Antagonist antibodies against GDF-8 and uses therefor
The disclosure provides improved neutralizing anti-GDF-8 antibodies capable of substantially higher levels of expression in host cells compared to previous anti-GDF-8 antibodies. Also provided are methods of using compositions comprising such antibodies to increase muscle mass or strength, and to treat or prevent muscular disorders, neuromuscular disorders, metabolic disorders, adipose tissue disorders or bone disorders.
1. An antibody, or antigen binding fragment thereof, that specifically binds GDF-8, said antibody or fragment comprising:
an antibody variable heavy (VH) region comprising the first, second and third complementarity determining regions (CDR) from the VH region defined by the amino acid sequence of SEQ ID NO:44; and
an antibody variable light (VL) region comprising the first, second and third complementarity determining regions (CDR) from the VL region defined by the amino acid sequence of SEQ ID NO:46;
wherein said VH region comprises leucine at the amino acid position corresponding to residue number 111 of SEQ ID NO:44 (Kabat position 108).
2. The antibody or fragment of claim 1 , wherein VH CDR1 comprises SEQ ID NO:10 or SEQ ID NO:20, VH CDR2 comprises SEQ ID NO:11 or SEQ ID NO:21, VH CDR3 comprises SEQ ID NO:12, VL CDR1 comprises SEQ ID NO:13, VL CDR2 comprises SEQ ID NO:14, and VL CDR3 comprises SEQ ID NO:15.
3. The antibody or fragment of claim 1 , wherein the fourth framework region (FR4) of said VH region comprises amino acids 106-116 of SEQ ID NO:44.
4. The antibody or fragment of claim 1 , wherein said VL region comprises glycine at the amino acid position corresponding to residue number 100 of SEQ ID NO:46 (Kabat position 100).
5. The antibody or fragment of claim 1 , wherein said VL region comprises glycine at the amino acid position corresponding to residue number 100 of SEQ ID NO:46 (kabat position 100).
6. The antibody or fragment of claim 4 , wherein the fourth framework region of said VL region comprises amino acids 98-107 of SEQ ID NO:46.
7. The antibody or fragment of claim 5 , wherein the fourth framework region of said VL region comprises amino acids 98-107 of SEQ ID NO:9.
8. The antibody or fragment of claim 1 , wherein the VH region comprises the amino acid sequence of SEQ ID NO:44.
9. The antibody or fragment of claim 8 , wherein the VL region comprises the amino acid sequence of SEQ ID NO:46.
10. The antibody or fragment of claim 8 , wherein the VL region comprises the amino acid sequence of SEQ ID NO:9.
11. The antibody or fragment of claim 1 , further comprising an antibody constant heavy (CH) region derived from an antibody subtype selected from the group consisting of IgA, IgG, IgD, IgE, or IgM.
12. The antibody or fragment of claim 11 , wherein said IgG subtype is further selected from the group consisting of IgG1, IgG2, IgG3 and IgG4.
13. The antibody or fragment of claim 12 , wherein said IgG subtype is IgG1.
14. The antibody or fragment of claim 12 , wherein said IgG subtype is comprises at least one mutation that alters Fc domain function.
15. The antibody or fragment of claim 11 , wherein the heavy chain of said antibody or fragment comprises the amino acid sequence of SEQ ID NO:57.
16. The antibody or fragment of claim 1 , further comprising an antibody constant light (CL) region.
17. The antibody or fragment of claim 16 , wherein said CL region is a kappa or lambda CL region.
18. The antibody or fragment of claim 16 , wherein the light chain of said antibody or fragment comprises the amino acid sequence of SEQ ID NO:17.
19. The antibody or fragment of claim 8 , wherein said VH region is encoded by the nucleic acid sequence of SEQ ID NO:43.
20. An antibody, or antigen binding fragment thereof, that specifically binds GDF-8, said antibody or fragment comprising: a VH region at least 95% identical to the amino acid sequence of SEQ ID NO:44, and a VL region at least 95% identical to the amino acid sequence of SEQ ID NO:46, wherein said VH region comprises leucine at Kabat position 108.
21. An antibody that specifically binds GDF-8, comprising an antibody heavy chain defined by the amino acid sequence of SEQ ID NO:58 and an antibody light chain defined by the amino acid sequence of SEQ ID NO:59.
22. A pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically acceptable carrier.
23. An isolated polynucleotide comprising a nucleic acid sequence encoding at least one polypeptide chain of an antibody or fragment thereof that specifically binds GDF-8, said antibody or fragment comprising:
an antibody variable heavy (VH) region comprising the first, second and third complementarity determining regions (CDR) from the VH region defined by the amino acid sequence of SEQ ID NO:44,
wherein said VH region comprises leucine at the amino acid position corresponding to residue number 111 of SEQ ID NO:44 (Kabat position 108); and
an antibody variable light (VL) region comprising the first, second and third complementarity determining regions (CDR) from the VL region defined by the amino acid sequence of SEQ ID NO:46,
wherein said VL region comprises glycine at the amino acid position corresponding to residue number 100 of SEQ ID NO:46 (Kabat position 100).
24. A method of increasing the mass or strength of a muscle of a mammal, comprising administering to a mammal an amount of the antibody or antigen binding fragment thereof of claim 1 effective to increase the mass or strength of a muscle of the mammal.