Humanized antibodies that recognize beta amyloid peptide
AssigneesElan Pharma International Limited, Wyeth
InventorsGuriq Basi, Jose Saldanha
Life of this patent
Estimating the term…
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.
Claims55
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 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 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.
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 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 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 both the light and 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.
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 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 sequence;
- and
- (ii) a heavy chain comprising 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 sequence,
- 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 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.
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 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 sequence;
- and
- (ii) a heavy chain comprising 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 sequence,
- 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 12B4 light or heavy chain 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.
A humanized immunoglobulin which specifically binds beta amyloid peptide (Aβ), or antigen-binding fragment thereof, the humanized immunoglobulin comprising a light chain comprising three complementarity determining regions (CDRs) from the monoclonal antibody 12B4 light chain variable region sequence set forth as SEQ ID NO:2 and variable region framework residue L2 (Kabat numbering convention) from the monoclonal antibody 12B4 light chain, wherein the remainder of the light chain is from a human immunoglobulin, and a heavy chain comprising three complementarity determining regions (CDRs) from the monoclonal antibody 12B4 heavy chain variable sequence set forth as SEQ ID NO:4.
A humanized immunoglobulin which specifically binds beta amyloid peptide (Aβ), or antigen-binding fragment thereof, the humanized immunoglobulin or antigen-binding fragment comprising a light chain comprising three complementarity determining regions (CDRs) from the monoclonal antibody 12B4 light chain variable region sequence set forth as SEQ ID NO:2, and a heavy chain comprising three complementarity determining regions (CDRs) from the monoclonal antibody 12B4 heavy chain variable region sequence and variable framework residues H2, H24, H27, H29, H48, H49, H67, H71, and H78 (Kabat numbering convention) from the mono clonal antibody 12B4 heavy chain variable region sequence set forth as SEQ ID NO:4, wherein the remainder of the heavy chain is from a human immunoglobulin.
A humanized immunoglobulin which specifically binds beta amyloid peptide (Aβ), or antigen-binding fragment thereof, the humanized immunoglobulin comprising a light chain comprising three complementarity determining regions (CDRs) from the monoclonal antibody 12B4 light chain variable region sequence set forth as SEQ ID NO:2, and a heavy chain comprising three complementarity determining regions (CDRs) from the monoclonal antibody 12B4 heavy chain variable region sequence set forth as SEQ ID NO:4 and variable framework residues H24, H27, H29 and H71 (Kabat numbering convention) from the monoclonal antibody 12B4 heavy chain variable region sequence set forth as SEQ ID NO:4, wherein the remainder of the heavy chain is from a human immunoglobulin.
A humanized immunoglobulin which specifically binds beta amyloid peptide (Aβ), or antigen-binding fragment thereof, the humanized immunoglobulin comprising a light chain comprising three complementarity determining regions (CDRs) from the monoclonal antibody 12B4 light chain variable region sequence set forth as SEQ ID NO:2, and a heavy chain comprising three complementarity
- determining regions (CDRs) from the monoclonal antibody 12B4 heavy chain variable region sequence set forth as SEQ ID NO:4 and variable framework residues H24, H27, H29, H48, H71 and H78 (Kabat numbering convention) from the monoclonal antibody 12B4 heavy chain variable region sequence set forth as SEQ ID NO:4, wherein the remainder of the heavy chain is from a human immunoglobulin.
A humanized immunoglobulin which specifically binds beta amyloid peptide (Aβ), or antigen-binding fragment thereof, the humanized immunoglobulin comprising a light chain comprising three complementarity determining regions (CDRs) from the monoclonal antibody 12B4 light chain variable region sequence set forth as SEQ ID NO:2 and variable region framework residue L2 (Kabat numbering convention) from the monoclonal antibody 12B4 light chain, wherein the remainder of the light chain is from a human immunoglobulin, and a heavy chain selected from the group consisting of:
- (i) a heavy chain comprising three complementarity determining regions (CDRs) from the monoclonal antibody 12B4 heavy chain variable region sequence set forth as SEQ ID NO:4 and variable framework residues H2, H24, H27, H29, H48, H49, H67, H71, and H78 (Kabat numbering convention) from the monoclonal antibody 12B4 heavy chain variable region sequence set forth as SEQ ID NO:4, wherein the remainder of the heavy chain is from a human immunoglobulin,
- (ii) a heavy chain comprising three complementarity determining regions (CDRs) from the monoclonal antibody 12B4 heavy chain variable region sequence set forth as SEQ ID NO:4 and variable framework residues H24, H27, H29 and H71 (Kabat numbering convention) from the monoclonal antibody 12B4 heavy chain variable region sequence set forth as SEQ ID NO:4, wherein the remainder of the heavy chain is from a human immunoglobulin, and
- (iii) a heavy chain comprising three complementarity determining regions (CDRs) from the monoclonal antibody 12B4 heavy chain variable region sequence set forth as SEQ ID NO:4 and variable framework residues H24, H27, H29, H48, H71 and H78 (Kabat numbering convention) from the monoclonal antibody 12B4 heavy chain variable region sequence set forth as SEQ ID NO:4, wherein the remainder of the heavy chain is from a human immunoglobulin.
A humanized immunoglobulin which specifically binds amyloid beta peptide (Aβ), or antigen-binding fragment thereof, the humanized immunoglobulin comprising a light chain and a heavy chain, the light chain comprising the complementarity determining regions (CDR1, CDR2 and CDR3) of the 12B4 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 12B4 heavy chain variable region sequence set forth as SEQ ID NO:4.
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 set forth in SEQ ID NO:2 and the heavy chain variable region sequence set forth in SEQ ID NO:4, and comprising constant region sequences from a human immunoglobulin.
An immunoglobulin which specifically binds to beta amyloid peptide (Aβ), or antigen-binding fragment thereof, comprising a heavy chain variable region sequence as set forth in residues 1–123 of SEQ ID NO:8 and a light chain variable region sequence as set forth in residues 1–112 of SEQ ID NO:6.
An immunoglobulin which specifically binds to beta amyloid peptide or antigen-binding fragment thereof, comprising a heavy chain variable region sequence as set forth in residues 1–123 of SEQ ID NO:10 and a light chain variable region sequence as set forth in residues 1–112 of SEQ ID NO:6.
An immunoglobulin which specifically binds to beta amyloid peptide (Aβ), or antigen-binding fragment thereof, comprising a heavy chain variable region sequence as set forth in residues 1–123 of SEQ ID NO:12 and a light chain variable region sequence as set forth in residues 1–112 of SEQ ID NO:6.
An immunoglobulin comprising a heavy chain variable region sequence as set forth in residues 1–123 of SEQ ID NO:8 and a light chain variable region sequence as set forth in residues 1–112 of SEQ ID NO:6.
An immunoglobulin comprising a heavy chain variable region sequence as set forth in residues 1–123 of SEQ ID NO:10 and a light chain variable region sequence as set forth in residues 1–112 of SEQ ID NO:6.
An immunoglobulin comprising a heavy chain variable region sequence as set forth in residues 1–123 of SEQ ID NO:12 and a light chain variable region sequence as set forth in residues 1–112 of SEQ ID NO:6.
Dependencies are inferred from the claim text.