Prevention and treatment of amyloidogenic disease

• US 20050019330A1
• Filed: 08/20/2004
• Published: 01/27/2005
• Est. Priority Date: 12/02/1997
• Status: Active Grant

• Current Assignee: Janssen Alzheimer Immunotherapy (Johnson & Johnson)
• Original Assignee: Neuralab Ltd. (Perrigo Company PLC)
• Inventors: Schenk, Dale B.
• Granted Patent: US 8,034,339 B2
• Time in Patent Office: Days
• US Class Current: 424/146.100
• 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 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, active fragments thereof or an antibody thereto.

Claims

1. A method of preventing or treating a disease characterized by amyloid deposit in a patient, comprising administering an effective dosage of an antibody that specifically binds to the amyloid deposit or a component thereof to the patient.

2. The method of claim 1, wherein the disease is Alzheimer'"'"'s disease.

3. The method of claim 1, wherein the amyloid deposit comprises aggregated Aβ

peptide.

4. The method of claim 1, wherein the patient is a human.

5. The method of claim 1, wherein the patient is asymptomatic.

6. The method of claim 1, wherein the patient is under 50.

7. The method of claim 1, wherein the patient has inherited risk factors indicating susceptibility to Alzheimer'"'"'s disease.

8. The method of claim 1, wherein the patient has no known risk factors for Alzheimer'"'"'s disease.

9. The method of claim 2, wherein the antibody specifically binds to Aβ

peptide.

10. The method of claim 9, wherein the antibody is a human antibody.

11. The method of claim 9, wherein the antibody is a humanized antibody.

12. The method of claim 9, wherein the antibody is a chimeric antibody.

13. The method of claim 9, wherein the antibody is a mouse antibody.

14. The method of claim 9, wherein the antibody is a polyclonal antibody.

15. The method of claim 9, wherein the antibody is a monoclonal antibody.

16. The method of claim 14, wherein the antibody is a rabbit antibody.

17. The method of claim 1, further comprising administering an effective dosage of a second antibody that binds to the amyloid deposit or a component thereof.

18. The method of claim 15, wherein the isotype of the antibody is IgG1 or IgG4.

19. The method of claim 15, wherein the isotype of the antibody is IgG2 or IgG3.

20. The method of claim 9, wherein the antibody is a Fab fragment.

21. The method of claim 9, wherein a chain of the antibody is fused to a heterologous polypeptide.

22. The method of claim 9, wherein the dosage of antibody is at least 1 mg/kg body weight of the patient.

23. The method of claim 9, wherein the dosage of antibody is at least 10 mg/kg body weight of the patient.

24. The method of claim 9, wherein the antibody is administered with a carrier as a pharmaceutical composition.

25. The method of claim 9, wherein the antibody binds to an epitope within residues 1-28 of Aβ

,

26. The method of claim 25, wherein the antibody binds to an epitope within residues 1-10 of Aβ

27. The method of claim 25, wherein the antibody binds to an epitope within residues 1-16 of Aβ

.

28. The method of claim 25, wherein the antibody binds to an epitope within residues 1-5 of Aβ

.

29. The method of claim 9, wherein the antibody is a human antibody to Aβ

prepared from B cells from a human immunized with an Aβ

peptide.

31. The method of claim 9, wherein the antibody specifically binds to Aβ

peptide without binding to full-length amyloid precursor protein (APP).

32. The method of claim 1, wherein the agent is administered intraperitoneally, orally, subcutaneously, intramuscularly, topically or intravenously.

33. The method of claim 1, wherein the antibody is administered by administering a polynucleotide encoding at least one antibody chain to the patient, wherein the polynucleotide is expressed to produce the antibody chain in the patient.

34. The method of claim 33, wherein the polynucleotide encodes heavy and light chains of the antibody, which polynucleotide is expressed to produce the heavy and light chains in the patient.

36. The method of claim 1, wherein the antibody is administered in multiple dosages over a period of at least six months.

37. The method of claim 1, wherein the antibody is administered as a sustained release composition.

30. The method of claim , wherein the human immunized with Aβ

peptide is the patient.

35. The method of 1, further comprising monitoring the patient for level of administered antibody in the blood of the patient.

38. A method of preventing or treating Alzheimer'"'"'s disease, comprising administering an effective dosage of a polypeptide comprising an active fragment of Aβ

that induces an immune response to Aβ

in the patient.

39. The method of claim 38, wherein the fragment comprises an epitope within amino acids 1-12 of Aβ

.

40. The method of claim 38, wherein the fragment comprises an epitope within amino acids 1-16 of Aβ

.

41. The method of claim 38, wherein the fragment comprises an epitope within amino acids 13-28 of Aβ

.

42. The method of claim 38, wherein the fragment is free of at least the 5 C-terminal amino acids in Aβ

43.

43. The method of claim 38, wherein the fragment comprises up to 20 contiguous amino acids from Aβ

.

44. The method of claim 39, wherein the fragment is administered with an adjuvant that enhances the immune response to the Aβ

peptide.

45. The method of claim 44, wherein the adjuvant and the agent are administered together as a composition.

46. The method of claim 44, wherein the adjuvant is administered before the agent.

47. The method of claim 44, wherein the adjuvant is administered after the agent.

48. The method of claim 44, wherein the adjuvant is alum.

49. The method of claim 44, wherein the adjuvant is MPL.

50. The method of claim 44, wherein the adjuvant is QS-21.

51. The method of claim 44, wherein the adjuvant is incomplete Freund'"'"'s adjuvant.

52. The method of claim 44, wherein the dosage of the fragment is greater than 10 micrograms.

53. A pharmaceutical composition comprising an active fragment of Aβ

effective to induce a response to AB in a patient and an adjuvant.

54. A method of screening an antibody to Aβ

or an active fragment of Aβ

for use in treatment of Alzheimer'"'"'s disease, comprising;

administering an antibody that specifically binds to Aβ

or a fragment of AB to a transgenic animal disposed to develop characteristics of Alzheimer'"'"'s disease;

detecting a reduction in the extent or rate of development of the characteristics relative to a control transgenic animal.

55. The method of claim 54, further comprising screening a population of antibodies to identify an antibody that binds to an epitope within amino acids 1-28 of Aβ

.

56. A method of preventing or treating a disease characterized by amyloid deposit in a patient, comprising administering an effective dosage of an antibody that specifically binds to the amyloid deposit or a component thereof to the patient, wherein the antibody specifically binds to an epitope within residues 13-28 of Aβ

.

57. The method of claim 56, wherein the antibody is the monoclonal antibody designated as 266.

58. The method of claim 56, wherein the antibody competes with the monoclonal antibody designated as 266 for binding to Aβ

.

59. The method of claim 56, wherein the disease is Alzheimer'"'"'s disease.

60. The method of claim 56, wherein the amyloid deposit comprises aggregated Aβ

peptide.

61. The method of claim 56, wherein the patient is a human.

62. The method of claim 56, wherein the patient is asymptomatic.

63. The method of claim 56, wherein the patient is under 50.

64. The method of claim 56, wherein the patient has inherited risk factors indicating susceptibility to Alzheimer'"'"'s disease.

65. The method of claim 56, wherein the patient has no known risk factors for Alzheimer'"'"'s disease.

66. The method of claim 56, wherein the antibody is a fragment of an intact antibody that competes with the intact antibody for specific binding to Aβ

, and the antibody fragment is selected from the group consisting of Fab, Fab′

, F(ab′

)₂, Fabc, and Fv.

67. The method of claim 56, wherein the antibody is a human antibody.

68. The method of claim 66, wherein the human antibody is an antibody, fragment.

69. The method of claim 67, wherein the human antibody is produced by recombinant expression.

70. The method of claim 66, wherein the antibody is a human antibody.

71. The method of claim 56, wherein the antibody is a humanized antibody.

72. The method of claim 71, wherein the humanized antibody is an antibody fragment.

73. The method of claim 66, wherein the antibody is a humanized antibody.

74. The method of claim 56, wherein the antibody is a chimeric antibody.

75. The method of claim 74, wherein the chimeric antibody is an antibody fragment.

76. The method of claim 66, wherein the antibody is a chimeric antibody.

77. The method of claim 56, wherein the antibody is a bispecific antibody.

78. The method of claim 77, wherein the bispecific antibody is an antibody fragment.

79. The method of claim 66, wherein the antibody is a bispecific antibody.

80. The method of claim 56, wherein the antibody is a mouse antibody.

81. The method of claim 56, wherein the antibody is a polyclonal antibody.

82. The method of claim 56, wherein the antibody is a monoclonal antibody.

83. The method of claim 81, wherein the antibody is a rabbit antibody.

84. The method of claim 56, further comprising administering an effective dosage of a second antibody that binds to the amyloid deposit or a component thereof.

85. The method of claim 82, wherein the isotype of the antibody is IgG1.

86. The method of claim 56, wherein a chain of the antibody is fused to a heterologous polypeptide.

87. The method of claim 56, wherein the dosage of antibody is at least 1 mg/kg body weight of the patient.

88. The method of claim 56, wherein the dosage of antibody is at least 10 mg/kg body weight of the patient.

89. The method of claim 56, wherein the antibody is administered with a carrier as a pharmaceutical composition.

90. The method of claim 56, wherein the antibody is a human antibody to Aβ

prepared from B cells from a human immunized with an Aβ

peptide.

91. The method of claim 90, wherein the human immunized with Aβ

peptide is the patient.

92. The method of claim 56, wherein the agent is administered intraperitoneally, orally, subcutaneously, intramuscularly, topically or intravenously.

93. The method of claim 56, wherein the antibody is administered in multiple dosages over a period of at least six months.

94. The method of claim 56, wherein the antibody is administered as a sustained release composition.

95. A monoclonal antibody which specifically binds to an epitope within residues 13-28 of Aβ

wherein the monoclonal antibody is designated as 266.

96. A humanized antibody comprising a humanized antibody which specifically binds to an epitope within residues 13-28 of Aβ

, wherein the humanized antibody is the humanized form of the monoclonal antibody designated as 266.

97. A pharmaceutical composition comprising an antibody which specifically binds to an epitope within residues 13-28 of Aβ

effective to specifically bind to the amyloid deposit or a component thereof to the patient.

98. The pharmaceutical composition of claim 97, wherein the antibody is a humanized antibody.

99. The pharmaceutical composition of claim 97, wherein the antibody is designated as 266.

100. The pharmaceutical composition of claim 99, wherein the antibody is a humanized form of monoclonal antibody 266.

101. A humanized antibody that specifically binds an epitope contained within positions 13-28 of Aβ

.

104. The humanized antibody of claims 101, 102, or 103 that is an intact humanized antibody.

105. The humanized antibody of claims 101, 102, or 103 that is a fragment.

106. The humanized antibody of claims 101, 102, or 103 that specifically binds to an epitope having an amino acid between positions 10-20, 10-25, 13-28, 15-20, or 20-30 of Aβ

.

107. The humanized antibody of claims 101, 102, or 103 that specifically binds to an epitope within amino acid residues 10-20, 10-25, 13-28, 15-20, or 20-30 of Aβ

.

110. The humanized antibody of claims 101, 102, or 103 that specifically binds to an epitope of Aβ

to which antibody 266 binds.

114. The humanized antibody of claims 101, 102, or 103, which is a single chain antibody.

115. The humanized antibody of claims 101, 102, or 103, which comprises human framework regions.

116. The humanized antibody of claims 101, 102, or 103, which comprises CDR.

117. The humanized antibody of claims 101, 102, or 103, which is humanized Mab 266.

118. The humanized antibody, or fragment thereof, of claim 117, comprising a humanized light chain comprising the light chain complementarity determining regions (CDRs) from the mouse monoclonal antibody 266 and a light chain variable region framework sequence from a human immunoglobulin fight chain;

and a humanized heavy chain comprising the heavy chain CDRs from the mouse monoclonal antibody 266 and a heavy chain variable region framework sequence from a human immunoglobulin heavy chain.

119. An antibody fragment obtainable by enzymatic cleavage of the humanized antibody of any one of claims 101-118.

120. The fragment of claim 119 which is an Fab or F(ab′

)₂ fragment.

121. The fragment of claim 120, which is an F(ab′

)₂ fragment.

122. The fragment of claim 120, which is an F(ab′

)₂ fragment.

123. The humanized antibody or fragment of any one of claims 101-122 that is an IgG1 immunoglobulin isotype.

124. The humanized antibody or fragment of any one of claims 101-119, wherein the antibody or fragment thereof is produced in a host cell selected from the group consisting of a myeloma cell and a Chinese hamster ovary cell.

125. The humanized antibody or fragment of any one of claims 101-124, which is administered peripherally to a human subject, to exert its beneficial effects.

126. The humanized antibody or fragment of any one of claims 101-124, which, when administered peripherally to a human subject, does not need to cross the subject'"'"'s blood-brain barrier to exert its beneficial effects.

127. The humanized antibody or fragment of any one of claims 101-124, which, when administered peripherally to a human subject, does not require cellular responses in the subject'"'"'s brain to exert its beneficial effects.

128. The humanized antibody or fragment of any one of claims 101-124, which, when administered peripherally to a human subject, does not substantially bind aggregated Aβ

in the subject'"'"'s brain.

129. The humanized antibody or fragment of any one of claims 101-124, which, when administered peripherally to a human subject, exhibits beneficial effects without necessarily binding to Aβ

plaques in the brain.

130. A nucleic acid, comprising a sequence coding for the light chain or the heavy chain of the humanized antibody of any one of claims 101-129, or a fragment thereof.

131. One or more nucleic acids, which when expressed in a suitable host cell, yield an antibody of any one of claims 101-129.

132. An expression vector for expressing the antibody or fragment of any one of claims 101-129 comprising nucleotide sequences encoding said antibody or fragment.

133. A cell transfected with the expression vector of claim 132.

134. A cell transfected with two expression vectors of claim 132, wherein a first vector comprises a nucleotide sequence encoding a light chain and a second vector comprises a nucleotide sequence encoding a heavy chain, wherein the first and second nucleotide sequences are components of the vector of claim 132.

135. A recombinant cell that produces the humanized antibody or fragment of any one of claims 117-118.

136. The cell of any one of claims 133-135, wherein the cell is selected from the group consisting of a myeloma cell, a Chinese hamster ovary cell and a Syrian hamster ovary cell.

137. A pharmaceutical composition that comprises the humanized antibody or fragment of any one of claims 101-129, and a pharmaceutically acceptable excipient.

151. A method of reversing cognitive decline in a subject comprising administering to the subject an effective amount of a humanized antibody or fragment of any one of claims 101-129.

152. A method of improving cognition in a subject comprising administering to the subject an effective amount of a humanized antibody or fragment of any one of claims 101-129.

153. A method of treating cognitive decline in a subject comprising administering to the subject an effective amount of a humanized antibody or fragment of any one of claims 101-129.

154. A method of preventing cognitive decline in a subject comprising administering to the subject an effective amount of a humanized antibody or fragment of any one of claims 101-129.

155. The method of any one of claims 151-154, wherein said antibody or fragment is administered peripherally to humans.

156. The method of any one of claims 151-154, wherein said antibody or fragment, when administered peripherally to humans, does not need to cross the blood-brain barrier to affect cognition.

157. The method of any one of claims 151-154, wherein said antibody or fragment, when administered peripherally to humans, does not require cellular responses to affect cognition.

158. The method of any one of claims 151-154, wherein said antibody or fragment, when administered peripherally to humans, does not substantially bind aggregated Aβ

in the brain.

159. The method of any one of claims 151-157, wherein the subject is diagnosed with clinical or pre-clinical Alzheimer'"'"'s disease or Down'"'"'s syndrome.

160. The method of any one of claims 151-157, wherein the subject is not diagnosed with clinical or pre-clinical Alzheimer'"'"'s disease or Down'"'"'s syndrome.

161. The method of any one of claims 151-160, wherein the antibody is administered by a peripheral route.

162. The method of claim 161, wherein the antibody is administered by an oral, intraperitoneal, subcutaneous, intramuscular, or intravenous route.

163. A method of treating Alzheimer'"'"'s disease, comprising administering to a patient in need thereof an effective amount of the antibody or fragment of any one of claims 101-129.

102. A humanized antibody that binds to soluble Aβ

.

108. The humanized antibody of claims 102, or 103 that specifically binds to an epitope within amino acid residues 13-28 of Aβ

.

109. The humanized antibody of claims 102, or 103 that specifically binds to an epitope having an amino acid between positions 13-28 of Aβ

.

111. The humanized antibody of claims 102 or 103, which specifically binds an epitope contained in positions 10-20, 13-28, or 15-20 of said Aβ

peptide.

112. The humanized antibody of claim 111, which specifically binds an epitope that includes positions 15-20 of said Aβ

peptide.

113. The humanized antibody of claim 111, which specifically binds an epitope that includes positions 16, 17 or 18 of said Aβ

peptide.

103. A humanized antibody that sequesters Aβ

peptide from its bound, circulating form in the blood, and alters clearance of soluble and bound forms of Aβ

in central nervous system and plasma.

138. A method to inhibit the formation of amyloid plaques in humans, comprising administering to a human subject in need or such inhibition an effective amount of a humanized antibody or fragment thereof that specifically immunoreacts with an epitope contained in positions 13-28 of Aβ

.

144. The method of any of claims 138-143, wherein said antibody or fragment, when administered peripherally to humans, does not need to cross the blood-brain barrier to inhibit the formation of amyloid plaques.

145. The method of claim 138 or claim 139, wherein said antibody or fragment, when administered peripherally to humans, does not elicit cellular responses to inhibit the formation of amyloid plaques.

146. The method of any of claims 138-143, wherein said antibody or fragment, when administered peripherally to humans, does not substantially bind aggregated Aβ

in the brain.

147. The method of any one of claims 138-146, wherein the subject is diagnosed with clinical or pre-clinical Alzheimer'"'"'s disease or Down'"'"'s syndrome.

148. The method of any one of claims 138-146, wherein the subject is not diagnosed with clinical or pre-clinical Alzheimer'"'"'s disease or Down'"'"'s syndrome.

149. The method of any one of claims 138-139 or 144-148, wherein the antibody is administered by a peripheral route.

150. The method of claim 149, wherein the antibody is administered by an oral, intraperitoneal, subcutaneous, intramuscular, or intravenous route.

139. A method to reduce amyloid plaques in humans, comprising administering to a human subject in need of such reduction an effective amount of a humanized antibody or fragment thereof which specifically immunoreacts with an epitope contained in positions 13-28 of Aβ

.

140. A method to inhibit the formation of amyloid plaques in humans, comprising administering to a human subject in need of such inhibition an effective amount of a humanized antibody or fragment thereof that binds to soluble Aβ

peptide.

141. A method to inhibit the formation of amyloid plaques in humans, comprising administering to a human subject in need of such inhibition an effective amount of a humanized antibody or fragment thereof that sequesters Aβ

peptide from its bound, circulating form in blood.

142. A method to reduce amyloid plaques in humans, comprising administering to a human subject in need of such reduction an effective amount of a humanized antibody or fragment thereof which binds to soluble Aβ

peptide.

143. A method to reduce amyloid plaques in humans, comprising administering to a human subject in need of such reduction an effective amount of a humanized antibody or fragment thereof which sequesters Aβ

peptide from its bound, circulating form in blood.