Antibodies directed against amyloid-beta peptide and methods using same
Monoclonal antibody 9TL and antibodies derived from 9TL directed against amyloid-beta peptide and methods of using same for diagnosing and treatment of Alzheimer's disease and Aβ peptide associated diseases are described. Methods of using antibodies directed against amyloid-beta peptide having impaired effector function for treatment of Alzheimer's disease and Aβ peptide associated diseases are also described.
1. A method for treating a disease characterized by aberrant deposition of β-amyloid in a subject, comprising administering to the subject an effective amount of an antibody that specifically binds to a β-amyloid peptide or an aggregated form of a β-amyloid peptide(Aβ), wherein the antibody comprises a heavy chain variable region comprising:
(a) a CDR1 comprising the amino acid sequence of SEQ ID NO:3;
(b) a CDR2 comprising the amino acid sequence of SEQ ID NO:4; and
(c) a CDR3 comprising the amino acid sequence of SEQ ID NO:5;
and a light chain variable region comprising:
(d) a CDR1 comprising the amino acid sequence of SEQ ID NO:6;
(e) a CDR2 comprising the amino acid sequence of SEQ ID NO:7; and
(f) a CDR3 comprising the amino acid sequence of SEQ ID NO:8.
2. The method of claim 1 , wherein the subject is a human.
3. The method of claim 1 , wherein the disease is Alzheimer's disease.
4. The method of claim 1 , wherein the antibody is a monoclonal antibody.
5. The method of claim 1 , wherein the antibody is a humanized antibody.
6. The method of claim 1 , wherein the antibody is a human antibody.
7. The method of claim 1 , wherein the antibody binds to the Aβ peptide with a K D of about 100 nM or less.
8. The method of claim 1 , wherein the antibody binds to the Aβ peptide with a K D of about 20 nM or less.
9. The method of claim 1 , wherein the antibody binds to the Aβ peptide with a K D of about 2 nM or less.
10. The method of claim 1 , wherein the antibody binds to the C-terminus of the Aβ peptide.
11. The method of claim 1 , wherein the antibody specifically binds to an epitope within residues 28-40 of Aβ 1-40 , 28-42 of Aβ 1-42 , or 28-43 of Aβ 1-43 .
12. The method of claim 1 , wherein the antibody specifically binds to the C-terminus of the Aβ peptide selected from the group consisting of Aβ 1-36 , Aβ 1-37 , Aβ 1-38 , Aβ 1-39 , Aβ 1-40 , Aβ 1-42 , and Aβ 1-43 .
13. The method of claim 1 , wherein the antibody specifically binds to an epitope on Aβ 1-40 that includes amino acid 39 and/or 40.
14. The method of claim 13 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:1, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:2.
15. The method of claim 1 , wherein the antibody binds to Aβ 1-40 with higher affinity than to Aβ 1-42 or Aβ 1-43 .
16. The method of claim 1 , wherein the Fc region of the antibody is not N-glycosylated or has an N-glycosylation pattern that is altered with respect to a native Fc region.
17. The method of claim 1 , wherein the Fc region of the antibody comprises a mutation within the N-glycosylation recognition sequence, whereby the Fc region is not N-glycosylated.
18. The method of claim 1 , wherein the Fc region of the antibody is the Fc region of a human heavy chain IgG2a comprising the amino acid mutation from alanine to serine at position 330 and from proline to serine at position 331, wherein the amino acid position is based on Kabat numbering with reference to human wildtype IgG2a sequence.
19. The method of claim 1 , wherein the antibody comprises an Fc region having impaired effector function.
20. The method of claim 1 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:1.
21. The method of claim 20 , wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO:2.
22. The antibody of claim 21 wherein the Fc region of the method is the Fc region of a human heavy chain IgG2a comprising the amino acid mutation from alanine to serine at position 330 and from proline to serine at position 331, wherein the amino acid position is based on Kabat numbering with reference to human wildtype IgG2a sequence.
23. The method of claim 1 , wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO:2.
24. The method of claim 1 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:11.
25. The method of claim 24 , wherein the light chain comprises the amino acid sequence of SEQ ID NO:12.
26. The method of claim 1 , wherein the light chain comprises the amino acid sequence of SEQ ID NO:12.
27. The method of claim 1 , wherein the heavy chain variable region amino acid sequence consists of the sequence of SEQ ID NO:1 and wherein the light chain variable region amino acid sequence consists of the sequence of SEQ ID NO:2.
28. The method of claim 1 , wherein the heavy chain amino acid sequence consists of the sequence of SEQ ID NO:11 and wherein the light chain amino acid sequence consists of the sequence of SEQ ID NO:12.
29. The antibody of claim 28 wherein the Fc region of the method is the Fc region of a human heavy chain IgG2a comprising the amino acid mutation from alanine to serine at position 330 and from proline to serine at position 331, wherein the amino acid position is based on Kabat numbering with reference to human wildtype IgG2a sequence.
30. The method of claim 1 , wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO:2.
31. The method of claim 1 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:11.
32. The method of claim 31 , wherein the light chain comprises the amino acid sequence of SEQ ID NO:12.
33. The method of claim 1 , wherein the light chain comprises the amino acid sequence of SEQ ID NO:12.
34. A method for treating a disease associated with aberrant deposition of β-amyloid in a subject, comprising administering to the subject an effective amount of an antibody that specifically binds to a β-amyloid peptide or an aggregated form of a β-amyloid peptide, wherein the antibody comprises an Fc region with a variation from a naturally occurring Fc region, wherein the variation results in impaired effector function, and further wherein the antibody comprises a heavy chain variable region comprising:
(a) a CDR1 comprising the amino acid sequence of SEQ ID NO:3;
(b) a CDR2 comprising the amino acid sequence of SEQ ID NO:4; and
(c) a CDR3 comprising the amino acid sequence of SEQ ID NO:5; and a light chain variable region comprising:
(d) a CDR1 comprising the amino acid sequence of SEQ ID NO:6;
(e) a CDR2 comprising the amino acid sequence of SEQ ID NO:7; and
(f) a CDR3 comprising the amino acid sequence of SEQ ID NO:8.
35. The method of claim 34 , wherein the administration of the antibody with the variation in the Fc region causes less cerebral microhemorrhage than administration of an antibody without the variation.
36. The method of claim 34 , wherein the subject is a human.
37. The method of claim 34 , wherein the disease is Alzheimer's disease.
38. The method of claim 34 , wherein the antibody is a monoclonal antibody.
39. The method of claim 34 , wherein the antibody is a humanized antibody.
40. The method of claim 34 , wherein the antibody is a human antibody.
41. The method of claim 34 , wherein the antibody binds to the Aβ peptide with a K D of about 100 nM or less.
42. The method of claim 34 , wherein the antibody binds to the Aβ peptide with a K D of about 20 nM or less.
43. The method of claim 34 , wherein the antibody binds to the Aβ peptide with a K D of about 2 nM or less.
44. The method of claim 34 , wherein the antibody specifically binds to an epitope within residues 28-40 of Aβ 1-40 , 28-42 of Aβ 1-42 , or 28-43 of Aβ 1-43 .
45. The method of claim 34 , wherein the antibody specifically binds to the C-terminus of the Aβ peptide selected from the group consisting of Aβ 1-36 , Aβ 1-37 , Aβ 1-38 , Aβ 1-39 , Aβ 1-40 , Aβ 1-42 , and Aβ 1-43 .
46. The method of claim 34 , wherein the antibody specifically binds to an epitope on Aβ 1-40 that includes amino acid 39 and/or 40.
47. The method of claim 46 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:1, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:2.
48. The method of claim 34 , wherein the antibody binds to Aβ 1-40 with higher affinity than to Aβ 1-42 or Aβ 1-43 .
49. The method of claim 34 , wherein the Fc region of the antibody is not N-glycosylated or has an N-glycosylation pattern that is altered with respect to a native Fc region.
50. The method of claim 34 , wherein the Fc region of the antibody comprises a mutation within the N-glycosylation recognition sequence, whereby the Fc region is not N-glycosylated.
51. The method of claim 34 , wherein the Fc region of the antibody is the Fc region of a human heavy chain IgG2a comprising the amino acid mutation from alanine to serine at position 330 and from proline to serine at position 331, wherein the amino acid position is based on Kabat numbering with reference to human wildtype IgG2a sequence.
52. The method of claim 34 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:1.
53. The method of claim 52 , wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO:2.
54. The method of claim 34 , wherein the heavy chain variable region amino acid sequence consists of the sequence of SEQ ID NO:1 and wherein the light chain variable region amino acid sequence consists of the sequence of SEQ ID NO:2.
55. The method of claim 34 , wherein the heavy chain amino acid sequence consists of the sequence of SEQ ID NO:11 and wherein the light chain amino acid sequence consists of the sequence of SEQ ID NO:12.
56. A method for treating Alzheimers disease in a subject, comprising administering to the subject an effective amount of an antibody that specifically binds to a β-amyloid peptide, wherein the antibody comprises a heavy chain variable region comprising:
(a) a CDR1 comprising the amino acid sequence of SEQ ID NO:3;
(b) a CDR2 comprising the amino acid sequence of SEQ ID NO:4; and
(c) a CDR3 comprising the amino acid sequence of SEQ ID NO:5; and a light chain variable region comprising:
(d) a CDR1 comprising the amino acid sequence of SEQ ID NO:6;
(e) a CDR2 comprising the amino acid sequence of SEQ ID NO:7; and
(f) a CDR3 comprising the amino acid sequence of SEQ ID NO:8.
57. The method of claim 56 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:1.
58. The method of claim 57 , wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO:2.
59. The antibody of claim 58 wherein the Fc region of the method is the Fc region of a human heavy chain IgG2a comprising the amino acid mutation from alanine to serine at position 330 and from proline to serine at position 331, wherein the amino acid position is based on Kabat numbering with reference to human wildtype IgG2a sequence.
60. The method of claim 56 wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO:2.
61. The method of claim 56 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:11.
62. The method of claim 61 , wherein the light chain comprises the amino acid sequence of SEQ ID NO:12.
63. The method of claim 56 , wherein the light chain comprises the amino acid sequence of SEQ ID NO:12.
64. The method of claim 56 , wherein the heavy chain variable region amino acid sequence consists of the sequence of SEQ ID NO:1 and wherein the light chain variable region amino acid sequence consists of the sequence of SEQ ID NO:2.
65. The antibody of claim 64 wherein the Fc region of the method is the Fc region of a human heavy chain IgG2a comprising the amino acid mutation from alanine to serine at position 330 and from proline to serine at position 331, wherein the amino acid position is based on Kabat numbering with reference to human wildtype IgG2a sequence.
66. The method of claim 56 , wherein the heavy chain amino acid sequence consists of the sequence of SEQ ID NO:11 and wherein the light chain amino acid sequence consists of the sequence of SEQ ID NO:12.
67. The antibody of claim 56 , wherein the method specifically binds to an epitope on Aβ 1-40 that includes amino acid 39 and/or 40.
68. The method of claim 56 , wherein the antibody binds to Aβ 1-40 with higher affinity than to Aβ 1-42 or Aβ 1-43 .