Prevention and treatment of amyloidogenic disease

• US 20050059591A1
• Filed: 04/12/2004
• Published: 03/17/2005
• Est. Priority Date: 04/07/1998
• Status: Abandoned Application

• Current Assignee: Janssen Alzheimer Immunotherapy (Johnson & Johnson)
• Original Assignee: Neuralab Ltd. (Perrigo Company PLC)
• Inventors: Schenk, Dale B., Yednock, Theodore, Vasquez, Nicki
• Application Number:
  US10/822,968
• Publication Number:
  US 20050059591A1
• Time in Patent Office: Days
• US Class Current: 424/131.100
• 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 2317/77 Internalization into the cell
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention provides improved agents and methods for treatment of diseases associated with amyloid deposits of Aβ in the brain of a patient. Such methods entail administering agents that induce a beneficial immunogenic response against the amyloid deposit. The methods are useful for prophylactic and therapeutic treatment of Alzheimer'"'"'s disease. Preferred agents including N-terminal fragments of Aβ and antibodies binding to the same.

Claims

1-33. -33. (Cancel)

34. A peptide immunogen of about 20 to 100 amino acids long comprising:

(i) a helper T cell (Th) epitope selected from the group consisting of SEQ ID NOS;

3, 5, 6, 9, and 10;

(ii) an N-terminal fragment of Aβ

1-42 peptide, SEQ ID NO;

1;

consisting of from 10 to 28 amino acid residues wherein each fragment comprises amino acid residue 1 of the Aβ

1-42 peptide or an immunologically functional analog of the N-terminal fragment of Aβ

1-42 peptide; and

(iii) optionally a spacer consisting of at least an amino acid to separate the immunogenic domains.

35. A peptide immunogen of claim 34, further comprising a spacer consisting of at least an amino acid to separate the immunogenic domains.

36. A peptide immunogen of claim 34, wherein the spacer is selected from the group consisting of an amino acid, and (α

, ε

-N-Lys).

37. A peptide immunogen of claim 36, wherein the spacer is ε

-N-Lys.

38. A peptide immunogen of claim 34, wherein the N-terminal fragment of Aβ

1-42 peptide is selected from the group consisting of the first 10 amino acids of SEQ ID NO;

2 the first 12 amino acids of SEQ ID NO;

2, and the first 28 amino acids of SEQ ID NO;

2 and the immunologically functional analog thereof.

39. A peptide immunogen of any one of claims 35, 36, or 37, wherein the N-terminal fragment of Aβ

1-42 peptide is selected from the group consisting of the first 10 amino acids of SEQ ID NO;

2 the first 12 amino acids of SEQ ID NO;

2, and the first 28 amino acids of SEQ ID NO;

2.

40. A peptide immunogen of claim 34, wherein Th is selected from the group consisting of SEQ ID NOS:

3, 5, 6, 9, and 10.

41. A peptide immunogen of any one of claims 35, 36, or 37, wherein Th is selected from the group consisting of SEQ ID NOS:

3, 5, 6, 9, and 10.

51. A composition comprising a peptide immunogen of claim 35 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, saponin, squalene, monophosphoryl lipid A (MPL), polysorbate 80, QS21.

52. A composition comprising a peptide immunogen of claim 36 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, saponin, squalene, monophosphoryl lipid A (MPL), polysorbate 80, QS21.

54. A composition comprising a peptide immunogen of claim 38 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, saponin, squalene, monophosphoryl lipid A (MPL), polysorbate 80, QS21.

55. A composition comprising a peptide immunogen of claim 39 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, saponin, squalene, monophosphoryl lipid A (MPL), polysorbate 80, QS21.

56. A composition comprising a peptide immunogen of claim 40 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, saponin, squalene, monophosphoryl lipid A (MPL), polysorbate 80, QS21.

57. A composition comprising a peptide immunogen of claim 41 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, saponin, squalene, monophosphoryl lipid A (MPL), polysorbate 80, QS21.

67. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 52.

69. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 54.

70. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 55.

71. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 56.

72. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 57.

82. A method of producing antibodies to Aβ

1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 52.

84. A method of producing antibodies to Aβ

1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 54.

85. A method of producing antibodies to Aβ

1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 55.

86. A method of producing antibodies to Aβ

1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 56.

87. A method of producing antibodies to Aβ

1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 57.

42. The peptide immunogen represented by one of the following formulae:

(A)_n-(N-terminal fragment of Aβ

1-42 peptide)-(B)_o-(Th)_m-X;

or

(A)_n-(Th)_m-(B)_o-(N-terminal fragment of Aβ

1-42 peptide)-X;

wherein

each A is independently an amino acid;

each B is a linking group selected from the group consisting of an amino acid, and α

, ε

-N-Lys;

Th comprise an amino acid sequence that constitutes a helper T cell epitope, selected from the group consisting of SEQ ID NOS;

3, 5, 6, 9, and 10 and an immune enhancing analog thereof;

(N-terminal fragment of Aβ

1-42 peptide) is 10 to about 28 amino acid residues and wherein each fragment comprises EFRH of the Aβ

1-42 peptide and immunologically functional analog thereof;

X is an α

-COOH or α

-CONH₂ of an amino acid;

n is from 0 to about 10;

m is from 1 to about 4;

and o is from 0 to about 10.

43. A peptide immunogen of claim 42, wherein the spacer is ε

-N-Lys.

44. A peptide immunogen of claim 42, wherein the N-terminal fragment of Aβ

1-42 peptide is selected from the group consisting of the first 10 amino acids of SEQ ID NO;

2 the first 12 amino acids of SEQ ID NO;

2, and the first 28 amino acids of SEQ ID NO;

2 and the immunologically functional analog thereof.

45. A peptide immunogen of claim 43, wherein the N-terminal fragment of Aβ

1-42 peptide is selected from the group consisting of the first 10 amino acids of SEQ ID NO;

2 the first 12 amino acids of SEQ ID NO;

2, and the first 28 amino acids of SEQ ID NO;

2 and the immunologically functional analog thereof.

46. A peptide immunogen of claim 42, wherein Th is selected from the group consisting of SEQ ID NOS:

3, 5, 6, 9, and 10.

47. A peptide immunogen of claim 43 wherein Th is selected from the group consisting of SEQ ID NOS:

3, 5, 6, 9, and 10.

48. A peptide immunogen of claim 44 wherein Th is selected from the group consisting of SEQ ID NOS:

3, 5, 6, 9, and 10.

49. A peptide immunogen of claim 45 wherein Th is selected from the group consisting of SEQ ID NOS:

3, 5, 6, 9, and 10.

58. A composition comprising a peptide immunogen of claim 42 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, saponin, squalene, monophosphoryl lipid A (MPL), polysorbate 80, QS21.

59. A composition comprising a peptide immunogen of claim 43 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, saponin, squalene, monophosphoryl lipid A (MPL), polysorbate 80, QS21.

60. A composition comprising a peptide immunogen of claim 44 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, saponin, squalene, monophosphoryl lipid A (MPL), polysorbate 80, QS21.

61. A composition comprising a peptide immunogen of claim 45 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, saponin, squalene, monophosphoryl lipid A (MPL), polysorbate 80, QS21.

62. A composition comprising a peptide immunogen of claim 46 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, saponin, squalene, monophosphoryl lipid A (MPL), polysorbate 80, QS21.

63. A composition comprising a peptide immunogen of claim 47 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, saponin, squalene, monophosphoryl lipid A (MPL), polysorbate 80, QS21.

64. A composition comprising a peptide immunogen of claim 48 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, saponin, squalene, monophosphoryl lipid A (MPL), polysorbate 80, QS21.

65. A composition comprising a peptide immunogen of claim 49 and a pharmaceutically acceptable adjuvant and/or carrier selected from the group consisting of alum, saponin, squalene, monophosphoryl lipid A (MPL), polysorbate 80, QS21.

73. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 58.

74. A method of preventing Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 59.

75. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 60.

76. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 61.

77. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 62.

78. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 63.

79. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 64.

80. A method of preventing or treating Alzheimer'"'"'s disease by administrating to a mammal a composition of claim 65.

88. A method of producing antibodies to Aβ

1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 58.

89. A method of producing antibodies to Aβ

1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 59.

90. A method of producing antibodies to Aβ

1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 60.

91. A method of producing antibodies to Aβ

1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 61.

92. A method of producing antibodies to Aβ

1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 62.

93. A method of producing antibodies to Aβ

1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 63.

94. A method of producing antibodies to Aβ

1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 64.

95. A method of producing antibodies to Aβ

1-42 peptide that is cross reactive to soluble Aβ

peptides and brain tissue plaques formed therefrom by administering a composition of claim 65.

96. A composition comprising an Aβ

fragment linked to a tetanus toxoid or toxoid derivative carrier molecule to form a conjugate, wherein the Aβ

fragment is an N-terminal fragment selected from the group consisting of the first 10 amino acids of SEQ ID NO;

2 the first 12 amino acids of SEQ ID NO;

2, and the first 28 amino acids of SEQ ID NO;

2 and the immunogenic analogs thereof.

97. A composition comprising an Aβ

fragment linked to an E. Coli toxoid or toxoid derivative carrier molecule to form a conjugate, wherein the Aβ

fragment is an N-terminal fragment selected from the group consisting of the first 10 amino acids of SEQ ID NO;

2 the first 12 amino acids of SEQ ID NO;

2, and the first 28 amino acids of SEQ ID NO;

2 and the immunogenic analogs thereof.

98. A composition comprising an Aβ

fragment linked to a diphtheria toxoid or toxoid derivative carrier molecule to form a conjugate, wherein the Aβ

fragment is an N-terminal fragment selected from the group consisting of the first 10 amino acids of SEQ ID NO;

2 the first 12 amino acids of SEQ ID NO;

2, and the first 28 amino acids of SEQ ID NO;

2 and the immunogenic analogs thereof.

99. A composition comprising an Aβ

fragment linked to a T cell epitope molecule to form a conjugate, wherein the T cell epitope is malaria CS and the Aβ

fragment is an N-terminal fragment selected from the group consisting of the first 10 amino acids of SEQ ID NO;

2 the first 12 amino acids of SEQ ID NO;

2, and the first 28 amino acids of SEQ ID NO;

2 and the immunogenic analogs thereof.

100. A composition comprising an Aβ

fragment linked to a T cell epitope molecule to form a conjugate, wherein the T cell epitope is hepatitis B surface antigen CS and the Aβ

fragment is an N-terminal fragment selected from the group consisting of the first 10 amino acids of SEQ ID NO;

2 the first 12 amino acids of SEQ ID NO;

2, and the first 28 amino acids of SEQ ID NO;

2 and the immunogenic analogs thereof.