FcgammaRIIB Fusion Proteins and Compositions Thereof

Abstract

The present invention relates to molecules, preferably soluble (i.e., not membrane bound) polypeptides, most preferably soluble fusion polypeptides comprising the extracellular soluble regions of an FcγR, derivatives and analogs thereof, and nucleic acids encoding same. Molecules of the invention are particularly useful for the treatment, management, or prevention of, or amelioration of one or more symptoms of, an autoimmune disease, especially for ameliorating serum platelet deficiency associated with immune thrombocytopenic purpura. The invention provides methods and compositions for enhancing the therapeutic efficacy of standard, current or experimental therapies for an autoimmune disease by administering a molecule of the invention.

1 . A method for treating, preventing or ameliorating one or more symptoms of an autoimmune disorder, said method comprising:
 administering to a subject in need thereof a therapeutically effective amount of a dimeric fusion protein,   wherein said dimeric fusion protein comprises two identical polypeptide chains, each said chain comprising an extracellular region of an inhibitory FcγR comprising an Fc binding site, joined to the Fc region of a human immunoglobulin that binds an FcRn, wherein said Fc region comprises one or more amino acid modifications that modulate one or more effector functions of the Fc region and wherein the dimeric fusion protein specifically binds an immune complex via the Fc region of the inhibitory FcγR.   
     
     
         2 . The method of  claim 1 , wherein said autoimmune disorder is idiopathic thrombocytopenic purpura, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Rieter's Syndrome, psoriasis, systemic lupus erythematosus, autoimmune hemolytic anemia, scleroderma, autoantibody triggered urticaria, pemphigus, vasculitic syndromes, Goodpasture's syndrome, multiple sclerosis, Sjogren's syndrome, Kowasaki's disease, polymyositis, or dermatomyositis. 
     
     
         3 . The method of  claim 1 , further comprising administering to said subject a therapeutically effective amount of one or more anti-inflammatory agents and/or immunomodulatory agents. 
     
     
         4 . The method of  claim 3 , wherein at least one of said one or more immunomodulatory agents is a small organic molecule selected from the group consisting of methotrexate, leflunomide, cyclophosphamide, cyclosporin A, FK506, mycophenolate mofetil, rapamycin, mizoribine, deoxyspergualin, brequinar, malonitrolamide, steroid, and corticosteroid. 
     
     
         5 . The method of  claim 3 , wherein at least one of said one or more anti-inflammatory agents is a non-steroidal anti-inflammatory drug selected from the group consisting of aspirin, ibuprofen, diclofenac, nabumetone, naproxen, and ketoproten. 
     
     
         6 . The method of  claim 1 , wherein said immunoglobulin is an IgG molecule selected from the group consisting of IgG1, IgG2, IgG3, and IgG4. 
     
     
         7 . The method of  claim 1 , wherein said inhibitory FcγR is FcγRIIB. 
     
     
         8 . The method of  claim 7 , wherein said extracellular domain of said FcγRIIB is joined to a hinge-constant region of an IgG2, and wherein said one or more amino acid modifications occurs in said hinge-constant region. 
     
     
         9 . The method of  claim 1 , wherein said modification results in said Fc domain of said dimeric fusion protein lacking effector function. 
     
     
         10 . The method of  claim 8 , wherein said modification results in said IgG2 hinge-constant region of said dimeric fusion protein lacking effector function. 
     
     
         11 . The method of  claim 1 , wherein said Fc domain of said dimeric fusion protein is not glycosylated. 
     
     
         12 . The method of  claim 8 , wherein said IgG2 hinge-constant region of said dimeric fusion protein is not glycosylated. 
     
     
         13 . The method of  claim 1 , wherein said amino acid corresponding to position 297 in said Fc domain of said dimeric fusion protein is not glycosylated, and/or is not asparagine, and/or is glutamine. 
     
     
         14 . The method of  claim 8 , wherein said amino acid corresponding to position 297 in said IgG2 hinge-constant region of said dimeric fusion protein is not glycosylated, and/or is not asparagine, and/or is glutamine. 
     
     
         15 . The method of  claim 1 , wherein said autoimmune disorder is idiopathic thrombocytopenic purpura, and wherein said method further comprises administering to said subject a standard idiopathic thromboctopenic purpura therapy, said standard idiopathic thrombocytopenic purpura therapy being intravenous immunoglobulin therapy, corticosteroid therapy, splenectomy, or plamsapheresis. 
     
     
         16 . The method of  claim 1 , wherein said autoimmune disorder is idiopathic thrombocytopenic purpura, and wherein said subject is refractory to a standard idiopathic thrombocytopenic purpura therapy, said standard idiopathic thrombocytopenic purpura therapy being intravenous immunoglobulin therapy, corticosteroid therapy, splenectomy, or plamsapheresis. 
     
     
         17 . The method of  claim 15  wherein said subject is human, and/or is immunocompromised, and/or has cancer. 
     
     
         18 . The method of  claim 16  wherein said subject is human, and/or is immunocompromised, and/or has cancer. 
     
     
         19 . A method for treating, preventing or ameliorating one or more symptoms of an autoimmune disorder, said method comprising:
 administering to a subject in need thereof a therapeutically effective amount of a dimeric fusion protein,   wherein said dimeric fusion protein comprises two identical polypeptide chains, each chain comprising an amino acid sequence of one of SEQ ID NOs: 1, 4, 34, 36, 38, 40, or 42.   
     
     
         20 . A method for treating, preventing or ameliorating one or more symptoms of an autoimmune disorder, said method comprising administering to a subject in need thereof: (i) a therapeutically effective amount of an antibody which specifically binds a wild-type extracellular region of FcγRIIB comprising an Fcγ binding site; and (ii) a therapeutically effective amount of a dimeric fusion protein comprising two identical polypeptide chains, each said chain comprising a variant extracellular region of FcγRIIB, wherein said variant extracellular region comprises at least one amino acid modification relative to said wild-type extracellular region, such that said antibody binds said dimeric fusion protein with a lower affinity than said antibody binds said wild-type extracellular region, and wherein said dimeric fusion protein specifically binds an immune complex. 
     
     
         21 . The method of  claim 20 , wherein said antibody is produced by clone 2B6, having ATCC accession number PTA-4591, or by clone 3H7, having ATCC accession number PTA-4592.