Novel activin receptor and uses thereof

Abstract

The present invention provides novel activin IIB5 receptor polypeptides 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 receptor polypeptides. Compositions and methods for treating muscle-wasting, metabolic and other disorders are also provided.

What is claimed is: 
     
         1 . An isolated protein comprising a human IgG Fc polypeptide linked to an activin receptor IIB (ActRIIB) polypeptide comprising a sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO:2 or an antigen-binding fragment thereof, wherein the ActRIIB polypeptide or antigen-binding fragment thereof is capable of binding myostatin, activin A, or GDF-11, and wherein the protein comprises at least one of: (1) the protein has activin A neutralizing activity IC50 (nM) vs. 20 nM activin that is less than the activin A neutralizing activity IC50 (nM) vs. 20 nM activin of a control protein comprising amino acids 1-124 of the sequence set forth in SEQ ID NO:5 linked to human IgG1 Fc; and (2) the protein has myostatin-neutralizing activity IC50 (nM) vs. 4 nM myostatin that is less than the myostatin-neutralizing activity IC50 (nM) vs. 4 nM myostatin of the control protein. 
     
     
         2 . The protein of  claim 1 , wherein the Fc polypeptide is linked via a linker sequence. 
     
     
         3 . The protein of  claim 1 , wherein the Fc polypeptide is immunoglobulin class IgG 2  or IgG 1 . 
     
     
         4 . The protein of  claim 2 , wherein the linker sequence is a linker peptide. 
     
     
         5 . The protein of  claim 4 , wherein the linker peptide comprises polyglycine. 
     
     
         6 . The protein of  claim 1 , wherein the protein has a myostatin binding activity EC50 (nM) that is less than the myostatin binding activity EC50 (nM) of a control protein comprising amino acids 1-124 of the sequence set forth in SEQ ID NO:5 linked to human IgG1 Fc, as measured by a blocking assay. 
     
     
         7 . The protein of  claim 1 , wherein the protein has GDF-11 neutralizing activity IC50 (nM) vs. 20 nM activin that is greater than or equal to the GDF-11 neutralizing activity IC50 (nM) vs. 20 nM activin of a control protein comprising amino acids 1-124 of the sequence set forth in SEQ ID NO:5 linked to human IgG1 Fc. 
     
     
         8 . A pharmaceutical composition comprising the protein of  claim 1  in admixture with a pharmaceutically acceptable carrier. 
     
     
         9 . A method of inhibiting myostatin activity in a subject in need thereof comprising administering the protein of  claim 1  to the subject. 
     
     
         10 . A method for increasing lean muscle mass in a subject in need thereof comprising administering the protein of  claim 1  to the subject. 
     
     
         11 . A method for increasing the ratio of lean muscle mass to fat in a subject in need thereof comprising administering the protein of  claim 1  to the subject. 
     
     
         12 . A method for treating a muscle-wasting disease in a subject suffering from such as disease comprising administering the protein of  claim 1  to the subject. 
     
     
         13 . The method of  claim 12 , wherein the disease is cancer cachexia. 
     
     
         14 . The method of  claim 12 , wherein the disease selected from muscular dystrophy, amyotrophic lateral sclerosis, congestive obstructive pulmonary disease, chronic heart failure, cancer cachexia, AIDS, renal failure, uremia, rheumatoid arthritis, age-related sarcopenia, organ atrophy, carpal tunnel syndrome, androgen deprivation, and muscle-wasting due to prolonged bed rest, spinal cord injury, stroke, bone fracture, and aging. 
     
     
         15 . A method for treating a metabolic disorder in a subject in need thereof comprising administering the protein of  claim 1  to the subject. 
     
     
         16 . The method of  claim 15 , wherein the metabolic disorder is selected from diabetes, obesity, hyperglycemia, and bone loss. 
     
     
         17 . A method for treating a disease in which activin is over-expressed in a subject comprising administering the protein of  claim 1  to the subject. 
     
     
         18 . The method of  claim 17 , wherein the disease is cancer. 
     
     
         19 . A method for treating cancer in a subject comprising administering the protein of  claim 1  to the subject. 
     
     
         20 . An isolated nucleic acid molecule comprising a polynucleotide selected from the group consisting of:
 (a) a polynucleotide having the polynucleotide sequence set forth in SEQ ID NO: 1 or its complement;   (b) a polynucleotide encoding a polypeptide consisting of the amino acid sequence set forth in SEQ ID NO: 2; and   (c) the polynucleotide sequence that hybridizes to either (a) or (b) under conditions of moderate stringency in about 50% formamide, 6×SSC at about 42° C. and washing conditions of about 60° C., 0.5×SSC, 0.1% SDS, and wherein polypeptide encoded comprises a C terminal having an amino acid sequence set forth in SEQ ID NO: 3, and wherein the polypeptide is capable of binding myostatin, activin A, or GDF-11.   (d) the polynucleotide sequence that hybridizes to either (a) or (b) under conditions of moderate stringency in about 50% formamide, 6×SSC at about 42° C. and washing conditions of about 60° C., 0.5×SSC, 0.1% SDS, and wherein polypeptide encoded comprises a C terminal having an amino acid sequence at least 80% identical to SEQ ID NO: 3, and wherein the polypeptide is capable of binding myostatin, activin A, or GDF-11.