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.

We claim: 
     
         1 . A composition for therapeutic administration comprising a polypeptide and a pharmaceutically acceptable carrier, wherein the polypeptide comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 2 and wherein the polypeptide promotes erythropoiesis in vivo. 
     
     
         2 . The composition of  claim 1 , wherein the polypeptide is at least 98% pure as determined by size exclusion chromatography. 
     
     
         3 . The composition of  claim 1 , wherein the polypeptide comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 2. 
     
     
         4 . The composition of  claim 3 , wherein the polypeptide comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 2. 
     
     
         5 . The composition of  claim 4 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO: 2. 
     
     
         6 . The composition of  claim 1 , wherein the polypeptide is glycosylated and has a mammalian glycosylation pattern. 
     
     
         7 . The composition of  claim 6 , wherein the polypeptide has a glycosylation pattern obtainable from a chinese hamster ovary (CHO) cell line. 
     
     
         8 . The composition according to  claim 1 , wherein the N-terminal amino acid is isoleucine. 
     
     
         9 . The composition of  claim 8 , wherein the N-terminus of the polypeptide is ILGRSTQE 
     
     
         10 . The composition of  claim 1 , wherein the composition is substantially pyrogen free. 
     
     
         11 . The composition of  claim 1 , wherein the polypeptide further comprises a domain that enhances one or more of in vivo stability, in vivo half life, uptake/administration, tissue localization or distribution, formation of protein complexes, or purification. 
     
     
         12 . The composition of  claim 11 , wherein the domain is an immunoglobulin Fc domain. 
     
     
         13 . The composition of  claim 11 , wherein the domain is serum albumin. 
     
     
         14 . The composition of  claim 1 , wherein the serum half life of the polypeptide is 20-30 days. 
     
     
         15 . The composition of  claim 1 , wherein the polypeptide has one or more of the following characteristics: (i) binds to an ActRIIa ligand with a K D  of at least 10 −7  M; and (ii) inhibits ActRIIa signaling. 
     
     
         16 . The composition of  claim 1 , wherein the polypeptide is soluble and binds activin A. 
     
     
         17 . The composition of  claim 16 , wherein the polypeptide is an antagonist of activin A. 
     
     
         18 . A method for promoting erythropoiesis comprising administering an effective amount of the composition of  claim 1 . 
     
     
         19 . The method according to  claim 18 , wherein the compositions is administered no more frequently than once per month. 
     
     
         20 . The method according to  claim 19 , wherein the composition is administered no more frequently than once every two months.