Antagonists of bmp9, bmp10, alk1 and other alk1 ligands, and uses thereof

Abstract

In certain aspects, the present disclosure relates to the insight that a polypeptide comprising a ligand-binding portion of the extracellular domain of activin-like kinase I (ALK1) polypeptide may be used to inhibit angiogenesis in vivo, particularly in mammals suffering angiogenesis-related disorders. In certain aspects, the disclosure demonstrates that antagonists of BMP9 and/or BMP10, ligands for ALK1, may also be used to inhibit angiogenesis in vivo.

1 . A humanized or fully human antibody that binds to an ALK1 ligand and inhibits the binding of the ALK1 ligand to ALK1, wherein the ALK1 ligand is selected from the group consisting of BMP9 and BMP10. 
     
     
         2 . The antibody of  claim 1 , wherein the antibody binds to the ALK1 ligand with a K D  of less than 1×10 −10  M. 
     
     
         3 . The antibody of  claim 1 , wherein the antibody is a humanized form of MAB3209. 
     
     
         4 . The antibody of  claim 1 , wherein the antibody binds to and inhibits both of BMP9 and BMP10. 
     
     
         5 . A pharmaceutical preparation comprising the antibody of  claim 1 . 
     
     
         6 . A method of inhibiting angiogenesis in a mammal, the method comprising, administering to the mammal an effective amount of an agent selected from the group consisting of: an antagonist of BMP9, an antagonist of BMP10 and an antagonist of both BMP9 and BMP10. 
     
     
         7 - 18 . (canceled) 
     
     
         19 . The method of  claim 6 , wherein the method further comprises administering a second agent that inhibits angiogenesis. 
     
     
         20 . The method of  claim 6 , wherein the angiogenesis to be inhibited is angiogenesis occurring: in the eye of the mammal, in a tumor or in a bone or joint. 
     
     
         21 . The method of  claim 20 , wherein the angiogenesis to be inhibited is angiogenesis occurring in a tumor selected from the group consisting of: a bone tumor, multiple myeloma, a lung tumor, a breast tumor, a tumor metastasized to bone and a lung tumor. 
     
     
         22 . A method for treating rheumatoid arthritis in a mammal, the method comprising, administering to a mammal that has rheumatoid arthritis an effective amount of an agent that binds to an ALK1 ligand and inhibits the binding of the ALK1 ligand to ALK1, wherein the ALK1 ligand is selected from the group consisting of GDF5, GDF6, GDF7, BMP9 and BMP10. 
     
     
         23 - 24 . (canceled) 
     
     
         25 . A method for treating a tumor in a mammal, the method comprising, administering to a mammal that has a tumor an effective amount of an agent that binds to an ALK1 ligand and inhibits the binding of the ALK1 ligand to ALK1, wherein the ALK1 ligand is selected from the group consisting of GDF5, GDF6, GDF7, BMP9 and BMP10. 
     
     
         26 . (canceled) 
     
     
         27 . The method of  claim 25 , wherein the method further comprises administering a second agent that inhibits angiogenesis. 
     
     
         28 . The method of  claim 25  wherein the tumor is associated with bone. 
     
     
         29 . The method of  claim 28 , wherein the tumor is a myeloma or a tumor that has metastasized to the bone. 
     
     
         30 . The method of  claim 25 , wherein the tumor is associated with lung. 
     
     
         31 . The method of  claim 25 , wherein the tumor is associated with breast tissue. 
     
     
         32 . The method of  claim 31 , wherein the tumor is estrogen receptor positive (ER+). 
     
     
         33 . The method of  claim 31 , wherein the tumor is estrogen receptor negative (ER−). 
     
     
         34 . An ophthalmic pharmaceutical formulation comprising an agent that binds to an ALK1 ligand and inhibits the binding of the ALK1 ligand to ALK1, wherein the ALK1 ligand is selected from the group consisting of GDF5, GDF6, GDF7, BMP9 and BMP10. 
     
     
         35 . A method of treating an angiogenesis related disease of the eye comprising administering systemically or to said eye a pharmaceutical formulation comprising: an effective amount of an agent that binds to an ALK1 ligand and inhibits the binding of the ALK1 ligand to ALK1, wherein the ALK1 ligand is selected from the group consisting of GDF5, GDF6, GDF7, BMP9 and BMP10.