Activin receptor-like kinase-1 compositions and methods of use

Abstract

Disclosed herein are methods and compositions for treating disorders associated with angiogenesis or lymphangiogenesis using ALK-1 antagonists.

1 . A method of inhibiting lymphangiogenesis comprising administering to a subject in need of inhibition of lymphangiogenesis an effective amount of an ALK-1 antagonist, whereby the lymphangiogensis is inhibited. 
     
     
         2 . The method of  claim 1 , wherein the subject suffers from a tumor, cancer, cell proliferative disorder, macular degeneration, inflammatory mediated disease, rheumatoid arthritis, diabetic retinopathy or psoriasis. 
     
     
         3 . A method for treating a pathological condition associated with lymphangiogenesis in a subject comprising administering to the subject an effective amount of an ALK-1 antagonist, whereby the pathological condition associated with lymphangiogenesis is treated. 
     
     
         4 . The method of  claim 3 , wherein the pathological condition associated with lymphangiogenesis is a tumor, cancer, cell proliferative disorder, macular degeneration, inflammatory mediated disease, rheumatoid arthritis, diabetic retinopathy or psoriasis. 
     
     
         5 . The method of  claim 2  or  4 , wherein the tumor, cancer or cell proliferative disorder is carcinoma, lymphoma, blastoma, sarcoma, or leukemia. 
     
     
         6 . A method of inhibiting tumoral lymphangiogenesis in a subject comprising administering to the subject an effective amount of an ALK-1 antagonist, whereby the tumoral lymphangiogensis is inhibited. 
     
     
         7 . A method of inhibiting or preventing tumor metastasis in a subject comprising administering to the subject an effective amount of an ALK-1 antagonist, whereby the tumor metastasis is inhibited or prevented. 
     
     
         8 . The method of  claim 6  or  7 , wherein the subject has developed or is at risk for developing tumor metastasis. 
     
     
         9 . The method of  claim 8 , wherein said tumor metastasis is in the lymphatic system. 
     
     
         10 . The method of  claim 8 , wherein said tumor metastasis is in a distant organ. 
     
     
         11 . A method of disrupting pericyte organization in a subject comprising administering to the subject an effective amount of an ALK-1 antagonist, whereby the pericyte organization is disrupted. 
     
     
         12 . The method of  claim 11 , wherein the subject suffers from a tumor, cancer, cell proliferative disorder, macular degeneration, inflammatory mediated disease, rheumatoid arthritis, diabetic retinopathy or psoriasis. 
     
     
         13 . A method of inhibiting tumor growth in a subject comprising administering to the subject an effective amount of an ALK-1 antagonist, whereby the tumor growth is inhibited. 
     
     
         14 . A method of treating a tumor, cancer or cell proliferative disorder in a subject comprising administering to the subject an effective amount of an ALK-1 antagonist, whereby the tumor, cancer or cell proliferative disorder is treated. 
     
     
         15 . The method of  claim 13  or  14 , wherein the tumor, cancer or cell proliferative disorder is carcinoma, lymphoma, blastoma, sarcoma, or leukemia. 
     
     
         16 . The method of  claim 13  or  14 , further comprising administering to the subject an effective amount of an anti-angiogenesis agent. 
     
     
         17 . The method of  claim 16 , wherein the anti-angiogenesis agent is an antagonist of vascular endothelial growth factor (VEGF). 
     
     
         18 . The method of  claim 17 , wherein the antagonist of VEGF is an anti-VEGF antibody. 
     
     
         19 . The method of  claim 18 , wherein the anti-VEGF antibody is bevacizumab. 
     
     
         20 . A method of enhancing efficacy of an anti-angiogenesis agent in a subject having a pathological condition associated with angiogenesis, comprising administering to the subject an effective amount of an ALK-1 antagonist in combination with the anti-angiogenesis agent, thereby enhancing said anti-angiogenesis agent's inhibitory activity. 
     
     
         21 . The method of  claim 20 , wherein the pathological condition associated with angiogenesis is a tumor, cancer or cell proliferative disorder. 
     
     
         22 . The method of any one of  claims 1 - 21 , wherein the ALK-1 antagonist is an ALK-1 immunoadhesin. 
     
     
         23 . The method of  claim 22 , wherein the ALK-1 immunoadhesin comprises amino acid residues 22-352 of SEQ ID NO: 2, residues 22-349 of SEQ ID NO: 4, residues 22-347 of SEQ ID NO: 6, residues 22-350 of SEQ ID NO: 8 or residues 22-350 of SEQ ID NO: 10. 
     
     
         24 . The method of any one of  claims 1 - 21 , wherein the ALK-1 antagonist is an anti-ALK-1 antibody or antigen-binding fragment thereof. 
     
     
         25 . An ALK-1 antagonist for use in the prevention, inhibition or treatment of tumor metastasis or treatment of tumor, cancer or cell proliferative disorder. 
     
     
         26 . The ALK-1 antagonist of  claim 25 , wherein the ALK-1 antagonist is an ALK-1 immunoadhesin. 
     
     
         27 . The ALK-1 antagonist of  claim 26 , wherein the ALK-1 immunoadhesin comprises amino acid residues 22-352 of SEQ ID NO: 2, resiudes 22-349 of SEQ ID NO: 4, residues 22-347 of SEQ ID NO: 6, residues 22-350 of SEQ ID NO: 8 or residues 22-350 of SEQ ID NO: 10. 
     
     
         28 . The ALK-1 antagonist of  claim 25 , wherein the ALK-1 antagonist is an anti-ALK-1 antibody or antigen-binding fragment thereof.