Method of inhibitng complement activation with human anti-factor c3 antibodies and use thereof

Abstract

A method of inhibiting complement activation mediated by C3b inhibitors in a subject includes administering a C3B inhibitor to the subject to inhibit at least one of C3b binding to factors B and properdin, inhibit C3 cleavage, inhibit the activation of neutrophils, monocytes, platelets, and endothelium; or inhibit the formation of C3a, C5a, and MAC.

1 . A method of inhibiting C3 dependent complement activation in a subject, comprising:
 administering to the subject an amount of a C3b inhibitory agent effective to inhibit C3 dependent complement activation.   
     
     
         2 . The method of  claim 1  wherein the C3b inhibitory agent specifically binds to C3B protein sequences involved in C3B binding to properdin or factor B or C3B cleavage from C3. 
     
     
         3 . The method of  claim 1  wherein the C3b inhibitory agent is an antibody or fragment thereof that specifically binds to C3b 
     
     
         4 . The method of  claim 3  wherein the antibody or fragment thereof is monoclonal. 
     
     
         5 . The method of  claim 3  wherein the antibody or fragment thereof is polyclonal. 
     
     
         6 . The method of  claim 3  wherein the antibody or fragment thereof is a recombinant antibody. 
     
     
         7 . The method of  claim 3  wherein the antibody has reduced effector function. 
     
     
         8 . The method of  claim 3  wherein the antibody is a chimeric, humanized or human antibody. 
     
     
         9 . The method of  claim 3  wherein the antibody is produced in a C3 deficient transgenic animal. 
     
     
         10 . The method of  claim 1  wherein the C3b inhibitory agent is a peptide derived from the C3b sequence that inhibits properdin binding or factor B binding. 
     
     
         11 . The method of  claim 1  wherein the C3b inhibitory agent is a non-peptide agent that specifically inhibits properdin binding to C3b or factor B binding to C3b. 
     
     
         12 . A composition for inhibiting C3b-dependent complement activation in a subject comprising: a therapeutically effective amount of a C3b inhibitory agent and a pharmaceutically acceptable carrier. 
     
     
         13 . The composition of  claim 12  wherein the C3b inhibitory agent specifically binds to properdin binding sequences or factor B binding sequences on C3b. 
     
     
         14 . The composition of  claim 12  wherein the C3b inhibitory agent is an antibody or fragment thereof that specifically binds to a portion of C3b. 
     
     
         15 . The composition of  claim 14  wherein the antibody or fragment thereof is monoclonal. 
     
     
         16 . The composition of  claim 14  wherein the antibody is a chimeric, humanized or human antibody. 
     
     
         17 . The composition of  claim 14 , wherein the antibody is produced in a C3 deficient transgenic animal. 
     
     
         18 . A method of treating a subject suffering from a C3b-dependent complement mediated condition, comprising:
 administering to subject an amount of a C3b inhibitory agent effective to inhibit C3b-dependent complement activation.   
     
     
         19 . The method of  claim 18 , wherein the condition comprises at least one of a vascular condition, an ischemia-reperfusion injury, atherosclerosis, an inflammatory gastrointestinal disorder, a pulmonary condition, an extracorporeal reperfusion procedure, a musculoskeletal condition, a renal condition, a skin condition, an organ or tissue transplant procedure, a nervous system disorder, a blood disorder, a urogenital condition, diabetes, a neoplastic disorder, malignancy, endocrine disorder, or an ophthalmologic condition. 
     
     
         20 . The method of  claim 19  wherein the vascular condition comprises at least one of a cardiovascular condition, a cerebrovascular condition, a peripheral vascular condition, a renovascular condition, a mesenteric/enteric vascular condition, revascularization to transplants and/or replants, vasculitis, Henoch-Schonlein purpura nephritis, systemic lupus erythematosus-associated vasculitis, vasculitis associated with rheumatoid arthritis, immune complex vasculitis, Takayasu's disease, dilated cardiomyopathy, diabetic angiopathy, Kawasaki's disease, venous gas embolus (VGE), and restenosis following stent placement, rotational atherectomy or percutaneous transluminal coronary angioplasty (PTCA). 
     
     
         21 . The method of  claim 19 , wherein the ischemia-reperfusion injury is associated with at least one of aortic aneurysm repair, cardiopulmonary bypass, vascular reanastomosis in connection with organ transplants and/or extremity/digit replantation, stroke, myocardial infarction, and hemodynamic resuscitation following shock and/or surgical procedures. 
     
     
         22 . The method of  claim 19 , wherein the inflammatory gastrointestinal disorder is selected from the group consisting of pancreatitis, Crohn's disease, ulcerative colitis, irritable bowel syndrome and diverticulitis. 
     
     
         23 . The method of  claim 19  wherein the pulmonary condition is selected from the group consisting of acute respiratory distress syndrome, transfusion-related acute lung injury, ischemia/reperfusion acute lung injury, chronic obstructive pulmonary disease, asthma, Wegener's granulomatosis, antiglomerular basement membrane disease (Goodpasture's disease), meconium aspiration syndrome, bronchiolitis obliterans syndrome, idiopathic pulmonary fibrosis, acute lung injury secondary to burn, non-cardiogenic pulmonary edema, transfusion-related respiratory depression and emphysema. 
     
     
         24 . The method of  claim 19  wherein the extracorporeal reperfusion procedure is selected from the group consisting of hemodialysis, plasmapheresis, leukopheresis, extracorporeal membrane oxygenator (ECMO), heparin-induced extracorporeal membrane oxygenation LDL precipitation (HELP) and cardiopulmonary bypass (CPB). 
     
     
         25 . The method of  claim 19  wherein the musculoskeletal condition is selected from the group consisting of osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, gout, neuropathic arthropathy, psoriatic arthritis, spondyloarthropathy, crystalline arthropathy and systemic lupus erythematosus (SLE). 
     
     
         26 . The method of  claim 19  wherein the renal condition is selected from the group consisting of mesangioproliferative glomerulonephritis, membranous glomerulonephritis, membranoproliferative glomerulonephritis (mesangiocapillary glomerulonephritis), acute postinfectious glomerulonephritis (poststreptococcal glomerulonephritis), cryoglobulinemic glomerulonephritis, lupus nephritis, Henoch-Schonlein purpura nephritis and IgA nephropathy. 
     
     
         27 . The method of  claim 19  wherein the skin condition is selected from the group consisting of psoriasis, autoimmune bullous dermatoses, eosinophilic spongiosis, bullous pemphigoid, epidermolysis bullosa acquisita, herpes gestationis, thermal burn injury and chemical burn injury. 
     
     
         28 . The method of  claim 19  wherein the transplant procedure is selected from the group consisting of organ allotransplantation, organ xenotransplantation organ and tissue graft. 
     
     
         29 . The method of  claim 19  wherein the nervous system disorder or injury is selected from the group consisting of multiple sclerosis, myasthenia gravis, Huntington's disease, amyotrophic lateral sclerosis, Guillain Bane syndrome, reperfusion following stroke, degenerative discs, cerebral trauma, Parkinson's disease, Alzheimer's disease, Miller-Fisher syndrome, cerebral trauma and/or hemorrhage, demyellination and meningitis. 
     
     
         30 . The method of  claim 19  wherein the blood disorder is selected from the group consisting of sepsis, severe sepsis, septic shock, acute respiratory distress syndrome resulting from sepsis, systemic inflammatory response syndrome, hemorrhagic shock, hemolytic anemia, autoimmune thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. 
     
     
         31 . The method of  claim 19  wherein the urogenital condition is selected from the group consisting of painful bladder disease, sensory bladder disease, chronic abacterial cystitis, interstitial cystitis, infertility, placental dysfunction and miscarriage and pre-eclampsia. 
     
     
         32 . The method of  claim 19  wherein the diabetes comprises at least one of nonobese diabetes (Type-1 diabetes or Insulin-dependent diabetes mellitus) and/or complications associated with Type-1 or Type-2 (adult onset) diabetes. 
     
     
         33 . The method of  claim 32  wherein the complication associated with Type 1 or Type 2 diabetes is selected from the group consisting of angiopathy, neuropathy and retinopathy. 
     
     
         34 . The method of  claim 19  wherein the neoplastic condition includes a subject that has undergone, is undergoing, or will undergo chemotherapeutic treatment and/or radiation therapy. 
     
     
         35 . The method of  claim 19  wherein the endocrine disorder is selected from the group consisting of Hashimoto's thyroiditis, stress, anxiety, hormonal disorders involving regulated release of prolactin, growth or other insulin-like growth factor and adrenocorticotropin from the pituitary. 
     
     
         36 . The method of  claim 19  wherein the ophthalmologic condition is age-related macular degeneration.