Treatment of complement-associated disorders

Abstract

The present invention concerns a recently discovered macrophage specific receptor, CRIg, and its use in the treatment of complement-associated disorders.

What is claimed is: 
     
         1 . A method for the prevention or treatment of a complement-associated diseases or condition, comprising treating a subject in need of such treatment with a prophylactially or therapeutically effective amount of a CRIg polypeptide or an agonist thereof. 
     
     
         2 . The method of  claim 1  wherein said CRIg polypeptide is selected from the group consisting of CRIg polypeptides of SEQ ID NO: 2, 4, 6, 8, and the extracellular regions of such polypeptides. 
     
     
         3 . The method of  claim 2  wherein said CRIg polypeptide is fused to an immunoglobulin sequence. 
     
     
         4 . The method of  claim 3  wherein the immunoglobulin sequence is an immunoglobulin constant region sequence. 
     
     
         5 . The method of  claim 4  wherein the immunoglobulin constant region sequence is that of an immunoglobulin heavy chain. 
     
     
         6 . The method of  claim 5  wherein said immunoglobulin heavy chain constant region sequence is fused to an extracellular region of a CRIg polypeptide of SEQ ID NO: 2, 4, 6, or 8. 
     
     
         7 . The method of  claim 6  wherein said immunoglobulin heavy chain constant region sequence is that of an IgG. 
     
     
         8 . The method of  claim 7  wherein said IgG is selected from IgG-1 and IgG-3. 
     
     
         9 . The method of  claim 7  wherein the IgG-1 heavy chain constant region sequence comprises at least a hinge, CH2 and CH3 region. 
     
     
         10 . The method of  claim 7  wherein the IgG-1 heavy chain constant region sequence comprised a hinge, CH1, CH2 and CH3 region. 
     
     
         11 . The method of  claim 1  wherein said complement-associated disease is an inflammatory disease or an autoimmune disease. 
     
     
         12 . The method of  claim 11  wherein said complement-associated disease is selected from the group consisting of rheumatoid arthritis (RA), adult respiratory distress syndrome (ARDS), remote tissue injury after ischemia and reperfusion, complement activation during cardiopulmonary bypass surgery, dermatomyositis, pemphigus, lupus nephritis and resultant glomerulonephritis and vasculitis, cardiopulmonary bypass, cardioplegia-induced coronary endothelial dysfunction, type II membranoproliferative glomerulonephritis, IgA nephropathy, acute renal failure, cryoglobulemia, antiphospholipid syndrome, age-related macular degeneration, uveitis, diabetic retinopathy, allo-transplantation, hyperacute rejection, hemodialysis, chronic occlusive pulmonary distress syndrome (COPD), asthma, aspiration pneumonia, utricaria, chronic idiopathic utricaria, hemolytic ureinic syndrome, endometriosis, cardiogenic shock, ischemia reperfusio injury, and multiple schlerosis (MS). 
     
     
         13 . The method of  claim 11  wherein said complement-associated disease is selected from the group consisting of inflammatory bowel disease (IBD), systemic lupus erythematosus, rheumatoid arthritis, juvenile chronic arthritis, spondyloarthropathies, systemic sclerosis (scleroderma), idiopathic inflammatory myopathies (dermatomyositis, polymyositis), Sjögren's syndrome, systemic vaculitis, sarcoidosis, autoimmune hemolytic anemia (immune pancytopenia, paroxysmal nocturnal hemoglobinuria), autoimmune thrombocytopenia (idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia), thyroiditis (Grave's disease, Hashimoto's thyroiditis, juvenile lymphocytic thyroiditis, atrophic thyroiditis), diabetes mellitus, immune-mediated renal disease (glomerulonephritis, tubulointerstitial nephritis), demyelinating diseases of the central and peripheral nervous systems such as multiple sclerosis, idiopathic polyneuropathy, hepatobiliary diseases such as infectious hepatitis (hepatitis A, B, C, D, E and other nonhepatotropic viruses), autoimmune chronic active hepatitis, primary biliary cirrhosis, granulomatous hepatitis, and sclerosing cholangitis, inflammatory and fibrotic lung diseases (e.g., cystic fibrosis), gluten-sensitive enteropathy, Whipple's disease, autoimmune or immune-mediated skin diseases including bullous skin diseases, erythema multiforme and contact dermatitis, psoriasis, allergic diseases of the lung such as eosinophilic pneumonia, idiopathic pulmonary fibrosis and hypersensitivity pneumonitis, transplantation associated diseases including graft rejection, graft-versus host disease, Alzheimer's disease, paroxysmal nocturnal hemoglobinurea, hereditary angioedema and atherosclerosis. 
     
     
         14 . The method of  claim 11  wherein said complement-associated disease is rheumatoid arthritis (RA), psoriasis or asthma. 
     
     
         15 . The method of  claim 2  wherein said subject is a mammal. 
     
     
         16 . The method of  claim 14  wherein said mammal is a human. 
     
     
         17 . A method for inhibition of the production of C3b complement fragment in a mammal comprising administering to said mammal an effective amount of a CRIg polypeptide or an agonist thereof. 
     
     
         18 . The method of  claim 16  wherein said CRIg polypeptide is selected from the group consisting of CRIg polypeptides of SEQ ID NO: 2, 4, 6, 8, and the extracellular regions of such polypeptides. 
     
     
         19 . The method of  claim 17  wherein said CRIg polypeptide is fused to an immunoglobulin sequence. 
     
     
         20 . The method of  claim 18  wherein the immunoglobulin sequence is an immunoglobulin constant region sequence. 
     
     
         21 . The method of  claim 19  wherein the immunoglobulin constant region sequence is that of an immunoglobulin heavy chain. 
     
     
         22 . The method of  claim 20  wherein said immunoglobulin heavy chain constant region sequence is fused to an extracellular region of a CRIg polypeptide of SEQ ID NO: 2, 4, 6, or 8. 
     
     
         23 . The method of  claim 21  wherein said immunoglobulin heavy chain constant region sequence is that of an IgG. 
     
     
         24 . The method of  claim 22  wherein said IgG is selected from IgG-1 and IgG-3. 
     
     
         25 . The method of  claim 23  wherein the IgG-1 heavy chain constant region sequence comprises at least a hinge, CH2 and CH3 region. 
     
     
         26 . The method of  claim 23  wherein the IgG-1 heavy chain constant region sequence comprised a hinge, CH1, CH2 and CH3 region. 
     
     
         27 . A method for selective inhibition of the alternative complement pathway in a mammal, comprising administering to said mammal an effective amount of CRIg polypeptide or an agonist thereof. 
     
     
         28 . A method for the prevention or treatment of age-related macular degeneration (AMD) or choroidal neovascularization (CNV) in a subject, comprising administering to said subject an effective amount of a complement inhibitor. 
     
     
         29 . The method of  claim 28  wherein the complement inhibitor is a selective inhibitor of the alternative complement pathway. 
     
     
         30 . The method of  claim 29  wherein said complement inhibitor is an antibody or an antibody fragment. 
     
     
         31 . The method of  claim 29  wherein said complement inhibitor is a fusion protein. 
     
     
         32 . The method of  claim 31  wherein said fusion protein is an immunoadhesin. 
     
     
         33 . The method of  claim 29  wherein said complement inhibitor is a peptide or non-peptide small molecule. 
     
     
         34 . The method of  claim 29  wherein said complement inhibitor is CRIg or an agonist thereof. 
     
     
         35 . The method of  claim 34  wherein said agonist is a soluble CRIg. 
     
     
         36 . The method of  claim 34  wherein said agonist is a CRIg-Ig fusion protein. 
     
     
         37 . The method of  claim 34  wherein said agonist is a CRIg antibody or antibody fragment.