Humanized antibodies that recognize beta amyloid peptide
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.
1. A humanized immunoglobulin that binds to Aβ comprising a humanized immunoglobulin light chain comprising (i) three variable region complementarity determining regions (CDRs) from the 3D6 immunoglobulin light chain variable region sequence of 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 3D6 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; and
a humanized immunoglobulin heavy chain comprising (i) three variable region complementarity determining regions (CDRs) from the 3D6 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 3D6 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.
2. A humanized immunoglobulin that binds to APβ comprising
a humanized immunoglobulin light chain comprising (i) three variable region complementarity determining regions (CDRs) from the 3D6 immunoglobulin light chain,
a humanized immunoglobulin heavy chain comprising (i) three variable region complementarity determining regions (CDRs) from the 3D6 immunoglobulin heavy chain,
wherein 3D6 is an antibody of American Type Culture Collection deposit PTA-5130.
3. The humanized immunoglobulin of claim 2 , wherein at least one light or heavy chain variable region framework residue is substituted with the corresponding amino acid residue from the mouse 3D6 light or heavy chain variable region, 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.
4. A chimeric antibody that binds to Aβ comprising a 3D6 immunoglobulin light chain variable region joined to a human light chain constant region and a 3D6 immunoglobulin heavy chain variable region joined to a human heavy chain constant region, wherein 3D6 is an antibody of American Type Culture Collection deposit PTA-5130.