Treatment methods using antibodies to aminophospholipids

Abstract

Disclosed are the surprising discoveries that aminophospholipids, such as phosphatidylserine and phosphatidylethanolamine, are stable and specific markers accessible on the luminal surface of tumor blood vessels, and that the administration of an anti-aminophospholipid antibody alone is sufficient to induce thrombosis, tumor necrosis and tumor regression in vivo. This invention therefore provides anti-aminophospholipid antibody-based methods and compositions for use in the specific destruction of tumor blood vessels and in the treatment of solid tumors. Although various antibody conjugates and combinations are thus provided, the use of naked, or unconjugated, anti-phosphatidylserine antibodies is a particularly important aspect of the invention, due to simplicity and effectiveness of the approach.

What is claimed is: 
     
         1 . A kit comprising, in a pharmaceutically acceptable form, an amount of at least a first anti-cancer agent effective to treat an animal having a vascularized tumor, wherein said at least a first anti-cancer agent is at least a first isolated or purified unconjugated antibody, including the Fc portion of said antibody, that binds to an aminophospholipid or aminophospholipid-protein complex on the luminal surface of the vascular endothelial cells of the blood vessels of said vascularized tumor; and:
 (a) a detectably-labeled antibody, or antigen-binding fragment thereof, that binds to an aminophospholipid or aminophospholipid-protein complex on the luminal surface of the vascular endothelial cells of the blood vessels of said vascularized tumor; or   (b) at least a second anti-cancer agent.   
     
     
         2 . A method for treating an animal having a disease or disorder, comprising administering to said animal an amount of at least a first isolated or purified unconjugated antibody, or a dimeric antigen-binding fragment thereof, effective to treat said disease or disorder; wherein said at least a first isolated or purified unconjugated antibody or dimeric antigen-binding fragment thereof binds to phosphatidylserine or a phosphatidylserine-protein complex in said disease or disorder; and wherein said disease or disorder is selected from the group consisting of atherosclerosis, diabetic retinopathy, macular degeneration, vascular restenosis, restenosis following angioplasty, arteriovenous malformations, meningioma, hemangioma, neovascular glaucoma, psoriasis, angiofibroma, arthritis, rheumatoid arthritis, corneal graft neovascularization, hemophilic joints, hypertrophic scars, osler-weber syndrome, pyogenic granuloma retrolental fibroplasia, scleroderma, trachoma, vascular adhesions, synovitis, dermatitis, inflammatory disease and endometriosis. 
     
     
         3 . The method of  claim 2 , wherein said at least a first isolated or purified unconjugated antibody binds to phosphatidylserine in said disease or disorder. 
     
     
         4 . The method of  claim 2 , wherein said at least a first isolated or purified unconjugated antibody binds to a phosphatidylserine-protein complex in said disease or disorder. 
     
     
         5 . The method of  claim 4 , wherein said at least a first isolated or purified unconjugated antibody binds to a phosphatidylserine-β 2 -glycoprotein I complex in said disease or disorder. 
     
     
         6 . The method of  claim 4 , wherein said protein of said phosphatidylserine-protein complex in said disease or disorder is β 2 -glycoprotein I. 
     
     
         7 . The method of  claim 2 , wherein said at least a first isolated or purified unconjugated antibody is at least a first IgG, IgM, monoclonal, recombinant, bispecific, human, humanized or part-human chimeric antibody. 
     
     
         8 . The method of  claim 2 , wherein said at least a first isolated or purified unconjugated antibody is a chimeric antibody that comprises mouse antibody variable region domains that bind to said aminophospholipid or aminophospholipid-protein complex and wherein said mouse antibody variable region domains are attached to a human antibody constant region. 
     
     
         9 . The method of  claim 2 , wherein said at least a first isolated or purified unconjugated antibody is at least a first dimer, trimer or multimer of said antibody. 
     
     
         10 . The method of  claim 2 , wherein said at least a first isolated or purified unconjugated antibody is at least a first F(ab′) 2  antigen-binding fragment of said antibody. 
     
     
         11 . The method of  claim 2 , wherein said at least a first isolated or purified unconjugated antibody is administered to said animal by intravenous administration. 
     
     
         12 . The method of  claim 2 , wherein said method is part of a combined treatment method for said disease or disorder.