WO2023134767A1 - ANTIBODY TARGETING IL-18Rβ AND USES THEREOF - Google Patents

Abstract

Provided in the present invention are an antibody targeting IL-18Rβ or an antigen-binding fragment thereof, a preparation method therefor and the uses thereof. Specifically, the present invention also provides a nucleic acid molecule encoding the antibody or the antigen-binding fragment thereof, a corresponding expression vector, a host cell capable of expressing the antibody or the antigen-binding fragment thereof, and a production method for and the uses of the antibody or the antigen-binding fragment. The antibody targeting IL-18Rβ or the antigen-binding fragment thereof can specifically bind to human IL-18Rβ, has an affinity far higher than that of a wild-type antibody, and has high IL-18/IL-18R blocking activity. The antibody or the antigen-binding fragment thereof in the present invention provides a new technical means for prevention/diagnosis/treatment of diseases related to abnormal expression of an IL-18 receptor or related to high activity of an IL-18 signaling pathway.

Description

An Antibody Targeting IL-18RP and Its Application Technical Field The present invention belongs to the field of biomedicine, and in particular relates to an antibody specifically targeting IL-18RP and its antigen-binding fragment, its preparation method and application. Background Art Interleukin-18 (Interleukin-18, IL-18), also known as interferon-y inducible factor, regulates inflammatory responses mediated by various types of immune cells. IL-18 not only activates Thl cells and NK cells, but also promotes IFN- Y release, and regulate Th2, Thl7 and macrophage activation, is an important pro-inflammatory factor. Many studies have found that IL-18 is closely related to a variety of autoimmune diseases, such as hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndrome, atopic dermatitis, idiopathic pulmonary fibrosis , scleroderma, systemic juvenile idiopathic arthritis (Systemic juvenile idiopathic arthritis, sJIA), systemic lupus erythematosus (Systemic lupus erythematosus, SLE), and inflammatory bowel disease, etc.

The IL-18 receptor is a heterodimeric transmembrane protein composed of the ligand-binding IL-18R alpha (IL-18Ra) subunit and the IL-18R beta (IL-18R& ) subunit composition.

After IL-18 is hydrolyzed into an active form by protease Caspas-1, it acts on the IL-18 receptor on the cell surface and activates the downstream pro-inflammatory signaling pathway. IL-18 first binds to IL-18Ra with a lower affinity to form a dimer, but It cannot transmit signals, and only the dimer combines with IL-18RP to form a high-affinity receptor complex to transmit pro-inflammatory signals downstream. Blocking the formation of IL-18 and its receptor ternary complex and effectively inhibiting the downstream inflammatory signaling pathway of IL-18 is a promising method for the treatment of autoimmune diseases and inflammatory diseases.

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. Therefore, there is an urgent need in this field to develop an antibody specifically targeting IL-18RP for the treatment of autoimmune diseases and inflammatory diseases. SUMMARY OF THE INVENTION 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. In the first aspect of the present invention, an antibody against IL-18RP or an antigen-binding fragment thereof is provided. In another preferred embodiment, the antibody or its antigen-binding fragment can specifically bind IL- _18Rp. In another preferred embodiment, the antibody or its antigen-binding fragment is based on the wild-type recombinant shown in SEQ ID NO: 18 The chain variable region and/or the wild-type light chain variable region based on SEQ ID NO: 20 may include beneficial mutations selected from the group consisting of F27L, F27L F27V, S99A, S31F, A34D, A34E, or combinations thereof. In another preferred example, the antibody or antigen-binding fragment thereof further includes optionally added, deleted, modified and

In another preferred example, the antibody or antigen-binding fragment thereof may include beneficial mutations selected from the group consisting of F27L, F27L, F27V, S99A, or combination. In another preferred example, the antibody or antigen-binding fragment thereof may include beneficial mutations selected from the following group based on the wild-type light chain variable region shown in SEQ ID NO: 20: S31F, A34D, A34E, or a combination thereof . In another preferred example, the antibody or antigen-binding fragment thereof is based on the wild-type heavy chain variable region shown in SEQ ID NO: 18 and/or based on the wild-type light chain variable region shown in SEQ ID NO: 20 Having a beneficial mutation selected from the group, or a combination thereof:

S31F, A34E, F27L;

S31F, A34E, F27L S99A;

A34D, F27I, S99A;

S31F, A34D, F27L;

A34E, F27I;

A34D, F27I;

A34E, F27L;

S31F, A34D, F27V, S99A;

A34E, F27L, S99A; or

S31F, A34E, F27Lo In another preferred embodiment, 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. In another preferred example, 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. In another preferred example, 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. In another preferred example, 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

(b) light chain complementarity determining regions CDRL1, CDRL2, CDRL3, the amino acid sequences of CDRLk CDRL2, CDRL3 are shown in SEQ ID NO: 6, 7 and 8 respectively, or as shown in SEQ ID NO: 13 > 7 and 8 respectively or as shown in SEQ ID NO: 16, 7 and 8 respectively, or as shown in SEQ ID NO: 22, 7 and 8 respectively. In another preferred example, any amino acid sequence in the above amino acid sequence also includes at least one (such as 1-4) amino acid residues that are optionally added, deleted, modified and/or substituted and can retain the IL-18RP Derived sequences for specific binding capacity. In another preferred example, 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. In another preferred example, 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. In another preferred example, the CDRK CDR2 and CDR3 are separated by framework regions FR1, FR2, FR3 and FR4. In another preferred example, the antibody or antigen-binding fragment thereof further includes a framework region FRo. In another preferred example, 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. In another preferred example, the amino acids of the heavy chain variable region and the light chain variable region of the antibody or its antigen-binding fragment

In another preferred embodiment, the antibody or antigen-binding fragment thereof is a murine antibody, a chimeric antibody, a humanized antibody or a fully human antibody. In another preferred example, the antibody or antigen-binding fragment thereof may include a monomer, a bivalent antibody, and/or a multivalent antibody. In another preferred example, the bivalent antibody can also be a bispecific antibody. In another preferred example, the multivalent antibody can also be a multispecific antibody. In another preferred example, the antigen-binding fragment is selected from scFv, Fab, Fab\F(ab')2, Fv, disulfide bonded Fv (dsFv), or sdAbo In the second aspect of the present invention, there is provided A recombinant protein is provided, and the recombinant protein has:

(1) the antibody or antigen-binding fragment thereof according to the first aspect of the present invention; and

(ii) Optional tag sequences to aid in expression and/or purification. In another preferred example, the tag sequence includes Fc tag, HA tag, GGGS sequence U, FLAG tag, Myc tag, 6His tag, or a combination thereof. In another preferred example, the recombinant protein specifically binds IL- _18Rp. In another preferred example, the recombinant protein (or polypeptide) includes a fusion protein. In another preferred embodiment, the recombinant protein is a monomer, a dimer, or a multimer. In the third aspect of the present invention, there is provided a nucleic acid molecule, the polynucleotide encoding a protein selected from the following group: the antibody or antigen-binding fragment thereof as described in the first aspect of the present invention, or the second Aspects of the recombinant protein. In another preferred embodiment, the nucleic acid of the present invention can be RNA, DNA or cDNA. In another preferred example, the nucleic acid molecule includes a heavy chain nucleic acid sequence and a light chain nucleic acid sequence. In another preferred example, the heavy chain nucleotide sequence is selected from SEQ ID NO: 36, 38, 40, 42, 44, 46, or a combination thereof. In another preferred example, the light chain nucleic acid sequence is selected from SEQ ID NO: 37, 39, 41, 43, 45, 47, or a combination thereof. In another preferred example, 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 nucleotide sequence shown in SEQ ID NO: 46 and the sequence shown in SEQ ID NO: The light chain nucleotide sequence shown in 47. In the fourth aspect of the present invention, an expression vector is provided, which contains the expression vector described in the third aspect of the present invention Nucleic Acid Molecule. In another preferred embodiment, the expression vector is selected from the group consisting of DNA, RNA, viral vector, plasmid, transposon, other gene transfer systems, or a combination thereof. Preferably, the expression vector includes a viral vector, such as lentivirus, adenovirus, AAV virus, retrovirus, or a combination thereof. In another preferred example, the expression vector is selected from the following group: pTomo lentiviral vector, plenti, pLVTH, pLJMK pHCMV, pLBS.CAG, pHR, pLV, etc. In another preferred example, the expression vector further includes a promoter, a transcriptional enhancer element WPRE, a long terminal repeat sequence LTR, etc. selected from the group. In the fifth aspect of the present invention, a host cell is provided, the host cell contains the expression vector described in the fourth aspect of the present invention, or the nucleotide molecule described in the third aspect of the present invention is integrated in its genome . In another preferred example, the host cells include prokaryotic cells or eukaryotic cells. In another preferred example, the host cell is selected from the group consisting of Escherichia coli, yeast cells, and mammalian cells. In the sixth aspect of the present invention, 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 8 are shown. In another preferred example, the CAR further includes a signal peptide. In another preferred example, the CAR further includes other foreign proteins. In another preferred example, the CAR has a structure shown in formula la:

L-scFv-H-TM-C-CD3] (la) In the formula,

L is nothing or a signal peptide sequence; scFv is a domain that specifically binds IL-18R|3;

H is nothing or a chain region;

TM is the transmembrane domain;

C is costimulatory signal domain;

CD3] is a cytoplasmic signal transduction sequence derived from CD3] (including wild type, or a mutant/modified thereof); the connecting peptide or peptide bond. In another preferred example, the Ls are respectively selected from signal peptides of the following histones: CD8, GM-CSF, CD4, CD28, CD137, or mutants/modifications thereof, or combinations thereof. In another preferred example, the scFv targets IL-18R6. In another preferred example, the scFv is an IL-18R0 antibody or an antigen-binding fragment thereof. In another preferred embodiment, the H is selected from the H chain region of the following histones: CD8, CD28, CD137, IgG, or a combination thereof. In another preferred embodiment, 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. In another preferred example, 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,

In the seventh aspect of the present invention, there is provided an engineered immune cell expressing the exogenous CAR as described in the sixth aspect of the present invention. In another preferred example, the engineered immune cells are selected from the following group:

(i) chimeric antigen receptor T cells (CAR-T cells);

(ii) chimeric antigen receptor modified T cells (CAR-T cells);

(iii) chimeric antigen receptor NKT cells (CAR-NKT cells);

(iv) Chimeric antigen receptor NK cells (CAR-NK cells). In another preferred embodiment, the engineered immune cells include autologous or allogeneic Qiu T cells, secondary T cells, NKT cells, NK cells, or a combination thereof. In another preferred example, the engineered immune cells are CAR-T cells. In the eighth aspect of the present invention, there is provided a method for producing an antibody against IL-18RP or an antigen-binding fragment thereof, comprising the steps of:

(a) under suitable conditions, culturing the host cell according to the fifth aspect of the present invention, thereby obtaining a culture of an antibody or antigen-binding fragment thereof containing IL-18RP;

(b) isolating and/or recovering said antibody against IL-18RP or an antigen-binding fragment thereof from said culture; and

(c) Optionally, purifying and/or modifying the IL-18RP antibody or antigen-binding fragment thereof obtained in step (b). In the ninth aspect of the present invention, an immunoconjugate is provided, which contains:

(a) an antibody portion comprising the antibody or antigen-binding fragment thereof according to the first aspect of the present invention; and

(b) a conjugation moiety selected from the group consisting of detectable labels, drugs, toxins, cytokines, radionuclides, enzymes, gold nanoparticles/nanorods, nanomagnetic particles, viral coat proteins or VLPs, or combinations thereof . In another preferred example, the part (a) is coupled to the coupling part through a chemical bond or a linker. In another preferred example, the radionuclides include:

(i) isotopes for diagnosis, the isotopes for diagnosis are selected from the group consisting of Tc-99m, Ga-68, F-18, 1-123, I-125, 1-131, In-111, Ga-67, Cu-64, Zr-89, C-ll, Lu-177, Re-188, or combinations thereof; and/or

(ii) 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. In another preferred example, the coupling moiety is a drug or a toxin. In another preferred example, the drug is a drug for targeted treatment of IL-18-related diseases. In another preferred example, 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. In another preferred example, the IL-18-related disease is an autoimmune disease or an inflammatory disease. In another preferred example, 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 lupus erythematosus, septic arthritis, pyoderma gangrenosum, atopic dermatitis, atopic Idiopathic pulmonary fibrosis, scleroderma, systemic juvenile idiopathic arthritis (sJIA), inflammatory bowel disease (IBD), adult Still's disease (AOSD), chronic obstructive pulmonary disease (COPD), or Pulmonary nodules, or a combination thereof. In another preferred example, 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. In another preferred example, the drug is a cytotoxic drug. In another preferred example, 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. Examples of 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. In another preferred example, the toxin is selected from the group consisting of auristatins (for example, auristatin E, auristatin F, MMAE and MMAF), aureomycin, maytansinol, ricin, grate Anesthetic toxin A-chain, combretastatin, docarmycin, dolastatin, doxorubicin, daunorubicin, paclitaxel, cisbox, CC1065, ethidium bromide, mitomycin, etopol or, Tenoposide (Tenoposide), vincristine, vinblastine, colchicine, dihydroxyanthraxin diketone, actinomycin, diphtheria toxin, Pseudomonas exotoxin (PE) A, PE40, acacia Soybean toxin, abrin A chain, cucurbit root toxin A chain, a-sarcinia, gelonin, Mitogellin, Retstricttocin, phenomycin, enomycin, Curicin, crotonin, calicheamicin, Sapaonaria officinalis inhibitors, glucocorticoids, or combinations thereof. In another preferred example, the coupling moiety is a detectable label. In another preferred embodiment, the coupling moiety is selected from the group consisting of fluorescent or luminescent markers, radioactive markers, MRI (Magnetic Resonance Imaging) or CT (Computed X-ray Tomography) contrast agents, or capable of producing Detectable products of enzymes, radionuclides, biotoxins, cytokines (such as IL-2, etc.), antibodies, antibody Fc fragments, antibody scFv fragments, gold nanoparticles/nanorods, virus particles, liposomes, nanomagnetic particles , prodrug-activating enzymes (eg, DT-diaphorase (DTD) or biphenylhydrolase-like protein (BPHL) ) or nanoparticles in any form. In another preferred example, the immunoconjugate comprises: a multivalent (eg, bivalent) antibody or antigen-binding fragment thereof according to the first aspect of the present invention. In another preferred example, 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. In the tenth aspect of the present invention, a pharmaceutical composition is provided, which contains:

(1) 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 The engineered immune cells, or the immunoconjugate according to the ninth aspect of the present invention, or a combination thereof; and

(ii) A pharmaceutically acceptable carrier, diluent or excipient. In another preferred example, the dosage form of the pharmaceutical composition is selected from the group consisting of injections and freeze-dried preparations. In another preference, 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. In another preferred example, the concentration of the engineered immune cells in the active ingredient is 1x103-1x108 cells/mL, preferably 1x104-1x107 cells/mL. In the eleventh aspect of the present invention, there is provided a use of 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:

(a) Drugs for the prevention and/or treatment of IL-18-related diseases;

(b) Reagents for the detection of IL-18-associated diseases. In another preferred example, the reagent shown is a diagnostic reagent, preferably, the diagnostic reagent is a detection chip or a detection plate. In another preferred example, the diagnostic reagent is used for: detecting IL-18RP protein or its fragments in the sample. In another preferred example, 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. In another preferred example, the IL-18-related disease is an autoimmune disease or an inflammatory disease. In another preferred example, 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 activation syndrome, systemic lupus erythematosus, septic arthritis, pyoderma gangrenosum, atopic dermatitis , idiopathic pulmonary fibrosis, scleroderma, systemic juvenile idiopathic arthritis (sJIA), inflammatory bowel disease (IBD), adult-onset Still's disease (AOSD), chronic obstructive Comorbidity disease (COPD) or pulmonary nodules, or a combination thereof. In another preferred example, 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. In the twelfth aspect of the present invention, a method for in vitro detection of IL-18RP protein or its fragments in a sample is provided, the method comprising the steps of:

(1) In vitro, contacting the sample with the antibody or antigen-binding fragment thereof according to the first aspect of the present invention;

(2) Detect whether the antigen-antibody complex is formed, wherein the formation of the complex indicates that the corresponding target of IL-18RP protein or its fragment exists in the sample. In another preferred example, the detection includes diagnostic or non-diagnostic. 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 engineered immune cell according to the aspect, or the immunoconjugate according to the ninth aspect of the present invention, or the pharmaceutical composition according to the tenth aspect of the present invention, or a combination thereof; and/or

(2) a second container, which contains a secondary antibody against the contents of the first container; or, 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. In another preferred example, 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. In another preferred example, the kit is used for the detection of IL-18-related diseases. In another preferred example, 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. In another preferred example, 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 lupus erythematosus, septic arthritis, pyoderma gangrenosum, atopic dermatitis, atopic Idiopathic pulmonary fibrosis, scleroderma, systemic juvenile idiopathic arthritis (sJIA), inflammatory bowel disease (IBD), adult-onset Still's disease (AOSD), chronic obstructive pulmonary disease (COPD) ) or pulmonary nodules, or a combination thereof. In another preferred example, 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. In the fourteenth aspect of the present invention, there is provided a method for preventing and/or treating IL-18-related diseases, the method 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. In another preferred example, the subject includes a mammal, such as a human. In another preferred example, 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. In another preferred example, the IL-18-related disease is an autoimmune disease or an inflammatory disease. In another preferred example, 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 lupus erythematosus, septic arthritis, pyoderma gangrenosum, atopic dermatitis, atopic Idiopathic pulmonary fibrosis, scleroderma, systemic juvenile idiopathic arthritis (sJIA), inflammatory bowel disease (IBD), adult Still's disease (AOSD), chronic obstructive pulmonary disease (COPD), or Pulmonary nodules or a combination thereof, or a combination thereof. In another preferred example, 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. In another preferred example, the engineered immune cells or the CAR immune cells contained in the pharmaceutical composition are cells derived from the subject (autologous cells). In another preferred example, the engineered immune cells or the CAR immune cells contained in the pharmaceutical composition are cells (allogeneic cells) derived from healthy individuals. In another preferred example, the method can be used in combination with other treatment methods. In another preferred example, the other treatment methods include chemotherapy, radiotherapy, targeted therapy and other methods. In the fifteenth aspect of the present invention, a diagnostic method for IL-18-related diseases is provided, comprising the steps of:

(1) Obtain a sample from a diagnostic subject, combine the sample with the antibody or its antigen-binding fragment 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 recombinant protein as described in the seventh aspect of the present invention The engineered immune cell according to the aspect, or the immunoconjugate according to the ninth aspect of the present invention, or the pharmaceutical composition according to the tenth aspect of the present invention; and

(ii) Detecting whether an antigen-antibody complex is formed, wherein the formation of a complex indicates that the subject is a confirmed patient of an IL-18-related disease. In another preferred example, the samples are blood samples or throat swab samples, or samples from other tissues and organs. In another preferred example, 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. In another preferred example, the IL-18-related disease is an autoimmune disease or an inflammatory disease. In another preferred example, 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 lymphohistiocytic hypertrichosis, macrophage activation syndrome, systemic lupus erythematosus, septic arthritis, pyoderma gangrenosum, atopic dermatitis, idiopathic pulmonary fibrosis, scleroderma, systemic juvenile idiopathic arthritis (sJIA), inflammatory bowel disease (IBD), adult Still's disease (Adultonset Still's disease (AOSD), chronic obstructive pulmonary disease (COPD) or pulmonary nodules, or a combination thereof. In another preferred example, 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. It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be repeated here. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the sequence information of the IL-18R0 WT antibody. Figure 2 shows the 24h concentration-response curve of anti-IL-18RP antibody (IgG1) inhibiting IFN-γ in KG-1 cells. Figure 3 shows the 24h concentration-response curve of anti-IL-18RP antibody (IgG4) inhibiting IFN-γ in KG-1 cells. Figure 4 shows the 24h concentration-response curve (parallel experiment) of anti-IL-18RP antibody (IgG1) inhibiting IFN-γ in KG-1 cells. Figure 5 shows the 48h concentration-response curve of anti-IL-18RP antibody (IgG1) inhibiting IFN-γ in human PBMC cells. Figure 6 shows the 72h concentration-response curve of anti-IL-18RP antibody (IgG4) inhibiting IFN-γ in human PBMC cells. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS After extensive and in-depth research and extensive screening, the present inventors first developed a high-affinity IL-18RP-targeting antibody and its antigen-binding fragment. Specifically, 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. After further screening, 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. Terms As used herein, 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). Preferably, the antibody numbers of the present invention and the corresponding sequence numbers are shown in Table 1 below.

Preferably, the A035 antibody, A037 antibody, and A039 antibody of the present invention have two types of IgG1 and IgG4 respectively, wherein:

A035 antibody (IgG1) has a heavy chain sequence shown in SEQ ID NO: 30 and a light chain sequence shown in SEQ ID NO: 31; A037 antibody (IgG1) 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. Each heavy chain is composed of a heavy chain variable region (abbreviated as VH) and a heavy chain constant region. The heavy chain constant region consists of three domains, CHI, CH2 and CH3. Each light chain is composed of a light chain variable region (abbreviated as VL) and a light chain constant region. The light chain constant region consists of one domain, CL. The VH and VL regions can also be divided into hypervariable regions called complementarity determining regions (CDRs), which are separated by more conserved framework region (FR) regions. Each VH and VL is composed of three CDRs and four FRs, arranged in the order of FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 from the amino terminal to the carboxyl terminal. The 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. As the term is used herein, the antibody's "Antigen-binding fragment" (or antigen-binding portion) 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. Examples of binding fragments contained in the "antigen-binding portion" of an antibody include (i) a Fab fragment, a monovalent fragment composed of VL, VH, CL, and CH1; (ii) a F(ab ^, ) ₂ fragment, comprising a chain region disulfide (iii) Fd fragment composed of VH and CH1; (iv) Fv fragment composed of antibody single arm VL and VH; (v) dAb fragment composed of VH; ( vi) isolated complementarity determining regions (CDRs); and (vii) a Nanobody, a heavy chain variable region comprising a single variable domain and two constant domains. In addition, although 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)). 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. As used herein, 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. However, the variability is 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). The variable domains of the native heavy and light chains each contain four FR regions in a roughly |3-sheet configuration connected by three CDRs forming connecting loops and, in some cases, partial b-sheet structures . 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). As known to those skilled in the art, 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. As used herein, the terms "heavy chain variable region" and "VH" are used interchangeably. As used herein, the terms "light chain variable region" and "VL" are used interchangeably. As used herein, the term "variable region" and '' complementarity determining region (Complementarity determining region, CDR) are used interchangeably. In a preferred embodiment of the present invention, the heavy chain variable region of the antibody includes three complementarity determining regions, CDRHk, CDRH2, and CDRH3. In a preferred embodiment of the present invention, the heavy chain of the antibody includes the above-mentioned heavy chain variable region and heavy chain constant region. In a preferred embodiment of the present invention, the light chain variable region of the antibody includes three complementarity determining regions CDRL1, CDRL2, and CDRL3. In a preferred embodiment of the present invention, the light chain of the antibody includes the above-mentioned light chain variable region and light chain constant region. In the present invention, 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. Specifically, 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. Generally, the antigen-binding properties of an antibody can be described by three specific regions located in the variable region of the heavy chain, called the variable region (CDR), which is separated into four framework regions (FR), and four FR amino acids The sequence is relatively conservative and does not directly participate in the binding reaction. These CDRs form a ring structure, and the |3 folds formed by the FRs in between are close to each other in the spatial structure. The CDRs on the heavy chain and the corresponding CDRs on the light chain constitute the antigen-binding site of the antibody. Which amino acids constitute FR or CDR regions can be determined by comparing the amino acid sequences of antibodies of the same type. The variable regions of the heavy chains of the antibodies of the invention are of particular interest because at least some of them are involved in binding antigen. Therefore, the present invention includes those molecules having antibody heavy chain variable regions with CDRs, as long as their CDRs have more than 90% (preferably more than 95%, and most preferably more than 98%) homology with the CDRs identified here sex. The present invention includes not only complete antibodies, but also fragments of antibodies with immunological activity or fusion proteins formed by antibodies and other sequences. Therefore, the present invention also includes fragments, derivatives and analogs of said antibodies. As used herein, the terms "fragment", "derivative" and "analogue" refer to a polypeptide that substantially retains the same biological function or activity of the antibody of the present invention. 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). Based on the teaching herein, these fragments, derivatives and analogs are within the scope of those skilled in the art. 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. For example, in this field, substitutions with amino acids with similar or similar properties generally do not change the function of the protein. As another example, 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. In addition to substantially full-length polypeptides, the invention also includes fragments of the antibodies of the invention. Typically, 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. In the present 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. An amino acid is replaced by an amino acid with similar or similar properties to form a polypeptide. These conservative variant polypeptides are preferably produced by amino acid substitutions according to Table 2. Table 2

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. In the present invention, "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%. Moreover, the polypeptide encoded by the hybridizable polynucleotide has the same biological function and activity as the mature polypeptide. The full-length nucleotide sequence of the antibody of the present invention or its fragments can usually be obtained by PCR amplification, recombination or artificial synthesis. A feasible method is to use artificial synthesis to synthesize related sequences, especially when the fragment length is short. Often, fragments with very long sequences are obtained by synthesizing multiple small fragments and then ligating them. In addition, the coding sequence of the heavy chain and an expression tag (such as 6His) can also be fused together to form a fusion protein. Once the relevant sequences are obtained, recombinant methods can be used to obtain the relevant sequences in large quantities. Usually, it is cloned into a vector, then transformed into a cell, and then the relevant sequence is isolated from the proliferated host cell by conventional methods. The biomolecules (nucleic acid, protein, etc.) involved in the present invention include biomolecules in an isolated form. At present, 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. In addition, 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. These vectors can be used to transform appropriate host cells so that they are capable of expressing the protein. 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. 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. When the host is a prokaryotic organism such as E. coli, competent cells capable of taking up DNA can be harvested after the exponential growth phase and treated with the CaCl2 method using procedures well known in the art. Another method is to use MgCl2o. If desired, the transformation can also be performed by electroporation. When the host is a eukaryote, the following DNA transfection methods can be used: calcium phosphate co-precipitation method, conventional mechanical methods such as microinjection, electroporation, liposome packaging, etc. The obtained transformant can be cultured by conventional methods to express the polypeptide encoded by the gene of the present invention. The medium used in the culture can be selected from various conventional media according to the host cells used. The culture is carried out under conditions suitable for the growth of the host cells. After the host cells have grown to an appropriate cell density, 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.

IL-18, IL-18R, and IL-18RP Interleukin-18 (IL18, also known as interferon-y inducible factor) is a protein that in humans is encoded by the IL-18 gene. The protein encoded by this gene is a pro-inflammatory cytokine. Many cell types, both hematopoietic and non-hematopoietic, have the potential to produce IL-18.

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. Effectively inhibiting the pro-inflammatory signaling pathway downstream of IL-18 is currently a promising approach for the treatment of autoimmune and inflammatory diseases. Pharmaceutical composition The present invention also provides a composition. Preferably, the composition is a pharmaceutical composition, which contains the above-mentioned antibody or its active fragment or its fusion protein, and a pharmaceutically acceptable carrier. Generally, 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. In addition, the polypeptides of the invention can also be used with other therapeutic agents. When using the pharmaceutical composition, 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. Of course, 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. Antibodies against IL-18RP or antigen-binding fragments thereof In the present invention, the antibodies against IL-18RP or antigen-binding fragments thereof include monomers, bivalents (bivalent antibodies), tetravalents (tetravalent antibodies) , and/or a multivalent body (multivalent antibody), which can be a murine antibody, a chimeric antibody, a humanized antibody or a fully human antibody. Typically, 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. In a preferred embodiment of the present invention, 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. In a preferred example of the present invention, 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. In a preferred embodiment of the present invention, 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. In the detection method of the present invention, 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. In a preferred example 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. Application As mentioned above, the antibody of the present invention has a wide range of biological and clinical application values, and its application involves the treatment of IL-18-related diseases, taking into account the diagnosis of high expression of IL-18, basic medical research, biological research, etc. fields. A preferred application is for clinical prevention and treatment against IL-18RP protein. The present invention also provides a method for stimulating an immune response mediated by T cells targeting mammalian tumor cell groups or tissues, which includes the following steps: administering the CAR-T cells of the present invention to mammals. In one embodiment, the present invention includes a type of cell therapy, in which a patient's own T cells (or a heterologous donor) are isolated, activated and genetically modified to produce CAR-T cells, and then injected into the same patient. In this way, the probability of graft-versus-host reaction is extremely low, and the antigen is recognized by T cells without MHC restriction. Furthermore, a single CAR-T can treat all cancers that express that antigen. Unlike antibody therapies, CAR-T cells are able to replicate in vivo, resulting in long-term persistence that can lead to sustained tumor control. In one embodiment, the CAR-T cells of the present invention can undergo stable in vivo expansion and last for several months to several years. In addition, 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. For example, 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. Generally, 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. The CAR-T cells of the present invention can be administered alone or as a pharmaceutical composition with a diluent and/or in combination with other components such as IL-2, IL-17 or other cytokines or cell populations. Briefly, a pharmaceutical composition of the invention may comprise a target cell population as described herein, in combination with one or more pharmaceutically or physiologically acceptable carriers, diluents or excipients. The pharmaceutical composition of the present invention can be administered in a manner suitable for the disease to be treated (or prevented). The amount and frequency of administration will be determined by factors such as the patient's condition, and the type and severity of the patient's disease, or may be determined by clinical trials. When an "immunologically effective amount", "antitumor effective amount", "tumor-suppressive effective amount" or "therapeutic amount" is indicated, the precise amount of the composition of the invention to be administered can be determined by a physician, taking into account the patient (subject ) age, weight, Individual differences in tumor size, degree of infection or metastasis, and condition. Pharmaceutical 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 μ 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. J. of Med. 319: 1676, 1988). The optimal dosage and treatment regimen for a particular patient can be readily determined by one skilled in the medical art by monitoring the patient for signs of disease, and adjusting treatment accordingly. Administration of the compositions to a subject may be by any convenient means, including by nebulization, injection, swallowing, infusion, implantation or implantation. The compositions described herein can be administered to a patient subcutaneously, intradermally, intratumorally, intranodally, intraspinally, intramuscularly, by intravenous injection or intraperitoneally. In one embodiment, a T cell composition of the invention is administered to a patient by intradermal or subcutaneous injection. In another embodiment, 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. In certain embodiments of the invention, 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. In a further embodiment, 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. In a further embodiment, 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. For example, in one embodiment, a subject may undergo standard treatment with high-dose chemotherapy followed by peripheral blood stem cell transplantation. In some embodiments, following transplantation, the subject receives an infusion of expanded immune cells of the invention. In an additional embodiment, 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:

1. 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.

2. 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.

3. Compared with other components of the IL-18 signaling pathway, the IL-18RP antibody or antigen-binding fragment thereof of the present invention has advantages in terms of specificity, effectiveness and safety.

4. The antibody to IL-18RP of the present invention or its antigen-binding fragment can efficiently block IL-18-stimulated KG-1 intracellular The release of IFN-Y, the activity potency reached 20 times that of WT.

5. The IL-18RP antibody or antigen-binding fragment thereof of the present invention can efficiently block IL-18-stimulated IFN-γ release from human peripheral blood mononuclear cells, and the activity efficiency is significantly higher than that of WT.

6. 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. 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. The experimental method that does not indicate specific conditions in the following examples is usually according to conventional conditions, such as Sambrook et al., molecular cloning: the conditions described in the laboratory manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturing conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated. amino acid sequence

SEQ ID NO: 1 A035 antibody heavy chain variable region

EVQLVESGGGLVQPGGSLRLSCAASGINLYYSSMHWVRQAPGKGLEWVASIYSSNGR TYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARASFSHGYGWYGLDYW GQGTLVTVSS

SEQ ID NO: 2 A035, A039, A038 antibody heavy chain complementarity determining region CDRH1 GINLYYSSMH

SEQ ID NO: 3 A035, A037, A034, A039, A038, C056-WT antibody heavy chain complementarity determining region CDRH2 SIYSSNGRTYYADSVKG

SEQ ID NO: 4 A035 antibody heavy chain complementarity determining region CDRH3

ASFSHGYGWYGLDY

SEQ ID NO: 5 A035, A034 antibody light chain variable region

DIQMTQSPSSLSASVGDRVTITCRASQSVSFAVEWYQQKPGKAPKLLIYSASSLYSGVPS RFSGSRSGTDFTLTISSLQPEDFATYYCQQYGYHDAGLITFGQGTKVEIK

SEQ ID NO: 6 A035, A034 Antibody Light Chain Complementarity Determining Region CDRL1 RASQSVSFAVE

SEQ ID NO: 7 A035, A037, A034, A039, A038, C056-WT antibody light chain complementarity determining region CDRL2 SASSLYS

SEQ ID NO: 8 A035, A037, A034, A039, A038, C056-WT antibody light chain complementary determining region CDRL3 QQYGYHDAGLIT

SEQ ID NO: 9 A037, A034 antibody heavy chain variable region

EVQLVESGGGLVQPGGSLRLSCAASGLNLYYSSMHWVRQAPGKGLEWVASIYSSNGR TYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARSSFSHGYGWYGLDYW GQGTLVTVSS SEQ ID NO: 10 A037, A034 antibody heavy chain complementarity determining region CDRH1 GLNLYYSSMH

SEQ ID NO: 11 A037, A034, A039, A038, C056-WT antibody heavy chain complementarity determining region CDRH3 SSFSHGYGWYGLDY

SEQ ID NO: 12 A037 antibody light chain variable region

DIQMTQSPSSLSASVGDRVTITCRASQSVSFAVDWYQQKPGKAPKLLIYSASSLYSGVP

SRFSGSRSGTDFTLTISSLQPEDFATYYCQQYGYHDAGLITFGQGTKVEIK

SEQ ID NO: 13 A037 antibody light chain complementarity determining region CDRL1

RASQSVSFAVD

SEQ ID NO: 14 A039, A038 antibody heavy chain variable region

EVQLVESGGGLVQPGGSLRLSCAASGINLYYSSMHWVRQAPGKGLEWVASIYSSNGR

TYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARSSFSHGYGWYGLDYW GQGTLVTVSS

SEQ ID NO: 15 A039 antibody light chain variable region

DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVDWYQQKPGKAPKLLIYSASSLYSGVP

SRFSGSRSGTDFTLTISSLQPEDFATYYCQQYGYHDAGLITFGQGTKVEIK

SEQ ID NO: 16 A039 antibody light chain complementarity determining region CDRL1

RASQSVSSAVD

SEQ ID NO: 17 A038 antibody light chain variable region

DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVEWYQQKPGKAPKLLIYSASSLYSGVPS

RFSGSRSGTDFTLTISSLQPEDFATYYCQQYGYHDAGLITFGQGTKVEIK

SEQ ID NO: 18 C056-WT antibody heavy chain variable region

EVQLVESGGGLVQPGGSLRLSCAASGFNLYYSSMHWVRQAPGKGLEWVASIYSSNGR

TYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARSSFSHGYGWYGLDYW GQGTLVTVSS

SEQ ID NO: 19 C056-WT antibody heavy chain complementarity determining region CDRH1

GFNLYYSSMH

SEQ ID NO: 20 C056-WT antibody light chain variable region

DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVP

SRFSGSRSGTDFTLTISSLQPEDFATYYCQQYGYHDAGLITFGQGTKVEIK

SEQ ID NO: 21 C056-WT antibody light chain complementarity determining region CDRL1

RASQSVSSAVA

SEQ ID NO: 22 A038 antibody light chain complementarity determining region CDRL1

RASQSVSSAVE

SEQ ID NO: 23 IL-18Rp antigen sequence

1 MLCLGWIFLW LVAGERIKGF NISGCSTKKL LWTYSTRSEE EFVLFCDLPE PQKSHFCHRN 61 RLSPKQVPEH LPFMGSNDLS DVQWYQQPSN GDPLEDIRKS YPHIIQDKCT LHFLTPGVNN

121 SGSYICRPKM IKSPYDVACC VKMILEVKPQ TNASCEYSAS HKQDLLLGST GSISCPSLSC

181 QSDAQSPAVT WYKNGKLLSV ERSNRIVVDE VYDYHQGTYV CDYTQSDTVS SWTVRAVVQV

241 RTIVGDTKLK PDILDPVEDT LEVELGKPLT ISCKARFGFE RVFNPVIKWY IKDSDLEWEV

301 SVPEAKSIKS TLKDEIIERN IILEKVTQRD LRRKFVCFVQ NSIGNTTQSV QLKEKRGVVL

361 LYILLGTIGT LVAVLAASAL LYRHWIEIVL LYRTYQSKDQ TLGDKKDFDA FVSYAKWSSF

421 PSEATSSLSE EHLALSLFPD VLENKYGYSL CLLERDVAPG GVYAEDIVSI IKRSRRGIFI

481 LSPNYVNGPS IFELQAAVNL ALDDQTLKLI LIKFCYFQEP ESLPHLVKKA LRVLPTVTWR

541 GLKSVPPNSR FWAKMRYHMP VKNSQGFTWN QLRITSRIFQ WKGLSRTETT GRSSQPKEW

SEQ ID NO: 24 A035 antibody (IgG4) heavy chain

EVQLVESGGGLVQPGGSLRLSCAASGINLYYSSMHWVRQAPGKGLEWVASIYSSNGR

TYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARASFSHGYGWYGLDYW

GQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSG

VHTFPAVLQSSGLYSLSSVVTVPSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPP

CPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHN

AKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPR

EPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

SEQ ID NO: 25 A035 antibody (IgG4) light chain

DIQMTQSPSSLSASVGDRVTITCRASQSVSFAVEWYQQKPGKAPKLLIYSASSLYSGVPS

RFSGSRSGTDFTLTISSLQPEDFATYYCQQYGYHDAGLITFGQGTKVEIKRTVAAPSVFI

FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO: 26 A037 antibody (IgG4) heavy chain

EVQLVESGGGLVQPGGSLRLSCAASGLNLYYSSMHWVRQAPGKGLEWVASIYSSNGR

TYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARSSFSHGYGWYGLDYW

GQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSG

VHTFPAVLQSSGLYSLSSVVTVPSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPP

CPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHN

AKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPR

EPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

SEQ ID NO: 27 A037 antibody (IgG4) light chain

DIQMTQSPSSLSASVGDRVTITCRASQSVSFAVDWYQQKPGKAPKLLIYSASSLYSGVP

SRFSGSRSGTDFTLTISSLQPEDFATYYCQQYGYHDAGLITFGQGTKVEIKRTVAAPSVF

IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 28 A039 antibody (IgG4) heavy chain

EVQLVESGGGLVQPGGSLRLSCAASGINLYYSSMHWVRQAPGKGLEWVASIYSSNGR

TYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARSSFSHGYGWYGLDYW

GQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSG

VHTFPAVLQSSGLYSLSSVVTVPSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPP

CPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHN

AKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPR

EPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG

SFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

SEQ ID NO: 29 A039 antibody (IgG4) light chain

DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVDWYQQKPGKAPKLLIYSASSLYSGVP

SRFSGSRSGTDFTLTISSLQPEDFATYYCQQYGYHDAGLITFGQGTKVEIKRTVAAPSVF

IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS

LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO: 30 A035 antibody (IgG1) heavy chain

EVQLVESGGGLVQPGGSLRLSCAASGINLYYSSMHWVRQAPGKGLEWVASIYSSNGR

TYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARASFSHGYGWYGLDYW

GQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG

VHTFPAVLQSSGLYSLSSVVTVPSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT

CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV

HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG

QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS

DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

SEQ ID NO: 31 A035 antibody (IgG1) light chain

DIQMTQSPSSLSASVGDRVTITCRASQSVSFAVEWYQQKPGKAPKLLIYSASSLYSGVPS

RFSGSRSGTDFTLTISSLQPEDFATYYCQQYGYHDAGLITFGQGTKVEIKRTVAAPSVFI

FPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL

SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO: 32 A037 antibody (IgG1) heavy chain

EVQLVESGGGLVQPGGSLRLSCAASGLNLYYSSMHWVRQAPGKGLEWVASIYSSNGR

TYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARSSFSHGYGWYGLDYW

GQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG

VHTFPAVLQSSGLYSLSSVVTVPSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT

CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV

HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG

QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS

DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

SEQ ID NO: 33 A037 antibody (IgG1) light chain

DIQMTQSPSSLSASVGDRVTITCRASQSVSFAVDWYQQKPGKAPKLLIYSASSLYSGVP

SRFSGSRSGTDFTLTISSLQPEDFATYYCQQYGYHDAGLITFGQGTKVEIKRTVAAPSVF

IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS

LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO: 34 A039 antibody (IgG1) heavy chain

EVQLVESGGGLVQPGGSLRLSCAASGINLYYSSMHWVRQAPGKGLEWVASIYSSNGR

TYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARSSFSHGYGWYGLDYW GQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSG VHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKG QPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

SEQ ID NO: 35 A039 antibody (IgG1) light chain

DIQMTQSPSSLSASVGDRVTITCRASQSVSSAVDWYQQKPGKAPKLLIYSASSLYSGVP SRFSGSRSGTDFTLTISSLQPEDFATYYCQQYGYHDAGLITFGQGTKVEIKRTVAAPSVF IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTL TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

SEQ ID NO: 36 A035 antibody (IgG4) heavy chain nucleotide sequence

GCGGCCGCAAACTACAAGACAGACTTGCAAAAGAAGGCATGCACAGCTCAGCACT GCTCTGTTGCCTGGTCCTCCTGACTGGGGTGAGGGCCGAGGTGCAGCTGGTGGAGA GCGGGGGGGACTGGTGCAGCCAGGAGGAAGCCTGAGACTGAGCTGTGCCGCAAG CGGGATTAACCTGTATTACAGCAGCATGCACTGGGTGA GACAGGCACCTGGCAAA GGACTGGAGTGGGTGGCAAGCATATACAGCAGCAACGGAAGAACCTACTACGCCG ACAGTGTGAAGGGCAGATTCACTATCAGCGCCGACACCAGCAAAAACACCGCCTACCTGCAGATGAACAGCCTGAGAGCCGAAGACACCGCCGTGTACTACTGCGCCAGGGCCTCCTTCAGCCATGGCTACGGCTGGTACGGC CTGGACTACTGGGGACAAGGAAC ACTGGTGACAGTGAGCAGCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCGC CCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGAC TACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGT GCACACCTTCCCGGCTGTCC TACAGTCCTCAGGACTCTACTCCTCAGCAGCGTGGT GACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCCAAATATGGTCCCCCATGCCCACCATGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTC TCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG

TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGT GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTCAACAGCACGTACGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTA CAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCCTCCATCGAGAAA ACCATCTCCA AAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGA GGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCA GCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGAC CACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTA CAGCAGGCTAACCGT GGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAG GCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAATGATT CTAGA

SEQ ID NO: 37 A035 antibody (IgG4) light chain nucleotide sequence

GCGGCCGCAAACTACAAGACAGACTTGCAAAAGAAGGCATGCACAGCTCAGCACT GCTCTGTTGCCTGGTCCTCCTGACTGGGGTGAGGGCCGACATTCAGATGACCCAGA GCCCCAGCAGCCTGAGCGCCAGCGTGGGAGACAGAGTGACCATAACCTGCAGAGC CAGCCAAAGCGTTAGCTTTGCCGTTGAGTGGTATCAGCAGAAACCTGGCA AAGCCC CCAAGCTGCTCATCTACAGCGCCAGTAGCCTGTATAGCGGCGTGCCCAGCAGATTT AGCGGAAGCAGATCAGGCACCGACTTCACCCCTGACCATCTCCAGCCTGCAACCCGA AGACTTCGCCACCTACTACTGCCAGCAGTACGGATACCACGACGCAGGCCTCATCA CCTTCGGACAAGGAACCAAAGTGGAGATTAAGCGTACGGTGGCTGCACCATCTGTC TTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGC CTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGC AGGACAG CACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACAC AAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGTTCGCCCGTCACAAAGAG

CTTCAACAGGGGAGAGTGTTGATTCTAGA

SEQ ID NO: 38 A037 antibody (IgG4) heavy chain nucleotide sequence

GCGGCCGCAAACTACAAGACAGACTTGCAAAAGAAGGCATGCACAGCTCAGCACTGCTCTGTTGCCTGGTCCTCCTGACTGGGGTGAGGGCCGAGGTGCAGCTGGTGGAGA

GCGGGGGGGGACTGGTGCAGCCAGGAGGAAGCCTGAGACTGAGCTGTGCCGCAAG CGGGCTGAACCTGTACTATAGTAGCATGCACTGGGTGAGACAGGCACCCGGCAAA GGACTGGAGTGGGTGGCTAGCATTTACAGCAGCAATGGAAGAACATACTACGCCG

ATAGCGTGAAGGGCAGATTCACCATCATCAGCGCCGACACCAGCAAGAACACCGCCTACCTGCAGATGAACAGCCTGAGAGCCGAAGACACAGCAGTGTACTACTGCGCCAGG

AGCAGCTTTTCCCATGGCTATGGCTGGTACGGCCTGGACTACTGGGGCCAGGGCACCCTCGTGACCGTGAGCAGCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCGC

CCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGAC TACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGCTGTCCTACAGTCCTCAGGACTCTACTCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAAC GTAGATCACA AGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATG CCCACCATGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCC

AAAACCCAAAGGACACTCTCATGATCTCCCGGACCCTGAGGTCACGTGCGTGGTGG TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGT GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACACACGTACGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGA ACGGCAAGGAGTA CAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCTCTCCATCGAGAAAACCATCTCCA AAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGA

GGAGATGACCAAGAACCAGGTCAGCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGT GATGCATGAG GCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAATGATT CTAGA

SEQ ID NO: 39 A037 antibody (IgG4) light chain nucleotide sequence

GCGGCCGCAAACTACAAGACAGACTTGCAAAAGAAGGCATGCACAGCTCAGCACTGCTCTGTTGCCTGGTCCTCCTGACTGGGGTGAGGGCCGACATTCAGATGACCCAGA

GCCCCAGCAGCCTGAGCGCCAGCGTGGGAGACAGAGTGACCATAACCTGCAGAGC CAGCCAAAGCGTTAGCTTTGCCGTTGACTGGTATCAGCAGAAACCCGGCAAGGCCCCAAAACTGCTGATCTACAGCGCAAGTAGCCTGTACTCCGGCGTGCCCTCCCGCTTCAGCGGATCCAGATCCGGCACCGACTTCACCCTGACCATCAGCAGCCTCCAAC CCGA AGACTTCGCCACCTACTACTGCCAGCAATACGGATATCACGACGCTGGCCTCATCA

CCTTTGGCCAAGGCACCAAGGTGGAAATTAAGCGTACGGTGGCTGCACCATCTGTC TTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGC CTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGC AGGACAG CACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACAC AAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGTTCGCCCGTCACAAAGAG CTTCAACAGGGGAGAGTGTTGATTCTAGA

SEQ ID NO: 40 A039 antibody (IgG4) heavy chain nucleotide sequence

GCGGCCGCAAACTACAAGACAGACTTGCAAAAGAAGGCATGCACAGCTCAGCACT

GCTCTGTTGCCTGGTCCTCCTGACTGGGGTGAGGGCCGAGGTGCAGCTGGTGGAGA

GCGGGGGGGGACTGGTGCAGCCAGGAGGAAGCCTGAGACTGAGCTGTGCCGCAAG

CGGGATTAACCTGTATTACAGCAGCATGCACTGGGTGAGACAGGCACCTGGCAAA

GGACTGGAGTGGGTGGCAAGCATATACAGCAGCAACGGAAGAACCTACTACGCCG

ACAGTGTGAAGGGCAGATTCACTATCAGCGCCGACACCAGCAAAAACACCGCCTA

CCTGCAGATGAACAGCCTGAGAGCCGAAGACACCGCCGTGTACTACTGCGCCAGG

AGCTCCTTCAGCCATGGCTACGGCTGGTACGGCCTGGACTACTGGGGACAAGGAAC

ACTGGTGACAGTGAGCAGCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCGC

CCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGAC

TACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGT

GCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCTCTCAGCAGCGTGGT

GACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTACACCTGCAACGTAGATCACA

AGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATG

CCCACCATGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCC

AAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGG

TGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGT

GGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTAC

CGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTA

CAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCTCTCCATCGAGAAAACCATCTCCA

AAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGA

GGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCA

GCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGAC

CACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGT

GGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAG

GCTCTGCACAAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAATGATT CTAGA

SEQ ID NO: 41 A039 antibody (IgG4) light chain nucleotide sequence

GCGGCCGCAAACTACAAGACAGACTTGCAAAAGAAGGCATGCACAGCTCAGCACT

GCTCTGTTGCCTGGTCCTCCTGACTGGGGTGAGGGCCGACATTCAGATGACCCAGA

GCCCCAGCAGCCTGAGCGCCAGCGTGGGAGACAGAGTGACCATAACCTGCAGAGC

CAGCCAAAGCGTTAGCAGCGCCGTGGACTGGTATCAGCAGAAACCCGGAAAGGCC

CCAAAACTGCTGATCTACAGCGCAAGTAGCCTGTACTCAGGAGTGCCCAGCAGATT

CAGCGGCAGCAGATCCGGAACCGACTTCACCCTGACCATCAGCAGCAGCCTGCAACCTG

AGGATTTCGCCACCTACTACTGCCAGCAATACGGATACCACGACGCTGGTCTCATC

ACCTTCGGCCAAGGAACCAAGGTGGAAATTAAGCGTACGGTGGCTGCACCATCTGT

CTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTG

CCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAAC

GCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACA

GCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGTTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTGATTCTAGA

SEQ ID NO: 42 A035 antibody (IgG1) heavy chain nucleotide sequence

GCGGCCGCAAACTACAAGACAGACTTGCAAAAGAAGGCATGCACAGCTCAGCACT

GCTCTGTTGCCTGGTCCTCCTGACTGGGGTGAGGGCCGAGGTGCAGCTGGTGGAGAGCGGGGGGGGACTGGTGCAGCCAGGAGGAAGCCTGAGACTGAGCTGTGCCGCAAG CGGGATTAACCTGTATTACAGCAGCATGCACTGGGTGAGACAGGCACCTGGCAAA

GGACTGGAGTGGGTGGCAAGCATATACAGCAGCAACGGAAGAACCTACTACGCCG

ACAGTGTGAAGGGCAGATTCACTATCAGCGCCGACACCAGCAAAAACACCGCCTA

CCTGCAGATGAACAGCCTGAGAGCCGAAGACACCGCCGTGTACTACTGCGCCAGG

GCCTCCTTCAGCCATGGCTACGGCTGGTACGGCCTGGACTACTGGGGACAAGGAAC

ACTGGTGACAGTGAGCAGCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCAC

CCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGAC

TACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGT

GCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCTCTCAGCAGCGTGGT

GACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACA

AGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAAC

TCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCC

TCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCCCGAGGTCACA

TGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGT

GGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAAC

AGCACGTACCGTGTGGTCACCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGG

CAAGGAGTACAAGTGCAAGGTCTCCAAACAAAGCCCTCCCAGCCCCCATCGAGAAA

ACCATCTCCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCC

CATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGG

CTTCTATCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAAC

AACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGC

AAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGG GTAAATGATTCTAGA

SEQ ID NO: 43 A035 antibody (IgG1) light chain nucleotide sequence

GCGGCCGCAAACTACAAGACAGACTTGCAAAAGAAGGCATGCACAGCTCAGCACT

GCTCTGTTGCCTGGTCCTCCTGACTGGGGTGAGGGCCGACATTCAGATGACCCAGA

GCCCCAGCAGCCTGAGCGCCAGCGTGGGAGACAGAGTGACCATAACCTGCAGAGC

CAGCCAAAGCGTTAGCTTTGCCGTTGAGTGGTATCAGCAGAAACCTGGCAAAGCCC

CCAAGCTGCTCATTCTACAGCGCCAGTAGCCTGTATAGCGGCGTGCCCAGCAGATTT

AGCGGAAGCAGATCAGGCACCGACTTCACCCTGACCATCTCCAGCCTGCAACCCGA

AGACTTCGCCACCTACTACTGCCAGCAGTACGGATACCACGACGCAGGCCTCATCA

CCTTCGGACAAGGAACCAAAGTGGAGATTAAGCGTACGGTGGCTGCACCATCTGTC

TTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGC

CTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACG

CCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAG

CACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACAC AAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGTTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTGATTCTAGA

SEQ ID NO: 44 A037 antibody (IgG1) heavy chain nucleotide sequence

GCGGCCGCAAACTACAAGACAGACTTGCAAAAGAAGGCATGCACAGCTCAGCACT

GCTCTGTTGCCTGGTCCTCCTGACTGGGGTGAGGGCCGAGGTGCAGCTGGTGGAGA

GCGGGGGGGGACTGGTGCAGCCAGGAGGAAGCCTGAGACTGAGCTGTGCCGCAAG

CGGGCTGAACCTGTACTATAGTAGCATGCACTGGGTGAGACAGGCACCCGGCAAA

GGACTGGAGTGGGTGGCTAGCATTTACAGCAGCAATGGAAGAACATACTACGCCG

ATAGCGTGAAGGGCAGATTCACCATCAGCGCCGACACCAGCAAGAACACCGCCTA

CCTGCAGATGAACAGCCTGAGAGCCGAAGACACAGCAGTGTACTACTGCGCCAGG AGCAGCTTTTCCCATGGCTATGGCTGGTACGGCCTGGACTACTGGGGCCAGGGCAC

CCTCGTGACCGTGAGCAGCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCAC CCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGAC TACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGT GCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCTCAGCAGCGTGGT GACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCT GCAACGTGAATCACAAGCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCCGAGGTCACA

TGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGT GGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAAC AGCACGTACCGTGTGGTCACGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGG CAAGGAGTACAAGTGCAAGGTCTCCAAACAAAGCCCTCCCAGCCCC CATCGAGAAA ACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCC CATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGG CTTCTATCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAAC

AACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGC AAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGG GTAAATGATTCTAGA

SEQ ID NO: 45 A037 antibody (IgG1) light chain nucleotide sequence

GCGGCCGCAAACTACAAGACAGACTTGCAAAAGAAGGCATGCACAGCTCAGCACT GCTCTGTTGCCTGGTCCTCCTGACTGGGGTGAGGGCCGACATTCAGATGACCCAGA GCCCCAGCAGCCTGAGCGCCAGCGTGGGAGACAGAGTGACCATAACCTGCAGAGC CAGCCAAAGCGTTAGCTTTGCCGTTGACTGGTATCAGCAGAAACCCGGCA AGGCCC CAAAACTGCTGATCTACAGCGCAAGTAGCCTGTACTCCGGCGTGCCCTCCCGCTTC AGCGGATCCAGATCCGGCACCGACTTCACCCTGACCATCAGCAGCCTCCAACCCGA AGACTTCGCCACCTACTACTGCCAGCAATACGGATATCACGACGCTGGCCTCATCA

CCTTTGGCCAAGGCACCAAGGTGGAAATTAAGCGTACGGTGGCTGCACCATCTGTC TTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGC CTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGC AGGACAG CACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACAC AAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGTTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTGATTCTAGA

SEQ ID NO: 46 A039 antibody (IgG1) heavy chain nucleotide sequence

GCGGCCGCAAACTACAAGACAGACTTGCAAAAGAAGGCATGCACAGCTCAGCACT GCTCTGTTGCCTGGTCCTCCTGACTGGGGTGAGGGCCGAGGTGCAGCTGGTGGAGA GCGGGGGGGACTGGTGCAGCCAGGAGGAAGCCTGAGACTGAGCTGTGCCGCAAG CGGGATTAACCTGTATTACAGCAGCATGCACTGGGTGA GACAGGCACCTGGCAAA GGACTGGAGTGGGTGGCAAGCATATACAGCAGCAACGGAAGAACCTACTACGCCG ACAGTGTGAAGGGCAGATTCACTATCAGCGCCGACACCAGCAAAAACACCGCCTACCTGCAGATGAACAGCCTGAGAGCCGAAGACACCGCCGTGTACTACTGCGCCAGG

AGCTCCTTCAGCCATGGCTACGGCTGGTACGGCCTGGACTACTGGGGACAAGGAAC ACTGGTGACAGTGAGCAGCGCTAGCACCAAGGGCCCATCGGTCTTCCCCCCTGGCAC CCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGAC TACTTCCCCGAACCGGTGACGGTGTCGTGGAACTC AGGCGCCCTGACCAGCGGCGT GCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCTCAGCAGCGTGGT GACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAAC

TCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCC TCTTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCCCGAGGTCACA TGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGT GGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACT GGCTGAATGG CAAGGAGTACAAGTGCAAGGTCTCCAACAAAAGCCCTCCCAGCCCCCATCGAGAAA ACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCTAATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATG GGCAGCCGGAGAAC AACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGC AAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGT GATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGG GTAAATGATTCTAGA

SEQ ID NO: 47 A039 antibody (IgG1) light chain nucleotide sequence GCGGCCGCAAACTACAAGACAGACTTGCAAAAGAAGGCATGCACAGCTCAGCACT GCTCTGTTGCCTGGTCCTCCTGACTGGGGTGAGGGCCGACATTCAGATGACCCAGA GCCCCAGCAGCCTGAGCGCCAGCGTGGGAGACAGAGTGACCATAACCTGCAGAGC CAGC CAAAGCGTTAGCAGCGCCGTGGACTGGTATCAGCAGAAACCCGGAAAGGCC CCAAAACTGCTGATCTACAGCGCAAGTAGCCTGTACTCAGGAGTGCCCAGCAGATT CAGCGGCAGCAGATCCGGAACCGACTTCACCCTGACCATCAGCAGCCTGCAACCTG AGGATTTCGCCACCTACTACTGCCAGCAATACGGATACCACGACGCTGGTCTCA TC ACCTTCGGCCAAGGAACCAAGGTGGAAATTAAGCGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTG CCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGAGAGTGTCCAGAGCAGGACAGCA AGGACA GCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACA CAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGTTCGCCCGTCACAAAGA GCTTCAACAGGGGAGAGTGTTGATTCTAGA Example 1. The preparation of anti-IL-18R8 high-affinity antibody is shown in Figure 1. Humans used the WT antibody to IL-18RP (i.e. the wild-type antibody, C056-WT in Table 1) as the starting material to improve the affinity. A precision mutation library was constructed to introduce saturation mutations into all 73 residues of the six CDR regions of the WT antibody. After further screening, selected mutants were ranked by their dissociation rate constants measured by surface plasmon resonance (SPR). A combinatorial library is then constructed with random combinations of beneficial mutations. Lead Fab clones were also identified by SPR sequencing. All SPR screens were performed on a Biacore 8K. The running buffer was HBS-EP (10 mM HEPES, 500 mM NaCl, 3 mM EDTA, 0.05% Tween 20, pH 6.0). A secreted Fab was adsorbed to the SASA biosensor. After equilibration, antigen was injected for 120 s (association period) followed by running buffer for 360 s (dissociation period). Regenerate the sensor surface before injecting other selected clones. Use Biacore 8K evaluation software to locally fit the experimental data to a 1:1 interaction model to obtain the off-rate of the Fab clone. Finally, express the full-length IgG from the lead clone in HEK293 cells, and perform binding and functional assays to evaluate. As shown in Table 3, 44 hits were analyzed by SPR, and 7 beneficial mutants were determined to exhibit better binding affinity (ie > 2 times the affinity of the WT antibody, as shown in Table 4). The top 10 combined mutations with improved binding affinity (>10-fold the affinity of WT antibody) are listed in Table 5. select Five lead clones (A034, A035, A037, A038 and A039) were selected for full-length antibody production. Sequences are provided below. Table 3 Affinity and kinetics of IL-18 of 44 hit mutants

Table 4 Mutations in beneficial mutant regions identified by saturation mutagenesis screening

VL-31 S F

VL-34A D,E

VH-27F L,I,V

VH-99S A Table 5 Combinations of the top 10 beneficial mutants with enhanced human affinity

Example 2. Affinity evaluation of anti-IL-18R8 antibody The affinity of anti-IL-18R0 antibody to human IL-18RP protein was measured using surface plasmon resonance biosensor Biacore 8K (GE Healthcare). Measurements were performed at 25°C and the running buffer was HBS-EP+. Antibody was injected as capture onto Protein A on the Series S sensor chip. Diluted IL-18Rp (400, 200, 100, 50, 25, 12.5, 6.25 nM) was then injected on the surface of flow cells 1 and 2 as the binding phase. The binding time was 120 seconds. Buffer flow was maintained for 420 seconds for separation. Surfaces were regenerated by injecting 10 mM glycine-HCl pH 1.5 for 30 s. Data for dissociation (kd) rate constants and association (ka) rate constants were obtained using Biacore evaluation software. The equilibrium dissociation constant (KD) was calculated from the ratio of kd to ka. Table 6 summarizes the binding kinetics data for anti-IL-18RP antibodies. Binding affinity of A035, A037 and A039 In the 0.72-0.98 nm range, 16-22-fold improvement compared to parental antibody WT (15.8 nm). Table 6 Binding kinetics of anti-IL-18R & antibody Antibody Chi ² (RU ² ) ka (1/Ms) kd (1/s) KD (M) Rmax (RU) ratio

WT 2.00E+00 7.10E+04 1.12E-03 1.58E-08 98.3 1.0

A035 2.27E+00 1.13E+05 1.12E-04 9.87E-10 135.4 16.0

A037 1.55E+00 1.03E+05 7.44E-05 7.19E-10 132.4 22.0

A039 2.32E+00 1.08E+05 9.31E-05 8.63E-10 148.2 18.3 Embodiment 3. The activity of anti-IL-18RB antibody to the release of IFN-γ in KG-1 cells stimulated by IL-18 will be 3× ^{10 5} KG-1 cells (ATCC, #CCL-246) were seeded into each well of a 96-well plate. With 10 ng/mL IL-

18 lh prior to stimulation, serial dilutions of the antibody prepared in Example 1 were added to the wells. After 24 h incubation, cells were pelleted by centrifugation and IFN-yo was measured from the supernatant using an ELISA kit (R&D Systems, #VAL104C) according to the manufacturer's instructions. type) at least 3 replicates were performed, and the IC50 for each antibody is summarized in Tables 7 and 8. Table 7 IC50 of anti-IL-18RR antibody in KG-1 test (24 hours)

Table 8 IC50 (24 hours) of anti-IL-18R[3 antibody in KG-1 test

The resulting plots of the corresponding data are shown in Figures 2 and 3, and the A035, A037, and A039 antibodies were approximately 20-fold more potent than the WT antibody. In another group of repeated tests later, it was also proved that antibodies A035, A037 and A039 had excellent cytostatic activity comparable to the above tests, the results are shown in Table 9 and Figure 4 . Table 9 IC50 (24 hours) of anti-IL-18RB antibody in KG-1 repeated test

Example 4. Anti-IL-18R8 antibody blocks IL-18-stimulated activity of human peripheral blood mononuclear cells IFN-γ released from human peripheral blood mononuclear cells (PBMC) (TPCS, #PB025C-W) Seed in 96-well plates at a concentration of ¹ x 105 cells/well. Cells were then incubated with different concentrations of anti-IL-18RP antibody at 50 ng/mL IL-18 and 5 ng/mL IL-12 at 37°C and 5% CO _for 48 hours (IgG1 antibody) and 72 hours, respectively. hours (IgG4 antibodies). According to the manufacturer's instructions, using a human ELISA kit (R&D Systems,

Table 10 IC50 (48 hours) of anti-IL-18RP antibody in human peripheral blood mononuclear cell assay

Table 11 IC50 (72 hours) of anti-IL-18RP antibody in human peripheral blood mononuclear cell assay

All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

Claims

1. An IL-18RP antibody or its antigen-binding fragment, characterized in that, the antibody or its antigen-binding fragment is based on the heavy chain variable region shown in SEQ ID NO: 18 and/or based on SEQ ID NO: 20 The light chain variable region shown includes one or more beneficial mutations selected from the group consisting of: F27L, F27I, F27V, S99A, S31F, A34D, A34E; more specifically, the antibody or its antigen-binding fragment also includes an optional An antibody or an antigen-binding fragment thereof that can retain the ability to specifically bind IL-18RP after adding, deleting, modifying and/or substituting at least one (eg, 1-4) amino acid residues.

2. The antibody or antigen-binding fragment thereof according to claim 1, wherein the one or more beneficial mutations are respectively selected from the following one or more groups:

S31F, A34E, F27L;

S31F, A34E, F27L S99A;

A34D, F27L S99A;

S31F, A34D, F27L;

A34E, F27I;

A34D, F27I;

A34E, F27L;

S31F, A34D, F27V, S99A;

A34E, F27L, S99A; or

S31F, A34E, F27Lo

3. The antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region and a light chain complementarity determining region, and the heavy chain complementarity determining region comprises:

The composite fragment has a heavy chain variable region as shown in SEQ ID NO: K 9 or 14, and has a light chain variable region as shown in SEQ ID NO: 5, 12, 15 or 17; preferably, the Antibodies or antigen-binding fragments thereof having:

36 A heavy chain variable region as shown in SEQ ID NO: 9 and a light chain variable region as shown in SEQ ID NO: 5; or a heavy chain variable region as shown in SEQ ID NO: 1 and SEQ ID NO: 5 the light chain variable region shown; or the heavy chain variable region shown in SEQ ID NO: 9 and the light chain variable region shown in SEQ ID NO: 12; or the heavy chain variable region shown in SEQ ID NO: 14 chain variable region and the light chain variable region shown in SEQ ID NO: 17; or the heavy chain variable region shown in SEQ ID NO: 14 and the light chain variable region shown in SEQ ID NO: 15.

5. The antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody or antigen-binding fragment thereof has a heavy chain sequence as shown in SEQ ID NO: 24, 26, 28, 30, 32 or 34 , and having a light chain sequence as shown in SEQ ID NO: 25, 27, 29, 31, 33 or 35; preferably, the antibody or antigen-binding fragment thereof has: a heavy chain as shown in SEQ ID NO: 24 sequence and the light chain sequence shown in SEQ ID NO: 25; or the heavy chain sequence shown in SEQ ID NO: 26 and the light chain sequence shown in SEQ ID NO: 27; or the sequence shown in SEQ ID NO: 28 The heavy chain sequence and the light chain sequence shown in SEQ ID NO: 29; or the heavy chain sequence shown in SEQ ID NO: 30 and the light chain sequence shown in SEQ ID NO: 31; or the sequence shown in SEQ ID NO: 32 The heavy chain sequence shown in and the light chain sequence shown in SEQ ID NO: 33; or the heavy chain sequence shown in SEQ ID NO: 34 and the light chain sequence shown in SEQ ID NO: 35.

6. The antibody or antigen-binding fragment thereof according to any one of claims 1-5, wherein the antibody or antigen-binding fragment thereof is a murine antibody, a chimeric antibody, a humanized antibody or a fully human Antibody.

7. The antibody or antigen-binding fragment thereof according to any one of claims 1-5, wherein the antigen-binding fragment is selected from scFv, Fab, Fab\F(ab')2, Fv>disulfide Bonded Fv (dsFv), or sdAb.

8. The antibody or antigen-binding fragment thereof according to any one of claims 1-5, wherein the heavy chain constant region of the antibody or antigen-binding fragment thereof is selected from human IgG1, IgG2, IgG3 or IgG4, Preferably IgG1 or IgG4.

9. A nucleotide molecule, characterized in that, the nucleotide molecule encodes the antibody or antigen-binding fragment thereof according to any one of claims 1-8.

10. An expression vector, characterized in that, the expression vector contains the nucleotide molecule according to claim 9.

11. A host cell, characterized in that, the host cell contains the expression vector according to claim 10, or the nucleotide molecule according to claim 9 is integrated into its genome.

12. A method for producing an antibody against IL-18RP or an antigen-binding fragment thereof, comprising the steps of:

(a) cultivating the host cell according to claim 11 under suitable conditions, thereby obtaining a culture of an antibody or antigen-binding fragment thereof containing IL-18RP;

(b) isolating and/or recovering said antibody against IL-18RP or an antigen-binding fragment thereof from said culture; and

(c) Optionally, purifying and/or modifying the IL-18RP antibody or antigen-binding fragment thereof obtained in step (b).

13. A pharmaceutical composition, characterized in that, the pharmaceutical composition contains:

(i) an active ingredient selected from the group consisting of: the antibody or antigen-binding fragment thereof as claimed in any one of claims 1-8, or the nucleotide molecule as claimed in claim 9, or as The expression vector of claim 10, or

37 The host cell of claim 11, or a combination thereof; and

(ii) A pharmaceutically acceptable carrier, diluent or excipient.

14. A purposes of active ingredient, described active ingredient is selected from the group: antibody or antigen-binding fragment thereof as described in any one of claim 1-8, or nucleic acid molecule as described in claim 9 , or the expression vector as claimed in claim 10, or the host cell as claimed in claim 11, or the pharmaceutical composition as claimed in claim 13, or a combination thereof, wherein the active ingredient is used for Preparation:

(a) Drugs for the prevention and/or treatment of IL-18-related diseases;

(b) Reagents for the detection of IL-18-associated diseases.

15. A method for preventing and/or treating IL-18-related diseases, the method comprising: administering the antibody or antigen-binding fragment thereof as claimed in claims 1-8 to a subject in need, or as described in claim 9 The nucleotide molecule, or the expression vector as claimed in claim 10, or the host cell as claimed in claim 11, or the pharmaceutical composition as claimed in claim 13, or a combination thereof.

16. The use according to claim 14, characterized in that, the IL-18-related diseases include diseases with high expression of IL-18, related to abnormal expression of IL-18 receptor, or related to high activity of IL-18 signaling pathway diseases, IL-18R& mediated diseases.

17. The use according to claim 14, characterized in that, the IL-18-related diseases are autoimmune diseases or inflammatory diseases.

18. The use according to claim 14, characterized in that the IL-18-related diseases are selected from: tumors, 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' Disease, Hashimoto's Thyroiditis, Addison's Disease, Celiac Disease, Dermatomyositis, Multiple Sclerosis, Myasthenia Gravis, Pernicious Anemia, Sjögren's Syndrome, Type 1 Diabetes, Type 2 Diabetes, Vascular Inflammation, uveitis, sepsis, atherosclerosis, ankylosing spondylitis, hemophagocytic lymphohistiocytosis, macrophage activation syndrome, systemic lupus erythematosus, septic arthritis, pyoderma gangrenosum atopic dermatitis, idiopathic pulmonary fibrosis, scleroderma, systemic juvenile idiopathic arthritis (sJIA), inflammatory bowel disease (IBD), adult-onset Still's disease (AOSD) ), chronic obstructive pulmonary disease (COPD), or pulmonary nodules, or a combination thereof.

19. The use according to claim 18, wherein 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.