Methods of treatment of Alzheimer's disease

• US 6,875,434 B1
• Filed: 11/28/2000
• Issued: 04/05/2005
• Est. Priority Date: 12/02/1997
• Status: Expired due to Term

• Current Assignee: Janssen Alzheimer Immunotherapy (Johnson & Johnson)
• Original Assignee: Neuralab Ltd. (Perrigo Company PLC)
• Inventors: Schenk, Dale B.
• Primary Examiner(s): Kunz, Gary
• Assistant Examiner(s): NICHOLS, CHRISTOPHER J
• Application Number:
  US09/724,953
• Time in Patent Office: 1,589 Days
• Field of Search: 514/2, 514/4, 514/1, 514/12, 424/184.1, 424/188.1, 424/185.1, 530/306, 530/350
• US Class Current: 424/184.1
• 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 2039/55555 Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
• 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 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 39/0007 Nervous system antigens; Prions
• CPC Class Codes: C07K 14/4711 Alzheimer's disease; Amyloid plaque core protein
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: G01N 2800/2821 Alzheimer
• CPC Class Codes: G01N 33/6896 Neurological disorders, e.g. Alzheimer's disease

Abstract

Disclosed are pharmaceutical compositions and methods for preventing or treating a number of amyloid diseases, including Alzheimer'"'"'s disesase, prion diseases, familial amyloid neuropathies and the like. The pharmaceutical compositions include immunologically reactive amounts of amyloid fibril components, particularly fibril-forming peptides or proteins. Also disclosed are therapeutic compositions and methods which use immune reagents that react with such fibril components.

Claims

1. A method of treating Alzheimer'"'"'s disease in a mammalian subject, comprising administering to the subject a dosage of;

(a) an immunogenic Aβ

fragment effective to produce an immune response comprising antibodies against Aβ

; and

, (b) an adjuvant that augments the immune response to Aβ

, thereby treating Alzheimer'"'"'s disease.

2. The method of claim 1 wherein said Aβ

fragment induces an immune response directed against a neoepitope formed by amyloid deposits with respect to amyloid precursor protein (APP).

3. The method of claim 1, wherein said adjuvant is selected from the group consisting of STIMULON QS-21, 3-De-O-acylated-monophosphoryl lipid A, and alum.

4. The method of claim 1, wherein said immune response is characterized by a serum titer of the antibodies of a least 1:

1000 with respect to Aβ

.

5. The method of claim 4, wherein said serum titer of the antibodies is at least 1:

5000 with respect to Aβ

.

6. The method of claim 1, wherein said immune response is characterized by a serum titer of the antibodies Aβ

corresponding to greater than about four times higher than a serum titer of anti-Aβ

antibodies measured in a pre-treatment control serum sample.

7. The method of claim 6, wherein said serum titer of the antibodies is measured at a serum dilution of about 1:

100.

8. The method of claim 1, wherein the subject has a known risk of Alzheimer'"'"'s disease.

9. The method of claim 1, wherein said Aβ

fragment is linked to a carrier molecule to form a conjugate.

10. The method of claim 1, wherein said Aβ

fragment is Aβ

1-3.

11. The method of claim 10, wherein said Aβ

fragment is linked to a carrier molecule to form a conjugate.

12. The method of claim 1, wherein said Aβ

fragment is Aβ

1-4.

13. The method of claim 12, wherein said Aβ

fragment is linked to a carrier molecule to form a conjugate.

14. The method of claim 1, wherein said Aβ

fragment is Aβ

1-5.

15. The method of claim 14, wherein said Aβ

fragment is linked to a carrier molecule to form a conjugate.

16. The method of claim 1, wherein said Aβ

fragment is Aβ

1-6.

17. The method of claim 16, wherein said Aβ

fragment is linked to a carrier molecule to form a conjugate.

18. The method of claim 1, wherein said Aβ

fragment is Aβ

1-7.

19. The method of claim 18, wherein said Aβ

fragment is linked to a carrier molecule to form a conjugate.

20. The method of claim 1, wherein said Aβ

fragment is Aβ

1-10.

21. The method of claim 20, wherein said Aβ

fragment is linked to a carrier molecule to form a conjugate.

22. The method of claim 1, wherein said Aβ

fragment is Aβ

1-12.

23. The method of claim 22, wherein said Aβ

fragment is linked to a carrier molecule to form a conjugate.

24. The method of claim 1, wherein said Aβ

fragment is Aβ

13-28.

25. The method of claim 24, wherein said Aβ

fragment is linked to a carrier molecule to form a conjugate.

26. The method of claim 1, wherein said Aβ

fragment is Aβ

25-35.

27. The method of claim 26, wherein said Aβ

fragment is linked to a carrier molecule to form a conjugate.

28. The method of claim 1, wherein said Aβ

fragment is Aβ

33-42.

29. The method of claim 28, wherein said Aβ

fragment is linked to a carrier molecule to form a conjugate.

30. A method of prophylaxis of Alzheimer'"'"'s disease in a mammalian subject, comprising administering to the subject a dosage of:

(a) an immunogenic Aβ

fragment effective to produce an immune response comprising antibodies against Aβ and

, (b) an adjuvant that augments the immune response to the Aβ

, thereby effecting prophylaxis of Alzheimer'"'"'s disease.

31. The method of claim 30, wherein said Aβ

fragment induces an immune response directed against a neoepitope formed by amyloid deposits with respect to amyloid precursor protein (APP).

32. The method of claim 30, wherein said adjuvant is selected from the group consisting of STIMULON QS-21, 3 De-O-acylated-monophosphoryl lipid A, and alum.

33. The method of claim 30, wherein said immune response is characterized by a serum titer of the anti-Aβ

antibodies of at least 1;

1000 with respect to Aβ

.

34. The method of claim 33, wherein said serum titer of the antibodies is at least 1:

5000 with respect to Aβ

.

35. The method of claim 30, wherein said immune response is characterized by a serum titer of the anti-Aβ

antibodies corresponding to greater than about four times higher than a serum titer of anti-Aβ

antibodies measured in a pre-treatment control serum sample.

36. The method of claim 30, wherein said serum titer of the antibodies is measured at a serum dilution of about 1:

100.

37. The method of claim 30, wherein the subject has a known genetic risk of Alzheimer'"'"'s disease.

38. The method of claim 30, wherein said Aβ

fragment is linked to a carrier molecule to form a conjugate.

39. The method of claim 30, wherein said Aβ

fragment is Aβ

1-3.

40. The method of claim 39, wherein said Aβ

fragment is linked to a carrier molecule to form a conjugate.

41. The method of claim 30, wherein said Aβ

fragment is Aβ

1-4.

42. The method of claim 41, wherein said Aβ

fragment is linked to a carrier molecule to form a conjugate.

43. The method of claim 30, wherein said Aβ

fragment is Aβ

1-5.

44. The method of claim 43, wherein said Aβ

fragment is linked to a carrier molecule to form a conjugate.

45. The method of claim 30, wherein said Aβ

fragment is Aβ

1-6.

46. The method of claim 45, wherein said Aβ

fragment is linked to a carrier molecule to form a conjugate.

47. The method of claim 30, wherein said Aβ

fragment is Aβ

1-7.

48. The method of claim 47, wherein said Aβ

fragment is linked to a carrier molecule to form a conjugate.

49. The method of claim 30, wherein said Aβ

fragment is Aβ

1-10.

50. The method of claim 41, wherein said Aβ

fragment is linked to a carrier molecule to form a conjugate.

51. The method of claim 30, wherein said Aβ

fragment is Aβ

1-12.

52. The method of claim 51, wherein said Aβ

fragment is linked to a carrier molecule to form a conjugate.

53. The method of claim 30, wherein said Aβ

fragment is Aβ

13-28.

54. The method of claim 53, wherein said Aβ

fragment is linked to a carrier molecule to form a conjugate.

55. The method of claim 30, wherein said Aβ

fragment is Aβ

25-35.

56. The method of claim 55, wherein said Aβ

fragment is linked to a carrier molecule to form a conjugate.

57. The method of claim 30, wherein said Aβ

fragment is Aβ

33-42.

58. The method of claim 57, wherein said Aβ

fragment is linked to a carrier molecule to form a conjugate.