Antibodies that Bind Myostatin, Compositions and Methods

Abstract

There are disclosed selective myostatin antagonists (including antibodies), nucleic acids encoding them, and methods of making and using them.

1 . An isolated myostatin-specific antibody comprising at least one light chain and at least one heavy chain, wherein the light chain comprises a constant region and a variable region that comprises three complementarity determining regions (CDRs) disclosed in SEQ ID NO:39, SEQ ID NO:43, and SEQ ID NO:48, and the heavy chain comprises a constant region and a variable region that comprises three CDRs disclosed in SEQ ID NO:30, SEQ ID NO:33, and SEQ ID NO:36, and the antibody belongs to a subclass IgG1. 
     
     
         2 . (canceled) 
     
     
         3 . The antibody of  claim 1 , wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:13 wherein residue 50 of SEQ ID NO:13 is the amino acid Glutamine. 
     
     
         4 . (canceled) 
     
     
         5 . The isolated myostatin-specific antibody of  claim 1  that binds myostatin with a K d  of less than 100 pM. 
     
     
         6 . The isolated myostatin-specific antibody of  claim 1 , that binds GDF-11 with a K d  of greater than 10 nM. 
     
     
         7 . The isolated myostatin-specific antibody of  claim 1  that binds myostatin with an affinity at least 5,000 times greater than its affinity for GDF-11. 
     
     
         8 . The isolated myostatin-specific antibody of  claim 1  that exhibits selectivity for myostatin that is at least 5,000 times greater than for GDF-11. 
     
     
         9 . The isolated myostatin-specific antibody of  claim 1  that binds myostatin and blocks the interaction of myostatin with ALK4. 
     
     
         10 . The isolated myostatin-specific antibody of  claim 1  that binds myostatin and blocks the interaction of myostatin with ALK4 but co-binds with a myostatin/ActRIIA complex and/or a myostatin/ActRIIB complex. 
     
     
         11 . The isolated myostatin-specific antibody of  claim 1  that binds myostatin, wherein two regions in myostatin that are required for binding of myostatin to the myostatin-specific antibody locate at sequence near position 21 to 31 and position 50 to 60 of mature myostatin (SEQ ID NO:25) 
     
     
         12 . The isolated myostatin-specific antibody of  claim 1  that interacts with two regions in myostatin located at sequence near position 21 to 31 and position 50 to 60 of mature myostatin, so as to prevent chymotrypsin cleavage of peptide bonds within these regions. 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . An isolated nucleic acid encoding the isolated myostatin-specific antibody of  claim 1 . 
     
     
         16 . A vector comprising the nucleic acid of  claim 15 . 
     
     
         17 . An isolated host cell transfected or transformed with the vector of  claim 16 . 
     
     
         18 . A method for the production of a myostatin-specific antibody comprising culturing the host cell of  claim 17  under conditions promoting expression and recovering the myostatin-specific antibody from the culture medium. 
     
     
         19 . A composition comprising the myostatin-specific antibody of  claim 1  and a physiologically acceptable diluent, excipient or carrier. 
     
     
         20 . A method of inhibiting at least one activity of myostatin, comprising administering a composition according to  claim 19  to an individual such that at least one activity of myostatin is partially or fully inhibited. 
     
     
         21 . (canceled)