Humanized antibodies that recognize beta amyloid peptide

• US 20050118651A1
• Filed: 06/01/2004
• Published: 06/02/2005
• Est. Priority Date: 05/30/2003
• Status: Active Grant

• Current Assignee: Janssen Alzheimer Immunotherapy (Johnson & Johnson), Wyeth LLC (Pfizer Inc.)
• Original Assignee: Neuralab Ltd. (Perrigo Company PLC), Wyeth (Pfizer Inc.)
• Inventors: Saldanha, Jose, Basi, Guriq, Bard, Frederique
• Granted Patent: US 7,871,615 B2
• Time in Patent Office: Days
• US Class Current: 435/7.200
• CPC Class Codes: A61K 2039/505 comprising antibodies
• 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: 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 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/567 Framework region [FR]
• CPC Class Codes: C07K 2317/77 Internalization into the cell
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

The invention provides improved agents and methods for treatment of diseases associated with amyloid deposits of Aβ in the brain of a patient. Preferred agents include antibodies, e.g., humanized antibodies.

Claims

1. A humanized immunoglobulin light chain comprising (i) variable region complementarity determining regions (CDRs) from the 12A11 immunoglobulin light chain variable region sequence set forth as SEQ ID NO:

2, and (ii) a variable framework region from a human acceptor immunoglobulin light chain sequence.

24. A humanized immunoglobulin comprising the light chain of any one of claims 1, 2, 5-7, 11, 13, 15 and 18-20, and the heavy chain of any one of claims 3, 4, 8-10, 12, 14, 16-17 and 21-23, or antigen-binding fragment of said immunoglobulin.

25. The immunoglobulin or antigen binding fragment of claim 24, which specifically binds to beta amyloid peptide (Aβ

) with a binding affinity of at least 10<sup>−

7</sup> M.

26. The immunoglobulin or antigen binding fragment of claim 24, which specifically binds to beta amyloid peptide (Aβ

) with a binding affinity of at least 10<sup>−

8</sup> M.

27. The immunoglobulin or antigen binding fragment of claim 24, which specifically binds to beta amyloid peptide (Aβ

) with a binding affinity of at least 10<sup>−

9</sup> M.

28. The immunoglobulin or antigen binding fragment of claim 24, wherein the heavy chain isotype is γ

l.

29. The immunoglobulin or antigen binding fragment of claim 24, which binds to soluble beta amyloid peptide (Aβ

).

30. The immunoglobulin or antigen binding fragment of claim 24, which binds to aggregated beta amyloid peptide (Aβ

).

31. The immunoglobulin or antigen binding fragment of claim 24, which mediates phagocytosis of beta amyloid peptide (Aβ

).

32. The immunoglobulin or antigen binding fragment of claim 24, which crosses the blood-brain barrier in a subject.

33. The immunoglobulin or antigen binding fragment of claim 24, which reduces beta amyloid peptide (Aβ

) plaque burden in a subject.

45. A method of preventing or treating an amyloidogenic disease in a patient, comprising administering to the patient an effective dosage of the humanized immunoglobulin of any one of claims 24-43.

46. A method of preventing or treating Alzheimer'"'"'s disease in a patient, comprising administering to the patient an effective dosage of the humanized immunoglobulin of any one of claims 24-43.

47. The method of claim 46, wherein the effective dosage of humanized immunoglobulin is at least about 1 mg/kg body weight.

48. The method of claim 46, wherein the effective dosage of humanized immunoglobulin is at least about 10 mg/kg body weight.

49. A pharmaceutical composition comprising the immunoglobulin of any one of claims 24-43 and a pharmaceutical carrier.

66. An isolated nucleic acid molecule encoding the light chain of any one of claims 1, 2, 5-7, 11, 13, 15 and 18-20.

68. An isolated nucleic acid molecule encoding the polypeptide of any one of claims 46-65.

71. A vector comprising the nucleic acid molecule of any of claims 66-70.

72. A host cell comprising the nucleic acid molecule of any of claims 66-70.

73. A transgenic animal expressing a polypeptide encoded by the nucleic acid molecule of any of the preceding claims.

74. The transgenic animal of claim 73, wherein the polypeptide is expressed in the milk of said animal.

75. A method of producing an antibody, or fragment thereof, comprising culturing the host cell of claim 72 under conditions such that the antibody or fragment is produced and isolating said antibody from the host cell or culture.

86. A method of preventing or treating a disease associated with amyloid deposits of Aβ

in the brain of a patient, comprising administering to the patient an effective dosage of the humanized immunoglobulin of any one of the preceding claims.

87. The method of claim 86, wherein the disease is characterized by cognitive impairment.

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

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

90. The method of claim 86, wherein the disease is mild cognitive impairment.

91. The method of claim 86, wherein the antibody is of human isotype IgG1.

92. The method of any of the preceding claims, wherein the patient is human.

93. The method of any one of claims 86-92, wherein after administration the antibody binds to an amyloid deposit in the patient and induces a clearing response against the amyloid deposit.

94. The method of claim 93, wherein the clearing response is an Fc receptor-mediated phagocytosis response.

95. The method of claim 93 or 94, further comprising monitoring the clearing response.

96. The method of any one of claims 86-92, wherein after administration the antibody binds to soluble Aβ

in the patient.

97. The method of any one of claims 86-92, wherein after administration the antibody binds to soluble Aβ

in the serum, blood or cerebrospinal fluid of the patient.

98. The method of any of one of claims 86-97, wherein the patient is asymptomatic.

99. The method of any one of claims 86-98, wherein the patient is under 50 years of age.

100. The method of any one of claims 86-99, wherein the patient has an inherited risk factor indicating susceptibility to Alzheimer'"'"'s disease.

101. The method of any one of claims 86-100, wherein the dosage of antibody is at least 1 mg/kg body weight of the patient.

102. The method of any one of claims 86-100, wherein the dosage of antibody is at least 10 mg/kg body weight of the patient.

103. The method of any one of claims 86-102, wherein the antibody is administered with a carrier as a pharmaceutical composition.

104. The method of any one of claims 77-103, wherein the antibody is administered intraperitoneally, orally, intranasally, subcutaneously, intramuscularly, topically or intravenously.

105. A method for reducing plaque burden in a subject in need thereof comprising administering to the patient an effective dosage of the humanized immunoglobulin of any one of the preceding claims.

106. The method of claim 105, wherein after administration the antibody binds to an amyloid deposit in the patient and induces a clearing response against the amyloid deposit.

107. The method of claim 106, wherein the clearing response is an Fc receptor-mediated phagocytosis response.

108. The method of claim 106 or 107, further comprising monitoring the clearing response.

109. The method of claim 105, wherein after administration the antibody binds to soluble Aβ

in the patient.

110. The method of claim 105, wherein after administration the antibody binds to soluble Aβ

in the serum, blood or cerebrospinal fluid of the patient.

111. A humanized immunoglobulin of any one of the preceding claims, which comprises a Fc region having an altered effector function.

2. A humanized immunoglobulin light chain comprising (i) variable region complementarity determining regions (CDRs) from the 12A11 immunoglobulin light chain variable region sequence set forth as SEQ ID NO:

2, and (ii) a variable framework region from a human acceptor immunoglobulin light chain sequence, provided that at least one framework residue is substituted with the corresponding amino acid residue from the mouse 12A11 light chain variable region sequence, wherein the framework residue is selected from the group consisting of;

(a) a residue that non-covalently binds antigen directly;

(b) a residue adjacent to a CDR;

(c) a CDR-interacting residue; and

(d) a residue participating in the VL-VH interface.

5. The light chain of claim 2, wherein a CDR-interacting residue is identified by modeling the 12A11 light chain based on the solved structure of a murine immunoglobulin light chain that shares at least 70% sequence identity with the 12A11 light chain.

6. The light chain of claim 2, wherein a CDR-interacting residue is identified by modeling the 12A11 light chain based on the solved structure of a murine immunoglobulin light chain that shares at least 80% sequence identity with the 12A11 light chain.

7. The light chain of claim 2, wherein a CDR-interacting residue is identified by modeling the 12A11 light chain based on the solved structure of a murine immunoglobulin light chain that shares at least 90% sequence identity with the 12A11 light chain.

3. A humanized immunoglobulin heavy chain comprising (i) variable region complementarity determining regions (CDRs) from the 12A11 immunoglobulin heavy chain variable region sequence set forth as SEQ ID NO:

4, and (ii) a variable framework region from a human acceptor immunoglobulin heavy chain

4. A humanized immunoglobulin heavy chain comprising (i) variable region complementarity determining regions (CDRs) from the 12A11 immunoglobulin heavy chain variable region sequence set forth as SEQ ID NO:

4, and (ii) a variable framework region from a human acceptor immunoglobulin heavy chain, provided that at least one framework residue is substituted with the corresponding amino acid residue from the mouse 12A11 heavy chain variable region sequence, wherein the framework residue is selected from the group consisting of

(a) a residue that non-covalently binds antigen directly;

(b) a residue adjacent to a CDR;

(c) a CDR-interacting residue; and

(d) a residue participating in the VL-VH interface.

8. The heavy chain of claim 4, wherein a CDR-interacting residue is identified by modeling the 12A11 heavy chain based on the solved structure of a murine immunoglobulin heavy chain that shares at least 70% sequence identity with the 12A11 heavy chain.

9. The heavy chain of claim 4, wherein a CDR-interacting residue is identified by modeling the 12A11 heavy chain based on the solved structure of a murine immunoglobulin heavy chain that shares at least 80% sequence identity with the 12A11 heavy chain.

10. The heavy chain of claim 4, wherein a CDR-interacting residue is identified by modeling the 12A11 heavy chain based on the solved structure of a murine immunoglobulin heavy chain that shares at least 90% sequence identity with the 12A11 heavy chain.

67. An isolated nucleic acid molecule encoding the heavy chain of any one of claims 3, 4, 8-10, 12, 14, 16-17 and 21-23.

11. A humanized immunoglobulin light chain comprising (i) variable region complementarity determining regions (CDRs) from the 12A11 immunoglobulin light chain variable region sequence set forth as SEQ ID NO:

2, and (ii) a variable framework region from a human acceptor immunoglobulin light chain sequence, provided that at least one framework residue is substituted with the corresponding amino acid residue from the mouse 12A11 light chain variable region sequence, wherein the framework residue is a residue capable of affecting light chain variable region conformation or function as identified by analysis of a three-dimensional model of the 12A11 immunoglobulin light chain variable region.

13. The light chain of claim 11, wherein the framework residue is selected from the group consisting of a residue capable of interacting with antigen, a residue proximal to the antigen binding site, a residue capable of interacting with a CDR, a residue adjacent to a CDR, a residue within 6 Å

of a CDR residue, a canonical residue, a vernier zone residue, an interchain packing residue, a rare residue, and a glycoslyation site residue on the surface of the structural model.

15. The light chain of claim 11, wherein the framework residue is substituted in at least one position selected from the group consisting of position 2, 4, 36, 38, 40, 44, 46, 47, 48, 49, 64, 66, 68, 69, 71, 87 and 98 of the light chain as numbered according to Kabat.

18. The light chain of claim 11 or 13, wherein the framework residue is identified by modeling the 12A11 light chain based on the solved structure of a murine immunoglobulin light chain that shares at least 70% sequence identity with the 12A11 light chain.

19. The light chain of claim 11 or 13, wherein the framework residue is identified by modeling the 12A11 light chain based on the solved structure of a murine immunoglobulin light chain that shares at least 80% sequence identity with the 12A11 light chain.

20. The light chain of claim 11 or 13, wherein the framework residue is identified by modeling the 12A11 light chain based on the solved structure of a murine immunoglobulin light chain that shares at least 90% sequence identity with the 12A11 light chain.

12. A humanized immunoglobulin heavy chain comprising (i) variable region complementarity determining regions (CDRs) from the 12A11 immunoglobulin heavy chain variable region sequence set forth as SEQ ID NO:

4, and (ii) a variable framework region from a human acceptor immunoglobulin heavy chain, provided that at least one framework residue is substituted with the corresponding amino acid residue from the mouse 12A11 heavy chain variable region sequence, wherein the framework residue is a residue capable of affecting heavy chain variable region conformation or function as identified by analysis of a three-dimensional model of the 12A11 immunoglobulin heavy chain variable region.

14. The heavy chain of claim 12, wherein the framework residue is selected from the group consisting of a residue capable of interacting with antigen, a residue proximal to the antigen binding site, a residue capable of interacting with a CDR, a residue adjacent to a CDR, a residue within 6 Å

of a CDR residue, a canonical residue, a vernier zone residue, an interchain packing residue, an unusual residue, and a glycoslyation site residue on the surface of the structural model.

16. The heavy chain of claim 12, wherein the framework residue is substituted in at least one position selected from the group consisting of position 2, 24, 26, 27, 28, 29, 37, 39, 45, 47, 48, 67, 71, 73, 78, 91, 93, 94 and 103 of the heavy chain as numbered according to Kabat.

17. The heavy chain of claim 12, wherein the framework residue is substituted at a position selected from the group consisting of position 24, 28, 29, 37, 48, 67, 71, 73 and 78 of the heavy chain as numbered according to Kabat.

21. The heavy chain of claim 12 or 14, wherein the framework residue is identified by modeling the 12A11 heavy chain based on the solved structure of a murine immunoglobulin heavy chain that shares at least 70% sequence identity with the 12A11 heavy chain.

22. The heavy chain of claim 12 or 14, wherein the framework residue is identified by modeling the 12A11 heavy chain based on the solved structure of a murine immunoglobulin heavy chain that shares at least 80% sequence identity with the 12A11 heavy chain.

23. The heavy chain of claim 12 or 14, wherein the framework residue is identified by modeling the 12A11 heavy chain based on the solved structure of a murine immunoglobulin heavy chain that shares at least 90% sequence identity with the 12A11 heavy chain.

69. An isolated nucleic acid molecule encoding the immunoglobulin of any one of claims 21-44.

34. A humanized immunoglobulin comprising a humanized heavy chain and a humanized light chain, wherein

(a) the humanized light chain comprises three complementarity determining regions (CDR1, CDR2 and CDR3) having amino acid sequences from the corresponding complementarily determining regions of the mouse 12A11 immunoglobulin light chain variable domain designated SEQ ID NO:

2, and a variable region framework from a human light chain variable region framework sequence provided that at least one framework residue selected from the group consisting of a canonical residue, a vernier residue, a packing residue and a rare residue, is occupied by the same amino acid residue present in the equivalent position of the mouse 12A11 immunoglobulin light chain variable region framework; and

(b) the humanized heavy chain comprises three complementarity determining regions (CDR1, CDR2 and CDR3) having amino acid sequences from the corresponding complementarity determining regions of the mouse 12A11 immunoglobulin heavy chain variable domain designated SEQ ID NO;

4, and a variable region framework from a human heavy chain variable region framework sequence provided that at least one framework residue selected from a second group consisting of a canonical residue, a vernier residue, a packing residue and a rare residue, is occupied by the same amino acid residue present in the equivalent position of the mouse 12A11 immunoglobulin heavy chain variable region framework;

wherein the humanized immunoglobulin specifically binds to beta amyloid peptide (“

Aβ

”

) with a binding affinity of at least 10<sup>−

7</sup> M, wherein the 12A11 immunoglobulin has the light chain with a variable domain designated SEQ ID NO;

2 and the heavy chain with a variable domain designated SEQ ID NO;

4.

35. The humanized immunoglobulin of claim 34, wherein human light chain variable region framework is from a kappa light chain variable region.

36. The humanized immunoglobulin of claim 34, wherein human heavy chain variable region framework is from an IgG1 heavy chain variable region.

37. The humanized immunoglobulin of claim 34, wherein the light chain variable region framework is from a human immunoglobulin light chain having at least 70% sequence identity with light chain sequence of the 12A11 immunoglobulin.

38. The humanized immunoglobulin of claim 34, wherein the heavy chain variable region framework is from a human immunoglobulin heavy chain having at least 70% sequence identity with heavy chain sequence of the 12A11 immunoglobulin.

39. The humanized immunoglobulin of claim 34, wherein the humanized light chain comprises complementarity determining regions that are identical to the corresponding complementarity determining regions of the mouse 12A11 heavy chain, and the humanized heavy chain comprises complementarity determining regions that are identical to the corresponding complementarity determining regions of the mouse 12A11 heavy chain.

40. A humanized antibody comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of the 12A11 variable light chain sequence set forth as SEQ ID NO:

2.

41. A humanized antibody comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of the 12A11 variable heavy chain sequence set forth as SEQ ID NO:

4.

42. A humanized antibody, or antigen-binding fragment thereof, which specifically binds to beta amyloid peptide (Aβ

), comprising a variable region comprising complementarity determining regions (CDRs) corresponding to CDRs from the mouse 12A11 antibody.

43. A humanized immunoglobulin having the variable light chain amino acid sequence set forth as SEQ ID NO:

6 and having a variable heavy chain amino acid sequence selected from the group consisting of SEQ ID NO;

8, SEQ ID NO;

9 and SEQ ID NO;

10.

44. A chimeric immunoglobulin comprising variable region sequence substantially as set forth in SEQ ID NO:

2 or SEQ ID NO;

4, and constant region sequences from a human immunoglobulin.

50. An isolated polypeptide comprising a fragment of SEQ ID NO:

2 selected from the group consisting of amino acids 43-58 of SEQ ID NO;

2, amino acids 74-80 of SEQ ID NO;

2 and amino acids 113-121 of SEQ ID NO;

2.

51. An isolated polypeptide comprising amino acids 43-48 of SEQ ID NO:

2, amino acids 74-80 of SEQ ID NO;

2 and amino acids 113-121 of SEQ ID NO;

2.

52. An isolated polypeptide comprising a fragment of SEQ ID NO:

4 selected from the group consisting of amino acids 50-56 of SEQ ID NO;

4, amino acids 71-86 of SEQ ID NO;

4 and amino acids 119-128 of SEQ ID NO;

4.

53. An isolated polypeptide comprising amino acids 50-56 of SEQ ID NO:

4, amino acids 71-86 of SEQ ID NO;

4 and amino acids 119-128 of SEQ ID NO;

4.

54. An isolated polypeptide comprising amino acids 1-131 of SEQ ID NO:

2.

55. An isolated polypeptide comprising amino acids 1-139 of SEQ ID NO:

4.

56. An isolated polypeptide having at least 85% identity to amino acids 1-131 of SEQ ID NO:

2.

58. The isolated polypeptide of claim 56 or 57, wherein the polypeptide has at least 86% identity.

59. The isolated polypeptide of claim 56 or 57, wherein the polypeptide has at least 87% identity.

60. The isolated polypeptide of claim 56 or 57, wherein the polypeptide has at least 88% identity.

61. The isolated polypeptide of claim 56 or 57, wherein the polypeptide has at least 89% identity.

62. The isolated polypeptide of claim 56 or 57, wherein the polypeptide has at least 90% identity.

63. The isolated polypeptide of claim 56 or 57, wherein the polypeptide has at least 90% or more identity.

57. An isolated polypeptide having at least 85% identity to amino acids 1-139 of SEQ ID NO:

4.

64. A variant of a polypeptide comprising the amino acid sequence of SEQ ID NO:

2, said variant comprising at least one conservative amino acid substitution, wherein the variant retains the ability to specifically bind beta amyloid peptide (Aβ

) with a binding affinity of at least 10⁷ M<sup>−

1</sup>.

65. A variant of a polypeptide comprising the amino acid sequence of SEQ ID NO:

4, said variant comprising at least one conservative amino acid substitution, wherein the variant retains the ability to direct specific binding to beta amyloid peptide (Aβ

) with a binding affinity of at least 10⁷ M<sup>−

1</sup>.

70. An isolated nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:

1 or 3.

76. A method of producing an antibody or antibody fragment, comprising a fragment of SEQ ID NO:

2 selected from the group consisting of amino acids 43-58 of SEQ ID NO;

2, amino acids 74-80 of SEQ ID NO;

2 and amino acids 113-121 of SEQ ID NO;

2, said method comprising culturing a host cell comprising a nucleic acid molecule that encodes said antibody or antibody fragment under conditions such that the antibody or antibody fragment is produced, and isolating said antibody or antibody fragment from the host cell or culture.

77. A method of producing an antibody or antibody fragment, comprising a fragment of SEQ ID NO:

4 selected from the group consisting of amino acids 50-56 of SEQ ID NO;

4, amino acids 71-86 of SEQ ID NO;

4 and amino acids 119-128 of SEQ ID NO;

4, said method comprising culturing a host cell comprising a nucleic acid molecule that encodes said antibody or antibody fragment, under conditions such that the antibody or antibody fragment is produced, and isolating said antibody or antibody fragment from the host cell or culture.

78. A method for identifying residues amenable to substitution in a humanized 12A11 immunoglobulin variable framework region, comprising modeling the three-dimensional structure of the 12A11 variable region based on a solved immunoglobulin structure and analyzing said model for residues capable of affecting 12A11 immunoglobulin variable region conformation or function, such that residues amenable to substitution are identified.

79. Use of the variable region sequence set forth as SEQ ID NO:

2 or SEQ ID NO;

4, or any portion thereof, in producing a three-dimensional image of a 12A11 immunoglobulin, 12A11 immunoglobulin chain, or domain thereof.

80. A methods of imaging amyloid deposits in the brain of a patient comprising administering to the patient an agent that specifically binds to Aβ

, and detecting the antibody bound to Aβ

.

81. The method of claim 80, wherein the agent is an antibody comprising a light chain variable sequence as set forth in SEQ ID NO:

2 and a heavy chain variable region sequence as set forth in SEQ ID NO;

4, or an antigen-binding fragment of said antibody.

82. The method of claim 80, wherein the antigen-binding fragment is a Fab fragment.

83. A kit for imaging according to the method of any one of claims 80-82 including instructions for use.

84. A method of treating an amyloidogenic disease comprising administering to a patient having said amyloidogenic disease, a nucleic acid molecule that encodes an immunoglobulin light chain comprising the CDRs of the amino acid sequence of SEQ ID NO:

2 and a nucleic acid molecule that encodes an immunoglobulin heavy chain that comprises the CDRs of the amino acid sequence of SEQ ID NO;

4, under conditions such that said immunoglobulin chains are expressed, such that a beneficial therapeutic response in said patient is generated.

85. A method of treating an amyloidogenic disease comprising administering to a patient having said amyloidogenic disease, a nucleic acid molecule that encodes an immunoglobulin light chain comprising the amino acid sequence of SEQ ID NO:

7 and a nucleic acid molecule that encodes an immunoglobulin heavy chain that comprises the amino acid sequence of SEQ ID NO;

10 or the amino acid sequence of any one of SEQ ID NOs;

13-31, under conditions such that said immunoglobulin chains are expressed, such that a beneficial therapeutic response in said patient is generated.

112. A method for reducing neuritic burden in a subject in need thereof comprising administering to the subject an effective dose of a humanized 12A11 antibody which binds to an epitope within amino acids 3-7 of beta amyloid peptide (Aβ

), wherein the antibody is of the IgG1 isotype.

113. The method of claim 112, wherein the subject has an amyloidogenic disease.

114. The method of claim 113, wherein the amyloidogenic disease is Alzheimer'"'"'s disease.

115. A method for treating an amyloidogenic disease in a patient comprising administering to the patient an effective dose of a humanized 12A11 antibody capable of reducing beta amyloid peptide (Aβ

) burden and neuritic dystrophy in the patient, wherein the antibody binds to an epitope within amino acids 3-7 of Aβ and

is of the IgG1 isotype.

116. The method of claim 115, wherein the amyloidogenic disease is Alzheimer'"'"'s disease.

117. A method for reducing beta amyloid peptide (Aβ

) burden and neuritic dystrophy in a mammal comprising administering to the mammal an effective dose of a humanized 12A11 antibody capable of reducing beta amyloid peptide (Aβ

) burden and neuritic dystrophy, wherein the antibody binds to an epitope within amino acids 3-7 of Aβ and

is of the IgG1 isotype.

118. The method of claim 117, wherein the mammal is a human.

119. The method of claim 117 or 118, wherein the mammal has an amyloidogenic disease.

120. The method of claim 119, wherein the amyloidogenic disease is Alzheimer'"'"'s disease.

121. A therapeutic composition comprising a humanized 12A11 antibody of the IgG1 isotype which binds to an epitope within amino acids 3-7 of beta amyloid peptide (Aβ

), wherein the antibody is capable of reducing neuritic burden in a subject.

122. A method for treating an amyloidogenic disease in a patient comprising administering to the patient an effective dose of a humanized 12A11 antibody which binds to soluble beta amyloid peptide (Aβ

) and reduces neuritic dystrophy in the patient, wherein the antibody binds to an epitope within amino acids 3-7 of Aβ and

is of the IgG1 isotype.

123. The method of claim 122, wherein the amyloidogenic disease is Alzheimer'"'"'s disease.

124. A therapeutic composition comprising a humanized 12A11 antibody of the IgG1 isotype which binds to soluble beta amyloid peptide (Aβ

), wherein the antibody binds to an epitope within amino acids 3-7 of Aβ and

is capable of reducing neuritic burden in a subject.