Immunogenic peptide composition for the prevention and treatment of Altzheimers Disease

• US 20030068325A1
• Filed: 05/25/2001
• Published: 04/10/2003
• Est. Priority Date: 05/25/2001
• Status: Active Grant

• Current Assignee: United Neuroscience Ltd. (Vaxxinity, Inc.)
• Original Assignee: United Biomedical, Inc.
• Inventors: Wang, Chang Yi
• Granted Patent: US 6,906,169 B2
• Time in Patent Office: Days
• US Class Current: 424/185.1
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• 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 37/04 Immunostimulants
• CPC Class Codes: C07K 14/4711 Alzheimer's disease; Amyloid plaque core protein
• CPC Class Codes: Y10S 530/806 Antigenic peptides or proteins
• CPC Class Codes: Y10S 530/81 Carrier - bound or immobilized peptides or proteins and the preparation thereof, e.g. biological cell or cell fragment as carrier

Abstract

The present invention relates to a composition comprsing a peptide immunogen useful for the prevention and treatment of Alzheimer'"'"'s Disease. More particularly, the peptide immunogen comprises a main functional/regulatory site, an N-terminal fragment of Amyloid β (Aβ) peptide linked to a helper T cell epitope (Th) having multiple class II MHC binding motifs. The peptide immunogen elicit a site-directed immune response against the main functional/regulatory site of the Aβ peptide and generate antibodies, which are highly cross-reactive to the soluble Aβ_1-42 peptide and the amyloid plaques formed in the brain of Alzheimer'"'"'s Disease patients. The antibodies elicited being cross reactive to the soluble Aβ_1-42 peptide, promote fibril disaggregation and inhibit fibrillar aggregation leading to immunoneutralization of the “soluble Aβ-derived toxins”; and being cross-reactive to the amyloid plaques, accelerate the clearance of these plaques from the brain. Thus, the composition of the invention comprising the peptide immunogen is useful for the prevention and treatment of Alzheimer'"'"'s Disease.

Claims

1. A peptide immunogen of about 20 to 100 amino acids long comprising:

(i) a helper T cell (Th) epitope selected from the group consisting of SEQ ID Nos;

1 to 64;

(ii) an N-terminal fragment of Aβ

_1-42 peptide, SEQ ID NO;

65, consisting of from 10 to 28 amino acid residues wherein each fragment comprises amino acid residue 1 of the Aβ

_1-42 peptide or an immunologically functional analog of the N-teminal fragment of Aβ

_1-42 peptide; and

(iii) optionally a spacer consisting of at least an amino acid to separate the immunogenic domains.

2. A peptide immunogen of claim 1, wherein the spacer is selected from the group consisting of an amino acid, Gly-Gly, ((α

, ε

-N)-Lys, and Pro-Pro-Xaa-Pro-Xaa-Pro (SEQ ID NO;

73).

3. A peptide immunogen of claim 2, wherein the spacer is Gly-Gly.

4. A peptide immunogen of claim 2, wherein the spacer is ε

-N-Lys.

5. A peptide immunogen of claim 1, wherein the N-terminal fragment of Aβ

_1-42 peptide is selected from the group consisting of SEQ ID NOs;

66-69 and an immunologically functional analog thereof.

6. A peptide immunogen of any one of claims 2, 3, or 4, wherein the N-terminal fragment of Aβ

_1-42 peptide is selected from the group consisting of SEQ ID NOs;

66-69 and an immunologically functional analog thereof.

7. A peptide immunogen of claim 1, wherein Th is selected from the group consisting of SEQ ID NOs:

1, 3, 4, 5, 6, 7, 8, 9, 20, 38-40, 47-51 and 52-54.

8. A peptide immunogen of any one of claims 2, 3, or 4, wherein Th is selected from the group consisting of SEQ ID NOs:

1, 3, 4, 5, 6, 7, 8, 9, 20, 38-40, 47-51 and 52-54.

21. A composition comprising a pepetide immunogen of claim 1 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, liposyn, saponin, squalene, L121, emulsigen monophosphyryl lipid A (MPL), polysorbate 80, QS21, Montamide ISA51, ISA35, ISA206 and ISA 720.

22. A composition comprising a pepetide immunogen of claim 2 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, liposyn, saponin, squalene, L121, emulsigen monophosphyryl lipid A (MPL), polysorbate 80, QS21, Montamide ISA51, ISA35, ISA206 and ISA 720.

23. A composition comprising a pepetide immunogen of claim 3 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, liposyn, saponin, squalene, L121, emulsigen monophosphyryl lipid A (MPL), polysorbate 80, QS21, Montamide ISA51, ISA35, ISA206 and ISA 720.

24. A composition comprising a pepetide immunogen of claim 4 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, liposyn, saponin, squalene, L121, emulsigen monophosphyryl lipid A (MPL), polysorbate 80, QS21, Montamide ISA51, ISA35, ISA206 and ISA 720.

25. A composition comprising a pepetide immunogen of claim 5 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, liposyn, saponin, squalene, L121, emulsigen monophosphyryl lipid A (MPL), polysorbate 80, QS21, Montamide ISA51, ISA35, ISA206 and ISA 720.

26. A composition comprising a pepetide immunogen of claim 6 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, liposyn, saponin, squalene, L121, emulsigen monophosphyryl lipid A (MPL), polysorbate 80, QS21, Montamide ISA51, ISA35, ISA206 and ISA 720.

27. A composition comprising a pepetide immunogen of claim 7 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, liposyn, saponin, squalene, L121, emulsigen monophosphyryl lipid A (MPL), polysorbate 80, QS21, Montamide ISA51, ISA35, ISA206 and ISA 720.

28. A composition comprising a pepetide immunogen of claim 8 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, liposyn, saponin, squalene, L121, emulsigen monophosphyryl lipid A (MPL), polysorbate 80, QS21, Montamide ISA51, ISA35, ISA206 and ISA 720.

41. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 21.

42. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 22.

43. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 23.

44. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 24.

45. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 25.

46. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 26.

47. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 27.

48. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 28.

61. A method of producing antibodies to Aβ

_1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 21.

62. A method of producing antibodies to Aβ

_1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 22.

63. A method of producing antibodies to Aβ

_1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 23.

64. A method of producing antibodies to Aβ

_1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 24.

65. A method of producing antibodies to Aβ

_1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 25.

66. A method of producing antibodies to Aβ

_1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 26.

67. A method of producing antibodies to Aβ

_1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 27.

68. A method of producing antibodies to Aβ

_1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 28.

9. A peptide immunogen selected from the group consisting of SEQ ID NOs:

70, 71, 72, 73, and 74.

10. A peptide immunogen of claim 9 consisting of SEQ ID NO:

73.

11. A peptide immunogen of claim 9 consisting of SEQ ID NO:

74.

29. A composition comprising a pepetide immunogen of claim 9 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, liposyn, saponin, squalene, L121, emulsigen monophosphyryl lipid A (MPL), polysorbate 80, QS21, Montamide ISA51, ISA35, ISA206 and ISA 720.

30. A composition comprising a pepetide immunogen of claim 10 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, liposyn, saponin, squalene, L121, emulsigen monophosphyryl lipid A (MPL), polysorbate 80, QS21, Montamide ISA51, ISA35, ISA206 and ISA 720.

31. A composition comprising a pepetide immunogen of claim 11 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, liposyn, saponin, squalene, L121, emulsigen monophosphyryl lipid A (MPL), polysorbate 80, QS21, Montamide ISA51, ISA35, ISA206 and ISA 720.

49. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 29.

50. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 30.

51. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 31.

69. A method of producing antibodies to Aβ

_1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 29.

70. A method of producing antibodies to Aβ

_1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 30.

71. A method of producing antibodies to Aβ

_1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 31.

12. The peptide immunogen represented by one of the following formulae:

(A)_n-(N-terminal fragment of Aβ

_1-42 peptide)-(B)_o-(Th)_m-X;

or (A)_n-(Th)_m-(B)_o-(N-terminal fragment of Aβ

_1-42 peptide)-X;

wherein

each A is independently an amino acid;

each B is a linking group selected from the group consisting of an amino acid, gly-gly, (α

, ε

-N)-Lys, and Pro-Pro-Xaa-Pro-Xaa-Pro (SEQ ID NO;

73);

Th comprise an amino acid sequence that constitutes a helper T cell epitope, selected from the group consisting of SEQ ID NOs;

1-64 and an immune enhancing analog thereof;

(N-terminal fragment of Aβ

_1-42 peptide) is 10 to about 28 amino acid residues and wherein each fragment comprises EFRH of the Aβ

_1-42 peptide and immunologically functional analog thereof;

X is an α

-COOH or α

-CONH₂ of an amino acid;

n is from 0 to about 10;

m is from 1 to about 4; and

o is from 0 to about 10.

13. A peptide immunogen of claim 12, wherein the spacer is Gly-Gly.

14. A peptide immunogen of claim 12, wherein the spacer is ε

-N-Lys.

15. A peptide immunogen of claim 12, wherein the N-terminal fragment of Aβ

_1-42 peptide is selected from the group consisting of SEQ ID NOs;

66-69 and an immunologically effective analog thereof.

16. A peptide immunogen of any one of claims 13, or 14, wherein the N-terminal fragment of Aβ

_1-42 peptide is selected from the group consisting of SEQ ID NOs;

66-69 and an immunologically functional analog thereof

17. A peptide immunogen of claim 12, wherein Th is selected from the group consisting of SEQ ID NOs:

1, 3,4, 5, 6, 7, 8, 9, 20, 38-40, 47-51 and 52-54.

18. A peptide immunogen of any one of claims 13, or 14 wherein Th is selected from the group consisting of SEQ ID NOs:

1, 3, 4, 5, 6, 7, 8, 9, 20, 38-40, 47-51 and 52-54.

19. A peptide immunogen of claim 15 wherein Th is selected from the group consisting of SEQ ID NOs:

1, 3, 4, 5, 6, 7, 8, 9, 20, 38-40, 47-51 and 52-54.

20. A peptide immunogen of claim 16 wherein Th is selected from the group consisting of SEQ ID NOs:

1, 3,4, 5, 6, 7, 8, 9, 20, 38-40,47-51 and 52-54.

32. A composition comprising a pepetide immunogen of claim 12 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, liposyn, saponin, squalene, L121, emulsigen monophosphyryl lipid A (MPL), polysorbate 80, QS21, Montamide ISA51, ISA35, ISA206 and ISA 720

33. A composition comprising a pepetide immunogen of claim 13 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, liposyn, saponin, squalene, L121, emulsigen monophosphyryl lipid A (MPL), polysorbate 80, QS21, Montamide ISA51, ISA35, ISA206 and ISA 720.

34. A composition comprising a pepetide immunogen of claim 14 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, liposyn, saponin, squalene, L121, emulsigen monophosphyryl lipid A (MPL), polysorbate 80, QS21, Montamide ISA51, ISA35, ISA206 and ISA 720.

35. A composition comprising a pepetide immunogen of claim 15 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, liposyn, saponin, squalene, L121, emulsigen monophosphyryl lipid A (MPL), polysorbate 80, QS21, Montamide ISA51, ISA35, ISA206 and ISA 720.

36. A composition comprising a pepetide immunogen of claim 16 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, liposyn, saponin, squalene, L121, emulsigen monophosphyryl lipid A (MPL), polysorbate 80, QS21, Montamide ISA51, ISA35, ISA206 and ISA 720.

37. A composition comprising a pepetide immunogen of claim 17 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, liposyn, saponin, squalene, L121, emulsigen monophosphyryl lipid A (MPL), polysorbate 80, QS21, Montamide ISA51, ISA35, ISA206 and ISA 720.

38. A composition comprising a pepetide immunogen of claim 18 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, liposyn, saponin, squalene, L121, emulsigen monophosphyryl lipid A (MPL), polysorbate 80, QS21, Montamide ISA51, ISA35, ISA206 and ISA 720.

39. A composition comprising a pepetide immunogen of claim 19 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, liposyn, saponin, squalene, L121, emulsigen monophosphyryl lipid A (MPL), polysorbate 80, QS21, Montamide ISA51, , ISA35, ISA206 and ISA 720.

40. A composition comprising a pepetide immunogen of claim 20 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, liposyn, saponin, squalene, L121, emulsigen monophosphyryl lipid A (MPL), polysorbate 80, QS21, Montamide ISA51, ISA35, ISA206 and ISA 720.

52. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 32.

53. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 33.

54. A method of preventing Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 34.

55. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 35.

56. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 36.

57. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 37.

58. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 38.

59. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 39.

60. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 40.

72. A method of producing antibodies to Aβ

_1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 32.

73. A method of producing antibodies to Aβ

_1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 33.

74. A method of producing antibodies to Aβ

_1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 34.

75. A method of producing antibodies to Aβ

_1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 35.

76. A method of producing antibodies to Aβ

_1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 36.

77. A method of producing antibodies to Aβ

_1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 37.

78. A method of producing antibodies to Aβ

_1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 38.

79. A method of producing antibodies to Aβ

_1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 39.

80. A method of producing antibodies to Aβ

_1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 40.