Compositions and methods for enhancing body weight and lean muscle mass using antagonists against leptin receptor, GDF8 and activin A

A method for increasing lean mass and decreasing the proportion of fat mass to lean mass, in a subject in need thereof, comprising administering a therapeutically effective amount of a combination comprising a leptin receptor antagonist in association with a GDF8 antagonist in association with an Activin A antagonist to the subject, wherein:

• the leptin receptor (LEPR) antagonist is an antibody or antigen-binding fragment thereof that binds specifically to LEPR comprising a heavy chain variable region that comprises three heavy chain complementary determining regions (CDR-H1, CDR-H2, CDR-H3) of a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO:1, and a light chain variable region that comprises three light chain complementary determining regions (CDR-L1, CDR-L2, CDR-L3) of a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO:2,
• the growth and differentiation factor-8 (GDF8) antagonist is an antibody or antigen-binding fragment thereof that binds specifically to GDF8 comprising a heavy chain variable region that comprises three heavy chain complementarity determining regions (CDR-H1, CDR-H2, CDR-H3) of a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO:
• 9, and a light chain variable region that comprises three light chain complementary determining regions (CDR-L1, CDR-L2, CDR-L3) of a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO:
• 10;
• and
• the Activin A antagonist is an antibody or antigen-binding fragment thereof that binds specifically to Activin A comprising a heavy chain variable region that comprises three heavy chain complementarity determining regions (CDR-H1, CDR-H2, CDR-H3) of a heavy chain variable region comprising the amino acid sequence as set forth in SEQ ID NO:17, and a light chain variable region that comprises three light chain complementary determining regions (CDR-L1, CDR-L2, CDR-L3) of a light chain variable region comprising the amino acid sequence as set forth in SEQ ID NO:18;
• wherein said increase in lean mass and said decrease in the proportion of fat mass to lean mass in said subject is compared to lean mass and proportion of fat mass to lean mass in said subject prior to said administering.