Humanized antibodies that recognize beta amyloid peptide

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.

We claim:  
     
         1 . Humanized 10D5 antibody.  
     
     
         2 . A humanized antibody, or fragment thereof, comprising a humanized light chain comprising three light chain complementarily determining regions (CDRs) from the mouse monoclonal antibody 10D5 and a light chain variable region framework sequence from a human immunoglobulin light chain; and a humanized heavy chain comprising three heavy chain CDRs from the mouse monoclonal antibody 10D5 and a heavy chain variable region framework sequence from a human immunoglobulin heavy chain; wherein the light chain CDRs have the following amino acid sequences: 
 light chain CDR1:                              Arg Ser Ser Gln Asn Ile Ile His Ser Asn Gly   (residues 24-39 of SEQ ID NO:14)               Asn Thr Tyr Leu Glu                           light chain CDR2:                              Lys Val Ser Asn Arg Phe Ser   (residues 55-61 of SEQ ID NO:14)                             light chain CDR3:                              Phe Gln Gly Ser His Val Pro Leu Thr   (residues 94-102 of SEQ ID NO:14)                             and the heavy chain CDRs have the following amino acid sequences:    heavy chain CDR1:                              Thr Ser Gly Met Gly Val Ser   (residues 31-37 of SEQ ID NO:16)                             heavy chain CDR2:                          His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser Leu Lys               Ser (residues 52-67 of SEQ ID NO: 16) and,                           heavy chain CDR3:                                      Arg Pro Ile Thr Pro Val Leu Val Asp Ala Met Asp Tyr                       (residues 100-112 of SEQ ID NO: 16).                               
     
     
         3 . An antibody fragment obtainable by enzymatic cleavage of the humanized antibody of any one of claims  1 - 2 .  
     
     
         4 . An Fab or F(ab′)2 fragment of any one of the humanized antibodies of claims  1 - 2 .  
     
     
         5 . The F(ab′)2 fragment of  claim 4 .  
     
     
         6 . The Fab fragment of  claim 4 .  
     
     
         7 . The humanized antibody or fragment of any one of claims  1 - 6 , which is a single chain antibody.  
     
     
         8 . The humanized antibody or fragment of any one of claims  1 - 7  that is an IgG1 immunoglobulin isotype.  
     
     
         9 . The humanized antibody or fragment of any one of claims  1 - 8 , wherein the antibody or fragment thereof is produced in a host cell selected from the group consisting of a myeloma cell and a chinese hamster ovary (CHO) cell.  
     
     
         10 . A polynucleotide compound, comprising a sequence coding for the light chain or the heavy chain of the humanized antibody of any one of claims  1 - 9 , or a fragment thereof.  
     
     
         11 . A polynucleotide sequence, which when expressed in a suitable host cell, yields an antibody of any one of claims  1 - 9 .  
     
     
         12 . An expression vector for expressing the antibody of any one of claims  1 - 9  comprising the polynucleotide sequence of any one of claims  10 - 11 .  
     
     
         13 . A cell transfected with the expression vector of  claim 12 .  
     
     
         14 . A cell transfected with two expression vectors of  claim 12 , wherein a first vector comprises the polynucleotide sequence coding for the light chain and a second vector comprises the sequence coding for the heavy chain.  
     
     
         15 . A cell that is capable of expressing the humanized antibody or fragment of any one of claims  1 - 9 .  
     
     
         16 . The cell of any one of claims  13 - 15 , wherein the cell is selected from the group consisting of a myeloma cell and a chinese hamster ovary (CHO) cell.  
     
     
         17 . A pharmaceutical composition comprising the humanized antibody or fragment of any one of claims  1 - 9 , and a pharmaceutically acceptable excipient.  
     
     
         18 . A method of treating Down's syndrome or clinical or pre-clinical Alzheimer's disease in a human subject, comprising administering to the human subject an effective amount of a humanized antibody or fragment of any one of claims  1 - 9 .  
     
     
         19 . A method to inhibit the formation of Aβ plaque in the brain of a human subject, comprising administering to the human subject an effective amount of the humanized antibody or fragment of any one of claims  1 - 9 .  
     
     
         20 . A method to reduce Aβ plaque in the brain of a human subject, comprising administering to the human subject an effective amount of a humanized antibody or fragment of any one of claims  1 - 9 .  
     
     
         21 . The method of either of claims  19 - 20 , wherein the subject is diagnosed with clinical or pre-clinical Alzheimer's disease or Down's syndrome.  
     
     
         22 . The method of any one of claims  19 - 20 , wherein the subject is not diagnosed with clinical or pre-clinical Alzheimer's disease or Down's syndrome.  
     
     
         23 . Use of the humanized antibody or a fragment thereof according to any one of claims  1 - 9  for the manufacture of a medicament, including prolonged expression of recombinant sequences of the antibody or antibody fragment in human tissues, for treating clinical or pre-clinical Alzheimer's disease or Down's syndrome.  
     
     
         24 . Use of the humanized antibody or fragment of any one of claims  1 - 9  for the manufacture of a medicament for treating Alzheimer's disease.