Antagonists of activin-actriia 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 - 2 . (canceled) 
     
     
         3 . A method for increasing red blood cell levels and bone formation in a patient in need thereof, the method comprising administering to the patient an effective amount of an activin-ActRIIa antagonist. 
     
     
         4 . (canceled) 
     
     
         5 . A method for increasing the release of red blood cells from the spleen, the method comprising administering to the patient an effective amount of an activin-ActRIIa antagonist. 
     
     
         6 . The method of  claim 5 , wherein the patient has a disorder of the bone marrow. 
     
     
         7 . A method for increasing red blood cell levels in a patient, the method comprising administering an effective amount of an activin antagonist and an erythropoietin agonist. 
     
     
         8 . The method of any of  claim 3 , wherein the activin-ActRIIa antagonist is an antibody that binds to a target protein selected from the group consisting of: an activin and ActRIIa. 
     
     
         9 . The method of  claim 3 , wherein the activin-ActRIIa antagonist is inhibin or a conservative variant of inhibin. 
     
     
         10 . The method of  claim 3 , wherein the activin-ActRIIa antagonist is a protein comprising a follistatin domain that binds to and antagonizes activin. 
     
     
         11 . The method of  claim 3 , wherein the activin-ActRIIa antagonist is a protein selected from the group consisting of: follistatin, FLRG and a conservative variant of the forgoing. 
     
     
         12 . The method of  claim 3 , wherein the activin-ActRIIa antagonist is an ActRIIa polypeptide selected from the group consisting of:
 a) a polypeptide comprising an amino acid sequence at least 90% identical to SEQ ID NO: 2;   b) a polypeptide comprising an amino acid sequence at least 90% identical to SEQ ID NO: 3;   c) a polypeptide comprising at least 50 consecutive amino acids selected from SEQ ID NO: 2;   d) a polypeptide comprising an amino acid sequence at least 90% identical to SEQ ID NO: 7; and   e) a polypeptide comprising an amino acid sequence that is encoded by a nucleic acid that hybridizes under stringent conditions to the complement of SEQ ID NO:5.   
     
     
         13 . The method of  claim 12 , 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 in a cell.   
     
     
         14 . The method of  claim 12 , wherein said polypeptide is a fusion protein including, in addition to an ActRIIa polypeptide domain, 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. 
     
     
         15 . The method of  claim 12 , wherein said fusion protein includes a polypeptide portion selected from the group consisting of: an immunoglobulin Fc domain and a serum albumin. 
     
     
         16 . The method of  claim 12 , wherein said 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. 
     
     
         17 . The method of  claim 12 , wherein the ActRIIa-Fc fusion protein comprises an amino acid sequence selected from the group consisting of:
 a) the amino acid sequence of SEQ ID NO: 3,   b) the amino acid sequence of SEQ ID NO: 2,   c) the amino acid sequence of SEQ ID NO: 7.   
     
     
         18 - 29 . (canceled) 
     
     
         30 . The method of  claim 3 , wherein the patient has anemia and bone loss. 
     
     
         31 . The method of  claim 3 , wherein the patient has a disorder selected from the group consisting of: inflammatory bowel diseases, rheumatoid arthritis, multiple myeloma, a solid tumor, and a kidney disorder. 
     
     
         32 . The method of  claim 3 , wherein the patient has end stage renal disease.