Antibodies to myostatin

Abstract

The present invention relates to antibodies including human antibodies and antigen-binding portions thereof that bind to myostatin, and that function to inhibit myostatin. The invention also relates to human anti-myostatin antibodies and antigen-binding portions thereof. The invention also relates to antibodies that are chimeric, bispecific, derivatized, single chain antibodies or portions of fusion proteins. The invention also relates to isolated heavy and light chain immunoglobulins derived from human anti-myostatin antibodies and nucleic acid molecules encoding such immunoglobulins. The present invention also relates to methods of making human anti-myostatin antibodies, compositions comprising these antibodies and methods of using the antibodies and compositions for diagnosis and treatment. The invention also provides gene therapy methods using nucleic acid molecules encoding the heavy and/or light immunoglobulin molecules that comprise the human anti-myostatin antibodies. The invention also relates to transgenic animals or plants comprising nucleic acid molecules of the present invention.

1 - 23 . (canceled) 
     
     
         24 . A method for promoting muscle growth in an animal, comprising the step of administering to said animal a monoclonal antibody or an antigen-binding portion thereof that specifically binds to myostatin and inhibits myostatin activity, wherein said antibody or antigen-binding portion has at least one property selected from the group consisting of:
 (a) competes for binding to myostatin with an antibody selected from: 1 — 116 — 1 (PTA-6566); 1 — 136 — 3 (PTA-6568); 1 — 257 — 1 (PTA-6569); 1 — 46 — 1 (PTA-6572); 2 — 112 — 1 (PTA-6574); 1 — 314 — 1 (PTA-6571); 1 — 66 — 1 (PTA-6573); 2 — 43 — 1 (PTA-6575); 2 — 177 — 1 (PTA-6576); 1 — 132 — 1 (PTA-6567); or 1 — 268 — 1 (PTA-6570);   (b) binds to the same epitope of myostatin as an antibody selected from: 1 — 116 — 1 (PTA-6566); 1 — 136 — 3 (PTA-6568); 1 — 257 — 1 (PTA-6569); 1 — 46 — 1 (PTA-6572); 2 — 112 — 1 (PTA-6574); 1 — 314 — 1 (PTA-6571); 1 — 66 — 1 (PTA-6573); 2 — 43 — 1 (PTA-6575); 2 — 177 — 1 (PTA-6576); 1 — 132 — 1 (PTA-6567); or 1 — 268 — 1 (PTA-6570);   (c) binds to myostatin peptide 1 (SEQ ID NO: 103);   (d) binds to myostatin peptide 5 (SEQ ID NO:107); and   (e) is cross-reactive with myostatin peptide 1 (SEQ ID NO: 103) and myostatin peptide 5 (SEQ ID NO:107).   
     
     
         25 . The method of  claim 24 , wherein said antibody or antigen-binding portion selectively binds myostatin over Growth and Differentiation Factor 11 (GDF11) by at least 50-fold. 
     
     
         26 . The method of  claim 24 , wherein said antibody or antigen-binding portion comprises human CDRs. 
     
     
         27 . The method of  claim 24 , wherein said antibody or antigen-binding portion is a non-competitive neutralizing antibody. 
     
     
         28 . The method of  claim 24 , wherein said antibody or antigen-binding portion is chimeric. 
     
     
         29 . The method of  claim 24 , wherein the animal is a chicken or a turkey. 
     
     
         30 . The method of  claim 24 , wherein said antibody or antigen-binding portion comprises
 (a) the amino acid sequences of the heavy chain CDR1, CDR2, and CDR3 included in SEQ ID NO: 45 and the amino acid sequences of the light chain CDR1, CDR2, and CDR3 included in SEQ ID NO: 47;   (b) the amino acid sequences of the heavy chain CDR1, CDR2, and CDR3 included in SEQ ID NO: 49 and the amino acid sequences of the light chain CDR1, CDR2, and CDR3 included in SEQ ID NO: 51;   (c) the amino acid sequences of the heavy chain CDR1, CDR2, and CDR3 included in SEQ ID NO: 53 and the amino acid sequences of the light chain CDR1, CDR2, and CDR3 included in SEQ ID NO: 55;   (d) the amino acid sequences of the heavy chain CDR1, CDR2, and CDR3 included in SEQ ID NO: 57 and the amino acid sequences of the light chain CDR1, CDR2, and CDR3 included in SEQ ID NO: 59;   (e) the amino acid sequences of the heavy chain CDR1, CDR2, and CDR3 included in SEQ ID NO: 61 and the amino acid sequences of the light chain CDR1, CDR2, and CDR3 included in SEQ ID NO: 63;   (f) the amino acid sequences of the heavy chain CDR1, CDR2, and CDR3 included in SEQ ID NO: 65 and the amino acid sequences of the light chain CDR1, CDR2, and CDR3 included in SEQ ID NO: 67;   (g) the amino acid sequences of the heavy chain CDR1, CDR2, and CDR3 included in SEQ ID NO: 69 and the amino acid sequences of the light chain CDR1, CDR2, and CDR3 included in SEQ ID NO: 71;   (h) the amino acid sequences of the heavy chain CDR1, CDR2, and CDR3 included in SEQ ID NO: 73 and the amino acid sequences of the light chain CDR1, CDR2, and CDR3 included in SEQ ID NO: 75;   (i) the amino acid sequences of the heavy chain CDR1, CDR2, and CDR3 included in SEQ ID NO: 77 and the amino acid sequences of the light chain CDR1, CDR2, and CDR3 included in SEQ ID NO: 79;   (j) the amino acid sequences of the heavy chain CDR1, CDR2, and CDR3 included in SEQ ID NO: 81 and the amino acid sequences of the light chain CDR1, CDR2, and CDR3 included in SEQ ID NO: 83;   (k) the amino acid sequences of the heavy chain CDR1, CDR2, and CDR3 included in SEQ ID NO: 85 and the amino acid sequences of the light chain CDR1, CDR2, and CDR3 included in SEQ ID NO: 87; or   (l) the amino acid sequences of the heavy chain CDR1, CDR2, and CDR3 included in SEQ ID NO: 118 and the amino acid sequences of the light chain CDR1, CDR2, and CDR3 included in SEQ ID NO: 120,   wherein said CDR regions have less than 3 conservative amino acid substitutions.   
     
     
         31 . The method of  claim 24 , wherein:
 (a) the heavy chain of said antibody or antigen-binding portion comprises the heavy chain CDR1, CDR2 and CDR3 amino acid sequences of an antibody selected from: 1 — 116 — 1 (PTA-6566); 1 — 136 — 3 (PTA-6568); 1 — 257 — 1 (PTA-6569); 1 — 46 — 1 (PTA-6572); 2 — 112 — 1 (PTA-6574); 1 — 314 — 1 (PTA-6571); 1 — 66 — 1 (PTA-6573); 2 — 43 — 1 (PTA-6575); 2 — 177 — 1 (PTA-6576); 1 — 132 — 1 (PTA-6567); or 1 — 268 — 1 (PTA-6570);   (b) the light chain of said antibody or antigen-binding portion comprises the light chain CDR1, CDR2 and CDR3 amino acid sequences of an antibody selected from: 1 — 116 — 1 (PTA-6566); 1 — 136 — 3 (PTA-6568); 1 — 257 — 1 (PTA-6569); 1 — 46 — 1 (PTA-6572); 2 — 112 — 1 (PTA-6574); 1 — 314 — 1 (PTA-6571); 1 — 66 — 1 (PTA-6573); 2 — 43 — 1 (PTA-6575); 2 — 177 — 1 (PTA-6576); 1 — 132 — 1 (PTA-6567); or 1 — 268 — 1 (PTA-6570); or   (c) said antibody or antigen-binding portion comprises a heavy chain of (a) and a light chain of (b).   
     
     
         32 . The method of  claim 24 , wherein said antibody or antigen-binding portion is selected from the group consisting of:
 (a) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 2 and SEQ ID NO: 4.   (b) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 6 and SEQ ID NO: 8;   (c) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 10 and SEQ ID NO: 12;   (d) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 14 and SEQ ID NO: 16;   (e) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 18 and SEQ ID NO: 20;   (f) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 22 and SEQ ID NO: 24;   (g) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 26 and SEQ ID NO: 28;   (h) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 30 and SEQ ID NO: 32;   (i) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 34 and SEQ ID NO: 36;   (j) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 38 and SEQ ID NO: 40;   (k) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 42 and SEQ ID NO: 44; and   (l) an antibody comprising the amino acid sequences set forth in SEQ ID NO: 115 and SEQ ID NO: 117.   
     
     
         33 . The method of  claim 24 , wherein said antibody or antigen-binding portion is selected from the group consisting of:
 (a) an antibody or antigen-binding portion comprising the variable domain amino acid sequences set forth in SEQ ID NO: 2 and SEQ ID NO: 4.   (b) an antibody or antigen-binding portion comprising the variable domain amino acid sequences set forth in SEQ ID NO: 6 and SEQ ID NO: 8;   (c) an antibody or antigen-binding portion comprising the variable domain amino acid sequences set forth in SEQ ID NO: 10 and SEQ ID NO: 12;   (d) an antibody or antigen-binding portion comprising the variable domain amino acid sequences set forth in SEQ ID NO: 14 and SEQ ID NO: 16;   (e) an antibody or antigen-binding portion comprising the variable domain amino acid sequences set forth in SEQ ID NO: 18 and SEQ ID NO: 20;   (f) an antibody or antigen-binding portion comprising the variable domain amino acid sequences set forth in SEQ ID NO: 22 and SEQ ID NO: 24;   (g) an antibody or antigen-binding portion comprising the variable domain amino acid sequences set forth in SEQ ID NO: 26 and SEQ ID NO: 28;   (h) an antibody or antigen-binding portion comprising the variable domain amino acid sequences set forth in SEQ ID NO: 30 and SEQ ID NO: 32;   (i) an antibody or antigen-binding portion comprising the variable domain amino acid sequences set forth in SEQ ID NO: 34 and SEQ ID NO: 36;   (j) an antibody or antigen-binding portion comprising the variable domain amino acid sequences set forth in SEQ ID NO: 38 and SEQ ID NO: 40;   (k) an antibody or antigen-binding portion comprising the variable domain amino acid sequences set forth in SEQ ID NO: 42 and SEQ ID NO: 44; and   (l) an antibody or antigen-binding portion comprising the variable domain amino acid sequences set forth in SEQ ID NO: 115 and SEQ ID NO: 117.   
     
     
         34 . The method of  claim 24 , wherein said antibody or antigen-binding portion comprises a first CDR sequence set comprising a first CDR1, first CDR2 and first CDR3 and a second CDR sequence set comprising a second CDR1, second CDR2 and second CDR3, wherein said first CDR set and said second CDR set each sequentially together have at least 90% identity to the CDR1, CDR2 and CDR3 sequences, sequentially together, of:
 (a) SEQ ID NO: 2 and SEQ ID NO: 4, respectively;   (b) SEQ ID NO: 6 and SEQ ID NO: 8, respectively;   (c) SEQ ID NO:10 and SEQ ID NO:12, respectively;   (d) SEQ ID NO:14 and SEQ ID NO:16, respectively;   (e) SEQ ID NO:18 and SEQ ID NO:20, respectively;   (f) SEQ ID NO:22 and SEQ ID NO:24, respectively;   (g) SEQ ID NO:26 and SEQ ID NO:28, respectively;   (h) SEQ ID NO:30 and SEQ ID NO:32, respectively;   (i) SEQ ID NO:34 and SEQ ID NO:36, respectively;   (j) SEQ ID NO:38 and SEQ ID NO:40, respectively;   (k) SEQ ID NO:42 and SEQ ID NO:44, respectively; and   (l) SEQ ID NO:115 and SEQ ID NO:117, respectively.   
     
     
         35 . The method of  claim 24 , wherein said antibody or antigen-binding portion comprises a first CDR sequence set comprising a first CDR1, first CDR2 and first CDR3 and a second CDR sequence set comprising a second CDR1, second CDR2 and second CDR3, wherein said first CDR set and said second CDR set are each the CDR1, CDR2 and CDR3 sequences, sequentially together, of:
 (a) SEQ ID NO: 2 and SEQ ID NO: 4, respectively;   (b) SEQ ID NO: 6 and SEQ ID NO: 8, respectively;   (c) SEQ ID NO:10 and SEQ ID NO:12, respectively;   (d) SEQ ID NO:14 and SEQ ID NO:16, respectively;   (e) SEQ ID NO:18 and SEQ ID NO:20, respectively;   (f) SEQ ID NO:22 and SEQ ID NO:24, respectively;   (g) SEQ ID NO:26 and SEQ ID NO:28, respectively;   (h) SEQ ID NO:30 and SEQ ID NO:32, respectively;   (i) SEQ ID NO:34 and SEQ ID NO:36, respectively;   (j) SEQ ID NO:38 and SEQ ID NO:40, respectively;   (k) SEQ ID NO:42 and SEQ ID NO:44, respectively; and   (l) SEQ ID NO:115 and SEQ ID NO:117, respectively.   
     
     
         36 . The method of  claim 24 , wherein said antibody is produced by a cell having ATCC Deposit Designation Number selected from the group consisting of PTA-6566, PTA-6567, PTA-6568, PTA-6569, PTA-6570, PTA-6571, PTA-6572, PTA-6573, PTA-6574, PTA-6575, and PTA-6576. 
     
     
         37 . The method of  claim 24 , wherein said monoclonal antibody or antigen-binding portion binds to myostatin peptide 1 (SEQ ID NO: 103). 
     
     
         38 . The method of  claim 24 , wherein said monoclonal antibody or antigen-binding portion binds to myostatin peptide 5 (SEQ ID NO:107). 
     
     
         39 . The method of  claim 24 , wherein said monoclonal antibody or antigen-binding portion is cross-reactive with myostatin peptide 1 (SEQ ID NO: 103) and myostatin peptide 5 (SEQ ID NO:107). 
     
     
         40 . The method of  claim 24 , wherein said antibody or antigen-binding portion competes for binding to myostatin with an antibody selected from: 1 — 116 — 1 (PTA-6566); 1 — 136 — 3 (PTA-6568); 1 — 257 — 1 (PTA-6569); 1 — 46 — 1 (PTA-6572); 2 — 112 — 1 (PTA-6574); 1 — 314 — 1 (PTA-6571); 1 — 66 — 1 (PTA-6573); 2 — 43 — 1 (PTA-6575); 2 — 177 — 1 (PTA-6576); 1 — 132 — 1 (PTA-6567); or 1 — 268 — 1 (PTA-6570). 
     
     
         41 . The method of  claim 24 , wherein said antibody or antigen-binding portion binds to the same epitope of myostatin as an antibody selected from: 1 — 116 — 1 (PTA-6566); 1 — 136 — 3 (PTA-6568); 1 — 257 — 1 (PTA-6569); 1 — 46 — 1 (PTA-6572); 2 — 112 — 1 (PTA-6574); 1 — 314 — 1 (PTA-6571); 1 — 66 — 1 (PTA-6573); 2 — 43 — 1 (PTA-6575); 2 — 177 — 1_(PTA-6576); 1 — 132 — 1 (PTA-6567); or 1 — 268 — 1 (PTA-6570).