Polypeptides and uses thereof for treatment of autoimmune disorders and infection

Abstract

This invention relates to C1ORF32 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 . An isolated polypeptide, comprising an amino acid sequence of C1ORF32 IgV domain fragment, set forth in any one of SEQ ID NOs: 29, 30, 41-105, with the proviso that the amino acid sequence does not include the complete, exact sequence of SEQ ID NO: 35 or SEQ ID NO:36. 
     
     
         2 . The isolated peptide of  claim 1 , wherein the isolated polypeptide has less than 90% identity with SEQ ID NO:35 or SEQ ID NO:36. 
     
     
         3 . The isolated peptide of  claim 2 , wherein the isolated peptide has less than 85% identity with SEQ ID NO:35 or SEQ ID NO:36. 
     
     
         4 . The isolated peptide of  claim 3 , wherein the isolated peptide has less than 80% identity with SEQ ID NO:35 or SEQ ID NO:36. 
     
     
         5 . The isolated peptide of any of  claims 1 - 4 , wherein the isolated polypeptide consists essentially of the amino acid sequence as set forth in any one of SEQ ID NOs: 29, 30, 41-105, or optionally an amino acid sequence that is up to 95% identical thereof 
     
     
         6 . A fusion protein comprising the polypeptide according to any of  claims 1 - 5 , fused to a heterologous sequence, directly or indirectly via a linker peptide, a polypeptide sequence or a chemical linker. 
     
     
         7 . The fusion protein of 6, wherein the heterologous sequence comprises at least a portion of an immunoglobulin constant domain. 
     
     
         8 . The fusion protein of  claim 7 , comprising an immunoglobulin heavy chain constant region corresponding to an antibody isotype selected from the group consisting of an IgG1, IgG2, IgG3, IgG4, IgM, IgE, IgA and IgD. 
     
     
         9 . The fusion protein of 8, wherein the immunoglobulin constant domain comprises the hinge, CH2 and CH3 regions of a human IgG immunoglobulin, selected from the group consisting of Cγ1, Cγ2, Cγ3 and Cγ4 chain. 
     
     
         10 . The fusion protein of any of  claims 6 - 9 , further comprising a domain that mediates dimerization or multimerization of the fusion protein to form homodimers, heterodimers, homomultimers, or heteromultimers. 
     
     
         11 . The fusion protein of 10, wherein the domain that mediates dimerization or multimerization is selected from the group consisting of one or more cysteines that are capable of forming an intermolecular disulfide bond with a cysteine on the partner fusion protein, a coiled-coil domain, an acid patch, a zinc finger domain, a calcium hand domain, a CHI region, a CL region, a leucine zipper domain, an SH2 (src homology 2) domain, an SH3 (src Homology 3) domain, a PTB (phosphotyrosine binding) domain, a WW domain, a PDZ domain, a 14-3-3 domain, a WD40 domain, an EH domain, a Lim domain, an isoleucine zipper domain, and a dimerization domain of a receptor dimer pair. 
     
     
         12 . The fusion protein of any of  claims 6 - 11 , comprising a polypeptide having an amino acid sequence set forth in any one of SEQ ID NOs: 20, 21, 31 or 115. 
     
     
         13 . The fusion protein of  claim 12 , wherein said fusion protein comprises the amino acid sequence set forth in anyone of SEQ ID NOs: 29, 30, 41-105, fused to human IgG1 Fc set forth in any one of SEQ ID NOs: 20, 21, or 115. 
     
     
         14 . The fusion protein of  claim 13 , wherein the amino acid sequence of said fusion protein is set forth in SEQ ID NO: 39, 108-112, 116-190. 
     
     
         15 . The fusion protein of  claim 14 , wherein the amino acid sequence is set forth in any of SEQ ID NOs:112, 120 or alternatively in any of SEQ ID NOs:110, 136. 
     
     
         16 . A dimeric protein comprising a first and a second fusion protein, wherein the first and the second fusion proteins comprise the fusion protein of any of  claims 6 - 13 , wherein the first and the second fusion proteins are bound to one another by covalent or noncovalent bonds to form a dimer. 
     
     
         17 . A pharmaceutical composition comprising a protein of any of  claims 1 - 5  or a fusion protein of any of  claims 6 - 16 , and a pharmaceutically acceptable diluent or carrier, adapted for treatment of any immune related disorder and infectious disorder. 
     
     
         18 . A use of a protein of any of  claims 1 - 5  or a fusion protein of any of  claims 6 - 16  or pharmaceutical composition according to  claim 20  for treatment of any of immune related disorder and infectious disorder. 
     
     
         19 . The use according to  claim 18 , wherein the polypeptide is attached to a detectable or therapeutic moiety. 
     
     
         20 . 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 polypeptide of any of  claims 1 - 5  or fusion protein of any of  claims 6 - 16  or pharmaceutical composition according to  claim 17 . 
     
     
         21 . The method of 20, wherein administering an effective amount of the polypeptide of any of  claims 1 - 5  or fusion protein of any of  claims 6 - 16  or pharmaceutical composition according to  claim 20  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 Th1, Th17, and/or Th22, other cells that secrete, or cells that cause other cells to secrete, inflammatory molecules. 
     
     
         22 . The method of 20, wherein the polypeptide of any of  claims 1 - 5  or fusion protein of any of  claims 6 - 16  or pharmaceutical composition according to  claim 17  is administered in an effective amount to inhibit or reduce differentiation of, proliferation of, activity of, and/or cytokine production and/or secretion by Th1, Th17 and/or Th22 cells. 
     
     
         23 . The method of  claim 20 , wherein the polypeptide of any of  claims 1 - 5  or fusion protein of any of  claims 6 - 16  or pharmaceutical composition according to  claim 17  is administered in an effective amount to enhance the suppressive or immunomodulatory effect of Tregs and/or Th2 cells on Th1 or Th17 cells. 
     
     
         24 . The method of  claim 20 , wherein the polypeptide of any of  claims 1 - 5  or fusion protein of any of  claims 6 - 16  or pharmaceutical composition according to  claim 17  is administered in an effective amount to promote or enhance IL-10 production. 
     
     
         25 . The method of  claim 20 , wherein the polypeptide of any of  claims 1 - 5  or fusion protein of any of  claims 6 - 16  or pharmaceutical composition according to  claim 17  is administered in an effective amount to increase cell numbers or increase populations of any of Tregs and/or Th2 cells. 
     
     
         26 . The method of  claim 20 , wherein the polypeptide of any of  claims 1 - 5  or fusion protein of any of  claims 6 - 16  or pharmaceutical composition according to  claim 17  is administered in an effective amount to inhibit the Th1 and/or Th17 pathways and to enhance the activity of Tregs and/or Th2 cells on the Th1 and Th17 pathways and/or to promote or enhance IL-10 secretion. 
     
     
         27 . The method of  claim 20 , wherein the polypeptide of any of  claims 1 - 5  or fusion protein of any of  claims 6 - 16  or pharmaceutical composition according to  claim 17  is administered in an effective amount for reducing proinflammatory molecule production in a subject. 
     
     
         28 . The method according to any one of  claims 20 - 27  further comprising administering a second therapeutic agent effective for treatment of any immune related disorder and infectious disorder. 
     
     
         29 . The C1ORF32 polypeptide, fusion protein, pharmaceutical composition, method, or use according to any of the above claims, 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. 
     
     
         30 . The C1ORF32 polypeptide, fusion protein, pharmaceutical composition, method, or use according to  claim 29 , 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. 
     
     
         31 . The C1ORF32 polypeptide, fusion protein, pharmaceutical composition, method, or use according to  claim 29 , 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 urticarial vasculitis, hypocomplementemic urticarial 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). 
     
     
         32 . The C1ORF32 polypeptide, fusion protein, pharmaceutical composition, method, or use according to  claim 29 , wherein the autoimmune disease is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, type I diabetes, psoriasis, systemic lupus erythematosus, inflammatory Bowel's disease, uveitis, and Sjogren's syndrome. 
     
     
         33 . The C1ORF32 polypeptide, fusion protein, pharmaceutical composition, method, or use according to  claim 32 , 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. 
     
     
         34 . The C1ORF32 polypeptide, fusion protein, pharmaceutical composition, method, or use according to  claim 32 , 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-Schönlein purpura, Psoriatic arthritis, Reactive arthritis, Spondyloarthropathy, septic arthritis, HaemochromatosisHepatitis, 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. 
     
     
         35 . The C1ORF32 polypeptide, fusion protein, pharmaceutical composition, method, or use according to  claim 32 , wherein the uveitis is selected from the group consisting of anterior uveitis (or iridocyclitis), intermediate uveitis (pars planitis), posterior uveitis (or chorioretinitis) and the panuveitic form. 
     
     
         36 . The C1ORF32 polypeptide, fusion protein, pharmaceutical composition, method, or use according to  claim 32 , wherein the inflammatory bowel disease is selected from the group consisting of Crohn's disease and ulcerative colitis (UC) and condition relating to IBD selected from the group consisting of Collagenous colitis, Lymphocytic colitis, Ischaemic colitis, Diversion colitis, Behçet's disease, Indeterminate colitis. 
     
     
         37 . The C1ORF32 polypeptide, fusion protein, pharmaceutical composition, method, or use according to  claim 32 , 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. Optionally, conditions relating to psoriasis include, e.g., drug-induced psoriasis, Inverse psoriasis, Napkin psoriasis, Seborrheic-like psoriasis, Guttate psoriasis, Nail psoriasis, Psoriatic arthritis. 
     
     
         38 . The C1ORF32 polypeptide, fusion protein, pharmaceutical composition, method, or use according to  claim 32 , 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. 
     
     
         39 . The C1ORF32 polypeptide, fusion protein, pharmaceutical composition, method, or use according to  claim 32 , 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. Other complications include pneumonia, polmunary fibrosis, interstitial nephritis, inflammation of the tissue around the kidney's filters, glomerulonephritis, renal tubular acidosis, carpal tunnel syndrome, peripheral neuropathy, cranial neuropathy, primary biliary cirrhosis (PBC), cirrhosis, Inflammation in the esophagus, stomach, pancreas, and liver (including hepatitis), Polymyositis, Raynaud's phenomenon, Vasculitis, Autoimmune thyroid problems, lymphoma. 
     
     
         40 . The C1ORF32 polypeptide, fusion protein, pharmaceutical composition, method, or use according to  claim 32 , 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, such as 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-Barré syndrome, aseptic meningitis, demyelinating syndrome, mononeuropathy, mononeuritis multiplex, myasthenia gravis, myelopathy, cranial neuropathy, polyneuropathy, vasculitis. 
     
     
         41 . The C1ORF32 polypeptide, fusion protein, pharmaceutical composition, method, or use according to  claim 32 , wherein treating comprises one or more of preventing, curing, managing, reversing, attenuating, alleviating, minimizing, suppressing, managing, or halting the deleterious effects of the above-described diseases. 
     
     
         42 . The C1ORF32 polypeptide, fusion protein, pharmaceutical composition, method, or use according to  claim 41 , wherein the treating comprises treatment of immune related disorder without global immunosuppression. 
     
     
         43 . The C1ORF32 polypeptide, fusion protein, pharmaceutical composition, method, or use according to  claim 41 , wherein the treatment of immune related disorder comprises induction of immune tolerance. 
     
     
         44 . The C1ORF32 polypeptide, fusion protein, pharmaceutical composition, method, or use according to  claim 41 , wherein the treatment and/or prevention comprises inhibition of infiltration of reactive T lymphocytes into the central nervous system. 
     
     
         45 . The C1ORF32 polypeptide, fusion protein, pharmaceutical composition, method, or use according to  claim 41 , wherein the treatment and/or prevention comprises prevention of damage to the myelin coat of neural cells in the central nervous system. 
     
     
         46 . The C1ORF32 polypeptide, fusion protein, pharmaceutical composition, method, or use according to  claim 41 , wherein treatment comprises reducing the severity of the disease, reducing the frequency of episodes of the disease, reducing the duration of such episodes, or reducing the severity of such episodes or a combination thereof. 
     
     
         47 . A method for selecting a subject for treatment with a C1ORF32 fusion protein comprising screening subjects for levels of one or more cytokines selected from the group consisting of IL-1beta, TNF-alpha, TGF-beta, IFN-gamma, IL-10, IL-17, IL-6, IL-23, IL-22, and IL-21, or MMPs, comparing the levels of the cytokines to the levels of cytokines or MMPs in a control subject that does not have an immune related disorder, and administering to the subject an effective amount of the polypeptide of any of  claims 1 - 5  or fusion protein of any of  claims 6 - 16  or pharmaceutical composition according to  claim 17  to inhibit or reduce one or more symptoms of the immune related disorder if the levels of one or more cytokines are elevated in the subject compared to levels in the control subject that does not have the immune related disorder. 
     
     
         48 . A method for selecting a subject for treatment with a C1ORF32 fusion protein comprising screening subjects for levels of mRNA encoding one or more cytokines selected from the group consisting of IL-1beta, TNF-alpha, TGF-beta, IFN-gamma, IL-10, IL-17, IL-6, IL-23, IL-22, and IL-21, or MMPs, comparing the levels of the mRNAs encoding cytokines or MMPs to levels of the mRNAs encoding cytokines or MMPs in a control subject that does not have an inflammatory disorder, and administering to the subject an effective amount of the polypeptide of any of  claims 1 - 5  or fusion protein of any of  claims 6 - 16  or pharmaceutical composition according to  claim 17  to inhibit or reduce one or more symptoms of an immune related disorder if the levels of one or more mRNAs encoding cytokines are elevated in the subject compared to levels in the control subject that does not have an immune related disorder. 
     
     
         49 . The method of any of the above claims, wherein the subject did not previously respond to treatment with TNF blockers. 
     
     
         50 . A method for combining therapeutic vaccination with an antigen along with administration of any one of the polypeptide of any of  claims 1 - 5  or fusion protein of any of  claims 6 - 16  or pharmaceutical composition according to  claim 17 , for treatment of infection. 
     
     
         51 . A method for combining of any one of the polypeptide of any of  claims 1 - 5  or fusion protein of any of  claims 6 - 16  or pharmaceutical composition according to  claim 17 , used as adjuvant, along with an antigen in a vaccine, in order to increase the immune response. 
     
     
         52 . The method of  claim 50  or  51 , wherein the antigen is a viral antigen, bacterial antigen, fungal antigen, parasite antigen, and/or other pathogen's antigen.