Polypeptides and uses thereof for treatment of autoimmune disorders and infection

Abstract

This invention relates to C10RF32 protein and its variants and fragments and fusion proteins thereof, pharmaceutical composition comprising same and methods of use therof for treatment of immune related disorders and infections.

What is claimed is: 
     
         1 . A fusion protein comprising an isolated polypeptide fused to a heterologous sequence, directly or indirectly via a linker peptide, a polypeptide sequence or a chemical linker wherein the amino acid sequence of said fusion protein is set forth in SEQ ID NO: 38, 39, 108-112, 116-190. 
     
     
         2 . The fusion protein of  claim 2 , wherein the amino acid sequence is set forth in any of SEQ ID NOs: 118 or 122. 
     
     
         3 . A pharmaceutical composition comprising a fusion protein of any of  claims 2 - 3 , and a pharmaceutically acceptable diluent or carrier, adapted for treatment of any immune related disorder and infectious disorder. 
     
     
         4 . A method for treating an immune related disorder or an infectious disorder in a subject in need thereof, comprising administering to the subject an effective amount of the fusion protein of  claim 1  or pharmaceutical composition thereof. 
     
     
         5 . The method of 4, wherein administering an effective amount of the fusion protein-or pharmaceutical composition thereof to the subject inhibits or reduces differentiation of, proliferation of, activity of, and/or cytokine production and/or secretion by an immune cell selected from the group consisting of Thl, Thl7, and/or Th22, other cells that secrete, or cells that cause other cells to secrete, inflammatory molecules. 
     
     
         6 . The method of 4, wherein the fusion protein or pharmaceutical composition thereof is administered in an effective amount to inhibit or reduce differentiation of, proliferation of, activity of, and/or cytokine production and/or secretion by Thl, Thl7 and/or Th22 cells. 
     
     
         7 . The method of  claim 4 , wherein the fusion protein or pharmaceutical composition thereof is administered in an effective amount to enhance the suppressive or immunomodulatory effect of Tregs and/or Th2 cells on Thl or Thl 7 cells. 
     
     
         8 . The method of  claim 4 , wherein the fusion protein or pharmaceutical composition thereof is administered in an effective amount to promote or enhance IL-10 production. 
     
     
         9 . The method of  claim 4 , wherein the fusion protein or pharmaceutical composition thereof is administered in an effective amount to increase cell numbers or increase populations of any of Tregs and/or Th2 cells. 
     
     
         10 . The method of  claim 4 , wherein the fusion protein or pharmaceutical composition thereof is administered in an effective amount to inhibit the Th1 and/or Th1 7 pathways and to enhance the activity of Tregs and/or Th2 cells on the Thl and Thl 7 pathways and/or to promote or enhance IL-10 secretion. 
     
     
         11 . The method of  claim 4 , wherein the fusion protein or pharmaceutical composition thereof is administered in an effective amount for reducing proinflammatory molecule production in a subject. 
     
     
         12 . The method according to  claim 4  further comprising administering a second therapeutic agent effective for treatment of said immune related disorder and/or infectious disorder. 
     
     
         13 . The method according to  claim 4 , wherein the immune related disorder is selected from the group consisting of autoimmune disease and immune disorder associated with graft transplantation rejection, and wherein the infectious disorder is selected from the disease caused by bacterial infection, viral infection, fungal infection and/or other parasite infection. 
     
     
         14 . The method according to  claim 13 , wherein the immune disorder associated with graft transplantation rejection is selected from the group consisting of acute and chronic rejection of organ transplantation, allogeneic stem cell transplantation, autologous stem cell transplantation, bone marrow transplantation, and graft versus host disease. 
     
     
         15 . The method according to  claim 13 , wherein the autoimmune disease is selected from the group consisting of multiple sclerosis, rheumatoid arthritis; psoriatic arthritis, discoid lupus erythematosus, systemic lupus erythematosus (SLE); ulcerative colitis; Crohn's disease; benign lymphocytic angiitis, autoimmune lymphoproliferative syndrome, sarcoidosis, autoimmune thrombocytopenic purpura, idiopathic thrombocytopenic purpura, pure red cell aplasia, Sjogren's syndrome, rheumatic disease, polymyalgia rheumatica, mixed connective tissue disease, inflammatory rheumatism, degenerative rheumatism, extra-articular rheumatism, juvenile arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis, arthritis uratica, muscular rheumatism, chronic polyarthritis, reactive arthritis, Reiter's syndrome, rheumatic fever, relapsing polychondritis, Raynaud's phenomenon, vasculitis, cryoglobulinemic vasculitis, ANCA-associated vasculitis, temporal arteritis, giant cell arteritis, Takayasu arteritis, Behcet's disease, antiphospholipid syndrome, myasthenia gravis, autoimmune haemolytic anaemia, Guillain-Barre syndrome, chronic immune polyneuropathy, chronic inflammatory demyelinating polyneuropathy, autoimmune thyroiditis, insulin dependent diabetes mellitus, type I diabetes, Addison's disease, membranous glomerulonephropathy, polyglandular autoimmune syndromes, Goodpasture's disease, autoimmune gastritis, autoimmune atrophic gastritis, pernicious anaemia,pemphigus, pemphigus vulgaris, cirrhosis, primary biliary cirrhosis, idiopathic pulmonary fibrosis, myositis, dermatomyositis, juvenile dermatomyositis, polymyositis, fibromyositis, myogelosis, celiac disease, celiac sprue dermatitis, immunoglobulin A nephropathy, Henoch-Schonlein purpura, Evans syndrome, atopic dermatitis, psoriasis, psoriasis vulgaris, psoriasis arthropathica, Graves' disease, Graves' ophthalmopathy, scleroderma, systemic scleroderma, progressive systemic scleroderma, diffuse scleroderma, localized scleroderma, Crest syndrome, asthma, allergic asthma, allergy, primary biliary cirrhosis, Hashimoto's thyroiditis, fibromyalgia, chronic fatigue and immune dysfunction syndrome (CFIDS), primary myxedema, sympathetic ophthalmia, autoimmune inner ear disease, autoimmune uveitis, autoimmune chronic active hepatitis, collagen diseases, ankylosing spondylitis, periarthritis humeroscapularis, panarteritis nodosa, polyarteritis nodosa, chondrocalcinosis, Wegener's granulomatosis, microscopic polyangiitis, chronic urticaria, bullous skin disorders, pemphigoid, bullous pemphigoid, cicatricial pemphigoid, vitiligo, atopic eczema, eczema, chronic urticaria, autoimmune urticaria, normocomplementemic urticaria! vasculitis, hypocomplementemic urticaria! vasculitis, alopecia areata, alopecia universalis, alopecia totalis, Devic's disease, pernicious anemia, childhood autoimmune hemolytic anemia, idiopathic 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, gastritis, gout, gouty arthritis, idiopathic pericarditis, anti-synthetase syndrome, scleritis, macrophage activation syndrome, PAPA Syndrome, Blau's Syndrome, adult and juvenile Still's disease, cryopyrin associated periodic syndrome, Muckle-Wells syndrome, familial cold auto-inflammatory syndrome, neonatal onset multisystem inflammatory disease, chronic infantile neurologic cutaneous and articular syndrome, familial Mediterranean fever, Hyper IgD syndrome, Schnitzler's syndrome, autoimmune retinopathy, age-related macular degeneration, and TNF receptor-associated periodic syndrome (TRAPS). 
     
     
         16 . The method according to  claim 13 , wherein the autoimmune disease is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, type I diabetes, psoriasis, atopic dermatitis, psoriasis vulgaris, psoriasis arthropathica, systemic lupus erythematosus, inflammatory bowel disease, uveitis, ulcerative colitis; Crohn's disease, and Sjogren's syndrome. 
     
     
         17 . The method according to  claim 16 , wherein the multiple sclerosis is selected from the group consisting of benign multiple sclerosis, relapsing remitting multiple sclerosis, secondary progressive multiple sclerosis, primary progressive multiple sclerosis, chronic progressive multiple sclerosis, transitional/progressive multiple sclerosis, progressive relapsing multiple sclerosis, rapidly worsening multiple sclerosis, clinically-definite multiple sclerosis, malignant multiple sclerosis, also known as Marburg's Variant, acute multiple sclerosis and condition relating to multiple sclerosis, selected from the group consisting of Devic's disease, also known as Neuromyelitis Optica; acute disseminated encephalomyelitis, acute demyelinating optic neuritis, demyelinative transverse myelitis, Miller-Fisher syndrome, encephalomyelradiculoneuropathy, acute demyelinative polyneuropathy, tumefactive multiple sclerosis and Balo's concentric sclerosis. 
     
     
         18 . The method according to  claim 16 , wherein the rheumatoid arthritis is selected from the group consisting of rheumatoid arthritis, gout and pseudo-gout, juvenile idiopathic arthritis, juvenile rheumatoid arthritis, Still's disease, ankylosing spondylitis, rheumatoid vasculitis, and conditions relating to rheumatoid arthritis, selected from the group consisting of osteoarthritis, sarcoidosis, Henoch-Schonlein purpura, Psoriatic arthritis, Reactive arthritis, Spondyloarthropathy, septic arthritis, Haemochromatosis, Hepatitis, vasculitis, Wegener's granulomatosis, Lyme disease, Familial Mediterranean fever, Hyperimmunoglobulinemia D with recurrent fever, TNF receptor associated periodic syndrome, and Enteropathic arthritis associated with inflammatory bowel disease. 
     
     
         19 . The method according to  claim 16 , wherein the uveitis is selected from the group consisting of anterior uveitis, iridocyclitis, intermediate uveitis pars planitis, posterior uveitis, chorioretinitis and the panuveitis form. 
     
     
         20 . The method according to  claim 16 , wherein the inflammatory bowel disease is selected from the group consisting of Crohn's disease and ulcerative colitis (UC) and conditions relating to IBD selected from the group consisting of Collagenous colitis, Lymphocytic colitis, Ischaemic colitis, Diversion colitis, Beçhet's disease, Indeterminate colitis. 
     
     
         21 . The method according to  claim 16 , wherein the psoriasis is selected from the group consisting of Nonpustular Psoriasis including Psoriasis vulgaris and Psoriatic erythroderma, erythrodermic psoriasis, Pustular psoriasis including Generalized pustular psoriasis, pustular psoriasis of von Zumbusch, Pustulosis palmaris et plantaris, persistent palmoplantar pustulosis, pustular psoriasis of the Barber type, pustular psoriasis of the extremities, Annular pustular psoriasis, Acrodermatitis continua, Impetigo herpetiformis, conditions relating to psoriasis include, drug-induced psoriasis, Inverse psoriasis, Napkin psoriasis, Seborrheic-like psoriasis, Guttate psoriasis, Nail psoriasis, and Psoriatic arthritis. 
     
     
         22 . The method according to  claim 16 , wherein the diabetes is selected from the group consisting of insulin-dependent diabetes mellitus, idiopathic diabetes, juvenile type 1 diabetes, maturity onset diabetes of the young, latent autoimmune diabetes in adults, gestational diabetes, and condition relating to type 1 diabetes selected from the group consisting of neuropathy including polyneuropathy, mononeuropathy, peripheral neuropathy and autonomicneuropathy; eye complications: glaucoma, cataracts, retinopathy. 
     
     
         23 . The method according to  claim 16 , wherein the Sjogren's syndrome is selected from the group consisting of Primary Sjogren's syndrome and Secondary Sjogren's syndrome and condition relating to Sjogren's syndrome selected from the group consisting of connective tissue disease, such as rheumatoid arthritis, systemic lupus erythematosus, or scleroderma. 
     
     
         24 . The method according to  claim 16 , wherein the systemic lupus erythematosus is selected from the group consisting of discoid lupus, lupus arthritis, lupus pneumonitis, lupus nephritis, and condition relating to systemic lupus erythematosus, selected from the group consisting of osteoarticular tuberculosis, antiphospholipid antibody syndrome, inflammation of various parts of the heart, selected from the group pericarditis, myocarditis, and endocarditis, Lung and pleura inflammation, pleuritis, pleural effusion, chronic diffuse interstitial lung disease, pulmonary hypertension, pulmonary emboli, pulmonary hemorrhage, and shrinking lung syndrome, lupus headache, Guillain-Barre syndrome, aseptic meningitis, demyelinating syndrome, mononeuropathy, mononeuritis multiplex, myasthenia gravis, myelopathy, cranial neuropathy, polyneuropathy, and vasculitis. 
     
     
         25 . The method according to  claim 4 , wherein the treating comprises treatment of immune related disorder without global immunosuppression. 
     
     
         26 . The method of  claim 4 , wherein the subject does not respond to treatment with TNF blockers. 
     
     
         27 . A method for treating an immune related disorder or an infectious disorder in a subject in need thereof, comprising administering to the subject an effective amount of the fusion protein of  claim 2  or pharmaceutical composition thereof. 
     
     
         28 . The method of 28, wherein administering an effective amount of the fusion protein to the subject inhibits or reduces differentiation of, proliferation of, activity of, and/or cytokine production and/or secretion by an immune cell selected from the group consisting of Thl, Thl7, and/or Th22, other cells that secrete, or cells that cause other cells to secrete, inflammatory molecules.