Humanized antibodies that sequester abeta peptide
View Patent ↗A method to treat conditions characterized by formation of amyloid plaques both prophylactically and therapeutically is described. The method employs humanized antibodies which sequester soluble Aβ peptide from human biological fluids or which preferably specifically bind an epitope contained within position 13–28 of the amyloid beta peptide Aβ.
1. A humanized antibody comprising:
(a) a light chain comprising a light chain variable region comprising the following sequence:
(SEQ ID NO:7)
1 5 10
Asp Xaa Val Met Thr Gln Xaa Pro Leu Ser Leu Pro Val
15 20 25
Xaa Xaa Gly Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser
30 35
Gln Ser Leu Xaa Tyr Ser Asp Gly Asn Ala Tyr Leu His
40 45 50
Trp Phe Leu Gln Lys Pro Gly Gln Ser Pro Xaa Leu Leu
55 60 65
Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro Asp
70 75
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
80 85 90
Lys Ile Ser Arg Val Glu Ala Glu Asp Xaa Gly Val Tyr
95 100
Tyr Cys Ser Gln Ser Thr His Val Pro Trp Thr Phe Gly
105 110
Xaa Gly Thr Xaa Xaa Glu Ile Lys Arg
wherein:
Xaa at position 2 is Vle or Ile;
Xaa at position 7 is Ser or Thr;
Xaa at position 14 is Thr or Ser;
Xaa at position 15 is Leu or Pro;
Xaa at position 30 is Ile or Val;
Xaa at position 50 is Arg, Gln, or Lys;
Xaa at position 88 is Val or Leu;
Xaa at position 105 is Gln or Gly;
Xaa at position 108 is Lys or Arg; and
Xaa at position 109 is Val or Leu; and
(b) a heavy chain comprising a heavy chain variable region comprising the following sequence:
(SEQ ID NO:8)
1 5 10
Xaa Val Gln Leu Val Glu Xaa Gly Gly Gly Leu Val Gln
15 20 25
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
30 35
Phe Thr Phe Ser Arg Tyr Ser Met Ser Trp Val Arg Gln
40 45 50
Ala Pro Gly Lys Gly Leu Xaa Leu Val Ala Gln Ile Asn
55 60 65
Ser Val Gly Asn Ser Thr Tyr Tyr Pro Asp Xaa Val Lys
70 75
Gly Arg Phe Thr Ile Ser Arg Asp Asn Xaa Xaa Asn Thr
80 85 90
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Xaa Asp Thr
95 100
Ala Val Tyr Tyr Cys Ala Ser Gly Asp Tyr Trp Gly Gln
105 100
Gly Thr Xaa Val Thr Val Ser Ser
wherein:
Xaa at position 1 is Glu or Gln;
Xaa at position 7 is Ser or Leu;
Xaa at position 46 is Glu, Val, Asp, or Ser;
Xaa at position 63 is Thr or Ser;
Xaa at position 75 is Ala, Ser, Val or Thr;
Xaa at position 76 is Lys or Arg;
Xaa at position 89 is Glu or Asp; and
Xaa at position 107 is Leu or Thr
and wherein the humanized antibody binds to an abeta peptide.
2. The humanized antibody of claim 1 comprising a light chain variable region of the sequence given by SEQ ID NO:9 and a heavy chain variable region given by SEQ ID NO:10.
3. The humanized antibody of claim 1 comprising a light chain of the sequence given by SEQ ID NO:11 and a heavy chain of the sequence given by SEQ ID NO:12.
4. The humanized antibody of claim 1 that is an IgG1 immunoglobulin isotype.
5. The humanized antibody of claim 1 , wherein the antibody is produced in a host cell selected from the group consisting of a meyeloma cell, a chinese hamster ovary cell, a syrian hamster ovary cell, and a human embryonic kidney cell.
6. A pharmaceutical composition that comprises the humanized antibody of claim 1 , and a pharmaceutically acceptable excipient.
7. A pharmaceutical composition that comprises the humanized antibody of claim 3 , and a pharmaceutically acceptable excipient.
8. The humanized antibody of claim 1 , wherein Xaa at position 30 of the light chain variable region is lie and wherein Xaa at position 63 of the heavy chain variable region is Thr.
9. The humanized antibody of claim 2 that is an IgG1 immunoglobulin isotype.
10. The humanized antibody of claim 3 that is an IgG1 immunoglobulin isotype.
11. The humanized antibody of claim 2 , wherein the antibody is produced in a chinese hamster ovary cell.
12. The humanized antibody of claim 3 , wherein the antibody is produced in a chinese hamster ovary cell.