Pharmaceutical compositions and methods for treatment of amyloid diseases

• US 6,890,535 B1
• Filed: 11/28/2000
• Issued: 05/10/2005
• 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:
  US09/724,567
• Time in Patent Office: 1,624 Days
• Field of Search: 424/184.1, 424/185.1, 514/2, 514/12, 514/14, 514/17, 530/300, 530/360
• 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 prophylaxis of Alzheimer'"'"'s disease in a mammalian subject, comprising:

administering to the subject a dosage of synuclein-NAC effective to produce an immune response comprising anti-synuclein antibodies and an adjuvant that augments that immune response to the synuclein, wherein said administering further comprises administering an immunogenic Aβ

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

2. The method of claim 1, wherein said adjuvant is selected from the group consisting of STIMULON QS21, 3 De-O-acylated-monophosphoryl lipid A, and alum.

3. The method of claim 1, wherein said immune response is characterized by a serum titer of the anti-synuclein antibodies of at least 1:

1000 with respect to synuclein.

4. The method of claim 3, wherein said serum titer of the anti-synuclein antibodies is at least 1:

5000 with respect to synuclein.

5. The method of claim 1, wherein said immune response is characterized by a serum titer of the anti-synuclein antibodies corresponding to greater than about four times higher than a serum titer of anti-synuclein antibodies measured in a pre-treatment control serum sample.

6. The method of claim 5, wherein said serum titer of the antibodies is measured at a serum dilution of about 1:

100.

14. The method of claim 1, wherein said Aβ

fragment is Aβ

1-3.

15. The method of claim 1, wherein said Aβ

fragment is Aβ

1-4.

16. The method of claim 1, wherein said Aβ

fragment is Aβ

1-5.

17. The method of claim 1, wherein said Aβ

fragment is Aβ

1-6.

18. The method of claim 1, wherein said Aβ

fragment is Aβ

3-7.

19. The method of claim 1, wherein said Aβ

fragment is Aβ

1-10.

20. The method of claim 1, wherein said Aβ

fragment is Aβ

1-12.

21. The method of claim 1, wherein said Aβ

fragment is Aβ

13-28.

22. The method of claim 1, wherein said Aβ

fragment is Aβ

25-35.

23. The method of claim 1, wherein said Aβ

fragment is Aβ

33-42.

24. The method of claim 1, wherein said Aβ

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

25. The method of claim 14, wherein said Aβ

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

26. The method of claim 15, wherein said Aβ

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

27. The method of claim 16, wherein said Aβ

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

28. The method of claim 17, wherein said Aβ

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

29. The method of claim 18, wherein said Aβ

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

30. The method of claim 19, wherein said Aβ

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

31. The method of claim 20, wherein said Aβ

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

32. The method of claim 21, wherein said Aβ

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

33. The method of claim 22, wherein said Aβ

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

34. The method of claim 23, wherein said Aβ

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

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

7. A method of treating Alzheimer'"'"'s disease in a mammalian subject, comprising administering to the subject a dosage of synuclein-NAC effective to produce an immune response comprising anti-synuclein antibodies and an adjuvant that augments the immune response to the synuclein, wherein said administering further comprises administering an immunogenic Aβ

fragment, and thereby treating the disease.

8. The method of claim 7, wherein said synuclein-NAC is linked to a carrier molecule to form a conjugate.

9. The method of claim 7, wherein said adjuvant is selected from the group consisting of STIMULON QS-21, 3 De-O-acylated-monophosphoryl lipid, and alum.

10. The method of claim 7, wherein said immune response is characterized by a serum titer of the anti-synuclein antibodies of at least 1:

1000 with respect to synuclein.

11. The method of claim 10, wherein said serum titer of the anti-synuclein antibodies is at least 1:

5000 with respect to synuclein.

12. The method of claim 7, wherein said immune response is characterized by a serum titer of anti-synuclein antibodies corresponding to greater than about four times higher than a serum titer of anti-synuclein antibodies of measured in a pre-treatment control serum sample.

13. The method of claim 12, wherein said serum titer of the anti-synuclein antibodies is measured at a serum dilution of about 1:

100.

35. The method of claim 7, wherein said Aβ

fragment is Aβ

1-3.

36. The method of claim 7, wherein said Aβ

fragment is Aβ

1-4.

37. The method of claim 7, wherein said Aβ

fragment is Aβ

1-5.

38. The method of claim 7, wherein said Aβ

fragment is Aβ

1-6.

39. The method of claim 7, wherein said Aβ

fragment is Aβ

3-7.

40. The method of claim 7, wherein said Aβ

fragment is Aβ

1-10.

41. The method of claim 7, wherein said Aβ

fragment is Aβ

1-12.

42. The method of claim 7, wherein said Aβ

fragment is Aβ

13-28.

43. The method of claim 7, wherein said Aβ

fragment is Aβ

25-35.

44. The method of claim 7, wherein said Aβ

fragment is Aβ

33-42.

45. The method of claim 7, wherein said Aβ

fragment is linked to a carrier to form a conjugate.

46. The method of claim 35, wherein said Aβ

fragment is linked to a carrier to form a conjugate.

47. The method of claim 36, wherein said Aβ

fragment is linked to a carrier to form a conjugate.

48. The method of claim 37, wherein said Aβ

fragment is linked to a carrier to form a conjugate.

49. The method of claim 38, wherein said Aβ

fragment is linked to a carrier to form a conjugate.

50. The method of claim 39, wherein said Aβ

fragment is linked to a carrier to form a conjugate.

51. The method of claim 40, wherein said Aβ

fragment is linked to a carrier to form a conjugate.

52. The method of claim 41, wherein said Aβ

fragment is linked to a carrier to form a conjugate.

53. The method of claim 42, wherein said Aβ

fragment is linked to a carrier to form a conjugate.

54. The method of claim 43, wherein said Aβ

fragment is linked to a carrier to form a conjugate.

55. The method of claim 44, wherein said Aβ

fragment is linked to a carrier to form a conjugate.

57. The method of claim 7, wherein the subject has a known genetic risk of Alzheimer'"'"'s disease.