Humanized antibodies that recognize beta amyloid peptide
First Claim
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1. A method for reducing neuritic burden in a subject in need thereof comprising administering to the subject an effective dose of a humanized immunoglobulin which binds to an epitope within amino acids 3-7 of beta amyloid peptide (Aβ
- ), wherein the immunoglobulin is of the IgG1 isotype, such that neuritic burden is reduced, wherein the humanized immunoglobulin comprises;
(i) a light chain comprising the three complementarity determining regions (CDRs) from the 12B4 immunoglobulin light chain variable region sequence set forth as SEQ ID NO;
2, and a variable framework region from a human acceptor immunoglobulin light chain; and
(ii) a heavy chain comprising the three complementarity determining regions (CDRs) from the 12B4 immunoglobulin heavy chain variable region sequence set forth as SEQ ID NO;
4, and a variable framework region from a human acceptor immunoglobulin heavy chain,provided that at least one framework residue in the light or heavy chain is substituted with the corresponding amino acid residue from the mouse 12B4 light or 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.
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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 humanized antibodies.
326 Citations
15 Claims
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1. A method for reducing neuritic burden in a subject in need thereof comprising administering to the subject an effective dose of a humanized immunoglobulin which binds to an epitope within amino acids 3-7 of beta amyloid peptide (Aβ
- ), wherein the immunoglobulin is of the IgG1 isotype, such that neuritic burden is reduced, wherein the humanized immunoglobulin comprises;
(i) a light chain comprising the three complementarity determining regions (CDRs) from the 12B4 immunoglobulin light chain variable region sequence set forth as SEQ ID NO;
2, and a variable framework region from a human acceptor immunoglobulin light chain; and(ii) a heavy chain comprising the three complementarity determining regions (CDRs) from the 12B4 immunoglobulin heavy chain variable region sequence set forth as SEQ ID NO;
4, and a variable framework region from a human acceptor immunoglobulin heavy chain,provided that at least one framework residue in the light or heavy chain is substituted with the corresponding amino acid residue from the mouse 12B4 light or 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. - View Dependent Claims (2, 3, 12, 13, 14, 15)
- ), wherein the immunoglobulin is of the IgG1 isotype, such that neuritic burden is reduced, wherein the humanized immunoglobulin comprises;
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4. A method for treating an amyloidogenic disease in a patient comprising administering to the patient an effective dose of a humanized immunoglobulin capable of reducing beta amyloid peptide (Aβ
- ) burden and neuritic dystrophy in the patient, wherein the immunoglobulin binds to an epitope within amino acids 3-7 of Aβ and
is of the IgG1 isotype, such that a beneficial therapeutic response in said patient is generated, wherein the humanized immunoglobulin comprises;(i) a light chain comprising the three complementarity determining regions (CDRs) from the 12B4 immunoglobulin light chain variable region sequence set forth as SEQ ID NO;
2, and a variable framework region from a human acceptor immunoglobulin light chain; and(ii) a heavy chain comprising the three complementarity determining regions (CDRs) from the 12B4 immunoglobulin heavy chain variable region sequence set forth as SEQ ID NO;
4, and a variable framework region from a human acceptor immunoglobulin heavy chain,provided that at least one framework residue in the light or heavy chain is substituted with the corresponding amino acid residue from the mouse 12B4 light or 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. - View Dependent Claims (5)
- ) burden and neuritic dystrophy in the patient, wherein the immunoglobulin binds to an epitope within amino acids 3-7 of Aβ and
-
6. 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 immunoglobulin capable of reducing beta amyloid peptide (Aβ
) burden and neuritic dystrophy, wherein the immunoglobulin binds to an epitope within amino acids 3-7 of Aβ and
is of the IgG1 isotype, such that Aβ
burden and neuritic dystrophy are reduced, wherein the humanized immunoglobulin comprises;(i) a light chain comprising the three complementarity determining regions (CDRs) from the 12B4 immunoglobulin light chain variable region sequence set forth as SEQ ID NO;
2, and a variable framework region from a human acceptor immunoglobulin light chain; and(ii) a heavy chain comprising the three complementarity determining regions (CDRs) from the 12B4 immunoglobulin heavy chain variable region sequence set forth as SEQ ID NO;
4, and a variable framework region from a human acceptor immunoglobulin heavy chain,provided that at least one framework residue in the light or heavy chain is substituted with the corresponding amino acid residue from the mouse 12B4 light or 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. - View Dependent Claims (7, 8, 9)
- ) burden and neuritic dystrophy in a mammal comprising administering to the mammal an effective dose of a humanized immunoglobulin capable of reducing beta amyloid peptide (Aβ
-
10. A method for treating an amyloidogenic disease in a patient comprising administering to the patient an effective dose of a humanized immunoglobulin which binds to soluble beta amyloid peptide (Aβ
- ) and reduces neuritic dystrophy in the patient, wherein the immunoglobulin binds to an epitope within amino acids 3-7 of Aβ and
is of the IgG1 isotype, such that a beneficial therapeutic response in said patient is generated, wherein the humanized immunoglobulin comprises;(i) a light chain comprising the three complementarity determining regions (CDRs) from the 12B4 immunoglobulin light chain variable region sequence set forth as SEQ ID NO;
2, and a variable framework region from a human acceptor immunoglobulin light chain; and(ii) a heavy chain comprising the three complementarity determining regions (CDRs) from the 12B4 immunoglobulin heavy chain variable region sequence set forth as SEQ ID NO;
4, and a variable framework region from a human acceptor immunoglobulin heavy chain,provided that at least one framework residue in the light or heavy chain is substituted with the corresponding amino acid residue from the mouse 12B4 light or 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. - View Dependent Claims (11)
- ) and reduces neuritic dystrophy in the patient, wherein the immunoglobulin binds to an epitope within amino acids 3-7 of Aβ and
Specification