Anti-Activin A Antibodies and Uses Thereof

Abstract

The disclosure provides compositions and methods relating to or derived from anti-activin A binding proteins, including antibodies. In particular embodiments, the disclosure provides fully human, humanized, and chimeric anti-activin A antibodies that bind human activin A, activin A-binding fragments and derivatives of such antibodies, and activin A-binding polypeptides comprising such fragments. Other embodiments provide nucleic acids encoding such antibodies, antibody fragments and derivatives and polypeptides, cells comprising such polynucleotides, methods of making such antibodies, antibody fragments and derivatives and polypeptides, and methods of using such antibodies, antibody fragments and derivatives and polypeptides, including methods of treating or diagnosing subjects having activin A-related disorders or conditions including cachexia related to gonadal cancer, other cancers, rheumatoid arthritis, and other diseases.

1 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and an isolated antigen binding protein that specifically binds a cysteine knot domain in Activin A, wherein the antigen binding protein binds a region selected from the group consisting of amino acids 11-33 of SEQ ID NO:1, amino acids 81-111 of SEQ ID NO:1, and amino acids 11-33 and 81-111 of SEQ ID NO:1. 
     
     
         2 . The composition of  claim 1 , wherein the protein, when bound to a human activin A, inhibits binding of human activin A to human activin A receptor. 
     
     
         3 . The composition of  claim 1 , wherein the antigen binding protein possesses at least one in vivo biological activity of a human anti-Activin A antibody. 
     
     
         4 . The composition of  claim 3 , wherein said biological activity is selected from attenuation of cachexia, attenuating cachexia in colon tumor-bearing mice, ameliorating the loss of body weight in colon tumor-bearing mice, ameliorating the loss of body weight in a collagen-induced animal model of rheumatoid arthritis, ameliorating the loss of muscle mass in a collagen-induced animal model of rheumatoid arthritis, ameliorating the loss of fat mass in a collagen-induced animal model of rheumatoid arthritis, and ameliorating the loss of body weight in a AAV-activin A transfected animal model. 
     
     
         5 . The composition of  claim 1 , wherein the protein is a fully human isolated antibody. 
     
     
         6 . The composition according to  claim 5 , wherein the antibody:
 a) specifically binds to the cysteine knot region (amino acids C11-S33 and/or amino acids C81-E111) of activin A, wherein said antigen binding protein inhibits the binding of activin A to activin A receptor in vitro, or   b) specifically binds to the cysteine knot region (amino acids C11-S33 and/or amino acids C81-E111) of activin A, wherein said antigen binding protein inhibits the binding of activin A to activin A receptor in vivo.   
     
     
         7 . The composition of  claim 1 , wherein the protein is an antibody or antigen binding fragment thereof. 
     
     
         8 . The composition of  claim 7 , wherein the isolated antibody or antigen binding fragment thereof, that when bound to activin A:
 a inhibits activin A;   b. cross-competes with a reference antibody for binding to activin A;   c. binds to the same epitope of activin A as said reference antibody;   d. binds to activin A with substantially the same Kd as said reference antibody; and/or   e. binds to activin A with substantially the smile off rate as said reference antibody; wherein said reference antibody comprises a combination of light chain and heavy chain variable domain sequences of the amino acid sequence set forth in SEQ ID NOS: 9 and 10.   
     
     
         9 . The pharmaceutical composition of  claim 7 , wherein the isolated antibody or antigen binding fragment thereof further comprises a light chain constant sequence of the amino acid sequence set forth in SEQ ID NO: 84 and a heavy chain constant sequence of the amino acid sequence set forth in SEQ ID NO: 214. 
     
     
         10 . The pharmaceutical composition of  claim 7 , wherein the isolated antibody or antigen binding fragment thereof has a binding affinity (K D ) for human activin A of less than or equal to 1×10 −11  M. 
     
     
         11 . The pharmaceutical composition of  claim 7 , wherein the isolated antibody or antigen binding fragment thereof further comprises a light chain constant sequence of the amino acid sequence set forth in SEQ ID NO: 84, 100, or 108, and/or a heavy chain constant sequence of the amino acid sequence set forth in SEQ ID NO: 214, 215, or 221. 
     
     
         12 . The pharmaceutical composition according to  claim 1 , further comprising one or more substances selected from the group consisting of a buffer, an antioxidant, a low molecular weight polypeptide, a protein, an amino acid, a carbohydrate, a chelating agent, and a stabilizer. 
     
     
         13 . The pharmaceutical composition of  claim 7 , wherein the isolated antibody or antigen binding fragment thereof is a fully human antibody. 
     
     
         14 . The pharmaceutical composition of  claim 7 , wherein the isolated antibody or antigen binding fragment thereof is an IgG2 antibody. 
     
     
         15 . The pharmaceutical composition of  claim 7 , wherein the isolated antibody or antigen binding fragment thereof is an IgG2 kappa antibody. 
     
     
         16 . An isolated polynucleotide comprising a sequence that encodes the isolated antigen binding protein, of  claim 1 . 
     
     
         17 . A vector comprising the polynucleotide according to  claim 16 . 
     
     
         18 . The vector according to  claim 17 , which is selected from the group consisting of a plasmid, a viral vector, non-episomal mammalian vector, expression vector and a recombinant expression vector. 
     
     
         19 . An isolated cell comprising a polynulceotide according to  claim 16 . 
     
     
         20 . The isolated cell according to  claim 19 , which is a hybridoma or a Chinese Hamster Ovary (CHO) cell.