Variant activin receptor polypeptides and uses thereof

Abstract

The present invention provides variant activin IIB soluble receptor polypeptides and proteins capable of binding and inhibiting the activities of activin A, myostatin, or GDF-11. The present invention also provides polynucleotides, vectors and host cells capable of producing the variant polypeptides and proteins. Compositions and methods for treating muscle-wasting and other diseases and disorders are also provided.

What is claimed: 
     
         1 . A method of reducing the size of an activin A-expressing tumor in a subject comprising:
 administering an isolated protein comprising a polypeptide comprising an amino acid sequence having at least 95% identity to the amino acid sequence set forth at amino acids 25 through 134 of SEQ ID NO: 18, wherein the polypeptide comprises an amino acid substitution at position 28 of the sequence set forth in SEQ ID NO: 18, and wherein the polypeptide is capable of binding myostatin, activin A, or GDF-11; and   administering a chemotherapeutic agent.   
     
     
         2 . The method of  claim 1 , wherein the amino acid substitution at position 28 of the polypeptide is selected from the group consisting of A, F, Q, V, I, L, M, K, H, W, and Y for E. 
     
     
         3 . The method of  claim 1 , wherein the chemotherapeutic agent is an anti-neoplastic agent. 
     
     
         4 . The method of  claim 3 , wherein the anti-neoplastic agent is doxorubicin. 
     
     
         5 . The method of  claim 1 , wherein the protein is formulated for injection. 
     
     
         6 . The method of  claim 1 , wherein the protein is formulated in an aqueous solution. 
     
     
         7 . The method of  claim 1 , wherein the protein is formulated with an excipient. 
     
     
         8 . The method of  claim 1 , wherein the protein is formulated with a buffer. 
     
     
         9 . The method of  claim 1 , wherein the protein is formulated with a polysorbate. 
     
     
         10 . The method of  claim 1 , wherein the tumor is a solid tumor. 
     
     
         11 . The method of  claim 1 , wherein the protein and the chemotherapeutic agent are administered simultaneously. 
     
     
         12 . The method of  claim 1 , wherein the protein and the chemotherapeutic agent are administered separately. 
     
     
         13 . A method of treating a subject having an activin A-expressing tumor, comprising:
 administering an isolated protein comprising a polypeptide comprising an amino acid sequence having at least 95% identity to the amino acid sequence set forth at amino acids 25 through 134 of the sequence set forth in SEQ ID NO: 18, wherein the polypeptide comprises an amino acid substitution at position 28, and wherein the polypeptide is capable of binding myostatin, activin A, or GDF-11; and   administering a chemotherapeutic agent.   
     
     
         14 . The method of  claim 13 , wherein the amino acid substitution at position 28 of the polypeptide is selected from the group consisting of A, F, Q, V, I, L, M, K, H, W, and Y for E. 
     
     
         15 . The method of  claim 13 , wherein the chemotherapeutic agent is an anti-neoplastic agent. 
     
     
         16 . The method of  claim 15 , wherein the anti-neoplastic agent is doxorubicin. 
     
     
         17 . The method of  claim 13 , wherein the protein is formulated for injection. 
     
     
         18 . The method of  claim 13 , wherein the protein is formulated in an aqueous solution. 
     
     
         19 . The method of  claim 13 , wherein the protein is formulated with an excipient, a buffer, or a polysorbate. 
     
     
         20 . The method of  claim 13 , wherein the tumor is a solid tumor.