Humanized Aβ antibodies for use in improving cognition
View Patent ↗The invention provides improved agents and methods for treatment of diseases associated with beta amyloid (Aβ). Preferred agents include antibodies, e.g., humanized antibodies specific for Aβ.
1. A method for effecting rapid improvement in cognition in a subject, comprising administering to the subject an effective dose of a 12A11 immunological reagent, such that rapid improvement in cognition is observed within one month of the administering step, wherein the 12A11 immunological reagent is a humanized 12A11 immunoglobulin or antigen binding fragment comprising a humanized heavy chain and a humanized light chain, wherein
(a) the humanized light chain comprises three complementarity determining regions (CDR1, CDR2 and CDR3) having amino acid sequences from the corresponding complementarity determining regions of the mouse 12A11 immunoglobulin light chain variable domain designated SEQ ID NO:2, and a variable region framework from a human light chain variable region framework sequence designated SEQ ID NO:8; and
(b) the humanized heavy chain comprises three complementarity determining regions (CDR1, CDR2 and CDR3) having amino acid sequences from the corresponding complementarity determining regions of the mouse 12A11 immunoglobulin heavy chain variable domain designated SEQ ID NO:4, and a variable region framework from a human heavy chain variable region framework sequence designated SEQ ID NO:11 provided that at least one position selected from a group consisting of H24, H28, H29, H37, H48, H67, H71, H73 and H78 (Kabat numbering convention) is occupied by the same amino acid residue present in the equivalent position of the mouse 12A11 immunoglobulin heavy chain variable region framework;
wherein the humanized immunoglobulin specifically binds to beta amyloid peptide (A13) with a binding affinity of at least 10 7 M −1 , wherein the mouse 12A11 immunoglobulin has the light chain with a variable domain designated SEQ ID NO:2 and the heavy chain with a variable domain designated SEQ ID NO: 4.
2. The method of claim 1 , wherein the subject has or is at risk for an Aβ-related disease or disorder.
3. The method of claim 1 , wherein the subject has or is at risk for an amyloidogenic disease or disorder.
4. The method of claim 3 , wherein the subject has or is at risk for Alzheimer's disease.
5. The method of claim 1 , wherein the patient is human.
6. The method of claim 1 , wherein the effective dose is from about 1 mg/kg to 10 mg/kg body weight of the patient.
7. The method of claim 1 , further comprising assessing cognitive skills or performance of the subject to observe the rapid improvement in cognition.
8. The method of claim 7 , wherein the dose is 0.01-5 mg/kg.
9. The method of claim 1 , wherein the dose is 300 μg-30 mg/kg.
10. The method of claim 1 , wherein the rapid improvement in cognition is achieved within 12 hours after administration of the 12A11 immunological reagent.
11. The method of claim 1 , wherein the rapid improvement in cognition is achieved within 24 hours after administration of the immunological reagent.
12. The method of claim 1 , wherein the rapid improvement in cognition is achieved within 36 hours after administration of the immunological reagent.
13. The method of claim 1 , wherein the rapid improvement in cognition is achieved within 48 hours after administration of the immunological reagent.
14. The method of claim 1 , wherein the humanized variable region light chain is designated SEQ ID NO:7.
15. The method of claim 1 , wherein the humanized heavy chain variable region framework positions H24, H28, H29, H37, H48, H67, H71, H73 and H78 (Kabat numbering convention) are occupied by F, S, L, I, L, L, K, T and V, respectively.
16. The method of claim 1 , wherein the humanized heavy chain variable region framework positions H24, H29, H37, H71, and H73 (Kabat numbering convention) are occupied by F, L, I, K, and T, respectively.
17. The method of 1 , wherein the humanized heavy chain variable region framework positions H24, H29, H37, and H71 (Kabat numbering convention) are occupied by F, L, I, and K, respectively.
18. The method of claim 1 , wherein the humanized heavy chain variable region framework positions H24, H29, and H37 (Kabat numbering convention) are occupied by F, L, and I, respectively.
19. The method of claim 1 , wherein the humanized heavy chain variable region framework positions H24, H29, H37, H48, H67, H71, H73, and H78 (Kabat numbering convention) are occupied by F, L, I, L, L, K, T, and V, respectively.
20. The method of claim 1 , wherein the humanized heavy chain variable region framework positions H24, H28, H29, H37, H67, H71, H73 and H78 (Kabat numbering convention) are occupied by F, S, L, I, L, K, T and V, respectively.
21. The method of claim 1 , wherein the humanized heavy chain variable region framework positions H24, H28, H29, H37, H48, H71, H73 and H78 (Kabat numbering convention) are occupied by F, S, L, I, L, K, T and V, respectively.
22. The method of claim 1 , wherein the humanized heavy chain variable region framework positions H24, H28, H29, H37, H48, H67, H71, and H73 (Kabat numbering convention) are occupied by F, S, L, I, L, L, K, and T respectively.
23. The method of claim 1 , wherein the humanized heavy chain variable region framework positions H24, H29, H37, H67, H71, H73 and H78 (Kabat numbering convention) are occupied by F, L, I, L, K, T and V, respectively.
24. The method of claim 1 , wherein the humanized heavy chain variable region framework positions H24, H29, H37, H48, H71, H73 and H78 (Kabat numbering convention) are occupied by F, L, I, L, K, T and V, respectively.
25. The method of claim 1 , wherein the humanized heavy chain variable region framework positions H24, H29, H37, H48, H67, H71, and H73 (Kabat numbering convention) are occupied by F, L, I, L, L, K, and T respectively.
26. The method of claim 1 , wherein the humanized heavy chain variable region framework positions H24, H28, H29, H37, H71, H73 and H78 (Kabat numbering convention) are occupied by F, S, L, I, K, T and V, respectively.
27. The method of claim 1 , wherein the humanized heavy chain variable region framework positions H24, H28, H29, H37, H67, H71, and H73 (Kabat numbering convention) are occupied by F, S, L, I, L, K, and T, respectively.
28. The method of claim 1 , wherein the humanized heavy chain variable region framework positions H24, H28, H29, H37, H48, H71, and H73 (Kabat numbering convention) are occupied by F, S, L, I, L, K, and T, respectively.
29. The method of claim 1 , wherein the humanized heavy chain variable region framework positions H24, H29, H37, H71, H73 and H78 (Kabat numbering convention) are occupied by F, L, I, K, T and V, respectively.
30. The method of claim 1 , wherein the humanized heavy chain variable region framework positions H24, H29, H37, H67, H71, and H73 (Kabat numbering convention) are occupied by F, L, I, L, K, and T, respectively.
31. The method of claim 1 , wherein the humanized heavy chain variable region framework positions H24, H29, H37, H48, H71, and H73 (Kabat numbering convention) are occupied by F, L, I, L, K, and T, respectively.
32. The method of claim 1 , wherein the humanized heavy chain variable region framework positions H24, H28, H29, H37, H71, and H73 (Kabat numbering convention) are occupied by F, S, L, I, K, and T, respectively.
33. The method of claim 1 , wherein the humanized heavy chain variable region framework positions H24, H29, H48, H67, H71, H73 and H78 (Kabat numbering convention) are occupied by F, L, L, L, K, T and V, respectively.
34. The method of claim 1 , wherein the humanized heavy chain variable region framework positions H24, H28, H29, H37, H48, H67, H71, and H78 (Kabat numbering convention) are occupied by F, S, L, I, L, L, K, and V, respectively.
35. The method of claim 1 , wherein the humanized heavy chain variable region has an amino acid sequence comprising amino acids 1-120 of SEQ ID NO:10 and the humanized light chain variable region has an amino acid sequence comprising amino acids 1-112 of SEQ ID NO:7.
36. The method of claim 1 , wherein the humanized heavy chain variable region has an amino acid sequence comprising amino acids 1-120 of a sequence selected from the group consisting of SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, and SEQ ID NO:31; and wherein the humanized light chain variable region has an amino acid sequence comprising amino acids 1-112 of SEQ ID NO:7.
37. The method of claim 1 , wherein the humanized heavy chain variable region has an amino acid sequence comprising amino acids 1-121 of SEQ ID NO:22 or SEQ ID NO:23; and wherein the humanized light chain variable region has an amino acid sequence comprising amino acids 1-112 of SEQ ID NO:7.