Tau immunotherapy
The invention provides antibodies to tau. The antibodies inhibit or delay tau-associated pathologies and associated symptomatic deterioration.
1. An antibody comprising a mature heavy chain variable region comprising three heavy chain CDRs of the amino acid sequence encoded by SEQ ID NO:25, the mature heavy chain variable region being at least 90% identical to the sequence encoded by SEQ ID NO:25 and a mature light chain variable region comprising three light chain CDRs of SEQ ID NO:22 provided positions L36 and L43 can be occupied by F and S respectively, the mature light chain variable region being at least 90% identical to SEQ ID NO:22.
2. The monoclonal antibody of claim 1 that is of human IgG isotype.
3. The monoclonal antibody of claim 2 , wherein the isotype is IgG1.
4. The monoclonal antibody of claim 2 , having at least one mutation in the constant region.
5. The monoclonal antibody of claim 2 that is of human IgG2 or IgG4 isotype.
6. The antibody of claim 1 , comprising CDRH1 of SEQ ID NO:11 or SEQ ID NO:24, CDRH-2 of SEQ ID NO:12 and CDRH-3 of SEQ ID NO:13 and CDR-L1 of SEQ ID NO:17, CDR-L2 of SEQ ID NO:18 and CDR-L3 of SEQ ID NO:19.
7. The antibody of claim 6 , wherein the mature heavy chain variable region has an amino acid sequence at least 99% identical to the sequence encoded by SEQ ID NO:25 and the mature light chain variable region has an amino acid sequence designated SEQ ID NO:21, 22, or 23.
8. The antibody of claim 6 , 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.
9. The antibody of claim 8 , wherein the heavy chain constant region is a mutant form of natural human constant region which has reduced binding to an Fcγ receptor relative to the natural human constant region.
10. The antibody of claim 8 , wherein the heavy chain constant region is of IgG1 isotype.
11. The antibody of claim 6 , provided at least one of positions H13, H48 and H91 is occupied by K, M and F respectively and at least one of positions L1, L4, L36 and L43 is occupied by N, L, F and S respectively.
12. The antibody of claim 11 , provided positions H13, H48 and H91 are occupied by K, M and F respectively and at least two of positions L1, L4, L36 and L43 is occupied by N, L, F and S respectively.
13. The antibody of claim 12 , provided positions H13, H48 and H91 are occupied by K, M and F respectively, and at least three of positions L1, L4, L36 and L43 are occupied by N, L, F and S respectively.
14. The antibody of claim 13 , provided positions H13, H48 and H91 are occupied by K, M and F respectively, and positions L1, L4, L36 and L43 are occupied by N, L, F and S respectively.
15. The antibody of claim 14 , comprising a mature heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence encoded by SEQ ID NO:25 and a mature light chain variable region at least 95% identical to SEQ ID NO:22.
16. The antibody of claim 14 , comprising a mature heavy chain variable region having an amino acid sequence at least 96% identical to the amino acid sequence encoded by SEQ ID NO:25 and a mature light chain variable region at least 96% identical to SEQ ID NO:22.
17. The antibody of claim 14 , comprising a mature heavy chain variable region having an amino acid sequence at least 97% identical to the amino acid sequence encoded by SEQ ID NO:25 and a mature light chain variable region at least 97% identical to SEQ ID NO:22.
18. The antibody of claim 14 , comprising a mature heavy chain variable region having an amino acid sequence at least 98% identical to the amino acids sequence encoded by SEQ ID NO:25 and a mature light chain variable region at least 98% identical to SEQ ID NO:22.
19. The antibody of claim 14 , comprising a mature heavy chain variable region having an amino acid sequence at least 99% identical to the amino acids sequence encoded by SEQ ID NO:25 and a mature light chain variable region at least 99% identical to SEQ ID NO:22.
20. The antibody of claim 19 , wherein the mature heavy chain variable region has an amino acid sequence at least 99% identical to the sequence encoded by SEQ ID NO:25 and the mature light chain variable region has the amino acid sequence encoded by designated SEQ ID NO:22.
21. The antibody of any one of claims 6 and 15 , wherein the antibody is a Fab fragment.
22. The antibody of any one of claims 6 - 15 , wherein the mature heavy chain variable region has the amino acid sequence encoded by the nucleic acid sequence of SEQ ID NO:25.
23. A polynucleotide comprising a nucleic acid encoding the heavy and/or light chains of an antibody as described in any one of claims 6 - 15 , 7 , 20 and 16 - 19 .
24. A method of humanizing an antibody, comprising:
determining the sequences of the heavy and light chain variable regions of a mouse antibody;
synthesizing a nucleic acid encoding a humanized heavy chain comprising CDRs of the mouse antibody heavy chain and a nucleic acid encoding a humanized light chain comprising CDRs of the mouse antibody light chain; and
expressing the nucleic acids in a host cell to produce a humanized antibody,
wherein the mouse antibody is characterized by a mature heavy chain variable region of SEQ ID NO:10 and a mature light chain variable region of SEQ ID NO:16.
25. A method of producing a humanized, chimeric or veneered antibody, comprising:
culturing cells transformed with nucleic acids encoding the heavy and light chains of the antibody, so that the cell secretes the antibody; and
purifying the antibody from cell culture media,
wherein the antibody is a humanized, chimeric or veneered form of a mouse antibody, which is characterized by a mature heavy chain variable region of SEQ ID NO:10 and a mature light chain variable region of SEQ ID NO:16.
26. A method of producing a cell line producing a humanized, chimeric or veneered antibody, comprising;
introducing a vector encoding heavy and light chains of an antibody and a selectable marker into cells;
propagating the cells under conditions to select for cells having increased copy number of the vector;
isolating single cells from the selected cells; and
banking cells cloned from a single cell selected based on yield of antibody; wherein the antibody is a humanized, chimeric or veneered form of a mouse antibody, which is characterized by a mature heavy chain variable region of SEQ ID NO:10 and a mature light chain variable region of SEQ ID NO:16.