Anti-activin a antibodies and uses thereof

Abstract

The present invention provides antibodies that bind to Activin A and methods of using the same. According to certain embodiments of the invention, the antibodies are fully human antibodies that bind to Activin A with high affinity. The antibodies of the invention are useful for the treatment of diseases and disorders characterized by decreased muscle mass or strength, such as sarcopenia, cachexia, muscle injury, muscle wasting/atrophy, cancer, fibrosis, and weight loss. The antibodies of the invention are also useful in combination with Growth and Differentiation Factor 8 (GDF8) binding proteins for the treatment of diseases and disorders characterized by decreased muscle mass or strength. The antibodies of the invention are also useful for the prevention, treatment, or amelioration of disorders and diseases caused by, promoted by, exacerbated by, and/or aggravated by Activin A, such as renal fibrosis.

1 . An isolated antibody or antigen-binding fragment thereof that specifically binds Activin A with a binding dissociation equilibrium constant (K D ) of less than about 5 pM as measured in a surface plasmon resonance assay at 25° C., wherein the Activin A-specific binding domain comprises: (a) the complementarity determining regions (CDRs) of a HCVR having an amino acid sequence of SEQ ID NO: 162 or which differs from SEQ ID NO: 162 by a single conservative amino acid substitution; and (b) the CDRs of a LCVR having an amino acid sequence of SEQ ID NO: 146 or which differs from SEQ ID NO: 146 by a single conservative amino acid substitution. 
     
     
         2 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the isolated antibody or antigen-binding fragment thereof specifically binds Activin A with a K D  of less than about 4 pM as measured in a surface plasmon resonance assay at 25° C. 
     
     
         3 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the isolated antibody or antigen-binding fragment thereof specifically binds Activin A with a binding association equilibrium constant (K a ) of less than about 500 nM. 
     
     
         4 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof blocks binding of at least one Activin A receptor to Activin A. 
     
     
         5 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof blocks activation of at least one Activin A receptor by Activin A. 
     
     
         6 . The isolated antibody or antigen-binding fragment thereof of  claim 5 , wherein the antibody or antigen-binding fragment thereof does not significantly block binding of Activin A to an Activin Type II receptor. 
     
     
         7 . The isolated antibody or antigen-binding fragment thereof of  claim 4 , wherein the antibody or antigen-binding fragment thereof blocks Activin A binding to an Activin A receptor with an IC 50  value of less than about 80 pM as measured in an in vivo receptor/ligand binding bioassay at 25° C. 
     
     
         8 . The isolated antibody or antigen-binding fragment thereof of  claim 7 , wherein the antibody or antigen-binding fragment thereof blocks Activin A binding to an Activin A receptor with an IC 50  value of less than about 60 pM as measured in an in vivo receptor/ligand binding bioassay at 25° C. 
     
     
         9 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof inhibits binding of Activin A to an Activin A receptor selected from the group consisting of Activin Type IIA receptor (ActRIIA), Activin Type IIB receptor (ActRIIB), and Activin Type I receptor. 
     
     
         10 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof inhibits Activin A-mediated activation of SMAD complex signaling. 
     
     
         11 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof competes for binding to Activin A with a reference antibody comprising a heavy chain variable region (HCVR)/light chain variable region (LCVR) amino acid sequence pair selected from the group consisting of SEQ ID NOs: 2/10, 138/146, and 194/146. 
     
     
         12 . The isolated antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof binds to the same epitope on Activin A as a reference antibody comprising an HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NOs: 2/10, 138/146, and 194/146. 
     
     
         13 . An isolated antibody or antigen-binding fragment thereof that specifically binds Activin A, wherein the antibody or antigen-binding fragment comprises: (a) the complementarity determining regions (CDRs) of a HCVR having an amino acid sequence of SEQ ID NO: 162 or which differs from SEQ ID NO: 162 by a single conservative amino acid substitution; and (b) the CDRs of a LCVR having an amino acid sequence of SEQ ID NO: 146 or which differs from SEQ ID NO: 146 by a single conservative amino acid substitution. 
     
     
         14 . The isolated antibody or antigen-binding fragment thereof of  claim 13 , wherein the antibody or antigen-binding fragment comprises the heavy and light chain CDRs of a HCVR/LCVR amino acid sequence pair consisting of: SEQ ID NOs: 162/146 or wherein one of SEQ ID NO: 162 or SEQ ID NO: 146 differs by a single conservative amino acid substitution. 
     
     
         15 . The isolated antibody or antigen-binding fragment thereof of  claim 13 , wherein the antibody or antigen-binding fragment thereof comprises six complementarity determining region (CDR) domains: HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 domains, respectively, having the amino acid sequences of: SEQ ID NOs: 164-166-168-148-150-152 or wherein one of the CDR domains differs by a single conservative amino acid substitution. 
     
     
         16 . An isolated antibody or antigen-binding fragment thereof that specifically binds Activin A, wherein the antibody or antigen-binding fragment comprises: (a) a HCVR having an amino acid sequence of SEQ ID NO: 162 or which differs from SEQ ID NO: 162 by a single conservative amino acid substitution; and (b) a LCVR having an amino acid sequence of SEQ ID NO: 146 or which differs from SEQ ID NO: 146 by a single conservative amino acid substitution. 
     
     
         17 . The isolated antibody or antigen-binding fragment thereof of  claim 16 , wherein the antibody or antigen-binding fragment comprises a HCVR/LCVR amino acid sequence pair of: SEQ ID NOs: 162/146 or wherein one of SEQ ID NO: 162 or SEQ ID NO: 146 differs by a single conservative amino acid substitution. 
     
     
         18 . A pharmaceutical composition comprising the antibody or antigen-binding fragment of  claim 1 , and a pharmaceutically acceptable carrier or diluent. 
     
     
         19 . A method for increasing muscle mass or strength in a subject, the method comprising administering to the subject the pharmaceutical composition of  claim 18 . 
     
     
         20 . A pharmaceutical composition comprising the antibody or antigen-binding fragment of  claim 1 , a GDF8 antagonist, and a pharmaceutically acceptable carrier or diluent. 
     
     
         21 . The pharmaceutical composition of  claim 20 , wherein GDF8 antagonist is selected from the group consisting of a GDF8-inhibiting fusion protein, an anti-GDF8 antibody, and an antigen-binding fragment of an anti-GDF8 antibody. 
     
     
         22 . The method of  claim 19 , further comprising the administration of a GDF8 antagonist, wherein the GDF8 antagonist is an anti-GDF8 antibody or antigen-binding fragment thereof. 
     
     
         23 . The method of  claim 22 , wherein the GDF8 antagonist is an anti-GDF8 antibody or antigen-binding fragment thereof comprising the heavy chain complementarity determining regions (HCDRs) of a HCVR comprising SEQ ID NO:217, and the light chain complementarity determining regions (LCDRs) of a LCVR comprising SEQ ID NO:221. 
     
     
         24 . The method of  claim 22 , wherein the GDF8 antagonist is an anti-GDF8 antibody or antigen-binding fragment thereof comprising:
 a) three HCDRs comprising SEQ ID NO:218, SEQ ID NO:219, and SEQ ID NO:220, and   b) three LCDRs comprising SEQ ID NO:222, SEQ ID NO:223, and SEQ ID NO:224.   
     
     
         25 . A method for increasing muscle mass or strength in a subject, the method comprising administering to the subject the pharmaceutical composition of  claim 20 . 
     
     
         26 . A method for increasing muscle mass or strength in a subject, the method comprising administering to the subject an antigen-binding molecule comprising an Activin A-specific binding domain and a GDF8-specific binding domain. 
     
     
         27 . The method of  claim 26 , wherein the Activin A-specific binding domain comprises a HCVR and a LCVR. 
     
     
         28 . The method of  claim 26 , wherein the GDF8-specific binding domain comprises a HCVR and a LCVR. 
     
     
         29 . The method of  claim 27 , wherein the HCVR comprises:
 (a) the CDRs of a HCVR having an amino acid sequence of SEQ ID NO: 162 or which differs from SEQ ID NO: 162 by a single conservative amino acid; and   (b) the CDRs of a LCVR having an amino acid sequence SEQ ID NO: 146 or which differs from SEQ ID NO: 146 by a single conservative amino acid.   
     
     
         30 . The method of  claim 28 , wherein the HCVR comprises three heavy chain complementarity determining regions (HCDRs) comprising SEQ ID NO:218, SEQ ID NO:219, and SEQ ID NO:220, and wherein the LCVR comprises three light chain complementarity determining regions (LCDRs) comprising SEQ ID NO:222, SEQ ID NO:223, and SEQ ID NO:224. 
     
     
         31 . The method of  claim 26 , wherein the Activin A-specific binding domain comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), and wherein the GDF8-specific binding domain comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR). 
     
     
         32 . The method of  claim 26 , wherein the antigen-binding molecule is a bispecific antibody. 
     
     
         33 . A method for treating, preventing or ameliorating a disease or disorder characterized by decreased muscle mass or strength, the method comprising administering to a subject in need thereof an Activin A-specific binding protein. 
     
     
         34 . A method for treating, preventing or ameliorating a disease or disorder characterized by decreased muscle mass or strength, the method comprising administering to a subject in need thereof an Activin A-specific binding protein and a GDF8-specific binding protein. 
     
     
         35 . The method of  claim 34 , wherein the disease or disorder characterized by decreased muscle mass or strength is selected from the group consisting of sarcopenia, cachexia, muscle injury, muscle wasting/atrophy, cancer, obesity, diabetes, arthritis, multiple sclerosis, muscular dystrophy, amyotrophic lateral sclerosis, Parkinson's disease, osteoporosis, osteoarthritis, osteopenia, and a metabolic syndrome. 
     
     
         36 . The method of  claim 35 , wherein the cachexia is idiopathic or is cachexia secondary to another condition. 
     
     
         37 . The method of  claim 36 , wherein the condition is cancer, chronic renal failure, or chronic obstructive pulmonary disease. 
     
     
         38 . The method of  claim 35 , wherein the muscle wasting/atrophy is caused by or associated with a condition selected from the group consisting of disuse, immobilization, bed rest, injury, medical treatment, surgical intervention and by necessity of mechanical ventilation. 
     
     
         39 . The method of  claim 38 , wherein the surgical intervention is selected from the group consisting of hip fracture, hip replacement, and knee replacement. 
     
     
         40 . The method of  claim 35 , wherein the metabolic syndrome includes a disease or disorder selected from the group consisting of diabetes, obesity, nutritional disorders, organ atrophy, chronic obstructive pulmonary disease, and anorexia. 
     
     
         41 . A method for treating, preventing or ameliorating 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 an Activin A-specific binding domain and a GDF8-specific binding domain. 
     
     
         42 . A method for treating, preventing or ameliorating a disease or disorder that is caused by, promoted by, exacerbated by, or aggravated by Activin A activity, the method comprising administering to a subject in need thereof an Activin A antibody or antigen-binding fragment thereof. 
     
     
         43 . The method of  claim 42 , wherein the disease or disorder is renal fibrosis. 
     
     
         44 . The method of  claim 42 , wherein the disease or disorder is cachexia.