Antibodies directed against amyloid-beta peptide and methods using same

• US 20060057701A1
• Filed: 08/01/2005
• Published: 03/16/2006
• Est. Priority Date: 07/30/2004
• Status: Active Grant

• Current Assignee: Rinat Neuroscience Corp. (Pfizer Inc.)
• Original Assignee: Rinat Neuroscience Corp. (Pfizer Inc.)
• Inventors: Rosenthal, Arnon, Pons, Jaume, Grimm, Jan Markus, Ho, Wei-Hsien
• Granted Patent: US 7,927,594 B2
• Time in Patent Office: Days
• US Class Current: 435/252.300
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/00 Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies antibodies with enzymatic activity, e.g. abzymes C12N9/0002
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/41 Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/52 Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

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.

Claims

1. A method for treating a disease characterized by aberrant deposition of a protein in the brain of a subject, comprising administering to the subject an effective amount of an antibody that specifically binds to the protein or an aggregated form of the protein, wherein the antibody comprises an Fc region having impaired effector function.

2. The method of claim 1, wherein the subject is a human.

3. The method of claim 1, wherein the disease is associated with aberrant deposition of a β

-amyloid peptide.

4. The method of claim 3, wherein the disease is Alzheimer'"'"'s disease.

5. The method of claim 3, wherein the disease is Down'"'"'s syndrome.

6. The method of claim 3, wherein the disease is cerebral amyloid angiopathy.

7. The method of claim 3, wherein the antibody specifically binds to the β

-amyloid (Aβ

) peptide or an aggregated form of the Aβ

peptide

8. The method of claim 7, wherein the antibody is a monoclonal antibody.

9. The method of claim 7, wherein the antibody is a humanized antibody.

10. The method of claim 7, wherein the antibody is a human antibody.

11. The method of claim 7, wherein the antibody binds to the Aβ

peptide with a K_D of about 100 nM or less.

12. The method of claim 7, wherein the antibody binds to the Aβ

peptide with a K_D of about 20 nM or less.

13. The method of claim 7, wherein the antibody binds to the Aβ

peptide with a K_D of about 2 nM or less.

14. The method of claim 7, wherein the antibody binds to the C-terminus of the Aβ

peptide.

15. The method of claim 7, 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.

16. The method of claim 7, 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.

17. The method of claim 7, wherein the antibody specifically binds to an epitope on Aβ

_1-40 that includes amino acid 39 and/or 40.

18. The method of claim 17, wherein the antibody comprises a heavy chain variable region comprising amino acid sequence shown in SEQ ID NO:

1, and a light chain variable region comprising amino acid sequence shown in SEQ ID NO;

2.

19. The method of claim 7, wherein the antibody binds to Aβ

_1-40 with higher affinity than to Aβ

_1-42 or Aβ

_1-43.

20. The method of claim 7, wherein the antibody binds to an epitope on Aβ

_1-40 that includes amino acids 25-34 and 40.

21. The method of claim 20, wherein the antibody comprises a heavy chain variable region comprising amino acid sequence shown in SEQ ID NO:

26, and a light chain variable region comprising amino acid sequence shown in SEQ ID NO;

27.

22. The method of claim 7, wherein the antibody specifically binds to an epitope within residues 1-16 of the Aβ

peptide.

23. The method of claim 7, wherein the antibody specifically binds to the N-terminus of the Aβ

peptide.

24. The method of claim 7, wherein the antibody specifically binds to an epitope within residues 16-28 of the Aβ

peptide.

25. The method of claim 7, 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.

26. The method of claim 7, wherein the Fc region of the antibody comprises a mutation within the N-glycosylation recognition sequence, whereby the Fc region is not N-glycosylated.

27. The method of claim 7, 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.

28. 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.

29. The method of claim 28, 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.

30. The method of claim 28, wherein the subject is a human.

31. The method of claim 28, wherein the disease is Alzheimer'"'"'s disease.

32. The method of claim 28, wherein the antibody is a monoclonal antibody.

33. The method of claim 28, wherein the antibody is a humanized antibody.

34. The method of claim 28, wherein the antibody is a human antibody.

35. The method of claim 28, wherein the antibody binds to the Aβ

peptide with a K_D of about 100 nM or less.

36. The method of claim 28, wherein the antibody binds to the Aβ

peptide with a K_D of about 20 nM or less.

37. The method of claim 28, wherein the antibody binds to the Aβ

peptide with a K_D of about 2 nM or less.

38. The method of claim 28, 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.

39. The method of claim 28, 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.

40. The method of claim 28, wherein the antibody specifically binds to an epitope on Aβ

_1-40 that includes amino acid 39 and/or 40.

41. The method of claim 40, wherein the antibody comprises a heavy chain variable region comprising amino acid sequence shown in SEQ ID NO:

1, and a light chain variable region comprising amino acid sequence shown in SEQ ID NO;

2.

42. The method of claim 28, wherein the antibody binds to Aβ

_1-40 with higher affinity than to Aβ

_1-42 or Aβ

_1-43.

43. The method of claim 28, wherein the antibody binds to an epitope on Aβ

_1-40 that includes amino acids 25-34 and 40.

44. The method of claim 43, wherein the antibody comprises a heavy chain variable region comprising amino acid sequence shown in SEQ ID NO:

26, and a light chain variable region comprising amino acid sequence shown in SEQ ID NO;

27.

45. The method of claim 28, wherein the antibody specifically binds to an epitope within residues 1-16 of the Aβ

peptide.

46. The method of claim 28, wherein the antibody specifically binds to the N-terminus of the Aβ

peptide.

47. The method of claim 28, wherein the antibody specifically binds to an epitope within residues 16-28 of the Aβ

peptide.

48. The method of claim 28, 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.

49. The method of claim 28, wherein the Fc region of the antibody comprises a mutation within the N-glycosylation recognition sequence, whereby the Fc region is not N-glycosylated.

50. The method of claim 28, 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.

51. An antibody comprising a heavy chain variable region comprising:

(a) a CDR1 region shown in SEQ ID NO;

3;

(b) a CDR2 region shown in SEQ ID NO;

4; and

(c) a CDR3 region shown in SEQ ID NO;

5, wherein L1 is L, V, or I;

wherein Y2 is Y or W;

wherein S3 is S, T, or G;

wherein L4 is L, R, A, V, S, T, Q, or E;

wherein V6 is V, I, T, P, C, Q, S, N, or F and wherein Y7 is Y, H, F, W, S, I, V, or A.

wherein the antibody specifically binds to an Aβ

peptide.

52. The antibody of claim 51, wherein the heavy chain variable region comprises:

(a) a CDR1 region shown in SEQ ID NO;

3;

(b) a CDR2 region shown in SEQ ID NO;

4; and

(c) a CDR3 region shown in SEQ ID NO;

5.

53. The antibody of claim 51, wherein the antibody further comprises a light chain variable region.

54. The antibody of claim 51, wherein the antibody is a humanized antibody.

64. The antibody of claim 51, wherein the antibody comprises an Fc region having impaired effector function.

65. The antibody of claim 64, 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.

66. The antibody of claim 64, wherein the Fc region of the antibody comprises a mutation within the N-glycosylation recognition sequence, whereby the Fc region is not N-glycosylated.

67. The antibody of claim 64, 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.

72. A polynucleotide comprising a sequence encoding the antibody of any of claims 51-71.

73. A vector comprising the polynucleotide of claim 72.

74. A host cell comprising the polynucleotide of claim 72.

75. A pharmaceutical composition comprising (a) the antibody of any of claims 51-71, and (b) a pharmaceutically acceptable excipient.

76. A kit comprising the antibody of any of claims 51-71.

77. A method of making an antibody that specifically binds to an Aβ

peptide, said method comprising culturing a host cell comprising the polynucleotide of claim 72 under a condition that the antibody is produced.

78. The method of claim 77, said method further comprising isolating the produced antibody.

55. An antibody comprising a light chain variable region comprising:

(a) a CDR1 region shown in SEQ ID NO;

6, wherein Y8 is Y, A, or H;

wherein A11 is A or S; and

wherein K12 is K or A;

(b) a CDR2 region shown in SEQ ID NO;

7; and

(c) a CDR3 region shown in SEQ ID NO;

8, wherein L1 is L, M, N, C, F, V, K, S, Q, G, S;

wherein G3 is G, S, or T;

wherein T4 is T or S;

wherein H5 is H or L;

wherein Y6 is Y, P, A, W, Q, M, S, or E;

wherein V8 is V, L, K, H, T, A, E, or M; and

wherein L9 is L, I, T, S, or V;

wherein the antibody specifically binds to an Aβ

peptide.

56. The antibody of claim 55, wherein the antibody is a humanized antibody.

57. The antibody of claim 55, wherein the light chain variable region comprises:

(a) a CDR1 region shown in SEQ ID NO;

6;

(b) a CDR2 region shown in SEQ ID NO;

7; and

(c) a CDR3 region shown in SEQ ID NO;

8.

58. The antibody of claim 55, wherein the antibody further comprises a heavy chain variable region.

59. The antibody of claim 57, wherein the antibody further comprises a heavy chain variable region comprising:

(a) a CDR1 region shown in SEQ ID NO;

3;

(b) a CDR2 region shown in SEQ ID NO;

4; and

(c) a CDR3 region shown in SEQ ID NO;

5.

60. The antibody of claim 59, wherein the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:

1.

61. The antibody of claim 59, wherein the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:

2.

62. The antibody of claim 61, wherein the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:

1.

63. The antibody of claim 62, wherein the heavy chain comprises the amino acid sequence shown in SEQ ID NO:

11; and

the light chain comprises the amino acid sequence shown in SEQ ID NO;

12.

68. The antibody of claim 55, wherein the antibody comprises an Fc region having impaired effector function.

69. The antibody of claim 68, 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.

70. The antibody of claim 68, wherein the Fc region of the antibody comprises a mutation within the N-glycosylation recognition sequence, whereby the Fc region is not N-glycosylated.

71. The antibody of claim 68, 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.