Humanized antibodies that recognize beta amyloid peptide
First Claim
Patent Images
1. A humanized immunoglobulin which specifically binds beta amyloid peptide (Aβ
- ), or antigen-binding fragment thereof, the humanized immunoglobulin comprising;
(i) a light chain comprising three complementarity determining regions (CDRs) from the 15C11 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 three complementarity determining regions (CDRs) from the 15C11 immunoglobulin heavy chain variable region sequence set forth as SEQ ID NO;
4, and 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 15C11 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.
8 Assignments
0 Petitions
Accused Products
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.
321 Citations
22 Claims
-
1. A humanized immunoglobulin which specifically binds beta amyloid peptide (Aβ
- ), or antigen-binding fragment thereof, the humanized immunoglobulin comprising;
(i) a light chain comprising three complementarity determining regions (CDRs) from the 15C11 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 three complementarity determining regions (CDRs) from the 15C11 immunoglobulin heavy chain variable region sequence set forth as SEQ ID NO;
4, and 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 15C11 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, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22)
- ), or antigen-binding fragment thereof, the humanized immunoglobulin comprising;
-
2. A humanized immunoglobulin which specifically binds beta amyloid peptide (Aβ
- ), or antigen-binding fragment thereof, the humanized immunoglobulin comprising;
(i) a light chain comprising three complementarity determining regions (CDRs) from the 15C11 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 three complementarity determining regions (CDRs) from the 15C11 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 both the light and heavy chain is substituted with the corresponding amino acid residue from the mouse 15C11 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.
- ), or antigen-binding fragment thereof, the humanized immunoglobulin comprising;
-
3. A humanized immunoglobulin which specifically binds beta amyloid peptide (Aβ
- ), or antigen-binding fragment thereof, the humanized immunoglobulin comprising;
(i) a light chain comprising three complementarity determining regions (CDRs) from the 15C11 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 three complementarity determining regions (CDRs) from the 15C11 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 15C11 light chain or heavy variable region sequence, wherein the framework residue is a residue capable of affecting the light or heavy chain variable region conformation or function as identified by analysis of a three-dimensional model of the variable region. - View Dependent Claims (5, 6, 7, 8)
- ), or antigen-binding fragment thereof, the humanized immunoglobulin comprising;
-
4. A humanized immunoglobulin which specifically binds beta amyloid peptide (Aβ
- ), or antigen-binding fragment thereof, the humanized immunoglobulin comprising;
(i) a light chain comprising three complementarity determining regions (CDRs) from the 15C11 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 three complementarity determining regions (CDRs) from the 15C11 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 and heavy chain is substituted with the corresponding amino acid residue from the mouse 15C11 light or 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 variable region.
- ), or antigen-binding fragment thereof, the humanized immunoglobulin comprising;
-
9. A humanized immunoglobulin which specifically binds beta amyloid peptide (Aβ
- ), or antigen-binding fragment thereof, the human immunoglobulin comprising;
(a) a light chain comprising three complementarity determining regions (CDR1, CDR2 and CDR3) from the monoclonal antibody 15C11 light chain variable region sequence set forth as SEQ ID NO;
2, and a variable framework region from a human acceptor immunoglobulin light chain provided that at least one framework residue in the light chain is substituted with the corresponding amino acid residue from the 15C11 light chain variable region sequence, wherein the framework residue is selected from the group consisting of a canonical residue, a vernier residue, a packing residue and a rare residue; and(b) a heavy chain comprising three complementarity determining regions (CDR1, CDR2 and CDR3) from the monoclonal antibody 15C11 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 heavy chain is substituted with the corresponding amino acid residue from the 15C11 heavy chain variable region sequence, wherein the framework residue is selected from a second group consisting of a canonical residue, a vernier residue, a packing residue and a rare residue.
- ), or antigen-binding fragment thereof, the human immunoglobulin comprising;
-
10. A humanized immunoglobulin which specifically binds beta amyloid peptide (Aβ
- ), or antigen-binding fragment thereof, the human immunoglobulin comprising a light chain and a heavy chain, the light chain comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of the 15C11 light chain variable region sequence set forth as SEQ ID NO;
2, and the heavy chain comprising the complementarity determining regions (CDR1, CDR2, and CDR3) of the 15C11 heavy chain variable region sequence set forth as SEQ ID NO;
4.
- ), or antigen-binding fragment thereof, the human immunoglobulin comprising a light chain and a heavy chain, the light chain comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of the 15C11 light chain variable region sequence set forth as SEQ ID NO;
-
21. A chimeric immunoglobulin, which specifically binds beta amyloid peptide (Aβ
- ) with a binding affinity of at least 107M−
1, comprising the light chain variable region sequence as set forth in amino acid residues 1-111 of SEQ ID NO;
2 and the heavy chain variable region sequence set forth in amino acid residues 1-112 of SEQ ID NO;
4, and comprising constant region sequences from a human immunoglobulin.
- ) with a binding affinity of at least 107M−
Specification