Anti-myostatin antibodies, polypeptides containing variant Fc regions, and methods of use
The disclosure provides anti-myostatin antibodies and methods of making and using the same. Nucleic acids encoding the anti-myostatin antibodies and host cells comprising the nucleic acids are also provided. The anti-myostatin antibodies have uses that include treating a muscle wasting disease, reducing body fat accumulation, and increasing mass and strength of muscle tissue. The disclosure also provides polypeptides containing a variant Fc region and methods of making and using the same. Nucleic acids encoding the polypeptides and host cells comprising the nucleic acids are also provided. The polypeptides have uses that include suppressing the activation of immune cells; treating an immunological inflammatory disease, autoimmune disease, or viral infection; and increasing muscle mass and strength or reducing body fat accumulation.
1. An isolated antibody that binds to latent myostatin, wherein the antibody comprises:
(a) a HVR-H1 comprising the amino acid sequence X 1 X 2 DIS (SEQ ID NO: 126), wherein X 1 is S or H, X 2 is Y, T, D or E;
(b) a HVR-H2 comprising the amino acid sequence IISX 1 AGX 2 X 3 YX 4 X 5 X 6 W AKX 7 (SEQ ID NO: 127), wherein X 1 is Y or H, X 2 is S or K, X 3 is T, M or K, X 4 is Y or K, X 5 is A, M or E, X 6 is S or E, X 7 is G or K;
(c) a HVR-H3 comprising the amino acid sequence GVPAX 1 SX 2 GGDX 3 (SEQ ID NO: 128), wherein X 1 is Y or H, X 2 is T or H, X 3 is L or K;
(d) a HVR-L1 comprising the amino acid sequence X 1 X 2 SQX 3 VX 4 X 5 X 6 NWLS (SEQ ID NO: 129), wherein X 1 is Q or T, X 2 is S or T, X 3 is S or E, X 4 is Y or F, X 5 is D or H, X 6 is N, D, A or E;
(e) a HVR-L2 comprising the amino acid sequence WAX 1 TLAX 2 (SEQ ID NO: 130), wherein X 1 is S or E, X 2 is S, Y, F or W (SEQ ID NO: 130); and
(f) a HVR-L3 comprising the amino acid sequence AGGYGGGX 1 YA (SEQ ID NO: 131), wherein X 1 is L or R.
2. The antibody of claim 1 , wherein,
(a) the antibody of claim 1 further comprises a heavy chain variable domain framework FR1 comprising the amino acid sequence of SEQ ID NO: 132, 133, or 134; FR2 comprising the amino acid sequence of SEQ ID NO: 135 or 136; FR3 comprising the amino acid sequence of SEQ ID NO: 137; and FR4 comprising the amino acid sequence of SEQ ID NO: 138; or
(b) the antibody of claim 1 further comprises a light chain variable domain framework FR1 comprising the amino acid sequence of SEQ ID NO: 139; FR2 comprising the amino acid sequence of SEQ ID NO: 140 or 141; FR3 comprising the amino acid sequence of SEQ ID NO: 142 or 143; and FR4 comprising the amino acid sequence of SEQ ID NO: 144.
3. The antibody of claim 1 , which is a full length IgG antibody.
4. The antibody of claim 3 , wherein the IgG antibody is IgG1, IgG2, IgG3 or IgG4.
5. The antibody of claim 4 wherein the IgG antibody is IgG1.
6. The antibody of claim 1 , which comprises a variant Fc region amino acid sequence of SEQ ID NO: 229-380, or 381.
7. A pharmaceutical formulation comprising the antibody of claim 1 and a pharmaceutically acceptable carrier.
8. An isolated antibody that binds to latent myostatin, comprising (a) a VH sequence of SEQ ID NO: 13, 16-30, 32-34, 86-94, or 95; and (b) a VL sequence of SEQ ID NO:15, 31, 35-38, 96-98, or 99.
9. The antibody of claim 8 , further comprising a variant Fc region amino acid sequence of SEQ ID NO: 229-380, or 381.
10. The antibody of claim 8 , which is a full length IgG antibody.
11. The antibody of claim 10 , wherein the IgG antibody is IgG1, IgG2, IgG3 or IgG4.
12. The antibody of claim 11 , wherein the IgG antibody is IgG1.
13. A pharmaceutical composition comprising the antibody of claim 8 and a pharmaceutically acceptable carrier.
14. An isolated antibody that binds to latent myostatin, wherein the antibody comprises a VH and VL pair selected from the group consisting of:
(a) a VH of SEQ ID NO: 87 and a VL of SEQ ID NO: 96;
(b) a VH of SEQ ID NO: 88 and a VL of SEQ ID NO: 96;
(c) a VH of SEQ ID NO: 89 and a VL of SEQ ID NO: 96;
(d) a VH of SEQ ID NO: 90 and a VL of SEQ ID NO: 96;
(e) a VH of SEQ ID NO: 91 and a VL of SEQ ID NO: 96;
(f) a VH of SEQ ID NO: 93 and a VL of SEQ ID NO: 97;
(g) a VH of SEQ ID NO: 94 and a VL of SEQ ID NO: 97;
(h) a VH of SEQ ID NO: 86 and a VL of SEQ ID NO: 98; and
(i) a VH of SEQ ID NO: 95 and a VL of SEQ ID NO: 97.
15. The antibody of claim 14 , which is a full length IgG antibody.
16. The antibody of claim 15 , wherein the IgG antibody is IgG1, IgG2, IgG3 or IgG4.
17. The antibody of claim 16 , wherein the IgG antibody is IgG1.
18. The antibody of claim 14 , which comprises a variant Fc region amino acid sequence of SEQ ID NO: 229-380, or 381.
19. A pharmaceutical composition comprising the antibody of claim 14 and a pharmaceutically acceptable carrier.
20. An isolated antibody that binds to latent myostatin and comprises a VH of SEQ ID NO: 86 and a VL of SEQ ID NO: 96.
21. The antibody of claim 20 , which is a full length IgG antibody.
22. The antibody of claim 21 , wherein the IgG antibody is IgG1, IgG2, IgG3 or IgG4.
23. The antibody of claim 22 , wherein the IgG antibody is IgG1.
24. The antibody of claim 20 , which comprises a variant Fc region amino acid sequence of SEQ ID NO: 229-380, or 381.
25. A pharmaceutical composition comprising the antibody of claim 20 and a pharmaceutically acceptable carrier.
26. An isolated antibody that binds to latent myostatin and comprises a VH of SEQ ID NO: 92 and a VL of SEQ ID NO: 97.
27. The antibody of claim 26 , which is a full length IgG antibody.
28. The antibody of claim 27 , wherein the IgG antibody is IgG1, IgG2, IgG3 or IgG4.
29. The antibody of claim 28 , wherein the IgG antibody is IgG1.
30. The antibody of claim 26 , further comprising a variant Fc region amino acid sequence of SEQ ID NO: 229-380, or 381.
31. A pharmaceutical composition comprising the antibody of claim 26 and a pharmaceutically acceptable carrier.
32. An isolated antibody that binds to latent myostatin, wherein the antibody comprises:
(a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 114;
(b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 58;
(c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63;
(d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122 or 123;
(e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and
(f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 74.
33. The antibody of claim 32 , wherein the antibody comprises:
(a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 114;
(b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 58;
(c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63;
(d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122;
(e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and
(f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 74.
34. The antibody of claim 32 , wherein the antibody comprises:
(a) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 114;
(b) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 58;
(c) a HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63;
(d) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 123;
(e) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and
(f) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 74.
35. The antibody of claim 32 , wherein the antibody comprises the VH of SEQ ID NO: 92.
36. The antibody of claim 32 , wherein the antibody comprises the VH of SEQ ID NO: 86.
37. The antibody of claim 32 , wherein the antibody comprises the VL of SEQ ID NO: 96.
38. The antibody of claim 32 , wherein the antibody comprises the VL of SEQ ID NO: 97.
39. The antibody of claim 32 , which is a full length IgG antibody.
40. The antibody of claim 39 , wherein the IgG antibody is IgG1, IgG2, IgG3 or IgG4.
41. The antibody of claim 40 wherein the IgG antibody is IgG1.
42. The antibody of claim 32 , which comprises a variant Fc region amino acid sequence of SEQ ID NO: 229-380, or 381.
43. A pharmaceutical composition comprising the antibody of claim 32 and a pharmaceutically acceptable carrier.