Prevention and treatment of amyloidogenic disease

• US 20040081657A1
• Filed: 05/02/2003
• Published: 04/29/2004
• Est. Priority Date: 12/02/1997
• Status: Abandoned Application

• Current Assignee: Janssen Alzheimer Immunotherapy (Johnson & Johnson), Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Original Assignee: Athena Neurosciences Incorporated (Perrigo Company PLC), Neuralab Ltd. (Perrigo Company PLC)
• Inventors: Schenk, Dale B.
• Application Number:
  US10/429,216
• Publication Number:
  US 20040081657A1
• Time in Patent Office: Days
• 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 pharmaceutical composition comprising an agent effective to induce an immunogenic response against Aβ

in a patient, and a pharmaceutically acceptable adjuvant.

2. The pharmaceutical composition of claim 1, wherein the agent is Aβ

or an active fragment thereof.

3. The pharmaceutical composition of claim 1 or 2, wherein the adjuvant comprises alum.

4. The pharmaceutical composition of claim 1 or 2, wherein the adjuvant comprises monophosphoryl lipid (MPL)

5. The pharmaceutical composition of claim 1 or 2, wherein the adjuvant comprises QS21.

6. The pharmaceutical composition of any of the preceding claims, wherein the Aβ

or fragment is a component of a particle.

7. The pharmaceutical composition of claim 6, wherein the particle is a polylactide polyglycolide copolymer (PLPG) particle.

11. The method of any of the preceding claims, wherein the disease is Alzheimer'"'"'s disease.

12. The method of any of the preceding claims, wherein the patient is asymptomatic.

13. The method of any of the preceding claims, wherein the patient is under 50.

14. The method of any of the preceding claims, wherein the patient has inherited risk factors indicating susceptibility to Alzheimer'"'"'s disease.

16. The method of any of the preceding claims, wherein the agent comprises Aβ

peptide or an active fragment thereof.

17. The method of any of the preceding claims, wherein the agent is Aβ

peptide or an active fragment thereof.

18. The method of claim 17, wherein the dose of Aβ

peptide administered to the patient at least 50 μ

g.

19. The method of claim 17, wherein the dose of Aβ

peptide administered to the patient is at least 100 μ

g.

20. The method of any of the preceding claims, wherein the Aβ

peptide is Aβ

42.

21. The method of claim 20, wherein the Aβ

peptide is administered in aggregated form.

22. The method of claim any of the preceding claims, wherein the immune response comprises antibodies that bind to the Aβ

peptide.

23. The method of any of the preceding claims, wherein the immune response comprises T-cells that bind to the Aβ

peptide as a component of an MHC I or MHC II complex.

26. The method of any of the preceding claims, wherein the agent is administered orally, subcutaneously, intramuscularly, topically or intravenously.

27. The method of any of the preceding claims, wherein the agent is administered intramuscularly or subcutaneously.

28. The method of any of the preceding claims, further comprising screening a library of compounds to identify a compound reactive with antibodies to Aβ

, and administering the

32. The method of any of the preceding claims, further comprising monitoring the patient for the immune response.

33. The method of any of the preceding claims, further comprising administering an adjuvant that enhances the immune response to the Aβ

peptide.

34. The method of claim 33, wherein the adjuvant and the agent are administered together as a composition.

35. The method of claim 33, wherein the adjuvant is administered before the agent.

36. The method of claim 33, wherein the adjuvant is administered after the agent.

37. The method of any one of claims 33-36, wherein the adjuvant is alum.

38. The method of any one of claims 33-36, wherein the adjuvant is MPL.

39. The method of any one of claims 33-36, wherein the adjuvant is QS21.

40. The method of anyone of claims 33-36, wherein the dose of Aβ

peptide is greater than 10 μ

g.

8. A method of preventing or treating a disease characterized by amyloid deposit in a patient, comprising:

administering an agent effective to induce an immune response against a peptide component of an amyloid deposit in the patient.

9. The method of claim 8, wherein the amyloid deposit comprises aggregated Aβ

peptide.

10. The method of claim 8 or 9, wherein the patient is a human.

15. The method of any of claims 8-13, wherein the patient has no known risk factors for Alzheimer'"'"'s disease.

24. The method of any one of claims 8, or 10-15 wherein agent is an antibody to Aβ

which induces an immune response by binding to Aβ

in the patient.

25. The method of claims 8 or 10-15, wherein T-cells are removed from the patient, contacted with Aβ

peptide under conditions in which the T-cells are primed, and the primed T-cells are administered to the patient.

29. The method of any one of claims 8, 10-15, 26 or 27, wherein the agent is an effective dose of a nucleic acid encoding Aβ

or an active fragment thereof, whereby the nucleic acid is expressed in the patient to produce Aβ

or the active fragment thereof, which induces the immune response.

30. The method of claim 29, wherein the nucleic acid is administered through the skin.

31. The method of claim 30, wherein the nucleic acid is applied to the skin by a patch.

41. A method of preventing or treating Alzheimer'"'"'s disease comprising administering an effective dose of Aβ

peptide to a patient.

42. Use of Aβ

peptide, or an antibody thereto, in the manufacture of a medicament for prevention or treatment of Alzheimer'"'"'s disease.

43. The use of claim 42, wherein the Aβ

peptide is combined with a pharmaceutically acceptable adjuvant in the manufacture of the medicament.

44. A composition comprising Aβ

or a fragment linked to a conjugate molecule that promotes delivery of Aβ

to the bloodstream of a patient and/or promotes an immune response against Aβ

.

45. The composition of claim 44, wherein the conjugates promotes an immune response against Aβ

.

46. The composition of claim 44 or 45, wherein the conjugate is cholera toxin.

47. The composition of claim 44 or 45, wherein the conjugate is an immunoglobulin.

48. The composition of claim 44 or 45, wherein the conjugate is attenuated diphtheria toxin CRM 197.

49. A pharmaceutical composition comprising an agent effect to induce an immunogenic response against Aβ

in a patient with the proviso that the composition is free of Complete Freund'"'"'s adjuvant.

50. A composition comprising a viral vector encoding Aβ

or a fragment thereof effective to induce an immune response against Aβ

.

51. A composition of claim 50, wherein the viral vector is herpes, adenovirus, adenoassociated virus, a retrovirus, sindbis, semiliki forest virus, vaccinia or avian pox.

52. A method of assessing efficacy of an Alzheimer'"'"'s treatment method in a patient, comprising

determining a baseline amount of antibody specific for Aβ

peptide in tissue sample from the patient before treatment with an agent,

comparing an amount of antibody specific for Aβ

peptide in the tissue sample from the patient after treatment with the agent to the baseline amount of Aβ

peptide-specific antibody,

wherein an amount of Aβ

peptide-specific antibody measured after the treatment that is significantly greater than the baseline amount of Aβ

peptide-specific antibody indicates a positive treatment outcome.

53. The method of claim 52, wherein the amounts of antibody are measured as antibody titers.

54. The method of claim 53, wherein the amounts of antibody are measured by an ELISA assay.

55. A method of assessing efficacy of an Alzheimer'"'"'s treatment method in a patient, comprising

determining a baseline amount of antibody specific for Aβ

peptide in tissue sample from a patient before treatment with an agent;

comparing an amount of antibody specific for Aβ

peptide in the tissue sample from the subject after treatment with the agent to the baseline amount of Aβ

peptide-specific antibody,

wherein a reduction or lack of significant difference between the amount of Aβ

peptide-specific antibody measured after the treatment compared to the baseline amount of Aβ

peptide-specific antibody indicates a negative treatment outcome.

56. A method of assessing efficacy of an Alzheimer'"'"'s treatment method in a patient, comprising

determining a control amount of antibody specific for Aβ

peptide in tissue samples from a control population,

comparing an amount of antibody specific for Aβ

peptide in a tissue sample from the patient after administering an agent to the control amount of Aβ

peptide-specific antibody,

wherein an amount of Aβ

peptide-specific antibody measured after the treatment that is significantly greater than the control amount of Aβ

peptide-specific antibody indicates a positive treatment outcome.

57. A method of assessing efficacy of an Alzheimer'"'"'s treatment method in a patient, comprising

determining a control amount of antibody specific for Aβ

peptide in tissues samples from a control population,

comparing an amount of antibody specific for Aβ

peptide in a tissue sample from the patient after administering an agent to said control amount of Aβ

peptide-specific antibody,

wherein a lack of significant difference between the amount of Aβ

peptide-specific antibody measured after beginning said treatment compared to the control amount of Aβ

peptide-specific antibody indicates a negative treatment outcome.

61. The method of any one of claims 57-60, wherein the detecting comprises detecting an antibody that specifically binds to Aβ

peptide.

62. The method of any one of claims 57-60, wherein the detecting comprises detecting T-cells specifically reactive with Aβ

peptide.

58. A method of monitoring Alzheimer'"'"'s disease or susceptibility thereto in a patient, comprising:

detecting an immune response against Aβ

peptide in a sample from the patient.

59. The method of claim 58, wherein the patient is being administered an agent effective to treat or prevent Alzheimer'"'"'s disease, and the level of the response determines the future treatment regime of the patient.

60. The method of claim 59, wherein the agent is Aβ

peptide.

63. A method of assessing efficacy of an Alzheimer'"'"'s treatment method in a patient, comprising

determining a value for an amount of antibody specific for Aβ

peptide in tissue sample from a patient who has been treated with an agent;

comparing the value with a control value determined from a population of patient experiencing amelioriation of, or freedom from, symptoms of Alzheimer'"'"'s disease due to treatment with the agent;

wherein a value in the patient at least equal to the control value indicates a positive response to treatment.