WO2023134767A1 - ANTICORPS CIBLANT IL-18Rβ ET SES UTILISATIONS - Google Patents

ANTICORPS CIBLANT IL-18Rβ ET SES UTILISATIONS Download PDF

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WO2023134767A1
WO2023134767A1 PCT/CN2023/072444 CN2023072444W WO2023134767A1 WO 2023134767 A1 WO2023134767 A1 WO 2023134767A1 CN 2023072444 W CN2023072444 W CN 2023072444W WO 2023134767 A1 WO2023134767 A1 WO 2023134767A1
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antibody
seq
antigen
binding fragment
cancer
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PCT/CN2023/072444
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English (en)
Chinese (zh)
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杜勇
陈永锋
刘淑素
张玉华
孔德升
卢小容
吴瑶
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和径医药科技（上海）有限公司
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Priority claimed from PCT/CN2022/072143 external-priority patent/WO2023133842A1/fr
Priority claimed from CN202210108473.8A external-priority patent/CN116554322A/zh
Application filed by 和径医药科技（上海）有限公司 filed Critical 和径医药科技（上海）有限公司
Priority to CN202380011140.6A priority Critical patent/CN117177999A/zh
Publication of WO2023134767A1 publication Critical patent/WO2023134767A1/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
    • 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
    • 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
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • 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
    • C12N5/10—Cells modified by introduction of foreign genetic material

Definitions

  • IL-18Ra is widely expressed and can also combine with the inflammatory inhibitor IL-37, which is more complicated in the regulation of inflammation.
  • IL-18RP is specifically expressed in immune cells and is a receptor necessary for IL-18 to transmit signals. Therefore, antibodies targeting IL-18RP can specifically and effectively inhibit IL-18 signaling. Due to the natural existence of IL-18 high-affinity decoy receptor IL-18BP in the body and the existence of membrane-bound IL-18, the targeting of IL-18 itself is affected by many aspects, and the mechanism of action is relatively complicated. In summary, antibodies targeting IL-18RP have advantages in terms of specificity, efficacy and safety compared to other components of the IL-18 signaling pathway.
  • the purpose of the present invention is to provide a new treatment method for autoimmune diseases and inflammatory diseases.
  • Another object of the present invention is to provide an antibody against IL-18RP and its application.
  • an antibody against IL-18RP or an antigen-binding fragment thereof is provided.
  • the antibody or its antigen-binding fragment can specifically bind IL- 18Rp.
  • the antibody or antigen-binding fragment thereof has beneficial mutations selected from the group consisting of F27I, S99A, or A combination thereof; and/or a beneficial mutation selected from the group consisting of S31F, A34E, or a combination thereof based on the wild-type light chain variable region shown in SEQ ID NO: 20.
  • the antibody or antigen-binding fragment thereof has beneficial mutations selected from the following group based on the wild-type heavy chain variable region shown in SEQ ID NO: 18: F27L; and/or based on SEQ ID NO:
  • the wild-type light chain variable region shown in 20 has beneficial mutations selected from the group consisting of S31F, A34D, or a combination thereof.
  • the antibody or antigen-binding fragment thereof has beneficial mutations selected from the following group based on the wild-type heavy chain variable region shown in SEQ ID NO: 18: F27I; and/or based on SEQ ID NO:
  • the wild-type light chain variable region shown at 20 has a beneficial mutation selected from the group consisting of: A34D.
  • the antibody or antigen-binding fragment thereof includes: (a) heavy chain complementarity determining regions CDRH1, CDRH2, CDRH3, the amino acid sequences of the CDRHk CDRH2, CDRH3 are respectively shown in SEQ ID NO: 2, 3 and 4, or respectively shown in SEQ ID NO: 10.3 and 11 , or respectively as shown in SEQ ID NO: 2, 3 and 11; and
  • the antibody or antigen-binding fragment thereof has 6 CDRs (CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, CDRL3) of the A034, A035, A037, A038, or A039 antibody in Table 1.
  • the derivative sequence that has undergone addition, deletion, modification and/or substitution of at least one amino acid and can retain the specific binding ability to IL-18RP has a homology or sequence identity of at least 85% %, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the amino acid sequence.
  • the CDRK CDR2 and CDR3 are separated by framework regions FR1, FR2, FR3 and FR4.
  • the antibody or antigen-binding fragment thereof further includes a framework region FRo.
  • the antibody or antigen-binding fragment thereof has a heavy weight as shown in SEQ ID NO: 1, 9 or 14 chain variable region, and having a light chain variable region as shown in SEQ ID NO: 5, 12, 15 or 17.
  • the amino acids of the heavy chain variable region and the light chain variable region of the antibody or its antigen-binding fragment is a murine antibody, a chimeric antibody, a humanized antibody or a fully human antibody.
  • the antibody or antigen-binding fragment thereof may include a monomer, a bivalent antibody, and/or a multivalent antibody.
  • the bivalent antibody can also be a bispecific antibody.
  • the multivalent antibody can also be a multispecific antibody.
  • the antigen-binding fragment is selected from scFv, Fab, Fab ⁇ F(ab')2, Fv, disulfide bonded Fv (dsFv), or sdAbo
  • scFv fragment-binding fragment-binding fragment-binding fragment-binding fragment-binding fragment-binding fragment.
  • Fab fragment antigen-binding fragment
  • Fab ⁇ F(ab')2 Fv
  • dsFv disulfide bonded Fv
  • sdAbo sdAbo
  • the tag sequence includes Fc tag, HA tag, GGGS sequence U, FLAG tag, Myc tag, 6His tag, or a combination thereof.
  • the recombinant protein specifically binds IL- 18Rp.
  • the recombinant protein (or polypeptide) includes a fusion protein.
  • the recombinant protein is a monomer, a dimer, or a multimer.
  • the light chain nucleic acid sequence is selected from SEQ ID NO: 37, 39, 41, 43, 45, 47, or a combination thereof.
  • the nucleotide molecule includes: a heavy chain nucleotide sequence as shown in SEQ ID NO: 36 and a light chain nucleotide sequence as shown in SEQ ID NO: 37; or as shown in The heavy chain nucleotide sequence shown in SEQ ID NO: 38 and the light chain nucleotide sequence shown in SEQ ID NO: 39; or the heavy chain nucleotide sequence shown in SEQ ID NO: 40 and the sequence shown in SEQ ID NO: the light chain nucleotide sequence shown in 41; or the heavy chain nucleotide sequence shown in SEQ ID NO: 42 and the light chain nucleotide sequence shown in SEQ ID NO: 43; or as SEQ ID NO : the heavy chain nucleotide sequence shown in 44 and the light chain nucleotide sequence shown in SEQ ID NO: 45; or the heavy chain
  • an expression vector which contains the expression vector described in the third aspect of the present invention Nucleic Acid Molecule.
  • the expression vector is selected from the group consisting of DNA, RNA, viral vector, plasmid, transposon, other gene transfer systems, or a combination thereof.
  • the expression vector includes a viral vector, such as lentivirus, adenovirus, AAV virus, retrovirus, or a combination thereof.
  • the expression vector is selected from the following group: pTomo lentiviral vector, plenti, pLVTH, pLJMK pHCMV, pLBS.CAG, pHR, pLV, etc.
  • a chimeric antigen receptor CAR is provided, the antigen-binding region scFv of the CAR is a binding region that specifically binds to IL-18RP, and the heavy chain variable region of the scFv Including: heavy chain complementarity determining regions CDRHk CDRH2, CDRH3, the amino acid sequences of said CDRHk CDRH2, CDRH3 are respectively shown in SEQ ID NO: 2 > 3 and 4, or respectively shown in SEQ ID NO: 10, 3 and 11, Or as shown in SEQ ID NO: 2, 3 and 11 respectively; and/or the light chain variable region of the scFv includes: light chain complementarity determining regions CDRL1, CDRL2, CDRL3, the amino acid sequences of the CDRLK CDRL2, CDRL3 respectively As shown in SEQ ID NO: 6, 7 and 8, or respectively as shown in SEQ ID NO: 13, 7 and 8, or respectively as shown in SEQ ID NO: 16, 7 and 8, or respectively as shown in SEQ ID NO: 22, 7 and
  • L is nothing or a signal peptide sequence
  • scFv is a domain that specifically binds IL-18R
  • H is nothing or a chain region
  • TM is the transmembrane domain
  • the TM is selected from the transmembrane region of the following histones: CD28, CD3 epsilon > CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134 , CD137, CD154, CD278, CD152, CD279, CD233, or a mutation/modification thereof, or a combination thereof.
  • the C is selected from the co-stimulatory domains of the following histones: OX40, CD2, CD7, CD27, CD28, CD30, CD40, CD70, CD134, 4-1BB (CD137), PD-1, DaplO, LIGHT. NKG2C,
  • an engineered immune cell expressing the exogenous CAR as described in the sixth aspect of the present invention.
  • the engineered immune cells are selected from the following group:
  • CAR-T cells chimeric antigen receptor T cells
  • the engineered immune cells include autologous or allogeneic Qiu T cells, secondary T cells, NKT cells, NK cells, or a combination thereof.
  • the engineered immune cells are CAR-T cells.
  • an immunoconjugate which contains:
  • the part (a) is coupled to the coupling part through a chemical bond or a linker.
  • the radionuclides include:
  • therapeutic isotopes selected from the group consisting of: Lu-177, Y-90, Ac-225, As-21k Bi-212, Bi-213, Cs-137, Cr-5K Co -60, Dy-165, Er-169, Fm-255, Au-198, Ho-166, I-125, 1-131, Ir-192, Fe-59, Pb-212, Mo-99, Pd-103 , P-32, K-42, Re-186, Re-188, Sm- 153, Ra223, Ru-106, Na24, Sr89, Tb-149, Th-227, Xe-133, Yb-169. Yb-177 , or a combination thereof.
  • the IL-18-related diseases are selected from: tumors, leukemia, diabetic nephropathy, Alzheimer's disease, Parkinson's disease, arthritis, rheumatoid arthritis, multiple sclerosis, psoriasis disease, psoriatic arthritis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, lupus, systemic lupus erythematosus, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, Graves' disease, Hashimoto's thyroiditis, Addison's disease, celiac disease, dermatomyositis, multiple sclerosis, myasthenia gravis, pernicious anemia, Sjogren's syndrome, type I diabetes, type II diabetes, vasculitis, uveitis, sepsis atherosclerosis, ankylosing spondylitis, hemophagocytic lymphohistiocytosis, macrophage activation syndrome, systemic
  • the tumor is selected from: bladder cancer, liver cancer, colon cancer, rectal cancer, endometrial cancer, leukemia, lymphoma, pancreatic cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, urinary tract Cancer, head and neck cancer, gastrointestinal cancer, stomach cancer, esophageal cancer, ovarian cancer, kidney cancer, melanoma, prostate cancer, thyroid cancer, or a combination thereof.
  • the drug is a cytotoxic drug.
  • the cytotoxic drugs are selected from the group consisting of anti-tubulin drugs, DNA minor groove binding agents, DNA replication inhibitors, alkylating agents, antibiotics, folic acid antagonists, antimetabolites, chemotherapy A sensitizer, a topoisomerase inhibitor, a vinca alkaloid, or a combination thereof.
  • particularly useful cytotoxic drugs include, for example, DNA minor groove binding agents, DNA alkylating agents, and tubulin inhibitors.
  • Typical cytotoxic drugs include, for example, Auristatins.
  • Camptothecin (Camptothecins), Duocarmycins/Duocarmycins, Etoposides, Maytansines and Maytansinoids (such as DM1 and DM4), Taxanes (Taxanes ), benzodiazepines (Benzodiazepines) or drugs containing benzodiazepines (Benzodiazepine containing drugs) (such as pyrrolo [1,4] benzodiazepines (PBDs), mouth cited noise H Lin benzo two Indolinobenzodiazepines and Oxazolidinobenzodiazepines), Vinca alkaloids, or combinations thereof.
  • the immunoconjugate comprises: a multivalent (eg, bivalent) antibody or antigen-binding fragment thereof according to the first aspect of the present invention.
  • the multivalent means that the amino acid sequence of the immunoconjugate contains multiple repetitions of the same or different antibodies or antigen-binding fragments thereof as described in the first aspect of the present invention.
  • a pharmaceutical composition is provided, which contains:
  • the active ingredient, the active ingredient is selected from the following group: the antibody or antigen-binding fragment thereof according to the first aspect of the present invention, or the recombinant protein according to the second aspect of the present invention, or the seventh aspect of the present invention
  • a pharmaceutically acceptable carrier, diluent or excipient is selected from the group consisting of injections and freeze-dried preparations.
  • the pharmaceutical composition includes 0.01 ⁇ 99.99% of the antibody or antigen-binding fragment thereof as described in the first aspect of the present invention, or the recombinant protein as described in the second aspect of the present invention, or The engineered immune cell according to the seventh aspect of the present invention, or the immunoconjugate according to the ninth aspect of the present invention, or a combination thereof and 0.01-99.99% of the pharmaceutical carrier, the percentage is the percentage of the drug The mass percent of the composition.
  • the concentration of the engineered immune cells in the active ingredient is 1x103-1x108 cells/mL, preferably 1x104-1x107 cells/mL.
  • an active ingredient selected from the group consisting of: the antibody or antigen-binding fragment thereof according to the first aspect of the present invention, or the second aspect of the present invention.
  • the recombinant protein, or the engineered immune cell according to the seventh aspect of the present invention, or the immunoconjugate according to the ninth aspect of the present invention, or a combination thereof, the active ingredient is used to prepare:
  • the reagent shown is a diagnostic reagent, preferably, the diagnostic reagent is a detection chip or a detection plate.
  • the diagnostic reagent is used for: detecting IL-18RP protein or its fragments in the sample.
  • the IL-18-related diseases include diseases with high expression of IL-18, diseases related to abnormal expression of IL-18 receptor or high activity of IL-18 signaling pathway, IL-18RP-mediated disease.
  • the IL-18-related disease is an autoimmune disease or an inflammatory disease.
  • the disease with high expression of IL-18 is selected from: tumor, leukemia, diabetic nephropathy, Alzheimer's disease, Parkinson's disease, arthritis, rheumatoid arthritis, multiple sclerosis, Psoriasis, Psoriatic Arthritis, Crohn's Disease, Inflammatory Bowel Disease, Ulcerative Colitis, Lupus, Systemic Lupus Erythematosus, Juvenile Rheumatoid Arthritis, Juvenile Idiopathic Arthritis, Graves' Hashimoto's thyroiditis, Addison's disease, celiac disease, dermatomyositis, multiple sclerosis, myasthenia gravis, pernicious anemia, Sjögren's syndrome, type I diabetes, type II diabetes, vasculitis, uveitis, Sepsis, atherosclerosis, ankylosing spondylitis, hemophagocytic lymphohistiocytosis, macrophage
  • the tumor is selected from: bladder cancer, liver cancer, colon cancer, rectal cancer, endometrial cancer, leukemia, lymphoma, pancreatic cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, urinary tract Cancer, head and neck cancer, gastrointestinal cancer, stomach cancer, esophageal cancer, ovarian cancer, kidney cancer, melanoma, prostate cancer, thyroid cancer, or a combination thereof.
  • a method for in vitro detection of IL-18RP protein or its fragments in a sample comprising the steps of:
  • a thirteenth aspect of the present invention provides a kit, which includes: (1) The first container, which contains the antibody or antigen-binding fragment thereof according to the first aspect of the present invention, or the recombinant protein according to the second aspect of the present invention, or the seventh aspect of the present invention.
  • the kit contains a detection plate, and the detection plate includes: a substrate (support plate) and A test strip, the test strip contains the antibody or antigen-binding fragment thereof as described in the first aspect of the present invention, or the recombinant protein as described in the second aspect of the present invention, or the engineered protein as described in the seventh aspect of the present invention immune cells, or the immunoconjugate as described in the ninth aspect of the present invention, or the pharmaceutical composition as described in the tenth aspect of the present invention, or a combination thereof.
  • the kit also contains an instruction, and according to the instruction, the kit is used to non-invasively detect the expression of IL-18 in the subject.
  • the IL-18-related diseases are selected from: tumors, leukemia, diabetic nephropathy, Alzheimer's disease, Parkinson's disease, arthritis, rheumatoid arthritis, multiple sclerosis, psoriasis disease, psoriatic arthritis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, lupus, systemic lupus erythematosus, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, Graves' disease, Hashimoto's thyroiditis, Addison's disease, celiac disease, dermatomyositis, multiple sclerosis, myasthenia gravis, pernicious anemia, Sjogren's syndrome, type I diabetes, type II diabetes, vasculitis, uveitis, sepsis atherosclerosis, ankylosing spondylitis, hemophagocytic lymphohistiocytosis, macrophage activation syndrome, systemic
  • the tumor is selected from: bladder cancer, liver cancer, colon cancer, rectal cancer, endometrial cancer, leukemia, lymphoma, pancreatic cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, urinary tract Cancer, head and neck cancer, gastrointestinal cancer, stomach cancer, esophageal cancer, ovarian cancer, kidney cancer, melanoma, prostate cancer, thyroid cancer, or a combination thereof.
  • a method for preventing and/or treating IL-18-related diseases comprising: administering the antibody or its antigen as described in the first aspect of the present invention to a subject in need Binding fragments, or recombinant proteins as described in the second aspect of the present invention, or engineered immune cells as described in the seventh aspect of the present invention, or immunoconjugates as described in the ninth aspect of the present invention, or as described in the present invention
  • the pharmaceutical composition of the tenth aspect, or a combination thereof includes a mammal, such as a human.
  • the IL-18-related diseases include diseases with high expression of IL-18, diseases related to abnormal expression of IL-18 receptor or high activity of IL-18 signaling pathway, IL-18R0-mediated disease.
  • the IL-18-related disease is an autoimmune disease or an inflammatory disease.
  • the IL-18-related diseases are selected from: tumors, leukemia, diabetic nephropathy, Alzheimer's disease, Parkinson's disease, arthritis, rheumatoid arthritis, multiple sclerosis, psoriasis disease, psoriatic arthritis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, lupus, systemic lupus erythematosus, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, Graves' disease, Hashimoto's thyroiditis, Addison's disease, celiac disease, dermatomyositis, multiple sclerosis, myasthenia gravis, pernicious anemia, Sjogren's syndrome, type I diabetes, type II diabetes, vasculitis, uveitis, sepsis atherosclerosis, ankylosing spondylitis, hemophagocytic lymphohistiocytosis, macrophage activation syndrome, systemic
  • the tumor is selected from: bladder cancer, liver cancer, colon cancer, rectal cancer, endometrial cancer, leukemia, lymphoma, pancreatic cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, urinary tract Cancer, head and neck cancer, gastrointestinal cancer, stomach cancer, esophageal cancer, ovarian cancer, kidney cancer, melanoma, prostate cancer, thyroid cancer, or a combination thereof.
  • the engineered immune cells or the CAR immune cells contained in the pharmaceutical composition are cells derived from the subject (autologous cells).
  • the engineered immune cells or the CAR immune cells contained in the pharmaceutical composition are cells (allogeneic cells) derived from healthy individuals.
  • the samples are blood samples or throat swab samples, or samples from other tissues and organs.
  • the IL-18-related diseases include diseases with high expression of IL-18, diseases related to abnormal expression of IL-18 receptor or high activity of IL-18 signaling pathway, IL-18RP-mediated disease.
  • the IL-18-related disease is an autoimmune disease or an inflammatory disease.
  • the tumor is selected from: bladder cancer, liver cancer, colon cancer, rectal cancer, endometrial cancer, leukemia, lymphoma, pancreatic cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, urinary tract Cancer, head and neck cancer, gastrointestinal cancer, stomach cancer, esophageal cancer, ovarian cancer, kidney cancer, melanoma, prostate cancer, thyroid cancer, or a combination thereof.
  • Figure 6 shows the 72h concentration-response curve of anti-IL-18RP antibody (IgG4) inhibiting IFN- ⁇ in human PBMC cells.
  • IgG4 anti-IL-18RP antibody
  • Figure 6 shows the 72h concentration-response curve of anti-IL-18RP antibody (IgG4) inhibiting IFN- ⁇ in human PBMC cells.
  • the present inventors first developed a high-affinity IL-18RP-targeting antibody and its antigen-binding fragment.
  • the present invention uses the WT antibody of IL-18RP as the starting material for improving affinity to construct a precise mutation library, and introduces saturation mutations into all 73 residues of the six CDR regions of the WT antibody.
  • the selected mutants were sorted by the dissociation rate constants determined by surface plasmon resonance, and a combinatorial library was constructed with a random combination of beneficial mutations, thereby obtaining the IL-18RP antibody of the present invention with improved binding affinity and its Antigen-binding fragments.
  • the IL-18R0-targeting antibody and its antigen-binding fragment developed in the present invention can be used as a new therapeutic means for targeted treatment of diseases related to abnormal expression of IL-18 receptor or high activity of IL-18 signaling pathway.
  • the terms “antibody of the present invention”, “antibody of the present invention”, “antibody against IL-18RP of the present invention”, “antibody against IL-18RP”, “antibody against IL-18RJ3”, “IL -18RJ3 antibody” has the same The meanings, used interchangeably, all refer to antibodies that specifically recognize and bind to IL-18RP protein (including human IL-18RP protein).
  • the antibody numbers of the present invention and the corresponding sequence numbers are shown in Table 1 below.
  • the A035 antibody, A037 antibody, and A039 antibody of the present invention have two types of IgG1 and IgG4 respectively, wherein:
  • A035 antibody has a heavy chain sequence shown in SEQ ID NO: 30 and a light chain sequence shown in SEQ ID NO: 31;
  • A037 antibody has a heavy chain sequence shown in SEQ ID NO: 32 and The light chain sequence shown in SEQ ID NO: 33; the heavy chain sequence shown in SEQ ID NO: 34 and the light chain sequence shown in SEQ ID NO: 35 for the A039 antibody (IgG1).
  • the term "antibody” herein is intended to include full-length antibodies and any antigen-binding fragment (ie, antigen-binding portion) or single chains thereof.
  • Full-length antibodies are glycoproteins comprising at least two heavy (H) chains and two light (L) chains linked by disulfide bonds.
  • variable regions of the heavy and light chains contain the binding domains that interact with the antigen.
  • the constant region of the antibody can mediate the binding of the immunoglobulin to host tissues or factors, including various immune system cells (eg, effector cells) and the first component (Clq) of the traditional complement system.
  • the antibody's "Antigen-binding fragment” refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (eg, IL-18RP protein). It has been demonstrated that the antigen-binding function of antibodies Functions can be performed by fragments of full-length antibodies.
  • the two domains VL and VH of the Fv fragment are encoded by different genes, they can be linked by recombinant methods via a synthetic linker making the two into a single protein chain, wherein the VL and VH regions pair to form a monovalent molecule) (called is a single-chain Fc (scFv)).
  • scFv single-chain Fc
  • These single chain antibodies are also intended to be included within the meaning of the term.
  • These antibody fragments can be obtained by common techniques known to those skilled in the art, and the fragments can be functionally screened in the same manner as whole antibodies.
  • the term "variable" means that certain portions of the variable regions of antibodies differ in sequence, which contribute to the binding and specificity of each particular antibody for its particular antigen.
  • variable domains are not evenly distributed throughout antibody variable domains. It is concentrated in three segments called complementarity determining regions (CDRs) or hypervariable regions in the light and heavy chain variable regions. The more conserved portions of the variable domains are called the framework regions (FR).
  • CDRs complementarity determining regions
  • FR framework regions
  • the variable domains of the native heavy and light chains each contain four FR regions in a roughly
  • the CDRs in each chain are brought into close proximity by the FR regions and together with the CDRs of the other chain form the antigen-binding site of the antibody (see Kabat et al., NIH Publ. No. 91-3242, Vol. I, pp. 647-669 (1991)).
  • the constant regions are not directly involved in the binding of the antibody to the antigen, but they exhibit different effector functions, for example involved in the antibody-dependent cytotoxicity of the antibody.
  • Those skilled in the art can define the amino acid sequence boundaries of CDRs using any of a variety of known numbering schemes, including those set forth in: Kabat et al., supra ("Kabat”) numbering scheme); Al-Lazikani et al., 1997, J.Mol.Biol., 273:927-948 ("Chothia” numbering scheme); Lefhmc et al., Dev. Comp. Immunol., 2003, 27:55-77 (“IMGT” numbering scheme).
  • immunoconjugates and fusion expression products include: drugs, toxins, cytokines (Cytokine), radionuclides, enzymes and other diagnostic or therapeutic molecules combined with antibodies or fragments thereof of the present invention formed of conjugates.
  • the present invention also includes cell surface markers or antigens that bind to the antibody against IL-18RP or its fragments.
  • the terms “heavy chain variable region” and “VH” are used interchangeably.
  • the terms “light chain variable region” and “VL” are used interchangeably.
  • variable region and '' complementarity determining region (Complementarity determining region, CDR) are used interchangeably.
  • the heavy chain variable region of the antibody includes three complementarity determining regions, CDRHk, CDRH2, and CDRH3.
  • the heavy chain of the antibody includes the above-mentioned heavy chain variable region and heavy chain constant region.
  • the light chain variable region of the antibody includes three complementarity determining regions CDRL1, CDRL2, and CDRL3.
  • the light chain of the antibody includes the above-mentioned light chain variable region and light chain constant region.
  • the terms "antibody of the present invention”, “protein of the present invention”, or “polypeptide of the present invention” are used interchangeably, and all refer to a polypeptide that specifically binds IL-18RP protein, such as a protein with a heavy chain variable region or peptides. They may or may not contain starting methionine.
  • the invention also provides other proteins or fusion expression products having the antibodies of the invention.
  • the present invention includes any protein or protein conjugates and fusion expression products (ie, immunoconjugates and fusion expression products) having a heavy chain containing a variable region, as long as the variable region and the heavy chain of the antibody of the present invention The variable regions are identical or at least 90% homologous, preferably at least 95% homologous.
  • variable region which is separated into four framework regions (FR), and four FR amino acids
  • FR framework regions
  • FR framework regions
  • the polypeptide fragments, derivatives or analogs of the present invention may be (1) a polypeptide having one or more conservative or non-conservative amino acid residues (preferably conservative amino acid residues) substituted, and such substituted amino acid residues may be It may also not be encoded by the genetic code, or (ii) have a substituent in one or more amino acid residues, or (iii) combine the mature polypeptide with another compound (such as a compound that extends the half-life of the polypeptide, such as polyethylene glycol A polypeptide formed by fusion of a diol), or (iv) a polypeptide formed by fusing an additional amino acid sequence to the polypeptide sequence (such as a leader sequence or a secretory sequence or a sequence used to purify the polypeptide or a proprotein sequence, or with a 6His tag formed fusion protein).
  • another compound such as a compound that extends the half-life of the polypeptide, such as polyethylene glycol A polypeptide formed by fusion
  • the antibody of the present invention refers to a polypeptide that has IL-18RP protein binding activity and includes the above CDR region.
  • the term also includes variant forms of polypeptides comprising the above CDR regions that have the same function as the antibodies of the present invention. These variations include (but are not limited to): one or more (usually 1-50, preferably 1-30, more preferably 1-20, and most preferably 1-10) amino acid deletions , insertion and/or substitution, and addition of one or several (usually within 20, preferably within 10, more preferably within 5) amino acids at the C-terminal and/or N-terminal.
  • substitutions with amino acids with similar or similar properties generally do not change the function of the protein.
  • substitutions with amino acids with similar or similar properties generally do not change the function of the protein.
  • at the C-terminal and/or N-terminal Adding one or several amino acids to the end usually does not change the function of the protein.
  • the term also includes active fragments and active derivatives of the antibodies of the invention.
  • Variant forms of the polypeptide include: homologous sequences, conservative variants, allelic variants, natural mutants, induced mutants, and DNAs that can hybridize with the DNA encoding the antibody of the present invention under high or low stringency conditions The encoded protein, and the polypeptide or protein obtained by using the antiserum against the antibody of the present invention.
  • the invention also provides other polypeptides, such as fusion proteins comprising antibodies or fragments thereof.
  • the invention also includes fragments of the antibodies of the invention.
  • the fragment has at least about 50 contiguous amino acids, preferably at least about 50 contiguous amino acids, more preferably at least about 80 contiguous amino acids, and most preferably at least about 100 contiguous amino acids of an antibody of the invention.
  • the "conservative variant of the antibody of the present invention” refers to at most 10, preferably at most 8, more preferably at most 5, and most preferably at most 3 amino acid sequences compared with the amino acid sequence of the antibody of the present invention.
  • the present invention also provides a polynucleotide molecule encoding the above-mentioned antibody or its fragment or its fusion protein.
  • the polynucleic acid of the present invention can be in the form of DNA or RNA.
  • Forms of DNA include cDNA, genomic DNA or synthetic DNA.
  • DNA can be single-stranded or double-stranded.
  • DNA can be either the coding strand or the non-coding strand.
  • a polynucleotide encoding a mature polypeptide of the present invention includes: a coding sequence that encodes only the mature polypeptide; a coding sequence for the mature polypeptide and various additional coding sequences; a coding sequence for the mature polypeptide (and optional additional coding sequences) and non-coding sequences .
  • the term "polynucleotide encoding a polypeptide" may include the polynucleotide encoding the polypeptide, or may also include the attached Polynucleotides with coding and/or non-coding sequences added.
  • the present invention also relates to polynucleotides that hybridize to the above-mentioned sequences and have at least 50%, preferably at least 70%, and more preferably at least 80% identity between the two sequences.
  • the present invention particularly relates to a polynucleotide hybridizable to the polynucleotide of the present invention under stringent conditions.
  • stringent conditions refer to: (1) hybridization and elution at lower ionic strength and higher temperature, such as 0.2xSSC, 0.1%SDS, 60°C; or (2) hybridization with With denaturant, such as 50% (v/v) formamide, 0.1% calf serum/0.1% Ficoll, 42°C, etc.; or (3) only if the identity between the two sequences is at least 90%, better Hybridization occurs only when it is more than 95%.
  • the polypeptide encoded by the hybridizable polynucleotide has the same biological function and activity as the mature polypeptide.
  • the biomolecules (nucleic acid, protein, etc.) involved in the present invention include biomolecules in an isolated form.
  • the DNA sequence encoding the protein of the present invention (or its fragment, or its derivative) can be obtained completely through chemical synthesis.
  • This DNA sequence can then be introduced into various existing DNA molecules (or eg vectors) and cells known in the art.
  • mutations can also be introduced into the protein sequences of the invention by chemical synthesis.
  • the present invention also relates to vectors comprising the above-mentioned appropriate DNA sequences and appropriate promoter or control sequences.
  • the host cell may be a prokaryotic cell, such as a bacterial cell; or a lower eukaryotic cell, such as a yeast cell; or a higher eukaryotic cell, such as a mammalian cell.
  • a prokaryotic cell such as a bacterial cell
  • a lower eukaryotic cell such as a yeast cell
  • a higher eukaryotic cell such as a mammalian cell.
  • Representative examples are: Escherichia coli, Streptomyces; bacterial cells of Salmonella typhimurium; fungal cells such as yeast; insect cells of Drosophila S2 or Sf9; animal cells of CHO, COS7, 293 cells, etc. Transformation of host cells with recombinant DNA can be performed using conventional techniques well known to those skilled in the art.
  • the host is a prokaryotic organism such as E.
  • the selected promoter is induced by an appropriate method (such as temperature shift or chemical induction), and the cells are cultured for an additional period of time.
  • the recombinant polypeptide in the above method can be expressed inside the cell, or on the cell membrane, or secreted outside the cell.
  • the recombinant protein can be isolated and purified by various separation methods by taking advantage of its physical, chemical and other properties, if necessary. this These methods are well known to those skilled in the art.
  • Examples of these methods include, but are not limited to: conventional refolding treatment, treatment with protein precipitating agents (salting out method), centrifugation, osmotic disruption, supertreatment, ultracentrifugation, molecular sieve chromatography (gel filtration), adsorption layer Analysis, ion exchange chromatography, high performance liquid chromatography (HPLC) and various other liquid chromatography techniques and combinations of these methods.
  • the antibodies of the present invention can be used alone, or can be combined or conjugated with detectable markers (for diagnostic purposes), therapeutic agents, PK (protein kinase) modifying moieties, or any combination of these substances.
  • Detectable markers for diagnostic purposes include, but are not limited to: fluorescent or luminescent markers, radioactive markers, MRI (magnetic resonance imaging) or CT (computed tomography) contrast agents, or enzyme.
  • Therapeutic agents that can be combined or coupled with the antibody of the present invention include, but are not limited to: 1. Radionuclides; 2. Biotoxins; 3. Cytokines such as IL-2, etc.; 4. Gold nanoparticles/nanorods; 5. Viruses 6. Liposomes; 7. Nanomagnetic particles; 8. Prodrug-activating enzymes (for example, DT-diaphorase (DTD) or biphenylhydrolase-like protein (BPHL)), etc.
  • DTD DT-diaphorase
  • BPHL biphenylhydrolase-like protein
  • IL-18 Interleukin-18
  • IL-18 also known as interferon-y inducible factor
  • IL-18 is a protein that in humans is encoded by the IL-18 gene.
  • the protein encoded by this gene is a pro-inflammatory cytokine.
  • the IL-18 receptor consists of an inducible component, IL-18Ra, which binds mature IL-18 with low affinity, and a constitutively expressed co-receptor, IL-18RP. Binding of IL-18 to the ligand receptor IL-18Ra induces the recruitment of IL-18Rp to form a high-affinity complex that signals through the toll/interleukin-1 receptor (TIR) domain. This signaling domain activates the pro-inflammatory program and the MyD88 adapter protein of the NF-KB pathway. IL-18 is specifically expressed in immune cells and is a receptor necessary for IL-18 to transmit signals. Therefore, antibodies targeting IL-18RP can specifically and effectively inhibit IL-18 signaling.
  • TIR toll/interleukin-1 receptor
  • compositions which contain the above-mentioned antibody or its active fragment or its fusion protein, and a pharmaceutically acceptable carrier.
  • these materials can be formulated in a non-toxic, inert and pharmaceutically acceptable aqueous carrier medium, wherein the pH is usually about 5-8, preferably about 6-8, although the pH value can vary with the Depending on the nature of the substance formulated and the condition to be treated.
  • the formulated pharmaceutical composition can be administered by conventional routes, including (but not limited to): intraperitoneal, intravenous, or topical administration.
  • the pharmaceutical composition of the present invention contains a safe and effective amount (such as 0.001-99 wt%, preferably 0.01-90 wt%, more preferably 0.1-80 wt%) of the above-mentioned antibody (or its conjugate) of the present invention and pharmaceutically acceptable carrier or excipient.
  • Such carriers include (but are not limited to): saline, buffer, glucose, water, glycerol, ethanol, and combinations thereof.
  • the pharmaceutical formulation should match the mode of administration.
  • the pharmaceutical composition of the present invention can be prepared in the form of injection, for example, by conventional methods using physiological saline or aqueous solution containing glucose and other adjuvants. Pharmaceutical compositions such as injections and solutions are preferably Manufactured under sterile conditions.
  • the active ingredient is administered in a therapeutically effective amount, eg, about 10 micrograms/kg body weight to about 50 mg/kg body weight per day.
  • a therapeutically effective amount eg, about 10 micrograms/kg body weight to about 50 mg/kg body weight per day.
  • the polypeptides of the invention can also be used with other therapeutic agents.
  • a safe and effective amount of the immunoconjugate is administered to the mammal, wherein the safe and effective amount is usually at least about 10 micrograms/kg body weight, and in most cases no more than about 50 mg/kg body weight, Preferably the dose is about 10 micrograms/kg body weight to about 10 mg/kg body weight.
  • factors such as the administration route and the patient's health status should also be considered for the specific dose, which are within the skill of skilled physicians.
  • the antibody or antigen-binding fragment thereof of the present invention is based on the heavy chain variable region shown in SEQ ID NO: 18 and/or based on the light chain variable region shown in SEQ ID NO: 20 comprises selected from the group Beneficial mutations: F27L, F27I, F27V, S99A, S31F, A34D, A34E; the antibody or its antigen-binding fragment also includes at least one (such as 1-4) amino acids that are optionally added, deleted, modified and/or substituted An antibody or an antigen-binding fragment thereof that can retain the ability to specifically bind to IL-18RP.
  • the antibody or antigen-binding fragment thereof has a heavy chain variable region as shown in SEQ ID NO: 1, 9 or 14, and has a heavy chain variable region as shown in SEQ ID NO: 5, 12, 15 Or the light chain variable region shown in 17.
  • the antibody against IL-18RP or its antigen-binding fragment includes one or more heavy chains as shown in SEQ ID NO: 24, 26, 28, 30, 32 or 34, and having a light chain as shown in SEQ ID NO: 25, 27, 29, 31, 33 or 35.
  • Labeled antibody In a preferred embodiment of the present invention, the antibody bears a detectable label. More preferably, the label is selected from the group consisting of isotopes, colloidal gold labels, colored labels or fluorescent labels.
  • Colloidal gold labeling can be performed by methods known to those skilled in the art.
  • the antibody against IL-18RP protein is labeled with colloidal gold to obtain a colloidal gold-labeled antibody.
  • the antibody against IL-18RP of the present invention can effectively bind IL-18RP protein.
  • Detection methods The present invention also relates to methods for detecting IL-18RP protein or fragments thereof. The steps of the method are roughly as follows: obtain a cell and/or tissue sample; dissolve the sample in a medium; detect the level of IL-18RP protein in the dissolved sample.
  • the sample used is not particularly limited, and a representative example is a cell-containing sample present in a cell preservation solution.
  • Kit The present invention also provides a kit containing the antibody (or a fragment thereof) or a detection plate of the present invention.
  • the kit further includes a container, an instruction manual, a buffer, etc. .
  • the present invention also provides a detection kit for detecting the level of IL-18RP protein, which includes an antibody for recognizing IL-18R& protein, a lysis medium for dissolving samples, general reagents and buffers required for detection, such as various buffer, detection label, detection substrate, etc.
  • the test kit may be an in vitro diagnostic device.
  • CAR-T can treat all cancers that express that antigen.
  • CAR-T cells are able to replicate in vivo, resulting in long-term persistence that can lead to sustained tumor control.
  • the CAR-T cells of the present invention can undergo stable in vivo expansion and last for several months to several years.
  • the CAR-mediated immune response can be part of an adoptive immunotherapy step, in which CAR-T cells can induce a specific immune response to tumor cells with high expression of the antigen recognized by the CAR antigen-binding domain.
  • the CAR-T cells of the present invention elicit a specific immune response against tumor cells with high expression of IL-18RP.
  • Treatable cancers include tumors that are not or substantially not vascularized, as well as vascularized tumors.
  • Cancer types treated with the CAR of the present invention include, but are not limited to: gastric cancer, lung cancer, liver cancer, osteosarcoma, breast cancer, pancreatic cancer, lymphoma, and the like.
  • cells activated and expanded as described herein can be used for the treatment and prevention of diseases such as tumors. Accordingly, the present invention provides a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a CAR-T cell of the present invention.
  • compositions comprising T cells described herein can be dosed at 1.4 to 10.
  • a dose of 2 cells/kg body weight, preferably 1.5 to 10 ⁇ cells/kg body weight (including all integer values within the range) is administered.
  • T cell compositions can also be administered multiple times at these doses.
  • Cells can be administered using infusion techniques well known in immunotherapy (see, eg, Rosenberg et al., New Eng.
  • compositions described herein can be administered to a patient subcutaneously, intradermally, intratumorally, intranodally, intraspinally, intramuscularly, by intravenous injection or intraperitoneally.
  • a T cell composition of the invention is administered to a patient by intradermal or subcutaneous injection.
  • the T cell composition of the invention is preferably administered by intravenous injection.
  • compositions of T cells can be injected directly into tumors, lymph nodes or sites of infection.
  • cells activated and expanded using the methods described herein, or other methods known in the art to expand T cells to therapeutic levels are combined with any number of relevant treatment modalities (e.g., previously , simultaneously or subsequently) to the patient in the form of treatment including but not limited to treatment with agents such as antiviral therapy, cidofovir and interleukin-2, cytarabine (also known ARA-C) or natalizumab in MS patients or erfatizumab in psoriasis or other treatments in PML.
  • agents such as antiviral therapy, cidofovir and interleukin-2, cytarabine (also known ARA-C) or natalizumab in MS patients or erfatizumab in psoriasis or other treatments in PML.
  • the T cells of the present invention can be used in combination with: chemotherapy, radiation, immunosuppressants, such as cyclosporine, thiazolin, methotrexate, mycophenolate mofetil and FK506, antibodies or other immunotherapeutic agents.
  • the cell composition of the invention is administered in combination with (eg, before, simultaneously with or after) bone marrow transplantation, the use of chemotherapeutic agents such as fludarabine, external beam radiation therapy (XRT), cyclophosphamide patient.
  • chemotherapeutic agents such as fludarabine, external beam radiation therapy (XRT), cyclophosphamide patient.
  • a subject may undergo standard treatment with high-dose chemotherapy followed by peripheral blood stem cell transplantation.
  • the subject receives an infusion of expanded immune cells of the invention.
  • the expanded cells are administered before or after surgery. Dosages administered to a patient for the above treatments will vary with the precise nature of the condition being treated and the recipient of the treatment. Dosage ratios for human administration can be implemented according to practice accepted in the art. Usually, 1 x 105 to 1 x 10 modified T cells of the present invention can be administered to the patient for each treatment or each course of treatment, for example, through intravenous infusion.
  • the main advantages of the present invention include:
  • the IL-18RP antibody or antigen-binding fragment thereof of the present invention can specifically bind IL-18RP with high affinity, which is more than ten times higher than that of WT, and the highest is 22 times higher.
  • the IL-18RP antibody or antigen-binding fragment thereof of the present invention has good IL-18/IL-18R blocking activity, and can effectively inhibit IL-18 downstream inflammatory signaling pathways.
  • the IL-18RP antibody or antigen-binding fragment thereof of the present invention has advantages in terms of specificity, effectiveness and safety.
  • the IL-18RP antibody or antigen-binding fragment thereof of the present invention is effective in treating IL-18-related diseases (including but not limited to diseases with high expression of IL-18, related to abnormal expression of IL-18 receptor or related to IL-18 signaling Contribute to the prevention/diagnosis/treatment of diseases related to high activity of pathways, IL-18RP-mediated diseases), and provide new methods and technical means.
  • IL-18-related diseases including but not limited to diseases with high expression of IL-18, related to abnormal expression of IL-18 receptor or related to IL-18 signaling
  • Contribute to the prevention/diagnosis/treatment of diseases related to high activity of pathways, IL-18RP-mediated diseases Contribute to the prevention/diagnosis/treatment of diseases related to high activity of pathways, IL-18RP-mediated diseases.
  • the present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention but not to limit the scope of the present invention.
  • SEQ ID NO: 30 A035 antibody (IgG1) heavy chain
  • SEQ ID NO: 32 A037 antibody (IgG1) heavy chain

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Abstract

La présente invention concerne un anticorps ciblant IL-18Rβ ou un fragment de liaison à l'antigène de celui-ci, son procédé de préparation et ses utilisations. Plus particulièrement, la présente invention concerne également une molécule d'acide nucléique codant pour l'anticorps ou le fragment de liaison à l'antigène de celui-ci, un vecteur d'expression correspondant, une cellule hôte capable d'exprimer l'anticorps ou le fragment de liaison à l'antigène de celui-ci, et un procédé de production et les utilisations de l'anticorps ou du fragment de liaison à l'antigène. L'anticorps ciblant l'IL-18Rβ ou le fragment de liaison à l'antigène de celui-ci peut se lier de manière spécifique à l'IL-18Rβ humaine, a une affinité bien supérieure à celle d'un anticorps de type sauvage, et a une activité de blocage d'IL-18/IL-18 élevée. L'anticorps ou le fragment de liaison à l'antigène de celui-ci selon la présente invention fournit un nouveau moyen technique pour la prévention/le diagnostic/le traitement de maladies associées à une expression anormale d'un récepteur d'IL-18 ou associées à une activité élevée d'une voie de signalisation d'IL-18.
PCT/CN2023/072444 2022-01-14 2023-01-16 ANTICORPS CIBLANT IL-18Rβ ET SES UTILISATIONS WO2023134767A1 (fr)

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CN202210108473.8 2022-01-28
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030190318A1 (en) * 1996-12-26 2003-10-09 Kakuji Torigoe Interleukin-18-receptor proteins
US20080063644A1 (en) * 2004-07-16 2008-03-13 Atsuo Sekiyama Il-18 Receptor Antagonist and Pharmaceutical Composition Containing the Antagonist
CN101835489A (zh) * 2007-07-24 2010-09-15 安美基公司 Il-18受体抗原结合蛋白
CN103080132A (zh) * 2010-08-25 2013-05-01 弗·哈夫曼-拉罗切有限公司 抗il-18r1的抗体及其用途
CN112638945A (zh) * 2018-06-19 2021-04-09 上海科技大学 人白介素18受体α和β的人抗体

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JOP20200308A1 (ar) * 2012-09-07 2017-06-16 Novartis Ag جزيئات إرتباط il-18

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030190318A1 (en) * 1996-12-26 2003-10-09 Kakuji Torigoe Interleukin-18-receptor proteins
US20080063644A1 (en) * 2004-07-16 2008-03-13 Atsuo Sekiyama Il-18 Receptor Antagonist and Pharmaceutical Composition Containing the Antagonist
CN101835489A (zh) * 2007-07-24 2010-09-15 安美基公司 Il-18受体抗原结合蛋白
CN103080132A (zh) * 2010-08-25 2013-05-01 弗·哈夫曼-拉罗切有限公司 抗il-18r1的抗体及其用途
CN112638945A (zh) * 2018-06-19 2021-04-09 上海科技大学 人白介素18受体α和β的人抗体

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