Prevention and treatment of amyloidogenic disease

• US 6,787,139 B1
• Filed: 11/28/2000
• Issued: 09/07/2004
• Est. Priority Date: 12/02/1997
• Status: Expired due to Term

• Current Assignee: Janssen Alzheimer Immunotherapy (Johnson & Johnson), Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Original Assignee: Neuralab Ltd. (Perrigo Company PLC)
• Inventors: Schenk, Dale B.
• Primary Examiner(s): SCHEINER, LAURIE A
• Application Number:
  US09/724,102
• Time in Patent Office: 1,379 Days
• Field of Search: 435/7.95, 435/70.21, 435/7.1, 435/7.92, 435/810, 436/548, 436/518, 436/811, 436/86, 514/2, 514/21, 424/1.57, 424/185.1, 424/9.2
• US Class Current: 424/185.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/53 DNA (RNA) vaccination
• CPC Class Codes: A61K 2039/55505 Inorganic adjuvants
• CPC Class Codes: A61K 2039/55566 Emulsions, e.g. Freund's adjuvant, MF59
• CPC Class Codes: A61K 2039/55572 Lipopolysaccharides; Lipid A; Monophosphoryl lipid A
• CPC Class Codes: A61K 2039/55577 Saponins; Quil A; QS21; ISCOMS
• CPC Class Codes: A61K 2039/6037 Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT]
• CPC Class Codes: A61K 2039/605 MHC molecules or ligands thereof
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 38/193 Colony stimulating factors [CSF]
• CPC Class Codes: A61K 39/0007 Nervous system antigens; Prions
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: G01N 2800/2821 Alzheimer
• CPC Class Codes: Y10T 436/105831 Protein or peptide standard or control [e.g., hemoglobin, etc.]

Abstract

The invention provides compositions and methods for treatment of amyloidogenic diseases. Such methods entail administering an agent that induces a beneficial immune response against an amyloid deposit in the patient. The methods are particularly useful for prophylactic and therapeutic treatment of Alzheimer'"'"'s disease. In such methods, a suitable agent is Aβ peptide or an antibody thereto.

Claims

1. A method of prophylactically or therapeutically treating a disease characterized by an amyloid deposit of Aβ

in a patient, comprising;

administering an effective dose of a polypeptide comprising an immunogenic fragment of Aβ and

an adjuvant in a regime effective to induce an immune response comprising antibodies to the Aβ

fragment, the adjuvant enhancing the immune response to the Aβ

fragment, and thereby prophylactically or therapeutically treat the disease in the patient.

2. The method of claim 1, wherein the Aβ

fragment is from the N-terminal half of Aβ

.

3. The method of claim 1, wherein the patient is a human.

4. The method of claim 1, wherein the disease is Alzheimer'"'"'s disease.

5. The method of any one of claims 1-4, wherein the patient is asymptomatic.

6. The method of any one of claims 1-4, wherein the patient is under 50.

7. The method of any one of claims 1-4, wherein the patient has inherited risk factors indicating susceptibility to Alzheimer'"'"'s disease.

8. The method of any one of claims 1-4, wherein the patient has no known risk factors for Alzheimer'"'"'s disease.

9. The method of claim 1, wherein the Aβ

fragment is administered in aggregated form.

10. The method of claim 2, wherein the Aβ

fragment is administered in aggregated form.

11. The method of any one of claims 1-4, wherein the Aβ

fragment is administered orally, subcutaneously, intramuscularly, topically or intravenously.

12. The method of any one of claims 1-4, wherein the Aβ

fragment is administered intramuscularly or subcutaneously.

13. The method of any one of claims 1-4, further comprising monitoring the patient for the immune response.

14. The method of claim 1, wherein the adjuvant and the Aβ

fragment are administered together as a composition.

15. The method of claim 2, wherein the adjuvant and the Aβ

fragment are administered together as a composition.

16. The method of claim 1, wherein the adjuvant is administered before the Aβ

fragment.

17. The method of claim 2, wherein the adjuvant is administered before the Aβ

fragment.

18. The method of claim 1, wherein the adjuvant is administered after the Aβ

fragment.

19. The method of claim 2, wherein the adjuvant is administered after the Aβ

fragment.

20. The method of claim 1, wherein the adjuvant is alum.

21. The method of claim 2, wherein the adjuvant is alum.

22. The method of claim 1, wherein the adjuvant is monophosphoryl lipid MPL.

23. The method of claim 2, wherein the adjuvant is monophosphoryl lipid MPL.

24. The method of claim 1, wherein the adjuvant is QS21.

25. The method of claim 2, wherein the adjuvant is QS21.

26. The method of claim 1, wherein the adjuvant is M-CSF.

27. The method of claim 2, wherein the adjuvant is M-CSF.

28. The method of claim 1, wherein the adjuvant is GM-CSF.

29. The method of claim 2, wherein the adjuvant is GM-CSF.

30. The method of claim 1, wherein the Aβ

fragment is administered with GM-CSF in the regime.

31. The method of claim 2, wherein the Aβ

fragment is administered with GM-CSF in the regime.

32. The method of claim 1, wherein the dose of the Aβ

fragment is greater than 10 μ

g.

33. The method of claim 2, wherein the dose of the Aβ

fragment is greater than 10 μ

g.

34. The method of claim 1, wherein the dosage is greater than 20 μ

g.

35. The method of claim 2, wherein the dosage is greater than 20 μ

g.

36. A method of prophylactically or therapeutically treating a disease characterized by an amyloid deposit of Aβ

in a patient, comprising;

administering an immunogenic fragment of Aβ

peptide in a regime effective to induce an immune response comprising antibodies to the Aβ

fragment and thereby prophylactically or therapeutically treat the disease in the patient, wherein the dose of the Aβ

fragment administered to the patient at least 50 μ

g.

37. The method of claim 36, wherein the Aβ

fragment is from the N-terminal half of Aβ

.

38. The method of claim 36, wherein the patient is a human.

39. The method of claim 36, wherein the disease is Alzheimer'"'"'s disease.

40. The method of any one of claims 36-39, wherein the patient is asymptomatic.

41. The method of any one of claims 36-39, wherein the patient is under 50.

42. The method of any one of claims 36-39, wherein the patient has inherited risk factors indicating susceptibility to Alzheimer'"'"'s disease.

43. The method of any one of claims 36-39, wherein the patient has no known risk factors for Alzheimer'"'"'s disease.

44. The method of claim 36, wherein the Aβ

fragment is administered in aggregated form.

45. The method of claim 37, wherein the Aβ

fragment is administered in aggregated form.

46. The method of any one of claims 36-39, wherein the Aβ

fragment is administered orally, subcutaneously, intramuscularly, topically or intravenously.

47. The method of any one of claims 36-39, wherein the Aβ

fragment is administered intramuscularly or subcutaneously.

48. The method of claim 36, wherein the dose of Aβ

fragment administered to the patient is at least 100 μ

g.

49. The method of claim 37, wherein the dose of Aβ

fragment administered to the patient is at least 100 μ

g.

50. The method of any one of claims 36-39, further comprising monitoring the patient for the immune response.

51. A method of prophylactically or therapeutically treating a disease characterized by an amyloid deposit of Aβ

in a patient, comprising;

administering an Aβ

fragment in a regime effective to induce an immune response comprising antibodies to the Aβ

fragment and thereby prophylactically or therapeutically treat the disease in the patient; and

monitoring the patient for the immune response, wherein the monitoring comprises detecting antibodies having Aβ

fragment binding specificity.

52. The method of claim 51, wherein the Aβ

fragment is from the N-terminal half of Aβ

.

53. A pharmaceutical composition comprising an immunogenic fragment of Aβ

and a pharmaceutically acceptable adjuvant effective to induce an immune response comprising antibodies to the Aβ

fragment, wherein the adjuvant enhances the immune to the Aβ

fragment.

54. The pharmaceutical composition of claim 53, wherein the Aβ

fragment is from the N-terminal half of Aβ

.

55. The pharmaceutical composition of claim 53, wherein the adjuvant is alum.

56. The pharmaceutical composition of claim 54, wherein the adjuvant is alum.

57. The pharmaceutical composition of claim 53, wherein the adjuvant is monophosphoryl lipid MPL.

58. The pharmaceutical composition of claim 54, wherein the adjuvant is monophosphoryl lipid MPL.

59. The pharmaceutical composition of claim 53, wherein the adjuvant is QS21.

60. The pharmaceutical composition of claim 54, wherein the adjuvant is QS21.

61. The pharmaceutical composition of claim 53, wherein the adjuvant is M-CSF.

62. The pharmaceutical composition of claim 54, wherein the adjuvant is M-CSF.

63. The pharmaceutical composition of claim 53, wherein the adjuvant is GM-CSF.

64. The pharmaceutical composition of claim 54, wherein the adjuvant is GM-CSF.

65. The pharmaceutical composition of claim 53, wherein the Aβ

fragment is a component of a particle.

66. The pharmaceutical composition of claim 54, wherein the Aβ

fragment is a component of a particle.

67. The pharmaceutical composition of any one of claims 55-64, wherein the Aβ

fragment is a component of a particle.

68. The pharmaceutical composition of claim 65, wherein the particle is a polylactide polyglycolide copolymer (PLPG) particle.

69. The pharmaceutical composition of claim 66, wherein the particle is a polylactide polyglycolide copolymer (PLPG) particle.

70. The pharmaceutical composition of claim 67, wherein the particle is a polylactide-polyglycolide copolymer (PLPG) particle.