Natural IGM Antibodies and Inhibitors Thereof

Abstract

The invention provides natural IgM antibody inhibitors that may be used to treat various inflammatory diseases or disorders.

1 .- 47 . (canceled) 
     
     
         48 . An inhibitor of natural IgM antibodies, wherein the inhibitor is an isolated antibody or antigen-binding fragment thereof that inhibits binding of a natural IgM antibody to a self-antigen. 
     
     
         49 . The inhibitor of  claim 48 , wherein the antibody or antigen-binding fragment thereof inhibits complement activation. 
     
     
         50 . The inhibitor of  claim 48 , wherein the natural IgM antibody is a pathogenic antibody. 
     
     
         51 . The inhibitor of  claim 48 , wherein the inhibitor is an isolated antibody or antigen-binding fragment thereof that competes with natural IgMs in binding to the self-antigen. 
     
     
         52 . The inhibitor of  claim 51 , wherein the isolated antibody or antigen-binding fragment thereof blocks binding of a natural IgM antibody to a self-antigen and inhibits complement activation. 
     
     
         53 . The inhibitor of  claim 51 , wherein the self-antigen comprises the amino acid sequence of SEQ ID NO:38. 
     
     
         54 . The inhibitor of  claim 51 , wherein the antibody inhibits the binding of natural IgM antibody IgM CM-22  to the amino acid sequence of SEQ ID NO:38. 
     
     
         55 . The inhibitor of  claim 51 , wherein the antibody is a monoclonal antibody. 
     
     
         56 . The inhibitor of  claim 55 , wherein the antibody is selected from the group consisting chimeric, CDR-grafted, and humanized antibodies. 
     
     
         57 . The inhibitor of  claim 48 , wherein the inhibitor is an antigen-binding fragment. 
     
     
         58 . The inhibitor of  claim 57 , wherein antigen binding fragment is a Fab fragment, a F(ab′) 2  fragment, or scFv fragment. 
     
     
         59 . The inhibitor of  claim 48 , wherein the antibody comprises an antigen-binding fragment of natural IgM antibody IgM CM-22 . 
     
     
         60 . A method of for treating an inflammatory condition in a subject in need thereof comprising administering to said subject an effective amount of the antibody of  claim 48 . 
     
     
         61 . The method of  claim 60 , wherein the inflammatory condition is selected from the group consisting of reperfusion injury, ischemia injury, stroke, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, rheumatoid arthritis, celiac disease, hyper-IgM immunodeficiency, arteriosclerosis, coronary artery disease, sepsis, myocarditis, encephalitis, transplant rejection, hepatitis, thyroiditis, osteoporosis, polymyositis, dermatomyositis, Type I diabetes, gout, dermatitis, alopecia areata, systemic lupus erythematosus, lichen sclerosis, ulcerative colitis, diabetic retinopathy, pelvic inflammatory disease, periodontal disease, arthritis, juvenile chronic arthritis, psoriasis, osteoporosis, nephropathy in diabetes mellitus, asthma, pelvic inflammatory disease, chronic inflammatory liver disease, chronic inflammatory lung disease, lung fibrosis, liver fibrosis, rheumatoid arthritis, chronic inflammatory liver disease, chronic inflammatory lung disease, lung fibrosis, liver fibrosis, Crohn's disease, ulcerative colitis, burn injury, and other acute and chronic inflammatory diseases of the Central Nervous System, gastrointestinal system, the skin and associated structures, the immune system, the hepato-biliary system, or any site in the body where pathology can occur with an inflammatory component. 
     
     
         62 . The method of  claim 61 , wherein the inflammatory condition is reperfusion injury or ischemia injury. 
     
     
         63 . The method of  claim 62 , wherein the reperfusion or ischemic injury follows a naturally occurring episode. 
     
     
         64 . The method of  claim 63 , wherein the naturally occurring episode is stroke or myocardial infarction. 
     
     
         65 . The method of  claim 63 , wherein the reperfusion or ischemic injury follows a surgical procedure. 
     
     
         66 . The use of  claim 65 , wherein the surgical procedure is selected from the group consisting of angioplasty, stenting procedure, atherectomy, and bypass surgery. 
     
     
         67 . The method of  claim 62 , wherein the reperfusion or ischemic injury occurs in a cardiovascular tissue. 
     
     
         68 . The inhibitor of  claim 48 , wherein the antibody or antigen-binding fragment is an IgG. 
     
     
         69 . A pharmaceutical composition comprising the inhibitor of  claim 48 , and a pharmaceutically acceptable excipient. 
     
     
         70 . A pharmaceutical composition comprising the inhibitor of  claim 51 , and a pharmaceutically acceptable excipient.