Humanized antibodies that recognize alpha-synuclein
The present application discloses humanized 1H7 antibodies. The antibodies bind to human alpha synuclein and can be used for treatment and diagnosis of Lewy body disease.
1. An antibody comprising a mature heavy chain variable region comprising the three Kabat CDRs of SEQ ID NO: 44, and being at least 90% identical to SEQ ID NO: 44, and a mature light chain comprising the three Kabat CDRs of SEQ ID NO: 45, and being at least 90% identical to SEQ ID NO: 45, wherein: (a) position L46 (Kabat numbering) is occupied by F, position L49 (Kabat numbering) is occupied by C and position L83 (Kabat numbering) is occupied by A; or (b) position H67 (Kabat numbering) is occupied by A and position H71 (Kabat numbering) is occupied by A.
2. A pharmaceutical composition comprising an antibody as defined by claim 1 .
3. The pharmaceutical composition of claim 2 , wherein position L46 (Kabat numbering) is occupied by F, position L49 (Kabat numbering) is occupied by C and position L83 (Kabat numbering) is occupied by A.
4. The pharmaceutical composition of claim 3 , wherein position H67 (Kabat numbering) is occupied by A and position H71 (Kabat numbering) is occupied by A.
5. The pharmaceutical composition of claim 4 , wherein the mature heavy chain variable region has an amino acid sequence comprising SEQ ID NO: 23 and the mature light chain variable region has an amino acid sequence comprising SEQ ID NO: 33.
6. The pharmaceutical composition of claim 5 , wherein the light chain constant region has the amino acid sequence of SEQ ID NO: 49.
7. The pharmaceutical composition of claim 5 , wherein the heavy chain constant region has the amino acid sequence of SEQ ID NO: 52 provided the C terminal lysine residue may be omitted.
8. The pharmaceutical composition of claim 7 , wherein the mature heavy chain variable region is fused to a heavy chain constant region having the amino acid sequence of SEQ ID NO: 52 provided the C terminal lysine residue may be omitted and the mature light chain variable region is fused to a light chain constant region having the amino acid sequence of SEQ ID NO: 49.
9. The antibody of claim 1 , wherein position H11 (Kabat numbering) is occupied by V, position H28 (Kabat numbering) is occupied by T, position H38 (Kabat numbering) is occupied by R, position H48 (Kabat numbering) is occupied by M, position H69 (Kabat numbering) is occupied by M, position H91 (Kabat numbering) is occupied by Y or a combination thereof.
10. The antibody of claim 9 , wherein position H11 (Kabat numbering) is occupied by V.
11. The antibody of claim 9 , wherein position H28 (Kabat numbering) is occupied by T.
12. The antibody of claim 9 , wherein position H38 (Kabat numbering) is occupied by R.
13. The antibody of claim 9 , wherein position H48 (Kabat numbering) is occupied by M.
14. The antibody of claim 9 , wherein position H69 (Kabat numbering) is occupied by M.
15. The antibody of claim 9 , wherein position H91 (Kabat numbering) is occupied by Y.
16. The antibody of claim 1 , wherein position L46 (Kabat numbering) is occupied by F, position L49 (Kabat numbering) is occupied by C and position L83 (Kabat numbering) is occupied by A.
17. The antibody of claim 16 , wherein position H67 (Kabat numbering) is occupied by A and position H71 (Kabat numbering) is occupied by A.
18. The antibody of claim 17 , wherein the mature heavy chain variable region has an amino acid sequence comprising SEQ ID NO: 23 and the mature light chain variable region has an amino acid sequence comprising SEQ ID NO: 33.
19. The antibody of claim 18 , wherein the mature heavy chain variable region is fused to a heavy chain constant region having the amino acid sequence of SEQ ID NO: 52 provided the C-terminal lysine residue may be omitted and the mature light chain variable region is fused to a light chain constant region having the amino acid sequence of SEQ ID NO: 49.
20. The antibody of claim 18 , wherein the mature heavy chain variable region is fused to a heavy chain constant region and the mature light chain variable region is fused to a light chain constant region.
21. The antibody of claim 20 , wherein the heavy chain constant region has the amino acid sequence of SEQ ID NO: 52 provided the C-terminal lysine residue may be omitted.
22. The antibody of claim 20 , wherein the light chain constant region has the amino acid sequence of SEQ ID NO: 49.