Antibodies against the RGM A protein and uses thereof
View Patent ↗The subject invention relates to isolated proteins, particularly monoclonal antibodies, which bind and neutralize RGM A protein. Specifically, these antibodies have the ability to inhibit the binding of RGM A to its receptor and/or coreceptors. These antibodies or portions thereof of the invention are useful for detecting RGM A and for inhibiting RGM A activity, for example in a human suffering from a disorder including but nor limited to multiple sclerosis, mammalian brain trauma, spinal cord injury, stroke, neurodegenerative diseases, and schizophrenia.
1. An isolated antibody comprising an antigen binding domain, said antibody capable of binding an epitope of a RGM molecule, said antigen binding domain comprising a heavy chain variable domain having three complementary determining regions
and a light chain variable domain having three complementary determining regions, wherein the three complementary determining regions of the heavy chain variable domain have the amino acid sequence of SEQ ID NO:57, SEQ ID NO:58 and SEQ ID NO:59 and the three complementary determining regions of the light chain variable domain have the amino acid sequence of SEQ ID NO: 60, SEQ ID NO:61 and SEQ ID NO:62.
2. The antibody of claim 1 , wherein said antibody further comprises a human acceptor framework, wherein said human acceptor framework comprises at least one amino acid sequence selected from the group consisting of: SEQ ID NO: 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 and 33.
3. An antigen binding fragment of the antibody of claim 1 .
4. A pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically acceptable carrier.
5. A pharmaceutical composition comprising the antibody of claim 2 and a pharmaceutically acceptable carrier.
6. An isolated antibody comprising an antigen binding domain, said antibody capable of binding an epitope of a RGM molecule, said antigen binding domain comprising a heavy chain variable domain having three complementary determining regions and a light chain variable domain having three complementary determining regions, wherein the three complementary determining regions of the heavy chain variable domain have the amino acid sequence of SEQ ID NO:63, SEQ ID NO:64 and SEQ ID NO:65 and the three complementary determining regions of the light chain variable domain have the amino acid sequence of SEQ ID NO: 66, SEQ ID NO:67 and SEQ ID NO:68.
7. The antibody of claim 6 , wherein said antibody further comprises a human acceptor framework, wherein said human acceptor framework comprises at least one amino acid sequence selected from the group consisting of: SEQ ID NO: 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 and 33.
8. An antigen binding fragment of the antibody of claim 6 .
9. A pharmaceutical composition comprising the antibody of claim 6 and a pharmaceutically acceptable carrier.
10. A pharmaceutical composition comprising the antibody of claim 7 and a pharmaceutically acceptable carrier.
11. An isolated antibody comprising an antigen binding domain, said antibody capable of binding an epitope of a RGM molecule, said antigen binding domain comprising a heavy chain variable domain and a light chain variable wherein the heavy chain variable domain has the amino acid sequence selected from the group consisting of: SEQ ID NOS: 35, 36, 37, 38, 39, 40, 41, 42, 43, 47, 48, 49 and 50 and wherein the light chain variable domain has the amino acid sequence selected from the group consisting of SEQ ID NO:44, 45, 46, 51, 52, 53 and 54.
12. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:35 and the light chain variable domain has the amino acid sequence of SEQ ID NO: 44.
13. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:36 and the light chain variable domain has the amino acid sequence of SEQ ID NO: 44.
14. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:37 and the light chain variable domain has the amino acid sequence of SEQ ID NO: 44.
15. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:38 and the light chain variable domain has the amino acid sequence of SEQ ID NO: 44.
16. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:39 and the light chain variable domain has the amino acid sequence of SEQ ID NO: 44.
17. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:40 and the light chain variable domain has the amino acid sequence of SEQ ID NO: 44.
18. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:41 and the light chain variable domain has the amino acid sequence of SEQ ID NO: 44.
19. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:42 and the light chain variable domain has the amino acid sequence of SEQ ID NO: 44.
20. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:43 and the light chain variable domain has the amino acid sequence of SEQ ID NO: 44.
21. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:35 and the light chain variable domain has the amino acid sequence of SEQ ID NO: 45.
22. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:36 and the light chain variable domain has the amino acid sequence of SEQ ID NO: 45.
23. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:37 and the light chain variable domain has the amino acid sequence of SEQ ID NO: 45.
24. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:38 and the light chain variable domain has the amino acid sequence of SEQ ID NO: 45.
25. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:39 and the light chain variable domain has the amino acid sequence of SEQ ID NO: 45.
26. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:40 and the light chain variable domain has the amino acid sequence of SEQ ID NO: 45.
27. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:41 and the light chain variable domain has the amino acid sequence of SEQ ID NO: 45.
28. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:42 and the light chain variable domain has the amino acid sequence of SEQ ID NO: 45.
29. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:43 and the light chain variable domain has the amino acid sequence of SEQ ID NO: 45.
30. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:35 and the light chain variable domain has the amino acid sequence of SEQ ID NO: 46.
31. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:36 and the light chain variable domain has the amino acid sequence of SEQ ID NO: 46.
32. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:37 and the light chain variable domain has the amino acid sequence of SEQ ID NO: 46.
33. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:38 and the light chain variable domain has the amino acid sequence of SEQ ID NO: 46.
34. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:39 and the light chain variable domain has the amino acid sequence of SEQ ID NO: 46.
35. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:40 and the light chain variable domain has the amino acid sequence of SEQ ID NO: 46.
36. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:41 and the light chain variable domain has the amino acid sequence of SEQ ID NO: 46.
37. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:42 and the light chain variable domain has the amino acid sequence of SEQ ID NO: 46.
38. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:43 and the light chain variable domain has the amino acid sequence of SEQ ID NO: 46.
39. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:47 and the light chain variable domain has the amino acid sequence of SEQ ID NO:44.
40. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:47 and the light chain variable domain has the amino acid sequence of SEQ ID NO:45.
41. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:47 and the light chain variable domain has the amino acid sequence of SEQ ID NO:46.
42. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:47 and the light chain variable domain has the amino acid sequence of SEQ ID NO:51.
43. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:47 and the light chain variable domain has the amino acid sequence of SEQ ID NO:52.
44. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:47 and the light chain variable domain has the amino acid sequence of SEQ ID NO:53.
45. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:47 and the light chain variable domain has the amino acid sequence of SEQ ID NO:54.
46. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:48 and the light chain variable domain has the amino acid sequence of SEQ ID NO:44.
47. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:48 and the light chain variable domain has the amino acid sequence of SEQ ID NO:45.
48. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:48 and the light chain variable domain has the amino acid sequence of SEQ ID NO:46.
49. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:48 and the light chain variable domain has the amino acid sequence of SEQ ID NO:51.
50. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:48 and the light chain variable domain has the amino acid sequence of SEQ ID NO:52.
51. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:48 and the light chain variable domain has the amino acid sequence of SEQ ID NO:53.
52. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:48 and the light chain variable domain has the amino acid sequence of SEQ ID NO:54.
53. A pharmaceutical composition comprising the antibody of any one of claims 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 or 52 and a pharmaceutically acceptable carrier.
54. The antibody of claim 1 , wherein the antibody is a monoclonal antibody, a chimeric antibody, a CDR-grafted antibody, a humanized antibody, a multispecific antibody, a dual specific antibody or a bispecific antibody.
55. The antibody of claim 2 , wherein the antibody is a monoclonal antibody, a chimeric antibody, a CDR-grafted antibody, a humanized antibody, a multispecific antibody, a dual specific antibody or a bispecific antibody.
56. The antibody of claim 6 , wherein the antibody is a monoclonal antibody, a chimeric antibody, a CDR-grafted antibody, a humanized antibody, a multispecific antibody, a dual specific antibody or a bispecific antibody.
57. The antibody of claim 7 , wherein the antibody is a monoclonal antibody, a chimeric antibody, a CDR-grafted antibody, a humanized antibody, a multispecific antibody, a dual specific antibody or a bispecific antibody.
58. The antibody of claim 11 , wherein the antibody is a monoclonal antibody, a chimeric antibody, a CDR-grafted antibody, a humanized antibody, a multispecific antibody, a dual specific antibody or a bispecific antibody.
59. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:49 and the light chain variable domain has the amino acid sequence of SEQ ID NO:44.
60. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:50 and the light chain variable domain has the amino acid sequence of SEQ ID NO:44.
61. The antibody of claim 11 , wherein the heavy chain variable donain has the amino acid sequence of SEQ ID NO:49 and the light chain variable domain has the amino acid sequence of SEQ ID NO:45.
62. The antibody of claim 11 , wherein the heavy chain variable donain has the amino acid sequence of SEQ ID NO:50 and the light chain variable domain has the amino acid sequence of SEQ ID NO:45.
63. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:49 and the light chain variable domain has the amino acid sequence of SEQ ID NO:46.
64. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:50 and the light chain variable domain has the amino acid sequence of SEQ ID NO:46.
65. The antibody of claim 11 , wherein the heavy chain variable doamin has the amino acid sequence of SEQ ID NO:50 and the light chain variable domain has the amino acid sequence of SEQ ID NO:51.
66. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:50 and the light chain variable domain has the amino acid sequence of SEQ ID NO:52.
67. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:50 and the light chain variable domain has the amino acid sequence of SEQ ID NO:53.
68. The antibody of claim 11 , wherein the heavy chain variable domain has the amino acid sequence of SEQ ID NO:50 and the light chain variable domain has the amino acid sequence of SEQ ID NO:54.
69. A pharmaceutical composition comprising the antibody of claims 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , or 68 and a pharmaceutical acceptable carrier.