Compositions and methods for increasing muscle mass and muscle strength by specifically antagonizing gdf8 and or activin a

Abstract

The present invention provides compositions and methods which involve specifically antagonizing GDF8 and Activin A. In certain embodiments, compositions are provided which comprise a GDF8-specific binding protein and an Activin A-specific binding protein. For example, the invention includes compositions comprising an anti-GDF8 antibody and an anti-Activin A antibody. In other embodiments, antigen-binding molecules are provided which comprise a GDF8-specific binding domain and an Activin A-specific binding domain. For example, the invention includes bispecific antibodies that bind GDF8 and Activin A. The compositions of the present invention are useful for the treatment of diseases and conditions characterized by reduced muscle mass or strength, as well as other conditions which are treatable by antagonizing GDF8 and/or Activin A activity.

1 . A composition comprising a GDF8-specific binding protein and an Activin A-specific binding protein, wherein the GDF8-specific binding protein is an anti-GDF-8 antibody or antigen-binding fragment thereof, and wherein the Activin A-specific binding protein is an anti-Activin A antibody or antigen-binding fragment thereof, wherein the anti-GDF8 antibody or antigen-binding fragment thereof comprises the heavy chain complementarity determining regions (HCDRs) of a heavy chain variable region (HCVR) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1, 9, and 17, and the light chain complementarity determining regions (LCDRs) of a light chain variable region (LCVR) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 5, 13, and 21. 
     
     
         2 . The composition of  claim 1 , wherein the anti-GDF-8 antibody or antigen-binding fragment thereof comprises a heavy and light chain variable region sequence pair (HCVR/LCVR) selected from the group consisting of SEQ ID NOs: 1/5; 9/13; and 17/21. 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         6 . The composition of  claim 1 , wherein the anti-GDF8 antibody or antigen-binding fragment thereof comprises three HCDRs comprising the amino acid sequences selected from the group consisting of SEQ ID NOs: 2/3/4; 10/11/12; and 18/19/20, and three LCDRs comprising the amino acid sequences selected from the group consisting of SEQ ID NOs: 6/7/8; 14/15/16; and 22/23/24. 
     
     
         7 . An antigen-binding molecule comprising a GDF8-specific binding domain and an Activin A-specific binding domain, wherein the GDF8-specific binding domain comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), and wherein the Activin A-specific binding domain comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), wherein the HCVR of the GDF8-specific binding domain comprises three heavy chain complementarity determining regions (HCDRs) comprising the amino acid sequences selected from the group consisting of SEQ ID NOs: 2/3/4; 10/11/12; and 18/19/20, and wherein the LCVR of the GDF8-specific binding domain comprises three light chain complementarity determining regions (LCDRs) comprising the amino acid sequences selected from the group consisting of SEQ ID NOs: 6/7/8; 14/15/16; and 22/23/24. 
     
     
         8 . The antigen-binding molecule of  claim 7 , wherein the HCVR of the GDF8-specific binding domain comprises three heavy chain complementarity determining regions, HCDR1, HCDR2, and HCDR3, and the LCVR of the GDF8-specific binding domain comprises three light chain complementarity determining regions, LCDR1, LCDR2 and LCDR3, wherein the HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3 comprise amino acid sequences selected from the group consisting of SEQ ID NOs: 2/3/4/6/7/8; 10/11/12/14/15/16; and 18/19/20/22/23/24. 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . The antigen-binding molecule of  claim 7 , wherein the antigen-binding molecule is a bispecific antibody. 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . A method for increasing muscle mass or strength in a subject, the method comprising administering to the subject a GDF8-specific binding protein and an Activin A-specific binding protein, wherein the GDF8-specific binding protein is an anti-GDF-8 antibody or antigen-binding fragment thereof, and wherein the Activin A-specific binding protein is an anti-Activin A antibody or antigen-binding fragment thereof, wherein the anti-GDF8 antibody or antigen-binding fragment thereof comprises the heavy chain complementarity determining regions (HCDRs) of a heavy chain variable region (HCVR) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1, 9, and 17, and the light chain complementarity determining regions (LCDRs) of a light chain variable region (LCVR) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 5, 13, and 21. 
     
     
         16 . (canceled) 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . The method of  claim 15 , wherein the anti-GDF8 antibody or antigen-binding fragment thereof comprises the heavy chain complementarity determining regions (HCDRs) of a heavy chain variable region (HCVR), and the light chain complementarity determining regions (LCDRs) of a light chain variable region (LCVR), wherein the heavy and light chain variable region sequence pair (HCVR/LCVR) is selected from the group consisting of SEQ ID NOs: 1/5; 9/13; and 17/21. 
     
     
         20 . The method of  claim 19 , wherein the anti-GDF8 antibody or antigen-binding fragment thereof comprises three HCDRs comprising the amino acid sequences selected from the group consisting of SEQ ID NOs: 2/3/4; 10/11/12; and 18/19/20, and three LCDRs comprising the amino acid sequences selected from the group consisting of SEQ ID NOs: 6/7/8; 14/15/16; and 22/23/24. 
     
     
         21 . A method for increasing muscle mass or strength in a subject, the method comprising administering to the subject an antigen-binding molecule comprising a GDF8-specific binding domain and an Activin A-specific binding domain, wherein the GDF8-specific binding domain comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), and wherein the Activin A-specific binding domain comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), wherein the GDF8-specific binding domain comprises the heavy chain complementarity determining regions (HCDRs) of a heavy chain variable region (HCVR) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1, 9, and 17, and the light chain complementarity determining regions (LCDRs) of a light chain variable region (LCVR) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 5, 13, and 21. 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . The method of  claim 21 , wherein the HCVR of the GDF8-specific binding domain comprises three heavy chain complementarity determining regions, HCDR1, HCDR2, HCDR3, and wherein the LCVR of the GDF8-specific binding domain comprises three light chain complementarity determining regions, LCDR1, LCDR2, LCDR3, wherein the HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3 comprise amino acid sequences selected from the group consisting of SEQ ID NOs: 2/3/4/6/7/8; 10/11/12/14/15/16; and 18/19/20/22/23/24. 
     
     
         25 . (canceled) 
     
     
         26 . The method of  claim 24 , wherein the antigen-binding molecule is a bispecific antibody. 
     
     
         27 . (canceled) 
     
     
         28 . A method for treating a disease or disorder characterized by decreased muscle mass or strength, the method comprising administering to a subject in need thereof a GDF8-specific binding protein and an Activin A-specific binding protein, wherein the GDF8-specific binding protein is an anti-GDF-8 antibody or antigen-binding fragment thereof, and wherein the Activin A-specific binding protein is an anti-Activin A antibody or antigen-binding fragment thereof, wherein the anti-GDF8 antibody or antigen-binding fragment thereof comprises the heavy chain complementarity determining regions (HCDRs) of a heavy chain variable region (HCVR) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1, 9, and 17, and the light chain complementarity determining regions (LCDRs) of a light chain variable region (LCVR) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 5, 13, and 21. 
     
     
         29 . A method for treating a disease or disorder characterized by decreased muscle mass or strength, the method comprising administering to a subject in need thereof an antigen-binding molecule comprising a GDF8-specific binding domain and an Activin A-specific binding domain, wherein the GDF8-specific binding domain comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), and wherein the Activin A-specific binding domain comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), wherein the GDF8-specific binding domain comprises the heavy chain complementarity determining regions (HCDRs) of a heavy chain variable region (HCVR) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1, 9, and 17, and the light chain complementarity determining regions (LCDRs) of a light chain variable region (LCVR) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 5, 13, and 21. 
     
     
         30 . The method of  claim 28 , wherein the anti-GDF-8 antibody or antigen-binding fragment thereof comprises a heavy and light chain variable region sequence pair (HCVR/LCVR) selected from the group consisting of SEQ ID NOs: 1/5; 9/13; and 17/21. 
     
     
         31 . The method of  claim 30 , wherein the anti-GDF8 antibody or antigen-binding fragment thereof comprises three HCDRs comprising the amino acid sequences selected from the group consisting of SEQ ID NOs: 2/3/4; 10/11/12; and 18/19/20, and three LCDRs comprising the amino acid sequences selected from the group consisting of SEQ ID NOs: 6/7/8; 14/15/16; and 22/23/24.