Activin-actrii antagonists and uses for increasing red blood cell levels

Abstract

In certain aspects, the present invention provides compositions and methods for increasing red blood cell and/or hemoglobin levels in vertebrates, including rodents and primates, and particularly in humans.

1 - 20 . (canceled) 
     
     
         21 . A method for promoting erythropoiesis comprising administering to a subject in need thereof an effective amount of a polypeptide selected from:
 a) a polypeptide comprising an amino acid sequence at least 95% identical to SEQ ID NO:2; and   b) a polypeptide comprising an amino acid sequence at least 95% identical to SEQ ID NO:3;   
       and wherein the polypeptide binds to activin. 
     
     
         22 . The method of  claim 21 , wherein the polypeptide has one or more of the following characteristics:
 i) binds to activin with a K D  of at least 10 −7 M; and   ii) inhibits activin signaling in a cell.   
     
     
         23 . The method of  claim 21 , wherein the polypeptide is a fusion protein including, in addition to the polypeptide, one or more polypeptide portions that enhance one or more of in vivo stability, in vivo half-life, uptake/administration, tissue localization or distribution, formation of protein complexes, and/or purification. 
     
     
         24 . The method of  claim 23 , wherein the fusion protein includes a polypeptide portion selected from: an immunoglobulin Fc domain and a serum albumin. 
     
     
         25 . The method of  claim 21 , wherein the polypeptide includes one or more modified amino acid residues selected from: a glycosylated amino acid, a PEGylated amino acid, a farnesylated amino acid, an acetylated amino acid, a biotinylated amino acid, an amino acid conjugated to a lipid moiety, and an amino acid conjugated to an organic derivatizing agent. 
     
     
         26 . The method of  claim 24 , wherein the fusion protein includes an immunoglobulin Fc domain. 
     
     
         27 . The method of  claim 21 , wherein the method causes less than 15% increase in the patient's skeletal muscle mass. 
     
     
         28 . The method of  claim 26 , wherein the fusion protein is administered so as to reach a serum concentration in the patient of at least 100 ng/ml for a period of about 20 to 30 days. 
     
     
         29 . The method of  claim 26 , wherein the fusion protein is administered so as to reach a serum concentration in the patient in the range of 100 ng/ml to 1000 ng/ml. 
     
     
         30 . The method of  claim 26 , wherein the fusion protein has a serum half-life of between 15 and 30 days. 
     
     
         31 . The method of  claim 26 , wherein the fusion protein is administered to the patient no more frequently than once per week. 
     
     
         32 . The method of  claim 26 , wherein the fusion protein is administered to the patient no more frequently than once per month. 
     
     
         33 . The method of  claim 21 , wherein the polypeptide comprises an amino acid sequence at least 95% identical to SEQ ID NO:7. 
     
     
         34 . The method of  claim 33 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO:7. 
     
     
         35 . The method of  claim 21 , wherein the polypeptide comprises an amino acid sequence at least 95% identical to SEQ ID NO:12. 
     
     
         36 . The method of  claim 35 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO: 12. 
     
     
         37 . The method of  claim 21 , wherein the polypeptide binds to activin A, activin B, and GDF-11. 
     
     
         38 . The method of  claim 26 , wherein the fusion protein includes an immunoglobulin IgG1 Fc domain. 
     
     
         39 . The method of  claim 21 , wherein the polypeptide comprises an amino acid sequence at least 95% identical to SEQ ID NO:2. 
     
     
         40 . The method of  claim 39 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO:2. 
     
     
         41 . The method of  claim 21 , wherein the polypeptide comprises an amino acid sequence at least 95% identical to SEQ ID NO:3. 
     
     
         42 . The method of  claim 41 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO:3. 
     
     
         43 . The method of  claim 21 , wherein the subject is at risk for developing undesirably low red blood cell levels or hemoglobin levels. 
     
     
         44 . The method of  claim 43 , wherein the polypeptide is administered prior to the subject undergoing surgery or other procedures that may result in substantial blood loss. 
     
     
         45 . The method of  claim 43 , wherein the polypeptide is administered prior to the subject having blood drawn.