals.
  • the antibody is of human, murine, donkey, rabbit, goat, camel, llama, horse or chicken origin.
  • isolated used in the present invention with respect to cells, nucleic acids, polypeptides, antibodies, etc., for example, "isolated" DNA, RNA, polypeptides, antibodies refers to the isolated components of the cell's natural environment, such as DNA or RNA. One or more of the isolated molecules.
  • isolated as used herein also refers to a nucleic acid or peptide that is substantially free of cellular material, viral material, or cell culture medium when produced by recombinant DNA techniques, or chemical precursors or other chemicals when chemically synthesized.
  • isolated nucleic acid is intended to include fragments of nucleic acid that do not occur in nature, and do not exist in nature.
  • Isolated is also used to refer to cells or polypeptides that are separated from other cellular proteins or tissues. Isolated polypeptide is intended to include purified and recombinant polypeptides. Isolated polypeptides, antibodies, etc. will usually be prepared by at least one purification step. In some embodiments, the purity of the isolated nucleic acid, polypeptide, antibody, etc. is at least about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 99%, or some of these values The range between any two values of , including the endpoints, or any value therein.
  • encoding when applied to a polynucleotide refers to a polynucleotide which is said to "encode” a polypeptide which, in its native state or when manipulated by methods well known to those skilled in the art, is transcribed and/or Or translation may result in the polypeptide and/or fragments thereof.
  • Treatment means therapeutic treatment and prophylactic or preventive measures, the purpose of which is to prevent, slow down, ameliorate or stop an undesirable physiological change or disorder, such as the progression of a disease, including but not limited to the following whether detectable or undetectable Relief of symptoms, reduction of disease extent, stabilization of disease state (i.e. not worsening), delay or slowing of disease progression, amelioration, remission, alleviation or disappearance of disease state (whether partial or total), prolongation and Expected survival without treatment, etc.
  • Those in need of treatment include patients already with a condition or disorder, susceptible to the condition or disorder, or in need of prevention of the condition or disorder, who can or are expected to benefit from administration of an antibody, antigen-binding fragment or pharmaceutical composition disclosed herein For patients who would benefit from testing, diagnostic procedures and/or treatment.
  • the effective dose and regimen for treating a particular patient will depend on various factors, including the particular antibody, antigen-binding fragment or derivative used, the patient's age and weight, general health, sex and diet, and the time of administration, Frequency of excretion, drug combination, and severity of the particular condition being treated. These factors are in the judgment of the medical caregiver, who is within the purview of those of ordinary skill in the art.
  • the dosage used can be determined by principles of pharmacology and pharmacokinetics well known in the art.
  • the antibody of the present invention is administered to a patient at a dose of 0.01 mg/kg to 100 mg/kg of the patient's body weight each time. In some embodiments, administration is weekly, or monthly.
  • “Pharmaceutically acceptable” means a material listed in a Pharmacopoeia for use in medicine for animals, especially for humans.
  • a “pharmaceutically acceptable carrier and/or excipient” will generally be any type of non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary.
  • carrier refers to a diluent, adjuvant, excipient or carrier with which the active ingredient can be administered to a patient.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, Propylene, Ethylene Glycol, Water, Ethanol wait.
  • the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents such as acetates, citrates or phosphates.
  • Antibacterial agents such as benzyl alcohol or methylparaben, antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as ethylenediaminetetraacetic acid, and tonicity adjusting agents such as sodium chloride or dextrose are also contemplated.
  • These compositions may take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained release formulations and the like.
  • the composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
  • Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like.
  • compositions will contain a clinically effective dose of the antibody or antigen-binding fragment, preferably in purified form, together with suitable amounts of carriers and/or excipients to provide a form suitable for administration to the patient.
  • the formulation should be suitable for the mode of administration.
  • the parent formulation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • the composition is formulated into a pharmaceutical composition suitable for intravenous injection to human body according to conventional procedures.
  • Compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
  • the composition may also contain a solubilizer and a local anesthetic such as lidocaine to relieve pain at the injection site.
  • the active ingredients are presented alone or in combination in unit dosage form, eg, as a dry lyophilized powder or water-free concentrate, in a hermetically sealed container such as an ampoule or sachet indicating the quantity of active agent.
  • the composition may be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampoule of sterile water or saline for injection can be used so that the active ingredient can be mixed before administration.
  • Antibodies or antigen-binding fragments of the invention include neutral or salt forms.
  • Pharmaceutically acceptable salts include, but are not limited to, those formed with anions derived from, for example, hydrochloric, phosphoric, acetic, oxalic, tartaric acids, and with anions derived from, for example, sodium, potassium, ammonium, calcium, ferric hydroxide, isopropylamine, triethylamine, Salts formed by cations of amines, 2-ethylaminoethanol, histidine, procaine, etc.
  • the antibodies described herein can be neutral, ie, have substantially no net charge, eg, the antibody is electrically neutral when the pH of the antibody-containing composition is the isoelectric point of the antibody.
  • the antibodies described herein may exist in a positive ion form, eg, when the pH is below the isoelectric point, the antibody molecule exhibits an overall positive charge.
  • the antibodies described herein may exist in the form of negative ions, such as when the pH is above the isoelectric point, the antibody molecule as a whole exhibits a negative charge.
  • EC 50 means the half-maximal effect concentration (concentration for 50% of maximal effect) refers to the concentration that can cause 50% of the maximal effect.
  • Figure 1 Binding curves of different anti-CD28 antibodies to human CD28.
  • Figure 5 Test of the ability of anti-CD28 antibody to activate T cells with the participation of anti-CD3 antibody, in which ⁇ CD3 in the figure is mouse anti-human CD3 antibody.
  • Antibodies can be prepared using conventional recombinant DNA techniques. Antibody-producing vectors, cell lines, and the like can be selected, constructed, and cultured using techniques known to those skilled in the art. These techniques are described in various laboratory manuals and major publications, such as Recombinant DNA Technology for Production of Protein Therapeutics in Cultured Mammalian Cells, D.L. hacker, F.M. Wurm, in Reference Module in Life Sciences, 2017, which in its entirety includes The supplementary content is incorporated by reference in its entirety.
  • the DNA encoding the antibody can be designed and synthesized according to the amino acid sequence of the antibody described herein in a conventional manner, placed into an expression vector, and then transfected into a host cell, and cultured in a medium to produce the transfected host cell.
  • Monoclonal antibodies Monoclonal antibodies.
  • an antibody expression vector includes at least one promoter element, an antibody coding sequence, a transcription termination signal, and a polyA tail. Other elements include enhancers, Kozak sequences, and donor and acceptor sites for RNA splicing flanking the inserted sequence.
  • High-efficiency transcription can be obtained through the early and late promoters of SV40, long terminal repeats from retroviruses such as RSV, HTLV1, HIVI, and early promoters of cytomegalovirus, and other cellular promoters such as muscle Kinetin promoter.
  • Suitable expression vectors may include pIRES1neo, pRetro-Off, pRetro-On, PLXSN, or Plncx, pcDNA3.1(+/-), pcDNA/Zeo(+/-), pcDNA3.1/Hygro(+/-), PSVL, PMSG, pRSVcat, pSV2dhfr, pBC12MI and pCS2 etc.
  • Commonly used mammalian host cells include HEK293 cells, Cos1 cells, Cos7 cells, CV1 cells, mouse L cells, and CHO cells.
  • the inserted gene fragment needs to contain selection markers, common selection markers include dihydrofolate reductase, glutamine synthetase, neomycin resistance, hygromycin resistance and other selection genes, so as to facilitate transfection Screening of successful cell isolation.
  • selection markers include dihydrofolate reductase, glutamine synthetase, neomycin resistance, hygromycin resistance and other selection genes, so as to facilitate transfection Screening of successful cell isolation.
  • the obtained antibody can be separated or purified by conventional technical means, such as protein A-sepharose, ion exchange chromatography, hydroxylapatite chromatography, gel electrophoresis, dialysis or affinity chromatography and the like.
  • the nucleic acid encoding the variable region of the antibody described in Table 1 is transferred into an expression vector containing the human Ig kappa light chain constant region framework (SEQ ID NO: 8) and the IgG1 heavy chain constant region framework (SEQ ID NO: 9) , and expressed antibodies by transient transfection of HEK293F host cells.
  • Human Ig kappa light chain constant region sequence (SEQ ID NO: 8):
  • Human IgG1 heavy chain constant region sequence (SEQ ID NO: 9):
  • the initial concentration of anti-CD28 antibody was 10 ⁇ g/mL, diluted 3 times, and the secondary antibody was HRP-coupled goat anti-human IgG (Jackson, catalog number: 109-035-098). ELISA tests showed that these 6 antibodies were different from human CD28 degree of integration (see Figure 1 and Table 2).
  • the human CD28 protein was coupled with biotin, and the affinity of different concentrations of anti-CD28 monoclonal antibodies to the human CD28 antigen was detected on a Fortebio instrument using an SA sensor.
  • the affinity values of the six antibodies are shown in Table 3.
  • CD28 monoclonal antibody Dilute the CD28 monoclonal antibody with PBS as the diluent to a final concentration of 1 ⁇ g/mL, add 100 ⁇ l per well to the ELISA plate, and coat overnight at 2-8°C. The next day, discard the coating solution and block the ELISA plate with 5% skimmed milk, 250 ⁇ l per well, and incubate in a 37°C incubator for 2 hours. After washing the ELISA plate twice with PBST buffer, add rat CD28 protein (Sino Biological, Cat. The concentration is 3 ⁇ g/mL, 3-fold dilution, 100 ⁇ l per well, and then incubated at 37°C for 1 hour.
  • the genetically engineered Jurkat T cell system was used to detect the ability of CD28 monoclonal antibody to activate T cells.
  • This cellular system consists of a luciferase reporter gene driven by expression of the NFAT-responsive element (NFAT-RE) or NF- ⁇ b-responsive element or IL-2 promoter.
  • NFAT-RE NFAT-responsive element
  • IL-2 NF- ⁇ b-responsive element
  • IL-2 NFAT-responsive element
  • RPMI 1640 medium purchased from Gibco
  • FBS fetal bovine serum
  • 200,000 IL-2-Jurkat cells/well were added to the corresponding wells of the 96-well plate, 50 ⁇ L per well.
  • the final concentration of CD28 monoclonal antibody was 1 ⁇ g/mL
  • the final concentration of positive control mouse anti-human CD28 antibody (BD Biosciences, CAT#555725) and negative control human IgG1 isotype control was also 1 ⁇ g/mL.
  • the final concentration of anti-human IgG Fc specific (Sigma, CAT#I2136-BULK) was 2.5 ⁇ g/mL.
  • the amount of diluted antibody in the corresponding well was 50 ⁇ L, and the final volume of each well was 100 ⁇ L.
  • After adding the samples incubate in a 37°C CO 2 cell incubator for 6 hours, add 50 ⁇ L of luciferase substrate reaction solution, and then shake in a microplate reader for 10 seconds to detect relative light units (RLU).
  • RLU relative light units
  • CD28 monoclonal antibody alone in solution state will not cause T cell activation, but after adding anti-human IgG Fc specific for cross-linking, antibodies P64-1B11, P64-1H3, P64-2D6, P64-1G12, P64- 2D5 and P64-2D8 can induce the activation of T cells (see Figure 4).
  • immunoglobulin As we all know, there is a certain amount of immunoglobulin (IgG) in the human body. If these immunoglobulins are cross-linked with CD28 antibody, it may prompt CD28 antibody to activate T cells, resulting in a large release of cytokines, resulting in some adverse reactions. reaction. It can be seen from Figure 4 that under the same conditions, compared with other monoclonal antibodies, P64-2D6 has a lower ability to activate T cells after adding anti-human IgG Fc specific for cross-linking, indicating that it is safer.
  • mouse anti-human CD3 antibody (BD Biosciences, CAT#555336) was coated overnight, The next day, the coating solution was discarded, and IL-2-Jurkat cells and CD28 monoclonal antibody were added. The amount of cells added and the concentration and amount of antibodies added were consistent with those shown in Figure 4.
  • the Fab fragment of the anti-human CD3 antibody used in this example can specifically recognize the CD3 ⁇ chain in the TCR-CD3 complex, activate T cells, and initially activate T cells. But only with the participation of the first signal, CD3 antibody alone is not enough to activate T cells, but combined with P64-1B11 or P64-2D6 can strongly activate T cells, that is, with the joint participation of the second signal, it can make T cells T cells were further activated (see Figure 5).

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Abstract

La présente invention concerne un anticorps anti-CD28 ou un fragment de liaison à l'antigène, et son utilisation dans le traitement ou la prévention d'une tumeur, d'une maladie auto-immune ou d'une maladie inflammatoire. L'anticorps anti-CD28 ou le fragment de liaison à l'antigène comprend une région variable de chaîne lourde représentée par une séquence dans l'une quelconque des SEQ ID NO : 1 à 6, et une région variable de chaîne légère représentée par une séquence dans SEQ ID NO : 7.
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WO2024077118A2 (fr) 2022-10-06 2024-04-11 Bicara Therapeutics Inc. Protéines multispécifiques et procédés associés

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