ANTIBODIES TO THE C3d FRAGMENT OF COMPLEMENT COMPONENT 3

Abstract

The present invention relates to methods and materials for modulating the complement alternative pathway (CAP), the complement classical pathway (CCP), the complement lectin/mannose pathway (CMP), or combinations thereof, as well as methods and materials for targeting prophylactic or therapeutic agents to localized areas of tissue within the body where they may more directly exert their effects upon the intended target cells or tissue, with reduced, associated systemic effects compared with administration of the same or similar agents in an untargeted, systemic manner. The methods and materials of the present invention may therefore allow for increased efficacy, lower threshold effective dosages and/or lower effective maintenance doses, and/or reduced associated undesired or adverse effects in terms of frequency or severity of occurrence, or both. The present invention also relates to methods and materials for modulating a host humoral immune response, especially reducing, inhibiting, or preventing a host humoral immune response.

What we claim is: 
     
         1 . An antibody or an antigen-binding fragment thereof comprising
 light chain complementarity determining regions (CDR) 1, 2 and 3, wherein light chain CDR 1 is SEQ ID NO:14 or SEQ ID NO:24, light chain CDR 2 is SEQ ID NO:15 or SEQ ID NO:25 and light chain CDR 3 is SEQ ID NO:16 or 26; or   heavy chain complementarity determining regions (CDR) 1, 2 and 3, wherein heavy chain CDR 1 is SEQ ID NO:17 or SEQ ID NO:27, heavy chain CDR 2 is SEQ ID NO:18 or SEQ ID NO:28 and heavy chain CDR 3 is SEQ ID NO:19 or 29.   
     
     
         2 . The antibody of  claim 1  or an antigen-binding fragment thereof comprising
 light chain complementarity determining regions (CDR) 1, 2 and 3, wherein light chain CDR 1 is SEQ ID NO:14 or SEQ ID NO:24, light chain CDR 2 is SEQ ID NO:15 or SEQ ID NO:25 and light chain CDR 3 is SEQ ID NO:16 or 26; and 
 heavy chain complementarity determining regions (CDR) 1, 2 and 3, wherein heavy chain CDR 1 is SEQ ID NO:17 or SEQ ID NO:27, heavy chain CDR 2 is SEQ ID NO:18 or SEQ ID NO:28 and heavy chain CDR 3 is SEQ ID NO:19 or 29. 
 
     
     
         3 . The antibody of  claim 2  or an antigen-binding fragment thereof, wherein light chain CDR 1 is SEQ ID NO:14, light chain CDR 2 is SEQ ID NO:15, light chain CDR 3 is SEQ ID NO:16, heavy chain CDR 1 is SEQ ID NO:17, heavy chain CDR 2 is SEQ ID NO:18, and heavy chain CDR 3 is SEQ ID NO:19. 
     
     
         4 . The antibody of  claim 2  or an antigen-binding fragment thereof, wherein light chain CDR 1 is SEQ ID NO:24, light chain CDR 2 is SEQ ID NO:25, light chain CDR 3 is SEQ ID NO:26, heavy chain CDR 1 is SEQ ID NO:27, heavy chain CDR 2 is SEQ ID NO:28, and heavy chain CDR 3 is SEQ ID NO:29. 
     
     
         5 . An antibody or an antigen-binding fragment thereof comprising
 a light chain variable region amino acid sequence 90% identical to SEQ ID NO:12 or SEQ ID NO:22; or   a heavy chain variable region amino acid sequence 90% identical to SEQ ID NO:13 or SEQ ID NO:23.   
     
     
         6 . The antibody of  claim 5  or an antigen-binding fragment thereof comprising
 a light chain variable region amino acid sequence 90% identical to SEQ ID NO:12 or SEQ ID NO:22; and 
 a heavy chain variable region amino acid sequence 90% identical to SEQ ID NO:13 or SEQ ID NO:23. 
 
     
     
         7 . The antibody of  claim 6  or an antigen-binding fragment thereof comprising
 a light chain variable region amino acid sequence 90% identical to SEQ ID NO:12; and 
 a heavy chain variable region amino acid sequence 90% identical to SEQ ID NO:13. 
 
     
     
         8 . The antibody of  claim 6  or an antigen-binding fragment thereof comprising
 a light chain variable region amino acid sequence 90% identical to SEQ ID NO:22; and 
 a heavy chain variable region amino acid sequence 90% identical to SEQ ID NO:23. 
 
     
     
         9 . The antibody of  claim 1 , or an antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment thereof is selected from the group consisting of: a monoclonal antibody or antigen-binding fragment thereof, chimerized or chimeric antibody or antigen-binding fragment thereof, humanized antibody or antigen-binding fragment thereof, deimmunized human antibody or antigen-binding fragment thereof, fully human antibody or antigen-binding fragment thereof, single chain antibody, single chain Fv fragment (scFv), Fv, Fd fragment, Fab fragment, Fab′ fragment, F(ab′) 2  fragment, diabody or antigen-binding fragment thereof, minibody or antigen-binding fragment thereof, triabody or antigen-binding fragment thereof, domain antibody or antigen-binding fragment thereof, camelid antibody or antigen-binding fragment thereof, dromedary antibody or antigen-binding fragment thereof, a bispecific antibody or antibody fragment, a monovalent antibody or antibody fragment, or phage-displayed antibody or antigen-binding fragment thereof. 
     
     
         10 . A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of  claim 1  and a pharmaceutically-acceptable excipient. 
     
     
         11 . A construct comprising:
 a) a C3d binding portion comprising the antibody of  claim 1 , or an antigen-binding fragment thereof; and   b) a complement modulator portion, wherein (a) and (b) are joined.   
     
     
         12 . The construct of  claim 11 , wherein said C3d binding portion and said complement modulator portion are joined by a linker. 
     
     
         13 . The construct of  claim 12 , wherein said linker is selected from the group consisting of: (GlySer) n , wherein n=1 to 8; (GlyGlyGlySer) n , wherein n=1 to 4; (GlyGlyGlyGlySer) n , wherein n=1 to 8; and (GlySerSerGly) n , wherein n=1 to 4. 
     
     
         14 . The construct of  claim 11 , wherein said complement inhibitor or biologically active fragment thereof is selected from the group consisting of: human membrane complement protein (MCP), human decay accelerating factor (DAF), human CD59, human complement receptor 1 (CR1), human factor H, Crry, and biologically active fragments or variants of any of the foregoing. 
     
     
         15 . A pharmaceutical composition comprising the construct of  claim 11  and a pharmaceutically-acceptable excipient. 
     
     
         16 . A method of decreasing a humoral immune response in a mammal comprising administering to said mammal the antibody or antigen-binding fragment thereof of  claim 1  in an amount effective to decrease a humoral immune response in a mammal. 
     
     
         17 . A method of modulating complement activation in a mammal comprising administering to said mammal the antibody or antigen-binding fragment thereof of  claim 1  in an amount effective to modulating complement activation in a mammal. 
     
     
         18 . A method of modulating complement activation in a mammal comprising administering to said mammal the construct of  claim 11  in an amount effective to modulate complement activation in a mammal. 
     
     
         19 . A method of treating a mammal having or suspected of having a disease or preventing a subject from developing a disease wherein said disease is selected from the group consisting of: tissue damage resulting from ischemia-reperfusion injury, an inflammatory disorder, transplant rejection (cellular or antibody mediated), a pregnancy-related disease, an adverse drug reaction, glomerulonephritis, IgG4 associated or mediated diseases, ocular inflammatory diseases, ocular degenerative diseases, ocular autoimmune diseases, and an autoimmune or immune complex disorder, said method comprising administering to said mammal a therapeutically effective amount of the antibody or antigen-binding fragment thereof of  claim 1 . 
     
     
         20 . A method of treating a mammal having or suspected of having a disease or preventing a subject from developing a disease wherein said disease is selected from the group consisting of: tissue damage resulting from ischemia-reperfusion injury, an inflammatory disorder, transplant rejection (cellular or antibody mediated), a pregnancy-related disease, an adverse drug reaction, glomerulonephritis, IgG4 associated or mediated diseases, ocular inflammatory diseases, ocular degenerative diseases, ocular autoimmune diseases, and an autoimmune or immune complex disorder, said method comprising administering to said mammal a therapeutically effective amount of the construct of  claim 11 . 
     
     
         21 . The method of  claim 19 , wherein said tissue damage resulting from ischemia-reperfusion injury is associated with a disorder selected from the group consisting of: myocardial infarction, aneurysm, stroke, hemorrhagic shock, crush injury, multiple organ failure, hypovolemic shock, intestinal ischemia, spinal cord injury and traumatic brain injury. 
     
     
         22 . The method of  claim 19 , wherein said inflammatory disorder is selected from the group consisting of: burns, endotoxemia, septic shock, adult respiratory distress syndrome, cardiopulmonary bypass, hemodialysis, anaphylactic shock, asthma, angioedema, Crohn's disease, sickle cell anemia, poststreptococcal glomerulonephritis, membranous nephritis, and pancreatitis. 
     
     
         23 . The method of  claim 19 , wherein said transplant rejection is hyperacute xenograft rejection. 
     
     
         24 . The method of  claim 19 , wherein said pregnancy-related disease is selected from the group consisting of: HELLP syndrome (Hemolytic anemia, Elevated Liver enzymes and Low Platelet count), recurrent fetal loss, and pre-eclampsia. 
     
     
         25 . The method of  claim 19 , wherein said adverse drug reaction is selected from the group consisting of: drug allergy and IL-2 induced vascular leakage syndrome. 
     
     
         26 . The method of  claim 19 , wherein said autoimmune or immune complex disorder is selected from the group consisting of: myasthenia gravis, Alzheimer's disease, multiple sclerosis, rheumatoid arthritis, neuromyelitis optica, osteoarthritis, systemic lupus erythematosus, lupus nephritis, IgG4 associated diseases, insulin-dependent diabetes mellitus, acute disseminated encephalomyelitis, Addison's disease, antiphospholipid antibody syndrome, thrombotic thrombycytopenic purpura, autoimmune hepatitis, Crohn's disease, Goodpasture's syndromes, Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, idiopathic thrombocytopenic purpura, pemphigus, Sjögren's syndrome, Takayasu's arteritis, autoimmune glomerulonephritis, membranoproliferative glomerulonephritis type II, membranous disease, paroxysmal nocturnal hemoglobinuria, age-related macular degeneration, diabetic maculopathy, uveitis, retinal degeneration disorders, diabetic nephropathy, focal segmental glomerulosclerosis, ANCA associated vasculitis, hemolytic uremic syndrome, Shiga-toxin-associated hemolytic uremic syndrome, and atypical hemolytic uremic syndrome. 
     
     
         27 . The method of  claim 26 , wherein said autoimmune glomerulonephritis is selected from the group consisting of: immunoglobulin A nephropathy and membranoproliferative glomerulonephritis type I.