Immune inhibitory receptor KIR3DL3 and uses thereof

Abstract

This specification describes antibodies, immunogenic binding fragments thereof and compositions thereof that target the killer cell immunoglobulin-like receptor protein KIR3DL3, and methods of using same in the treatment of human diseases, including cancer.

Description

[Technical field]

[0001] Statement of U.S. Government Support This invention was made with government support under grant numbers R01CA175498 and R01DK100525 awarded by the NIH. The U.S. Government has certain rights in this invention.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 911,169, filed October 4, 2019, the entire contents of which are incorporated herein by reference.

[0003] Sequence Listing This application contains a Sequence Listing submitted in ASCII format via USPTO EFS-Web, which is incorporated herein in its entirety. The ASCII file, created on October 1, 2020, is named SequenceListing.txt and is 140KB in size. [Background technology]

[0004] Killer cell immunoglobulin-like receptor (KIR) proteins contain two (KIR2D) or three (KIR3D) immunoglobulin-like extracellular domains (Beziat 2017). KIR3DL3 is a member of the KIR family, but its function has been unknown (Beziat 2017). Provided herein are results demonstrating that KIR3DL3 is an inhibitory receptor of the immune system. Provided herein further are antibodies and immunogenic binding fragments thereof against KIR3DL3 or one or more epitopes thereof, as well as compositions and methods of using same. According to certain aspects provided herein, blocking KIR3DL3 function with antibodies or immunogenic binding fragments thereof, ligand fusion polypeptides or small molecules can be used to treat cancer and infectious diseases, and stimulating KIR3DL3 function with antibodies or immunogenic binding fragments thereof, ligand fusion polypeptides or small molecules can be used to treat autoimmune diseases and transplantation.

[0005] Drugs that suppress immune responses can be used to effectively treat patients with autoimmune diseases or prevent rejection in transplants. For example, currently available drugs for rheumatoid arthritis and kidney transplants include abatacept (ORENCIA®) ​​and belatacept (NEUROGIX®), which are modified antibody fusion polypeptides combining the Fc region of IgG1 with the extracellular domain of human cytotoxic T-lymphocyte antigen 4 (CTLA-4). Conversely, drugs that activate immune responses may be used to effectively treat diseases and disorders, including cancer and infectious diseases. For example, ipilimumab (YERVOY®) is a monoclonal antibody that activates immune responses by targeting CTLA-4 and can be used to treat melanoma. Pembrolizumab (KEYTRUDA®) is a humanized antibody against human programmed death receptor 1 (PD-1) and is prescribed as an anti-PD-1 immunotherapy for certain cancers. Nivolumab (Opdivo®) is another anti-PD-1 antibody used in immunotherapy to treat certain cancers. Summary of the Invention

[0006] In one aspect, the invention relates to an antibody or immunogenic binding fragment thereof that specifically binds to KIR3DL3 protein (SEQ ID NO: 335). In particular embodiments, the invention relates to an antibody or immunogenic binding fragment thereof that specifically binds to KIR3DL3 protein, wherein the antibody or immunogenic binding fragment thereof specifically binds to an epitope of KIR3DL3 that includes all or a portion of the extracellular domain. In some embodiments, the antibody or immunogenic binding fragment thereof binds to the DO domain of KIR3DL3 (SEQ ID NO: 337), the D1 domain of KIR3DL3 (SEQ ID NO: 338), or the D2 domain of KIR3DL3 (SEQ ID NO: 339).

[0007] In one aspect, the antibodies or immunogen-binding fragments thereof described herein comprise a VH region comprising CDR1, CDR2 and CDR3 having the amino acid sequence set forth in SEQ ID NO: 7, 9, 11, 31, 33, 35, 54, 56, 76, 78, 80, 100, 102, 104, 124, 126, 128, 148, 150, 152, 172, 174, 176, 196, 198, 200, 220, 222, 224, 244, 246, 248, 268, 270, 272, 292, 294, 296, 316, 318 or 320.

[0008] In one aspect, the antibodies or immunogen-binding fragments thereof provided herein comprise a VH region comprising at least one CDR that is 80% identical to an amino acid sequence selected from SEQ ID NO: 7, 9, 11, 31, 33, 35, 54, 56, 76, 78, 80, 100, 102, 104, 124, 126, 128, 148, 150, 152, 172, 174, 176, 196, 198, 200, 220, 222, 224, 244, 246, 248, 268, 270, 272, 292, 294, 296, 316, 318, or 320.

[0009] In one aspect, the antibodies or immunogen-binding fragments thereof provided herein comprise a VH region comprising at least two CDRs that are 80% identical to an amino acid sequence selected from SEQ ID NO: 7, 9, 11, 31, 33, 35, 54, 56, 76, 78, 80, 100, 102, 104, 124, 126, 128, 148, 150, 152, 172, 174, 176, 196, 198, 200, 220, 222, 224, 244, 246, 248, 268, 270, 272, 292, 294, 296, 316, 318, or 320.

[0010] In one aspect, the antibodies or immunogen-binding fragments thereof provided herein comprise a VH region comprising at least three CDRs that are 80% identical to an amino acid sequence selected from SEQ ID NO: 7, 9, 11, 31, 33, 35, 54, 56, 76, 78, 80, 100, 102, 104, 124, 126, 128, 148, 150, 152, 172, 174, 176, 196, 198, 200, 220, 222, 224, 244, 246, 248, 268, 270, 272, 292, 294, 296, 316, 318, or 320.

[0011] In one aspect, the antibodies or immunogen-binding fragments thereof provided herein comprise a VL region comprising CDR1, CDR2 and CDR3 having the amino acid sequence set forth in SEQ ID NO: 19, 21, 23, 43, 45, 47, 64, 66, 68, 88, 90, 92, 112, 114, 116, 136, 138, 140, 160, 162, 164, 184, 186, 188, 208, 210, 212, 232, 234, 236, 256, 258, 260, 280, 282, 284, 304, 306, 308, 328, 330 or 332.

[0012] In one aspect, the antibodies or immunogen-binding fragments thereof provided herein comprise a VL region comprising at least one CDR that is 80% identical to an amino acid sequence selected from SEQ ID NO: 19, 21, 23, 43, 45, 47, 64, 66, 68, 88, 90, 92, 112, 114, 116, 136, 138, 140, 160, 162, 164, 184, 186, 188, 208, 210, 212, 232, 234, 236, 256, 258, 260, 280, 282, 284, 304, 306, 308, 328, 330, or 332.

[0013] In one aspect, the antibodies or immunogen-binding fragments thereof provided herein comprise a VL region comprising at least two CDRs that are 80% identical to an amino acid sequence selected from SEQ ID NO: 19, 21, 23, 43, 45, 47, 64, 66, 68, 88, 90, 92, 112, 114, 116, 136, 138, 140, 160, 162, 164, 184, 186, 188, 208, 210, 212, 232, 234, 236, 256, 258, 260, 280, 282, 284, 304, 306, 308, 328, 330, or 332.

[0014] In one aspect, the antibodies or immunogen-binding fragments thereof provided herein comprise a VL region comprising at least three CDRs that are 80% identical to an amino acid sequence selected from SEQ ID NO: 19, 21, 23, 43, 45, 47, 64, 66, 68, 88, 90, 92, 112, 114, 116, 136, 138, 140, 160, 162, 164, 184, 186, 188, 208, 210, 212, 232, 234, 236, 256, 258, 260, 280, 282, 284, 304, 306, 308, 328, 330, or 332.

[0015] In a particular aspect, the antibodies or immunogenic binding fragments thereof provided herein include monoclonal antibodies.

[0016] In certain aspects, the antibodies or immunogenic binding fragments thereof provided herein include chimeric antibodies, human antibodies or humanized antibodies.

[0017] In one aspect, the antibodies or immunogen-binding fragments thereof provided herein are selected from the group consisting of SEQ ID NOs: 7, 9, 11, 19, 21, 23, 31, 33, 35, 43, 45, 47, 54, 56, 64, 66, 68, 76, 78, 80, 88, 90, 92, 100, 102, 104, 112, 114, 116, 124, 126, 128, 136, 138, 140, 148, 150, 152, 160, 162, 164, 172, 176, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 228, 230, 230, 231, 232, 233, 234, 235, 236, 2 74, 176, 184, 186, 188, 196, 198, 200, 208, 210, 212, 220, 222, 224, 232, 234, 236, 244, 246, 248, 256, 258, 260, 268, 270, 272, 280, 282, 284, 292, 294, 296, 304, 306, 308, 316, 318, 320, 328, 330 or 332.

[0018] In one aspect, provided herein is an antibody or immunogen-binding fragment thereof, wherein the antibody is monoclonal antibody 8G7, monoclonal antibody 26E10, monoclonal antibody 26E2, monoclonal antibody 31C4, monoclonal antibody 34B10, monoclonal antibody 37A3, monoclonal antibody 12A10, monoclonal antibody 3B7, monoclonal antibody 11G8, monoclonal antibody 14F8, monoclonal antibody 15D2, monoclonal antibody 29H7, monoclonal antibody 30D10, or monoclonal antibody 51C3.

[0019] In one aspect, provided herein is an antibody or immunogen-binding fragment thereof, wherein the antibody is humanized antibody 8G7, humanized antibody 26E10, humanized antibody 26E2, humanized antibody 31C4, humanized antibody 34B10, humanized antibody 37A3, humanized antibody 12A10, humanized antibody 3B7, humanized antibody 11G8, humanized antibody 14F8, humanized antibody 15D2, humanized antibody 29H7, humanized antibody 30D10, or humanized antibody 51C3.

[0020] In another aspect, there is provided a fusion polypeptide comprising an antibody or immunogen-binding fragment thereof according to this disclosure.

[0021] In certain aspects, compositions comprising an antibody or immunogenic binding fragment thereof, or a fusion protein according to this disclosure are provided.

[0022] In another aspect, the compositions provided herein further comprise a pharma- ceutically acceptable carrier.

[0023] In another aspect, the compositions provided herein further comprise a pharma- ceutically acceptable excipient.

[0024] In certain aspects, an antibody or immunogen-binding fragment thereof, fusion polypeptide or composition according to this disclosure may be or include a component of a chimeric antigen receptor or antibody-drug conjugate (e.g., an antibody or immunogen-binding fragment thereof conjugated to a cytotoxic agent or molecule).

[0025] In a particular aspect, there is provided an antibody or immunogenic binding fragment thereof, fusion polypeptide or composition according to this disclosure for use in therapy.

[0026] In a particular aspect, there is provided an antibody or immunogenic binding fragment thereof, fusion polypeptide or composition according to this disclosure for use in the manufacture of a medicament.

[0027] In another aspect, there is provided a nucleic acid comprising a nucleic acid encoding an antibody or immunogenic binding fragment thereof according to this disclosure.

[0028] In another aspect, a nucleic acid is provided that comprises a nucleic acid encoding a fusion polypeptide according to this disclosure.

[0029] In certain aspects, there is provided a method of treating a subject with a disease comprising administering to the subject a therapeutically effective amount of an antibody or immunogenic binding fragment thereof, fusion polypeptide, or composition according to this disclosure.

[0030] In some aspects, methods are provided for treating a subject with a disease comprising administering to the subject a therapeutically effective amount of an antibody or immunogenic binding fragment thereof, fusion polypeptide, or composition according to this disclosure, wherein the disease in the subject is cancer. In some embodiments, the cancer is selected from the group consisting of chronic lymphocytic leukemia (CLL), acute leukemia, acute lymphocytic leukemia (ALL), B-cell acute lymphocytic leukemia (B-ALL), T-cell lymphoma, B-cell lymphoma, T-cell acute lymphocytic leukemia (T-ALL), chronic myelogenous leukemia (CML), B-cell prolymphocytic leukemia, T-cell lymphoma, Hodgkin's disease, B-cell non-Hodgkin's lymphoma, blastic plasmacytoma, and the like. The cancer is selected from the group consisting of follicular dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell follicular lymphoma, large cell follicular lymphoma, malignant lymphoproliferative dysplasia, mucosa-associated lymphoid tissue (MALT) lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndromes, non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom's macroglobulinemia, or preleukemia. In another aspect, the cancer is selected from the group consisting of colon cancer, rectal cancer, renal cell carcinoma, liver cancer, lung cancer, kidney cancer, stomach cancer, gallbladder cancer, small intestine cancer, esophageal cancer, melanoma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, cancer of the vulva, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, sarcoma of soft tissue, urethral cancer, penile cancer, solid tumors of childhood, bladder cancer, cancer of the kidney or ureter, renal pelvis cancer, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, tumors of the spinal axis, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, environmentally induced cancer, combinations of cancers, and metastatic lesions of cancer. In another embodiment, the cancer is a human hematological malignancy.In certain aspects, the human hematological malignancies are selected from the group consisting of myeloid neoplasms, acute myeloid leukemia (AML), AML with recurrent genetic abnormalities, AML with myelodysplastic changes, therapy-related AML, acute leukemia of ambiguous lineage, myeloproliferative neoplasms, essential thrombocythemia, polycythemia vera, myelofibrosis (MF), primary myelofibrosis, systemic mastocytosis, myelodysplastic syndromes (MDS), myeloproliferative / myelodysplastic syndromes, chronic myeloid leukemia, chronic neutrophilic leukemia, Chronic eosinophilic leukemia, myelodysplastic syndrome (MDS), refractory anemia with ringed sideroblasts, refractory cytopenia with polycythemia vera, refractory anemia with increased blasts (type 1), refractory anemia with increased blasts (type 2), MDS with isolated chromosomal abnormality of deletion of the long arm of chromosome 5, unclassifiable MDS, myeloproliferative / myelodysplastic syndrome, chronic myelomonocytic leukemia, atypical chronic myelogenous leukemia, juvenile myelomonocytic leukemia, unclassifiable myeloproliferative / Myelodysplastic syndrome, Lymphoid neoplasms, Precursor lymphoid neoplasms, B-cell lymphoblastic leukemia, B-cell lymphoblastic lymphoma, T-cell lymphoblastic leukemia, T-cell lymphoblastic lymphoma, Mature B-cell neoplasms, Diffuse large B-cell lymphoma, Primary central nervous system lymphoma, Primary mediastinal B-cell lymphoma, Burkitt lymphoma / leukemia, Follicular lymphoma, Chronic lymphocytic leukemia, Small lymphocytic lymphoma, B-cell prolymphocytic leukemia, Lymphoid Selected from plasma cell lymphoma, Waldenstrom's macroglobulinemia, mantle cell lymphoma, marginal zone lymphoma, post-transplant lymphoproliferative dysplasia, HIV-associated lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, primary cutaneous B-cell lymphoma, hairy cell leukemia, multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma, or plasmacytoma (isolated bone and extramedullary).

[0031] In some embodiments, the cancer is a metastatic cancer.

[0032] In some aspects, the method of treating a subject with cancer comprising administering to the subject a therapeutically effective amount of an antibody or immunogenic binding fragment thereof, fusion polypeptide, or composition according to this disclosure further comprises treating the subject with one or more cancer treatments selected from chemotherapy, radiation therapy, immunotherapy, surgery, and combinations thereof.

[0033] In some aspects, there is provided a method of treating a subject with a disease comprising administering to the subject a therapeutically effective amount of an antibody or immunogenic binding fragment thereof, fusion polypeptide or composition according to this disclosure, wherein the disease in the subject is an infectious disease. In certain embodiments, the infectious disease is caused by a pathogen. In certain embodiments, the pathogen is a virus. In some embodiments, the virus is selected from the group consisting of human immunodeficiency virus, influenza virus, papilloma virus, coronavirus, hepatitis virus, or herpes virus. In other embodiments, the pathogen is a bacterium. In some embodiments, the bacterium is Mycobacterium tuberculosis. In other embodiments, the pathogen is a prion. In other embodiments, the pathogen is a fungus. In certain embodiments, the fungus is Pneumocystis jirovecii (PJP). In other embodiments, the pathogen is a parasite.

[0034] In some aspects, a method of treating a subject with a disease is provided, comprising administering to the subject a therapeutically effective amount of an antibody or immunogen-binding fragment thereof, fusion polypeptide, or composition according to this disclosure, wherein the disease in the subject is an autoimmune disease or disorder. In some embodiments, the autoimmune disease or disorder is selected from the group consisting of acute disseminated encephalomyelitis (ADEM), alopecia areata, antiphospholipid syndrome, autoimmune cardiomyopathy, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disorder, autoimmune lipoproliferative syndrome, autoimmune peripheral neuropathy, autoimmune pancreatitis, autoimmune polyendocrine syndrome, autoimmune progesterone dermatitis, autoimmune thrombocytopenic purpura, autoimmune urticaria, autoimmune uveitis, Behcet's disease, celiac disease, Chagas disease, cold agglutinin disease, Crohn's disease, The autoimmune disease or disorder is selected from the group consisting of dermatomyositis, type 1 diabetes, eosinophilic fasciitis, gastrointestinal pemphigoid, Goodpasture's syndrome, Graves' syndrome, Guillain-Barre syndrome, Hashimoto's encephalopathy, Hashimoto's thyroiditis, lupus erythematosus, Miller Fisher syndrome, mixed connective tissue disease, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polymyositis, psoriasis, psoriatic arthritis, relapsing polychondritis, rheumatoid arthritis, rheumatic fever, Sjogren's syndrome, temporal arteritis, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, vasculitis, and Wegener's granulomatosis. In a particular embodiment, the autoimmune disease or disorder is rheumatoid arthritis in adults.

[0035] In some aspects, there is provided a method of treating a subject with a disease comprising administering to the subject a therapeutically effective amount of an antibody or immunogenic binding fragment thereof, fusion polypeptide, or composition according to this disclosure, wherein the disease in the subject is transplantation. In some embodiments, the transplantation is selected from a stem cell transplant or a bone marrow transplant. In some embodiments, the transplantation is selected from the group consisting of a kidney transplant, a lung transplant, a heart transplant, a pancreas transplant, a cornea transplant, or a liver transplant.

[0036] In a particular aspect, there is provided a composition comprising an antibody, an immunogenic binding fragment thereof, a fusion polypeptide, or a combination thereof, according to this technology, for use in treating a diseased subject.

[0037] In some aspects, compositions are provided comprising an antibody, immunogenic binding fragment thereof, fusion polypeptide, or combination thereof from this technology for use in treating a subject with a disease, said disease being cancer. In some embodiments, the cancer is selected from the group consisting of chronic lymphocytic leukemia (CLL), acute leukemia, acute lymphocytic leukemia (ALL), B-cell acute lymphocytic leukemia (B-ALL), T-cell lymphoma, B-cell lymphoma, T-cell acute lymphocytic leukemia (T-ALL), chronic myelogenous leukemia (CML), B-cell prolymphocytic leukemia, T-cell lymphoma, Hodgkin's disease, B-cell non-Hodgkin's lymphoma, blastic plasmacytoma, and the like. The cancer is selected from the group consisting of follicular dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell follicular lymphoma, large cell follicular lymphoma, malignant lymphoproliferative dysplasia, mucosa-associated lymphoid tissue (MALT) lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndromes, non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom's macroglobulinemia, or preleukemia. In another aspect, the cancer is selected from the group consisting of colon cancer, rectal cancer, renal cell carcinoma, liver cancer, lung cancer, kidney cancer, stomach cancer, gallbladder cancer, small intestine cancer, esophageal cancer, melanoma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, cancer of the vulva, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, sarcoma of soft tissue, urethral cancer, penile cancer, solid tumors of childhood, bladder cancer, cancer of the kidney or ureter, renal pelvis cancer, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, tumors of the spinal axis, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, environmentally induced cancer, combinations of cancers, and metastatic lesions of cancer. In another embodiment, the cancer is a human hematological malignancy.In certain aspects, the human hematological malignancies are selected from the group consisting of myeloid neoplasms, acute myeloid leukemia (AML), AML with recurrent genetic abnormalities, AML with myelodysplastic changes, therapy-related AML, acute leukemia of ambiguous lineage, myeloproliferative neoplasms, essential thrombocythemia, polycythemia vera, myelofibrosis (MF), primary myelofibrosis, systemic mastocytosis, myelodysplastic syndromes (MDS), myeloproliferative / myelodysplastic syndromes, chronic myeloid leukemia, chronic neutrophilic leukemia, Chronic eosinophilic leukemia, myelodysplastic syndrome (MDS), refractory anemia with ringed sideroblasts, refractory cytopenia with polycythemia vera, refractory anemia with increased blasts (type 1), refractory anemia with increased blasts (type 2), MDS with isolated chromosomal abnormality of deletion of the long arm of chromosome 5, unclassifiable MDS, myeloproliferative / myelodysplastic syndrome, chronic myelomonocytic leukemia, atypical chronic myelogenous leukemia, juvenile myelomonocytic leukemia, unclassifiable myeloproliferative / Myelodysplastic syndrome, Lymphoid neoplasms, Precursor lymphoid neoplasms, B-cell lymphoblastic leukemia, B-cell lymphoblastic lymphoma, T-cell lymphoblastic leukemia, T-cell lymphoblastic lymphoma, Mature B-cell neoplasms, Diffuse large B-cell lymphoma, Primary central nervous system lymphoma, Primary mediastinal B-cell lymphoma, Burkitt lymphoma / leukemia, Follicular lymphoma, Chronic lymphocytic leukemia, Small lymphocytic lymphoma, B-cell prolymphocytic leukemia, Lymphoid Selected from plasma cell lymphoma, Waldenstrom's macroglobulinemia, mantle cell lymphoma, marginal zone lymphoma, post-transplant lymphoproliferative dysplasia, HIV-associated lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, primary cutaneous B-cell lymphoma, hairy cell leukemia, multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma, or plasmacytoma (isolated bone and extramedullary).

[0038] In some embodiments, the cancer is a metastatic cancer.

[0039] In some aspects, compositions are provided comprising an antibody, immunogenic binding fragment thereof, fusion polypeptide, or combinations thereof according to this technology for use in treating a diseased subject, said composition being administered to the subject concomitantly with one or more additional cancer treatments selected from chemotherapy, radiation therapy, immunotherapy, surgery, or combinations thereof.

[0040] In some aspects, compositions are provided comprising an antibody, immunogenic binding fragment thereof, fusion polypeptide, or combination thereof according to this technology for use in treating a subject with a disease, said disease being an infectious disease. In certain embodiments, the infectious disease is caused by a pathogen. In certain embodiments, the pathogen is a virus. In some embodiments, the virus is selected from the group consisting of human immunodeficiency virus, influenza virus, papilloma virus, coronavirus, hepatitis virus, or herpes virus. In other embodiments, the pathogen is a bacterium. In some embodiments, the bacterium is Mycobacterium tuberculosis. In other embodiments, the pathogen is a prion. In other embodiments, the pathogen is a fungus. In certain embodiments, the fungus is Pneumocystis jirovecii (PJP). In other embodiments, the pathogen is a parasite.

[0041] In some aspects, compositions are provided comprising the antibodies, immunological fragments thereof, fusion polypeptides, or combinations thereof from this technology for use in treating a diseased subject, the disease being an autoimmune disease or disorder. In some embodiments, the autoimmune disease or disorder is selected from the group consisting of acute disseminated encephalomyelitis (ADEM), alopecia areata, antiphospholipid syndrome, autoimmune cardiomyopathy, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disorder, autoimmune lipoproliferative syndrome, autoimmune peripheral neuropathy, autoimmune pancreatitis, autoimmune polyendocrine syndrome, autoimmune progesterone dermatitis, autoimmune thrombocytopenic purpura, autoimmune urticaria, autoimmune uveitis, Behcet's disease, celiac disease, Chagas disease, cold agglutinin disease, Crohn's disease, The autoimmune disease or disorder is selected from the group consisting of dermatomyositis, type 1 diabetes, eosinophilic fasciitis, gastrointestinal pemphigoid, Goodpasture's syndrome, Graves' syndrome, Guillain-Barre syndrome, Hashimoto's encephalopathy, Hashimoto's thyroiditis, lupus erythematosus, Miller Fisher syndrome, mixed connective tissue disease, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polymyositis, psoriasis, psoriatic arthritis, relapsing polychondritis, rheumatoid arthritis, rheumatic fever, Sjogren's syndrome, temporal arteritis, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, vasculitis, and Wegener's granulomatosis. In a particular embodiment, the autoimmune disease or disorder is rheumatoid arthritis in adults.

[0042] In some aspects, compositions are provided comprising an antibody, immunogenic binding fragment thereof, fusion polypeptide, or combination thereof from this technology for use in treating a subject with a disease, said disease being transplantation. In some embodiments, the transplantation is selected from a stem cell transplant or a bone marrow transplant. In some embodiments, the transplantation is selected from the group consisting of a kidney transplant, a lung transplant, a heart transplant, a pancreas transplant, a cornea transplant, and a liver transplant.

[0043] This list is intended to be representative and explanatory, rather than exhaustive and limiting, and additional aspects and embodiments are set forth or may be apparent from the remainder of this technology and the claims. [Brief description of the drawings]

[0044] [Figure 1A] Figure 1A shows that KIR3DL3 protein is expressed on the surface of human adaptive and innate immune cells. Figure 1A shows fluorescence-activated cell sorting (FACS) analysis of peripheral blood mononuclear cells (PBMCs). FACS analysis showed that KIR3DL3 protein was detected on the surface of human innate immune cells, including natural killer (NK) cells, natural killer T (NKT) cells, and γδ T cells, as well as human adaptive immune cells, including CD8+ T cells and CD4+ T cells. [Figure 1B] Figure 1B shows that KIR3DL3 protein is expressed on the surface of human adaptive and innate immune cells, and shows the percentage of KIR3DL3-positive cells in different populations of immune cells in PBMCs from six donors. [Figure 2A] Figure 2A shows that HHLA2 binds to KIR3DL3 but not to its closest homologues KIR3DL1 and KIR3DL2, and that the D0 domain and the entire extracellular domain of KIR3DL3 bind to HHLA2. Figure 2A shows histograms of 3T3 cell lines expressing KIR3DL1, KIR3DL2 or KIR3DL3 stained with HHLA2-Ig fusion polypeptide (open) or control Ig (shaded). [Figure 2B] Figure 2B shows that HHLA2 binds to KIR3DL3 but not to its closest homologues KIR3DL1 and KIR3DL2, and that the D0 domain and the entire extracellular domain of KIR3DL3 bind to HHLA2. Figure 2B is a plot of the results of a cell-cell conjugation assay showing that 3T3 cell lines expressing HHLA2 bind to 3T3 cell lines expressing KIR3DL3 but not to control 3T3 cell lines. [Figure 2C]Figure 2C shows that HHLA2 binds to KIR3DL3 but not to its closest homologues KIR3DL1 and KIR3DL2, and that the DO domain and the entire extracellular domain of KIR3DL3 bind to HHLA2. Figure 2C shows histograms of 3T3 cell lines expressing HHLA2 bound to the DO domain of KIR3DL3 (red) or the entire extracellular domain of KIR3DL3 (red). [Diagram 3] Figures 3A and 3B show that TMIGD2 and KIR3DL3 bind to non-overlapping sites on HHLA2. Figure 3A shows the mean fluorescence intensity (MFI) of 3T3 cells expressing HHLA2 incubated with various concentrations of TMIGD2-mIg fusion polypeptide or control mIgG before staining with 10 μg / ml KIR3DL3-hIg followed by allophycocyanin (APC)-conjugated anti-human IgG Fc. Figure 3B shows the MFI of 3T3 cells expressing HHLA2 incubated with various concentrations of KIR3DL3-hIg fusion polypeptide or control hIgG before staining with 10 μg / ml TMIGD2-mIg followed by APC anti-mouse IgG Fc. [Figure 4A] Figure 4A shows that KIR3DL3 suppresses immune cell function. Figure 4A shows plots of FACS analysis and quantification of specific lysis. KIR3DL3 expression was examined by FACS and KIR3DL3+ and KIR3DL3- NK92 cells were sorted. Cytotoxicity assays were performed by incubating NK92 cells with targets, control K562 or HHLA2 expressing K562 (HHLA2 / K562), at specific effector to target cell ratios (E:T=1, 2, 5, 10). [Figure 4B]Figure 4B shows that KIR3DL3 suppresses immune cell function. Figure 4B shows the percentage of specific lysis after cytotoxicity assay of KIR3DL3+ CD8+ T cells (terminally differentiated effector cells) obtained by FACS sorting PBMCs and expanding in vitro with anti-CD3 / CD28, IL-2 and feeder cells. Cytotoxicity assay was performed by incubating KIR3DL3+ CD8+ T cells with control K562 or HHLA2 / K562 targets at the indicated effector to target cell ratios. *P<0.05; **P<0.01. [Figure 5A] Figure 5A shows that anti-KIR3DL3 blocking monoclonal antibodies (mAbs) neutralize KIR3DL3-induced immune suppression. Figure 5A shows a histogram of KIR3DL3+ NK92 cells pre-incubated with anti-KIR3DL3 mAbs (clones 26E10, 34B10, 30D10, 8G7) for 45 minutes at room temperature (RT). [Figure 5B] Figure 5B shows that anti-KIR3DL3 blocking monoclonal antibodies (mAbs) neutralize KIR3DL3-induced immune suppression. Figure 5B quantifies the percentage of specific lysis after cytotoxicity assay. Cytotoxicity assays were performed using control K562 or HHLA2 / K562 as targets at an E:T ratio of 5:1. *P<0.05; **P<0.01. [Figure 6A] Figure 6A shows that monoclonal antibodies against the IgV1 domain of HHLA2 can block the binding of HHLA2 to KIR3DL3 and neutralize KIR3DL3-induced immunosuppression. Figure 6A shows the mean fluorescence intensity (MFI) of HHLA2-expressing 3T3 cells stained with various concentrations of KIR3DL3-Ig protein after preincubation with anti-HHLA2 mAb or control mouse IgG. The binding of KIR3DL3-Ig protein to HHLA2 was examined by FACS. [Figure 6B]Figure 6B shows that monoclonal antibodies against the IgV1 domain of HHLA2 can block the binding of HHLA2 to KIR3DL3 and neutralize KIR3DL3-induced immune suppression. Figure 6B shows the percentage of specific lysis after toxicity assay of HHLA2 / K562 target cells preincubated with anti-HHLA2 mAb (clones B5B5, A3H11, 566.1) or isotype mIgG1. Cytotoxicity assays were performed by incubating KIR3DL3+ NK92 cells with control K562 or HHLA2 / K562 at an E:T ratio of 5:1 for 4 hours at 37°C. *P<0.05; **P<0.01. [Figure 7] FIG. 7 is a FACS plot showing the expression patterns of two receptors, KIR3DL3 and TMIGD2, in human NK cells, CD8+ T cells, and CD4+ T cells. [Figure 8] FIG. 8 shows histograms of 3T3 cell lines expressing TMIGD2 stained with HHLA2-EC-Ig-Fc fusion polypeptide (left red histogram), HHLA2-IgV1-hIgG fusion polypeptide (right red histogram) or control Ig (black histogram). [Figure 9] Figure 9 shows the color-coded percentage of KIRDL3 mRNA expression in 1425 human tumor cell lines. Many tumor cell lines from human hematological malignancies expressed KIR3DL3 mRNA. The top 40 lines expressing the highest levels of KIR3DL3 mRNA are shown in Figure 9. [Figure 10A] Figure 10A shows that the ITIM motif of KIR3DL3 suppresses NK cells by recruiting SHR1 / 2. Figure 10A shows the illustration of wild-type (WT) KIR3DL3 and an ITIM mutant of KIR3DL3 (Y381F) with a tyrosine (Y) to phenylalanine (F) mutation in the ITIM sequence (YAQL) and their expression by flow cytometry. [Figure 10B] Figure 10B shows that the ITIM motif of KIR3DL3 suppresses NK cells by recruiting SHR1 / 2.Figure 10B shows tyrosine phosphorylation of KIR3DL3 WT and Y381F mutant upon pervanadate treatment. [Figure 10C] Figure 10C shows that the ITIM motif of KIR3DL3 suppresses NK cells by recruiting SHR1 / 2. Figure 10C shows cytotoxicity assays in which KIR3DL3 WT or Y381F NK92 cells were incubated with K562 (top, control K562 or HHLA2 / K562) or Raji (bottom, control Raji or HHLA2 / Raji) at various E:T ratios. One out of three experiments is shown. *P<0.05, **P<0.01; NS, not significant. [Figure 10D] Figure 10D shows that the ITIM motif of KIR3DL3 suppresses NK cells by recruiting SHR1 / 2.Figure 10D shows co-immunoprecipitation images showing that KIR3DL3 interacts with SHP-1 and SHP-2. [Figure 11] Figure 11 shows that KIR3DL3 is expressed in tumor-infiltrating immune cells in a variety of human cancers, including renal, gastric, lung, gallbladder, and pancreatic cancers. Representative images of human cancers with co-expression of KIR3DL3 and CD45 (DAPI: blue, CD45: red, KIR3DL3: green). Left: overlay of all markers, center: CD45 and DAPI, right: KIR3DL3 and DAPI. Scale bar, 50 μm. [Figure 12-1] Figures 12A and 12B show that KIR3DL3 blockade promotes antitumor immunity. Figures 12A and 12B show intraperitoneal tumor model mice treated with primary NK cells and anti-KIR3DL3 mAb. Figure 12A shows an outline of the experiment. Figure 12B shows bioluminescence measurements of tumor growth in the 26E10 group (blue line) and the mIgG1 group (black line). Data are the mean ± SEM of total flux of ventral imaging of each mouse. [Figure 12-2]Figures 12C and 12D show that KIR3DL3 blockade promotes anti-tumor immunity. Figures 12C and 12D show tumor model mice with lung metastasis treated with primary NK cells and anti-KIR3DL3 mAb. Figure 12C shows an outline of the experiment. Figure 12D shows bioluminescence measurements of tumor growth in the 26E10 group (blue) and the mIgG1 group (black). Data are the mean ± SEM of total flux of dorsal and ventral imaging of each mouse. P values ​​are two-way ANOVA. [Figure 12-3] Figures 12E and 12F show that KIR3DL3 blockade promotes anti-tumor immunity. Figures 12E and 12F show subcutaneous tumor model mice treated with primary NK cells and anti-KIR3DL3 mAb. Figure 12E shows the experimental outline. Figure 12F shows tumor growth. Mean tumor volume ± SEM is shown. ip: intraperitoneal, iv: intravenous, sc: subcutaneous. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0045] Killer cell immunoglobulin-like receptor (KIR) proteins contain two (KIR2D) or three (KIR3D) immunoglobulin-like extracellular domains (Beziat 2017). KIR3DL3 is a member of the KIR family, but its function is unknown (Beziat 2017). KIR3DL3 proteins are expressed on the surface of human adaptive and innate immune cells. The results presented herein show that KIR3DL3 suppresses the function of human immune cells. Thus, blocking KIR3DL3 function with antibodies, ligand fusion polypeptides or small molecules can be used to treat cancer and infectious diseases, and stimulating KIR3DL3 function with antibodies, ligand fusion polypeptides or small molecules can be used to treat autoimmune diseases and transplantation. KIR3DL3 is expressed in a variety of human hematological malignancies, so killing KIR3DL3-positive tumor cells using antibodies or other molecules can be used to treat human hematological malignancies. This technology provides antibodies to KIR3DL3 or one or more epitopes thereof, as well as compositions and methods of using same.

[0046] This technique provides results showing that KIR3DL3 suppresses immune cell function. Moreover, administration of anti-KIR3DL3 blocking mAbs as described herein neutralizes KIR3DL3-induced immune suppression. Such isolated antibodies (including monoclonal antibodies) against KIR3DL3 can act to block KIR3DL3 function, thereby enhancing immune cell function. Furthermore, the results presented herein show that HHLA2 binds to KIR3DL3 but not to its closest homologues, KIR3DL1 and KIR3DL2. Thus, antibodies against the IgV1 domain of HHLA2 can block the binding of HHLA2 to KIR3DL3, thereby neutralizing KIR3DL3-induced immune suppression.

[0047] Definitions and Abbreviations Unless otherwise stated, the following terms have the meanings set forth in this section.

[0048] The indefinite articles "a" and "an" refer to at least one of the following noun and are used interchangeably with the terms "at least one" and "one or more." For example, the phrase "a module" means at least one module or more than one module.

[0049] The conjunctions "and" and "and / or" are used interchangeably.

[0050] In this specification, the term "antibody" is used to refer to naturally occurring antibodies as well as genetically engineered or otherwise modified immunoglobulins, including chimeric, human, humanized, or synthetic antibodies. The antibodies disclosed herein may be monoclonal or polyclonal. In embodiments where the antibody is an immunologically active portion of an immunoglobulin molecule, the antibody includes, but is not limited to, a single chain Fv antibody (scFv), a disulfide-linked Fv, a single domain antibody (dAb), a Fab, a Fab', a Fab fragment, a F(ab')2, or a diabody. The antibodies disclosed herein, including immunogenic binding fragments of an immunoglobulin molecule, retain the ability to bind to a particular antigen (e.g., KIR3DL3) or one or more epitopes thereof.

[0051] "Domain" is used to refer to a portion of a protein or nucleic acid. Unless otherwise indicated, a domain does not necessarily have a particular function.

[0052] "Subject" means a human, mouse, or non-human primate. The human may be of any age (e.g., infant, child, adolescent, or adult) and may be suffering from a disease, such as cancer. In some embodiments, the subject is afflicted with a disease, disorder, or condition. In some embodiments, the subject is susceptible to a disease, disorder, or condition. In some embodiments, the subject exhibits one or more symptoms or characteristics of a disease, disorder, or condition. In some embodiments, the subject does not exhibit symptoms or characteristics of a disease, disorder, or condition. In some embodiments, the subject has one or more characteristics of susceptibility or risk for a disease, disorder, or condition. In some embodiments, the subject is a patient. In some embodiments, the subject is an individual for whom diagnosis and / or treatment is to be and / or has been performed.

[0053] As used herein, the term "treatment" refers to the treatment of a disease in a subject (e.g., a human) and includes one or more of: inhibiting the disease, i.e., suppressing or preventing its onset or progression; alleviating the disease, i.e., reducing the pathology; alleviating one or more symptoms of the disease, and curing the disease.

[0054] As used herein, the term "prevention" refers to the prevention of disease in a subject (e.g., a human), and includes (a) avoiding or hindering disease; (b) affecting predisposition to disease; and (c) preventing or delaying the onset and / or suffering of at least one symptom of disease.

[0055] The terms "polynucleotide", "nucleotide sequence", "nucleic acid", "nucleic acid molecule", "nucleic acid sequence" and "oligonucleotide" refer to a series of nucleotide bases (also called "nucleotides") in DNA and RNA, meaning a chain of two or more nucleotides. Polynucleotides can be single-stranded or double-stranded, chimeric mixtures, derivatives or modified versions thereof. Oligonucleotides can be modified in the bases, sugars or phosphate backbones, for example, to improve the stability of the molecule, its hybridization parameters, etc. The nucleotide sequence usually contains the genetic information, including the information used by cells to produce proteins and enzymes. These terms include double-stranded or single-stranded genomic DNA, RNA, synthetic and engineered polynucleotides, as well as sense and antisense polynucleotides. This also includes nucleic acids with modified bases.

[0056] The nucleotide sequences shown in Table 1 below use conventional IUPAC notation (see also Cornish-Bowden 1985, incorporated herein by reference), where it should be noted that to the extent that the sequence (e.g., the gRNA sequence) is encoded by either DNA or RNA, "T" stands for "thymine or uracil."

[0057] [Table 1]

[0058] The terms "protein," "peptide," and "polypeptide" are used interchangeably to refer to a chain of amino acids linked through peptide bonds. The terms include individual proteins, groups or complexes of associated proteins, as well as fragments, variants, derivatives, and analogs of such proteins. Peptide sequences are represented in conventional notation with the amino or N-terminus at the left-hand end and the carboxyl or C-terminus at the right-hand end. Conventional one-letter or three-letter notations may be used.

[0059] Production and sequence of mAb against human KIR3DL3 KIR3DL3 is a type of KIR, but its function has been unknown until now (Beziat 2017). The extracellular domain of KIR3DL3 consists of three domains (D0, D1, and D2). According to the embodiments shown in this specification, the following fusion polypeptides were obtained by a previously reported method (Zhao 2013): 1) KIR3DL3 D0-Ig fusion polypeptide in which the D0 coding region of KIR3DL3 (Q26-A128) is fused with a human IgG1 Fc tag, and 2) KIR3DL3 D0D1D2-Ig fusion polypeptide in which the D0-D2 coding region of KIR3DL3 (Q26-L325) is fused with a human IgG1 Fc tag. In some embodiments, the fusion polypeptides were expressed in the S2 system and then purified. Mice were immunized with KIR3DL3 D0(Q26-A128)-Ig fusion polypeptide or KIR3DL3 D0(Q26-A128)-Ig fusion polypeptide, and hybridomas were prepared from splenocytes fused with NS0 myeloma cells by standard techniques. The sequence of human KIR3DL3 is shown in Table 2 below.

[0060] [Table 2-1]

[0061] [Table 2-2]

[0062] In some embodiments, mAbs against KIR3DL3 protein were obtained from the above hybridomas. The binding affinity of each mAb is shown in Table 3 below.

[0063] [Table 3]

[0064] In some embodiments, the hybridomas were sequenced after evaluating the binding affinity. The 14 mAbs obtained were found to have unique VH and VL sequences. Each VH or VL has three CDRs (CDR1, CDR2, and CDR3). These sequences are shown in SEQ ID NOs: 1 to 333 and annotated in Table 4 below.

[0065] [Table 4-1]

[0066] [Table 4-2]

[0067] [Table 4-3]

[0068] [Table 4-4]

[0069] [Table 4-5]

[0070] [Table 4-6]

[0071]

Table 4-7

[0072]

Table 4-8

[0073]

Table 4-9

[0074]

Table 4-10

[0075]

Table 4-11

[0076]

Table 4-12

[0077]

Table 4-13

[0078]

Table 4-14

[0079]

Table 4-15

[0080]

Table 4-16

[0081]

Table 4-17

[0082]

Table 4-18

[0083]

Table 4-19

[0084]

Table 4-20

[0085]

Table 4-21

[0086]

Table 4-22

[0087]

Table 4-23

[0088]

Table 4-24

[0089]

Table 4-25

[0090]

Table 4-26

[0091]

Table 4-27

[0092]

Table 4-28

[0093]

Table 4-29

[0094]

Table 4-30

[0095]

Table 4-31

[0096]

Table 4-32

[0097]

Table 4-33

[0098]

Table 4-34

[0099]

Table 4-35

[0100]

Table 4-36

[0101]

Table 4-37

[0102] [Table 4-38]

[0103] [Table 4-39]

[0104] In some embodiments, the provided antibodies or immunogen-binding fragments thereof comprise a sequence that is at least 80% identical (e.g., at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% identical) to one or more complementarity determining regions (CDRs) (e.g., CDR1, CDR2, or CDR3) shown in Table 4. In some embodiments, the provided antibodies or immunogen-binding fragments thereof comprise a sequence that is at least 80% identical to the CDRs of one or more VHs shown in Table 4. In some embodiments, the provided antibodies or immunogen-binding fragments thereof comprise a sequence that is at least 80% identical to the CDRs of two or more VHs shown in Table 4. In some embodiments, the provided antibodies or immunogen-binding fragments thereof comprise a sequence that is at least 80% identical to the CDRs of three or more VHs shown in Table 4. In some embodiments, the provided antibodies or immunogen-binding fragments thereof comprise a sequence that is at least 80% identical to the CDRs of one or more VLs shown in Table 4. In some embodiments, the antibodies or immunogen-binding fragments thereof provided comprise sequences that are at least 80% identical to the CDRs of two or more VLs shown in Table 4. In some embodiments, the antibodies or immunogen-binding fragments thereof provided comprise sequences that are at least 80% identical to the CDRs of three or more VLs shown in Table 4.

[0105] In some embodiments, the antibody is or comprises a humanized antibody. "Humanized" forms of non-human (e.g. rodent) antibodies are chimeric antibodies that contain sequences of non-human antibodies. Often, humanized antibodies are human immunoglobulins in which residues from a hypervariable domain of a species of interest are replaced by residues from a hypervariable domain of a non-human species (e.g. mouse, rat, rabbit or non-human primate) (donor antibody) having the desired specificity, affinity and capacity. In some cases, residues from framework regions (FR) of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not present in the recipient or donor antibody. In some embodiments, such modifications can be made to further improve antibody performance. In general, a humanized antibody may comprise substantially at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FRs correspond to those of a human immunoglobulin sequence. Furthermore, the humanized antibody may optionally comprise at least a portion of an immunoglobulin constant domain (Fc), or may generally comprise a human immunoglobulin constant domain. Techniques for humanizing monoclonal antibodies are well known to those skilled in the art and have been previously described. See, for example, U.S. Patent Nos. 4,816,567; 5,807,715; 5,866,692; 6,331,415; 5,530,101; 5,693,761; 5,693,762; 5,585,089 and 6,180,370; Jones 1986; Riechmann 1988; Vaswani & Hamilton 1998; Harris 1995; Hurle & Gross 1994. In certain aspects, this technique provides nucleic acid encoding a humanized antibody. The nucleic acids provided herein may be present in cells, in a cell lysate, in an isolated, partially purified or substantially purified form.A nucleic acid is said to be "isolated," "partially purified," or "substantially purified" when it is separated from other components of a cell or from components of other cells (e.g., nucleic acids or proteins of other cells) by techniques known to those of skill in the art, including, but not limited to, alkaline / SDS treatment, CsCl binding, column chromatography, agarose gel electrophoresis, or other suitable techniques. The nucleic acid in this context may be, for example, DNA or RNA, and may or may not contain intron sequences.

[0106] nucleic acid The technology includes nucleic acids comprising one or more nucleotide sequences encoding one or more heavy chains, heavy chain variable domains, heavy chain framework regions, heavy chain CDRs, heavy chain constant domains, light chains, light chain variable domains, light chain framework regions, light chain CDRs, light chain constant domains, other immunoglobulin-like sequences, antibodies, or binding molecules disclosed herein. In some embodiments, such nucleotide sequences may be present in a vector (e.g., a plasmid or viral vector). In some embodiments, such nucleotides may be present in the genome of a cell (e.g., a cell of a subject in need of treatment) or a cell for antibody production (e.g., a mammalian cell).

[0107] KIR3DL3 protein expression and binding Fluorescence-activated cell sorting (FACS) analysis of PBMCs using the anti-KIR3DL3 mAb presented herein demonstrated that KIR3DL3 protein is widely expressed on the surface of innate immune cells (NK cells, NKT cells, γδT cells) and adaptive immune cells (CD8 T cells and CD4 T cells) (Figure 1). In CD8 T cells, KIR3DL3 is expressed mainly on terminally differentiated effector CD8 T cells.

[0108] Previous studies have shown that HHLA2, as the newest member of the B7 family, can suppress T cell proliferation and function (Zhao 2013; U.S. Patent No. 10,093,737). Subsequent studies have reported that HHLA2 is overexpressed in various human cancers (Cheng 2018; Cheng 2017; Koirala 2016; Janakiram 2015). To test the binding of HHLA2 to KIR3DL1, KIR3DL2, and KIR3DL3, we generated 3T3 cell lines stably expressing KIR3DL1, KIR3DL2, or KIR3DL3 on the cell surface. FACS assays showed that HHLA2 protein bound to 3T3 cells expressing KIR3DL3, but not to 3T3 cells expressing KIR3DL1 or KIR3DL2 (Figure 2A). Furthermore, cell-cell conjugation assays showed that 3T3 cell lines expressing HHLA2 bound to 3T3 cell lines expressing KIR3DL3, but not to control 3T3 cell lines (Figure 2B). These results indicate that HHLA2 binds to KIR3DL3, but not to its closest homologues, KIR3DL1 and KIR3DL2.

[0109] The results presented herein further demonstrate that the DO domain and the entire extracellular domain of KIR3DL3 bind to HHLA2 (Figure 2C), suggesting that the DO domain of KIR3DL3 is a functional domain in the interaction between KIR3DL3 and HHLA2.

[0110] Because HHLA2 can bind to KIR3DL3 and / or TMIGD2, we performed a competition assay using FACS and showed that TMIGD2 could not inhibit the binding of KIR3DL3 to HHLA2 (Figure 3A), and KIR3DL3 could not inhibit the binding of TMIGD2 to HHLA2 (Figure 3B), suggesting that KIR3DL3 and TMIGD2 bind to non-overlapping sites on HHLA2.

[0111] KIR3DL3 suppresses the function of human immune cells, and anti-KIR3DL3 blocking mAb neutralizes KIR3DL3-induced immune suppression In contrast to KIR3DL1 and KIR3DL2, which bind to HLA-A and / or HLA-B, KIR3DL3 binds to HHLA2, but the function of KIR3DL3 has been unknown until now (Beziat 2017). To elucidate the function of KIR3DL3, the human NK cell line NK92 was subjected to FACS analysis to screen the KIR3DL3 positive population (KIR3DL3 + NK92) and the KIR3DL3-negative population (KIR3DL3 - NK92). - NK92 cells were isolated from HHLA2-positive K562 cells (HHLA2 + K562) and HHLA2-negative K562 cells (HHLA2 - K562) equally killed both IL-1 and IL-2 (Fig. 4A), but KIR3DL3 + NK92 cells are HHLA2 + Compared with K562 cells, HHLA2 - We next used FACS to analyze KIR3DL3 + CD8 T cells (terminally differentiated effector cells) were selected and expanded in vitro with anti-CD3 / CD28, IL-2 and feeder cells to obtain sufficient cells. CD8 T cell-mediated killing assays were then performed to detect KIR3DL3 + CD8 T cells are HHLA2 + The results showed that KIR3DL3 killed control K562 cells much more efficiently than KIR3DL3-dependent K562 cells (Figure 4B). These results indicate that KIR3DL3 inhibits immune cell function when bound to HHLA2.

[0112] After showing that KIR3DL3 induces immune suppression (Figure 4A,B), we performed experiments to determine whether anti-KIR3DL3 mAbs (as described herein) could block KIR3DL3 function. +NK92 cells were preincubated with anti-KIR3DL3 mAb or a negative control mouse IgG1 antibody. Four anti-KIR3DL3 mAbs were examined (26E10, 34B10, 30D10, 8G7). After preincubation, the NK cell-mediated killing assay employed in Figure 4A was performed. After cytotoxicity assay, cells preincubated with mouse IgG1 showed no effect, whereas cells preincubated with anti-KIR3DL3 mAb (26E10, 34B10, 30D10, 8G7) showed a significant increase in the NK cell-mediated killing of the target HHLA2. + Significantly enhanced KIR3DL3 in K562 cells + We demonstrated NK92 cell-mediated killing (Figure 5A, Figure 5B).

[0113] The extracellular domain of HHLA2 contains IgV1, IgC, and IgV2 domains (Zhao 2013). In a previous study, an anti-HHLA2 mAb (566.1) that recognizes IgCIgV2 was obtained (Zhao 2013). Subsequently, two anti-HHLA2 mAbs (A3H11 and B5B5) were obtained. These two antibodies recognize the IgV1 domain. In this study, binding competition assays revealed that A3H11 and B5B5, but not 566.1, blocked the binding of KIR3DL3 protein to HHLA2 (Figure 6A). Furthermore, NK cell killing assays showed that A3H11 and B5B5, but not 566.1, neutralized KIR3DL3-induced immune suppression (Figure 6B). These results indicate that the IgV1 domain of HHLA2 binds to KIR3DL3 to suppress immune cells, and that mAbs against the IgV1 domain of HHLA2 can block the binding of HHLA2 to KIR3DL3 and neutralize KIR3DL3-induced immune suppression.

[0114] The expression patterns of KIR3DL3 and TMIGD2 are unclear. Therefore, we performed experiments using FACS to examine the expression of these two receptors on human immune cells in PBMCs. These experiments showed that KIR3DL3-positive CD8 T cells and CD4 T cells were TMIGD2-negative, whereas NK cells expressed KIR3DL3. + / TMIGD2 + , KIR3DL3 + / TMIGD2 - , KIR3DL3 - / TMIGD2 + or KIR3DL3 - / TMIGD2 - These results indicate that both TMIGD2 and KIR3DL3 are receptors for HHLA2, but have different expression patterns.

[0115] To examine the binding of TMIGD2 to HHLA2, 3T3 cell lines expressing TMIGD2 were stained with HHLA2-EC-Ig-Fc fusion polypeptide, HHLA2-IgV1-hIgG fusion polypeptide, or Ig (control) (Figure 8). These results showed that the IgV1 domain and the entire extracellular domain of HHLA2 bound to TMIGD2 (Figure 8), suggesting that the IgV1 domain of HHLA2 is a functional domain in the interaction between HHLA2 and TMIGD2.

[0116] KIR3DL3 suppresses human immune cell function by recruiting SHP1 / 2 via its ITIM motif To further investigate the mechanism by which KIR3DL3 suppresses immune cells, the Y381F mutant of KIR3DL3 was obtained by substituting the tyrosine (Y) residue at position 381 of the YAQL sequence in the ITIM motif with a phenylalanine (F) residue (Figure 10A). -) NK92 cells were transduced with wild-type KIR3DL3 or the Y381F mutant, and KIR3DL3 expression was examined by flow cytometry. Expression of wild-type and Y381F mutant KIR3DL3 was detected in each transduced cell (Figure 10A). Then, tyrosine phosphorylation of wild-type and Y381F mutant KIR3DL3 was examined. Briefly, transfected NK92 cells were cultured at 37°C for 5 min in the presence (+) or absence (-) of pervanadate (VO4, 1 mM). Pervanadate is an inhibitor of protein tyrosine phosphatase and promotes phosphorylation of proteins at tyrosine residues. Cell lysates were immunoprecipitated with anti-KIR3DL3 antibody, and tyrosine phosphorylation was examined by immunoblotting using KIR3DL3 antibody and phosphotyrosine antibody (4G10). The results of whole cell lysates (WCL) and immunoprecipitation samples (IP) are shown (FIG. 10B). As expected, tyrosine phosphorylation was detected in WT KIR3DL3 but not in Y381F.

[0117] Cytotoxicity assays were then performed by incubating NK92 cells expressing KIR3DL3 wild type or Y381F mutant with K562 or Raji cells expressing HHLA2 or control K562 or Raji cells at different effector to target cell (E:T) ratios (Figure 10C). The percentage of specific lysis was calculated and plotted against the E:T ratio. As shown in the figure, in both K562 and Raji cells, NK92 cells expressing KIR3DL3 WT showed significant differences in cytotoxicity between control and HHLA2 expressing cells, which was consistent with previous experimental results. However, NK92 cells expressing KIR3DL3 Y381F showed no difference in cytotoxicity, suggesting that KIR3DL3 suppression of HHLA2-induced immune cell function acted via the ITIM motif of KIR3DL3.

[0118] Finally, given the importance of tyrosine phosphorylation of ITIM motifs in KIR3DL3 function and the role of protein tyrosine phosphatases SHP-1 / SHP-2 in immune cells, we tested whether KIR3DL3 interacts with SHP-1 or SHP-2. + NK cells (35×10 6 Cells) were treated with (+) or without (-) pervanadate (VO4, 1 mM) for 5 min at 37°C. Immunoprecipitates (IP) and whole cell lysates (WCL) were analyzed sequentially for KIR3LD3, SHP-1 and SHP-2 by Western blotting with anti-KIR3DL3 (lanes 2, 4) or mIgG1 (lanes 1, 3). As shown in Figure 10D, co-immunoprecipitation experiments showed that KIR3DL3 interacted with both SHP-1 and SHP-2, suggesting that KIR3DL3 suppressed the function of human immune cells by recruiting SHP1 / 2 via the ITIM motif.

[0119] KIR3DL3 Expression in Cancer To examine KIR3DL3 mRNA expression levels in human tumors, applicants surveyed 1425 human tumor lines. The top 40 tumor lines expressing the highest levels of KIR3DL3 mRNA are shown in Figure 9. Among the top 40 tumors (those showing the highest mRNA abundance), many tumor lines are human hematological malignancies, suggesting a particular role for targeting KIR3DL3 in the treatment of these cancers.

[0120] We also investigated the expression of KIR3DL3 at the protein level in human tumors and found that KIR3DL3 was expressed in tumor-infiltrating immune cells in various human cancers, including renal, gastric, lung, gallbladder, and pancreatic cancers (Figure 11). Collectively, these data suggest that the KIR3DL3 pathway is a novel immunosuppressive mechanism within the tumor microenvironment and an attractive target for the treatment of human cancers.

[0121] composition In some aspects, the technology provides compositions comprising an antibody, fusion polypeptide, nucleic acid, or small molecule according to the embodiments disclosed and described herein.

[0122] In some embodiments, the composition further comprises a pharma- ceutically acceptable additive. Non-limiting examples of pharma- ceutically acceptable additives include those described in "Remington: The Science and Practice of Pharmacy", 19th ed. (1995) or more recently published by Mack Publishing Co; A. Gennaro (2000) "Remington: The Science and Practice of Pharmacy", 20th ed., Lippincott, Williams, & Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) HC Ansel et al., eds., 7th ed., Lippincott, Williams, & Wilkins; and Handbook of Pharmaceutical Excipients (2000) AH Kibbe et al., eds., 3rd ed. Amer. Pharmaceutical Assoc. In some embodiments, the composition is suitable for administration to a subject, e.g., a sterile composition. In some embodiments, the compositions are suitable for administration to humans, eg, the compositions are sterile and free of detectable pyrogens and / or other toxins.

[0123] In some embodiments, the compositions contain other ingredients such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, dextrose, sucrose, magnesium, carbonates, etc. In some embodiments, the compositions contain pharma- ceutically acceptable auxiliary substances required to approximate physiological conditions, such as pH adjusting agents, buffers, isotonicity agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, hydrochloride salts, sulfates, solvates (e.g., mixed ionic salts, water, organics), hydrates (e.g., water).

[0124] In some embodiments, the composition is a liquid, powder, granule, tablet, pill, suppository, capsule, suspension, spray, etc. The composition may contain pharma- ceutically acceptable additives, pharma-ceutically acceptable salts, excipients, carriers, vehicles, and other inactive ingredients known to those skilled in the art. Vehicles and additives commonly used in pharmaceuticals include, for example, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, and the like. Solutions can be prepared using water or physiologically compatible organic solvents such as ethanol, 1,2-propylene glycol, polyglycols, dimethyl sulfoxide, fatty alcohols, triglycerides, partial esters of glycerin, and the like. Parenteral compositions may be prepared by conventional techniques that may include sterile isotonic saline, water, 1,3-butanediol, ethanol, 1,2-propylene glycol, polyglycols mixed with water, Ringer's solution, and the like. In some aspects, colorants are added to facilitate proper placement of the composition at the intended treatment site.

[0125] The composition may contain preservatives and / or stabilizers. Non-limiting examples of preservatives include methyl-, ethyl-, propyl-paraben, sodium benzoate, benzoic acid, sorbic acid, potassium sorbate, propionic acid, benzalkonium chloride, benzyl alcohol, thimerosal, phenylmercuric salts, chlorhexidine, phenol, 3-cresol, quaternary ammonium compounds (QACs), chlorbutanol, 2-ethoxyethanol, and imidurea.

[0126] To control isotonicity, the composition may contain a physiological salt such as a sodium salt. Sodium chloride (NaCl) is preferred and may be at a concentration of 1-20 mg / ml. Other salts that may be present include potassium chloride, potassium dihydrogen phosphate, disodium phosphate dihydrate, magnesium chloride and calcium chloride.

[0127] The composition may contain one or more buffers. Representative buffers include phosphate buffer, Tris buffer, borate buffer, succinate buffer, histidine buffer, or citrate buffer. The concentration of the buffer is usually 5 to 20 mM. The pH of the composition is generally 5 to 8, more typically 6 to 8, for example 6.5 to 7.5 or 7.0 to 7.8.

[0128] The compositions can be administered by any suitable route that will be apparent to one skilled in the art depending on the disease or condition to be treated. Exemplary routes of administration include intravenous, intraarterial, intramuscular, subcutaneous, intracerebral, intranasal or intraperitoneal.

[0129] In some embodiments, the composition may include a cryoprotectant, non-limiting examples of which include glycols (e.g., ethylene glycol, propylene glycol, and glycerin), dimethyl sulfoxide (DMSO), formamide, sucrose, trehalose, dextrose, and combinations thereof.

[0130] The compositions may contain pharma- ceutically acceptable additives, pharma- ceutically acceptable salts, excipients, carriers, vehicles, and other inactive ingredients well known to those skilled in the art. Vehicles and additives commonly used in pharmaceuticals include, for example, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, and the like. Solutions may be prepared using water or physiologically compatible organic solvents, such as ethanol, 1,2-propylene glycol, polyglycols, dimethyl sulfoxide, fatty alcohols, triglycerides, partial esters of glycerin, and the like. Parenteral compositions may be prepared by conventional techniques, which may include sterile isotonic saline, water, 1,3-butanediol, ethanol, 1,2-propylene glycol, polyglycols mixed with water, Ringer's solution, and the like. In some aspects, colorants are added to facilitate proper placement of the composition at the intended treatment site.

[0131] In a particular aspect, provided herein is a nucleic acid molecule encoding an antibody or an immunogenic binding fragment thereof.

[0132] In one aspect, a vector is provided that encodes a nucleic acid molecule described herein. In particular aspects, a host cell is provided that comprises a nucleic acid molecule described herein or a vector described herein.

[0133] In certain embodiments, the antibody is humanized.

[0134] In one aspect, kits are provided that contain the compositions described above, and may further include written or instructional materials describing protocols for preparing the antibodies, fusion polypeptides, nucleic acids and / or small molecules and / or for administering them to a subject in need thereof.

[0135] Methods for use in treatment Provided herein are methods for use in treating a subject in need thereof. In some aspects, provided are antibodies, fusion polypeptides, nucleic acids and / or small molecules for use in treatment. In other aspects, provided are antibodies, fusion polypeptides, nucleic acids and / or small molecules for use in the manufacture of a medicament.

[0136] Also provided herein are methods of treating a subject, comprising administering to the subject a therapeutically effective amount of an antibody, fusion polypeptide, nucleic acid and / or small molecule according to the embodiments disclosed and described herein.

[0137] Also provided herein are compositions comprising an antibody (e.g., in a chimeric antigen receptor and / or an antibody drug conjugate), an immunogenic binding fragment thereof, a fusion polypeptide, or a combination thereof, according to the embodiments disclosed and described herein, for use in treating a diseased subject.

[0138] In certain embodiments, administration of an antibody of the invention is accomplished by administering to a subject a nucleic acid encoding the antibody. A nucleic acid encoding an antibody of the invention can be incorporated into a genetic construct used as part of a gene therapy regimen to deliver a nucleic acid that can be used to express and produce the antibody in a cell. Such an expression construct of components may be administered in a therapeutically effective carrier, such as a formulation or composition that can effectively deliver the gene to a cell in vivo. This method includes inserting a nucleic acid encoding the antibody of the invention into a viral vector, such as a recombinant retrovirus, adenovirus, adeno-associated virus, lentivirus, herpes simplex virus 1 (HSV-1), or a recombinant bacterial or eukaryotic plasmid. Viral vectors can directly transfect cells; plasmid DNA can be delivered with the aid of, for example, cationic liposomes (e.g., Lipofectin®), derivatization, polylysine complexes, gramicidin S, artificial viral membranes or other suitable intracellular carriers, direct injection, or CaPO4 precipitation (see, for example, WO 04 / 060407). Examples of suitable retroviruses include, but are not limited to, pLJ, pZIP, pWE and pEM, which are known in the art (see, e.g., Eglitis 1985; Danos & Mulligan 1988; Wilson 1988; Armentano 1990; Huber 1991; Ferry 1991; Chowdhury 1991; van Beusechem 1992; Kay 1992; Dai 1992; Hwu 1993; U.S. Pat. Nos. 4,868,116 and 4,980,286; WO 89 / 07136; WO 89 / 02468; WO 89 / 05345 and WO 92 / 07573). Another viral gene delivery system that may be used to deliver antibodies, or nucleic acids encoding antibodies, by this technique utilizes adenovirus-derived vectors (see, e.g., Berkner 1988; Rosenfeld 1991; Rosenfeld 1992). Suitable adenovirus vectors derived from the adenovirus strain Ad type 5 dl324 or other strains of adenovirus (e.g., Ad2, Ad3, Ad7, etc.) are known to those of skill in the art.Yet another viral vector system that may be used to deliver antibodies, or nucleic acids encoding antibodies, by this technique is the adeno-associated virus (AAV). See, e.g., Flotte 1992; Samulski 1989 and McLaughlin 1988.

[0139] In some embodiments, the subject suffers from a condition that would benefit from an enhanced immune response, such as an infection, disease, or cancer. In these embodiments, the compositions provided herein (including antibodies, fusion polypeptides, nucleic acids, and / or small molecules) may be used to block KIR3DL3 function. In other embodiments, the subject suffers from or has a condition that would benefit from an inhibited immune response, such as an autoimmune disease or transplant. In these embodiments, the compositions provided herein (including antibodies, fusion polypeptides, nucleic acids, and / or small molecules) may be used to stimulate KIR3DL3 function.

[0140] In some embodiments, the cancer is selected from the group consisting of chronic lymphocytic leukemia (CLL), acute leukemia, acute lymphocytic leukemia (ALL), B-cell acute lymphocytic leukemia (B-ALL), T-cell acute lymphocytic leukemia (T-ALL), T-cell lymphoma, B-cell lymphoma, chronic myelogenous leukemia (CML), acute myeloid leukemia, B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B-cell lymphoma, Follicular lymphoma, hairy cell leukemia, small cell follicular lymphoma, large cell follicular lymphoma, malignant lymphoproliferative dysplasia, mucosa-associated lymphoid tissue (MALT) lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndromes, non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom's macroglobulinemia or preleukemia.

[0141] In some embodiments, the cancer is a human hematological malignancy. For example, in some embodiments, the human hematological malignancy is a myeloid neoplasm, acute myeloid leukemia (AML), AML with recurrent genetic abnormalities, AML with myelodysplastic changes, therapy-related AML, acute leukemia of ambiguous lineage, myeloproliferative neoplasm, essential thrombocythemia, polycythemia vera, myelofibrosis (MF), primary myelofibrosis, systemic mastocytosis, myelodysplastic syndrome (MDS), myeloproliferative / myelodysplastic syndrome, chronic myeloid leukemia, chronic neutrophilic leukemia, chronic myelogenous leukemia, chronic myeloblastic ... Leukemia, chronic eosinophilic leukemia, myelodysplastic syndromes (MDS), refractory anemia with ringed sideroblasts, refractory cytopenia with polycythemia vera, refractory anemia with excess blasts (type 1), refractory anemia with excess blasts (type 2), MDS with isolated deletion of the long arm of chromosome 5, unclassifiable MDS, myeloproliferative / myelodysplastic syndrome, chronic myelomonocytic leukemia, atypical chronic myelogenous leukemia, juvenile myelomonocytic leukemia, unclassifiable myeloproliferative / myelodysplastic syndrome, lymphoid neoplasms, precursor lymphoid neoplasms, B-cell lymphoblastic leukemia, B-cell lymphoblastic lymphoma, T-cell lymphoblastic leukemia, T-cell lymphoblastic lymphoma, mature B-cell neoplasms, diffuse large B-cell lymphoma, primary central nervous system lymphoma, primary mediastinal B-cell lymphoma, Burkitt lymphoma / leukemia, follicular lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphomorph It may be selected from plasma cell lymphoma, Waldenstrom's macroglobulinemia, mantle cell lymphoma, marginal zone lymphoma, post-transplant lymphoproliferative dysplasia, HIV-associated lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, primary cutaneous B-cell lymphoma, hairy cell leukemia, multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma, or plasmacytoma (isolated bone and extramedullary).

[0142] In some embodiments, the cancer is adrenal gland cancer, anal cancer, basal and squamous cell skin cancer, bile duct cancer, bladder cancer, osteosarcoma, brain and spinal cord tumors, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, Ewing's sarcoma family of tumors, eye cancer (ocular melanoma), gallbladder cancer, gastric cancer, gastrointestinal neuroendocrine (carcinoid) tumors, gastrointestinal stromal tumors (GIST), gestational trophoblastic disease, Kaposi's sarcoma, renal cancer, laryngeal and hypopharyngeal cancer, liver cancer, lung cancer, pulmonary carcinoid tumors, malignant mesothelioma, melanoma, Merkel cell skin cancer, nasal and paranasal cancer, Cancer of the nasal cavity, nasopharyngeal cancer, neuroblastoma, non-small cell lung cancer, neoplasms of the central nervous system (CNS), cancer of the oral cavity and oropharynx, osteosarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors (NETs), penile cancer, pituitary tumors, prostate cancer, retinoblastoma, rhabdomyosarcoma, cancer of the salivary glands, cancer of the skin, small cell lung cancer, small intestine cancer, soft tissue sarcoma, gastric cancer, testicular tumor, thymic cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, Wilms' tumor, squamous cell carcinoma, environmentally induced cancer, combinations of cancers, and metastatic lesions of cancer. In some embodiments, the cancer is leukemia or lymphoma, such as lymphoblastic lymphoma or B-cell non-Hodgkin's lymphoma. In some embodiments, the cancer is metastatic cancer.

[0143] In some embodiments, a method of treating a subject with cancer includes administering to the subject a therapeutically effective amount of an antibody, fusion polypeptide, nucleic acid, and / or small molecule according to the embodiments disclosed and described herein in combination with one or more other cancer treatments targeted to the specific cancer for an extended period of time to obtain an improved or synergistic therapeutic effect. In some embodiments, the one or more other cancer treatments are selected from chemotherapy, radiation therapy, immunotherapy, surgery, and combinations thereof. For example, the antibody, fusion polypeptide, nucleic acid, small molecule, and / or composition thereof can be administered in combination with one or more chemotherapeutic agents. As another example, the antibody, fusion polypeptide, nucleic acid, small molecule, and / or composition thereof can be administered in combination with one or more immunotherapeutic agents. Such methods can be used to treat cancers or tumors in which KIR3DL3 plays a role in regulating immune cell function, including, but not limited to, the primary, recurrent, and metastatic cancers described above.

[0144] A "therapeutically effective amount" of an antibody, fusion polypeptide, nucleic acid, and / or small molecule herein is an amount of the antibody, fusion polypeptide, nucleic acid, and / or small molecule that produces a desired effect in a subject, e.g., a therapeutic effect, to treat and / or prevent a disease. In certain embodiments, a therapeutically effective amount is an amount of the antibody, fusion polypeptide, nucleic acid, and / or small molecule that produces a maximal therapeutic effect. In other embodiments, a therapeutically effective amount produces a therapeutic effect that is less than the maximal therapeutic effect. For example, a therapeutically effective amount may be an amount that produces a therapeutic effect while avoiding one or more side effects that occur at the dose that produces the maximal therapeutic effect. The therapeutically effective amount of a particular composition will vary based on a variety of factors, including, but not limited to, the characteristics of the therapeutic composition (e.g., activity, pharmacokinetics, pharmacodynamics, and bioavailability), the physiological state of the subject (e.g., age, weight, sex, disease state and stage, medical history, health status, dose response, and medications being taken), pharmacologic carriers, additives, and preservatives in the composition, and the route of administration. Those skilled in the art of clinical and pharmacological sciences can routinely determine a therapeutically effective amount by monitoring the subject's response to administration of the antibody, fusion polypeptide, nucleic acid and / or small molecule and adjusting the dose accordingly. For further guidance, see, e.g., Remington: The Science and Practice of Pharmacy, 22nd ed., Pharmaceutical Press, London, 2012 and Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12th ed., McGraw-Hill, New York, NY, 2011, the entire disclosures of which are incorporated herein by reference.

[0145] In some embodiments, the therapeutically effective amount of the antibody, fusion polypeptide, nucleic acid and / or small molecule disclosed herein is about 10 mg / kg to about 150 mg / kg, 30 mg / kg to about 120 mg / kg, 60 mg / kg to about 90 mg / kg. In some embodiments, the therapeutically effective amount of the antibody, fusion polypeptide, nucleic acid and / or small molecule disclosed herein is about 15 mg / kg, about 30 mg / kg, about 45 mg / kg, about 60 mg / kg, about 75 mg / kg, about 90 mg / kg, about 105 mg / kg, about 120 mg / kg, about 135 mg / kg or about 150 mg / kg. The antibody, fusion polypeptide, nucleic acid and / or small molecule may be administered to the subject in a single dose or multiple doses. In some embodiments, the antibody, fusion polypeptide, nucleic acid and / or small molecule is administered once or multiple times per day.

[0146] Those skilled in the art are aware of various routes that are suitable for the conditions available for administration to a subject, e.g., a human. For example, in some forms, administration may be systemic or local. In some embodiments, administration may be oral or parenteral. Furthermore, it is within the purview of those skilled in the art to select an appropriate route of administration, such as oral, subcutaneous, intravenous, intramuscular, intradermal, intracerebral or intraperitoneal. To treat a subject in need, the antibody, fusion polypeptide, nucleic acid and / or small molecule can be administered continuously or intermittently for immediate release, controlled release or sustained release. The antibody, fusion polypeptide, nucleic acid and / or small molecule can also be administered once a day, twice a day, three times a day or four times a day for 3 days, 5 days, 7 days, 10 days, 2 weeks, 3 weeks, 4 weeks, 8 weeks or 12 weeks. In certain aspects, the antibodies, fusion polypeptides, nucleic acids and / or small molecules can be administered daily, every 2 days, every 3 days, weekly, biweekly (i.e., every other week), 3 weeks, monthly, February or March. The antibodies, fusion polypeptides, nucleic acids and / or small molecules may be administered for a pre-determined period of time. Alternatively, the antibodies, fusion polypeptides, nucleic acids and / or small molecules may be administered until a particular therapeutic goal is reached. In certain aspects, the methods provided herein include evaluating one or more therapeutic goals, for example, but not limited to, the amount of a particular biomarker in a biological sample, such as tumor cells in blood, a biopsy or urine, to determine whether to continue administration of the antibodies, fusion polypeptides, nucleic acids and / or small molecules. In certain aspects involving cancer, the antibodies, fusion polypeptides, nucleic acids and / or small molecules may be administered until tumor growth is inhibited or the tumor shrinks, until one or more tumors disappear, or until the number of cancer cells is reduced to a particular amount.

[0147] As shown in the Examples, antibody-mediated KIR3DL3 blockade promotes antitumor immunity and suppresses tumor growth in a mouse model of lung adenocarcinoma. Standard treatments for early stages of lung cancer, including non-small cell lung cancer (NSCLC), include surgery, photodynamic therapy, laser therapy, brachytherapy, chemotherapy and radiation therapy, and / or combinations thereof. For advanced stages of lung cancer, standard treatments include chemotherapy, radiation therapy, immunotherapy, and / or combinations thereof. In certain embodiments, chemotherapeutic agents for lung cancer include, but are not limited to, cisplatin (Platinol), carboplatin (Paraplatin), docetaxel (Taxotere), gemcitabine (Gemzar), paclitaxel (Taxol), vinorelbine (Navelbine), pemetrexed (Alimta), albumin-bound paclitaxel (Abraxane), etoposide (Bepcid or Etopofos), doxorubicin (Adriamycin), ifosfamide (Ifex), irinotecan (Camptosar), topotecan (Hycamtin), vinblastine (Oncovir), and vincristine (Oncovin). In certain embodiments, immunotherapeutics for lung cancer include, but are not limited to, pembrolizumab (Keytruda), nivolumab (Opdivo), ipilimumab (Yervoy), bevacizumab (Avastin), atezolizumab (Tecentriq), and necitumumab (Portraza).

[0148] In some embodiments, the infectious disease is caused by a pathogen. In certain embodiments, the pathogen may be a virus, a bacterium, a prion, a fungus, or a parasite. Non-limiting examples of viruses that are addressed by this technology include human immunodeficiency virus (HIV) (e.g., HIV-1 and HIV-2), influenza virus (e.g., influenza A, B, C), papilloma virus, coronavirus (e.g., human respiratory coronavirus), hepatitis virus (e.g., hepatitis virus A-G), herpes virus (e.g., HSV1-9), West Nile virus, Zika virus, encephalomyocarditis virus, dengue virus, or Ebola virus. Non-limiting examples of bacteria that may be addressed by this technology include Mycobacterium tuberculosis, Campylobacter jejuni, Staphylococcus aureus, Borrelia burgdorferi, Helicobacter pylori, Salmonella enterica, Escherichia coli, Streptococcus pyogenes, multidrug-resistant Staphylococcus aureus, Chlamydia pneumoniae, Clostridium botulinum, Vibrio vulnificus, Parachlamydia, Corynebacterium amycolatum, Klebsiella pneumoniae, Linezolid-resistant Enterococcus (E. faecalis, and E. faecium). faecium, and multidrug-resistant Acinetobacter baumannii. Non-limiting examples of fungi addressed by this technology include Pneumocystis jirovecii (PJP), Candida, Blastomyces, Coccidioides, Cryptococcus, Histoplasma, Paracoccidioides, Aspergillus, Talaromyces, and Sporothrix.In particular embodiments, the infectious disease is HIV, Pneumocystis, or Mycobacterium tuberculosis.

[0149] In some embodiments, the autoimmune disease is acute disseminated encephalomyelitis (ADEM), alopecia areata, antiphospholipid syndrome, autoimmune cardiomyopathy, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disorder, autoimmune lipoproliferative syndrome, autoimmune peripheral neuropathy, autoimmune pancreatitis, autoimmune polyendocrine syndrome, autoimmune progesterone dermatitis, autoimmune thrombocytopenic purpura, autoimmune urticaria, autoimmune uveitis, Behcet's disease, celiac disease, Chagas disease, cold agglutinin disease, Crohn's disease, skin The disease is selected from the group consisting of myositis, type 1 diabetes, eosinophilic fasciitis, gastrointestinal pemphigoid, Goodpasture's syndrome, Graves' syndrome, Guillain-Barre syndrome, Hashimoto's encephalopathy, Hashimoto's thyroiditis, lupus erythematosus, Miller Fisher syndrome, mixed connective tissue disease, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polymyositis, psoriasis, psoriatic arthritis, relapsing polychondritis, rheumatoid arthritis, rheumatic fever, Sjogren's syndrome, temporal arteritis, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, vasculitis, and Wegener's granulomatosis.

[0150] In one embodiment, the autoimmune disease being treated is rheumatoid arthritis in adults.

[0151] In some embodiments, the disease is a transplant. In these embodiments, the compositions and methods provided herein may be used to inhibit rejection in transplants. In certain embodiments, the transplant is a stem cell transplant or a bone marrow transplant, for example in a subject with graft-versus-host disease. In certain embodiments, the transplant is selected from the group consisting of a kidney transplant, a lung transplant, a heart transplant, a pancreas transplant, a cornea transplant, or a liver transplant.

[0152] In some embodiments, the antibodies of the invention may be included in a treatment that further comprises administration of at least one additional agent to the subject.

[0153] In some embodiments, the methods provided herein may be combined with another method of treatment, e.g., a combination therapy. In certain embodiments, the other method of treatment may be a method of treatment for an immune-related disorder or condition, including the methods of treatment disclosed herein. For example, the compositions disclosed herein may be administered to a subject concurrently with, before, or after radiation therapy, chemotherapy, hormonal therapy, cell therapy, and / or another anti-tumor or anti-autoimmune therapy. In some embodiments, the compositions may be administered to a subject concurrently with, before, or after organ transplantation.

[0154] In some embodiments, another agent administered in combination with an antibody of the invention may be administered simultaneously with the antibody, on the same day as the antibody, or in the same week as the antibody. In some embodiments, another agent administered in combination with an antibody of the invention may be administered in a single formulation. In certain embodiments, the another agent may be administered at a time separate from the administration of the antibody of the invention, for example, one or more hours before or after, one or more days before or after, one or more weeks before or after, one or more months before or after the administration of the antibody. In various embodiments, the frequency of administration of one or more another agents may be the same as, similar to, or different from the frequency of administration of the antibody of the invention.

[0155] In some embodiments, the combination therapy may be a treatment method comprising the administration of two different antibodies of the invention and / or a treatment method comprising the administration of an antibody of the invention via multiple formulations and / or routes of administration.

[0156] In some embodiments, the additional agent may be or include one or more drugs. For example, in some embodiments, the additional agent may be or include one or more drugs that function to suppress an immune response, for example, to effectively treat patients with autoimmune diseases or to help prevent rejection in transplants. For example, current treatments for rheumatoid arthritis and kidney transplants include abatacept (ORENCIA®) ​​and belatacept (NEUROGIX®), which are modified antibody fusion polypeptides that include the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) bound to the Fc region of IgG1. Conversely, drugs that activate or inactivate the immune response may be used as additional agents to effectively treat diseases or disorders, including cancer or infectious diseases. For example, ipilimumab (YERVOY®) is a monoclonal antibody that activates the immune response by targeting CTLA-4 and can be used to treat melanoma. Pembrolizumab (Keytruda®) is a humanized antibody against the human programmed death receptor 1 (PD-1) and is prescribed as an anti-PD-1 immunotherapy for certain cancers. Nivolumab (Opdivo®) is another anti-PD-1 antibody used as an immunotherapy to treat certain cancers.

[0157] It will be appreciated from the foregoing that, for purposes of illustration, specific embodiments of the invention have been described in the specification, but various modifications can be made without departing from the scope of the invention. The invention is therefore not to be limited except as by the appended claims. EXAMPLES

[0158] Example 1 This example shows the efficacy of antibody-based KIR3DL3 blockade in promoting antitumor immunity and suppressing tumor growth in a mouse model of lung adenocarcinoma (Figure 12A, Figure 12B). The intraperitoneal tumor model mice were treated with 4 x 10 luciferase-transduced KIR3DL3 cells. 6 HHLA2 +HCC827 cells (Luc2-HCC827) were generated by intraperitoneal (ip) injection into NSG mice (n=6 per group) (FIG. 12A). Four days later, mice were assigned to 26E10 (anti-KIR3DL3 mAb) or mIgG1 groups based on baseline bioluminescence. Each mouse was then intraperitoneally injected with 1×10 IgG1 along with 1 μg IL-2, 1 μg IL-15, and 200 μg 26E10 (or mIgG1). 7 KIR3DL3 + NK cells were injected every other day (a total of five times). Imaging was started 5–10 min after intraperitoneal injection of D-luciferin (150 μg / g body weight), and bioluminescence was measured with an IVIS Spectrum Imager (Capiler Perkin Elmer) and analyzed with Living Image 3.0 software. Bioluminescence measurements of tumor growth showed that anti-KIR3DL3 monoclonal antibodies reduced tumor growth compared to controls (Figure 12B), suggesting that targeting KIR3DL3-mediated immune suppression is an effective approach for cancer therapy by promoting anti-tumor immunity.

[0159] The efficacy of antibody-based KIR3DL3 blockade was also tested in a mouse model of metastatic lung cancer (Figure 12C, Figure 12D). 5 Luc2-HCC827 cells were injected intravenously into NSG mice (n=4 per group). Four days later, mice were assigned to 26E10 (anti-KIR3DL3) or mIgG1 groups based on baseline bioluminescence. Each mouse was then intravenously injected with 7×10 IgG1 cells along with 1 μg IL-2, 1 μg IL-15, and 200 μg 26E10 (or mIgG1). 6 KIR3DL3 +NK cells were injected every other day (3 times in total). Imaging was started 10-18 min after intraperitoneal injection of D-luciferin (150 μg / g body weight), and bioluminescence was measured with an IVIS Spectrum Imager (Capiler Perkin Elmer) and analyzed with Living Image 3.0 software (Figure 12C). Again, it was observed that anti-KIR3DL3 monoclonal antibodies significantly reduced tumor growth compared to controls (Figure 12D), suggesting that inhibition of KIR3DL3-mediated immune suppression and the resulting increase in antitumor immunity may also be effective in the treatment of metastatic cancer.

[0160] Finally, the efficacy of KIR3DL3 blockade was confirmed in a subcutaneous tumor model mouse (Figure 12E and Figure 12F). Human lung adenocarcinoma HCC827 cells (3 × 10 6 Twelve days later, the tumor-bearing mice were randomized to the 26E10 or mIgG1 group (n=4 in each group) and administered KIR3DL3 + NK cells (10×10 6 Cells) and treated with 26E10 or isotype mIgG1 (200 μg) every other day for 2 weeks (FIG. 12E). Tumor growth was assessed as before. Consistent with previous experiments, anti-KIR3DL3 monoclonal antibodies significantly reduced tumor growth compared to controls (FIG. 12F), confirming that KIR3DL3 is a potentially novel target for cancer immunotherapy.

[0161] An antibody or an immunogenic binding fragment thereof that specifically binds to a KIR3DL3 protein.

[0162] The antibody or immunogen-binding fragment thereof of paragraph 0161, wherein the antibody or immunogen-binding fragment thereof specifically binds to an epitope of KIR3DL3 that includes all or a portion of the extracellular domain.

[0163] The antibody or immunogen-binding fragment thereof of paragraph 0162, wherein the antibody or immunogen-binding fragment thereof binds to the DO domain of KIR3DL3, the D1 domain of KIR3DL3, or the D2 domain of KIR3DL3.

[0164] The antibody or immunogen-binding fragment thereof of paragraph 0161 or 0162, comprising a VH region including CDR1, CDR2 and CDR3, and having an amino acid sequence represented by SEQ ID NO: 7, 9, 11, 31, 33, 35, 54, 56, 76, 78, 80, 100, 102, 104, 124, 126, 128, 148, 150, 152, 172, 174, 176, 196, 198, 200, 220, 222, 224, 244, 246, 248, 268, 270, 272, 292, 294, 296, 316, 318 or 320.

[0165] 3. The antibody or immunogen-binding fragment thereof of paragraph 0161 or 0162, comprising a VH region comprising at least one CDR that is 80% identical to an amino acid sequence selected from SEQ ID NO: 7, 9, 11, 31, 33, 35, 54, 56, 76, 78, 80, 100, 102, 104, 124, 126, 128, 148, 150, 152, 172, 174, 176, 196, 198, 200, 220, 222, 224, 244, 246, 248, 268, 270, 272, 292, 294, 296, 316, 318 or 320.

[0166] 3. The antibody or immunogen-binding fragment thereof of paragraph 0161 or 0162, comprising a VH region comprising at least two CDRs that are 80% identical to an amino acid sequence selected from SEQ ID NO: 7, 9, 11, 31, 33, 35, 54, 56, 76, 78, 80, 100, 102, 104, 124, 126, 128, 148, 150, 152, 172, 174, 176, 196, 198, 200, 220, 222, 224, 244, 246, 248, 268, 270, 272, 292, 294, 296, 316, 318 or 320.

[0167] 3. The antibody or immunogen-binding fragment thereof of paragraph 0161 or 0162, comprising a VH region comprising at least three CDRs that are 80% identical to an amino acid sequence selected from SEQ ID NO: 7, 9, 11, 31, 33, 35, 54, 56, 76, 78, 80, 100, 102, 104, 124, 126, 128, 148, 150, 152, 172, 174, 176, 196, 198, 200, 220, 222, 224, 244, 246, 248, 268, 270, 272, 292, 294, 296, 316, 318 or 320.

[0168] The antibody or immunogen-binding fragment thereof of paragraph 0161 or 0162, comprising a VL region including CDR1, CDR2 and CDR3, and having an amino acid sequence represented by SEQ ID NO: 19, 21, 23, 43, 45, 47, 64, 66, 68, 88, 90, 92, 112, 114, 116, 136, 138, 140, 160, 162, 164, 184, 186, 188, 208, 210, 212, 232, 234, 236, 256, 258, 260, 280, 282, 284, 304, 306, 308, 328, 330 or 332.

[0169] 19, 21, 23, 43, 45, 47, 64, 66, 68, 88, 90, 92, 112, 114, 116, 136, 138, 140, 160, 162, 164, 184, 186, 188, 208, 210, 212, 232, 234, 236, 256, 258, 260, 280, 282, 284, 304, 306, 308, 328, 330 or 332.

[0170] 19, 21, 23, 43, 45, 47, 64, 66, 68, 88, 90, 92, 112, 114, 116, 136, 138, 140, 160, 162, 164, 184, 186, 188, 208, 210, 212, 232, 234, 236, 256, 258, 260, 280, 282, 284, 304, 306, 308, 328, 330 or 332.

[0171] 19, 21, 23, 43, 45, 47, 64, 66, 68, 88, 90, 92, 112, 114, 116, 136, 138, 140, 160, 162, 164, 184, 186, 188, 208, 210, 212, 232, 234, 236, 256, 258, 260, 280, 282, 284, 304, 306, 308, 328, 330 or 332.

[0172] The antibody of any one of paragraphs 0161 to 0171, wherein the antibody is a monoclonal antibody.

[0173] The antibody of any one of paragraphs 0161 to 0171, wherein the antibody is a chimeric antibody, a human antibody, or a humanized antibody.

[0174] SEQ ID NO: 7, 9, 11, 19, 21, 23, 31, 33, 35, 43, 45, 47, 54, 56, 64, 66, 68, 76, 78, 80, 88, 90, 92, 100, 102, 104, 112, 114, 116, 124, 126, 128, 136, 138, 140, 148, 150, 152, 160, 162, 164, 172, 174, 176, 184, 186, 188, 196, 198, 200, 20 8, 210, 212, 220, 222, 224, 232, 234, 236, 244, 246, 248, 256, 258, 260, 268, 270, 272, 280, 282, 284, 292, 294, 296, 304, 306, 308, 316, 318, 320, 328, 330, or 332.

[0175] The antibody of paragraph 0172, wherein the antibody is monoclonal antibody 8G7, monoclonal antibody 26E10, monoclonal antibody 26E2, monoclonal antibody 31C4, monoclonal antibody 34B10, monoclonal antibody 37A3, monoclonal antibody 12A10, monoclonal antibody 3B7, monoclonal antibody 11G8, monoclonal antibody 14F8, monoclonal antibody 15D2, monoclonal antibody 29H7, monoclonal antibody 30D10 or monoclonal antibody 51C3.

[0176] The antibody of paragraph 0173, wherein the antibody is humanized antibody 8G7, humanized antibody 26E10, humanized antibody 26E2, humanized antibody 31C4, humanized antibody 34B10, humanized antibody 37A3, humanized antibody 12A10, humanized antibody 3B7, humanized antibody 11G8, humanized antibody 14F8, humanized antibody 15D2, humanized antibody 29H7, humanized antibody 30D10 or humanized antibody 51C3.

[0177] A fusion polypeptide comprising any one of the antibodies or immunogen-binding fragments thereof described in paragraphs 0161 to 0176.

[0178] A composition comprising an antibody or an immunogen-binding fragment thereof of any one of paragraphs 0161 to 0176, or a fusion polypeptide of 0177.

[0179] The composition of paragraph 0178, further comprising a pharma- ceutically acceptable carrier.

[0180] The composition of paragraph 0178 or 0179, further comprising a pharma- ceutically acceptable excipient.

[0181] The antibody or immunogen-binding fragment thereof of any one of paragraphs 0161 to 0176, the fusion polypeptide of paragraph 0177, or the composition of any one of paragraphs 0178 to 0180 for use in therapy.

[0182] The antibody or immunogen-binding fragment thereof of any one of paragraphs 0161 to 0176, the fusion polypeptide of paragraph 0177, or the composition of any one of paragraphs 0178 to 0180 for use in the manufacture of a medicament.

[0183] A nucleic acid comprising a nucleic acid encoding an antibody or an immunogen-binding fragment thereof, wherein the antibody or immunogen-binding fragment thereof is an antibody or immunogen-binding fragment thereof of any one of paragraphs 0161 to 0176.

[0184] A nucleic acid comprising a nucleic acid encoding a fusion peptide, said fusion peptide being the fusion peptide of paragraph 0177.

[0185] 1. A method of treating a diseased subject, comprising administering to the subject a therapeutically effective amount of an antibody or immunogen-binding fragment thereof of any one of paragraphs 0161-0176, a fusion polypeptide of paragraph 0177, or a composition of any one of paragraphs 0178-0180.

[0186] The method of paragraph 0185, wherein the disease is cancer.

[0187] The cancers include chronic lymphocytic leukemia (CLL), acute leukemia, acute lymphocytic leukemia (ALL), B-cell acute lymphocytic leukemia (B-ALL), T-cell lymphoma, B-cell lymphoma, T-cell acute lymphocytic leukemia (T-ALL), chronic myeloid leukemia (CML), B-cell prolymphocytic leukemia, T-cell lymphoma, Hodgkin's disease, B-cell non-Hodgkin's lymphoma, blastic plasmacytoid dendritic 5. The method of paragraph number 0186, wherein the tumor is selected from the group consisting of B-cell neoplasm, Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell follicular lymphoma, large cell follicular lymphoma, malignant lymphoproliferative disorders, mucosa-associated lymphoid tissue (MALT) lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndromes, non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom's macroglobulinemia, or preleukemia.

[0188] The cancers include colon cancer, rectal cancer, renal cell cancer, liver cancer, lung cancer, kidney cancer, stomach cancer, gallbladder cancer, small intestine cancer, esophageal cancer, melanoma, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulva cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, The method of paragraph 0186, wherein the cancer is selected from the group consisting of adenocarcinoma, adrenal gland cancer, sarcoma of soft tissue, urethral cancer, penile cancer, solid tumors of childhood, bladder cancer, cancer of the kidney or ureter, renal pelvis cancer, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, tumors of the spinal axis, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, environmentally induced cancer, combinations of cancers, and metastatic lesions of cancer.

[0189] The method of paragraph 0186, wherein the cancer is a human hematological malignancy.

[0190] The human hematological malignancies include myeloid neoplasms, acute myeloid leukemia (AML), AML with recurrent genetic abnormalities, AML with myelodysplastic changes, therapy-related AML, acute leukemia of ambiguous lineage, myeloproliferative neoplasms, essential thrombocythemia, polycythemia vera, myelofibrosis (MF), primary myelofibrosis, systemic mastocytosis, myelodysplastic syndromes (MDS), myeloproliferative / myelodysplastic syndromes, chronic myeloid leukemia, chronic neutrophilic leukemia, chronic eosinophil ... Hematologic malignancies, myelodysplastic syndromes (MDS), refractory anemia with ringed sideroblasts, refractory cytopenia with polycythemia gravis, refractory anemia with increased blasts (type 1), refractory anemia with increased blasts (type 2), MDS with a deletion of the long arm of chromosome 5 as the sole chromosomal abnormality, unclassifiable MDS, myeloproliferative / myelodysplastic syndrome, chronic myelomonocytic leukemia, atypical chronic myelogenous leukemia, juvenile myelomonocytic leukemia, unclassifiable myeloproliferative / myelodysplastic syndrome, Lymphoid neoplasms, precursor lymphoid neoplasms, B-cell lymphoblastic leukemia, B-cell lymphoblastic lymphoma, T-cell lymphoblastic leukemia, T-cell lymphoblastic lymphoma, mature B-cell neoplasms, diffuse large B-cell lymphoma, primary central nervous system lymphoma, primary mediastinal B-cell lymphoma, Burkitt lymphoma / leukemia, follicular lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, vasculitis, pulmonary arterial leukemia, pulmonary edema ... The method of paragraph 0189, wherein the tumor is selected from Ludenstrom's macroglobulinemia, mantle cell lymphoma, marginal zone lymphoma, post-transplant lymphoproliferative dysplasia, HIV-associated lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, primary cutaneous B-cell lymphoma, hairy cell leukemia, multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma, or plasmacytoma (isolated bone and extramedullary).

[0191] The method of paragraph 0186, wherein the cancer is a metastatic cancer.

[0192] The method of paragraph 0186, further comprising administering to the subject one or more cancer treatments selected from chemotherapy, radiation therapy, immunotherapy, surgery, and combinations thereof.

[0193] The method of paragraph 0185, wherein the disease is an infectious disease.

[0194] The method of paragraph 0193, wherein the infectious disease is caused by a pathogen.

[0195] The method of paragraph 0194, wherein the pathogen is a virus.

[0196] The method of paragraph 0195, wherein the virus is selected from the group consisting of a human immunodeficiency virus, an influenza virus, a papilloma virus, a coronavirus, a hepatitis virus, or a herpes virus.

[0197] The method of paragraph 0194, wherein the pathogen is a bacterium.

[0198] The method of paragraph 0197, wherein the bacterium is Mycobacterium tuberculosis.

[0199] The method of paragraph 0194, wherein the pathogen is a prion.

[0200] The method of paragraph 0194, wherein the pathogen is a fungus.

[0201] The method of paragraph 0200, wherein the fungus is Pneumocystis jirovecii (PJP).

[0202] The method of paragraph 0194, wherein the pathogen is a parasite.

[0203] The method of paragraph 0185, wherein the disease is an autoimmune disease or disorder.

[0204] The autoimmune disease or disorder includes acute disseminated encephalomyelitis (ADEM), alopecia areata, antiphospholipid syndrome, autoimmune cardiomyopathy, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disorder, autoimmune lipoproliferative syndrome, autoimmune peripheral neuropathy, autoimmune pancreatitis, autoimmune polyendocrine syndrome, autoimmune progesterone dermatitis, autoimmune thrombocytopenic purpura, autoimmune urticaria, autoimmune uveitis, Behcet's disease, celiac disease, Chagas disease, cold agglutinin disease, Crohn's disease, dermatomyositis, and type 1 diabetes. , eosinophilic fasciitis, gastrointestinal pemphigoid, Goodpasture's syndrome, Graves' syndrome, Guillain-Barre syndrome, Hashimoto's encephalopathy, Hashimoto's thyroiditis, lupus erythematosus, Miller Fisher syndrome, mixed connective tissue disease, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polymyositis, psoriasis, psoriatic arthritis, relapsing polychondritis, rheumatoid arthritis, rheumatic fever, Sjogren's syndrome, temporal arteritis, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, vasculitis, and Wegener's granulomatosis.

[0205] The method of paragraph 0203, wherein the autoimmune disease or disorder is rheumatoid arthritis in adults.

[0206] The method of paragraph 0185, wherein the disease is transplantation.

[0207] The method of paragraph 0206, wherein the transplant is selected from a stem cell transplant or a bone marrow transplant.

[0208] The method of paragraph 0206, wherein the transplant is selected from the group consisting of a kidney transplant, a lung transplant, a heart transplant, a pancreas transplant, a cornea transplant, or a liver transplant.

[0209] The composition described in any one of paragraphs 0178 to 0180 for use in a method of treating a diseased subject.

[0210] The composition of paragraph 0209, wherein the disease is cancer.

[0211] The cancers include chronic lymphocytic leukemia (CLL), acute leukemia, acute lymphocytic leukemia (ALL), B-cell acute lymphocytic leukemia (B-ALL), T-cell lymphoma, B-cell lymphoma, T-cell acute lymphocytic leukemia (T-ALL), chronic myeloid leukemia (CML), B-cell prolymphocytic leukemia, T-cell lymphoma, Hodgkin's disease, B-cell non-Hodgkin's lymphoma, blastic plasmacytoid dendritic 13. The composition of paragraph number 0210, wherein the tumor is selected from the group consisting of myeloma, myelodysplasia, myelodysplastic syndromes, myelodysplastic syndromes, myeloproliferative disorders ...

[0212] The cancers include colon cancer, rectal cancer, renal cell cancer, liver cancer, lung cancer, kidney cancer, stomach cancer, gallbladder cancer, small intestine cancer, esophageal cancer, melanoma, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulva cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, The composition of paragraph 0210, wherein the cancer is selected from the group consisting of adenocarcinoma, adrenal gland cancer, sarcoma of soft tissue, urethral cancer, penile cancer, solid tumors of childhood, bladder cancer, cancer of the kidney or ureter, renal pelvis cancer, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, tumors of the spinal axis, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, environmentally induced cancer, combinations of cancers, and metastatic lesions of cancer.

[0213] The composition of paragraph 0210, wherein the cancer is a human hematological malignancy.

[0214] The human hematological malignancies include myeloid neoplasms, acute myeloid leukemia (AML), AML with recurrent genetic abnormalities, AML with myelodysplastic changes, therapy-related AML, acute leukemia of ambiguous lineage, myeloproliferative neoplasms, essential thrombocythemia, polycythemia vera, myelofibrosis (MF), primary myelofibrosis, systemic mastocytosis, myelodysplastic syndromes (MDS), myeloproliferative / myelodysplastic syndromes, chronic myeloid leukemia, chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic myeloid leukemia, chronic myeloblastic ... Myelodysplastic syndrome (MDS), refractory anemia with ringed sideroblasts, refractory cytopenia with polycythemia vera, refractory anemia with excess blasts (type 1), refractory anemia with excess blasts (type 2), MDS with isolated deletion of the long arm of chromosome 5 as the chromosome abnormality, unclassifiable MDS, myeloproliferative / myelodysplastic syndrome, chronic myelomonocytic leukemia, atypical chronic myelogenous leukemia, juvenile myelomonocytic leukemia, unclassifiable myeloproliferative / myelodysplastic syndrome, leukemia Lymphoid neoplasms, precursor lymphoid neoplasms, B-cell lymphoblastic leukemia, B-cell lymphoblastic lymphoma, T-cell lymphoblastic leukemia, T-cell lymphoblastic lymphoma, mature B-cell neoplasms, diffuse large B-cell lymphoma, primary central nervous system lymphoma, primary mediastinal B-cell lymphoma, Burkitt lymphoma / leukemia, follicular lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, wart The composition of paragraph 0213, wherein the tumor is selected from Denstrom's macroglobulinemia, mantle cell lymphoma, marginal zone lymphoma, post-transplant lymphoproliferative dysplasia, HIV-associated lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, primary cutaneous B-cell lymphoma, hairy cell leukemia, multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma, or plasmacytoma (isolated bone and extramedullary).

[0215] The composition of paragraph 0210, wherein the cancer is a metastatic cancer.

[0216] The composition of paragraph 0210, wherein the composition is administered to the subject simultaneously with one or more cancer treatments selected from chemotherapy, radiation therapy, immunotherapy, surgery, and combinations thereof.

[0217] The composition of paragraph 0209, wherein the disease is an infectious disease.

[0218] The composition of paragraph 0217, wherein the infectious disease is caused by a pathogen.

[0219] The composition of paragraph 0218, wherein the pathogen is a virus.

[0220] The composition of paragraph 0219, wherein the virus is selected from the group consisting of a human immunodeficiency virus, an influenza virus, a papilloma virus, a coronavirus, a hepatitis virus, or a herpes virus.

[0221] The composition of paragraph 0218, wherein the pathogen is a bacterium.

[0222] The composition of paragraph 0221, wherein the bacterium is Mycobacterium tuberculosis.

[0223] The composition of paragraph 0218, wherein the pathogen is a prion.

[0224] The composition of paragraph 0218, wherein the pathogen is a fungus.

[0225] The composition of paragraph 0224, wherein the fungus is Pneumocystis jirovecii (PJP).

[0226] The composition of paragraph 0218, wherein the pathogen is a parasite.

[0227] The composition of paragraph 0209, wherein the disease is an autoimmune disease or disorder.

[0228] The autoimmune disease or disorder includes acute disseminated encephalomyelitis (ADEM), alopecia areata, antiphospholipid syndrome, autoimmune cardiomyopathy, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disorder, autoimmune lipoproliferative syndrome, autoimmune peripheral neuropathy, autoimmune pancreatitis, autoimmune polyendocrine syndrome, autoimmune progesterone dermatitis, autoimmune thrombocytopenic purpura, autoimmune urticaria, autoimmune uveitis, Behcet's disease, celiac disease, Chagas disease, cold agglutinin disease, Crohn's disease, dermatomyositis, type 1 diabetes, The composition of paragraph 0227, wherein the disease is selected from the group consisting of eosinophilic fasciitis, gastrointestinal pemphigoid, Goodpasture's syndrome, Graves' syndrome, Guillain-Barre syndrome, Hashimoto's encephalopathy, Hashimoto's thyroiditis, lupus erythematosus, Miller Fisher syndrome, mixed connective tissue disease, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polymyositis, psoriasis, psoriatic arthritis, relapsing polychondritis, rheumatoid arthritis, rheumatic fever, Sjogren's syndrome, temporal arteritis, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, vasculitis, and Wegener's granulomatosis.

[0229] The composition of paragraph 0227, wherein the autoimmune disease or disorder is rheumatoid arthritis in adults.

[0230] The composition of paragraph 0209, wherein the disease is transplantation.

[0231] The composition of paragraph 0230, wherein the transplant is selected from a stem cell transplant or a bone marrow transplant.

[0232] The composition of paragraph 0230, wherein the transplant is selected from the group consisting of a kidney transplant, a lung transplant, a heart transplant, a pancreas transplant, a cornea transplant or a liver transplant.

[0233] References Armentano et al. Proc Natl Acad Sci USA 87(16):6141-6145 (1990) Berkner Biotechniques 6(7):616-629 (1988) Beziat et al. Immunology 150(3):248-264 (2017) Cheng et al. Clin Cancer Res 24(8):1954-1964 (2018) Cheng et al. Clin Cancer Res 23(3):825-832 (2017) Chowdhury et al. Science 254(5039):1802-1805 (1991) Dai et al. Proc Natl Acad Sci USA 89(22):10892-10895 (1992) Danos & Mulligan Proc Natl Acad Sci USA 85(17):6460-6464 (1988) Eglitis et al. Science 230(4732):1395-1398 (1985) Ferry et al. Proc Natl Acad Sci USA 88(19):8377-8381 (1991) Fleet et al. Am J Respir Cell Mol Biol 7(3):349-356 (1992) Harris Biochem Soc Trans 23(4):1035–1038 (1995) Huber et al. Proc Natl Acad Sci USA 88(18):8039-8043 (1991) Hurle & Gross Curr Opin Biotechnol 5(4):428-433 (1994) Hwu et al. J Immunol 150(9):4104–4115 (1993) Janakiram et al. Clin Cancer Res 21(10):2359–2366 (2015) Jones et al. Nature 321(6069):522-525 (1986) Kay et al. Hum Gene Ther 3(6):641-647 (1992) Koirala et al. Sci Rep 6:31154 (2016) McLaughlin et al. J Virol 62(6):1963-1973 (1988) Presta Curr Opin Biotechnol 3(4):394-398 (1992) Riechmann et al. Nature 332(6162):323-327 (1988) Rosenfeld et al. Science 252(5004):431-434 (1991) Rosenfeld et al. Cell 68(1):143-155 (1992) Samulski et al. J Virol 63(9):3822-3828 (1989) van Beusechem et al. Proc Natl Acad Sci USA 89(16):7640-7644 (1992) Vaswani & Hamilton Ann Allergy Asthma Immunol 81(2):105-115 (1998) Wilson et al. Proc Natl Acad Sci USA 85(9):3014-3018 (1988) Zhao et al. Proc Natl Acad Sci USA 110(24):9879-9884 (2013)

Claims

1. An antibody or immunogenic binding fragment thereof that specifically binds to a KIR3DL3 protein, A VH region comprising CDR1, CDR2 and CDR3 having the amino acid sequences represented by SEQ ID NOs: 31, 33 and 35; A VL region comprising CDR1, CDR2 and CDR3 having the amino acid sequences represented by SEQ ID NOs: 43, 45 and 47; An antibody or an immunogen-binding fragment thereof.

2. The antibody of claim 1 , wherein the antibody is a monoclonal antibody.

3. The antibody of claim 1 or 2, wherein the antibody is a chimeric antibody or a humanized antibody.

4. The antibody of claim 2, wherein the antibody is monoclonal antibody 26E10.

5. The antibody of claim 3, wherein the antibody is humanized 26E10.

6. A fusion polypeptide comprising an antibody or an immunogen-binding fragment thereof according to any one of claims 1 to 5.

7. A pharmaceutical composition comprising the antibody or immunogen-binding fragment thereof according to any one of claims 1 to 5.

8. A pharmaceutical composition comprising the fusion polypeptide described in claim 6.

9. 9. The pharmaceutical composition of claim 7 or 8, further comprising a pharma- ceutically acceptable carrier.

10. The pharmaceutical composition according to any one of claims 7 to 9, further comprising a pharma- ceutically acceptable additive.

11. A nucleic acid comprising a nucleic acid encoding an antibody or immunogen-binding fragment thereof, said antibody or immunogen-binding fragment thereof being an antibody or immunogen-binding fragment thereof according to any one of claims 1 to 5.

12. A nucleic acid comprising a nucleic acid encoding a fusion peptide, said fusion peptide being the fusion peptide of claim 6.

13. A pharmaceutical composition according to any one of claims 7 to 10 for use in the treatment of a diseased subject.

14. The pharmaceutical composition of claim 13, wherein the disease is cancer.

15. The cancers include chronic lymphocytic leukemia (CLL), acute leukemia, acute lymphocytic leukemia (ALL), B-cell acute lymphocytic leukemia (B-ALL), T-cell lymphoma, B-cell lymphoma, T-cell acute lymphocytic leukemia (T-ALL), chronic myeloid leukemia (CML), B-cell prolymphocytic leukemia, T-cell lymphoma, Hodgkin's disease, B-cell non-Hodgkin's lymphoma, blastic plasmacytoid dendritic 15. The pharmaceutical composition of claim 14, wherein the tumor is selected from the group consisting of B-cell neoplasm, Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell follicular lymphoma, large cell follicular lymphoma, malignant lymphoproliferative dysplasia, mucosa-associated lymphoid tissue (MALT) lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndromes, non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom's macroglobulinemia, or preleukemia.

16. The cancers include colon cancer, rectal cancer, renal cell cancer, liver cancer, lung cancer, kidney cancer, stomach cancer, gallbladder cancer, small intestine cancer, esophageal cancer, melanoma, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulva cancer, endocrine system cancer, thyroid cancer, and parathyroid cancer.

15. The pharmaceutical composition of claim 14, wherein the cancer is selected from the group consisting of cancer, adrenal gland cancer, sarcoma of soft tissue, urethral cancer, penile cancer, solid tumors of childhood, bladder cancer, cancer of the kidney or ureter, renal pelvis cancer, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, tumors of the spinal axis, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, environmentally induced cancer, combinations of cancers, and metastatic lesions of cancer.

17. 15. The pharmaceutical composition of claim 14, wherein the cancer is a human hematological malignancy.

18. The human hematological malignancies include myeloid neoplasms, acute myeloid leukemia (AML), AML with recurrent genetic abnormalities, AML with myelodysplastic changes, therapy-related AML, acute leukemia of ambiguous lineage, myeloproliferative neoplasms, essential thrombocythemia, polycythemia vera, myelofibrosis (MF), primary myelofibrosis, systemic mastocytosis, myelodysplastic syndromes (MDS), myeloproliferative / myelodysplastic syndromes, chronic myeloid leukemia, chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic myeloid leukemia, chronic myeloblastic ... Myelodysplastic syndrome (MDS), refractory anemia with ringed sideroblasts, refractory cytopenia with polycythemia vera, refractory anemia with increased blasts (type 1), refractory anemia with increased blasts (type 2), MDS with isolated deletion of the long arm of chromosome 5, unclassifiable MDS, myeloproliferative / myelodysplastic syndrome, chronic myelomonocytic leukemia, atypical chronic myelogenous leukemia, juvenile myelomonocytic leukemia, unclassifiable myeloproliferative / myelodysplastic syndrome, rheumatoid arthritis ... Lymphoid neoplasms, precursor lymphoid neoplasms, B-cell lymphoblastic leukemia, B-cell lymphoblastic lymphoma, T-cell lymphoblastic leukemia, T-cell lymphoblastic lymphoma, mature B-cell neoplasms, diffuse large B-cell lymphoma, primary central nervous system lymphoma, primary mediastinal B-cell lymphoma, Burkitt's lymphoma / leukemia, follicular lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldemar-Davidson lymphoma, 18. The pharmaceutical composition of claim 17, wherein the tumor is selected from: Stront's macroglobulinemia, mantle cell lymphoma, marginal zone lymphoma, post-transplant lymphoproliferative dysplasia, HIV-associated lymphoma, primary effusion lymphoma, intravascular large B-cell lymphoma, primary cutaneous B-cell lymphoma, hairy cell leukemia, multiple myeloma, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma, or plasmacytoma (isolated bone and extramedullary).

19. The pharmaceutical composition of claim 14, wherein the cancer is a metastatic cancer.

20. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is administered to the subject concurrently with one or more cancer treatments selected from chemotherapy, radiation therapy, immunotherapy, surgery, and combinations thereof.

21. The pharmaceutical composition of claim 13, wherein the disease is an infectious disease.

22. The pharmaceutical composition of claim 21 , wherein the infectious disease is caused by a pathogen.

23. 23. The pharmaceutical composition of claim 22, wherein the pathogen is a virus.

24. 24. The pharmaceutical composition of claim 23, wherein the virus is selected from the group consisting of human immunodeficiency virus, influenza virus, papilloma virus, coronavirus, hepatitis virus or herpes virus.

25. 23. The pharmaceutical composition of claim 22, wherein the pathogen is selected from the group consisting of a bacterium, Mycobacterium tuberculosis, a prion, a fungus, Pneumocystis jirovecii (PJP) or a parasite.

26. The pharmaceutical composition of claim 13, wherein the disease is an autoimmune disease or disorder.

27. The autoimmune disease or disorder may be acute disseminated encephalomyelitis (ADEM), alopecia areata, antiphospholipid syndrome, autoimmune cardiomyopathy, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disorder, autoimmune lipoproliferative syndrome, autoimmune peripheral neuropathy, autoimmune pancreatitis, autoimmune polyendocrine syndrome, autoimmune progesterone dermatitis, autoimmune thrombocytopenic purpura, autoimmune urticaria, autoimmune uveitis, Behcet's disease, celiac disease, Chagas disease, cold agglutinin disease, Crohn's disease, dermatomyositis, type 1 diabetes, and the like.

27. The pharmaceutical composition of claim 26, wherein the disease is selected from the group consisting of eosinophilic fasciitis, gastrointestinal pemphigoid, Goodpasture's syndrome, Graves' syndrome, Guillain-Barre syndrome, Hashimoto's encephalopathy, Hashimoto's thyroiditis, lupus erythematosus, Miller Fisher syndrome, mixed connective tissue disease, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polymyositis, psoriasis, psoriatic arthritis, relapsing polychondritis, rheumatoid arthritis, rheumatic fever, Sjogren's syndrome, temporal arteritis, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, vasculitis, and Wegener's granulomatosis.

28. 27. The pharmaceutical composition of claim 26, wherein the autoimmune disease or disorder is rheumatoid arthritis in adults.

29. 27. The pharmaceutical composition of claim 26, wherein the disease is transplantation.

30. 30. The pharmaceutical composition of claim 29, wherein the transplant is selected from a stem cell transplant or a bone marrow transplant.

31. 30. The pharmaceutical composition of claim 29, wherein the transplant is selected from the group consisting of a kidney transplant, a lung transplant, a heart transplant, a pancreas transplant, a cornea transplant, or a liver transplant.

Images