Polypeptides and polynucleotides, and uses thereof for treatment of immune related disorders and cancer

Abstract

This invention relates to LY6G6F, VSIG10, TMEM25 and LSR proteins, which are suitable targets for immunotherapy, treatment of cancer, infectious disorders, and/or immune related disorders, and drug development. This invention further relates to soluble LY6G6F, VSIG10, TMEM25 and LSR molecules, extracellular domains of LY6G6F, VSIG10, TMEM25 and LSR and conjugates, which are suitable drugs for immunotherapy, treatment of cancer, infectious disorders, and/or immune related disorders. This invention further relates to antibodies and antigen binding fragments and conjugates containing same, and/or alternative scaffolds, specific for LY6G6F, VSIG10, TMEM25 or LSR molecules, which are suitable drugs for immunotherapy, treatment of cancer, infectious disorders, and/or immune related disorders.

1 - 69 . (canceled) 
     
     
         70 . An isolated polypeptide comprising at least 36 amino acids of the soluble ectodomain of a sequence selected from the group consisting of SEQ ID NOs:3 and 5; or an isolated polypeptide consisting essentially of an amino acid sequence as set forth in SEQ ID NO: 5 or variant thereof that possesses at least 95% sequence identity therewith. 
     
     
         71 . A polypeptide of  claim 70 , consisting of between 36 and 393 amino acids of the sequence selected from the group consisting of SEQ ID NOs:3 and 5. 
     
     
         72 . A polypeptide of  claim 70 , wherein said isolated polypeptide is selected from the group consisting of a polypeptide consisting of between 36 to 70, 80 to 100, 170 to 200, 265 to 290, 365 to 393 amino acids of the sequence selected from the group consisting of SEQ ID NOs:3 and 5. 
     
     
         73 . A polypeptide of  claim 70 , consisting of 46, 49, 58, 60, 87, 89, 93, 94, 178, 182, 185, 187, 273, 279, 282, 374 or 383 amino acids of SEQ ID NOs:3 and 5. 
     
     
         74 . A polypeptide of  claim 70 , consisting essentially of an amino acid sequence having at least 95% sequence identity with amino acid sequences set forth in any one of SEQ ID NOs: 4, 6, 60, 61; 82-93, or 97-100. 
     
     
         75 . A polypeptide of  claim 74 , wherein said polypeptide consists essentially of the amino acid sequence set forth in any one of SEQ ID NOs: 4, 6, 60, 61; 82-93, or 97-100. 
     
     
         76 . A fusion protein comprising the polypeptide of  claim 74  joined to a heterologous sequence. 
     
     
         77 . A fusion protein according to  claim 76 , wherein the heterologous sequence comprises at least a portion of an immunoglobulin molecule. 
     
     
         78 . A fusion protein of  claim 77 , wherein the immunoglobulin molecule portion is an immunoglobulin heavy chain constant region Fc fragment. 
     
     
         79 . A fusion protein of  claim 78  wherein the immunoglobulin heavy chain constant region is derived from an immunoglobulin isotype selected from the group consisting of an IgG1, IgG2, IgG3, IgG4, IgM, IgE, IgA and IgD. 
     
     
         80 . A nucleic acid sequence encoding the polypeptide of  claim 75 . 
     
     
         81 . A nucleic acid sequence according to  claim 80 , selected from the group consisting of SEQ ID NOs: 34, 35, 36, 183, or 184, or variant thereof that possesses at least 95% sequence identity therewith, or a degenerative variant thereof. 
     
     
         82 . An expression vector or a virus, containing at least one nucleic acid sequence according to  claim 81 . 
     
     
         83 . A recombinant cell comprising an expression vector or a virus containing a nucleic acid sequence according to  claim 82 , wherein the cell constitutively or inducibly expresses the polypeptide encoded by the DNA segment. 
     
     
         84 . A method of producing a VSIG10 soluble ectodomain polypeptide, or fragment or fusion protein thereof, comprising culturing the recombinant cell according to  claim 83 , under conditions whereby the cell expresses the polypeptide encoded by the DNA segment or nucleic acid and recovering said polypeptide. 
     
     
         85 . A monoclonal or polyclonal antibody or an antigen binding fragment thereof comprising an antigen binding site that binds specifically to any one of the polypeptides of  claim 70 . 
     
     
         86 . An antibody of  claim 85 , wherein said antigen binding site binds specifically to a polypeptide of  claim 75 . 
     
     
         87 . An antibody or fragment according to  claim 86 , wherein the antibody is a fully human antibody, chimeric antibody, humanized or primatized antibody. 
     
     
         88 . An antibody or the antigen binding fragment according to  claim 87 , wherein the antibody is selected from the group consisting of Fab, Fab′, F(ab′)2, F(ab′), F(ab), Fv or scFv fragment and minimal recognition unit. 
     
     
         89 . An antibody or the antigen binding fragment according to  claim 86 , wherein the antibody is coupled to a moiety selected from a drug, a radionuclide, a fluorophore, an enzyme, a toxin, a therapeutic agent, or a chemotherapeutic agent; and wherein the detectable marker is a radioisotope, a metal chelator, an enzyme, a fluorescent compound, a bioluminescent compound or a chemiluminescent compound. 
     
     
         90 . An antibody or the antigen binding fragment of  claim 88 , wherein said antibody elicits apoptosis or lysis of cancer cells. 
     
     
         91 . An antibody or the antigen binding fragment of  claim 90 , wherein the cancer cells express a VSIG10 protein. 
     
     
         92 . An antibody or the antigen binding fragment of  claim 91 , wherein the cancer cells express a polypeptide consisting essentially of the amino acid sequence set forth in any one of SEQ ID NOs: 3, 4, 5, 6, 60, 61; 82-93, or 97-100. 
     
     
         93 . An antibody or the antigen binding fragment of  claim 92 , wherein said apoptosis or lysis involves CDC or ADCC activity of the antibody. 
     
     
         94 . A pharmaceutical composition comprising an isolated polypeptide having a sequence according to  claim 70 , and further comprising a pharmaceutically acceptable diluent or carrier. 
     
     
         95 . A pharmaceutical composition comprising an isolated polypeptide having a sequence according to any of SEQ ID Nos 4, 6, 60, 61; 82-93, or 97-100, or an antibody according to  claim 94 , and further comprising a pharmaceutically acceptable diluent or carrier. 
     
     
         96 . A method of treatment by administering an isolated polypeptide having a sequence according to any of SEQ ID Nos 4, 6, 60, 61; 82-93, or 97-100, wherein administration of such to the subject inhibits or reduces activation of T cells. 
     
     
         97 . A method of treatment of cancer of a subject in need of treatment thereof, comprising administering an antibody according to  claim 85  or a pharmaceutical composition comprising same to the subject. 
     
     
         98 . A method of  claim 97 , wherein the treatment is combined with another moiety or therapy useful for treating cancer, wherein the therapy is radiation therapy, antibody therapy, chemotherapy, photodynamic therapy, adoptive T cell therapy, Treg depletion, surgery or in combination therapy with conventional drugs; or wherein the moiety is selected from the group consisting of immunosuppressants, cytotoxic drugs, tumor vaccines, antibodies (bevacizumab, erbitux), peptides, pepti-bodies, small molecules, chemotherapeutic agents such as cytotoxic and cytostatic agents (paclitaxel, cisplatin, vinorelbine, docetaxel, gemcitabine, temozolomide, irinotecan, SFU, carboplatin), immunological modifiers such as interferons and interleukins, immunostimulatory antibodies, growth hormones or other cytokines, folic acid, vitamins, minerals, aromatase inhibitors, RNAi, Histone Deacetylase Inhibitors, and proteasome inhibitors. 
     
     
         99 . A method of  claim 97  wherein the cancer is selected from a group consisting of breast cancer, cervical cancer, ovary cancer, endometrial cancer, melanoma, bladder cancer, lung cancer, pancreatic cancer, colon cancer, prostate cancer, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, B-cell lymphoma, Burkitt's lymphoma, multiple myeloma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, myeloid leukemia, acute myelogenous leukemia (AML), chronic myelogenous leukemia, thyroid cancer, thyroid follicular cancer, myelodysplastic syndrome (MDS), fibrosarcomas and rhabdomyosarcomas, melanoma, uveal melanoma, teratocarcinoma, neuroblastoma, glioma, glioblastoma, benign tumor of the skin, keratoacanthomas, renal cancer, anaplastic large-cell lymphoma, esophageal squamous cells carcinoma, hepatocellular carcinoma, follicular dendritic cell carcinoma, intestinal cancer, muscle-invasive cancer, seminal vesicle tumor, epidermal carcinoma, spleen cancer, bladder cancer, head and neck cancer, stomach cancer, liver cancer, bone cancer, brain cancer, cancer of the retina, biliary cancer, small bowel cancer, salivary gland cancer, cancer of uterus, cancer of testicles, cancer of connective tissue, prostatic hypertrophy, myelodysplasia, Waldenstrom's macroglobinaemia, nasopharyngeal, neuroendocrine cancer, myelodysplastic syndrome, mesothelioma, angiosarcoma, Kaposi's sarcoma, carcinoid, oesophagogastric, fallopian tube cancer, peritoneal cancer, papillary serous mullerian cancer, malignant ascites, gastrointestinal stromal tumor (GIST), Li-Fraumeni syndrome and Von Hippel-Lindau syndrome (VHL), and wherein the cancer is non-metastatic, invasive or metastatic. 
     
     
         100 . A method of treatment of an infectious disease in a subject in need of treatment thereof, comprising administering an antibody according to  claim 85  or a pharmaceutical composition comprising same to the subject. 
     
     
         101 . The method of  claim 100 , wherein the infectious disease is selected from the disease caused by bacterial infection, viral infection, fungal infection and/or other parasite infection. 
     
     
         102 . The method of  claim 101 , wherein the infectious disease is selected from hepatitis B, hepatitis C, infectious mononucleosis, EBV, cytomegalovirus, AIDS, HIV-1, HIV-2, tuberculosis, malaria and schistosomiasis. 
     
     
         103 . A method of performing one or more of the following in a subject:
 a. upregulating cytokines;   b. inducing expansion of T cells;   c. promoting antigenic specific T cell immunity;   d. promoting CD4+ and/or CD8+ T cell activation;   
       comprising administering an antibody according to  claim 85  or a pharmaceutical composition comprising same to the subject. 
     
     
         104 . A method for treating an immune system related condition comprising administering to a subject in need thereof an effective amount of an isolated polypeptide having a sequence according to any of SEQ ID Nos 4, 6, 60, 61; 82-93, or 97-100 or a pharmaceutical composition comprising same, wherein the immune system related condition comprises an immune related condition, autoimmune diseases as recited herein, transplant rejection and graft versus host disease. 
     
     
         105 . The method of  claim 104 , wherein the treatment is combined with another moiety useful for treating immune related condition, wherein the moiety is selected from the group consisting of immunosuppressants such as corticosteroids, cyclosporin, cyclophosphamide, prednisone, azathioprine, methotrexate, rapamycin, tacrolimus, biological agents, TNF-alpha blockers or antagonists, or any other biological agent targeting any inflammatory cytokine, nonsteroidal antiinflammatory drugs/Cox-2 inhibitors, hydroxychloroquine, sulphasalazopryine, gold salts, etanercept, infliximab, mycophenolate mofetil, basiliximab, atacicept, rituximab, cytoxan, interferon beta-1a, interferon beta-1b, glatiramer acetate, mitoxantrone hydrochloride, anakinra and/or other biologies and/or intravenous immunoglobulin (IVIG), interferons, IFN-beta-1a and IFN-beta-1b; glatiramer acetate, a polypeptide; natalizumab, mitoxantrone, a cytotoxic agent, a calcineurin inhibitor, cyclosporin A or FK506; an immunosuppressive macrolide, rapamycine or a derivative thereof; 40-O-(2-hydroxy)ethyl-rapamycin, a lymphocyte homing agent, FTY720 or an analog thereof, corticosteroids; cyclophosphamide; azathioprene; methotrexate; leflunomide or an analog thereof; mizoribine; mycophenolic acid; mycophenolate mofetil; 15-deoxyspergualine or an analog thereof; immunosuppressive monoclonal antibodies, monoclonal antibodies to leukocyte receptors, MHC, CD2, CD3, CD4, CD 11a/CD18, CD7, CD25, CD 27, B7, CD40, CD45, CD58, CD 137, ICOS, CD150 (SLAM), OX40, 4-1BB or their ligands; or other immunomodulatory compounds, CTLA4-Ig, CD28-Ig, B7-H4-Ig, or other costimulatory agents, or adhesion molecule inhibitors, mAbs or low molecular weight inhibitors including LFA-1 antagonists, selectin antagonists and VLA-4 antagonists, or another immunomodulatory agent. 
     
     
         106 . The method of  claim 105  wherein the autoimmune disease is selected from a group consisting of multiple sclerosis, including relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, and secondary progressive multiple sclerosis; psoriasis; rheumatoid arthritis; psoriatic arthritis, systemic lupus erythematosus (SLE); ulcerative colitis; Crohn's disease; benign lymphocytic angiitis, thrombocytopenic purpura, idiopathic thrombocytopenia, idiopathic autoimmune hemolytic anemia, pure red cell aplasia, Sjogren's syndrome, rheumatic disease, connective tissue disease, inflammatory rheumatism, degenerative rheumatism, extra-articular rheumatism, juvenile rheumatoid arthritis, arthritis uratica, muscular rheumatism, chronic polyarthritis, cryoglobulinemic vasculitis, ANCA-associated vasculitis, antiphospholipid syndrome, myasthenia gravis, autoimmune haemolytic anaemia, Guillian-Barre syndrome, chronic immune polyneuropathy, autoimmune thyroiditis, insulin dependent diabetes mellitus, type I diabetes, Addison's disease, membranous glomerulonephropathy, Goodpasture's disease, autoimmune gastritis, autoimmune atrophic gastritis, pernicious anaemia, pemphigus, pemphigus vulgarus, cirrhosis, primary biliary cirrhosis, dermatomyositis, polymyositis, fibromyositis, myogelosis, celiac disease, immunoglobulin A nephropathy, Henoch-Schonlein purpura, Evans syndrome, atopic dermatitis, psoriasis, psoriasis arthropathica, Graves' disease, Graves' ophthalmopathy, scleroderma, systemic scleroderma, progressive systemic scleroderma, asthma, allergy, primary biliary cirrhosis, Hashimoto's thyroiditis, primary myxedema, sympathetic ophthalmia, autoimmune uveitis, hepatitis, chronic action hepatitis, collagen diseases, ankylosing spondylitis, periarthritis humeroscapularis, panarteritis nodosa, chondrocalcinosis, Wegener's granulomatosis, microscopic polyangiitis, chronic urticaria, bullous skin disorders, pemphigoid, atopic eczema, Devic's disease, childhood autoimmune hemolytic anemia, Refractory or chronic Autoimmune Cytopenias, Prevention of development of Autoimmune Anti-Factor VIII Antibodies in Acquired Hemophilia A, Cold Agglutinin Disease, Neuromyelitis Optica, Stiff Person Syndrome, gingivitis, periodontitis, pancreatitis, myocarditis, vasculitis, gastritis, gout, gouty arthritis, and inflammatory skin disorders, selected from the group consisting of psoriasis, atopic dermatitis, eczema, rosacea, urticaria, and acne, normocomplementemic urticarial vasculitis, pericarditis, myositis, anti-synthetase syndrome, scleritis, macrophage activation syndrome, Bechet's Syndrome, PAPA Syndrome, Blau's Syndrome, gout, adult and juvenile Still's disease, cryropyrinopathy, Muckle-Wells syndrome, familial cold-induced auto-inflammatory syndrome, neonatal onset multisystemic inflammatory disease, familial Mediterranean fever, chronic infantile neurologic, cutaneous and articular syndrome, systemic juvenile idiopathic arthritis, Hyper IgD syndrome, Schnitzler's syndrome, autoimmune retinopathy, age-related macular degeneration, atherosclerosis, chronic prostatitis and TNF receptor-associated periodic syndrome (TRAPS). 
     
     
         107 . A method for diagnosing a disease in a subject, comprising detecting in the subject or in a sample obtained from said subject any one of the polypeptides of any of SEQ ID NOs: 3, 4, 5, 6, 60, 61; 82-93, or 97-100.