WO2024056049A1 - Anticorps anti-ctla4 dépendant du ph ou fragment de liaison à l'antigène - Google Patents

Anticorps anti-ctla4 dépendant du ph ou fragment de liaison à l'antigène Download PDF

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WO2024056049A1
WO2024056049A1 PCT/CN2023/118987 CN2023118987W WO2024056049A1 WO 2024056049 A1 WO2024056049 A1 WO 2024056049A1 CN 2023118987 W CN2023118987 W CN 2023118987W WO 2024056049 A1 WO2024056049 A1 WO 2024056049A1
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amino acid
seq
acid sequence
sequence shown
variable region
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PCT/CN2023/118987
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English (en)
Chinese (zh)
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崔东冰
顾津明
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同润生物医药(上海)有限公司
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Publication of WO2024056049A1 publication Critical patent/WO2024056049A1/fr

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    • 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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • 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

Definitions

  • the invention belongs to the field of biomedicine, and specifically relates to a pH-dependent anti-CTLA4 antibody or antigen-binding fragment.
  • Immune checkpoints are a large class of immunosuppressive molecules, including Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). Under normal physiological conditions, immune checkpoints can regulate immune responses, prevent self-tissue damage, and are important in maintaining immune tolerance. However, during the occurrence and development of tumors, the activation and high expression of immune checkpoint molecules will inhibit the function of immune cells, weaken the ability of immune cells to kill tumor cells, and mediate tumor immune escape. Immune checkpoint blockers are treatments that improve anti-tumor immune responses by inhibiting negative regulatory signals and regulating immune cell activity.
  • CTL-4 Cytotoxic T lymphocyte-associated antigen-4
  • CTLA-4 also known as CD152
  • CD152 is an immunosuppressive receptor expressed on T cells. It plays an inhibitory role in the proliferation of T cells and also affects related cell cycle processes and cytokines such as interleukin-2 (IL-2). ), the secretion of interferon ⁇ (IFN- ⁇ ) is also inhibited to varying degrees.
  • Ipilimumab which is already on the market, is an anti-CTLA-4 immunomodulatory monoclonal antibody (mAb). It is currently used as a single drug or in combination, in melanoma, lung cancer, kidney cancer, etc. It has been approved or conducted clinical trials for several tumor indications and achieved remarkable results.
  • ipilimumab still exhibits dose-limiting toxicities. This greatly limits the administration of higher doses for tumor treatment. Therefore, certain forms of modification of ipilimumab are needed in order to demonstrate enhanced anti-tumor activity while reducing side effects.
  • the invention provides an anti-CTLA4 antibody or antigen-binding fragment, wherein the antibody or fragment comprises a heavy chain variable region sequence of HCDR1, HCDR2 and HCDR3 sequences and a light chain variable region sequence of LCDR1, LCDR2 and LCDR3 sequences, in:
  • the HCDR1 has a histidine (H) residue
  • the HCDR2 has at least one histidine (H) residue
  • the HCDR3 has zero or 1 histidine (H) residue
  • the LCDR1 has at least one acidic amino acid residue
  • the LCDR2 has the same amino acid sequence as ipilimumab LCDR2;
  • the LCDR3 has the same amino acid sequence as ipilimumab LCDR3.
  • the heavy chain variable region HCDR1 contains any one of residues 31H and 32H, and the amino acid at position 35 is not H.
  • the heavy chain variable region HCDR1 includes 31H.
  • the heavy chain variable region HCDR1 includes 32H.
  • the 35th amino acid is not histidine (H).
  • the heavy chain variable region HCDR1 region includes 35A, 35G, 35V, 35L, 35I, 35F, 35W, 35Y, 35D, 35N, 35E, 35K, 35Q, 35M, Any residue among 35S, 35T, 35C, 35P, and 35R.
  • the heavy chain variable region HCDR1 region includes any one of residues 35A, 35V, 35L, 35I, 35F, 35Y, 35S, and 35N.
  • the heavy chain variable region includes 30H.
  • the heavy chain variable region wherein the heavy chain variable region HCDR1 region contains 35H.
  • the heavy chain variable region HCDR2 includes 56H residue.
  • the heavy chain variable region HCDR3 contains zero H residues.
  • the acidic amino acid residues in the light chain variable region LCDR1 are selected from aspartic acid (D) or glutamic acid (E).
  • the light chain variable region LCDR1 includes any one of the amino acid residues 24D, 26D, 28E, 31E, 33E, and 35D.
  • the antibody or fragment comprises a heavy chain variable region sequence of HCDR1, HCDR2 and HCDR3 sequences and a light chain sequence of LCDR1, LCDR2 and LCDR3 sequences.
  • Variable region sequence where:
  • the HCDR1 includes the amino acid sequence shown in SEQ ID NO: 7;
  • the HCDR2 includes the amino acid sequence shown in SEQ ID NO: 2;
  • the HCDR3 includes the amino acid sequence shown in SEQ ID NO: 3;
  • the LCDR1 includes the amino acid sequence shown in SEQ ID NO: 4;
  • the LCDR2 includes the amino acid sequence shown in SEQ ID NO: 5;
  • the LCDR3 includes the amino acid sequence shown in SEQ ID NO: 6.
  • the antibody or fragment includes heavy chain variable region sequences of HCDR1, HCDR2 and HCDR3 sequences and light chain variable region sequences of LCDR1, LCDR2 and LCDR3 sequences, wherein:
  • the HCDR1 includes the amino acid sequence shown in SEQ ID NO: 8;
  • the HCDR2 includes the amino acid sequence shown in SEQ ID NO: 2;
  • the HCDR3 includes the amino acid sequence shown in SEQ ID NO: 3;
  • the LCDR1 includes the amino acid sequence shown in SEQ ID NO: 4;
  • the LCDR2 includes the amino acid sequence shown in SEQ ID NO: 5;
  • the LCDR3 includes the amino acid sequence shown in SEQ ID NO: 6.
  • the antibody or fragment includes heavy chain variable region sequences of HCDR1, HCDR2 and HCDR3 sequences and light chain variable region sequences of LCDR1, LCDR2 and LCDR3 sequences, wherein:
  • the HCDR1 includes the amino acid sequence shown in SEQ ID NO: 9;
  • the HCDR2 includes the amino acid sequence shown in SEQ ID NO: 2;
  • the HCDR3 includes the amino acid sequence shown in SEQ ID NO: 3;
  • the LCDR1 includes the amino acid sequence shown in SEQ ID NO: 4;
  • the LCDR2 includes the amino acid sequence shown in SEQ ID NO: 5;
  • the LCDR3 includes the amino acid sequence shown in SEQ ID NO: 6.
  • the antibody or fragment includes heavy chain variable region sequences of HCDR1, HCDR2 and HCDR3 sequences and light chain variable region sequences of LCDR1, LCDR2 and LCDR3 sequences, wherein:
  • the HCDR1 includes the amino acid sequence shown in SEQ ID NO: 10;
  • the HCDR2 includes the amino acid sequence shown in SEQ ID NO: 2;
  • the HCDR3 includes the amino acid sequence shown in SEQ ID NO: 3;
  • the LCDR1 includes the amino acid sequence shown in SEQ ID NO: 4;
  • the LCDR2 includes the amino acid sequence shown in SEQ ID NO: 5;
  • the LCDR3 includes the amino acid sequence shown in SEQ ID NO: 6.
  • the antibody or fragment includes heavy chain variable region sequences of HCDR1, HCDR2 and HCDR3 sequences and light chain variable region sequences of LCDR1, LCDR2 and LCDR3 sequences, wherein:
  • the HCDR1 includes the amino acid sequence shown in SEQ ID NO: 11;
  • the HCDR2 includes the amino acid sequence shown in SEQ ID NO: 2;
  • the HCDR3 includes the amino acid sequence shown in SEQ ID NO: 3;
  • the LCDR1 includes the amino acid sequence shown in SEQ ID NO: 4;
  • the LCDR2 includes the amino acid sequence shown in SEQ ID NO: 5;
  • the LCDR3 includes the amino acid sequence shown in SEQ ID NO: 6.
  • the antibody or fragment includes heavy chain variable region sequences of HCDR1, HCDR2 and HCDR3 sequences and light chain variable region sequences of LCDR1, LCDR2 and LCDR3 sequences, wherein:
  • the HCDR1 includes the amino acid sequence shown in SEQ ID NO: 12;
  • the HCDR2 includes the amino acid sequence shown in SEQ ID NO: 2;
  • the HCDR3 includes the amino acid sequence shown in SEQ ID NO: 3;
  • the LCDR1 includes the amino acid sequence shown in SEQ ID NO: 4;
  • the LCDR2 includes the amino acid sequence shown in SEQ ID NO: 5;
  • the LCDR3 includes the amino acid sequence shown in SEQ ID NO: 6.
  • the antibody or fragment includes heavy chain variable region sequences of HCDR1, HCDR2 and HCDR3 sequences and light chain variable region sequences of LCDR1, LCDR2 and LCDR3 sequences, wherein:
  • the HCDR1 includes the amino acid sequence shown in SEQ ID NO: 13;
  • the HCDR2 includes the amino acid sequence shown in SEQ ID NO: 2;
  • the HCDR3 includes the amino acid sequence shown in SEQ ID NO: 3;
  • the LCDR1 includes the amino acid sequence shown in SEQ ID NO: 4;
  • the LCDR2 includes the amino acid sequence shown in SEQ ID NO: 5;
  • the LCDR3 includes the amino acid sequence shown in SEQ ID NO: 6.
  • the antibody or fragment includes heavy chain variable region sequences of HCDR1, HCDR2 and HCDR3 sequences and light chain variable region sequences of LCDR1, LCDR2 and LCDR3 sequences, wherein:
  • the HCDR1 includes the amino acid sequence shown in SEQ ID NO: 14;
  • the HCDR2 includes the amino acid sequence shown in SEQ ID NO: 2;
  • the HCDR3 includes the amino acid sequence shown in SEQ ID NO: 3;
  • the LCDR1 includes the amino acid sequence shown in SEQ ID NO: 4;
  • the LCDR2 includes the amino acid sequence shown in SEQ ID NO: 5;
  • the LCDR3 includes the amino acid sequence shown in SEQ ID NO: 6.
  • the antibody or fragment includes heavy chain variable region sequences of HCDR1, HCDR2 and HCDR3 sequences and light chain variable region sequences of LCDR1, LCDR2 and LCDR3 sequences, wherein:
  • the HCDR1 includes the amino acid sequence shown in SEQ ID NO: 15;
  • the HCDR2 includes the amino acid sequence shown in SEQ ID NO: 2;
  • the HCDR3 includes the amino acid sequence shown in SEQ ID NO: 3;
  • the LCDR1 includes the amino acid sequence shown in SEQ ID NO: 4;
  • the LCDR2 includes the amino acid sequence shown in SEQ ID NO: 5;
  • the LCDR3 includes the amino acid sequence shown in SEQ ID NO: 6.
  • the antibody or fragment includes heavy chain variable region sequences of HCDR1, HCDR2 and HCDR3 sequences and light chain variable region sequences of LCDR1, LCDR2 and LCDR3 sequences, wherein:
  • the HCDR1 includes the amino acid sequence shown in SEQ ID NO: 16;
  • the HCDR2 includes the amino acid sequence shown in SEQ ID NO: 2;
  • the HCDR3 includes the amino acid sequence shown in SEQ ID NO: 3;
  • the LCDR1 includes the amino acid sequence shown in SEQ ID NO: 4;
  • the LCDR2 includes the amino acid sequence shown in SEQ ID NO: 5;
  • the LCDR3 includes the amino acid sequence shown in SEQ ID NO: 6.
  • the antibody or fragment includes heavy chain variable region sequences of HCDR1, HCDR2 and HCDR3 sequences and light chain variable region sequences of LCDR1, LCDR2 and LCDR3 sequences, wherein:
  • the HCDR1 includes the amino acid sequence shown in SEQ ID NO: 16;
  • the HCDR2 includes the amino acid sequence shown in SEQ ID NO: 2;
  • the HCDR3 includes the amino acid sequence shown in SEQ ID NO: 3;
  • the LCDR1 includes the amino acid sequence shown in SEQ ID NO: 17;
  • the LCDR2 includes the amino acid sequence shown in SEQ ID NO: 5;
  • the LCDR3 includes the amino acid sequence shown in SEQ ID NO: 6.
  • the antibody or fragment includes heavy chain variable region sequences of HCDR1, HCDR2 and HCDR3 sequences and light chain variable region sequences of LCDR1, LCDR2 and LCDR3 sequences, wherein:
  • the HCDR1 includes the amino acid sequence shown in SEQ ID NO: 16;
  • the HCDR2 includes the amino acid sequence shown in SEQ ID NO: 2;
  • the HCDR3 includes the amino acid sequence shown in SEQ ID NO: 3;
  • the LCDR1 includes the amino acid sequence shown in SEQ ID NO: 18;
  • the LCDR2 includes the amino acid sequence shown in SEQ ID NO: 5;
  • the LCDR3 includes the amino acid sequence shown in SEQ ID NO: 6.
  • the antibody or fragment includes heavy chain variable region sequences of HCDR1, HCDR2 and HCDR3 sequences and light chain variable region sequences of LCDR1, LCDR2 and LCDR3 sequences, wherein:
  • the HCDR1 includes the amino acid sequence shown in SEQ ID NO: 16;
  • the HCDR2 includes the amino acid sequence shown in SEQ ID NO: 2;
  • the HCDR3 includes the amino acid sequence shown in SEQ ID NO: 3;
  • the LCDR1 includes the amino acid sequence shown in SEQ ID NO: 19;
  • the LCDR2 includes the amino acid sequence shown in SEQ ID NO: 5;
  • the LCDR3 includes the amino acid sequence shown in SEQ ID NO: 6.
  • the antibody or fragment comprises a heavy chain selected from the group consisting of: Variable region and light chain variable region sequence pairs:
  • a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 31 and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 32;
  • a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 31 and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 33;
  • the antibody or fragment comprises a heavy chain sequence and a light chain sequence selected from the following:
  • the antibody or antigen-binding fragment is a monoclonal antibody, a bispecific antibody, a multispecific antibody, a recombinant antibody, a chimeric antibody, a diavalent antibody, an anti-idiotypic antibody or a fusion protein .
  • the present invention also provides a nucleic acid molecule encoding the antibody or antigen-binding fragment described in any of the above-mentioned items of the present invention.
  • the nucleic acid molecule of the invention is operably linked to a promoter.
  • the present invention also provides a recombinant expression vector containing the nucleic acid molecule of the present invention.
  • the present invention also provides a plasmid containing the nucleic acid molecule of the present invention.
  • the present invention also provides a host cell containing the nucleic acid molecule of the present invention, the recombinant expression vector of the present invention or the plasmid of the present invention.
  • the present invention also provides a pharmaceutical composition, including any of the above antibodies or antigen-binding fragments thereof of the present invention, and a pharmaceutically acceptable carrier.
  • the present invention also provides a kit, including any of the above-mentioned antibodies of the present invention or antigen-binding fragments thereof.
  • the present invention also provides a method for treating cancer, which includes administering any of the above-mentioned antibodies or antigen-binding fragments thereof of the present invention to a subject in need thereof.
  • Figure 1 shows the binding parameters at pH 6.0 and pH 7.4 for selected ipilimumab sequence variants of the invention.
  • the antibodies or antigen-binding fragments of the invention are preferably fully human.
  • fully human is meant that the antibody or antigen-binding fragment thereof is defined herein as being non-chimeric (eg, not “humanized”) and not derived (whether in whole or in part) from a non-human species.
  • Fully human antibodies or antigen-binding fragments thereof may be of human origin, or may be synthetic human antibodies.
  • Another example of a fully human antibody or antigen-binding fragment thereof is a human antibody encoded by a nucleic acid isolated from a library of antibody sequences of human origin (eg, such a library based on antibodies drawn from natural human sources).
  • the antibody or antigen-binding fragment thereof of the present invention is a monoclonal antibody, bispecific antibody, multispecific antibody, recombinant antibody, chimeric antibody, diavalent antibody, anti-idiotype antibody or fusion protein.
  • the invention also provides antibodies or antigen-binding fragments capable of binding CTLA4, which are bispecific antibodies or bispecific antigen-binding fragments.
  • the bispecific antibodies or bispecific antigen-binding fragments can be isolated.
  • the term "bispecific” refers to the ability of an antigen-binding molecule to specifically bind at least two different antigenic determinants.
  • the bispecific antibodies and bispecific antigen-binding fragments comprise antigen-binding fragments according to the invention.
  • the bispecific antibodies and bispecific antigen-binding fragments comprise antigen-binding fragments capable of binding to CTLA4, wherein the antigen-binding fragments capable of binding to CTLA4 comprise antigen-binding fragments according to the invention.
  • the bispecific antibodies and bispecific antigen-binding fragments comprise an antigen-binding fragment capable of binding to CTLA4, and an antigen-binding fragment capable of binding to another target protein.
  • the bispecific antibody or antigen-binding fragment comprises an antigen-binding molecule capable of binding CTLA4 and an antigen-binding molecule capable of binding other than CTLA4.
  • the antigen other than CTLA4 is an immune cell surface molecule.
  • the antigen other than CTLA4 is a cancer cell antigen.
  • the antigen other than CTLA4 is a receptor molecule, such as a cell surface receptor.
  • the invention provides nucleic acids encoding said monoclonal antibodies or antigen-binding fragments or bispecific antibodies or chimeric antigen receptors.
  • the invention provides plasmids comprising the nucleic acids, optionally operably linked to regulatory sequences, such as promoters, enhancers, etc.
  • the invention provides host cells comprising the plasmid, and methods for producing and optionally recovering the monoclonal antibody or antigen-binding fragment or bispecific antibody or chimeric antigen receptor.
  • the host cell of the present invention can be any prokaryotic or eukaryotic cell, including but not limited to bacterial cells (such as Escherichia coli, Bacillus subtilis), insect cells (such as using baculovirus expression systems), yeast or mammalian cells (such as CHO or BHK cell lines). Other suitable host cells are known to those skilled in the art.
  • bacterial cells such as Escherichia coli, Bacillus subtilis
  • insect cells such as using baculovirus expression systems
  • yeast or mammalian cells such as CHO or BHK cell lines.
  • Other suitable host cells are known to those skilled in the art.
  • the disease described in the present invention is cancer, including but not limited to lymphoma, blastoma, sarcoma (including liposarcoma), neuroendocrine tumors, mesothelioma, schwannoma, meningioma, adenoma, and melanoma. and nonleukemic leukemias or lymphoid malignancies.
  • squamous cell carcinoma e.g., squamous cell carcinoma
  • lung cancer small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma
  • peritoneal cancer hepatocellular carcinoma
  • gastric cancer e.g., gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer , kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penis cancer, testicular cancer, esophageal cancer, bile duct tumors, head cancer, neck cancer, bone marrow stromal tumor, osteoclastoma, multiple Myeloma, osteolytic bone cancers, central nervous system tumors, brain tumors (glioma, neuroblastoma,
  • the antibodies or antigen-binding fragments or bispecific antibodies or chimeric antigen receptors or nucleic acid molecules thereof, plasmids or cells expressing the chimeric antigen receptors, and pharmaceutical compositions of the present invention can be administered through various different routes of administration.
  • the route of administration will generally depend on the characteristics of the disease being treated.
  • the methods of the present invention may be carried out using any medically acceptable mode of administration, including oral, rectal, topical, intraocular, intracisternal, intracerebroventricular, intratracheal, intranasal instillation.
  • Infusion transdermal, subcutaneous, intrathecal, intramuscular, intraperitoneal, intraperitoneal, intracranial infusion or intravenous infusion.
  • Antibody as used herein means a protein consisting of one or more polypeptides encoded by substantially all or part of a recognized immunoglobulin gene.
  • the recognized immunoglobulin genes include the kappa ( ⁇ ), lambda ( ⁇ ) and heavy chain loci, which contain numerous variable region genes and encode IgM, IgD, IgG and IgE respectively. and IgA isotype constant region genes mu( ⁇ ), delta( ⁇ ), gamma ( ⁇ ), epsilon( ⁇ ), alpha( ⁇ ).
  • Antibodies as used herein are meant to include full-length antibodies and antibody fragments, as well as natural antibodies from any organism, engineered antibodies, or recombinantly produced antibodies for experimental, therapeutic purposes, or other purposes as further specified below.
  • the term “antibody” includes antibody fragments, as are known in the art, such as Fab, Fab', F(ab')2, Fv, scFv or other antigen-binding subsequences of an antibody, or by modifying the intact antibody or using recombinant DNA technology Antibody fragments produced by de novo synthesis of those antibodies.
  • the term “antibody” includes monoclonal as well as polyclonal antibodies.
  • Antibodies can be antagonists, agonists, neutralizing antibodies, or inhibitory antibodies, or stimulatory antibodies.
  • the antibodies of the invention may be non-human antibodies, chimeric antibodies, humanized antibodies or fully human antibodies.
  • monoclonal antibody refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the population comprising a single antibody is identical except for possible mutations (eg, natural mutations) that may be present in very small amounts. of. Therefore, the term “monoclonal” indicates the nature of the antibody, that is, it is not a mixture of discrete antibodies. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), monoclonal antibody preparations have each monoclonal antibody directed against a single determinant on the antigen.
  • monoclonal antibody preparations are generally not contaminated by other immunoglobulins.
  • the term "monoclonal” should not be understood as requiring that the antibody be produced by any particular method.
  • the term monoclonal antibody specifically includes fully human antibodies. (ref CN201280067865-anti-FGFR2 antibodies and their uses-approval authorization).
  • complementarity determining region refers to the amino acid residues of the variable region of an antibody, the presence of which is necessary for antigen binding.
  • the "antigen-binding region” of an antibody is typically found in one or more hypervariable regions of the antibody, such as the CDR regions of CDR1, CDR2, and CDR3.
  • Each complementarity-determining region may comprise amino acid residues from a "complementarity-determining region” as defined by Kabat, for example, residues 24-34 (L1), 50-56 (L2) and 89- in the light chain variable region.
  • the numbering of the CDR region in this article adopts Kabat numbering.
  • “31H”, “32H”, “amino acid at position 35", etc. described herein refer to the amino acid at position 31 according to Kabat numbering. Histidine, histidine at position 32, amino acid at position 35.
  • Variable regions and CDRs in antibody sequences can also be determined according to other general rules that have been developed in the art. (e.g. Chothia, IMGT, Contact numbering system, etc.) or by comparing the sequence to a database of known variable regions. Methods for identifying these regions are described in Kontermann and Dubel, eds., Antibody Engineering, Springer, New York, NY, 2001 and Dinarello et al., Current Protocols in Immunology, John Wiley and Sons Inc., Hoboken, NJ, 2000.
  • Antigen as used herein means a compound, composition or substance that can stimulate antibody production or T cell response in an animal, including compositions injected or absorbed into the animal, which can be a protein, carbohydrate, lipid or other Pathogens.
  • a “functional fragment” or "antigen-binding fragment” of an antibody/immunoglobulin is defined herein as a fragment of an antibody/immunoglobulin that retains the antigen-binding region (eg, the variable region of an IgG).
  • the "antigen-binding region" of an antibody is typically found in one or more hypervariable regions of the antibody, such as the CDR1, -2, and/or -3 regions; however, variable “framework” regions can also play an important role in antigen binding , for example by providing a CDR scaffold.
  • the "antigen binding region” includes at least amino acid residues 4-103 of the variable light chain (VL) and amino acid residues 5-109 of the variable heavy chain (VH), more preferably amino acid residue 3 of the VL -107 and amino acid residues 4-111 of VH, and the complete VL and VH chains are particularly preferred (amino acid residues 1-109 of VL and amino acids 1-113 of VH; numbering according to WO97/08320).
  • Preferred immunoglobulins for use in the present invention are IgG.
  • amino acid means one of the 20 naturally occurring amino acids or any of the non-natural analogs, which may be at a specifically specified position.
  • Protein as used herein means at least two covalently linked amino acids, which includes proteins, polypeptides, oligopeptides and peptides. Proteins may be composed of naturally occurring amino acids and peptide bonds, or they may be composed of synthetic peptidomimetic structures, known as “analogs.”
  • Amino acid or “peptide residue” as used herein therefore means both naturally occurring and synthetic amino acids. For example, homophenylalanine, citrulline and norleucine are considered amino acids for the purposes of the present invention.
  • Amino acid also includes imino acid residues such as proline and hydroxyproline.
  • Side chains can be in the (R) or (S) configuration.
  • the amino acids are present in the (S) or L-configuration. If non-naturally occurring side chains are used, non-amino acid substitutions may be used, for example, to prevent or delay degradation in vivo.
  • Identity means similarity between nucleotide or amino acid sequences, otherwise known as sequence identity. Sequence identity is usually measured in terms of percent identity (or similarity or homology); the higher the percent, the more similar the two sequences are. Homologs or variants will have a relatively high degree of sequence identity when aligned using standard methods. Sequence alignment methods for comparison are well known in the art. various programs and Quasi-algorithms are described in: Smith and Waterman, Adv Appl. Math., 2:482, 1981; Needlema and Wunsch, J. Mol. Biol. 48:443, 1970; Pearson and Lipman, Proc. Natl. Acad. Sci.
  • NCBI Basic Local Alignment Search Tool (BLASTTM) (Altschul et al., J. Mol. Biol., 215:403-410, 1990.) is available from several sources, including the National Center for Biotechnology Information (NCBI, Bethesda, Md. ) and are available on the Internet for the sequence analysis programs blastp, blastn, blastx, tblastn and tblastx.
  • Nucleic acid as used herein means composed of nucleotide units (ribonucleotides, deoxyribonucleotides, related naturally occurring structural variants and their synthetic non-naturally occurring analogs) through phosphodiester bonds composed of polymers.
  • nucleotide polymers in which the nucleotides and the bonds between them include non-naturally occurring synthetic analogs such as, but not limited to, phosphorothioates, phosphoramidates, methyl phosphates, chiral Methyl phosphate, 2'-O-methylribonucleotide, peptide nucleic acid (PNA), etc.
  • these polynucleotides can be synthesized using an automated DNA synthesizer.
  • oligonucleotide generally refers to short polynucleotides, usually no greater than about 50 nucleotides. It will be understood that when a nucleotide sequence is represented by a DNA sequence (ie A, T, G, C), this also includes an RNA sequence in which "U” is substituted for "T” (ie A, U, G, C).
  • This article uses conventional symbols to describe nucleotide sequences: the left-hand 5' end of a single-stranded nucleotide sequence; the left-hand direction of a double-stranded nucleotide sequence is called the 5' direction.
  • the direction in which 5' to 3' nucleotides are added to the nascent RNA transcript is called the direction of transcription.
  • the DNA strand with the same sequence as the mRNA is called the coding strand.
  • coding means the inherent properties of a specific nucleotide sequence in a polynucleotide, such as a gene, cDNA, or mRNA, used in the synthesis of other polymers and macromolecules in biological processes with a defined nucleotide sequence.
  • the coding strand (whose nucleotide sequence is identical to the mRNA sequence and is usually provided in sequence listings) and the non-coding strand (used as a transcription template, gene or cDNA) can be referred to as coding proteins. or other products of the gene or cDNA.
  • a "nucleotide sequence encoding an amino acid sequence” includes all nucleotide sequences that are degenerate forms of each other and encode the same amino acid sequence. Nucleotide sequences encoding proteins and RNA may include introns.
  • Plasmid used in this article means human-made plasmids based on natural plasmids to adapt to laboratory operations. Artificially constructed plasmid. Nucleic acid molecules can be introduced into a host cell, thereby producing a transformed host cell.
  • the vector may include nucleic acid sequences that permit its replication in the host cell, such as an origin of replication, and may also include one or more selectable marker genes and other genetic elements known in the art.
  • “Pharmaceutically acceptable carrier” as used herein means conventional pharmaceutically acceptable carriers. Remington's Pharmaceutical Sciences, EW Martin, Mack Publishing Co., Easton, Pa., 15th ed. (1975), describes compositions suitable for pharmaceutical delivery of one or more therapeutic compounds or molecules (e.g., one or more antibodies) and preparations, as well as additional pharmaceutical agents.
  • diagnosis means determining the patient's condition and its progression after examining the patient.
  • Preventing means inhibiting its complete progression.
  • Treatment means therapeutic intervention to ameliorate the signs or symptoms of a disease or pathological condition after it has begun to develop.
  • administering means selecting a suitable route to introduce the substance into the subject. For example, if the chosen route is intravenous, the composition is administered by introducing the substance into the subject's vein.
  • Effective prophylactic/therapeutic dose means an amount of a particular agent sufficient to achieve the desired effect in a subject treated with the agent.
  • the precise dosage will depend on the purpose of treatment and can be determined by one skilled in the art using well-known techniques.
  • the dosage range may be 0.01-100 mg/kg body weight or greater, such as 0.1, 1, 10 or 50 mg/kg body weight, preferably 1-10 mg/kg.
  • the effects of antibody or Fc fusion degradation, systemic or local delivery, and new protease synthesis rates as well as age, weight, general health, sex, diet, timing of administration, drug interactions, and disease The extent to which adjustments may be necessary can be determined by routine experimentation by those skilled in the art.
  • Such agents include monomeric Fc domain molecules described herein.
  • this may be an amount of HIV-specific monomeric Fc domain (or HIV-specific CH3 domain molecule) used to prevent, treat or ameliorate HIV infection.
  • a therapeutically effective amount of antibody is an amount sufficient to prevent, treat, or ameliorate an infection or disease, such as caused by HIV infection in a subject, without causing significant cytotoxic effects in the subject.
  • the therapeutically effective amount of the agent used to prevent, ameliorate and/or treat a subject will depend on the subject being treated, the type and severity of suffering, and the manner in which the therapeutic composition is administered.
  • Cancer refers to solid tumors or hematogenous cancers.
  • the solid tumor of the present invention is a sarcoma or carcinoma, such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, or another sarcoma, synovial tumour, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, lymphoid malignancies, pancreatic cancer, breast cancer, lung cancer, ovarian cancer, prostate cancer, hepatocellular carcinoma, squamous cell carcinoma, basal cell carcinoma, Adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, Wil
  • the blood-borne cancer described in the present invention is leukemia, such as acute leukemia (such as acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloid leukemia and myeloblasts, promyelocytes, myelomonocytes, monocytes and erythroleukemia); chronic leukemias (such as chronic myelogenous (granulocytic) leukemia, chronic myelogenous leukemia, and chronic lymphocytic leukemia), polycythemia vera, lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma (indolent and advanced forms), multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, myelodysplastic syndrome, hairy cell leukemia, or myelodysplasia.
  • acute leukemia such as acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloid leukemia and myeloblast
  • Antibodies herein include all classes of antibodies (i.e. IgA, IgD, IgE, IgG and IgM) and all subclasses (i.e. IgGl, IgG2, IgG3, IgG4, IgAl and IgA2).
  • the antibodies may be chimeric, humanized or fully human monoclonal antibodies.
  • Antibodies usually contain a heavy chain variable region (VH) and a light chain variable region (VL).
  • VH and VL regions can be further divided into hypervariable regions separated by relatively conserved regions called framework regions (FR). complementary decision designated area (CDR)).
  • FR framework regions
  • CDR complementary decision designated area
  • Each VH and VL consists of 3 CDRs and 4 FRs in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 from N-terminus to C-terminus.
  • the variable regions (VH and VL) of each heavy chain/light chain pair respectively form the antigen binding site.
  • CDRs are known to be responsible for antigen binding, however, it has been found that not all 6 CDRs are essential or unchangeable.
  • one or more CDRs can be replaced or altered or modified while still substantially retaining or even improving the specific binding affinity for CTLA4.
  • the heavy chain CDR3 region is located in the center of the antigen-binding site and is therefore thought to have the most contact with the antigen and provide the most free energy for the affinity of the antibody to the antigen. It is also believed that heavy chain CDR3 is by far the most diverse CDR among antigen-binding sites in terms of length, amino acid composition, and conformation through various diversification mechanisms (Tonegawa S. Nature. 302:575-81). Diversity in heavy chain CDR3 is sufficient to generate most antibody specificities (Xu JL, Davis MM. Immunity. 13:37-45) as well as the required antigen binding affinity (Schier R et al., J Mol Biol. 263:551-67 ).
  • the antibody, or antigen-binding portion thereof comprises a heavy chain CDR3 (HCDR3) that includes or consists of the amino acid sequence of SEQ ID NO:3.
  • the antibody or antigen-binding portion thereof comprises: a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 3, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 4
  • the antibody or antigen-binding portion thereof comprises: a heavy chain CDR1 comprising an amino acid sequence selected from any one of SEQ ID NO: 7-16, an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 2 Heavy chain CDR2, heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:3, light chain CDR1 comprising the amino acid sequence of SEQ ID NO:4, light chain CDR2 comprising the amino acid sequence of SEQ ID NO:5 and SEQ ID NO :6 amino acid sequence of light chain CDR3.
  • a heavy chain CDR1 comprising an amino acid sequence selected from any one of SEQ ID NO: 7-16, an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 2
  • Heavy chain CDR2 heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:3
  • light chain CDR1 comprising the amino acid sequence of SEQ ID NO:4
  • light chain CDR2 comprising the amino acid sequence of SEQ ID NO:5 and SEQ ID NO :6 amino acid sequence of light
  • the antibody or antigen-binding portion thereof comprises: a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 16, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 3
  • the antibody or antigen-binding portion thereof comprises: a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 16, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 2 :The heavy chain CDR3 of the amino acid sequence of 3, comprising any one selected from SEQ ID NO:4 and 17-19
  • the antibody, or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL):
  • the VH includes: (i) the amino acid sequence shown in any one of SEQ ID NO: 22-31; or (ii) at least 85%, An amino acid sequence that is 90% or 95% identical and retains specific binding affinity for CTLA4 in combination with the VL region; and
  • the VL includes: (i) the amino acid sequence shown in any one of SEQ ID NO: 21 and 32-35; or (ii) the amino acid sequence shown in any one of SEQ ID NO: 21 and 32-35 Amino acid sequences that are at least 85%, 90%, or 95% identical and that in combination with the VH region retain specific binding affinity for CTLA4.
  • the above-described variants of at least 85%, 90% or 95% identical amino acid sequences comprise mutations that occur in the framework region rather than the CDR region, for example in the framework region there are one or more (e.g. 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10) addition, deletion and/or substitution of amino acids.
  • the substitutions are conservative substitutions.
  • conservative substitution refers to amino acid substitutions that do not adversely affect or alter the essential properties of the protein/polypeptide comprising the amino acid sequence.
  • conservative substitutions can be introduced by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis.
  • Conservative amino acid substitutions include substitutions in which an amino acid residue is replaced by another amino acid residue with a similar side chain, such as a physically or functionally similar residue (e.g., having similar size, shape, charge, chemical properties, including formation of covalent bonds or hydrogen bonding ability, etc.) to the corresponding amino acid residue. Families of amino acid residues with similar side chains have been defined in the art.
  • amino acids with basic side chains such as lysine, arginine, and histidine
  • amino acids with acidic side chains such as aspartic acid and glutamic acid
  • amino acids with non-polar side chains such as alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine
  • amino acids with ⁇ -branched side chains e.g., threonine, valine, isoleucine
  • amino acids with aromatic side chains e.g., tyrosine, phenylalanine, tryptophan, histidine.
  • the corresponding amino acid residue is preferably replaced by another amino acid residue from the same side chain family.
  • Methods for identifying conservative substitutions of amino acids are well known in the art (see, eg, Brummell et al., Biochem. 32:1180-1187 (1993); Kobayashi et al., Protein Eng. 12(10):879-884 (1999); and Burks et al., Proc. Natl. Acad. Sci. USA 94:412-417 (1997), which are incorporated herein by reference).
  • the antibodies and antigen-binding fragments provided herein may further comprise a human IgG constant region comprising an Fc region and optionally a hinge region.
  • the human IgG constant region may be a human IgGl, IgG2, IgG3 or IgG4 constant region.
  • the antibody comprises a human IgGl or IgG4 Fc region.
  • the Fc region may be a wild-type Fc region, or the Fc region may contain one or more amino acid modifications (eg, Leu234Ala/Leu235Ala or LALA substitutions) that alter antibody-dependent cellular cytotoxicity (ADCC) or other effector function.
  • ADCC antibody-dependent cellular cytotoxicity
  • the Fc modifications comprise LALA mutations, namely mutations according to EU numbering L234A and L235A of Kabat et al.
  • LALA mutations are probably the most commonly used mutations that disrupt antibody effector function, such as eliminating Fc binding to specific Fc ⁇ Rs and reducing ADCC activity mediated by PBMCs and monocytes.
  • Non-limiting examples of Fc modifications also include, for example, in the case involving the human IgG4 Fc region, mutation of serine (“S") at position 228 of the amino acid sequence to proline (“P").
  • S228P mutation reduces Fab arm exchange by stabilizing disulfide bonds in the core hinge of the IgG4 molecule and is therefore an IgG4 stabilizing mutation that helps prevent the formation of half-antibodies.
  • residue numbering system or "EU index” is typically used (eg, the EU index reported by Kabat et al., supra). Therefore, reference to residue numbering in an antibody constant domain refers to the residue numbering by the EU numbering system.
  • Antibody variable region amino acid sequence is amino acid sequence:
  • Example 1 Preparation of recombinant antibodies of the present invention
  • Dialysis Aspirate the high-concentration protein into the dialysis bag and place it in a beaker with 1XPBS for dialysis.
  • Preparation for the installation of the electrophoresis tank take out the glued glass clip and put it into the electrode holder. With the short glass facing the direction of the red electrode strip, put the electrode holder into the motor base and turn on the switch. Take out the glued glass clip and put it into the electrode holder. With the short glass facing the direction of the electrode's red adhesive strip, put the electrode holder into the motor base and turn on the switch. Place the base into the electrophoresis tank, and add electrophoresis buffer to the middle of the electrode frame until it is 1cm above the stacking gel. Then add electrophoresis buffer into the electrophoresis tank until the liquid level reaches the top of the stacking gel.
  • Samples of reducing gum are heated at 99°C for 6 minutes; samples of non-reducing gum are heated at 99°C for 3 minutes.
  • Electrophoresis conditions 180v, 45min
  • Protein staining instrument dyeing and destaining time is 15 minutes.
  • Gel imager Set the parameters to white light and take pictures.
  • sample positive control solution 2 times the concentration of the test solution + endotoxin standard (0.24EU/ml), mixed at 1:1
  • Example 2 pH dependence of binding parameters of ipilimumab variants of the invention
  • Figure 1 shows the pH-dependent binding parameters of various antibodies of the invention as a function of pH.
  • IPD52 is the control antibody ipilimumab
  • IPD53-IPD66 are ipilimumab variants.
  • the antibodies of the invention have higher binding (lower EC50 or higher OD450) under the acidic conditions of the tumor microenvironment than under neutral conditions.

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Abstract

L'invention concerne un anticorps anti-CTLA4 ou un fragment de liaison à l'antigène ayant différentes constantes de liaison avec un antigène CTLA4 dans différentes conditions de pH. Par comparaison avec le résultat dans une condition de neutralité, l'anticorps anti-CTLA4 a une constante de liaison plus élevée dans une condition acide d'un micro-environnement tumoral. L'anticorps anti-CTLA4 ou le fragment de liaison à l'antigène a un effet thérapeutique amélioré pour les tumeurs.
PCT/CN2023/118987 2022-09-16 2023-09-15 Anticorps anti-ctla4 dépendant du ph ou fragment de liaison à l'antigène WO2024056049A1 (fr)

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