Prevention and treatment of amyloidogenic disease

• US 6,972,127 B2
• Filed: 09/02/2004
• Issued: 12/06/2005
• 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): HOUSEL, JAMES C
• Application Number:
  US10/933,559
• Publication Number:
  US 20050019343A1
• Time in Patent Office: 460 Days
• Field of Search: 424/1.57, 424/9.2, 424/185.1, 436/86, 514/2, 514/21
• 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 2039/55555 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 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/739 Lipopolysaccharides
• 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: A61K 47/646 the entire peptide or protein drug conjugate elicits an immune response, e.g. conjugate vaccines
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• CPC Class Codes: A61K 9/2054 : Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/4866 : Organic macromolecular compounds
• CPC Class Codes: A61K 9/7023 : Transdermal patches and similar drug-containing composite devices, e.g. cataplasms galenical aspects of iontophoretic devices A61K9/0009; microneedle arrays A61K9/0021; buccal patches A61K9/006
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• 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 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/567 : Framework region [FR]
• CPC Class Codes: C07K 2319/00 : Fusion polypeptide

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 therapeutically treating a disease characterized by an amyloid deposit of Aβ

in a patient having the disease, comprising;

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

(SEQ ID NO;

1) 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 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.

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

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

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

8. The method of claim 1, wherein the Aβ

fragment is administered in aggregated form.

9. The method of claim 2, wherein the Aβ

fragment is administered in aggregated form.

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

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

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

fragment is administered intramuscularly or subcutaneously.

12. The method of any one of claims 1-4, further comprising monitoring the patient for the immune response, wherein the monitoring comprises detecting antibodies having Aβ

fragment binding specificity.

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

fragment are administered together as a composition.

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

fragment are administered together as a composition.

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

fragment.

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

fragment.

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

fragment.

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

fragment.

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

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

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

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

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

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

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

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

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

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

29. The method of claim 1, wherein the Aβ

fragment is administered with GM-CSF in the regime.

30. The method of claim 2, wherein the Aβ

fragment is administered with GM-CSF in the regime.

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

fragment is greater than 10 μ

g.

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

fragment is greater than 10 μ

g.

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

g.

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

g.

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

35. A method of therapeutically treating a disease characterized by an amyloid deposit of Aβ

in a patient having the disease, comprising;

administering an immunogenic fragment of Aβ

peptide (SEQ ID NO;

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

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

fragment administered to the patient at least 50 μ

g.

36. The method of claim 35, wherein the Aβ

fragment is from the N-terminal half of Aβ

.

37. The method of claim 35, wherein the patient is a human.

38. The method of claim 35, wherein the disease is Alzheimer'"'"'s disease.

39. The method of any one of claims 35-38, wherein the patient is under 50.

40. The method of any one of claims 35-38, wherein the patient has inherited risk factors indicating susceptibility to Alzheimer'"'"'s disease.

41. The method of any one of claims 35-38, wherein the patient has no known risk factors for Alzheimer'"'"'s disease.

42. The method of claim 35, wherein the Aβ

fragment is administered in aggregated form.

43. The method of claim 36, wherein the Aβ

fragment is administered in aggregated form.

44. The method of any one of claims 35-38, wherein the Aβ

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

45. The method of any one of claims 35-38, wherein the Aβ

fragment is administered intramuscularly or subcutaneously.

46. The method of claim 35, wherein the dose of Aβ

fragment administered to the patient is at least 100 μ

g.

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

fragment administered to the patient is at least 100 μ

g.

48. The method of any one of claims 35-38, further comprising monitoring the patient for the immune response, wherein the monitoring comprises detecting antibodies having Aβ

fragment binding specificity.

49. A method of therapeutically treating a disease characterized by an amyloid deposit of Aβ

in a patient, comprising;

administering an Aβ

fragment (SEQ ID NO;

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

fragment and thereby 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.

50. The method of claim 49, wherein the Aβ

fragment is from the N-terminal half of Aβ

.

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

in a patient susceptible to the disease, comprising;

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

(SEQ ID NO;

1) 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 treat the disease in the patient.

52. The method of claim 51, wherein the Aβ

fragment is from the N-terminal half of Aβ

.

53. The method of claim 51, wherein the patient is a human.

54. The method of claim 51, wherein the disease is Alzheimer'"'"'s disease.

55. The method of any one of claims 51-54, wherein the patient is asymptomatic.

56. The method of any one of claims 51-54, wherein the patient is under 50.

57. The method of any one of claims 51-54, wherein the patient has inherited risk factors indicating susceptibility to Alzheimer'"'"'s disease.

58. The method of any one of claims 51-54, wherein the patient has no known risk factors for Alzheimer'"'"'s disease.

59. The method of claim 51, wherein the Aβ

fragment is administered in aggregated form.

60. The method of claim 52, wherein the Aβ

fragment is administered in aggregated form.

61. The method of any one of claims 51-54, wherein the Aβ

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

62. The method of any one of claims 51-54, wherein the Aβ

fragment is administered intramuscularly or subcutaneously.

63. The method of any one of claims 51-54, further comprising monitoring the patient for the immune response, wherein the monitoring comprises detecting antibodies having Aβ

fragment binding specificity.

64. The method of claim 51, wherein the adjuvant and the Aβ

fragment are administered together as a composition.

65. The method of claim 52, wherein the adjuvant and the Aβ

fragment are administered together as a composition.

66. The method of claim 51, wherein the adjuvant is administered before the Aβ

fragment.

67. The method of claim 52, wherein the adjuvant is administered before the Aβ

fragment.

68. The method of claim 51, wherein the adjuvant is administered after the Aβ

fragment.

69. The method of claim 52, wherein the adjuvant is administered after the Aβ

fragment.

70. The method of claim 51, wherein the adjuvant is alum.

71. The method of claim 52, wherein the adjuvant is alum.

72. The method of claim 51, wherein the adjuvant is monophosphoryl lipid MPL.

73. The method of claim 52, wherein the adjuvant is monophosphoryl lipid MPL.

74. The method of claim 51, wherein the adjuvant is QS21.

75. The method of claim 52, wherein the adjuvant is QS21.

76. The method of claim 51, wherein the adjuvant is M-CSF.

77. The method of claim 52, wherein the adjuvant is M-CSF.

78. The method of claim 61, wherein the adjuvant is GM-CSF.

79. The method of claim 52, wherein the adjuvant is GM-CSF.

80. The method of claim 51, wherein the Aβ

fragment is administered with GM-CSF in the regime.

81. The method of claim 52, wherein the Aβ

fragment is administered with GM-CSF in the regime.

82. The method of claim 51, wherein the dose of the Aβ

fragment is greater than 10 μ

g.

83. The method of claim 52, wherein the dose of the Aβ

fragment is greater than 10 μ

g.

84. The method of claim 51, wherein the dosage is greater than 20 μ

g.

85. The method of claim 52, wherein the dosage is greater than 20 μ

g.

86. A method of prophylactically treating a disease characterized by an amyloid deposit of Aβ

in a patient, comprising;

administering an immunogenic fragment of Aβ

peptide (SEQ ID NO;

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

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

fragment administered to the patient at least 50 μ

g.

87. The method of claim 86, wherein the Aβ

fragment is from the N-terminal half of Aβ

.

88. The method of claim 86, wherein the patient is a human.

89. The method of claim 86, wherein the disease is Alzheimer'"'"'s disease.

90. The method of any one of claims 86-89, wherein the patient is asymptomatic.

91. The method of any one of claims 86-89, wherein the patient is under 50.

92. The method of any one of claims 86-89, wherein the patient has inherited risk factors indicating susceptibility to Alzheimer'"'"'s disease.

93. The method of any one of claims 86-89, wherein the patient has no known risk factors for Alzheimer'"'"'s disease.

94. The method of claim 86, wherein the Aβ

fragment is administered in aggregated form.

95. The method of claim 86, wherein the Aβ

fragment is administered in aggregated form.

96. The method of any one of claims 86-89, wherein the Aβ

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

97. The method of any one of claims 86-89, wherein the Aβ

fragment is administered intramuscularly or subcutaneously.

98. The method of claim 86, wherein the dose of Aβ

fragment administered to the patient is at least 100 μ

g.

99. The method of claim 87, wherein the dose of Aβ

fragment administered to the patient is at least 100 μ

g.

100. The method of any one of claims 86-89, further comprising monitoring the patient for the immune response, wherein the monitoring comprises detecting antibodies having Aβ

fragment binding specificity.

101. A method of prophylactically treating a disease characterized by an amyloid deposit of Aβ

in a patient susceptible to the disease, comprising;

administering an Aβ

fragment (SEQ ID NO;

1) 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.

102. The method of claim 101, wherein the Aβ

fragment is from the N-terminal half of Aβ

.

103. A pharmaceutical composition comprising an immunogenic fragment of Aβ

(SEQ ID NO;

1) 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.

104. The pharmaceutical composition of claim 103, wherein the Aβ

fragment is from the N-terminal half of Aβ

.

105. The pharmaceutical composition of claim 103, wherein the adjuvant is alum.

106. The pharmaceutical composition of claim 104, wherein the adjuvant is alum.

107. The pharmaceutical composition of claim 103, wherein the adjuvant is monophosphoryl lipid MPL.

108. The pharmaceutical composition of claim 104, wherein the adjuvant is monophosphoryl lipid MPL.

109. The pharmaceutical composition of claim 103, wherein the adjuvant is QS21.

110. The pharmaceutical composition of claim 104, wherein the adjuvant is QS21.

111. The pharmaceutical composition of claim 103, wherein the adjuvant is M-CSF.

112. The pharmaceutical composition of claim 104, wherein the adjuvant is M-CSF.

113. The pharmaceutical composition of claim 103, wherein the adjuvant is GM-CSF.

114. The pharmaceutical composition of claim 104, wherein the adjuvant is GM-CSF.

115. The pharmaceutical composition of claim 103, wherein the Aβ

fragment is a component of a particle.

116. The pharmaceutical composition of claim 104, wherein the Aβ

fragment is a component of a particle.

117. The pharmaceutical composition of any one of claims 105-113, wherein the Aβ

fragment is a component of a particle.

118. The pharmaceutical composition of claim 115, wherein the particle is a polylactide polyglycolide copolymer (PLPG) particle.

119. The pharmaceutical composition of claim 116, wherein the particle is a polylactide polyglycolide copolymer (PLPG) particle.

120. The pharmaceutical composition of claim 117, wherein the particle is a polylactide polyglycolide copolymer (PLPG) particle.