antibodies that recognize tau

Abstract

To provide antibodies that specifically bind tau.SOLUTION: Antibodies according to the present invention inhibit or delay tau-associated pathologies and associated symptomatic deterioration. In one aspect, the present invention provides an isolated monoclonal antibody that competes for binding to human tau with antibody 9F5.SELECTED DRAWING: Figure 1A

Description

[Technical Field]

[0001] Cross-references to related applications This application claims the interests of U.S. Provisional Patent Application No. 62 / 803,334 filed 8 February 2019, U.S. Provisional Patent Application No. 62 / 813,124 filed 3 March 2019, and U.S. Provisional Patent Application No. 62 / 855,434 filed 31 May 2019, each incorporated in whole for all purposes.

[0002] Reference to sequence list The sequence list written in the file 2020_02_07_542496WO_SEQLST.txt is 3560 kilobytes in size, was created on February 7, 2020, and is incorporated herein by reference. [Background technology]

[0003] Tau is a well-known human protein that can exist in a phosphorylated form (see, for example, Goedert, Proc. Natl. Acad. Sci. USA 85:4051-4055 (1988); Goedert, EMBO J. 8:393-399 (1989); Lee, Neuron 2:1615-1624 (1989); Goedert, Neuron 3:519-526 (1989); Andreadis, Biochemistry 31:10626-10633 (1992)). Tau has been reported to play a role in stabilizing microtubules, particularly those in the central nervous system. t-tau (total tau, i.e., phosphorylated and unphosphorylated forms), as well as phosphotau (p-tau, i.e., phosphorylated tau), are released by the brain in response to nerve damage and neurodegeneration, and have been reported to appear at higher levels in the CSF of Alzheimer's patients compared to the general population (Jack et al., Lancet Neurol 9: 119-28 (2010)).

[0004] Tau is a major component of neurofibrillary tangles, a characteristic feature of Alzheimer's disease, along with plaque. These tangles consist of abnormal fibrils, measured in diameter as 10 nm, existing in the form of helical structures wound in pairs with a regular periodicity of 80 nm. In neurofibrillary tangles, tau is abnormally phosphorylated (hyperphosphorylated), with phosphate groups bound to specific sites on the molecule. Significant intervention of neurofibrillary tangles is observed in neurons of layer II of the entorhinal cortex, CA1 and the hippocampal region of the hippocampus, the amygdala, and deeper layers of the neocortex (layers III, V, and surface layer VI). Hyperphosphorylated tau has also been reported to interfere with microtubule assembly, which may promote the breakdown of neural networks.

[0005] Tau inclusion is part of the neuropathology defining several neurodegenerative diseases, including Alzheimer's disease, frontotemporal lobar degeneration, progressive supranuclear palsy, and Pick's disease. [Overview of the project]

[0006] In one embodiment, the present invention provides isolated monoclonal antibodies that compete with antibody 9F5 for binding to human tau. In some such antibodies, the heavy chain CDR-H3 has an amino acid sequence including SEQ ID NO: 10. In some such antibodies, the heavy chain CDR-H1 has an amino acid sequence including SEQ ID NO: 8. In some such antibodies, the light chain CDRs CDR-L1, CDR-L2, and CDR-L3 have amino acid sequences including SEQ ID NOs: 12, 13, and 14, respectively. In some such antibodies, the heavy chain CDR-H1 has an amino acid sequence including SEQ ID NO: 8. Some such antibodies bind to the same epitope as 9F5 on human tau.

[0007] Some such antibodies include three light chain CDRs and three heavy chain CDRs of the monoclonal antibody 9F5, which is a mouse antibody characterized by a heavy chain variable region having an amino acid sequence containing SEQ ID NO: 7 and a light chain variable region having an amino acid sequence containing SEQ ID NO: 11.

[0008] In some such antibodies, the three heavy chain CDRs CDR-H1, CDR-H2, and CDR-H3 are as defined by the Kabat / Chothia compound (SEQ ID NOs. 8, 9, and 10, respectively), except that N or T can occupy position H28, I or V can occupy position H51, N or D can occupy position H54, and D or E can occupy position H56, and the three light chain CDRs CDR-L1, CDR-L2, and CDR-L3 can occupy position L27b if L, D, T, or Q, and position L27c if L, D, G, S, E, T, N, A, P, or I As defined by the Kabat / Chothia compound (sequences 12, 13, and 14, respectively), I, Y, E, K, G, or Q may occupy position L30, T, N, or G may occupy position L31, L, N, T, S, R, or G may occupy position L33, M, G, E, D, K, or I may occupy position L51, L, R, G, or T may occupy position L54, A or G may occupy position L89, L, D, E, G, Q, T, or I may occupy position L92, and E or G may occupy position L93.

[0009] In some antibodies, CDR-H1 has an amino acid sequence containing SEQ ID NO: 50. In some antibodies, CDR-H2 has an amino acid sequence containing SEQ ID NO: 51. In some antibodies, CDR-H2 has an amino acid sequence containing SEQ ID NO: 52. In some antibodies, CDR-L1 has an amino acid sequence containing SEQ ID NO: 53, SEQ ID NO: 54, and SEQ ID NOs. 172-193. In some antibodies, CDR-L2 has an amino acid sequence containing SEQ ID NO: 55, and SEQ ID NOs. 194-205. In some antibodies, CDR-L3 has an amino acid sequence containing SEQ ID NOs. 206-213. In some antibodies, CDR-H1 has an amino acid sequence containing SEQ ID NO: 50, and CDR-H2 has an amino acid sequence containing SEQ ID NO: 51. In some antibodies, CDR-L1 has an amino acid sequence containing SEQ ID NO: 53, and CDR-L2 has an amino acid sequence containing SEQ ID NO: 55. In some antibodies, CDR-L1 has an amino acid sequence containing SEQ ID NO: 54, and CDR-L2 has an amino acid sequence containing SEQ ID NO: 55.

[0010] Some antibodies are 9F5, or its chimeric, veneered, or humanized forms. In some antibodies, the variable heavy chain has more than 85% identity to the human sequence. In some antibodies, the variable light chain has more than 85% identity to the human sequence. In some antibodies, the variable heavy chain and variable light chain each have more than 85% identity to the human germline sequence. Some antibodies are humanized antibodies.

[0011] Some antibodies are humanized or chimeric 9F5 antibodies that specifically bind to human tau, where 9F5 is a mouse antibody characterized by the mature heavy chain variable region of SEQ ID NO: 7 and the mature light chain variable region of SEQ ID NO: 11. Some antibodies include a humanized mature heavy chain variable region containing three heavy chain CDRs of 9F5 and a humanized mature light chain variable region containing three light chain CDRs of 9F5. In some antibodies, the CDRs are defined as CDRs selected from the group consisting of Kabat, Chothia, Kabat / Chothia complex, AbM, and Contact.

[0012] In some antibodies, the humanized mature heavy chain variable region contains three 9F5 Kabat / Chothia compound heavy chain CDRs (SEQ ID NOs. 8-10), and the humanized mature light chain variable region contains three 9F5 Kabat / Chothia compound light chain CDRs (SEQ ID NOs. 12-14). In some antibodies, the humanized mature heavy chain variable region contains three 9F5 Kabat heavy chain CDRs (SEQ ID NOs. 40, 9, and 10), and the humanized mature light chain variable region contains three 9F5 Kabat light chain CDRs (SEQ ID NOs. 12-14). In some antibodies, the humanized mature heavy chain variable region contains three 9F5 Chothia heavy chain CDRs (SEQ ID NOs. 41, 42, and 10), and the humanized mature light chain variable region contains three 9F5 Chothia light chain CDRs (SEQ ID NOs. 12-14). In some antibodies, the humanized mature heavy chain variable region contains three 9F5 AbM heavy chain CDRs (SEQ ID NOs. 8, 43, and 10), and the humanized mature light chain variable region contains three 9F5 AbM light chain CDRs (SEQ ID NOs. 12-14). In some antibodies, the humanized mature heavy chain variable region contains three 9F5 Contact heavy chain CDRs (SEQ ID NOs. 44-46), and the humanized mature light chain variable region contains three 9F5 Contact light chain CDRs (SEQ ID NOs. 47-49).

[0013] For example, antibodies can be humanized antibodies, veneer-coated antibodies, or chimeric antibodies.

[0014] Some such antibodies include a humanized mature heavy chain variable region having an amino acid sequence that is at least 90% identical to one of SEQ ID NOs. 15-22 and SEQ ID NOs. 109-129, and a humanized mature light chain variable region having an amino acid sequence that is at least 90% identical to one of SEQ ID NOs. 23-29, SEQ ID NOs. 61-108, and SEQ ID NOs. 130-171.

[0015] In some antibodies, at least one of the following positions in the VH region is occupied by the indicated amino acids: H1 is occupied by E, H17 by T, H20 by I, H69 by M, H75 by T, H93 by T, H94 by T, and H109 by V. In some antibodies, positions H1, H17, H20, H69, H75, H94, and H109 are occupied by E, T, I, M, T, T, T, and V, respectively.

[0016] In some antibodies, at least one of the following positions in the VH region is occupied by the indicated amino acid: H66 is occupied by R, and H81 is occupied by E. In some antibodies, positions H66 and H81 are occupied by R and E, respectively.

[0017] In some antibodies, at least one of the following positions in the VH region is occupied by the indicated amino acid: H23 is occupied by I, and H83 is occupied by R. In some antibodies, positions H23 and H83 are occupied by K and R, respectively.

[0018] In some antibodies, at least one of the following positions in the VH region is occupied by the indicated amino acid: H43 is occupied by K, H51 by V, H76 by D, M80 by M, and H108 by L. In some antibodies, positions H43, H51, H76, H80, and H108 are occupied by K, V, D, M, and L, respectively.

[0019] In some antibodies, the H28 position in the VH region is occupied by T.

[0020] In some antibodies, at least one of the following positions in the VH region is occupied by the indicated amino acid: H54 is occupied by D, and H56 is occupied by E. In some antibodies, positions H54 and H56 are occupied by D and E, respectively.

[0021] In some antibodies, the H40 position in the VH region is occupied by A.

[0022] In some antibodies, at least one of the following positions in the VH region is occupied by the indicated amino acid: H5 is occupied by V, H11 by V, H12 by K, H38 by R, and H42 by G. In some antibodies, positions H5, H11, H12, H38, and H42 are occupied by V, V, K, R, and G, respectively.

[0023] In some antibodies, at least one of the following positions in the VH region is occupied by the listed amino acids: H1 is occupied by Q or E, H5 by Q or V, H11 by L or V, H12 by V or K, H17 by S or T, H20 by L or I, H23 by T or K, H28 by N or T, H38 by K, R, or Q, H40 by R or A, H42 by E or G, H43 by Q or K, H48 by I or M, H51 by I or V, H54 by N or D, H 56 is occupied by D or E, H66 is occupied by K or R, H69 is occupied by I or M, H75 is occupied by S or T, H76 is occupied by N or D, H79 is occupied by Y, Q, D, N, or G, H80 is occupied by L, M, P, D, G, or E, H81 is occupied by Q or E, H82 is occupied by L, P, K, R, E, or N, H82a is occupied by S or G, H82c is occupied by L, G, D, or S, H83 is occupied by T or R, H93 is occupied by A or T, H94 is occupied by S or T, H108 is occupied by T or L, and H109 is occupied by L or V.

[0024] In some antibodies, the positions H1, H17, H20, H69, H75, H93, H94, and H109 in the VH region are occupied by E, T, I, M, T, T, T, and V, respectively. In some antibodies, the positions H1, H17, H20, H66, H69, H75, H81, H93, H94, and H109 in the VH region are occupied by E, T, I, R, M, T, E, T, T, and V, respectively. In some antibodies, the positions H1, H17, H20, H23, H28, H66, H69, H75, H81, H83, H93, H94, and H109 in the VH region are occupied by E, T, I, K, T, R, M, T, E, R, T, T, and V, respectively. In some antibodies, the positions H1, H17, H20, H23, H28, H43, H51, H54, H56, H66, H69, H75, H76, H80, H81, H83, H93, H94, H108, and H109 in the VH region are occupied by E, T, I, K, T, K, V, D, E, R, M, T, D, M, E, R, T, T, L, and V, respectively. In some antibodies, the positions H1, H17, H20, H23, H28, H40, H43, H48, H51, H54, H56, H66, H69, H75, H76, H80, H81, H83, H93, H94, H108, and H109 in the VH region are occupied by E, T, I, K, T, A, K, M, V, D, E, R, M, T, D, M, E, R, T, T, L, and V, respectively. In some antibodies, the positions H1, H5, H11, H12, H17, H20, H23, H38, H40, H42, H43, H51, H54, H56, H66, H69, H75, H76, H80, H81, H83, H93, H94, H108, and H109 in the VH region are occupied by E, V, V, K, T, I, K, R, A, G, K, V, D, E, R, M, T, D, M, E, R, T, T, L, and V, respectively. In some antibodies, the positions H1, H5, H11, H12, H17, H20, H23, H38, H40, H42, H43, H51, H66, H69, H75, H76, H80, H81, H83, H93, H94, H108, and H109 in the VH region are occupied by E, V, V, K, T, I, K, R, A, G, K, V, R, M, T, D, M, E, R, T, T, L, and V, respectively.

[0025] In some antibodies, the positions H1, H5, H11, H12, H17, H20, H23, H38, H42, H43, H66, H69, H75, H80, H81, H83, H93, H94, H108, and H109 in the VH region are occupied by E, V, V, K, T, I, K, Q, G, K, R, M, T, M, E, R, T, T, L, and V, respectively. In some antibodies, the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 127.

[0026] In some antibodies, the positions H1, H5, H11, H12, H17, H20, H23, H38, H42, H43, H66, H69, H75, H80, H81, H83, H93, H94, H108, and H109 in the VH region are occupied by E, V, V, K, T, I, K, K, E, K, R, M, T, M, E, R, T, T, L, and V, respectively. In some antibodies, the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 128.

[0027] In some antibodies, the positions H1, H5, H11, H12, H17, H20, H23, H38, H42, H43, H66, H69, H75, H80, H81, H82c, H83, H93, H94, H108, and H109 in the VH region are occupied by E, V, V, K, T, I, K, K, E, K, R, M, T, M, E, G, R, T, T, L, and V, respectively.

[0028] In some antibodies, position H80 in the VH region is occupied by P. In some antibodies, position H80 in the VH region is occupied by D. In some antibodies, position H82c in the VH region is occupied by G. In some antibodies, position H82c in the VH region is occupied by D. In some antibodies, position H82 in the VH region is occupied by P. In some antibodies, position H80 in the VH region is occupied by G. In some antibodies, position H82 in the VH region is occupied by K. In some antibodies, position H82 in the VH region is occupied by R. In some antibodies, position H82 in the VH region is occupied by E. In some antibodies, position H82 in the VH region is occupied by N.

[0029] In some antibodies, position H79 in the VH region is occupied by D. In some antibodies, position H79 in the VH region is occupied by N. In some antibodies, position H79 in the VH region is occupied by G. In some antibodies, position H80 in the VH region is occupied by E. In some antibodies, position H80 in the VH region is occupied by G. In some antibodies, position H82c in the VH region is occupied by S. In some antibodies, position H79 in the VH region is occupied by Q. In some antibodies, position H82a in the VH region is occupied by G.

[0030] In some antibodies, at least one of the following positions in the VL region is occupied by the indicated amino acid: L7 is occupied by S, L8 by P, L15 by P, and L100 by Q. In some antibodies, positions L7, L8, L15, and L100 are occupied by S, P, P, and Q, respectively.

[0031] In some antibodies, position L66 in the VL region is occupied by G. In some antibodies, position L64 in the VL region is occupied by S.

[0032] In some antibodies, position L17 in the VL region is occupied by E. In some antibodies, at least one of the following positions in the VL region is occupied by the indicated amino acid: L11 is occupied by L, L51 is occupied by G, and L54 is occupied by R.

[0033] In some antibodies, positions L11, L51, and L54 are occupied by L, G, and R, respectively. In some antibodies, position L30 in the VL region is occupied by Y.

[0034] In some antibodies, at least one of the following positions in the VL region is occupied by the listed amino acids: L3 is V or Q, L7 is A or S, L8 is A or P, L9 is F or L, L11 is N or L, L15 is L or P, L17 is T or E, L18 is S or P, L27b is L, D, T, or Q, L27c is L, D, G, S, E, T, N, A, P, or I, L30 is I, Y, E, K, G, L31 is T, N, or G, L33 is L, N, T, S, R, or G, L37 is L, Q, G, or I, and L39 is R. L51 is M, G, E, D, K, or I, L54 is R, G, or T, L60 is N or D, L64 is G or S, L66 is E or G, L73 is L, P, or G, L74 is R or K, L75 is I, D, P, Q, or G, L76 is S, P, or G, L77 is R or D, L78 is V, R, D, E, P, K, G, or Q, L85 is V or G, L86 is Y or T, L89 is A or G, L92 is L, D, E, G, Q, T, or I, L93 is E or G, and L100 is G or Q.

[0035] In some antibodies, positions L64 and L66 in the VL region are occupied by S and G, respectively. In some antibodies, positions L7, L8, L15, L64, L66, and L100 in the VL region are occupied by S, P, P, S, G, and Q, respectively. In some antibodies, positions L7, L8, L15, L17, L66, and L100 in the VL region are occupied by S, P, P, E, G, and Q, respectively. In some antibodies, positions L7, L8, L11, L15, L17, L51, L54, L66, and L100 in the VL region are occupied by S, P, L, P, E, G, R, G, and Q, respectively.

[0036] In some antibodies, the light chain variable region contains one of the amino acid sequences of SEQ ID NOs: 133, 135-137, 142-144, 149, 158, 159, and 168. In some antibodies, the light chain variable region contains the amino acid sequence of SEQ ID NO: 133. In some antibodies, the light chain variable region contains the amino acid sequence of SEQ ID NO: 137. In some antibodies, the light chain variable region contains the amino acid sequence of SEQ ID NO: 149. In some antibodies, the light chain variable region contains the amino acid sequence of SEQ ID NO: 159.

[0037] In some antibodies, the VL region positions L7, L8, L11, L15, L17, L30, L51, L54, L66, and L100 are occupied by S, P, L, P, E, Y, G, R, G, and Q, respectively. In some antibodies, the VL region positions L7, L8, L9, L11, L15, L17, L18, L31, L39, L51, L54, L60, L66, L74, and L100 are occupied by S, P, L, L, P, E, P, N, K, G, R, D, G, K, and Q, respectively.

[0038] In some antibodies, the VL region positions L7, L8, L11, L15, L17, L39, L60, L64, L66, L74, and L100 are occupied by S, P, L, P, E, K, N, S, G, K, and Q, respectively. In some antibodies, the VL region position L3 is occupied by Q. In some antibodies, the VL region position L27c is occupied by D, G, I, L, or S; the VL region position L37 is occupied by G, I, L, or Q; the VL region position L51 is occupied by E, G, I, K, or M; the VL region position L54 is occupied by G, L, R, or T; and the VL region position L92 is occupied by G, I, or L. In some antibodies, position L27c in the VL region is occupied by D or S, position L37 in the VL region is occupied by G, L, or Q, position L51 in the VL region is occupied by G or K, position L54 in the VL region is occupied by R, and position L92 in the VL region is occupied by I.

[0039] In some antibodies, position L27c in the VL region is occupied by D, position L37 in the VL region is occupied by G, and position L51 in the VL region is occupied by G. In some antibodies, the heavy chain variable region has an amino acid sequence containing SEQ ID NO: 127, and the light chain variable region has an amino acid sequence containing SEQ ID NO: 149.

[0040] In some antibodies, position L27c in the VL region is occupied by D, position L37 in the VL region is occupied by Q, and position L51 in the VL region is occupied by G. In some antibodies, the heavy chain variable region has an amino acid sequence containing SEQ ID NO: 127, and the light chain variable region has an amino acid sequence containing SEQ ID NO: 137.

[0041] In some antibodies, position L27c in the VL region is occupied by S, position L37 in the VL region is occupied by L, and position L51 in the VL region is occupied by G. In some antibodies, the heavy chain variable region has an amino acid sequence containing SEQ ID NO: 127, and the light chain variable region has an amino acid sequence containing SEQ ID NO: 159.

[0042] In some antibodies, position L27c in the VL region is occupied by D, position L37 in the VL region is occupied by Q, and position L51 in the VL region is occupied by K. In some antibodies, the heavy chain variable region has an amino acid sequence containing SEQ ID NO: 127, and the light chain variable region has an amino acid sequence containing SEQ ID NO: 138.

[0043] In some antibodies, position L27c in the VL region is occupied by S, position L37 in the VL region is occupied by Q, and position L51 in the VL region is occupied by G. In some antibodies, the heavy chain variable region has an amino acid sequence containing SEQ ID NO: 127, and the light chain variable region has an amino acid sequence containing SEQ ID NO: 133.

[0044] In some antibodies, the VL region positions L7, L8, L11, L15, L17, L39, L60, L64, L66, L74, and L100 are occupied by S, P, L, P, E, K, D, S, G, K, and Q, respectively. In some antibodies, the VL region position L3 is occupied by Q. In some antibodies, the VL region position L27c is occupied by G or S, the VL region position L37 is occupied by G, I, or Q, the VL region position L51 is occupied by G, I, or K, the VL region position L54 is occupied by G or R, and the VL region position L92 is occupied by G, I, or L.

[0045] In some antibodies, position L27c in the VL region is occupied by G, position L37 in the VL region is occupied by G, position L51 in the VL region is occupied by G, and position L54 in the VL region is occupied by R. In some antibodies, position L92 in the VL region is occupied by I. In some antibodies, the heavy chain variable region has an amino acid sequence containing SEQ ID NO: 129, and the light chain variable region has an amino acid sequence containing SEQ ID NO: 168.

[0046] In some antibodies, position L51 in the VL region is occupied by E. In some antibodies, position L51 in the VL region is occupied by D. In some antibodies, position L27c in the VL region is occupied by D. In some antibodies, position L27c in the VL region is occupied by G. In some antibodies, position L27c in the VL region is occupied by S. In some antibodies, position L27c in the VL region is occupied by E. In some antibodies, position L30 in the VL region is occupied by E. In some antibodies, position L30 in the VL region is occupied by K. In some antibodies, position L27c in the VL region is occupied by T.

[0047] In some antibodies, position L27c in the VL region is occupied by N. In some antibodies, position L27b in the VL region is occupied by D. In some antibodies, position L30 in the VL region is occupied by G. In some antibodies, position L33, which is supplied to the VL region, is occupied by N. In some antibodies, position L27c in the VL region is occupied by A. In some antibodies, position L33 in the VL region is occupied by T. In some antibodies, position L33 in the VL region is occupied by S. In some antibodies, position L33 in the VL region is occupied by R. In some antibodies, position L30 in the VL region is occupied by Q. In some antibodies, position L27b in the VL region is occupied by T.

[0048] In some antibodies, position L31 in the VL region is occupied by G. In some antibodies, position L27b in the VL region is occupied by Q. In some antibodies, position L33 in the VL region is occupied by G. In some antibodies, position L27c in the VL region is occupied by P. In some antibodies, position L78 in the VL region is occupied by R. In some antibodies, position L75 in the VL region is occupied by D. In some antibodies, position L78 in the VL region is occupied by D. In some antibodies, position L78 in the VL region is occupied by E. In some antibodies, position L78 in the VL region is occupied by P. In some antibodies, position L78 in the VL region is occupied by K.

[0049] In some antibodies, position L77 in the VL region is occupied by D. In some antibodies, position L78 in the VL region is occupied by G. In some antibodies, position L76 in the VL region is occupied by P. In some antibodies, position L75 in the VL region is occupied by P. In some antibodies, position L75, which is supplied to the VL region, is occupied by Q. In some antibodies, position L75 in the VL region is occupied by G. In some antibodies, position L73 in the VL region is occupied by P. In some antibodies, position L73 in the VL region is occupied by G. In some antibodies, position L78 in the VL region is occupied by Q. In some antibodies, position L76 in the VL region is occupied by G.

[0050] In some antibodies, position L92 in the VL region is occupied by D. In some antibodies, position L86 in the VL region is occupied by T. In some antibodies, position L92 in the VL region is occupied by E. In some antibodies, position L92 in the VL region is occupied by G. In some antibodies, position L92 in the VL region is occupied by Q. In some antibodies, position L93 in the VL region is occupied by G. In some antibodies, position L85, which is supplied to the VL region, is occupied by G. In some antibodies, position L92 in the VL region is occupied by T. In some antibodies, position L89 in the VL region is occupied by G.

[0051] In some antibodies, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, Q, G, G, and I, respectively. In some antibodies, the VL region positions L3Q, L27c, L37, L51, L54, and L92 are occupied by Q, S, Q, G, R, and I. In some antibodies, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, Q, G, T, and I, respectively. In some antibodies, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, Q, G, R, and G, respectively. In some antibodies, the positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, Q, G, R, and I, respectively.

[0052] In some antibodies, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, D, Q, G, R, and I, respectively. In some antibodies, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, D, Q, K, R, and I, respectively. In some antibodies, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, G, Q, K, R, and I, respectively. In some antibodies, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, G, Q, K, G, and I, respectively. In some antibodies, the positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, K, G, and I, respectively.

[0053] In some antibodies, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, G, G, G, R, and I, respectively. In some antibodies, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, G, G, G, R, and G, respectively. In some antibodies, the VL region positions L3, L27c, L37, L51, and L54 are occupied by Q, G, G, G, and R, respectively. In some antibodies, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, G, G, G, T, and I. In some antibodies, the positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, G, G, T, and G, respectively.

[0054] In some antibodies, the VL region positions L3, L27c, L37, L51, and L54 are occupied by Q, G, G, G, and T, respectively. In some antibodies, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, G, G, T, and I, respectively. In some antibodies, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, D, G, G, R, and I, respectively. In some antibodies, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, I, I, R, and I, respectively. In some antibodies, the positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, I, G, and I, respectively.

[0055] In some antibodies, the VL region positions L3, L27c, L37, L51, and L54 are occupied by Q, S, Q, I, and G, respectively. In some antibodies, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, Q, E, R, and I, respectively. In some antibodies, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, G, Q, E, G, and I, respectively. In some antibodies, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, G, I, E, R, and I, respectively. In some antibodies, the positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, I, E, R, and G, respectively.

[0056] In some antibodies, the VL region positions L3, L27c, L37, L51, and L54 are occupied by Q, I, I, E, and R, respectively. In some antibodies, the VL region positions L3, L37, L51, L54, and L92 are occupied by Q, Q, G, R, and I, respectively. In some antibodies, the VL region positions L3, L27c, L51, L54, and L92 are occupied by Q, S, G, R, and I, respectively. In some antibodies, the VL region positions L3, L27c, L37, L54, and L92 are occupied by Q, S, Q, R, and I, respectively. In some antibodies, the VL region positions L3, L27c, L37, L51, and L92 are occupied by Q, S, Q, G, and I, respectively.

[0057] In some antibodies, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, Q, G, G, and I, respectively. In some antibodies, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, Q, G, R, and I, respectively. In some antibodies, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, Q, G, R, and G, respectively. In some antibodies, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, G, Q, G, R, and I, respectively. In some antibodies, the positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, Q, K, R, and I, respectively.

[0058] In some antibodies, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, Q, K, G, and I, respectively. In some antibodies, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, G, G, G, R, and I, respectively. In some antibodies, the VL region positions L3, L27c, L37, L51, and L54 are occupied by Q, G, G, G, and R, respectively. In some antibodies, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, I, I, R, and I. In some antibodies, the positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, I, G, and I, respectively.

[0059] Some antibodies include a mature heavy chain variable region having an amino acid sequence that is at least 95% identical to one of SEQ ID NOs. 15-22 and SEQ ID NOs. 109-129, and a mature light chain variable region having an amino acid sequence that is at least 95% identical to one of SEQ ID NOs. 23-29, SEQ ID NOs. 61-108, and SEQ ID NOs. 130-171. Some antibodies include a mature heavy chain variable region having an amino acid sequence that is at least 98% identical to one of SEQ ID NOs. 15-22 and SEQ ID NOs. 109-129, and a mature light chain variable region having an amino acid sequence that is at least 98% identical to one of SEQ ID NOs. 23-29, SEQ ID NOs. 61-108, and SEQ ID NOs. 130-171. In some antibodies, the mature heavy chain variable region has the amino acid sequence of one of SEQ ID NOs. 15-22 and SEQ ID NOs. 109-129, and the mature light chain variable region has the amino acid sequence of one of SEQ ID NOs. 23-29, SEQ ID NOs. 61-108, and SEQ ID NOs. 130-171.

[0060] In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 15, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 23. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 15, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 24. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 15, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 25. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 15, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 26. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 15, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 27. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 15, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 28. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 15, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 29.

[0061] In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 16, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 23. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 16, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 24. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 16, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 25. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 16, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 26. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 16, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 27. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 16, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 28. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 16, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 29.

[0062] In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 17, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 23. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 17, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 24. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 17, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 25. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 17, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 26. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 17, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 27. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 17, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 28. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 17, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 29.

[0063] In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 18, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 23. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 18, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 24. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 18, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 25. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 18, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 26. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 18, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 27. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 18, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 28. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 18, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 29.

[0064] In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 19, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 23. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 19, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 24. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 19, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 25. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 19, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 26. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 19, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 27. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 19, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 28. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 19, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 29.

[0065] In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 20, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 23. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 20, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 24. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 20, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 25. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 20, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 26. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 20, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 27. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 20, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 28. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 20, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 29.

[0066] In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 21, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 23. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 21, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 24. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 21, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 25. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 21, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 26. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 21, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 27. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 21, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 28. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 21, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 29.

[0067] In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 22, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 23. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 22, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 24. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 22, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 25. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 22, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 26. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 22, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 27. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 22, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 28. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 22, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 29.

[0068] In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 127, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 149. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 127, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 142. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 127, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 159. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 127, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 148.

[0069] In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 127, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 137. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 127, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 145. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 127, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 136. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 127, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 138.

[0070] In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 127, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 158. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 127, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 143. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 127, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 144. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 127, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 133.

[0071] In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 127, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 160. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 127, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 161. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 127, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 139. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 128, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 168.

[0072] Some such antibodies include three light chain CDRs and three heavy chain CDRs of monoclonal antibody 10C12, which is a mouse antibody characterized by a heavy chain variable region having an amino acid sequence containing SEQ ID NO: 7 and a light chain variable region having an amino acid sequence containing SEQ ID NO: 11.

[0073] In some such antibodies, the three heavy chain CDRs CDR-H1, CDR-H2, and CDR-H3 are defined by the Kabat / Chothia complex (sequences 8, 9, and 10, respectively), and the three light chain CDRs CDR-L1, CDR-L2, and CDR-L3 are defined by the Kabat / Chothia complex (sequences 12, 13, and 14, respectively).

[0074] Some antibodies are 10C12, or its chimeric, veneered, or humanized forms. In some antibodies, the variable heavy chain has 85% or more identity with the human sequence. In some antibodies, the variable light chain has 85% or more identity with the human sequence. In some antibodies, the variable heavy chain and variable light chain each have 85% or more identity with the human germline sequence. Some antibodies are humanized antibodies.

[0075] Some antibodies are humanized 10C12 or chimeric 10C12 antibodies that specifically bind to human tau, where 10C12 is characterized by the mature heavy chain variable region of SEQ ID NO: 7 and the mature light chain variable region of SEQ ID NO: 11. Some antibodies include a humanized mature heavy chain variable region containing three heavy chain CDRs of 10C12 and a humanized mature light chain variable region containing three light chain CDRs of 10C12. In some antibodies, the CDRs are defined as CDRs selected from the group consisting of Kabat, Chothia, Kabat / Chothia complex, AbM, and Contact.

[0076] In some antibodies, the humanized mature heavy chain variable region contains three 10C12 Kabat / Chothia compound heavy chain CDRs (SEQ ID NOs. 8-10), and the humanized mature light chain variable region contains three 10C12 Kabat / Chothia compound light chain CDRs (SEQ ID NOs. 12-14). In some antibodies, the humanized mature heavy chain variable region contains three 10C12 Kabat heavy chain CDRs (SEQ ID NOs. 40, 9, and 10), and the humanized mature light chain variable region contains three 10C12 Kabat light chain CDRs (SEQ ID NOs. 12-14). In some antibodies, the humanized mature heavy chain variable region contains three 10C12 Chothia heavy chain CDRs (SEQ ID NOs. 41, 42, and 10), and the humanized mature light chain variable region contains three 10C12 Chothia light chain CDRs (SEQ ID NOs. 12-14). In some antibodies, the humanized mature heavy chain variable region contains three 10C12 AbM heavy chain CDRs (SEQ ID NOs. 8, 43, and 10), and the humanized mature light chain variable region contains three 10C12 AbM light chain CDRs (SEQ ID NOs. 12-14). In some antibodies, the humanized mature heavy chain variable region contains three 10C12 Contact heavy chain CDRs (SEQ ID NOs. 44-46), and the humanized mature light chain variable region contains three 10C12 Contact light chain CDRs (SEQ ID NOs. 47-49).

[0077] For example, the antibody may be a humanized antibody, a veneer-coated antibody, or a chimeric antibody.

[0078] Some such antibodies include a humanized mature heavy chain variable region having an amino acid sequence that is at least 90% identical to one of sequence numbers 214-215, and a humanized mature light chain variable region having an amino acid sequence that is at least 90% identical to one of sequence numbers 216-217.

[0079] In some antibodies, at least one of the following positions in the VH region is occupied by the indicated amino acid: H24 is occupied by A, H48 by I, H67 by A, H69 by M, H93 by T, and H94 by T. In some antibodies, positions H24, H48, H67, H69, H93, and H94 are occupied by A, I, A, M, T, and T, respectively.

[0080] In some antibodies, at least one of the following positions in the VH region is occupied by the indicated amino acid: H1 is occupied by Q or E, H24 by A, H48 by I, H67 by A, H69 by M, H93 by T, and H94 by T.

[0081] In some antibodies, positions H24, H48, H67, H69, H93, and H94 are occupied by A, I, A, M, T, and T, respectively. In some antibodies, positions H1, H24, H48, H67, H69, H93, and H94 are occupied by E, A, I, A, M, T, and T, respectively.

[0082] In some antibodies, position L64 in the VL region is occupied by S.

[0083] In some antibodies, at least one of the following positions in the VL region is occupied by the indicated amino acid: L64 is S, and L104 is V or L. In some antibodies, position L64 is occupied by S. In some antibodies, positions L64 and L104 in the VL region are occupied by S and L, respectively.

[0084] Some antibodies include a mature heavy chain variable region having an amino acid sequence that is at least 95% identical to one of sequence numbers 214-215, and a mature light chain variable region having an amino acid sequence that is at least 95% identical to one of sequence numbers 216-217. Some antibodies include a mature heavy chain variable region having an amino acid sequence that is at least 98% identical to one of sequence numbers 214-215, and a mature light chain variable region having an amino acid sequence that is at least 98% identical to one of sequence numbers 216-217. In some antibodies, the mature heavy chain variable region has the amino acid sequence of one of sequence numbers 214-215, and the mature light chain variable region has the amino acid sequence of one of sequence numbers 216-217.

[0085] In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 214, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 216. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 214, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 217. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 215, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 216. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 215, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 217.

[0086] Some such antibodies include three light chain CDRs and three heavy chain CDRs of monoclonal antibody 12C4, which is a mouse antibody characterized by a heavy chain variable region having an amino acid sequence containing SEQ ID NO: 219 and a light chain variable region having an amino acid sequence containing SEQ ID NO: 11.

[0087] In some such antibodies, the three heavy chain CDRs CDR-H1, CDR-H2, and CDR-H3 are defined by the Kabat / Chothia complex (SEQ ID NOs. 8, 220, and 10, respectively), and the three light chain CDRs CDR-L1, CDR-L2, and CDR-L3 are defined by the Kabat / Chothia complex (SEQ ID NOs. 12, 13, and 14, respectively).

[0088] Some antibodies are 12C4, or their chimeric, veneered, or humanized forms. In some antibodies, the variable heavy chain has 85% or more identity with the human sequence. In some antibodies, the variable light chain has 85% or more identity with the human sequence. In some antibodies, the variable heavy chain and variable light chain each have 85% or more identity with the human germline sequence. Some antibodies are humanized antibodies.

[0089] Some antibodies are humanized 12C4 antibodies or chimeric 12C4 antibodies that specifically bind to human tau, where 12C4 is a mouse antibody characterized by the mature heavy chain variable region of SEQ ID NO: 219 and the mature light chain variable region of SEQ ID NO: 11. Some antibodies include a humanized mature heavy chain variable region containing three heavy chain CDRs of 12C4 and a humanized mature light chain variable region containing three light chain CDRs of 12C4. In some antibodies, the CDRs are defined as CDRs selected from the group consisting of Kabat, Chothia, Kabat / Chothia complex, AbM, and Contact.

[0090] In some antibodies, the humanized mature heavy chain variable region contains three 12C4 Kabat / Chothia compound heavy chain CDRs (SEQ ID NOs. 8, 220, and 10), and the humanized mature light chain variable region contains three 12C4 Kabat / Chothia compound light chain CDRs (SEQ ID NOs. 12-14). In some antibodies, the humanized mature heavy chain variable region contains three 12C4 Kabat heavy chain CDRs (SEQ ID NOs. 40, 220, and 10), and the humanized mature light chain variable region contains three 12C4 Kabat light chain CDRs. In some antibodies, the humanized mature heavy chain variable region contains three 12C4 Chothia heavy chain CDRs (SEQ ID NOs. 41, 42, and 10), and the humanized mature light chain variable region contains three 12C4 Chothia light chain CDRs (SEQ ID NOs. 12-14). In some antibodies, the humanized mature heavy chain variable region contains three 12C4 AbM heavy chain CDRs (SEQ ID NOs. 8, 257, and 10), and the humanized mature light chain variable region contains three 12C4 AbM light chain CDRs (SEQ ID NOs. 12-14). In some antibodies, the humanized mature heavy chain variable region contains three 12C4 Contact heavy chain CDRs (SEQ ID NOs. 44, 258, and 46), and the humanized mature light chain variable region contains three 12C4 Contact light chain CDRs (SEQ ID NOs. 47-49).

[0091] For example, the antibody may be a humanized antibody, a veneer-coated antibody, or a chimeric antibody.

[0092] Some such antibodies include a humanized mature heavy chain variable region having an amino acid sequence that is at least 90% identical to one of sequence numbers 221-222, and a humanized mature light chain variable region having an amino acid sequence that is at least 90% identical to one of sequence numbers 223-224.

[0093] In some antibodies, at least one of the following positions in the VH region is occupied by the indicated amino acid: H1 is occupied by Q or E, H48 by M or I, H93 by A or T, and H94 by R or T. In some antibodies, positions H1, H48, H93, and H94 in the VH region are occupied by E, I, T, and T, respectively.

[0094] In some antibodies, the VL region is occupied by the indicated amino acids: L64 is G or S, and L104 is V or L. In some antibodies, the VL region positions L64 and L104 are occupied by S and L, respectively.

[0095] Some antibodies include a mature heavy chain variable region having an amino acid sequence that is at least 95% identical to one of sequence numbers 221-222, and a mature light chain variable region having an amino acid sequence that is at least 95% identical to one of sequence numbers 223-224. Some antibodies include a mature heavy chain variable region having an amino acid sequence that is at least 98% identical to one of sequence numbers 221-222, and a mature light chain variable region having an amino acid sequence that is at least 98% identical to one of sequence numbers 223-224. In some antibodies, the mature heavy chain variable region has the amino acid sequence of one of sequence numbers 221-222, and the mature light chain variable region has the amino acid sequence of one of sequence numbers 223-224.

[0096] In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 221, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 223. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 221, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 224. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 222, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 223. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 222, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 224.

[0097] Some such antibodies include three light chain CDRs and three heavy chain CDRs of monoclonal antibody 17C12, which is a mouse antibody characterized by a heavy chain variable region having an amino acid sequence containing SEQ ID NO: 225 and a light chain variable region having an amino acid sequence containing SEQ ID NO: 228.

[0098] In some such antibodies, the three heavy chain CDRs CDR-H1, CDR-H2, and CDR-H3 are defined by the Kabat / Chothia complex (sequences 226, 227, and 10, respectively), and the three light chain CDRs CDR-L1, CDR-L2, and CDR-L3 are defined by the Kabat / Chothia complex (sequences 229, 230, and 231, respectively).

[0099] Some antibodies are 17C12, or its chimeric, veneered, or humanized forms. In some antibodies, the variable heavy chain has 85% or more identity with the human sequence. In some antibodies, the variable light chain has 85% or more identity with the human sequence. In some antibodies, the variable heavy chain and variable light chain each have 85% or more identity with the human germline sequence. Some antibodies are humanized antibodies.

[0100] Some antibodies are humanized 17C12 antibodies or chimeric 17C12 antibodies that specifically bind to human tau, where 17C12 is a mouse antibody characterized by the mature heavy chain variable region of SEQ ID NO: 225 and the mature light chain variable region of SEQ ID NO: 228. Some antibodies include a humanized mature heavy chain variable region containing three heavy chain CDRs of 17C12 and a humanized mature light chain variable region containing three light chain CDRs of 17C12. In some antibodies, the CDRs are defined as CDRs selected from the group consisting of Kabat, Chothia, Kabat / Chothia complex, AbM, and Contact.

[0101] In some antibodies, the humanized mature heavy chain variable region contains three 17C12 Kabat / Chothia compound heavy chain CDRs (SEQ ID NOs. 226, 227, and 10), and the humanized mature light chain variable region contains three 17C12 Kabat / Chothia compound light chain CDRs (SEQ ID NOs. 229-231). In some antibodies, the humanized mature heavy chain variable region contains three 17C12 Kabat heavy chain CDRs (SEQ ID NOs. 40, 227, and 10), and the humanized mature light chain variable region contains three 17C12 Kabat light chain CDRs (SEQ ID NOs. 229-231). In some antibodies, the humanized mature heavy chain variable region contains three 17C12 Chothia heavy chain CDRs (SEQ ID NO: 259, SEQ ID NO: 42, and SEQ ID NO: 10), and the humanized mature light chain variable region contains three 17C12 Chothia light chain CDRs (SEQ ID NOs: 229-231). In some antibodies, the humanized mature heavy chain variable region contains three 17C12 AbM heavy chain CDRs (SEQ ID NO: 226, SEQ ID NO: 260, and SEQ ID NO: 10), and the humanized mature light chain variable region contains three 17C12 AbM light chain CDRs (SEQ ID NOs: 229-231). In some antibodies, the humanized mature heavy chain variable region contains three 17C12 Contact heavy chain CDRs (SEQ ID NO: 44, SEQ ID NO: 261, and SEQ ID NO: 46), and the humanized mature light chain variable region contains three 17C12 Contact light chain CDRs (SEQ ID NOs: 262-264).

[0102] For example, the antibody may be a humanized antibody, a veneer-coated antibody, or a chimeric antibody.

[0103] Some such antibodies include a humanized mature heavy chain variable region having an amino acid sequence that is at least 90% identical to one of sequence numbers 232-233, and a humanized mature light chain variable region having an amino acid sequence that is at least 90% identical to one of sequence numbers 234-235.

[0104] In some antibodies, at least one of the following positions in the VH region is occupied by the indicated amino acid: H2 is occupied by I, H24 by A, H48 by I, H67 by A, H69 by M, H93 by T, and H94 by T. In some antibodies, positions H2, H24, H48, H67, H69, H93, and H94 are occupied by E, A, I, A, M, T, and T, respectively.

[0105] In some antibodies, at least one of the following positions in the VH region is occupied by the indicated amino acid: H1 is occupied by Q or E, H2 by I, H24 by A, H48 by I, H67 by A, H69 by M, H93 by T, H94 by T, H108 by T or L, and H113 by R or S. In some antibodies, the positions H2, H24, H48, H67, H69, H93, and H94 in the VH region are occupied by E, A, I, A, M, T, and T, respectively. In some antibodies, the positions H1, H2, H24, H48, H67, H69, H93, H94, H108, and H113 in the VH region are occupied by E, I, A, I, A, M, T, T, L, and S, respectively.

[0106] In some antibodies, at least one of the following positions in the VL region is occupied by the indicated amino acid: L2 is occupied by V, and L36 is occupied by L. In some antibodies, positions L2 and L36 are occupied by V and L, respectively.

[0107] In some antibodies, at least one of the following positions in the VL region is occupied by the indicated amino acid: L2 is V, L36 is L, and L43 is P or S. In some antibodies, positions L2 and L36 in the VL region are occupied by V and L, respectively. In some antibodies, positions L2, L36, and L43 in the VL region are occupied by V, L, and S, respectively.

[0108] Some antibodies contain a mature heavy chain variable region having an amino acid sequence that is at least 95% identical to one of sequence numbers 232-233, and a mature light chain variable region having an amino acid sequence that is at least 95% identical to one of sequence numbers 234-235. Some antibodies contain a mature heavy chain variable region having an amino acid sequence that is at least 98% identical to one of sequence numbers 232-233, and a mature light chain variable region having an amino acid sequence that is at least 98% identical to one of sequence numbers 234-235. In some antibodies, the mature heavy chain variable region has the amino acid sequence of one of sequence numbers 232-233, and the mature light chain variable region has the amino acid sequence of one of sequence numbers 234-235.

[0109] In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 232, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 234. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 232, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 235. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 233, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 234. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 233, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 235.

[0110] Some such antibodies include three light chain CDRs and three heavy chain CDRs of a monoclonal antibody 14H3, which is a mouse antibody characterized by a heavy chain variable region having an amino acid sequence containing SEQ ID NO: 240 and a light chain variable region having an amino acid sequence containing SEQ ID NO: 244.

[0111] In some such antibodies, the three heavy chain CDRs CDR-H1, CDR-H2, and CDR-H3 are as defined by the Kabat / Chothia complex, except that G or S can occupy position H35B (sequences 241, 242, and 243, respectively), and the three light chain CDRs CDR-L1, CDR-L2, and CDR-L3 are as defined by the Kabat / Chothia complex (sequences 245, 246, and 247, respectively). In some antibodies, CDR-H1 has the amino acid sequence including sequence number 277.

[0112] Some antibodies are 14H3, or their chimeric, veneered, or humanized forms. In some antibodies, the variable heavy chain has 85% or more identity with the human sequence. In some antibodies, the variable light chain has 85% or more identity with the human sequence. In some antibodies, the variable heavy chain and variable light chain each have 85% or more identity with the human germline sequence. Some antibodies are humanized antibodies.

[0113] Some antibodies are humanized 14H3 antibodies or chimeric 14H3 antibodies that specifically bind to human tau, where 14H3 is a mouse antibody characterized by the mature heavy chain variable region of SEQ ID NO: 240 and the mature light chain variable region of SEQ ID NO: 244. Some antibodies include a humanized mature heavy chain variable region containing three heavy chain CDRs of 14H3 and a humanized mature light chain variable region containing three light chain CDRs of 14H3. In some antibodies, the CDRs are defined as CDRs selected from the group consisting of Kabat, Chothia, Kabat / Chothia complex, AbM, and Contact.

[0114] In some antibodies, the humanized mature heavy chain variable region contains three 14H3 Kabat / Chothia compound heavy chain CDRs (SEQ ID NOs. 241-243), and the humanized mature light chain variable region contains three 14H3 Kabat / Chothia compound light chain CDRs (SEQ ID NOs. 245-247). In some antibodies, the humanized mature heavy chain variable region contains three 14H3 Kabat heavy chain CDRs (SEQ ID NOs. 265, 242, and 243), and the humanized mature light chain variable region contains three 14H3 Kabat light chain CDRs (SEQ ID NOs. 245-247). In some antibodies, the humanized mature heavy chain variable region contains three 14H3 Chothia heavy chain CDRs (SEQ ID NOs. 266, 267, and 243), and the humanized mature light chain variable region contains three 14H3 Chothia light chain CDRs (SEQ ID NOs. 245-247). In some antibodies, the humanized mature heavy chain variable region contains three 14H3 AbM heavy chain CDRs (SEQ ID NOs. 241, 268, and 243), and the humanized mature light chain variable region contains three 14H3 AbM light chain CDRs (SEQ ID NOs. 245-247). In some antibodies, the humanized mature heavy chain variable region contains three 14H3 Contact heavy chain CDRs (SEQ ID NOs. 269-271), and the humanized mature light chain variable region contains three 14H3 Contact light chain CDRs (SEQ ID NOs. 272-274).

[0115] For example, the antibody may be a humanized antibody, a veneer-coated antibody, or a chimeric antibody.

[0116] Some such antibodies include a humanized mature heavy chain variable region having an amino acid sequence that is at least 90% identical to one of sequence numbers 248-249, and a humanized mature light chain variable region having an amino acid sequence that is at least 90% identical to one of sequence numbers 250-251.

[0117] In some antibodies, the H35B position in the VH region is occupied by S.

[0118] In some antibodies, at least one of the following positions in the VH region is occupied by the indicated amino acid: H35B is occupied by S, H108 by M or L, and H113 by L or S. In some antibodies, the position H35B in the VH region is occupied by S. In some antibodies, the positions H35B, H108, and H113 in the VH region are occupied by S, L, and S, respectively.

[0119] In some antibodies, at least one of the following positions in the VL region is occupied by the indicated amino acid: L2 is occupied by V, and L87 is occupied by F. In some antibodies, positions L2 and L87 are occupied by V and F, respectively.

[0120] In some antibodies, at least one of the following positions in the VL region is occupied by the indicated amino acid: L2 is V, L7 is T or S, L37 is L or Q, L87 is F, L100 is G or Q, and L104 is V or L. In some antibodies, positions L2 and L87 in the VL region are occupied by V and F, respectively. In some antibodies, positions L2, L7, L37, L87, L100, and L104 in the VL region are occupied by V, S, Q, F, Q, and L, respectively.

[0121] Some antibodies include a mature heavy chain variable region having an amino acid sequence that is at least 95% identical to one of sequence numbers 248-249, and a mature light chain variable region having an amino acid sequence that is at least 95% identical to one of sequence numbers 250-251. Some antibodies include a mature heavy chain variable region having an amino acid sequence that is at least 98% identical to one of sequence numbers 248-249, and a mature light chain variable region having an amino acid sequence that is at least 98% identical to one of sequence numbers 250-251. In some antibodies, the mature heavy chain variable region has the amino acid sequence of one of sequence numbers 248-249, and the mature light chain variable region has the amino acid sequence of one of sequence numbers 250-251.

[0122] In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 248, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 250. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 248, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 251. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 249, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 250. In some antibodies, the mature heavy chain variable region has the amino acid sequence of SEQ ID NO: 249, and the mature light chain variable region has the amino acid sequence of SEQ ID NO: 251.

[0123] For example, an antibody may be a chimeric antibody. For example, an antibody may be a veneer-coated antibody.

[0124] This antibody may be an intact antibody. This antibody may be a binding fragment. In one embodiment, the binding fragment is a single-chain antibody, Fab, or Fab'2 fragment. This antibody may be a Fab fragment or a single-chain Fv. Some of this antibody may have a human IgG1 isotype, while others may have a human IgG2 or IgG4 isotype. Some antibodies have a mature light chain variable region fused to the light chain constant region and a mature heavy chain variable region fused to the heavy chain constant region. The heavy chain constant region of some antibodies is a mutant of the native human heavy chain constant region, with reduced binding to the Fcγ receptor compared to the native human heavy chain constant region. In some antibodies, the heavy chain constant region is the heavy chain constant region of the IgG1 isotype.

[0125] Some antibodies may have at least one mutation in the constant region, for example, a mutation that reduces complement fixation or activation by the constant region, for example, a mutation at one or more of the EU numbering positions 241, 264, 265, 270, 296, 297, 318, 320, 322, 329, and 331. Some antibodies have alanine at positions 318, 320, and 322. Some antibodies may be at least 95(w / w)% pure. These antibodies may be conjugated to therapeutic agents, cytotoxic agents, cell proliferation inhibitors, neurotrophic agents, or neuroprotective agents.

[0126] In another embodiment, the present invention provides a pharmaceutical composition comprising any of the antibodies disclosed herein and a pharmaceutically acceptable carrier.

[0127] In another embodiment, the present invention provides nucleic acids encoding the heavy and / or light chains of any of the antibodies disclosed herein, a recombinant expression vector comprising the nucleic acid, and host cells transformed with the recombinant expression vector. Some nucleic acids have sequences comprising any one of SEQ ID NOs. 38-39.

[0128] In another embodiment, the present invention provides a vector comprising a nucleic acid encoding a mature heavy chain variable region and a mature light chain variable region operably bound to one or more regulatory sequences that act on the expression of any of the antibodies disclosed herein in mammalian cells; a recombinant expression vector comprising the nucleic acid; a host cell transformed with the recombinant expression vector; and a host cell transformed with the nucleic acid. Some nucleic acids further encode a heavy chain constant region fused to the mature heavy chain variable region and a light chain constant region fused to the mature light chain variable region. In some vectors, the antibody is an scFv. In some vectors, the antibody is a Fab fragment. In some vectors, one or more regulatory sequences include one or more of a promoter, an enhancer, a ribosome binding site, and a transcription termination signal. In some vectors, the nucleic acid further encodes a signal peptide fused to the mature heavy chain variable region and the mature light chain variable region. In some vectors, the nucleic acid is codon-optimized for expression in host cells. In some vectors, one or more regulatory sequences include a eukaryotic promoter. In some vectors, the nucleic acid further encodes a selectable gene.

[0129] In yet another embodiment, the present invention provides a method for expressing an antibody in mammalian cells, comprising the step of expressing the antibody by incorporating the nucleic acid disclosed herein into the genome of a transgenic animal.

[0130] In a further different aspect, the present invention provides a first vector and a second vector, each comprising a nucleic acid encoding a mature heavy chain variable region and a mature light chain variable region, each being operably bound to one or more regulatory sequences for acting on the expression of any of the antibodies disclosed herein in mammalian cells, as well as a host cell comprising the nucleic acid. In some first and second vectors, the nucleic acid further encodes a heavy chain constant region fused to a mature heavy chain variable region and a light chain constant region fused to a mature light chain variable region, respectively.

[0131] In yet another embodiment, the present invention provides a method for expressing an antibody in mammalian cells, comprising the step of expressing the antibody by incorporating one of the nucleic acids disclosed herein into the genome of a transgenic animal.

[0132] In yet another embodiment, the present invention provides a method for humanizing any of the non-human antibodies described herein, for example, mouse antibody 9F5 characterized by the mature heavy chain variable region of SEQ ID NO: 7 and the mature light chain variable region of SEQ ID NO: 11; mouse antibody 10C12 characterized by the mature heavy chain variable region of SEQ ID NO: 7 and the mature light chain variable region of SEQ ID NO: 11; mouse antibody 2D11 characterized by the mature heavy chain variable region of SEQ ID NO: 7 and the mature light chain variable region of SEQ ID NO: 11; mouse antibody 12C4 characterized by the mature heavy chain variable region of SEQ ID NO: 219 and the mature light chain variable region of SEQ ID NO: 11; mouse antibody 17C12 characterized by the mature heavy chain variable region of SEQ ID NO: 225 and the mature light chain variable region of SEQ ID NO: 228; mouse antibody 14H3 characterized by the mature heavy chain variable region of SEQ ID NO: 240 and the mature light chain variable region of SEQ ID NO: 244. Such a method may include the steps of: selecting one or more acceptor antibodies; identifying the amino acid residues of the retained mouse antibody; synthesizing a nucleic acid encoding a humanized heavy chain containing the CDR of the mouse antibody's heavy chain and a nucleic acid encoding a humanized light chain containing the CDR of the mouse antibody's light chain; and expressing the nucleic acids in a host cell to produce a humanized antibody.

[0133] Methods are also provided for producing humanized antibodies, chimeric antibodies, or veneer-coated antibodies, such as humanized, chimeric, or veneer-coated forms of antibodies like 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3. In such a method, cells transformed with nucleic acids encoding the heavy and light chains of an antibody are cultured so that the cells secrete the antibody. This antibody can then be purified from the cell culture medium.

[0134] Cell lines producing any of the antibodies disclosed herein may be produced by introducing a vector encoding the heavy and light chains of the antibody as well as a selectable marker into cells, growing the cells under conditions for selecting cells with an increased copy number of the vector, isolating a single cell from the selected cells, and depositing cells cloned from the single cell selected based on the antibody yield.

[0135] Some cells can proliferate under selective conditions, at least 100 mg / L / 10 6 Screening can be performed for cell lines that spontaneously express and secrete at a rate of one cell / 24h. Single cells can be isolated from selected cells. Subsequently, cells cloned from single cells can be deposited. Single cells can be selected based on desirable properties such as antibody yield. Exemplary cell lines are those expressing 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3.

[0136] The present invention also provides a method for inhibiting or reducing tau aggregation in subjects having or at risk of developing tau-mediated amyloidosis, comprising the step of inhibiting or reducing tau aggregation in a subject by administering an effective regime of an antibody disclosed herein to the subject. Exemplary antibodies include humanized versions of 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3.

[0137] Furthermore, there is a method provided for treating or preventing tau-related diseases in a subject, comprising the step of administering an effective regime of antibodies disclosed herein to treat or prevent the disease. Examples of such disorders include Alzheimer's disease, Down syndrome, mild cognitive impairment, primary age-related tauopathy, post-encephalitis parkinsonism, post-traumatic dementia or boxer's dementia, Pick's disease, Niemann-Pick disease type C, supranuclear palsy, frontotemporal dementia, frontotemporal lobar degeneration, argyrophilic granulopathy, GGT (globular glial tauopathy), Guam amyotrophic lateral sclerosis / Parkinson's dementia complex, corticobasal degeneration (CBD), Lewy body dementia, Lewy body variant of Alzheimer's disease (LBVAD), chronic traumatic encephalopathy (CTE), GGT (globular glial tauopathy), Parkinson's disease, or progressive supranuclear palsy (PSP). In some cases, tau-related disorders are Alzheimer's disease. In some cases, the patient is a carrier of ApoE4.

[0138] Furthermore, a method for reducing tau transmission abnormalities is provided, comprising the step of reducing tau transmission by administering an effective regime of antibodies disclosed herein.

[0139] Furthermore, a method for inducing tau phagocytosis is provided, comprising the step of inducing tau phagocytosis by administering an effective regime of the antibody disclosed herein.

[0140] Furthermore, a method for inhibiting tau aggregation or precipitation is provided, comprising the step of inhibiting tau aggregation or precipitation by administering an effective regime of antibodies disclosed herein.

[0141] Furthermore, a method is provided for inhibiting the formation of tau fibrillation, comprising the step of administering an effective regime of the antibody disclosed herein.

[0142] The present invention also provides a method for detecting tau protein precipitates in subjects having or at risk of a disease related to tau aggregation or precipitation, comprising the steps of administering an antibody disclosed herein to the subject and detecting the antibody bound to tau in the subject. Examples of such diseases include Alzheimer's disease, Down syndrome, mild cognitive impairment, primary age-related tauopathy, post-encephalitis parkinsonism, post-traumatic dementia or boxer's dementia, Pick's disease, Niemann-Pick disease type C, supranuclear palsy, frontotemporal dementia, frontotemporal lobar degeneration, argyrophilic granulopathy, GGT (globular glial tauopathy), Guam amyotrophic lateral sclerosis / Parkinson's dementia complex, corticobasal degeneration (CBD), Lewy body dementia, Lewy body variant of Alzheimer's disease (LBVAD), chronic traumatic encephalopathy (CTE), GGT (globular glial tauopathy), Parkinson's disease, or progressive supranuclear palsy (PSP). In some embodiments, the antibody is administered intravenously into the subject's body. In some embodiments, the antibody is administered directly to the brain by intravenous injection or by making a hole in the target skull. In some embodiments, the antibody is labeled. In some embodiments, the antibody is labeled with a fluorescent label, a paramagnetic label, or a radioactive label. In some embodiments, the radioactive label is detected using positron emission tomography (PET) or single-photon emission computed tomography (SPECT).

[0143] The present invention also provides a method for measuring the effectiveness of a treatment in a subject being treated for a disease related to tau aggregation or precipitation, comprising the steps of: measuring a first level of tau protein precipitate in a subject before treatment by administering the antibody disclosed herein to the subject; detecting a first amount of the antibody bound to tau in the subject; performing the treatment on the subject; measuring a second level of tau protein precipitate in the subject after treatment by administering the antibody to the subject; and detecting the antibody bound to tau in the subject, wherein a decrease in the level of tau protein precipitate indicates a positive response to the treatment.

[0144] The present invention also provides a method for measuring the effectiveness of a treatment in a subject being treated for a disease related to tau aggregation or precipitation, comprising the steps of: measuring a first level of tau protein precipitate in a subject before treatment by administering the antibody disclosed herein to the subject; detecting a first amount of the antibody bound to tau in the subject; performing the treatment on the subject; measuring a second level of tau protein precipitate in the subject after treatment by administering the antibody to the subject; and detecting a second amount of the antibody bound to tau in the subject, wherein no change in the level of tau protein precipitate or a small increase in the level of tau protein precipitate indicates a positive response to the treatment.

[0145] The present invention also provides an isolated monoclonal antibody that specifically binds to a peptide consisting of the residue (Q / E)IVYK(S / P) (SEQ ID NO: 56). The present invention also provides an isolated monoclonal antibody that specifically binds to a peptide consisting of the residue QIVYKP (SEQ ID NO: 57). The present invention also provides an isolated monoclonal antibody that specifically binds to a peptide consisting of the residue EIVYKSP (SEQ ID NO: 58). The present invention also provides an isolated monoclonal antibody that specifically binds to a peptide consisting of the residue EIVYKS (SEQ ID NO: 277).

[0146] The present invention also provides isolated monoclonal antibodies that specifically bind to the polypeptide of SEQ ID NO: 1 via an epitope containing at least one residue from residues 307-312 of SEQ ID NO: 1. Some such antibodies bind to the epitope in residues 307-312 of SEQ ID NO: 1. The present invention also provides isolated monoclonal antibodies that specifically bind to the polypeptide of SEQ ID NO: 1 via an epitope containing at least one residue from residues 391-397 of SEQ ID NO: 1. Some such antibodies bind to the epitope in residues 391-397 of SEQ ID NO: 1. The present invention also provides isolated monoclonal antibodies that specifically bind to the polypeptide of SEQ ID NO: 1 via an epitope containing at least one residue from residues 391-396 of SEQ ID NO: 1. Some such antibodies bind to the epitope in residues 391-396 of SEQ ID NO: 1. The present invention also provides isolated monoclonal antibodies that specifically bind to the polypeptide of SEQ ID NO: 1 via an epitope containing at least one residue derived from residues 307-312 of SEQ ID NO: 1 and at least one residue derived from residues 391-397 of SEQ ID NO: 1. The present invention also provides an isolated monoclonal antibody that specifically binds to the polypeptide of SEQ ID NO: 1 with an epitope comprising at least one residue derived from residues 307-312 of SEQ ID NO: 1 and at least one residue derived from residues 391-396 of SEQ ID NO: 1.

[0147] The present invention also provides a method for treating or preventing tau-related diseases in a subject, comprising the step of administering an immunogen containing a tau peptide, which is a tau peptide of up to 20 consecutive amino acids from SEQ ID NO: 1 to which the antibody 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3 specifically binds, and which induces the formation of an antibody that specifically binds to tau in the subject. In some parts of such a method, the tau peptide consists of 4 to 7 consecutive amino acids derived from residues 307-312, or residues 391-397, or residues 391-396 of SEQ ID NO: 1. In some parts of such a method, the tau peptide consists of residue (Q / E)IVYK(S / P) (SEQ ID NO: 56). In some parts of such a method, the tau peptide consists of residue QIVYKP (SEQ ID NO: 57). In some parts of such a method, the tau peptide consists of residue EIVYKSP (SEQ ID NO: 58). In some of these methods, the tau peptide consists of the residue EIVYKS (SEQ ID NO: 277). In some of these methods, the tau peptide is bound to a heterogeneous conjugate molecule.

[0148] The present invention also provides a method for producing an antibody that specifically binds to an epitope containing (Q / E)IVYK(S / P) (SEQ ID NO: 56), comprising the steps of immunizing an animal with tau or a fragment thereof, and screening for an antibody that specifically binds to the epitope. In some parts of such a method, the animal is immunized with 383 amino acid human tau (4R0N). In some parts of such a method, the human tau contains the P301S mutation. In some parts of such a method, the human tau is a recombinant with a histagged N-terminus.

[0149] In some of these methods, screening is performed on 15-amino acid peptides containing any of the other consensus motifs presented by QIVYKP (SEQ ID NO: 57), EIVYKSP (SEQ ID NO: 58), EIVYKS (SEQ ID NO: 277), or (Q / E)IVYK(S / P) (SEQ ID NO: 56). In some of these methods, the peptides contain QIVYKP (SEQ ID NO: 57), EIVYKSP (SEQ ID NO: 58), or EIVYKS (SEQ ID NO: 277).

[0150] In some of these methods, animals are immunized with a tau fragment containing a peptide presented by (Q / E)IVYK(S / P) (SEQ ID NO: 56) bound to a carrier. In some of these methods, the peptide is QIVYKP (SEQ ID NO: 57), EIVYKSP (SEQ ID NO: 58), or EIVYKS (SEQ ID NO: 277). [Brief explanation of the drawing]

[0151] [Figure 1A] Figure 1A shows the alignment of the human germline heavy chain variable region sequence IGHV1-69-2*01 (SEQ ID NO: 33), the human acceptor heavy chain variable region sequence AAN16432-VH_huFrwk (AAN16432_H; SEQ ID NO: 31), and the human acceptor heavy chain variable region sequence 2RCS-VH_huFrwk (2RCS_H; SEQ ID NO: 32) with the heavy chain variable region of the mouse 9F5 antibody (SEQ ID NO: 7) and the heavy chain variable regions of the humanized versions of the 9F5 antibody (hu9F5VHv1, hu9F5VHv2, hu9F5VHv3, hu9F5VHv4, hu9F5VHv5, hu9F5VHv6, hu9F5VHv7, and hu9F5VHv8). hu9F5VHv1 is sequence number 15, hu9F5VHv2 is sequence number 16, hu9F5VHv3 is sequence number 17, hu9F5VHv4 is sequence number 18, hu9F5VHv5 is sequence number 19, hu9F5VHv6 is sequence number 20, hu9F5VHv7 is sequence number 21, and hu9F5VHv8 is sequence number 22. The CDR of mouse 9F5 VH is in bold, as defined by the Kabat / Chothia compound. [Figure 1B] Figure 1B shows the alignment of the human germline heavy chain variable region sequence IGHV1-69-2*01 (SEQ ID NO: 33), the human acceptor heavy chain variable region sequence AAN16432-VH_huFrwk (AAN16432_H; SEQ ID NO: 31), and the human acceptor heavy chain variable region sequence 2RCS-VH_huFrwk (2RCS_H; SEQ ID NO: 32) with the heavy chain variable regions of the mouse 9F5 antibody (SEQ ID NO: 7) and the humanized versions of the 9F5 antibody (hu9F5VHv1, hu9F5VHv2, hu9F5VHv3, hu9F5VHv4, hu9F5VHv5, hu9F5VHv6, hu9F5VHv7, and hu9F5VHv8). hu9F5VHv1 is sequence number 15, hu9F5VHv2 is sequence number 16, hu9F5VHv3 is sequence number 17, hu9F5VHv4 is sequence number 18, hu9F5VHv5 is sequence number 19, hu9F5VHv6 is sequence number 20, hu9F5VHv7 is sequence number 21, and hu9F5VHv8 is sequence number 22. The CDR of mouse 9F5 VH is in bold, as defined by the Kabat / Chothia compound. [Figure 2A]Figure 2A shows the alignment of the human germline light chain variable region sequence IGKV2-28*01&_IGKJ2*01 (IGKV2-28*01_IGKJ2*01; SEQ ID NO: 37), the human acceptor CAB51297-VL_huFrwk (CAB51297_L; SEQ ID NO: 35), and the human acceptor 1911357B-VL_huFRwk (1911357B_L; SEQ ID NO: 36) with the light chain variable region of the mouse 9F5 antibody (SEQ ID NO: 11) and the light chain variable regions of the humanized versions of the 9F5 antibody (hu9F5VLv1, hu9F5VLv2, hu9F5VLv3, hu9F5VLv4, hu9F5VLv5, hu9F5VLv6, and hu9F5VLv7). hu9F5VLv1 is sequence number 23, hu9F5VLv2 is sequence number 24, hu9F5VLv3 is sequence number 25, hu9F5VLv4 is sequence number 26, hu9F5VLv5 is sequence number 27, hu9F5VLv6 is sequence number 28, and hu9F5VLv7 is sequence number 29. The CDR of mouse 9F5 VL is in bold, as defined by Kabat. [Figure 2B] Figure 2B shows the alignment of the human germline light chain variable region sequence IGKV2-28*01&_IGKJ2*01 (IGKV2-28*01_IGKJ2*01; SEQ ID NO: 37), the human acceptor CAB51297-VL_huFrwk (CAB51297_L; SEQ ID NO: 35), and the human acceptor 1911357B-VL_huFRwk (1911357B_L; SEQ ID NO: 36) with the light chain variable region of the mouse 9F5 antibody (SEQ ID NO: 11) and the light chain variable regions of the humanized versions of the 9F5 antibody (hu9F5VLv1, hu9F5VLv2, hu9F5VLv3, hu9F5VLv4, hu9F5VLv5, hu9F5VLv6, and hu9F5VLv7). hu9F5VLv1 is sequence number 23, hu9F5VLv2 is sequence number 24, hu9F5VLv3 is sequence number 25, hu9F5VLv4 is sequence number 26, hu9F5VLv5 is sequence number 27, hu9F5VLv6 is sequence number 28, and hu9F5VLv7 is sequence number 29. The CDR of mouse 9F5 VL is in bold, as defined by Kabat. [Figure 3] Figure 3 shows the results of an assay demonstrating that the mouse 9F5 antibody blocks the internalization of tau into neurons. [Figure 4A] Figure 4A shows the alignment of the human germline heavy chain variable region sequence IGHV1-69-2*01 (SEQ ID NO: 33), the human acceptor heavy chain variable region sequence AAN16432-VH_huFrwk (AAN16432_H; SEQ ID NO: 31), and the human acceptor heavy chain variable region sequence 2RCS-VH_huFrwk (2RCS_H; SEQ ID NO: 32) with the heavy chain variable region of the mouse 9F5 antibody (SEQ ID NO: 7) and the heavy chain variable regions of the humanized versions of the 9F5 antibody (hu9F5VHv1, hu9F5VHv2, hu9F5VHv3, hu9F5VHv4, hu9F5VHv5, hu9F5VHv6, hu9F5VHv7, hu9F5VHv8, hu9F5VHv9, and hu9F5VHv10). hu9F5VHv1 is sequence number 15, hu9F5VHv2 is sequence number 16, hu9F5VHv3 is sequence number 17, hu9F5VHv4 is sequence number 18, hu9F5VHv5 is sequence number 19, hu9F5VHv6 is sequence number 20, hu9F5VHv7 is sequence number 21, hu9F5VHv8 is sequence number 22, hu9F5VHv9 is sequence number 127, and hu9F5VHv10 is sequence number 128. The CDR of mouse 9F5 VH is in bold, as defined by the Kabat / Chothia compound. Residues identical to those of mouse 9F5 VH are represented by "". [Figure 4B]Figure 4B shows the alignment of the human germline heavy chain variable region sequence IGHV1-69-2*01 (SEQ ID NO: 33), the human acceptor heavy chain variable region sequence AAN16432-VH_huFrwk (AAN16432_H; SEQ ID NO: 31), and the human acceptor heavy chain variable region sequence 2RCS-VH_huFrwk (2RCS_H; SEQ ID NO: 32) with the heavy chain variable region of the mouse 9F5 antibody (SEQ ID NO: 7) and the heavy chain variable regions of the humanized versions of the 9F5 antibody (hu9F5VHv1, hu9F5VHv2, hu9F5VHv3, hu9F5VHv4, hu9F5VHv5, hu9F5VHv6, hu9F5VHv7, hu9F5VHv8, hu9F5VHv9, and hu9F5VHv10). hu9F5VHv1 is sequence number 15, hu9F5VHv2 is sequence number 16, hu9F5VHv3 is sequence number 17, hu9F5VHv4 is sequence number 18, hu9F5VHv5 is sequence number 19, hu9F5VHv6 is sequence number 20, hu9F5VHv7 is sequence number 21, hu9F5VHv8 is sequence number 22, hu9F5VHv9 is sequence number 127, and hu9F5VHv10 is sequence number 128. The CDR of mouse 9F5 VH is in bold, as defined by the Kabat / Chothia compound. Residues identical to those of mouse 9F5 VH are represented by "". [Figure 5A]Figure 5A shows the human germline light chain variable region sequence IGKV2-28*01&_IGKJ2*01 (IGKV2-28*01_IGKJ2*01; SEQ ID NO: 37), the human acceptor CAB51297-VL_huFrwk (CAB51297_L; SEQ ID NO: 35), and the human acceptor 1911357B-VL_huFRwk (1911357B_L; sequence number 35). This shows the alignment of the light chain variable region (SEQ ID NO: 11) of the mouse 9F5 antibody and the light chain variable regions of the humanized versions of the 9F5 antibody (hu9F5VLv1, hu9F5VLv2, hu9F5VLv3, hu9F5VLv4, hu9F5VLv5, hu9F5VLv6, hu9F5VLv7, hu9F5VLv8, and hu9F5VLv9) with the number 36). hu9F5VLv1 is sequence number 23, hu9F5VLv2 is sequence number 24, hu9F5VLv3 is sequence number 25, hu9F5VLv4 is sequence number 26, hu9F5VLv5 is sequence number 27, hu9F5VLv6 is sequence number 28, hu9F5VLv7 is sequence number 2, hu9F5VLv8 is sequence number 130, and hu9F5VLv9 is sequence number 131. The CDR of mouse 9F5 VL is in bold, as defined by Kabt. Residues identical to those of mouse 9F5 VL are represented by "". [Figure 5B]Figure 5B shows the human germline light chain variable region sequence IGKV2-28*01&_IGKJ2*01 (IGKV2-28*01_IGKJ2*01; SEQ ID NO: 37), the human acceptor CAB51297-VL_huFrwk (CAB51297_L; SEQ ID NO: 35), and the human acceptor 1911357B-VL_huFRwk (1911357B_L; sequence number 35). This shows the alignment of the light chain variable region (SEQ ID NO: 11) of the mouse 9F5 antibody and the light chain variable regions of the humanized versions of the 9F5 antibody (hu9F5VLv1, hu9F5VLv2, hu9F5VLv3, hu9F5VLv4, hu9F5VLv5, hu9F5VLv6, hu9F5VLv7, hu9F5VLv8, and hu9F5VLv9) with the number 36). hu9F5VLv1 is sequence number 23, hu9F5VLv2 is sequence number 24, hu9F5VLv3 is sequence number 25, hu9F5VLv4 is sequence number 26, hu9F5VLv5 is sequence number 27, hu9F5VLv6 is sequence number 28, hu9F5VLv7 is sequence number 2, hu9F5VLv8 is sequence number 130, and hu9F5VLv9 is sequence number 131. The CDR of mouse 9F5 VL is in bold, as defined by Kabt. Residues identical to those of mouse 9F5 VL are represented by "". [Figure 6A]Figure 6A shows the light chain variable regions of the humanized versions of the 9F5 antibody: hu9F5VLv8_DIM1 (SEQ ID NO: 132), hu9F5VLv8_DIM2 (SEQ ID NO: 133), hu9F5VLv8_DIM3 (SEQ ID NO: 134), hu9F5VLv8_DIM4 (SEQ ID NO: 135), hu9F5VLv8_DIM5 (SEQ ID NO: 136), hu9F5VLv8_DIM6 (SEQ ID NO: 137), hu9F5VLv8_DIM7 (SEQ ID NO: 138), hu9F5VLv8_DIM8 (SEQ ID NO: 139), hu9F5VLv8_DIM9 (SEQ ID NO: 140), hu9F 5VLv8_DIM10 (SEQ ID NO: 141), hu9F5VLv8_DIM11 (SEQ ID NO: 142), hu9F5VLv8_DIM12 (SEQ ID NO: 143), hu9F5VLv8_DIM13 (SEQ ID NO: 144), hu9F5VLv8_DIM14 (SEQ ID NO: 145), hu9F5VLv8_DIM15 (SEQ ID NO: 146), hu9F5VLv8_DIM16 (SEQ ID NO: 147), hu9F5VLv8_DIM17 (SEQ ID NO: 148), hu9F5VLv8_DIM18 (SEQ ID NO: 149), hu9F5VLv8_DIM19 (SEQ ID NO: 150), h u9F5VLv8_DIM20 (sequence number 151), hu9F5VLv8_DIM21 (sequence number 152), hu9F5VLv8_DIM22 (sequence number 153), hu9F5VLv8_DIM23 (sequence number 154), hu9F5VLv8_DIM24 (sequence number 155), hu9F5VLv8_DIM25 (sequence number 156), hu9F5VLv8_DIM26 (sequence number 157), hu9F5VLv9_DIM1 (sequence number 162), hu9F5VLv9_DIM2 (sequence number 163), hu9F5VLv9_DIM4 (sequence number 164), h u9F5VLv9_DIM5 (sequence number 165), hu9F5VLv9_DIM8 (sequence number 166), hu9F5VLv9_DIM10 (sequence number 167), hu9F5VLv9_DIM11 (sequence number 168), hu9F5VLv9_DIM13 (sequence number 169), hu9F5VLv9_DIM19 (sequence number 170), hu9F5VLv9_DIM20 (sequence number 171), hu9F5VLv8_DIM27 (sequence number 158), hu9F5VLv8_DIM28 (sequence number 159), hu9F5VLv8_DIM29 (sequence number 160),This shows hu9F5VLv8_DIM30 (sequence number 161) and the alignment of the light chain variable region of hu9F5VLv8. The CDR of hu9F5VLv8 is shown in bold, as defined by Kabat. [Figure 6B]Figure 6B shows the light chain variable regions of the humanized versions of the 9F5 antibody: hu9F5VLv8_DIM1 (SEQ ID NO: 132), hu9F5VLv8_DIM2 (SEQ ID NO: 133), hu9F5VLv8_DIM3 (SEQ ID NO: 134), hu9F5VLv8_DIM4 (SEQ ID NO: 135), hu9F5VLv8_DIM5 (SEQ ID NO: 136), hu9F5VLv8_DIM6 (SEQ ID NO: 137), hu9F5VLv8_DIM7 (SEQ ID NO: 138), hu9F5VLv8_DIM8 (SEQ ID NO: 139), hu9F5VLv8_DIM9 (SEQ ID NO: 140), hu9F 5VLv8_DIM10 (SEQ ID NO: 141), hu9F5VLv8_DIM11 (SEQ ID NO: 142), hu9F5VLv8_DIM12 (SEQ ID NO: 143), hu9F5VLv8_DIM13 (SEQ ID NO: 144), hu9F5VLv8_DIM14 (SEQ ID NO: 145), hu9F5VLv8_DIM15 (SEQ ID NO: 146), hu9F5VLv8_DIM16 (SEQ ID NO: 147), hu9F5VLv8_DIM17 (SEQ ID NO: 148), hu9F5VLv8_DIM18 (SEQ ID NO: 149), hu9F5VLv8_DIM19 (SEQ ID NO: 150), h u9F5VLv8_DIM20 (sequence number 151), hu9F5VLv8_DIM21 (sequence number 152), hu9F5VLv8_DIM22 (sequence number 153), hu9F5VLv8_DIM23 (sequence number 154), hu9F5VLv8_DIM24 (sequence number 155), hu9F5VLv8_DIM25 (sequence number 156), hu9F5VLv8_DIM26 (sequence number 157), hu9F5VLv9_DIM1 (sequence number 162), hu9F5VLv9_DIM2 (sequence number 163), hu9F5VLv9_DIM4 (sequence number 164), h u9F5VLv9_DIM5 (sequence number 165), hu9F5VLv9_DIM8 (sequence number 166), hu9F5VLv9_DIM10 (sequence number 167), hu9F5VLv9_DIM11 (sequence number 168), hu9F5VLv9_DIM13 (sequence number 169), hu9F5VLv9_DIM19 (sequence number 170), hu9F5VLv9_DIM20 (sequence number 171), hu9F5VLv8_DIM27 (sequence number 158), hu9F5VLv8_DIM28 (sequence number 159), hu9F5VLv8_DIM29 (sequence number 160),This shows hu9F5VLv8_DIM30 (sequence number 161) and the alignment of the light chain variable region of hu9F5VLv8. The CDR of hu9F5VLv8 is shown in bold, as defined by Kabat. [Figure 6C]Figure 6C shows the light chain variable regions of the humanized versions of the 9F5 antibody: hu9F5VLv8_DIM1 (SEQ ID NO: 132), hu9F5VLv8_DIM2 (SEQ ID NO: 133), hu9F5VLv8_DIM3 (SEQ ID NO: 134), hu9F5VLv8_DIM4 (SEQ ID NO: 135), hu9F5VLv8_DIM5 (SEQ ID NO: 136), hu9F5VLv8_DIM6 (SEQ ID NO: 137), hu9F5VLv8_DIM7 (SEQ ID NO: 138), hu9F5VLv8_DIM8 (SEQ ID NO: 139), hu9F5VLv8_DIM9 (SEQ ID NO: 140), hu9F 5VLv8_DIM10 (SEQ ID NO: 141), hu9F5VLv8_DIM11 (SEQ ID NO: 142), hu9F5VLv8_DIM12 (SEQ ID NO: 143), hu9F5VLv8_DIM13 (SEQ ID NO: 144), hu9F5VLv8_DIM14 (SEQ ID NO: 145), hu9F5VLv8_DIM15 (SEQ ID NO: 146), hu9F5VLv8_DIM16 (SEQ ID NO: 147), hu9F5VLv8_DIM17 (SEQ ID NO: 148), hu9F5VLv8_DIM18 (SEQ ID NO: 149), hu9F5VLv8_DIM19 (SEQ ID NO: 150), h u9F5VLv8_DIM20 (sequence number 151), hu9F5VLv8_DIM21 (sequence number 152), hu9F5VLv8_DIM22 (sequence number 153), hu9F5VLv8_DIM23 (sequence number 154), hu9F5VLv8_DIM24 (sequence number 155), hu9F5VLv8_DIM25 (sequence number 156), hu9F5VLv8_DIM26 (sequence number 157), hu9F5VLv9_DIM1 (sequence number 162), hu9F5VLv9_DIM2 (sequence number 163), hu9F5VLv9_DIM4 (sequence number 164), h u9F5VLv9_DIM5 (sequence number 165), hu9F5VLv9_DIM8 (sequence number 166), hu9F5VLv9_DIM10 (sequence number 167), hu9F5VLv9_DIM11 (sequence number 168), hu9F5VLv9_DIM13 (sequence number 169), hu9F5VLv9_DIM19 (sequence number 170), hu9F5VLv9_DIM20 (sequence number 171), hu9F5VLv8_DIM27 (sequence number 158), hu9F5VLv8_DIM28 (sequence number 159), hu9F5VLv8_DIM29 (sequence number 160),This shows hu9F5VLv8_DIM30 (sequence number 161) and the alignment of the light chain variable region of hu9F5VLv8. The CDR of hu9F5VLv8 is shown in bold, as defined by Kabat. [Figure 7] Figure 7 shows the alignment of the human germline heavy chain variable region sequence IGHV1-69-2*01 (SEQ ID NO: 33) and the human acceptor heavy chain variable region sequence CAC20421 VH (SEQ ID NO: 218) with the heavy chain variable region of the mouse 10C12 antibody (SEQ ID NO: 7, labeled m10C12 VH in Figure 7) and the heavy chain variable regions of the humanized version of the 10C12 antibody (hu10C12VHv1 and hu10C12VHv2). hu10C12VHv1 is SEQ ID NO: 214, and hu10C12VHv2 is SEQ ID NO: 215. The CDR of mouse 10C12 VH is in bold, as defined by the Kabat / Chothia compound. [Figure 8] Figure 8 shows the alignment of the human germline light chain variable region sequence IGKV2-28*01 &_IGKJ2*01 (SEQ ID NO: 37) and the human acceptor CAB51297-VL_huFrwk (SEQ ID NO: 35) with the light chain variable region of mouse 10C12 (SEQ ID NO: 11) and the light chain variable regions of the humanized versions of the 10C12 antibody (hu10C12VLv1 and hu10C12VLv2). hu10C12VLv1 is SEQ ID NO: 216, and hu10C12VLv2 is SEQ ID NO: 217. The CDR of mouse 10C12 VL is in bold, as defined by Kabat. [Figure 9] Figure 9 shows the alignment of the human germline heavy chain variable region sequence IGHV1-69-2*01 (SEQ ID NO: 33) and the human acceptor heavy chain variable region sequence CAC20421 VH (SEQ ID NO: 218) with the heavy chain variable region of the mouse 12C4 antibody (SEQ ID NO: 219) and the heavy chain variable regions of the humanized versions of the 12C4 antibody (hu12C4VHv1 and hu12C4VHv2). hu12C4VHv1 is SEQ ID NO: 221, and hu12C4VHv2 is SEQ ID NO: 222. The CDR of mouse 12C4 VH is in bold, as defined by the Kabat / Chothia compound. [Figure 10]Figure 10 shows the alignment of the human germline light chain variable region sequence IGKV2-28*01 & IGKJ2*01 (SEQ ID NO: 37) and the human acceptor CAB51297 (SEQ ID NO: 35) with the light chain variable region of the mouse 12C4 antibody (SEQ ID NO: 11) and the light chain variable regions of the humanized versions of the 12C4 antibody (hu12C4VLv1 and huvVLv2). hu12C4VLv1 is SEQ ID NO: 223, and hu12C4VLv2 is SEQ ID NO: 224. The CDR of mouse 12C4 VL is shown in bold, as defined by Kabat. [Figure 11] Figure 11 shows the alignment of the human germline heavy chain variable region sequence IGHV1-69-2*01 (SEQ ID NO: 33) and the human acceptor heavy chain variable region sequence CAC20421 VH (SEQ ID NO: 218) with the heavy chain variable region of the mouse 17C12 antibody (SEQ ID NO: 225) and the heavy chain variable regions of the humanized versions of the 17C12 antibody (hu17C12VHv1 and hu17C12VHv2). hu17C12VHv1 is SEQ ID NO: 232, and hu17C12VHv2 is SEQ ID NO: 233. The CDR of mouse 17C12 VH is in bold, as defined by the Kabat / Chothia compound. [Figure 12] Figure 12 shows the alignment of the human germline light chain variable region sequences IGKV2-29*02 & IGKJ4*01 (SEQ ID NO: 239) and the human acceptor QDO16713 VL (SEQ ID NO: 238) with the light chain variable region of the mouse 17C12 antibody (SEQ ID NO: 228) and the light chain variable regions of the humanized versions of the 17C12 antibody (hu17C12VLv1 and hu17C12VLv2). hu17C12VLv1 is SEQ ID NO: 234, and hu17C12VLv2 is SEQ ID NO: 235. The CDR of mouse 17C12 VL is in bold, as defined by Kabat. [Figure 13]Figure 13 shows the alignment of the human germline heavy chain variable region sequence IGHV2-70*04 & IGHJ4*01 (SEQ ID NO: 254) and the human acceptor heavy chain variable region sequence QDJ57937VH hFrwk (SEQ ID NO: 253) with the heavy chain variable region of the mouse 14H3 antibody (SEQ ID NO: 240) and the heavy chain variable regions of the humanized versions of the 14H3 antibody (hu14H3VHv1 and hu14H3VHv2). hu14H3VHv1 is SEQ ID NO: 248, and hu14H3VHv2 is SEQ ID NO: 249. The CDR of mouse 14H3 VH is in bold, as defined by the Kabat / Chothia compound. [Figure 14] Figure 14 shows the alignment of the human germline light chain variable region sequence IGKV2-28*01 &_IGKJ2*01 (IGKV2-28*01_IGKJ2*01; SEQ ID NO: 37) and the human acceptor ABC66914VL_hFwrk (SEQ ID NO: 256) with the light chain variable region of the mouse 14H3 antibody (SEQ ID NO: 244) and the light chain variable regions of the humanized versions of the 14H3 antibody (hu14H3VLv1 and hu14H3VLv2). hu14H3VLv1 is SEQ ID NO: 250, and hu14H3VLv2 is SEQ ID NO: 251. The CDR of mouse 14H3 VL is in bold, as defined by Kabat. [Figure 15] Figure 15 shows assay results demonstrating that mouse 10C12 antibody, mouse 12C4 antibody, mouse 2D11 antibody, mouse 17C12 antibody, mouse 14H3 antibody, and mouse 9F5 antibody block the internalization of tau into neurons. [Figure 16] Figure 16 shows assay results (neuronal viability) demonstrating that mouse 10C12 antibody, mouse 12C4 antibody, mouse 2D11 antibody, and mouse 9F5 antibody inhibit tau toxicity in primary neurons. [Figure 17] Figure 17 shows assay results (LDH release) demonstrating that mouse 10C12 antibody, mouse 12C4 antibody, mouse 2D11 antibody, and mouse 9F5 antibody inhibit tau toxicity in primary neurons. [Figure 18]Figure 18 shows the results of a Western blot assay demonstrating that mouse 10C12 antibody, mouse 12C4 antibody, mouse 2D11 antibody, mouse 17C12 antibody, mouse 14H3 antibody, and mouse 9F5 antibody detect tau in brain samples from Alzheimer's disease patients. [Figure 19] Figure 19 shows the results of immunoprecipitation assays using mouse 10C12 antibody, mouse 12C4 antibody, mouse 2D11 antibody, mouse 17C12 antibody, mouse 14H3 antibody, and mouse 9F5 antibody, as well as brain samples from Alzheimer's disease patients. [Figure 20] Figure 20 shows the results of an assay to measure the characterization of a 9F5 humanized variant to withstand aggregation induced by stirring stress. [Figure 21] Figure 21 shows the results of an assay to measure the characteristics of a 9F5 humanized variant that tolerates exposure to low pH. [Figure 22] Figure 22 shows the results of an assay to characterize the 9F5 humanized variant that aggregates under simulated high-concentration conditions. [Figure 23A] Figure 23A shows the results of immunohistochemical assays using control, mouse 2D11, mouse 9F5, mouse 12C4, mouse 14H3, and mouse 17C12. [Figure 23B] Figure 23B shows the results of immunohistochemical assays using control, mouse 2D11, mouse 9F5, mouse 12C4, mouse 14H3, and mouse 17C12. [Figure 23C] Figure 23C shows the results of immunohistochemical assays using control, mouse 2D11, mouse 9F5, mouse 12C4, mouse 14H3, and mouse 17C12. [Figure 23D] Figure 23D shows the results of immunohistochemical assays using the control, mouse 2D11, mouse 9F5, mouse 12C4, mouse 14H3, and mouse 17C12. [Figure 23E] Figure 23E shows the results of immunohistochemical assays using control, mouse 2D11, mouse 9F5, mouse 12C4, mouse 14H3, and mouse 17C12. [Figure 23F] Figure 23F shows the results of immunohistochemical assays using control, mouse 2D11, mouse 9F5, mouse 12C4, mouse 14H3, and mouse 17C12. [Figure 24] Figure 24 shows the alignment of the heavy chain variable regions of mouse 9F5 antibody (SEQ ID NO: 7), mouse 10C12 antibody (SEQ ID NO: 7), mouse 2D11 antibody (SEQ ID NO: 7), mouse 12C4 antibody (SEQ ID NO: 219), mouse 14H3 antibody (SEQ ID NO: 240), and mouse 17C12 antibody (SEQ ID NO: 225). The CDR of mouse 9F5 VH is in bold, as it is defined by the Kabat / Chothia compound. [Figure 25] Figure 25 shows the alignment of the light chain variable regions (SEQ ID NO: 11) of the mouse 9F5 antibody, the mouse 10C12 antibody, the mouse 2D11 antibody, the mouse 12C4 antibody, the mouse 14H3 antibody, and the mouse 17C12 antibody, the mouse 17C12 antibody. The CDR of mouse 9F5 VL is shown in bold, as defined by Kabat. [Modes for carrying out the invention]

[0152] A brief explanation of arrays Sequence ID 1 represents the amino acid sequence of a human tau isoform (Swiss-Prot P10636-8).

[0153] Sequence ID 2 represents the amino acid sequence of a human tau isoform (Swiss-Prot P10636-7).

[0154] Sequence ID 3 represents the amino acid sequence of a human tau isoform (Swiss-Prot P10636-6), (4R0N human tau).

[0155] Sequence ID 4 represents the amino acid sequence of a human tau isoform (Swiss-Prot P10636-5).

[0156] Sequence ID 5 represents the amino acid sequence of a human tau isoform (Swiss-Prot P10636-4).

[0157] Sequence ID 6 represents the amino acid sequence of a human tau isoform (Swiss-Prot P10636-2).

[0158] Sequence ID 7 represents the amino acid sequence of the heavy chain variable region of the mouse 9F5 antibody.

[0159] Sequence ID 8 represents the amino acid sequence of the mouse 9F5 antibody Kabat / Chothia complex CDR-H1.

[0160] Sequence ID 9 represents the amino acid sequence of the mouse 9F5 antibody Kabat CDR-H2.

[0161] Sequence ID 10 represents the amino acid sequence of the mouse 9F5 antibody Kabat CDR-H3.

[0162] Sequence ID 11 represents the amino acid sequence of the light chain variable region of the mouse 9F5 antibody.

[0163] Sequence ID 12 represents the amino acid sequence of the mouse 9F5 antibody Kabat CDR-L1.

[0164] Sequence ID 13 represents the amino acid sequence of the mouse 9F5 antibody Kabat CDR-L2.

[0165] Sequence ID 14 represents the amino acid sequence of the mouse 9F5 antibody Kabat CDR-L3.

[0166] Sequence ID 15 represents the amino acid sequence of the humanized heavy chain variable region hu9F5VHv1.

[0167] Sequence ID 16 represents the amino acid sequence of the humanized heavy chain variable region hu9F5VHv2.

[0168] Sequence ID 17 represents the amino acid sequence of the humanized heavy chain variable region hu9F5VHv3.

[0169] Sequence ID 18 represents the amino acid sequence of the humanized heavy chain variable region hu9F5VHv4.

[0170] Sequence ID 19 represents the amino acid sequence of the humanized heavy chain variable region hu9F5VHv5.

[0171] Sequence ID 20 represents the amino acid sequence of the humanized heavy chain variable region hu9F5VHv6.

[0172] Sequence ID 21 represents the amino acid sequence of the humanized heavy chain variable region hu9F5VHv7.

[0173] Sequence ID 22 represents the amino acid sequence of the humanized heavy chain variable region hu9F5VHv8.

[0174] Sequence ID 23 represents the amino acid sequence of the humanized light chain variable region hu9F5VLv1.

[0175] Sequence ID 24 represents the amino acid sequence of the humanized light chain variable region hu9F5VLv2.

[0176] Sequence ID 25 represents the amino acid sequence of the humanized light chain variable region hu9F5VLv3.

[0177] Sequence ID 26 represents the amino acid sequence of the humanized light chain variable region hu9F5VLv4.

[0178] Sequence ID 27 represents the amino acid sequence of the humanized light chain variable region hu9F5VLv5 of the humanized 9F5 antibody.

[0179] Sequence ID 28 represents the amino acid sequence of the humanized light chain variable region hu9F5VLv6.

[0180] SEQ ID NO: 29 represents the amino acid sequence of the humanized light chain variable region hu9F5VLv7.

[0181] SEQ ID NO: 30 represents the amino acid sequence of the heavy chain variable region structural model PDB.# 5OBF-VH_mSt.

[0182] SEQ ID NO: 31 represents the amino acid sequence of the heavy chain variable region acceptor GenBank Acc.# AAN16432-VH_huFrwk.

[0183] SEQ ID NO: 32 represents the amino acid sequence of the heavy chain variable region acceptor PDB # 2RCS-VH_huFrwk.

[0184] SEQ ID NO: 33 is the heavy chain variable region germline sequence IMGT# IGHV1-69-2 * 01. represents its amino acid sequence.

[0185] SEQ ID NO: 34 represents the amino acid sequence of the light chain variable region structural model PDB # 5OBF-VL_mSt.

[0186] SEQ ID NO: 35 represents the amino acid sequence of the light chain variable region acceptor GenBank Acc. # CAB51297-VL_huFrwk.

[0187] SEQ ID NO: 36 represents the amino acid sequence of the light chain variable region acceptor GenBank Acc. # 1911357B-VL_huFrwk.

[0188] SEQ ID NO: 37 is the light chain variable region germline sequence IMGT# IGKV2-28 * 01 & IGKJ2 * 01. represents its amino acid sequence.

[0189] SEQ ID NO: 38 represents the nucleic acid sequence encoding the heavy chain variable region of the mouse 9F5 antibody.

[0190] SEQ ID NO: 39 represents the nucleic acid sequence encoding the light chain variable region of the mouse 9F5 antibody.

[0191] Sequence ID 40 represents the amino acid sequence of the mouse 9F5 antibody Kabat CDR-H1.

[0192] Sequence ID 41 represents the amino acid sequence of Chothia CDR-H1, a mouse 9F5 antibody.

[0193] Sequence ID 42 represents the amino acid sequence of Chothia CDR-H2, a mouse 9F5 antibody.

[0194] Sequence ID 43 represents the amino acid sequence of AbM CDR-H2, a mouse 9F5 antibody.

[0195] Sequence ID 44 represents the amino acid sequence of Contact CDR-H1, a mouse 9F5 antibody.

[0196] Sequence ID 45 represents the amino acid sequence of Contact CDR-H2, a mouse 9F5 antibody.

[0197] Sequence ID 46 represents the amino acid sequence of Contact CDR-H3, a mouse 9F5 antibody.

[0198] Sequence ID 47 represents the amino acid sequence of Contact CDR-L1, a mouse 9F5 antibody.

[0199] Sequence ID 48 represents the amino acid sequence of Contact CDR-L2, a mouse 9F5 antibody.

[0200] Sequence ID 49 represents the amino acid sequence of Contact CDR-L3 of the mouse 9F5 antibody.

[0201] Sequence ID 50 represents the amino acid sequence of another Kabat / Chothia complex CDR-H1 (present in hu9F5VHv4, hu9F5VHv5, and hu9F5VHv6) of the humanized 9F5 antibody.

[0202] Sequence ID 51 represents the amino acid sequence of another Kabat CDR-H2 (present in hu9F5VHv5, hu9F5VHv6, and hu9F5VHv7) of the humanized 9F5 antibody.

[0203] Sequence ID 52 represents the amino acid sequence of another Kabat CDR-H2 (present in hu9F5VHv8) of the humanized 9F5 antibody.

[0204] Sequence ID 53 represents the amino acid sequence of another Kabat CDR-L1 (present in hu9F5VLv5 and hu9F5VLv6) of the humanized 9F5 antibody.

[0205] Sequence ID 54 represents the amino acid sequence of another Kabat CDR-L1 (present in hu9F5VLv7) of the humanized 9F5 antibody.

[0206] Sequence ID 55 is another Kabat CDR-L2 humanized 9F5 antibody (hu9F5VLv4, hu9F5VLv5, hu9F5VLv6, hu9F5VLv7, hu9F5VLv8_DIM2, hu9F5VLv8_DIM4, hu9F5VLv8_DIM5, hu9F5VLv8_DIM6, hu9F5VLv8_DIM11, hu9F5VLv8_DIM12, hu9F5VLv8 Represents the amino acid sequence found in _DIM13, hu9F5VLv8_DIM18, hu9F5VLv8_DIM27, hu9F5VLv8_DIM28, hu9F5VLv9_DIM2, hu9F5VLv9_DIM4, hu9F5VLv9_DIM5, hu9F5VLv9_DIM11, and hu9F5VLv9_DIM13.

[0207] Sequence ID 56 represents the amino acid sequence of the epitope of antibody 9F5.

[0208] Sequence ID 57 represents the amino acid sequence of the consensus motif of the peptide to which antibody 9F5 binds.

[0209] Sequence ID 58 represents the amino acid sequence of the consensus motif of the peptide to which antibody 9F5 binds.

[0210] Sequence number 59 represents the amino acid sequence of the linker.

[0211] Sequence number 60 represents the amino acid sequence of the HA control peptide.

[0212] Sequence number 61 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_M51E).

[0213] Sequence number 62 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_M51D).

[0214] Sequence number 63 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27cD).

[0215] Sequence number 64 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27cG).

[0216] Sequence number 65 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27cS).

[0217] Sequence number 66 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27cE).

[0218] Sequence number 67 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_I30E).

[0219] Sequence number 68 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_I30K).

[0220] Sequence ID 69 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27cT).

[0221] Sequence ID 70 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27cN).

[0222] Sequence ID 71 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27bD).

[0223] Sequence ID 72 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_I30G).

[0224] Sequence ID 73 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L33N).

[0225] Sequence ID 74 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27cA).

[0226] Sequence ID 75 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L33T).

[0227] Sequence ID 76 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L33S).

[0228] Sequence ID 77 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L33R).

[0229] Sequence ID 78 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_I30Q).

[0230] Sequence ID 79 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27bT).

[0231] Sequence ID 80 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_T31G).

[0232] Sequence ID 81 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27bQ).

[0233] Sequence ID 82 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L33G).

[0234] Sequence ID 83 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27cP).

[0235] Sequence ID 84 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_V78R).

[0236] Sequence ID 85 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_I75D).

[0237] Sequence ID 86 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_V78D).

[0238] Sequence ID 87 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_V78E).

[0239] Sequence ID 88 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_V78P).

[0240] Sequence ID 89 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_V78K).

[0241] Sequence ID 90 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_R77D).

[0242] Sequence ID 91 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_V78G).

[0243] Sequence ID 92 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_S76P).

[0244] Sequence ID 93 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_I75P).

[0245] Sequence ID 94 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_I75Q).

[0246] Sequence ID 95 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_I75G).

[0247] Sequence ID 96 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L73P).

[0248] Sequence ID 97 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L73G).

[0249] Sequence ID 98 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_V78Q).

[0250] Sequence ID 99 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_S76G).

[0251] Sequence ID 100 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L92D).

[0252] Sequence ID 101 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_Y86T).

[0253] Sequence ID 102 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L92E).

[0254] Sequence ID 103 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L92G).

[0255] Sequence ID 104 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L92Q).

[0256] Sequence ID 105 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L93G).

[0257] Sequence ID 106 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_V85G).

[0258] Sequence ID 107 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L92T).

[0259] Sequence ID 108 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_A89G).

[0260] Sequence ID 109 represents the amino acid sequence of a variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L80P).

[0261] Sequence ID 110 represents the amino acid sequence of a variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L80D).

[0262] Sequence ID 111 represents the amino acid sequence of a variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L82cG).

[0263] Sequence ID 112 represents the amino acid sequence of a variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L82cD).

[0264] Sequence ID 113 represents the amino acid sequence of a variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L82P).

[0265] Sequence ID 114 represents the amino acid sequence of a variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L80G).

[0266] Sequence ID 115 represents the amino acid sequence of a variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L82K).

[0267] Sequence ID 116 represents the amino acid sequence of a variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L82R).

[0268] Sequence ID 117 represents the amino acid sequence of a variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L82E).

[0269] Sequence ID 118 represents the amino acid sequence of a variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L82N).

[0270] Sequence ID 119 represents the amino acid sequence of a variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_Y79D).

[0271] Sequence ID 120 represents the amino acid sequence of a variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_Y79N).

[0272] Sequence ID 121 represents the amino acid sequence of a variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_Y79G).

[0273] Sequence ID 122 represents the amino acid sequence of a variant of the hu9F5VHv5 heavy chain variable region (also known as hu9F5VHv5_M80E).

[0274] Sequence ID 123 represents the amino acid sequence of a variant of the hu9F5VHv5 heavy chain variable region (also known as hu9F5VHv5_M80G).

[0275] Sequence ID 124 represents the amino acid sequence of a variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L82cS).

[0276] Sequence ID 125 represents the amino acid sequence of a variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_Y79Q).

[0277] Sequence ID 126 represents the amino acid sequence of a variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_S82aG).

[0278] Sequence ID 127 represents the amino acid sequence of the heavy chain variable region hu9F5VHv9.

[0279] Sequence ID 128 represents the amino acid sequence of the heavy chain variable region hu9F5VHv10 (also known as hu9F5VHv9_Q38K_G42E).

[0280] Sequence ID 129 represents the amino acid sequence of the heavy chain variable region hu9F5VHv10_L82cG.

[0281] Sequence ID 130 represents the amino acid sequence of the light chain variable region hu9F5VLv8.

[0282] Sequence ID 131 represents the amino acid sequence of the light chain variable region hu9F5VLv9 (also known as hu9F5VLv8_N60D).

[0283] Sequence ID 132 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L54G, L92I, and hu9F5VLv8_DIM1).

[0284] Sequence ID 133 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L54R, L92I, and hu9F5VLv8_DIM2).

[0285] Sequence ID 134 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L54T, L92I, and hu9F5VLv8_DIM3).

[0286] Sequence ID 135 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L54R, L92G, and hu9F5VLv8_DIM4).

[0287] Sequence ID 136 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cG, L37Q, M51G, L54R, L92I, and hu9F5VLv8_DIM5).

[0288] Sequence ID 137 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cD, L37Q, M51G, L54R, L92I, and hu9F5VLv8_DIM6).

[0289] Sequence ID 138 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cD, L37Q, M51K, L54R, L92I, and hu9F5VLv8_DIM7).

[0290] Sequence ID 139 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cG, L37Q, M51K, L54R, L92I, and hu9F5VLv8_DIM8).

[0291] Sequence ID 140 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cG, L37Q, M51K, L54G, L92I, and hu9F5VLv8_DIM9).

[0292] Sequence ID 141 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cS, L37Q, M51K, L54G, L92I, and hu9F5VLv8_DIM10).

[0293] Sequence ID 142 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54R, L92I, and hu9F5VLv8_DIM11).

[0294] Sequence ID 143 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54R, L92G, and hu9F5VLv8_DIM12).

[0295] Sequence ID 144 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54R, and hu9F5VLv8_DIM13).

[0296] Sequence ID 145 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54T, L92I, and hu9F5VLv8_DIM14).

[0297] Sequence ID 146 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54T, L92G, and hu9F5VLv8_DIM15).

[0298] Sequence ID 147 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54T, and hu9F5VLv8_DIM16).

[0299] Sequence ID 148 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cS, L37G, M51G, L54T, L92I, and hu9F5VLv8_DIM17).

[0300] Sequence ID 149 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cD, L37G, M51G, L54R, L92I, and hu9F5VLv8_DIM18).

[0301] Sequence ID 150 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cS, L37I, M51I, L54R, L92I, and hu9F5VLv8_DIM19).

[0302] Sequence ID 151 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cS, L37Q, M51I, L54G, L92I, and hu9F5VLv8_DIM20).

[0303] Sequence ID 152 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cS, L37Q, M51I, L54G, and hu9F5VLv8_DIM21).

[0304] Sequence ID 153 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cS, L37Q, M51E, L54R, L92I, and hu9F5VLv8_DIM22).

[0305] Sequence ID 154 is a variant of the Hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cG, L37Q, M51E, L54G, L92I, and hu9F5VLv8_DIM23).

[0306] Sequence ID 155 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cG, L37I, M51E, L54R, L92I, and hu9F5VLv8_DIM24).

[0307] Sequence ID 156 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cG, L37I, M51E, L54R, L92G, and hu9F5VLv8_DIM25).

[0308] Sequence ID 157 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cI, L37I, M51E, L54R, and hu9F5VLv8_DIM26).

[0309] Sequence ID 158 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L37Q, M51G, L54R, L92I, and hu9F5VLv8_DIM27).

[0310] Sequence ID 159 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cS, M51G, L54R, L92I, and hu9F5VLv8_DIM28).

[0311] Sequence ID 160 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cS, L37Q, L54R, L92I, and hu9F5VLv8_DIM29).

[0312] Sequence ID 161 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (also known as hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L92I, and hu9F5VLv8_DIM30).

[0313] Sequence ID 162 represents the amino acid sequence of a variant of the hu9F5VLv9 light chain variable region (also known as hu9F5VLv9_V3Q, L27cS, L37Q, M51G, L54G, L92I, and hu9F5VLv9_DIM1).

[0314] Sequence ID 163 represents the amino acid sequence of a variant of the hu9F5VLv9 light chain variable region (also known as hu9F5VLv9_V3Q, L27cS, L37Q, M51G, L54R, L92I, and hu9F5VLv9_DIM2).

[0315] Sequence ID 164 represents the amino acid sequence of a variant of the hu9F5VLv9 light chain variable region (also known as hu9F5VLv9_V3Q, L27cS, L37Q, M51G, L54R, L92G, and hu9F5VLv9_DIM4).

[0316] Sequence ID 165 represents the amino acid sequence of a variant of the hu9F5VLv9 light chain variable region (also known as hu9F5VLv9_V3Q, L27cG, L37Q, M51G, L54R, L92I, and hu9F5VLv9_DIM5).

[0317] Sequence ID 166 represents the amino acid sequence of a variant of the hu9F5VLv9 light chain variable region (also known as hu9F5VLv9_V3Q, L27cG, L37Q, M51K, L54R, L92I, and hu9F5VLv9_DIM8).

[0318] Sequence ID 167 represents the amino acid sequence of a variant of the hu9F5VLv9 light chain variable region (also known as hu9F5VLv9_V3Q, L27cS, L37Q, M51K, L54G, L92I, and hu9F5VLv9_DIM10).

[0319] Sequence ID 168 represents the amino acid sequence of a variant of the hu9F5VLv9 light chain variable region (also known as hu9F5VLv9_V3Q, L27cG, L37G, M51G, L54R, L92I, and hu9F5VLv9_DIM11).

[0320] Sequence ID 169 represents the amino acid sequence of a variant of the hu9F5VLv9 light chain variable region (also known as hu9F5VLv9_V3Q, L27cG, L37G, M51G, L54R, and hu9F5VLv9_DIM13).

[0321] Sequence ID 170 represents the amino acid sequence of a variant of the hu9F5VLv9 light chain variable region (also known as hu9F5VLv9_V3Q, L27cS, L37I, M51I, L54R, L92I, and hu9F5VLv9_DIM19).

[0322] Sequence ID 171 represents the amino acid sequence of a variant of the hu9F5VLv9 light chain variable region (also known as hu9F5VLv9_V3Q, L27cS, L37Q, M51I, L54G, L92I, and hu9F5VLv9_DIM20).

[0323] Sequence ID 172 represents the amino acid sequence of another Kabat CDR-L1 (located at hu9F5VLv2_L27bD) of the humanized 9F5 antibody.

[0324] Sequence ID 173 represents the amino acid sequence of another Kabat CDR-L1 (located in hu9F5VLv2_L27bT) of the humanized 9F5 antibody.

[0325] Sequence ID 174 represents the amino acid sequence of another Kabat CDR-L1 (located at hu9F5VLv2_L27bQ) of the humanized 9F5 antibody.

[0326] Sequence ID 175 represents the amino acid sequence of another Kabat CDR-L1 (present in hu9F5VLv2_L27cD, hu9F5VLv8_DIM6, hu9F5VLv8_DIM7, and hu9F5VLv8_DIM18) of the humanized 9F5 antibody.

[0327] Sequence ID 176 is another humanized 9F5 antibody from Kabat CDR-L1 (hu9F5VLv2_L27cG, hu9F5VLv8_DIM5, hu9F5VLv8_DIM8, hu9F5VLv8_DIM9, hu9F5VLv8_DIM11, hu9F5VLv8_DIM12, hu9F5VLv8_DIM13, hu9F5VLv8_DIM14, hu9F5VLv8_DIM Represents the amino acid sequence (present in 15, hu9F5VLv8_DIM16, hu9F5VLv8_DIM23, hu9F5VLv8_DIM24, hu9F5VLv8_DIM25, hu9F5VLv9_DIM5, hu9F5VLv9_DIM8, hu9F5VLv9_DIM11, and hu9F5VLv9_DIM13).

[0328] Sequence ID 177 is another Kabat humanized 9F5 antibody. This represents the amino acid sequence of CDR-L1 (present in hu9F5VLv2_L27cS, hu9F5VLv8_DIM1, hu9F5VLv8_DIM2, hu9F5VLv8_DIM19, hu9F5VLv8_DIM20, hu9F5VLv8_DIM21, hu9F5VLv8_DIM22, hu9F5VLv8_DIM28, hu9F5VLv8_DIM29, hu9F5VLv8_DIM30, hu9F5VLv9_DIM1, hu9F5VLv9_DIM2, hu9F5VLv9_DIM4, hu9F5VLv9_DIM10, hu9F5VLv9_DIM19, and hu9F5VLv9_DIM20).

[0329] Sequence ID 178 represents the amino acid sequence of another Kabat CDR-L1 (located at hu9F5VLv2_L27cE) of the humanized 9F5 antibody.

[0330] Sequence ID 179 represents the amino acid sequence of another Kabat CDR-L1 (located at hu9F5VLv2_L27cT) of the humanized 9F5 antibody.

[0331] Sequence ID 180 represents the amino acid sequence of another Kabat CDR-L1 (located at hu9F5VLv2_L27cN) of the humanized 9F5 antibody.

[0332] Sequence ID 181 represents the amino acid sequence of another Kabat CDR-L1 (located at hu9F5VLv2_L27cA) of the humanized 9F5 antibody.

[0333] Sequence ID 182 represents the amino acid sequence of another Kabat CDR-L1 (located in hu9F5VLv2_L27cP) of the humanized 9F5 antibody.

[0334] Sequence ID 183 represents the amino acid sequence of another Kabat CDR-L1 (located at hu9F5VLv8_DIM26) of the humanized 9F5 antibody.

[0335] Sequence ID 184 represents the amino acid sequence of another Kabat CDR-L1 (located at hu9F5VLv2_I30E) of the humanized 9F5 antibody.

[0336] Sequence ID 185 represents the amino acid sequence of another Kabat CDR-L1 (located at hu9F5VLv2_I30K) of the humanized 9F5 antibody.

[0337] Sequence ID 186 represents the amino acid sequence of another Kabat CDR-L1 (present in hu9F5VLv2_I30G) of the humanized 9F5 antibody.

[0338] Sequence ID 187 represents the amino acid sequence of another Kabat CDR-L1 (located at hu9F5VLv2_I30Q) of the humanized 9F5 antibody.

[0339] Sequence ID 188 represents the amino acid sequence of another Kabat CDR-L1 (present in hu9F5VLv2_T31G) of the humanized 9F5 antibody.

[0340] Sequence ID 189 represents the amino acid sequence of another Kabat CDR-L1 (located at hu9F5VLv2_L33N) of the humanized 9F5 antibody.

[0341] Sequence ID 190 represents the amino acid sequence of another Kabat CDR-L1 (located at hu9F5VLv2_L33T) of the humanized 9F5 antibody.

[0342] Sequence ID 191 represents the amino acid sequence of another Kabat CDR-L1 (located at hu9F5VLv2_L33S) of the humanized 9F5 antibody.

[0343] Sequence ID 192 represents the amino acid sequence of another Kabat CDR-L1 (located at hu9F5VLv2_L33R) of the humanized 9F5 antibody.

[0344] Sequence ID 193 represents the amino acid sequence of another Kabat CDR-L1 (located at hu9F5VLv2_L33G) of the humanized 9F5 antibody.

[0345] Sequence ID 194 represents the amino acid sequence of another Kabat CDR-L2 (present in hu9F5VLv2_M51E) of the humanized 9F5 antibody.

[0346] Sequence ID 195 represents the amino acid sequence of another Kabat CDR-L2 (present in hu9F5VLv2_M51D) of the humanized 9F5 antibody.

[0347] Sequence ID 196 represents the amino acid sequence of another Kabat CDR-L2 (located in hu9F5VLv8_DIM30) of the humanized 9F5 antibody.

[0348] Sequence ID 197 represents the amino acid sequence of another Kabat CDR-L2 (located at hu9F5VLv8_DIM29) of the humanized 9F5 antibody.

[0349] Sequence ID 198 represents the amino acid sequence of another Kabat CDR-L2 (present in hu9F5VLv8_DIM1 and hu9F5VLv9_DIM1) of the humanized 9F5 antibody.

[0350] Sequence ID 199 represents the amino acid sequence of another Kabat CDR-L2 in the humanized 9F5 antibody (present in hu9F5VLv8_DIM3, hu9F5VLv8_DIM14, hu9F5VLv8_DIM15, hu9F5VLv8_DIM16, and hu9F5VLv8_DIM17).

[0351] Sequence ID 200 represents the amino acid sequence of another Kabat CDR-L2 (present in hu9F5VLv8_DIM7, hu9F5VLv8_DIM8, and hu9F5VLv9_DIM8) of the humanized 9F5 antibody.

[0352] Sequence ID 201 represents the amino acid sequence of another Kabat CDR-L2 (present in hu9F5VLv8_DIM9, hu9F5VLv8_DIM10, and hu9F5VLv9_DIM10) of the humanized 9F5 antibody.

[0353] Sequence ID 202 represents the amino acid sequence of another Kabat CDR-L2 (present in hu9F5VLv8_DIM19 and hu9F5VLv9_DIM19) of the humanized 9F5 antibody.

[0354] Sequence ID 203 represents the amino acid sequence of another Kabat CDR-L2 (present in hu9F5VLv8_DIM20, hu9F5VLv8_DIM21, and hu9F5VLv9_DIM20) of the humanized 9F5 antibody.

[0355] Sequence ID 204 represents the amino acid sequence of another Kabat CDR-L2 in the humanized 9F5 antibody (present in hu9F5VLv8_DIM22, hu9F5VLv8_DIM24, hu9F5VLv8_DIM25, and hu9F5VLv8_DIM26).

[0356] Sequence ID 205 represents the amino acid sequence of another Kabat CDR-L2 (located at hu9F5VLv8_DIM23) of the humanized 9F5 antibody.

[0357] Sequence ID 206 represents the amino acid sequence of another Kabat CDR-L3 (present in hu9F5VLv2_A89G) of the humanized 9F5 antibody.

[0358] Sequence ID 207 represents the amino acid sequence of another Kabat CDR-L3 (located at hu9F5VLv2_L92D) of the humanized 9F5 antibody.

[0359] Sequence ID 208 represents the amino acid sequence of another Kabat CDR-L3 (located at hu9F5VLv2_L92E) of the humanized 9F5 antibody.

[0360] Sequence ID 209 represents the amino acid sequence of another Kabat CDR-L3 in the humanized 9F5 antibody (present in hu9F5VLv8_DIM4, hu9F5VLv8_DIM12, hu9F5VLv8_DIM15, hu9F5VLv8_DIM25, and hu9F5VLv9_DIM4).

[0361] Sequence ID 210 represents the amino acid sequence of another Kabat CDR-L3 (located at hu9F5VLv2_L92Q) of the humanized 9F5 antibody.

[0362] Sequence ID 211 represents the amino acid sequence of another Kabat CDR-L3 (located in hu9F5VLv2_L92T) of the humanized 9F5 antibody.

[0363] Sequence ID 212 is another Kabat CDR-L3 humanized 9F5 antibody (hu9F5VLv8_DIM1, hu9F5VLv8_DIM2, hu9F5VLv8_DIM3, hu9F5VLv8_DIM5, hu9F5VLv8_DIM6, hu9F5VLv8_DIM7, hu9F5VLv8_DIM8, hu9F5VLv8_DIM9, hu9F5VLv8_DIM10, hu9F5VLv8_DIM11, hu9F5VLv8_DIM14, hu9F5VLv8_DIM17, hu9F5VLv8_DIM18, hu9F5VLv8_DIM19, hu9F5VL Represents the amino acid sequence found in v8_DIM22, hu9F5VLv8_DIM23, hu9F5VLv8_DIM24, hu9F5VLv8_DIM27, hu9F5VLv8_DIM28, hu9F5VLv8_DIM29, hu9F5VLv8_DIM30, hu9F5VLv9_DIM1, hu9F5VLv9_DIM2, hu9F5VLv9_DIM5, hu9F5VLv9_DIM8, hu9F5VLv9_DIM10, hu9F5VLv9_DIM11, hu9F5VLv9_DIM19, and hu9F5VLv9_DIM20.

[0364] Sequence ID 213 represents the amino acid sequence of another Kabat CDR-L3 (present in hu9F5VLv2_L93G) of the humanized 9F5 antibody.

[0365] Sequence ID 214 represents the amino acid sequence of the humanized heavy chain variable region hu10C12VHv1.

[0366] Sequence ID 215 represents the amino acid sequence of the humanized heavy chain variable region hu10C12VHv2.

[0367] Sequence ID 216 represents the amino acid sequence of the humanized light chain variable region hu10C12VLv1.

[0368] Sequence ID 217 represents the amino acid sequence of the humanized light chain variable region hu10C12VLv2.

[0369] Sequence ID 218 represents the amino acid sequence of the heavy chain variable region acceptor CAC20421-VH_huFrwk.

[0370] Sequence ID 219 represents the amino acid sequence of the heavy chain variable region of the mouse 12C4 antibody.

[0371] Sequence ID 220 represents the amino acid sequence of the mouse 12C4 antibody Kabat CDR-H2.

[0372] Sequence ID 221 represents the amino acid sequence of the humanized heavy chain variable region hu12C4VHv1.

[0373] Sequence ID 222 represents the amino acid sequence of the humanized heavy chain variable region hu12C4VHv2.

[0374] Sequence ID 223 represents the amino acid sequence of the humanized light chain variable region hu12C4VLv1.

[0375] Sequence ID 224 represents the amino acid sequence of the humanized light chain variable region hu12C4VLv2.

[0376] Sequence ID 225 represents the amino acid sequence of the heavy chain variable region of the mouse 17C12 antibody.

[0377] Sequence ID 226 represents the amino acid sequence of the Kabat / Chothia compound CDR H1 of the mouse 17C12 antibody.

[0378] Sequence ID 227 represents the amino acid sequence of the mouse 17C12 antibody Kabat CDR H2.

[0379] Sequence ID 228 represents the amino acid sequence of the light chain variable region of the mouse 17C12 antibody.

[0380] Sequence ID 229 represents the amino acid sequence of the mouse 17C12 antibody Kabat CDR-L1.

[0381] Sequence ID 230 represents the amino acid sequence of the mouse 17C12 antibody Kabat CDR-L2.

[0382] Sequence ID 231 represents the amino acid sequence of Kabat CDR-L3, a mouse 17C12 antibody.

[0383] Sequence ID 232 represents the amino acid sequence of the humanized heavy chain variable region hu17C12VHv1.

[0384] Sequence ID 233 represents the amino acid sequence of the humanized heavy chain variable region hu17C12VHv2.

[0385] Sequence ID 234 represents the amino acid sequence of the humanized light chain variable region hu17C12VLv1.

[0386] Sequence ID 235 represents the amino acid sequence of the humanized light chain variable region hu17C12VLv2.

[0387] Sequence ID 236 represents the amino acid sequence of the heavy chain variable region structural model 3PP3-VH_mSt.

[0388] Sequence ID 237 represents the amino acid sequence of the light chain variable region structural model 3PP3-VL_mSt.

[0389] Sequence ID 238 represents the amino acid sequence of the light chain variable region acceptor QDO16713-VL_huFrwk.

[0390] Sequence ID 239 is the light chain variable region germline sequence IGKV2-29 * 02 & IGKJ4 * This represents the amino acid sequence of 01.

[0391] Sequence ID 240 represents the amino acid sequence of the heavy chain variable region of the mouse 14H3 antibody.

[0392] Sequence ID 241 represents the amino acid sequence of the Kabat / Chothia complex CDR H1 of the mouse 14H3 antibody.

[0393] Sequence ID 242 represents the amino acid sequence of the mouse 14H3 antibody Kabat CDR H2.

[0394] Sequence ID 243 represents the amino acid sequence of the mouse 14H3 antibody Kabat CDR H3.

[0395] Sequence ID 244 represents the amino acid sequence of the light chain variable region of the mouse 14H3 antibody.

[0396] Sequence ID 245 represents the amino acid sequence of the mouse 14H3 antibody Kabat CDR L1.

[0397] Sequence ID 246 represents the amino acid sequence of Kabat CDR L2, a mouse 14H3 antibody.

[0398] Sequence ID 247 represents the amino acid sequence of Kabat CDR L3, a mouse 14H3 antibody.

[0399] Sequence ID 248 represents the amino acid sequence of the humanized heavy chain variable region hu14H3VHv1.

[0400] Sequence ID 249 represents the amino acid sequence of the humanized heavy chain variable region hu14H3VHv2.

[0401] Sequence ID 250 represents the amino acid sequence of the humanized light chain variable region hu14H3VLv1.

[0402] Sequence ID 251 represents the amino acid sequence of the humanized light chain variable region hu14H3VLv2.

[0403] Sequence ID 252 represents the amino acid sequence of the heavy chain variable region structural model 2VQ1-VH_mSt.

[0404] Sequence ID 253 represents the amino acid sequence of the heavy chain variable region acceptor QDJ57937-VH_huFrwk.

[0405] Sequence ID 254 is the heavy chain variable region germline sequence IGHV1-70 * 04 & IGHJ4 * This represents the amino acid sequence of 01.

[0406] Sequence ID 255 represents the amino acid sequence of the light chain variable region structural model 2VQ1-VL_mSt.

[0407] Sequence ID 256 represents the amino acid sequence of the light chain variable region acceptor ABC66914-VL_huFrwk.

[0408] Sequence ID 257 represents the amino acid sequence of the mouse 12C4 antibody AbM CDR-H2.

[0409] Sequence ID 258 represents the amino acid sequence of the mouse 12C4 antibody Contact CDR-H2.

[0410] Sequence ID 259 represents the amino acid sequence of Chothia CDR-H1, a mouse 17C12 antibody.

[0411] Sequence ID 260 represents the amino acid sequence of AbM CDR-H2, a mouse 17C12 antibody.

[0412] Sequence ID 261 represents the amino acid sequence of Contact CDR-H2, a mouse 17C12 antibody.

[0413] Sequence ID 262 represents the amino acid sequence of Contact CDR-L1, a mouse 17C12 antibody.

[0414] Sequence ID 263 represents the amino acid sequence of Contact CDR-L2 of the mouse 17C12 antibody.

[0415] Sequence ID 264 represents the amino acid sequence of Contact CDR-L3 of the mouse 17C12 antibody.

[0416] Sequence ID 265 represents the amino acid sequence of the mouse 14H3 antibody Kabat CDR-H1.

[0417] Sequence ID 266 represents the amino acid sequence of the mouse 14H3 antibody Chothia CDR-H1.

[0418] Sequence ID 267 represents the amino acid sequence of the mouse 14H3 antibody Chothia CDR-H2.

[0419] Sequence ID 268 represents the amino acid sequence of AbM CDR-H2, a mouse 14H3 antibody.

[0420] Sequence ID 269 represents the amino acid sequence of the mouse 14H3 antibody Contact CDR-H1.

[0421] Sequence ID 270 represents the amino acid sequence of Contact CDR-H2, a mouse 14H3 antibody.

[0422] Sequence ID 271 represents the amino acid sequence of the mouse 14H3 antibody Contact CDR-H3.

[0423] Sequence ID 272 represents the amino acid sequence of the mouse 14H3 antibody Contact CDR-L1.

[0424] SEQ ID NO: 273 represents the amino acid sequence of Contact CDR-L2 of the mouse 14H3 antibody.

[0425] SEQ ID NO: 274 represents the amino acid sequence of Contact CDR-L3 of the mouse 14H3 antibody.

[0426] SEQ ID NO: 275 represents the amino acid sequence of another Kabat / Chothia composite CDR H1 (present in hu14H3VHv1 and hu14H3VHv2) of the humanized 14H3 antibody.

[0427] SEQ ID NO: 276 represents the amino acid sequence of the consensus motif of the peptide to which antibodies 9F5, 10C12, 2D11, 12C4, 17C12, and 14H3 bind.

[0428] SEQ ID NO: 277 represents the amino acid sequence of the consensus motif of the peptide to which antibody 2D11 binds.

[0429] Definitions Monoclonal antibodies or other biological entities are usually provided in isolated form. This means that the antibody or other biological entity usually contains at least 50 (w / w)% purity of interfering proteins and other contaminating substances resulting from its production or purification, but does not exclude the possibility that the monoclonal antibody may be combined with an excess amount of a pharmaceutically acceptable carrier or other vehicle intended to facilitate its use. In some cases, the monoclonal antibody is interfering proteins and contaminating substances resulting from production or purification with a purity of at least 60 (w / w)%, 70 (w / w)%, 8 (w / w)%, 90 (w / w)%, 95 (w / w)%, or 99 (w / w)%. In many cases, the isolated monoclonal antibody or other biological entity is the major macromolecular species remaining after its purification.

[0430] The specific binding of an antibody to its target antigen is at least 10 6 10 7, 10 8 , 10 9 , 10 10 , 10 11 , or 10 12 M -1 This refers to affinity and / or binding activity. Specific binding is significant enough to be detectable and comparable to nonspecific binding that occurs to at least one unrelated target. Specific binding may result from the formation of specific functional group binding or specific spatial fit (e.g., lock and key types), while nonspecific binding is usually the result of van der Waals forces. However, specific binding does not necessarily imply that the antibody binds to only one target.

[0431] The basic structural unit of an antibody is a tetramer of subunits. Each tetramer contains a pair of two identical polypeptide chains, each pair having one "light" chain (approximately 25 kDa) and one "heavy" chain (approximately 50-70 kDa). The amino-terminus of each chain contains a variable region of approximately 100-110 or more amino acids, which primarily contributes to antigen recognition. This variable region is initially expressed by binding to a cleavable signal peptide. The variable region without a signal peptide is sometimes called the mature variable region. Therefore, for example, the light chain mature variable region means the light chain variable region without a light chain signal peptide. The carboxyl terminus of each chain defines a constant region that primarily contributes to effector function.

[0432] The light chain is classified as either κ or λ. The heavy chain is classified as gamma, mu, alpha, delta, or epsilon, defining the antibody isotype as IgG, IgM, IgA, IgD, and IgE, respectively. Within the light and heavy chains, the variable and constant regions are linked by a "J" region of approximately 12 or more amino acids, where the heavy chain also contains a "D" region of approximately 10 or more amino acids. For general information, see Fundamental Immunology, Paul, W., ed., 2nd ed. Raven Press, NY, 1989, Ch. 7 (the entire work is incorporated by reference for all purposes).

[0433] The variable regions of the light or heavy chain of an immunoglobulin (also referred herein as “light chain variable domains” (“VL domains”) or “heavy chain variable domains” (“VH domains”), respectively) consist of a “framework” region mediated by three “complementarity-determining regions” or “CDRs.” The framework region acts to align the CDRs for specific binding to the antigen’s epitope. The CDRs contain amino acid residues of the antibody that contribute primarily to antigen binding. From the amino terminus to the carboxyl terminus, the VL and VH domains include the following framework regions (FRs) and CDR regions: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The CDR1, 2, and 3 of the VL domain are also referred herein as CDR-L1, CDR-L2, and CDR-L3, respectively; the CDR1, 2, and 3 of the VH domain are also referred herein as CDR-H1, CDR-H2, and CDR-H3, respectively. Where this application discloses a VL sequence with R as the C-terminal residue, R may, alternatively, be considered the N-terminal residue of the light chain constant region. Therefore, this application should also be understood to disclose a VL sequence without R at the C-terminus.

[0434] The amino acid assignments to each VL and VH domain follow one of the conventional CDR definitions. Conventional definitions include Kabat's definition (Kabat, Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, MD, 1987 and 1991)) and Chothia's definition (Chothia & Lesk, J. Mol. Biol. 196:901-917, 1987; Chothia et al., Nature 342:878-883, 1989); the Chothia-Kabat CDR complex, where CDR-H1 is a complex of Chothia and Kabat CDRs; Oxford Examples include the definition of AbM used by Molecular's antibody modeling software, and the definition of contact by Martin et al. (bioinfo.org.uk / abs) (see Table 1). Kabat provides a widely used numbering system (Kabat numbering) in which corresponding residues between different heavy chains or different light chains are assigned the same number. When an antibody is said to contain a CDR by a specific definition of CDR (e.g., Kabat), this definition specifies the minimum number of CDR residues present in the antibody (i.e., Kabat CDRs). This does not exclude the presence of other residues that are in other conventional definitions of CDRs but outside the scope of the specified definition. For example, an antibody containing a CDR as defined by Kabat may, among other possibilities, include an antibody in which the CDR contains Kabat CDR residues but does not contain other CDR residues, and an antibody in which CDR H1 is a composite Chothia-Kabat CDR H1, other CDRs contain Kabat CDR residues, and no further CDR residues based on other definitions. [Table 1]

[0435] The term “antibody” includes intact antibodies and their binding fragments. Fragments, typically containing separate heavy and light chain Fab, Fab', F(ab')2, F(ab)c, Dabs, nanobodies, and Fv, compete with intact antibodies for specific binding to their targets. Fragments can be produced by recombinant DNA technology or by enzymatic or chemical separation of intact immunoglobulins. The term “antibody” also includes bispecific antibodies and / or humanized antibodies. Bispecific or bifunctional antibodies are artificial hybrid antibodies with two different heavy / light chain pairs and two different binding sites (see, for example, Songsivilai and Lachmann, Clin. Exp. Immunol., 79:315-321 (1990); Kostelny et al., J. Immunol., 148:1547-53 (1992)). In some bispecific antibodies, the two heavy / light chain pairs include a heavy / light chain pair of humanized 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3, and a heavy / light chain pair specific to a different epitope on tau other than the one to which 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3 binds.

[0436] In some bispecific antibodies, one heavy / light chain pair is a humanized 9F5 antibody, humanized 10C12 antibody, humanized 2D11 antibody, humanized 12C4 antibody, humanized 17C12 antibody, or humanized 14H3 antibody, as further disclosed below, and the other heavy / light chain pair is derived from an antibody that binds to receptors expressed in the blood-brain barrier, such as insulin receptors, insulin-like growth factor (IGF) receptors, leptin receptors, lipoprotein receptors, or transferrin receptors (Friden et al., Proc. Natl. Acad. Sci. USA 88:4771-4775, 1991; Friden et al., Science 259:373-377, 1993). Such bispecific antibodies can be transmitted across the blood-brain barrier by receptor-mediated transcytosis. Brain uptake of bispecific antibodies can be further enhanced by manipulating the bispecific antibodies to reduce their affinity for blood-brain barrier receptors. This reduction in receptor affinity resulted in a broader distribution in the brain (see, for example, Atwal et al., Sci. Trans. Med. 3, 84ra43, 2011; Yu et al., Sci. Trans. Med. 3, 84ra44, 2011).

[0437] Other exemplary bispecific antibodies include: (1) a dual variable domain antibody (DVD-Ig) (each light and heavy chain contains two variable domains in tandem via a short peptide bond (Wu et al., Generation and Characterization of a Dual Variable Domain Immunoglobulin (DVD-Ig(trademark)) Molecule, In: Antibody Engineering, Springer Berlin Heidelberg (2010))); (2) a tandab, a fusion of two single-chain diabodies resulting in a tetravalent bispecific antibody with two binding sites for each target antigen; (3) a flexibody, a combination of a diabody and scFv resulting in a multivalent molecule; and (4) a so-called "dock and docking" based on the "D / D domain (dimerization and docking domain)" of protein kinase A, which, when applied to Fab, can result in a trivalent bispecific binding protein consisting of two identical Fab fragments bound to different Fab fragments. (5) a so-called scorpion molecule containing, for example, two scFv fused to both ends of a human Fc region. Examples of platforms useful for preparing bispecific antibodies include BiTE (Micromet), DART (MacroGenics), Fcab and Mab2 (F-star), Fc-manipulated IgGl (Xencor), or DuoBody (Genmab, based on Fab arm exchange).

[0438] The term "epitope" refers to a site on an antigen to which an antibody binds. Epitopes can be formed from juxtaposed consecutive or discontinuous amino acids by the tertiary folding of one or more proteins. Epitopes formed from consecutive amino acids (also known as linear epitopes) are usually retained after exposure to denaturing solvents, whereas epitopes formed by tertiary folding (conceptual epitopes) are usually lost after treatment with denaturing solvents. Epitopes contain at least three, and usually at least five or eight to ten, amino acids in their unique spatial structure. Methods for determining the spatial structure of epitopes include, for example, X-ray crystallography and two-dimensional nuclear magnetic resonance. See, for example, Epitope Mapping Protocols, in Methods in Molecular Biology, Vol. 66, Glenn E. Morris, Ed. (1996).

[0439] Antibodies that recognize the same or overlapping epitopes can be identified by a simple immunoassay that characterizes one antibody to compete for binding to another antibody against the target antigen. The antibody's epitope can also be defined by X-ray crystallography of the antibody bound to that antigen to identify the exact residue. Alternatively, if all amino acid mutations in the antigen that reduce or eliminate binding of one antibody also reduce or eliminate binding of the other antibody, then the two antibodies have the same epitope. If some amino acid mutations that reduce or eliminate binding of one antibody also reduce or eliminate binding of the other antibody, then the two antibodies have overlapping epitopes.

[0440] Antibody competition is determined by an assay in which the test antibody inhibits the specific binding of a reference antibody to a common antigen (see, e.g., Junghans et al., Cancer Res. 50:1495, 1990). A test antibody competes with a reference antibody if, when an excess amount of test antibody (e.g., at least 2x, 5x, 10x, 20x, or 100x) is measured in a competitive binding assay, it inhibits the binding of the reference antibody by at least 50%. Some test antibodies inhibit the binding of the reference antibody by at least 75%, 90%, or 99%. Antibodies identified by competitive assays (competing antibodies) include antibodies that bind to the same epitope as the reference antibody, and antibodies that bind to an adjacent epitope that is sufficiently proximal to the epitope to which the reference antibody binds due to the resulting steric hindrance.

[0441] The term "pharmaceutically acceptable" means that a carrier, diluent, excipient, or adjuvant is compatible with the other components of the formulation and is not substantially harmful to its recipient.

[0442] The term "patient" includes human and other mammalian subjects receiving either preventive or therapeutic treatment.

[0443] If an individual has at least one known risk factor (genetic, biochemical, familial, and situational exposure) that places them at a statistically significantly higher risk of developing the disease compared to individuals without the risk factor, then that individual is at high risk of developing the disease.

[0444] The term “biological sample” refers to a sample of biological material in or available from a biological source, such as a human or mammalian subject. Such a sample may be an organ, organelle, tissue, tissue section, body fluid, peripheral blood, plasma, serum, cell, protein and peptide molecules, or any part or combination thereof. The term “biological sample” may also encompass all material derived from processing the sample. Derived material may include cells or their passages. Processing of a biological sample may include one or more of the following: filtration, distillation, extraction, concentration, fixation, inactivation of interfering components, etc.

[0445] The term "control sample" refers to a biological sample that is not known to contain or suspected to contain areas affected by tau-related disease, or a biological sample that is not known to contain or suspected to contain at least a certain type of disease area. A control sample may be obtained from an individual that is not affected by tau-related disease. Alternatively, a control sample may be obtained from a patient affected by tau-related disease. Such a biological sample may be obtained simultaneously with or under different circumstances from a biological sample that is thought to contain tau-related disease. Both the biological sample and the control sample may be obtained from the same tissue. Preferably, the control sample consists of an essentially or overall normal and healthy area and can be used for comparison with a biological sample that is thought to contain areas affected by tau-related disease. Preferably, the tissue of the control sample is the same type as the tissue of the biological sample. Preferably, cells affected by tau-related disease that are thought to be present in the biological sample originate from the same cell types (e.g., neurons or glial cells) as those in the control sample.

[0446] The term "disease" refers to any abnormal condition that impairs physiological function. This term is used broadly to encompass all disorders, illnesses, abnormalities, pathologies, ailments, conditions, or syndromes that impair physiological function, regardless of the nature of their etiology.

[0447] The term "symptoms" refers to subjective evidence of a disease, such as changes in gait, as perceived by the individual. "Signs" refers to objective evidence of a disease observed by a physician.

[0448] The term "positive response to treatment" refers to a more favorable response from an individual patient or the average response of a group of patients compared to the average response of a control group that did not receive treatment.

[0449] For the purpose of classifying amino acid substitutions as conserved or non-conserved, amino acids are grouped as follows: Group I (hydrophobic side chains): met, ala, val, leu, ile; Group II (neutral hydrophilic side chains): cys, ser, thr; Group III (acidic side chains): asp, glu; Group IV (basic side chains): asn, gln, his, lys, arg; Group V (residues affecting chain orientation): gly, pro; and Group VI (aromatic side chains): trp, tyr, phe. Conserved substitutions include substitutions between amino acids of the same class. Non-conservative substitutions consist of exchanging one member of these classes for another.

[0450] Percentage sequence identity is determined by antibody sequences that are maximally aligned according to Kabat numbering rules. After alignment, when the target antibody region (e.g., the entire maturation variable region of the heavy or light chain) is compared to the same region of the reference antibody, the percentage sequence identity between the target antibody region and the reference antibody region is calculated by dividing the number of positions occupied by the same amino acids in the target antibody and the reference antibody by the total number of aligned positions in the two regions, and multiplying by 100 to convert it to a percentage without calculating any gaps.

[0451] A composition or method that "comprises" or "includes" one or more of the described elements may include other elements not specifically described. For example, a composition that "includes" an antibody may include the antibody alone or the antibody in combination with other components.

[0452] The notation of a range of values ​​includes all integers within or defining that range, as well as all subranges defined by the integers within that range.

[0453] Unless other meanings are clear from the context, the term "approximately" encompasses very small values, such as the value within the standard error (e.g., SEM) of the measurement of the stated value.

[0454] Statistical significance means p ≤ 0.05.

[0455] The singular forms of articles, "a," "an," and "the," encompass the plural form unless the context explicitly states otherwise. For example, the term "a compound" or "at least one compound" can include multiple compounds, including mixtures thereof.

[0456] Detailed explanation I. General Provisions The present invention provides antibodies that bind to tau. Some antibodies specifically bind to the epitope in (Q / E)IVYK(S / P) (SEQ ID NO: 56). Some antibodies specifically bind to peptides containing the amino acid sequence QIVYKP (SEQ ID NO: 57, corresponding to residues 307-312 of the tau isoform in SEQ ID NO: 1). Some antibodies specifically bind to peptides containing the amino acid sequence EIVYKSP (SEQ ID NO: 58, corresponding to residues 391-397 of the tau isoform in SEQ ID NO: 1). These antibodies differ from 3D6 and other antibodies characterized by binding to the microtubule-binding region (MTBR) of human tau in that they have an additional epitope near the C-terminus of tau. The specificity of the additional C-terminus of the epitope provides a basis for the antibody to bind to an increasing number of morphologies of tau conformation associated with pathology. Some antibodies specifically bind to peptides containing the amino acid sequence EIVYKS (SEQ ID NO: 277, corresponding to residues 391-396 of the tau isoform in SEQ ID NO: 1). Exemplary antibodies of the present invention are 9F5, 10C12, 2D11, 12C4, 17C12, and 14H3. Some antibodies of the present invention act to inhibit or delay the exacerbation of tau-related pathologies and associated symptoms. While understanding the mechanism is not necessary for the practice of the present invention, the reduction of toxicity may occur as a result of antibodies that induce tau phagocytosis by stabilizing non-toxic conformations, inhibiting intercellular or intracellular transmission of pathogenic tau morphologies, blocking tau phosphorylation, preventing tau from binding to cells, or inducing proteolytic cleavage of tau, or preventing tau from aggregating intermolecularly or intramolecularly, or from binding to other molecules, among other mechanisms. Some antibodies of the present invention are useful for increasing tau aggregation by increasing the molecular weight of specific aggregated tau species to reduce increased toxicity / cellular uptake and / or clearance. Large aggregates of tau molecules may result in reduced uptake into nerve cells. Some antibodies of the present invention, through divalent binding to tau, bring other tau molecules closer, encouraging aggregation into tau aggregates that are too large to be taken up into nerve cells. Furthermore, Fc-mediated phagocytosis requires several tau-binding antibodies to be brought closer together.Large aggregations of tau molecules can have many bound anti-tau antibodies, providing clusters necessary for Fc-mediated phagocytosis by macrophages. The antibodies of the present invention or the agents that induce such antibodies can be used in a manner that treats or prevents tau-related Alzheimer's disease and other diseases.

[0457] II.Target molecule Unless other meanings are clear from the context, a reference to tau refers to the native human form of tau, including all isoforms, regardless of the presence of post-translational modifications (e.g., phosphorylation, glycation, or acetylation). There are six major isoforms (splice variants) of tau present in the human brain. The longest of these variants has 441 amino acids, and this first met residue is cleaved. The residues are numbered according to the 441 isoform. Therefore, for example, a reference to phosphorylation at position 404 refers to position 404 of the 441 isoform, or the corresponding position of any other isoform when maximally aligned with the 441 isoform. The amino acid sequences and Swiss-Prot numbers of the isoforms are listed below. [ka] JPEG0007843068000003.jpg178162

[0458] References to tau include known natural variations and their reorders, of which approximately 30 are listed in the Swiss-Prot database, as well as variations associated with tau pathologies, such as dementia, Pick's disease, and supranuclear palsy (see, for example, the Swiss-Prot database and Poorkaj, et al. Ann Neurol. 43:815-825 (1998)). Some examples of tau mutations, numbered by 441 isoforms, include: a mutation of lysine to threonine at amino acid residue 257 (K257T); a mutation of isoleucine to valine at amino acid position 260 (I260V); a mutation of glycine to valine at amino acid position 272 (G272V); a mutation of asparagine to lysine at amino acid position 279 (N279K); a mutation of asparagine to histidine at amino acid position 296 (N296H); a mutation of proline to serine at amino acid position 301 (P301S); and a mutation of proline to leucine at amino acid position 301 (P301L). These include: mutations of glycine to valine at amino acid position 303 (G303V); mutations of serine to asparagine at position 305 (S305N); mutations of glycine to serine at amino acid position 335 (G335S); mutations of valine to methionine at position 337 (V337M); mutations of glutamic acid to valine at position 342 (E342V); mutations of lysine to isoleucine at amino acid position 369 (K3691); mutations of glycine to arginine at amino acid position 389 (G389R); and mutations of arginine to tryptophan at amino acid position 406 (R406W).

[0459] Tau can be phosphorylated with one or more amino acid residues, including tyrosine at amino acid positions 18, 29, 97, 310, and 394; serine at amino acid positions 184, 185, 198, 199, 202, 208, 214, 235, 237, 238, 262, 293, 324, 356, 396, 400, 404, 409, 412, 413, and 422; and threonine at amino acid positions 175, 181, 205, 212, 217, 231, and 403.

[0460] Unless other meanings are evident from the context, references to tau or its fragments include native human amino acid sequences, including its isoforms, variants, and allele variants.

[0461] III. Antibodies A. Binding specificity and functional properties The present invention provides antibodies that specifically bind to tau. Some antibodies specifically bind to tau at epitopes formed by amino acids derived from one or both of two regions of tau having the common core motif of IVYK (SEQ ID NO: 276). These regions are defined, respectively, by residues 307-312 and 391-397 or 391-396 of SEQ ID NO: 1. Thus, an antibody containing one binding site for tau, such as scFv, can specifically bind to tau individually at epitopes formed from amino acids in either of these regions, or it can specifically bind to a hybrid epitope formed from amino acids derived from both of these regions. An antibody containing two binding sites for tau can also simultaneously bind from its two binding sites to epitopes within the ranges 307-312 and 391-397, or 391-396. These epitopes may be on the same or different molecules of tau. Some antibodies of the present invention specifically bind to peptides consisting of tau residues 307-312, i.e., residue QIVYKP (SEQ ID NO: 57). Some antibodies of the present invention specifically bind to peptides consisting of tau residues 391-397, i.e., EIVYKSP (SEQ ID NO: 58). Some antibodies of the present invention specifically bind to peptides consisting of tau residues 391-396, i.e., EIVYKS (SEQ ID NO: 277). Some antibodies of the present invention specifically bind to peptides consisting of the consensus motif (Q / E)IVYK(S / P) (SEQ ID NO: 56). These antibodies can be obtained by immunization with tau polypeptides purified from natural sources or expressed by recombinant technology. The antibodies can be screened for binding to tau in non-phosphorylated forms and in forms in which one or more phosphorylated residues are phosphorylated. The present invention also provides antibodies that bind to the same epitopes as any of the above antibodies, for example, 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3, and also includes antibodies that compete with any of the above antibodies, for example, 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3, for tau binding.In one embodiment, an antibody that binds to the same epitope as a reference antibody, such as 9F5, or an antibody that competes with the reference antibody, shares one or more of its functional properties, such as inhibiting the internalization of tau into neurons. Optionally, such properties are possessed to a similar degree, or to a higher degree than the reference antibody, within the margin of experimental error.

[0462] The present invention provides an antibody that competes with 9F5 for binding to tau and reduces tau-induced toxicity in neurons. The present invention also provides an antibody that competes with 9F5 for binding to tau and exhibits increased resistance to stirring stress. Exemplary 9F5 humanized antibodies that compete with 9F5 for tau binding and exhibit increased resistance to stirring stress include L27cS / L37Q / M51G / L54R(DIM2), also known as hu9F5VHv9 / hu9F5VLv8_DIM2 (SEQ ID NO: 127 / SEQ ID NO: 133), L27cG / L37G / M51G / L54T(DIM14), also known as hu9F5VHv9 / hu9F5VLv8_DIM14 (SEQ ID NO: 127 / SEQ ID NO: 145), and L27cG / L37G / M51G / L54R(DIM13), also known as hu9F5VHv9 / hu9F5VLv8_DIM13 (SEQ ID NO: 127 / SEQ ID NO: 144). The present invention provides antibodies that compete with 9F5 for tau binding and exhibit increased resistance to low pH stress. Exemplary 9F5 humanized antibodies that compete with 9F5 for tau binding and exhibit increased resistance to low pH stress include L27cS / L37Q / M51G / L54R(DIM2), also known as hu9F5VHv9 / hu9F5VLv8_DIM2 (SEQ ID NO: 127 / SEQ ID NO: 133), L27cD / L37Q / M51G / L54R(DIM6), also known as hu9F5VHv9 / hu9F5VLv8_DIM6 (SEQ ID NO: 127 / SEQ ID NO: 137), and L27cG / L37G / M51G / L54R(DIM13), also known as hu9F5VHv9 / hu9F5VLv8_DIM13 (SEQ ID NO: 127 / SEQ ID NO: 144).Exemplary 9F5 humanized antibodies that compete with 9F5 for tau binding, exhibit increased resistance to stirring stress, and increased resistance to low pH stress include DIM 2 [hu9F5VHv9 / hu9F5VLv8_DIM2 SEQ ID NO: 127 / SEQ ID NO: 133], DIM 6 [hu9F5VHv9 / hu9F5VLv8_DIM6 SEQ ID NO: 127 / SEQ ID NO: 137], DIM 7 [hu9F5VHv9 / hu9F5VLv8_DIM7 SEQ ID NO: 127 / SEQ ID NO: 138], DIM 8 [hu9F5VHv9 / hu9F5VLv8_DIM8 SEQ ID NO: 127 / SEQ ID NO: 139], and DIM 13 [hu9F5VHv9 / hu9F5VLv8_DIM13]. These are DIM18[hu9F5VHv9 / hu9F5VLv8_DIM18 DIM18 DIM127 / DIM149], DIM28[hu9F5VHv9 / hu9F5VLv8_DIM28 DIM127 / DIM159], and DIM30[hu9F5VHv9 / hu9F5VLv8_DIM30 DIM127 / DIM161].

[0463] The present invention provides an antibody that competes with 9F5 for binding to tau and has a reduced tendency to aggregate under high-concentration conditions. An exemplary antibody that competes with 9F5 for binding to tau and has a reduced tendency to aggregate under high-concentration conditions is L37Q / M51G / L54R(DIM27), also known as hu9F5VHv9 / hu9F5VLv8_DIM27 SEQ ID NO: 127 / SEQ ID NO: 158, combined with the original leucine at position L27c.

[0464] The antibodies described above can be produced de novo by immunizing with a tau peptide containing or comprising the amino acid sequence QIVYKP (SEQ ID NO: 57), a tau peptide containing the amino acid sequence EIVYKSP (SEQ ID NO: 58), a tau peptide containing the amino acid sequence EIVYKS (SEQ ID NO: 277), or a tau peptide containing or comprising the amino acid sequence (Q / E)IVYK(S / P) (SEQ ID NO: 56), or by immunizing with a full-length tau peptide or a fragment thereof containing such residues and screening for specific binding to peptides containing such residues. Preferably, such tau peptides are conjugated to heterogeneous conjugate molecules that help induce an antibody response to the peptide. Binding may be direct or mediated by spacer peptides or amino acids. Cysteine ​​is used as a spacer amino acid because its free SH group promotes the binding of carrier molecules. Polyglycine linkers (e.g., 2-6 glycine) with or without a cysteine ​​residue between glycine and the peptide may also be used. Carrier molecules act to provide T cell epitopes that facilitate the induction of an antibody response to peptides. Several carriers, particularly keyhole limpet hemocyanin (KLH), ovalbumin, and bovine serum albumin (BSA), are commonly used. Peptide spacers can be added to peptide immunogens as part of solid-phase peptide synthesis. Carriers are usually added by chemical crosslinking.Some examples of chemical crosslinking agents that may be used include cross-N-maleimide-6-aminocaproyl ester or m-maleimidebenzoyl-N-hydroxysuccinimide ester (MBS) (e.g., Harlow, E. et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY 1988; Sinigaglia et al., Nature, 336:778-780 (1988); Chicz et al., J. Exp. Med., 178:27-47 (1993); Hammer et al., Cell 74:197-203 (1993); Falk K. et al., Immunogenetics, 39:230-242 (1994); International Patent Publication No. 98 / 23635; and Southwood et al. J. Immunology, 160:3363-3373). (See 1998) are examples. Carriers and spacers, if present, may bind to either end of the immunogen.

[0465] Peptides containing optional spacers and carriers may be used to immunize experimental animals or B cells, as described in more detail below. The supernatant of hybridomas may be tested for its ability to bind to tau peptides containing or comprising the amino acid sequence QIVYKP (SEQ ID NO: 57), peptides containing or comprising the amino acid sequence EIVYKSP (SEQ ID NO: 58), peptides containing or comprising the amino acid sequence EIVYKS (SEQ ID NO: 277), or peptides containing or comprising the amino acid sequence (Q / E)IVYK(S / P) (SEQ ID NO: 56), and / or phosphorylated and unphosphorylated forms of tau, for example, the full-length isoform of tau having position 404 in the phosphorylated form. The peptides may be bound to carriers or other tags to facilitate screening assays. In this case, the carrier or tag is selectively different from the combination of spacer and carrier molecules used in immunization to exclude antibodies specific to the spacer or carrier rather than the tau peptide.

[0466] The antibody designated 9F5 is an exemplary antibody that specifically binds to tau. Unless otherwise stated in the context, references to 9F5 should be understood as referring to one of the mouse, chimeric, veneer, or humanized forms of this antibody. The antibody is deposited under the deposit number [DEPOSIT NUMBER]. This antibody specifically binds to peptides containing or consisting of the amino acid sequence QIVYKP (SEQ ID NO: 57), peptides containing or consisting of the amino acid sequence EIVYKSP (SEQ ID NO: 58), or peptides containing or consisting of the amino acid sequence (Q / E)IVYK(S / P) (SEQ ID NO: 56). The heavy chain Kabat / Chothia compound CDRs of 9F5 are designated SEQ ID NOs: 8, 9, and 10, respectively, and the light chain Kabat / Chothia compound CDRs of 9F5 are designated SEQ ID NOs: 12, 13, and 14, respectively.

[0467] Further antibodies that compete with 9F5 for binding to tau and / or bind to the same or overlapping epitopes as 9F5 have been isolated and are designated 10C12, 2D11, 12C4, 17C12, and 14H3, and are produced by hybridomas of the same names. 10C12 has a mature variable heavy chain region and a mature variable light chain region (after signal peptide cleavage), characterized by SEQ ID NOs. 7 and 11, respectively. Unless other meanings are clear from the context, references to 10C12 should be understood as referring to either the mouse morphology, chimeric morphology, veneer morphology, or humanized morphology of this antibody. 10C12 is deposited as [deposit number]. 10C12 is further characterized by its ability to bind to both non-pathological and pathological morphologies and conformations of tau, as well as to misfolded / aggregated morphologies of tau. 10C12 is associated with the structural properties of tau in Alzheimer's disease-derived tissues, such as fibrillation and degenerated neurites, and precipitates monomeric and aggregated tau from Alzheimer's disease extracts.

[0468] 2D11 possesses a mature variable heavy chain region and a mature variable light chain region (after signal peptide cleavage), characterized by Sequence ID No. 7 and Sequence ID No. 11, respectively. Unless other meanings are clear from the context, references to 2D11 should be understood to refer to one of the mouse, chimeric, veneer, or humanized forms of this antibody. 2D11 is deposited as [deposit number]. 2D11 is further characterized by its ability to bind to both non-pathological and pathological forms and conformations of tau, as well as its ability to bind to misfolded / aggregated forms of tau. 2D11 is related to the structural properties of tau in Alzheimer's disease-derived tissues, such as fibrillation and degenerated neurites, and precipitates monomeric and aggregated tau from Alzheimer's disease extracts.

[0469] 12C4 possesses a mature variable heavy chain region and a mature variable light chain region (after signal peptide cleavage), characterized by Sequence ID No. 219 and Sequence ID No. 11, respectively. Unless other meanings are clear from the context, references to 12C4 should be understood to refer to either the mouse morphology, chimeric morphology, veneer morphology, or humanized morphology of this antibody. 12C4 is deposited as [deposit number]. 12C4 is further characterized by its ability to bind to both non-pathological and pathological morphologies and conformations of tau, as well as the misfolded / aggregated morphology of tau. 12C4 is related to the structural properties of tau in Alzheimer's disease-derived tissues, such as fibrillation and degenerated neurites, and precipitates monomeric and aggregated tau from Alzheimer's disease extracts.

[0470] 17C12 possesses a mature variable heavy chain region and a mature variable light chain region (after signal peptide cleavage), characterized by Sequence ID No. 225 and Sequence ID No. 228, respectively. Unless other meanings are clear from the context, references to 17C12 should be understood to refer to one of the mouse, chimeric, veneer, or humanized forms of this antibody. 17C12 is deposited as [deposit number]. 17C12 is further characterized by its ability to bind to both non-pathological and pathological forms and conformations of tau, as well as to the misfolded / aggregated form of tau.

[0471] 14H3 possesses a mature variable heavy chain region and a mature variable light chain region (after signal peptide cleavage), characterized by Sequence IDs 240 and 244, respectively. Unless other meanings are clear from the context, references to 14H3 should be understood to refer to either the mouse morphology, chimeric morphology, veneer morphology, or humanized morphology of this antibody. 14H3 is deposited as [deposit number]. 14H3 is further characterized by its ability to bind to both non-pathological and pathological morphologies and conformations of tau, as well as to misfolded / aggregated morphologies of tau. 14H3 is related to the structural properties of tau in Alzheimer's disease-derived tissues, such as fibrillation and degenerated neurites.

[0472] The alignment of the mature heavy chain variable regions of mouse 9F5 antibody, 10C12 antibody, 2D11 antibody, 12C4 antibody, 14H3 antibody, and 17C12 antibody is shown in Figure 24, and the mature light chain variable regions of mouse 9F5 antibody, 10C12 antibody, 2D11 antibody, 12C4 antibody, 14H3 antibody, and 17C12 antibody are shown in Figure 25. The amino acid sequence of the mature heavy chain variable region of mouse 10C12 antibody has 100% sequence identity with the corresponding region of mouse 9F5 antibody, and the mature light chain variable region of mouse 10C12 antibody has 100% sequence identity with the corresponding region of mouse 9F5 antibody. The amino acid sequence of the mature heavy chain variable region of mouse 2D11 antibody has 100% sequence identity with the corresponding region of mouse 9F5 antibody, and the mature light chain variable region of mouse 2D11 antibody has 100% sequence identity with the corresponding region of mouse 9F5 antibody. The amino acid sequence of the mature heavy chain variable region of mouse 12C4 antibody has 96.6% sequence identity with the corresponding region of mouse 9F5 antibody, and the mature light chain variable region of mouse 12C4 antibody has 100% sequence identity with the corresponding region of mouse 9F5 antibody. The amino acid sequence of the mature heavy chain variable region of mouse 17C12 antibody has 95.9% sequence identity with the corresponding region of mouse 9F5 antibody, and the mature light chain variable region of mouse 17C12 antibody has 70.5% sequence identity with the corresponding region of mouse 9F5 antibody. The amino acid sequence of the mature heavy chain variable region of the mouse 14H3 antibody has 35.0% sequence identity with the corresponding region of the mouse 9F5 antibody, and the mature light chain variable region of the mouse 14H3 antibody has 73.2% sequence identity with the corresponding region of the mouse 9F5 antibody.

[0473] Optionally, the antibody of the present invention may not contain 10C12 antibody. Optionally, the antibody of the present invention may not contain 2D11 antibody. Optionally, the antibody of the present invention may not contain 12C4 antibody. Optionally, the antibody of the present invention may not contain 17C12 antibody. Optionally, the antibody of the present invention may not contain 14H3 antibody.

[0474] Some antibodies of the present invention bind to the same or overlapping epitopes as antibodies designated as 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3. The sequences of the heavy chain maturation variable region and light chain maturation variable region of 9F5 are designated as SEQ ID NOs. 7 and 11, respectively. The sequences of the heavy chain maturation variable region and light chain maturation variable region of 10C12 are designated as SEQ ID NOs. 7 and 11, respectively. The sequences of the heavy chain maturation variable region and light chain maturation variable region of 2D11 are designated as SEQ ID NOs. 7 and 11, respectively. The sequences of the heavy chain maturation variable region and light chain maturation variable region of 12C4 are designated as SEQ ID NOs. 219 and 11, respectively. The sequences of the heavy chain maturation variable region and light chain maturation variable region of 17C12 are designated as SEQ ID NOs. 225 and 228, respectively. The sequences of the heavy chain maturation variable region and light chain maturation variable region of 14H3 are designated as SEQ ID NOs. 240 and 244, respectively. Other antibodies with such binding specificity can be produced by immunizing mice with tau or a portion thereof containing a desired epitope (e.g., a tau peptide containing or comprising the amino acid sequence QIVYKP (SEQ ID NO: 57), a tau peptide containing or comprising the amino acid sequence EIVYKSP (SEQ ID NO: 58), a tau peptide containing or comprising the amino acid sequence EIVYKS (SEQ ID NO: 277), or a tau peptide containing or comprising the amino acid sequence (Q / E)IVYK(S / P) (SEQ ID NO: 56)), and screening the resulting antibodies for binding to tau by competing with antibodies having variable regions of mouse 9F5 (IgG1 / κ), 10C12 (IgG2a / κ), 2D11 (IgG2a / κ), 12C4 (IgG2a / κ), 17C12 (IgG2a / κ), or 14H3 (IgG2a / κ). A tau fragment containing a desired epitope may be bound to a carrier that assists in inducing an antibody response to the fragment, and / or combined with an adjuvant that assists in inducing such a response. Such antibodies may be screened for differential binding to tau or its fragment compared to variants of specified residues.Screening for these variants allows for the identification of antibodies whose binding is inhibited by mutagenesis of specific residues, and which may share functional properties with other exemplified antibodies, by more precisely defining binding specificity. These mutations may be systematic substitutions of alanine (or serine if alanine is already present), either at one residue at a time or across a wider spatial interval, across the target or across the section where the epitope is known to persist. If the same set of mutations significantly reduces the binding of two antibodies, these two antibodies bind to the same epitope.

[0475] Antibodies having binding specificity to selected mouse antibodies (e.g., 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3) can also be produced using atypical phage display methods. See Winter's International Patent Publication No. 92 / 20791. This method is particularly suitable for the production of human antibodies. In this method, the heavy chain variable region or light chain variable region of a selected mouse antibody is used as the initiator. For example, if a light chain variable region is selected as the initiator, a phage library is constructed in which members display the same light chain variable region (i.e., the mouse initiator) and different heavy chain variable regions. Heavy chain variable regions can be obtained, for example, from a library of rearranged human heavy chain variable regions. Phages that show strong specific binding to tau or its fragments (e.g., at least 10) 8 Preferably at least 10 9 M -1 A phage is selected. Next, the heavy chain variable region derived from this phage serves as initiation material for constructing a further phage library. In this library, each phage displays the same heavy chain variable region (i.e., the region identified from the initial display library) and a different light chain variable region. This light chain variable region can be obtained from a library of rearranged human variable light chain regions. Again, a phage showing strong specific binding to tau or its fragments is selected. The resulting antibody typically has the same or similar epitope specificity as the mouse initiation material.

[0476] The heavy chain Kabat / Chothia composite CDRs of 9F5 are denoted as sequence numbers 8-10, respectively, and the light chain Kabat / Chothia composite CDRs of 9F5 are denoted as sequence numbers 12-14, respectively.

[0477] The heavy chain Kabat / Chothia compound CDRs of 10C12 are denoted as sequence numbers 8-10, respectively, and the light chain Kabat / Chothia compound CDRs of 10C12 are denoted as sequence numbers 12-14, respectively.

[0478] The heavy chain Kabat / Chothia composite CDRs of 2D11 are denoted as sequence numbers 8-10, respectively, and the light chain Kabat / Chothia composite CDRs of 2D11 are denoted as sequence numbers 12-14, respectively.

[0479] Table 2 shows the CDRs for 9F5, 10C12, and 2D11 as defined by Kabat, Chothia, the Chothia and Kabat composite (also referred to herein as "Kabat / Chothia composite"), AbM, and Contact. [Table 2]

[0480] The Kabat / Chothia composite CDRs of the 12C4 heavy chain are denoted as sequence numbers 8, 220, and 10, respectively, while the Kabat CDRs of the 12C4 light chain are denoted as sequence numbers 12-14, respectively.

[0481] Table 3 represents the 12C4 CDRs as defined by Kabat, Chothia, the Chothia and Kabat composite (also referred to herein as the "Kabat / Chothia composite"), AbM, and Contact. [Table 3]

[0482] The heavy chain Kabat / Chothia composite CDRs of 17C12 are denoted as sequence numbers 226, 227, and 10, respectively, while the light chain Kabat CDRs of 17C12 are denoted as sequence numbers 229-231, respectively.

[0483] Table 4 represents the 17C12 CDR as defined by Kabat, Chothia, the Chothia and Kabat compound (also referred to herein as the "Kabat / Chothia compound"), AbM, and Contact. [Table 4]

[0484] The Kabat / Chothia composite CDRs of the heavy chain of 14H3 are denoted as sequence numbers 241-243, respectively, while the Kabat CDRs of the light chain of 14H3 are denoted as sequence numbers 245-247.

[0485] Table 5 represents 14H3 CDRs as defined by Kabat, Chothia, a composite of Chothia and Kabat (also referred to herein as "Kabat / Chothia composite"), AbM, and Contact. [Table 5]

[0486] Other antibodies may be obtained by mutagenesis of cDNA encoding the heavy and light chains of exemplary antibodies such as 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3. Monoclonal antibodies that are at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical to 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3 in the amino acid sequence of the mature heavy chain variable region and / or mature light chain variable region, while maintaining their functional properties and / or differing from each antibody by a small number of functionally less important amino acid substitutions (e.g., conservative substitutions), deletions, or insertions are also included in the present invention. The range also includes monoclonal antibodies having at least one or all six CDRs, preferably as defined by Kabat, which are 90%, 95%, 99%, or 100% identical to the corresponding CDRs of 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3, according to any conventional definition.

[0487] The present invention also provides antibodies having some or all (e.g., 3, 4, 5, and 6) CDRs derived entirely or substantially from 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3. Such antibodies may comprise a heavy chain variable region having at least two, usually three, CDRs derived entirely or substantially from the heavy chain variable region of 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3, and / or a light chain variable region having at least two, usually three, CDRs derived entirely or substantially from the light chain variable region of 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3. The antibody may comprise both the heavy chain and the light chain. A CDR is substantially derived from the corresponding 9F5 CDR if it contains 4, 3, 2, or 1 or fewer substitutions, insertions, or deletions, except that CDR-H2 (as defined by Kabat) may have 6, 5, 4, 3, 2, or 1 or fewer substitutions, insertions, or deletions. Such antibodies may have at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3 in the amino acid sequence of the mature heavy chain variable region and / or mature light chain variable region, maintain their functional properties, and / or differ from 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3 by a small number of functionally less important amino acid substitutions (e.g., conservative substitutions), deletions, or insertions.

[0488] Some antibodies identified by such assays may bind to tau monomeric, misfolded, aggregated, phosphorylated, or unphosphorylated forms, or other forms. Similarly, some antibodies are immunoreactive to non-pathological and pathological forms and conformations of tau.

[0489] Furthermore, the present invention provides means for specifically binding to peptides consisting of the residues (Q / E)IVYK(S / P) (SEQ ID NO: 56), QIVYKP (SEQ ID NO: 57), EIVYKSP (SEQ ID NO: 58), or EIVYKS (SEQ ID NO: 277). Exemplary means include antibodies containing heavy chain CDRs of SEQ ID NOs: 8-10 and light chain CDRs of SEQ ID NOs: 12-14. Exemplary means include antibodies containing heavy chain CDRs of SEQ ID NOs: 8, 220, and 10 and light chain CDRs of SEQ ID NOs: 12-14. Exemplary means include antibodies containing heavy chain CDRs of SEQ ID NOs: 226, 227, and 10 and light chain CDRs of SEQ ID NOs: 229-231. Exemplary means include antibodies containing heavy chain CDRs of SEQ ID NOs: 241-243 and light chain CDRs of SEQ ID NOs: 245-247.

[0490] B. Non-human antibodies The production of other non-human antibodies against tau or its fragments (e.g., peptides containing the amino acid sequence of QIVYKP (SEQ ID NO: 57), EIVYKSP (SEQ ID NO: 58), EIVYKS (SEQ ID NO: 277), or (Q / E)IVYK(S / P) (SEQ ID NO: 56)), such as antibodies against mice, guinea pigs, primates, rabbits, or rats, can be achieved, for example, by immunizing animals with tau or its fragments. See Harlow & Lane, Antibodies, A Laboratory Manual (CSHP NY, 1988) (incorporated by reference for all purposes). Optionally, the immunogen may be human tau (4R0N) with 383 amino acids. Optionally, the immunogen may be human tau containing the P301S mutation. Optionally, the immunogen may be human tau that is recombinantly His-tagged at the N-terminus. Optionally, animals are immunized with a tau fragment containing a peptide presented by (Q / E)IVYK(S / P) (SEQ ID NO: 56) bound to a carrier. Optionally, the peptide is QIVYKP (SEQ ID NO: 57), EIVYKSP (SEQ ID NO: 58), or EIVYKS (SEQ ID NO: 277). Such immunogens can be obtained from natural sources, by peptide synthesis, or by recombinant expression. Optionally, the immunogen may be administered fused to a carrier protein or by other means of complexing with the carrier protein. Optionally, the immunogen may be administered with an adjuvant. Several types of adjuvants may be used, as described below. Complete Freund's adjuvants, followed by incomplete adjuvants, may be used for immunization of experimental animals. Rabbits or guinea pigs are typically used for the production of polyclonal antibodies. Mice are typically used for the production of monoclonal antibodies. Antibodies are screened for specific binding to tau or epitopes within tau (e.g., QIVYKP (SEQ ID NO: 57), EIVYKSP (SEQ ID NO: 58), EIVYKS (SEQ ID NO: 277), or (Q / E)IVYK(S / P) (SEQ ID NO: 56)).Optionally, screening may be performed on 15-amino acid peptides containing any other consensus motif presented by QIVYKP (SEQ ID NO: 57), EIVYKSP (SEQ ID NO: 58), EIVYKS (SEQ ID NO: 277), or (Q / E)IVYK(S / P) (SEQ ID NO: 56). Optionally, the peptides may include QIVYKP (SEQ ID NO: 57), EIVYKSP (SEQ ID NO: 58), and EIVYKS (SEQ ID NO: 277). Such screening may be achieved by determining the binding of an antibody to a set of tau variants, such as tau variants containing or consisting of amino acid residues 307-312, 391-397, or 391-396 of SEQ ID NO: 1 or mutations within these residues, and determining whether the tau variants bind to the antibody. Binding may be evaluated, for example, by Western blotting, FACS, or ELISA.

[0491] C. Humanized antibodies Humanized antibodies are genetically engineered antibodies in which CDRs derived from non-human "donor" antibodies are grafted into the sequence of a human "acceptor" antibody (see, for example, U.S. Patents 5,530,101 and 5,585,089 (Queen); 5,225,539 (Winter); 6,407,213 (Carter); 5,859,205 (Adair); and 6,881,557 (Foote)). The sequence of the acceptor antibody may be, for example, the sequence of a mature human antibody, a composite of such sequences, the consensus sequence of a human antibody sequence, or a germline region sequence. Thus, a humanized antibody is an antibody having at least three, four, five, or all of the CDRs, which are entirely or substantially derived from the donor antibody, and, if present, a variable region framework sequence and a constant region, which are entirely or substantially derived from the human antibody sequence. Similarly, a humanized heavy chain has at least one, two, and usually three CDRs entirely or substantially derived from the donor antibody heavy chain, and, if present, a heavy chain variable region framework sequence and heavy chain constant region substantially derived from the human heavy chain variable region framework and constant region sequences. Similarly, a humanized light chain has at least one, two, and usually three CDRs entirely or substantially derived from the donor antibody light chain, and, if present, a light chain variable region framework sequence and light chain constant region substantially derived from the human light chain variable region framework and constant region sequences. Except for nanobodies and dAbs, a humanized antibody includes a humanized heavy chain and a humanized light chain. The CDRs of a humanized antibody are substantially derived from the corresponding CDRs in the non-human antibody if at least 85%, 90%, 95%, or 100% of the corresponding residues (as defined by any conventional definition, but preferably by Kabat) are identical between each CDR. The framework sequence of the variable region of an antibody chain or the constant region of an antibody chain substantially originates from the framework sequence of a human variable region or the human constant region, respectively, if at least 85%, 90%, 95%, or 100% of the corresponding residues, as defined by Kabat, are identical.Under the 2014 World Health Organization (WHO) definition of International Common Names (INNs), for a humanized antibody to be classified as humanized, it must have at least 85% identity with the human germline antibody sequence (i.e., before somatic mutation). A mixed antibody is one in which one antibody chain (e.g., heavy chain) matches the threshold, but the other chain (e.g., light chain) does not. If neither chain matches the threshold, even though the variable framework region in both chains is substantially human, albeit with some mouse reverse mutations, the antibody is classified as a chimera. See Jones et al. (2016) The INNs and outs of antibody nonproprietary names, mAbs 8:1, 1-9, DOI: 10.1080 / 19420862.2015.1114320. See also “WHO-INN: International nonproprietary names (INN) for biological and biotechnological substances (a review)” (Internet) 2014 (available from http: / / www.who.int / medicines / services / inn / BioRev2014.pdf) (incorporated herein by reference). To avoid misunderstanding, the term “humanized,” as used herein, is not intended to be limited to the WHO INN 2014 definition of humanized antibodies. Some of the humanized antibodies provided herein have at least 85% sequence identity with human germline sequences, while some of the humanized antibodies provided herein have less than 85% sequence identity with human germline sequences. Some of the heavy chains of the humanized antibodies provided herein have approximately 60-100% sequence identity with human germline sequences, for example, in the ranges of approximately 60-69%, 70-79%, 80-84%, or 85-89%.Some heavy chains fall below the 2014 WHO INN definition, having sequence identity of approximately 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, or 82%, 83%, or 84% relative to human germline sequences, while other heavy chains meet the 2014 WHO INN definition, having sequence identity of approximately 85%, 86%, 87%, 88%, 89%, or higher relative to human germline sequences. Some light chains of the humanized antibodies provided herein have sequence identity of approximately 60% to 100% relative to human germline sequences, for example, in the range of approximately 80% to 84% or 85% to 89%. Some light chains fall below the 2014 WHO INN definition, for example, having approximately 81%, 82%, 83%, or 84% sequence identity to the human germline sequence, while other light chains meet the 2014 WHO INN definition, having approximately 85%, 86%, 87%, 88%, 89%, or higher sequence identity to the human germline sequence. Some humanized antibodies provided herein that are “chimeras” under the 2014 WHO INN definition have a light chain with less than 85% identity to the human germline sequence paired with a heavy chain with less than 85% identity to the human germline sequence. For example, some humanized antibodies provided herein that have a light chain with less than 85% identity to the human germline sequence paired with a heavy chain with less than 85% identity to the human germline sequence, or vice versa, are “mixed” under the 2014 WHO INN definition. Some of the humanized antibodies provided herein meet the 2014 WHO INN definition of “humanized” and have a light chain having at least 85% sequence identity with a human germline sequence, paired with a heavy chain having at least 85% sequence identity with a human germline sequence. An example of a 12C4 antibody that meets the 2014 WHO INN definition of “humanized” includes an antibody having a mature light chain sequence having the amino acid sequence of SEQ ID NO: 223 or SEQ ID NO: 224, paired with a mature heavy chain having the amino acid sequence of SEQ ID NO: 221 or SEQ ID NO: 222.An example 14H3 antibody that meets the 2014 WHO INN definition of "humanized" includes an antibody having a mature light chain sequence having the amino acid sequence of SEQ ID NO: 251 or SEQ ID NO: 252 paired with a mature heavy chain having the amino acid sequence of SEQ ID NO: 248 or SEQ ID NO: 249. Some of the humanized antibodies provided herein meet the 2014 WHO INN definition of "mixed". An example 9F5 antibody that meets the 2014 WHO INN definition of "mixed" includes an antibody having a mature light chain sequence having the amino acid sequence of any of SEQ ID NOs: 26-29 and SEQ ID NOs: 130-131 paired with a mature heavy chain having the amino acid sequence of any of SEQ ID NOs: 15-22 and SEQ ID NOs: 127-128. An example 10C12 antibody that meets the 2014 WHO INN definition of "mixed" includes an antibody having a mature light chain sequence having the amino acid sequence of SEQ ID NO: 216 or 217 paired with a mature heavy chain having the amino acid sequence of SEQ ID NO: 214 or SEQ ID NO: 215. An exemplary 17C12 antibody that satisfies the 2014 WHO INN definition of "mixed" includes an antibody having a mature heavy chain having the amino acid sequence of SEQ ID NO: 232 or SEQ ID NO: 233 paired with a mature light chain having the amino acid sequence of SEQ ID NO: 235. Further humanized 9F5 antibodies of the present invention include an antibody having a mature heavy chain having the amino acid sequence of SEQ ID NO: 15-22 and SEQ ID NO: 127-128 paired with a mature light chain having the amino acid sequence of any of SEQ ID NO: 23-25. Further humanized 17C12 antibodies of the present invention include an antibody having a mature heavy chain having the amino acid sequence of SEQ ID NO: 232 or SEQ ID NO: 233 paired with a mature light chain having the amino acid sequence of SEQ ID NO: 234.

[0492] Humanized antibodies often incorporate all six CDRs (as defined by any conventional definition, but preferably by Kabat) derived from mouse antibodies, but they can also be constructed with fewer CDRs than all of the mouse antibody-derived CDRs (e.g., at least three, four, or five CDRs) (e.g., Pascalis et al., J. Immunol. 169:3076, 2002; Vajdos et al., J. of Mol. Biol., 320: 415-428, 2002; Iwahashi et al., Mol. Immunol. 36:1079-1091, 1999; Tamura et al, J. Immunol., 164:1432-1441, 2000).

[0493] For some antibodies, only a subset of the CDR, known as the SDR, i.e., a subset of the CDR residues necessary for binding, is required to maintain the binding of the humanized antibody. CDR residues that do not come into contact with the antigen and are not present in the SDR can be identified from regions of the Kabat CDR other than Chothia's hypervariable loop (Chothia, J. Mol. Biol. 196:901, 1987), by molecular modeling and / or empirical analysis, or based on previous studies as described in Gonzales et al., Mol. Immunol. 41: 863, 2004 (for example, residues H60-H65 of CDR H2 are often not required). In such humanized antibodies at positions where one or more donor CDR residues are absent or the entire donor CDR is excluded, the amino acid residue occupying that position may be the amino acid occupying the corresponding position in the acceptor antibody sequence (by Kabat numbering). The number of substitutions between the acceptor and donor amino acids in such included CDRs reflects a balance of competing considerations. Such substitutions are potentially preferable in reducing the number of mouse amino acids in humanized antibodies and consequently reducing potential immunogenicity, as well as in meeting the WHO INN definition of "humanization." However, substitutions can also result in changes in affinity, and a significant reduction in affinity is preferably avoided. The position of the substitution in the CDR and the amino acid to be substituted may also be selected empirically.

[0494] The sequence of the human acceptor antibody can be arbitrarily selected from many known human antibodies to provide a high degree of sequence identity (e.g., 65–85% identity) between the framework of the variable region of the human acceptor sequence and the framework of the corresponding variable region of the donor antibody chain. Some humanized and chimeric antibodies have the same or improved functional properties (within the margin of experimental error), such as binding affinity to human tau and inhibition of tau internalization into neurons, as described in the examples for the mouse antibodies from which they are derived. For example, some humanized and chimeric antibodies have binding affinity within a range of 3, 2, or 1 multiples of the mouse antibodies from which they are derived, or affinity that is indistinguishable within the margin of experimental error. Some humanized and chimeric antibodies inhibit tau internalization into neurons as described in the examples, within a range of 3, 2, or 1 multiples of the mouse antibodies from which they are derived, or inhibit it in the same way as the mouse antibodies from which they are derived, within the margin of experimental error.

[0495] An example of a 9F5 heavy chain acceptor sequence is the human mature heavy chain variable region of humanized 48G7 Fab, which has PDB accession code 2RCS-VH_huFrwk (SEQ ID NO: 32). Another example of a 9F5 heavy chain acceptor sequence is the human mature heavy chain GenBank AAN16432-VH_huFrwk (SEQ ID NO: 31). The variable domain of 9F5 and 48G7 Fab also share the same length in the CDR-H1,H2 loop. Another example of a 9F5 heavy chain acceptor sequence is the human mature heavy chain variable region IMGT# IGHV1-69-2 * This is 01 (sequence number 33). IMGT# IGHV1-69-2 * Chothia CDR-H1 (sequence number 01, sequence number 33) is canonical class 1, and Chothia CDR-H2 is canonical class 2. IMGT# IGHV1-69-2 *01 (SEQ ID NO: 33) belongs to human heavy chain subgroup 1. An example of an acceptor sequence for the 9F5 light chain is the human mature light chain variable region 1911357B-VL_huFrwk (SEQ ID NO: 36). Another example of an acceptor sequence for the 9F5 light chain is the human mature light chain variable region CAB51297-VL_huFrwk (SEQ ID NO: 35). The variable light chain domains of the 9F5 antibody and the CAB51297 & 1911357B antibody also share the same length in the CDR-L1, L2, and L3 loops. Another example of an acceptor sequence for the 9F5 light chain is IGKV2-28. * 01 & IGKJ2 * This is a human mature light chain variable region accompanied by 01 (sequence number 37). IGKV2-28 * 01 & IGKJ2 * Chothia CDR-L1, code 01 (sequence number 37), is canonical class 4. IGKV2-28 * 01 & IGKJ2 * Chothia CDR-L2, code 01 (sequence number 37), is canonical class 1. IGKV2-28 * 01 & IGKJ2 * Chothia CDR-L3, code 01 (sequence number 37), is canonical class 1. IGKV2-28 * 01 & IGKJ2 * 01 (sequence number 37) belongs to human κ subgroup 2.

[0496] An example of an acceptor sequence for the 10C12 heavy chain is human mature CAC20421 (sequence number 218). The variable domains of 10C12 and CAC20421 VH also share the same length in the CDR-H1,H2 loop. Another example of an acceptor sequence for the 10C12 heavy chain is human mature heavy chain variable region IMGT# IGHV1-69-2 * This is 01 (sequence number 33). IMGT# IGHV1-69-2 * Chothia CDR-H1 (sequence number 01, sequence number 33) is canonical class 1, and Chothia CDR-H2 is canonical class 2. IMGT# IGHV1-69-2 *01 (SEQ ID NO: 33) belongs to human heavy chain subgroup 1. An example of an acceptor sequence for the 10C12 light chain is the human mature light chain variable region CAB51297-VL_huFrwk (SEQ ID NO: 35). The variable light chain domain of 10C12 and CAB51297 VL also share the same length in the CDR-L1, L2, and L3 loops. Another example of an acceptor sequence for the 10C12 light chain is IGKV2-28. * 01 & IGKJ2 * This is a human mature light chain variable region accompanied by 01 (sequence number 37). IGKV2-28 * 01 & IGKJ2 * Chothia CDR-L1, code 01 (sequence number 37), is canonical class 4. IGKV2-28 * 01 & IGKJ2 * Chothia CDR-L2, code 01 (sequence number 37), is canonical class 1. IGKV2-28 * 01 & IGKJ2 * Chothia CDR-L3, code 01 (sequence number 37), is canonical class 1. IGKV2-28 * 01 & IGKJ2 * 01 (sequence number 37) belongs to human κ subgroup 2.

[0497] An example of an acceptor sequence for the 12C4 heavy chain is the human mature heavy chain variable region CAC20421-VH_huFrwk (SEQ ID NO: 218). The 12C4 variable domain and CAC20421 VH also share the same length in the CDR-H1,H2 loop. Another example of an acceptor sequence for the 12C4 heavy chain is the human mature heavy chain variable region IMGT# IGHV1-69-2 * This is 01 (sequence number 33). IMGT# IGHV1-69-2 * Chothia CDR-H1 (sequence number 01, sequence number 33) is canonical class 1, and Chothia CDR-H2 is canonical class 2. IMGT# IGHV1-69-2 *01 (SEQ ID NO: 33) belongs to human heavy chain subgroup 1. An example of an acceptor sequence for the 12C4 light chain is the human mature light chain variable region CAB51297-VL_huFrwk (SEQ ID NO: 35). The variable light chain domain of 12C4 and CAB51297 VL also share the same length in the CDR-L1, L2, and L3 loops. Another example of an acceptor sequence for the 12C4 light chain is IGKV2-28. * 01 & IGKJ2 * This is a human mature light chain variable region accompanied by 01 (sequence number 37). IGKV2-28 * 01 & IGKJ2 * Chothia CDR-L1, code 01 (sequence number 37), is canonical class 4. IGKV2-28 * 01 & IGKJ2 * Chothia CDR-L2, code 01 (sequence number 37), is canonical class 1. IGKV2-28 * 01 & IGKJ2 * Chothia CDR-L3, code 01 (sequence number 37), is canonical class 1. IGKV2-28 * 01 & IGKJ2 * 01 (sequence number 37) belongs to the human κ subgroup.

[0498] An example of an acceptor sequence for the 17C12 heavy chain is the human mature heavy chain variable region CAC20421-VH_huFrwk (SEQ ID NO: 218). The 17C12 variable heavy chain domain and CAC20421 also share the same length in the CDR-H1,H2 loop. Another example of an acceptor sequence for the 17C12 heavy chain is the human mature heavy chain variable region IMGT# IGHV1-69-2 * This is 01 (sequence number 33). IMGT# IGHV1-69-2 * Chothia CDR-H1 (sequence number 01, sequence number 33) is canonical class 1, and Chothia CDR-H2 is canonical class 2. IMGT# IGHV1-69-2 *01 (SEQ ID NO: 33) belongs to human heavy chain subgroup 1. An example of an acceptor sequence for the 17C12 light chain is the human mature light chain variable region QDO16713-VL_huFrwk (SEQ ID NO: 238). The variable light chain domains of the 17C12 and QDO16713 antibodies also share the same length in the CDR-L1, L2, and L3 loops. An example of an acceptor sequence for the 17C12 light chain is IGKV2-29. * 02 & IGKJ4 * This is a human mature light chain variable region accompanied by 01 (sequence number 239).

[0499] An example of an acceptor sequence for the 14H3 heavy chain is the human mature heavy chain variable region QDJ57937-VH_huFrwk (SEQ ID NO: 253). The variable domain of 14H3 and QDJ57937 VH share the same length in the CDR-H1, H2 loop. Another example of an acceptor sequence for the 14H3 heavy chain is the human mature heavy chain variable region IGHV1-70. * 04 & IGHJ4 * This is 01 (sequence number 254). An example of an acceptor sequence for the 14H3 light chain is the human mature light chain variable region ABC66914-VL_huFrwk (sequence number 256). The variable light chain domain of 14H3 and ABC66914 VL also share the same length in the CDR-L1, L2, and L3 loops. Another example of an acceptor sequence for the 14H3 light chain is IGKV2-28. * 01 & IGKJ2 * This is a human mature light chain variable region accompanied by 01 (sequence number 37). IGKV2-28 * 01 & IGKJ2 * Chothia CDR-L1, code 01 (sequence number 37), is canonical class 4. IGKV2-28 * 01 & IGKJ2 * Chothia CDR-L2, code 01 (sequence number 37), is canonical class 1. IGKV2-28 * 01 & IGKJ2 * Chothia CDR-L3, code 01 (sequence number 37), is canonical class 1. IGKV2-28 * 01 & IGKJ2 *01 (sequence number 37) belongs to human κ subgroup 2.

[0500] When more than one human acceptor antibody sequence is selected, a composite or hybrid of these acceptors can be used, and amino acids used at different positions in the humanized light chain variable region and heavy chain variable region can be taken from any of the human acceptor antibody sequences used. For example, humanized 48G7 Fab having the human mature heavy chain variable region of AAN16432-VH_huFrwk (SEQ ID NO: 31) and PDB accession code 2RCS-VH_huFrwk (SEQ ID NO: 32) was used as a hybrid acceptor sequence for humanization of the 9F5 mature heavy chain variable region. Examples of these two acceptors being in different positions include positions H1 (E or Q), H5 (V or Q), H11 (V or L), H12 (K or V), H20 (V or L), H23 (K or T), H28 (T or N), H38 (R or K), H40 (A or R), H42 (G or E), H43 (K or Q), H48 (M or I), H54 (D or N), H66 (R or K), H69 (M or I), H75 (T or S), H76 (D or N), H80 (M or L), H81 (E or Q), H83 (R or T), H108 (L or T), or H109 (V or L). Humanized versions of the 9F5 heavy chain variable region may contain any of these amino acids at any of these positions. Human germline sequence IMGT# IGHV1-69-2 *01 (SEQ ID NO: 25) was also used as an acceptor sequence for humanization of the 9F5 mature heavy chain variable region. For example, the human mature light chain variable regions CAB51297-VL_huFrwk (SEQ ID NO: 35) and 1911357B-VL_huFrwk (SEQ ID NO: 36) were used as hybrid acceptor sequences for humanization of the 9F5 mature light chain variable region. Examples of these two acceptors being located at different positions include L7 (S or A), L8 (P or A), L9 (L or F), L11 (L or N), L15 (P or L), L17 (E or T), L18 (P or S), L30 (Y or I), L31 (N or T), L54 (R or L), L60 (D or N), L66 (G or E), or L74 (K or R). The humanized version of the 9F5 light chain variable region may contain any of these amino acids at any of these positions. Human germline sequence IGKV2-28 * 01 & IGKJ2 * Sequence ID 01 (SEQ ID NO: 37) was also used as an acceptor sequence for humanization of the 9F5 mature light chain variable region.

[0501] Specific amino acids derived from residues within the human variable region framework may be selected for substitution based on their potential effects on the conformation of the CDR and / or its binding to the antigen. Investigation of such potential effects involves modeling, testing, or experimental observation of the effects of specific amino acid substitutions or mutagenesis.

[0502] For example, if the amino acids differ between the residues in the mouse variable region framework and the residues in the selected human variable region framework, the amino acids in the human framework are, (1) Direct non-covalent binding to the antigen, (2) Whether it is adjacent to the CDR area or located within the CDR, as defined by Chothia but not by Kabat, (3) Interacting with the CDR region in other ways (e.g., within a range of approximately 6 Å of the CDR region) (e.g., identified by modeling the analyzed structural light or heavy chain of homologous known immunoglobulin chains), or (4) Residues involved in the VL-VH interface Where reasonably predicted, the amino acids may be substituted with an equivalent framework derived from a mouse antibody.

[0503] In one embodiment, the humanized sequence is constructed using a two-step PCR protocol that allows for the introduction of multiple mutations, deletions, and insertions using QuikChange site-directed mutagenesis [Wang, W. and Malcolm, BA (1999) BioTechniques 26:680-682].

[0504] Framework residues of classes (1) to (3), as defined by Queen et al., U.S. Patent No. 5,530,101, are sometimes referred to as canonical and vernier residues instead. Framework residues that help define the three-dimensional structure of the CDR loop are sometimes called canonical residues (Chothia & Lesk, J. Mol. Biol. 196:901-917 (1987); Thornton & Martin, J. Mol. Biol. 263:800-815 (1996)). Framework residues that support the three-dimensional structure of the antigen-binding loop and play a role in fine-tuning the fit of the antibody to the antigen are sometimes called vernier residues (Foote & Winter, J. Mol. Biol 224:487-499 (1992)).

[0505] Other framework residues that are candidates for substitution are those that create potential glycosylation sites. Further candidates for substitution are amino acids of the acceptor human framework that are rare at this position in human immunoglobulins. These amino acids can be substituted with amino acids derived from the equivalent position in mouse donor antibodies or from the equivalent position in more typical human immunoglobulins.

[0506] Another framework residue that is a candidate for substitution is the N-terminal glutamine residue (Q), which can be replaced with glutamate (E) to minimize the possibility of conversion to pyroglutamate [Y. Diana Liu, et al., 2011, J. Biol. Chem., 286: 11211-11217]. The conversion of glutamate (E) to pyroglutamate (pE) is slower than the conversion from glutamine (Q). The loss of the primary amine in the conversion of glutamine to pE makes the antibody more acidic. Incomplete conversion results in antibody heterogeneity, which can be observed as multiple peaks using charge-based analytical methods. Differences in heterogeneity may represent the loss of process control. Exemplary 9F5 humanized heavy chain variable regions with substitution of N-terminal glutamine to glutamate are given by SEQ ID NOs: 16 (hu9F5VHv2), 17 (hu9F5VHv3), 18 (hu9F5VHv4), 19 (hu9F5VHv5), 20 (hu9F5VHv6), 21 (hu9F5VHv7), 22 (hu9F5VHv8), Sequence IDs 109 (hu9F5VHv4_L80P), 110 (hu9F5VHv4_L80D), 111 (hu9F5VHv4_L82cG), 112 (hu9F5VHv4_L82cD), 113 (hu9F5VHv4_L82P), 114 (hu9F5VHv4_L80G), 115 (hu9F5VHv4_L82K) ), Array No. 116 (hu9F5VHv4_L82R), Array No. 117 (hu9F5VHv4_L82E), Array No. 118 (hu9F5VHv4_L82N), Array No. 119 (hu9F5VHv4_Y79D), Array No. 120 (hu9F5VHv4_Y79N), Array No. 121 (hu9F5VHv4_Y79G), Array No. 122 (hu9F5VHv5_M80E ), 123(hu9F5VHv5_M80G), 124(hu9F5VHv4_L82cS), 125(hu9F5VHv4_Y79Q), 126(hu9F5VHv4_S82aG), 127(hu9F5VHv9), 128(hu9F5VHv10), and 129(hu9F5VHv10_L82cG).An exemplary 10C12 humanized heavy chain variable region with substitution of the N-terminal glutamine to glutamate is Sequence ID No. 215 (hu10C12VHv2). An exemplary 12C4 humanized heavy chain variable region with substitution of the N-terminal glutamine to glutamate is Sequence ID No. 222 (hu12C4VHv2). An exemplary 17C12 humanized heavy chain variable region with substitution of the N-terminal glutamine to glutamate is Sequence ID No. 233 (hu17C12VHv2).

[0507] An example of a humanized antibody is the humanized form of mouse 9F5, denoted as Hu9F5.

[0508] The mouse antibody 9F5 contains a mature heavy chain variable region and a mature light chain variable region having amino acid sequences including SEQ ID NO: 7 and SEQ ID NO: 11, respectively. The present invention includes 29 illustrated humanized mature heavy chain variable regions: hu9F5VHv1 (SEQ ID NO: 15), hu9F5VHv2 (SEQ ID NO: 16), hu9F5VHv3 (SEQ ID NO: 17), hu9F5VHv4 (SEQ ID NO: 18), hu9F5VHv5 (SEQ ID NO: 19), hu9F5VHv6 (SEQ ID NO: 20), hu9F5VHv7 (SEQ ID NO: 21), hu9F5VHv8 (SEQ ID NO: 22), hu9F5VHv4_L80P (SEQ ID NO: 109), hu9F5VHv4_L80D (SEQ ID NO: 110), hu9F5VHv4_L82cG (SEQ ID NO: 111), hu9F5VHv4_L82cD (SEQ ID NO: 112), hu9F5VHv4_L82P (SEQ ID NO: 113), hu9F5VHv4_L80G (SEQ ID NO: 114), hu9F5VHv4_L82K (SEQ ID NO: 115), hu9F5VHv4_L82R (sequence number 116), hu9F5VHv4_L82E (sequence number 117), hu9F5VHv4_L82N (sequence number 118), hu9F5VHv4_Y79D (sequence number 119), hu9F5VHv4_Y79N (sequence number 120), hu9F5VHv4_Y79G (sequence number 121), hu9F5VHv5_M80E (sequence number 122), h The following codes are provided: u9F5VHv5_M80G (sequence number 123), hu9F5VHv4_L82cS (sequence number 124), hu9F5VHv4_Y79Q (sequence number 125), hu9F5VHv4_S82aG (sequence number 126), hu9F5VHv9 (sequence number 127), hu9F5VHv10 (sequence number 128), and hu9F5VHv10_L82cG (sequence number 129). Furthermore, the present invention relates to 95 exemplified mature light chain variable regions hu9F5VLv1 (SEQ ID NO: 23), hu9F5VLv2 (SEQ ID NO: 24), hu9F5VLv3 (SEQ ID NO: 25), hu9F5VLv4 (SEQ ID NO: 26), hu9F5VLv5 (SEQ ID NO: 27), hu9F5VLv6 (SEQ ID NO: 28), hu9F5VLv7 (SEQ ID NO: 29), hu9F5VLv8 (SEQ ID NO: 130), hu9F5VLv9 (SEQ ID NO: 131), hu9F5VLv2_M51E (SEQ ID NO: 61), hu9F5VLv2_M51D (SEQ ID NO: 62), hu9F5VLv2_L27cD (SEQ ID NO: 63),hu9F5VLv2_L27cG (sequence number 64), hu9F5VLv2_L27cS (sequence number 65), hu9F5VLv2_L27cE (sequence number 66), hu9F5VLv2_I30E (sequence number 67), hu9F5VLv2_I30K (sequence number 68), hu9F5VLv2_L27cT (sequence number 69), hu9F5VLv2_L27cN (sequence number 70), hu9F5VLv2_L27bD (sequence number 71), hu9F5VLv2_I30G (sequence number 72), hu9F5VLv2_L33N (sequence number 73), hu9F5VLv2 _L27cA (SEQ ID NO: 74), hu9F5VLv2_L33T (SEQ ID NO: 75), hu9F5VLv2_L33S (SEQ ID NO: 76), hu9F5VLv2_L33R (SEQ ID NO: 77), hu9F5VLv2_I30Q (SEQ ID NO: 78), hu9F5VLv2_L27bT (SEQ ID NO: 79), hu9F5VLv2_T31G (SEQ ID NO: 80), hu9F5VLv2_L27bQ (SEQ ID NO: 81), hu9F5VLv2_L33G (SEQ ID NO: 82), hu9F5VLv2_L27cP (SEQ ID NO: 83), hu9F5VLv2_V78R (SEQ ID NO: 84) ), hu9F5VLv2_I75D (sequence number 85), hu9F5VLv2_V78D (sequence number 86), hu9F5VLv2_V78E (sequence number 87), hu9F5VLv2_V78P (sequence number 88), hu9F5VLv2_V78K (sequence number 89), hu9F5VLv2_R77D (sequence number 90), hu9F5VLv2_V78G (sequence number 91), hu9F5VLv2_S76P (sequence number 92), hu9F5VLv2_I75P (sequence number 93), hu9F5VLv2_I75Q (sequence number 94), hu9F5VLv2_I75 G (SEQ ID NO: 95), hu9F5VLv2_L73P (SEQ ID NO: 96), hu9F5VLv2_L73G (SEQ ID NO: 97), hu9F5VLv2_V78Q (SEQ ID NO: 98), hu9F5VLv2_S76G (SEQ ID NO: 99), hu9F5VLv2_L92D (SEQ ID NO: 100), hu9F5VLv2_Y86T (SEQ ID NO: 101), hu9F5VLv2_L92E (SEQ ID NO: 102), hu9F5VLv2_L92G (SEQ ID NO: 103), hu9F5VLv2_L92Q (SEQ ID NO: 104), hu9F5VLv2_L93G (SEQ ID NO: 105),hu9F5VLv2_V85G (sequence number 106), hu9F5VLv2_L92T (sequence number 107), hu9F5VLv2_A89G (sequence number 108), hu9F5VLv8_DIM1 (sequence number 132), hu9F5VLv8_DIM2 (sequence number 133), hu9F5VLv8_DIM3 (sequence number 134), hu9F5VLv8_DIM4 (sequence number 135), hu9F5VLv8_DIM5 (sequence number 136), hu9F5VLv8_DIM6 (sequence number 137), hu9F5VLv8_DIM7 (sequence number 138), hu9F5V Lv8_DIM8 (sequence number 139), hu9F5VLv8_DIM9 (sequence number 140), hu9F5VLv8_DIM10 (sequence number 141), hu9F5VLv8_DIM11 (sequence number 142), hu9F5VLv8_DIM12 (sequence number 143), hu9F5VLv8_DIM13 (sequence number 144), hu9F5VLv8_DIM14 (sequence number 145), hu9F5VLv8_DIM15 (sequence number 146), hu9F5VLv8_DIM16 (sequence number 147), hu9F5VLv8_DIM17 (sequence number 148), hu9F 5VLv8_DIM18 (SEQ ID NO: 149), hu9F5VLv8_DIM19 (SEQ ID NO: 150), hu9F5VLv8_DIM20 (SEQ ID NO: 151), hu9F5VLv8_DIM21 (SEQ ID NO: 152), hu9F5VLv8_DIM22 (SEQ ID NO: 153), hu9F5VLv8_DIM23 (SEQ ID NO: 154), hu9F5VLv8_DIM24 (SEQ ID NO: 155), hu9F5VLv8_DIM25 (SEQ ID NO: 156), hu9F5VLv8_DIM26 (SEQ ID NO: 157), hu9F5VLv8_DIM27 (SEQ ID NO: 158), hu9F5VLv8_DIM28 (sequence number 159), hu9F5VLv8_DIM29 (sequence number 160), hu9F5VLv8_DIM30 (sequence number 161), hu9F5VLv9_DIM1 (sequence number 162), hu9F5VLv9_DIM2 (sequence number 163), hu9F5VLv9_DIM4 (sequence number 164), hu9F5VLv9_DIM5 (sequence number 165), hu9F5VLv9_DIM8) (sequence number 166), hu9F5VLv9_DIM10 (sequence number 167), hu9F5VLv9_DIM11 (sequence number 168),(hu9F5VLv9_DIM13 (SEQ ID NO: 169), hu9F5VLv9_DIM19 (SEQ ID NO: 170), and hu9F5VLv9_DIM20 (SEQ ID NO: 171) are provided. Figures 1A-1B and 4A-4B show the alignment of the heavy chain variable region of mouse 9F5 and various humanized antibodies. Figures 2A-2B and 5A-5B show the alignment of the light chain variable region of mouse 9F5 and various humanized antibodies. Figures 6A-6C show the alignment of the light chain variable region of the humanized variant hu9F5VLv8 and various humanized antibodies.)

[0509] For reasons such as the possible effects on the three-dimensional structure of the CDR and / or its binding to the antigen, interactions between the heavy and light chains, mediation of interactions with the constant region, being a site for desirable or undesirable post-translational modifications, being a residue that is rare at that position in the human variable region sequence, thus potentially immunogenic, reducing the possibility of aggregation, and other reasons, the following 48 variable region framework locations are not used in 95 illustrated human mature light chains, as further detailed in the examples. The following were considered candidate substitutions in variable regions and 29 exemplified human mature light chain variable regions: L3(V3Q), L7(A7S), L8(A8P), L9(F9L), L11(N11L), L15(L15P), L17(T17E), L18(S18P), L37(L37Q, L37G, L37I), L39(R39K), L60(N60D), L64(G64S), L66(E66G), L73(L73P, L73G), L74(R74K), L75(I75D, I75P, I75Q, I75G), L7 6(S76P, S76G), L77(R77D), L78(V78R, V78D, V78E, V78P, V78K, V78G, V78Q), L85(V85G), L86(Y86T), L100(G100Q), H1(Q1E), H5(Q5V), H 11(L11V), H12(V12K), H17(S17T), H20(L20I), H23(T23K), H38(K38R, K38Q), H40(R40A), H42(E42G), H43(Q43K), H48(I48M), H66(K66R) ), H69(I69M), H75(S75T), H76(N76D), H79(Y79Q, Y79D, Y79N, Y79G), H80(L80M, L80P, L80D, L80G, L80E), H81(Q81E), H82(L82P, L82K, L82R, L82R, L82E, L82N), H82a(S82aG), H82c(L82cG, L82cD, L82cS), H83(T83R), H93(A93T), H94(S94T), H108(T108L), and H109(L109V).The following 14 locations of variable region CDRs were considered candidate substitutions in 95 illustrated human mature light chain variable regions and 29 illustrated human mature heavy chain variable regions, as further detailed in the examples: L27b (L27bD, L27bT, L27bQ), L27c (L27cD, L27cG, L27cS, L27cE, L27cT, L27cN, L27cA, L27cP, L27cI), L30 (I30Y, I30E, I30K, I30G, I30Q), L31(T31N, T31G), L33(L33N, L33T, L33S, L33R, L33G), L51(M51G, M51E, M51D, M51K, M51I), L54(L54R, L54G, L54T), L89(A89G), L92(L92D, L92E, L92G, L92Q, L92T, L92I), L93(E93G), H28(N28T), H51(I48M), H54(N54D), and H56(D56E). In some humanized 9F5 antibodies, the Kabat / Chothia compound CDR-H1 has an amino acid sequence including SEQ ID NO: 50. In some humanized 9F5 antibodies, the Kabat / Chothia compound CDR-H1 has an amino acid sequence containing SEQ ID NO: 50, and the Kabat CDR-H2 has an amino acid sequence containing SEQ ID NO: 51. In some humanized 9F5 antibodies, the Kabat CDR-H2 has an amino acid sequence containing SEQ ID NO: 51. In some humanized 9F5 antibodies, the Kabat CDR-H2 has an amino acid sequence containing SEQ ID NO: 52. In some humanized 9F5 antibodies, the Kabat CDR-L2 has an amino acid sequence containing SEQ ID NO: 55. In some humanized 9F5 antibodies, the Kabat CDR-L1 has an amino acid sequence containing SEQ ID NO: 53, and the Kabat CDR-L2 has an amino acid sequence containing SEQ ID NO: 55. In some humanized 9F5 antibodies, the Kabat CDR-L1 has an amino acid sequence containing SEQ ID NO: 54, and the Kabat CDR-L2 has an amino acid sequence containing SEQ ID NO: 55. In some humanized 9F5 antibodies, the Kabat CDR-L1 has an amino acid sequence containing a sequence selected from the group consisting of SEQ ID NOs: 172 to 193. In some humanized 9F5 antibodies, Kabat CDR-L2 has an amino acid sequence that includes a sequence selected from the group consisting of SEQ ID NOs. 194-205.In some humanized 9F5 antibodies, Kabat CDR-L3 has an amino acid sequence that includes a sequence selected from the group consisting of SEQ ID NOs. 206-213.

[0510] Here, as in other sections, the first mentioned residue is a residue of the humanized antibody formed by grafting a composite Chothia-Kabat CDR onto a human acceptor framework in the case of Kabat CDR or CDR-H1, and the second mentioned residue is a residue intended to replace that residue. Therefore, within the variable region framework, the first mentioned residue is human, and within the CDR, the first mentioned residue is mouse.

[0511] The demonstrated antibodies are any rearrangement or combination of the demonstrated mature heavy chain variable region and mature light chain variable region: hu9F5VHv1 / hu9F5VLv1, hu9F5VHv1 / hu9F5VLv2, hu9F5VHv1 / hu9F5VLv3, hu9F5VHv1 / hu9F5VLv4, hu9F5VLv1 / hu9F5VLv5, hu9F5VHv1 / hu9F5VLv6, hu9F5VHv1 / hu9F5VLv7, hu9F5VHv2 / hu9F5VLv1, hu9F5VHv2 / hu9F5VLv2, hu9F5VHv2 / hu9F5V Lv3, hu9F5VHv2 / hu9F5VLv4, hu9F5VLv2 / hu9F5VLv5, hu9F5VHv2 / hu9F5VLv6, hu9F5VHv2 / hu9F5VLv7, hu9F5VHv3 / hu9F5VLv1, hu9F5VHv3 / hu9F5VLv2, hu9F5VHv3 / hu9F5VLv3, hu9F5VHv3 / hu9F5VLv4, hu9F5VLv3 / hu9F5VLv5, hu9F5VHv3 / hu9F5VLv6, hu9F5VHv3 / hu9F5VLv7, hu9F5VHv4 / hu9F5VLv1, hu9F 5VHv4 / hu9F5VLv2, hu9F5VHv4 / hu9F5VLv3, hu9F5VHv4 / hu9F5VLv4, hu9F5VLv4 / hu9F5VLv5, hu9F5VHv4 / hu9F5VLv6, hu9F5VHv4 / hu9F5VLv7, hu9F5VHv 5 / hu9F5VLv1, hu9F5VHv5 / hu9F5VLv2, hu9F5VHv5 / hu9F5VLv3, hu9F5VHv5 / hu9F5VLv4, hu9F5VLv5 / hu9F5VLv5, hu9F5VHv5 / hu9F5VLv6, hu9F5VHv5 / hu 9F5VLv7, hu9F5VHv6 / hu9F5VLv1, hu9F5VHv6 / hu9F5VLv2, hu9F5VHv6 / hu9F5VLv3, hu9F5VHv6 / hu9F5VLv4, hu9F5VHv6 / hu9F5VLv5, hu9F5VHv6 / hu9F5V Lv6, hu9F5VHv6 / hu9F5VLv7, hu9F5VHv7 / hu9F5VLv1, hu9F5VHv7 / hu9F5VLv2, hu9F5VHv7 / hu9F5VLv3, hu9F5VHv7 / hu9F5VLv4, hu9F5VLv7 / hu9F5VLv5,Includes hu9F5VHv7 / hu9F5VLv6, hu9F5VHv7 / hu9F5VLv7, hu9F5VHv8 / hu9F5VLv1, hu9F5VHv8 / hu9F5VLv2, hu9F5VHv8 / hu9F5VLv3, hu9F5VHv8 / hu9F5VLv4, hu9F5VLv8 / hu9F5VLv5, hu9F5VHv8 / hu9F5VLv6, and hu9F5VHv8 / hu9F5VLv7.

[0512] The antibodies that have been exemplified include the exemplified mature light chain variable regions hu9F5VLv1 (SEQ ID NO: 23), hu9F5VLv2 (SEQ ID NO: 24), hu9F5VLv3 (SEQ ID NO: 25), hu9F5VLv4 (SEQ ID NO: 26), hu9F5VLv5 (SEQ ID NO: 27), hu9F5VLv6 (SEQ ID NO: 28), hu9F5VLv7 (SEQ ID NO: 29), hu9F5VLv8 (SEQ ID NO: 130), hu9F5VLv9 (SEQ ID NO: 131), hu9F5VLv2_M51E (SEQ ID NO: 61), hu9F5VLv2_M51D (SEQ ID NO: 62), and hu9F5VLv2_L 27cD (SEQ ID NO: 63), hu9F5VLv2_L27cG (SEQ ID NO: 64), hu9F5VLv2_L27cS (SEQ ID NO: 65), hu9F5VLv2_L27cE (SEQ ID NO: 66), hu9F5VLv2_I30E (SEQ ID NO: 67), hu9F5VLv2_I30K (SEQ ID NO: 68), hu9F5VLv2_L27cT (SEQ ID NO: 69), hu9F5VLv2_L27cN (SEQ ID NO: 70), hu9F5VLv2_L27bD (SEQ ID NO: 71), hu9F5VLv2_I30G (SEQ ID NO: 72), hu9F5VLv2_L33NL27cG (SEQ ID NO: 64), hu9F5VLv2_L27cS (SEQ ID NO: 65), hu9F5VLv2_L27cE (SEQ ID NO: 66), hu9F 73), hu9F5VLv2_L27cA (sequence number 74), hu9F5VLv2_L33T (sequence number 75), hu9F5VLv2_L33S (sequence number 76), hu9F5VLv2_L33R (sequence number 77), hu9F5VLv2_I30Q (sequence number 78), hu9F5VLv2_L27bT (sequence number 79), hu9F5VLv2_T31G (sequence number 80), hu9F5VLv2_L27bQ (sequence number 81), hu9F5VLv2_L33G (sequence number 82), hu9F5VLv2_L27cP (sequence number 83), hu9F5VL v2_V78R (sequence number 84), hu9F5VLv2_I75D (sequence number 85), hu9F5VLv2_V78D (sequence number 86), hu9F5VLv2_V78E (sequence number 87), hu9F5VLv2_V78P (sequence number 88), hu9F5VLv2_V78K (sequence number 89), hu9F5VLv2_R77D (sequence number 90), hu9F5VLv2_V78G (sequence number 91), hu9F5VLv2_S76P (sequence number 92), hu9F5VLv2_I75P (sequence number 93), hu9F5VLv2_I75Q (sequence number 94),hu9F5VLv2_I75G (sequence number 95), hu9F5VLv2_L73P (sequence number 96), hu9F5VLv2_L73G (sequence number 97), hu9F5VLv2_V78Q (sequence number 98), hu9F5VLv2_S76G (sequence number 99), hu9F5VLv2_L92D (sequence number 100), hu9F5VLv2_Y86T (sequence number 101), hu9F5VLv2_L92E (sequence number 102), hu9F5VLv2_L92G (sequence number 103), hu9F5VLv2_L92Q (sequence number 104), hu9F5VLv2_L93G (SEQ ID NO: 105), hu9F5VLv2_V85G (SEQ ID NO: 106), hu9F5VLv2_L92T (SEQ ID NO: 107), hu9F5VLv2_A89G (SEQ ID NO: 108), hu9F5VLv8_DIM1 (SEQ ID NO: 132), hu9F5VLv8_DIM2 (SEQ ID NO: 133), hu9F5VLv8_DIM3 (SEQ ID NO: 134), hu9F5VLv8_DIM4 (SEQ ID NO: 135), hu9F5VLv8_DIM5 (SEQ ID NO: 136), hu9F5VLv8_DIM6 (SEQ ID NO: 137), hu9F5VLv8_DIM7 (SEQ ID NO: 138) hu9F5VLv8_DIM8 (sequence number 139), hu9F5VLv8_DIM9 (sequence number 140), hu9F5VLv8_DIM10 (sequence number 141), hu9F5VLv8_DIM11 (sequence number 142), hu9F5VLv8_DIM12 (sequence number 143), hu9F5VLv8_DIM13 (sequence number 144), hu9F5VLv8_DIM14 (sequence number 145), hu9F5VLv8_DIM15 (sequence number 146), hu9F5VLv8_DIM16 (sequence number 147), hu9F5VLv8_DIM17 (sequence number 148), hu9F5VLv8_DIM18 (sequence number 149), hu9F5VLv8_DIM19 (sequence number 150), hu9F5VLv8_DIM20 (sequence number 151), hu9F5VLv8_DIM21 (sequence number 152), hu9F5VLv8_DIM22 (sequence number 153), hu9F5VLv8_DIM23 (sequence number 154), hu9F5VLv8_DIM24 (sequence number 155), hu9F5VLv8_DIM25 (sequence number 156), hu9F5VLv8_DIM26 (sequence number 157), hu9F5VLv8_DIM27 (sequence number 158),hu9F5VLv8_DIM28 (sequence number 159), hu9F5VLv8_DIM29 (sequence number 160), hu9F5VLv8_DIM30 (sequence number 161), hu9F5VLv9_DIM1 (sequence number 162), hu9F5VLv9_DIM2 (sequence number 163), hu9F5VLv9_DIM4 (sequence number 164), hu9F5VLv9_DIM5 (sequence number 165), hu9F5VLv9_DIM8 (sequence number 166), hu9F5VLv9_DIM10 (sequence number 167), hu9F5VLv9_DIM11 (sequence number 1 68), exemplified mature heavy chain variable regions hu9F5VHv1 (sequence number 15), hu9F5VHv2 (sequence number 16), hu9F5VHv3 (sequence number 17), hu9F5VHv4 (sequence number 18), hu9F5VHv5 (sequence number 19), hu9F5VHv6 (sequence number 20), hu9F5VHv7 (sequence number 21), hu9F5VHv8 (sequence number 68), accompanied by any of hu9F5VLv9_DIM13 (sequence number 169), hu9F5VLv9_DIM19 (sequence number 170), and hu9F5VLv9_DIM20 (sequence number 171), Number 22), hu9F5VHv9 (sequence number 127), hu9F5VHv10 (sequence number 128), hu9F5VHv10_L82cG (sequence number 129), hu9F5VHv4_L80P (sequence number 109), hu9F5VHv4_L80D (sequence number 110), hu9F5VHv4_L82cG (sequence number 111), hu9F5VHv4_L82cD (sequence number 112), hu9F5VHv4_L82P (sequence number 113), hu9F5VHv4_L80G (sequence number 114), hu9F5VHv4_L82K (sequence number 115), hu9F5VHv4_L82R (sequence number 116), hu9F5VHv4_L82E (sequence number 117), hu9F5VHv4_L82N (sequence number 118), hu9F5VHv4_Y79D (sequence number 119), hu9F5VHv4_Y79N (sequence number 120), hu9F5VHv4_Y79G (sequence number 121), hu9F5VHv5_M80E (sequence number 122), hu9F5VHv5_M80G (sequence number 123), hu9F5VHv4_L82cS (sequence number 124), hu9F5VHv4_Y79Q (sequence number 125),This includes any of the following rearrangements or combinations of hu9F5VHv4_S82aG (sequence number 126).

[0513] The present invention provides an antibody in which the humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with the humanized light chain variable region hu9F5VLv8_DIM18 (hu9F5VLv8_V3Q, L27cD, L37G, M51G, L54R, L92I, also known as SEQ ID NO: 149). The present invention also provides an antibody in which the humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with the humanized light chain variable region hu9F5VLv8_DIM11 (hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54R, L92I, also known as SEQ ID NO: 142). The present invention provides an antibody in which the humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with the humanized light chain variable region hu9F5VLv8_DIM28 (hu9F5VLv8_V3Q, L27cS, M51G, L54R, L92I, also known as SEQ ID NO: 159). The present invention also provides an antibody in which the humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with the humanized light chain variable region hu9F5VLv8_DIM17 (hu9F5VLv8_V3Q, L27cS, L37G, M51G, L54T, L92I, also known as SEQ ID NO: 148).

[0514] The present invention provides an antibody in which the humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with the humanized light chain variable region / hu9F5VLv8_DIM6 (hu9F5VLv8_V3Q, L27cD, L37Q, M51G, L54R, L92I, also known as SEQ ID NO: 137). The present invention also provides an antibody in which the humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with the humanized light chain variable region hu9F5VLv8_DIM14 (hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54T, L92I, also known as SEQ ID NO: 145). The present invention provides an antibody in which the humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with the humanized light chain variable region hu9F5VLv8_DIM5 (hu9F5VLv8_V3Q, L27cG, L37Q, M51G, L54R, L92I, also known as SEQ ID NO: 136). The present invention also provides an antibody in which the humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with the humanized light chain variable region hu9F5VLv8_DIM7 (hu9F5VLv8_V3Q, L27cD, L37Q, M51K, L54R, L92I, also known as SEQ ID NO: 138).

[0515] The present invention provides an antibody in which the humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with the humanized light chain variable region hu9F5VLv8_DIM27 (hu9F5VLv8_V3Q, L37Q, M51G, L54R, L92I, also known as SEQ ID NO: 158). The present invention also provides an antibody in which the humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with the humanized light chain variable region hu9F5VLv8_DIM12 (hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54R, L92G, also known as SEQ ID NO: 143). The present invention provides an antibody in which the humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with the humanized light chain variable region hu9F5VLv8_DIM13 (hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54R, also known as SEQ ID NO: 144). The present invention also provides an antibody in which the humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with the humanized light chain variable region hu9F5VLv8_DIM2 (hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L54R, L92I, also known as SEQ ID NO: 133).

[0516] The present invention provides an antibody in which the humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with the humanized light chain variable region hu9F5VLv8_DIM29 (hu9F5VLv8_V3Q, L27cS, L37Q, L54R, L92I, also known as SEQ ID NO: 160). The present invention also provides an antibody in which the humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with the humanized light chain variable region / hu9F5VLv8_DIM30 (hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L92I, also known as SEQ ID NO: 161). The present invention provides an antibody in which the humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with the humanized light chain variable region hu9F5VLv8_DIM8 (hu9F5VLv8_V3Q, L27cG, L37Q, M51K, L54R, L92I, also known as SEQ ID NO: 139).

[0517] The present invention provides an antibody in which the humanized heavy chain variable region hu9F5VHv10 (SEQ ID NO: 128) is combined with the humanized light chain variable region hu9F5VLv9_DIM11 (hu9F5VLv9_V3Q, L27cG, L37G, M51G, L54R, L92I, also known as SEQ ID NO: 168).

[0518] The present invention relates to a humanized mature heavy chain variable region, which is represented by hu9F5VHv1 (sequence number 15), hu9F5VHv2 (sequence number 16), hu9F5VHv3 (sequence number 17), hu9F5VHv4 (sequence number 18), hu9F5VHv5 (sequence number 19), hu9F5VHv6 (sequence number 20), hu9F5VHv7 (sequence number 21), hu9F5VHv8 (sequence number 22), hu9F5VHv9 (sequence number 127), hu9F5VHv10 (sequence number 128), hu9F5VHv10_L82cG (sequence number 129), hu9F5VHv4_L80P (sequence number Number 109), hu9F5VHv4_L80D (Sequence ID 110), hu9F5VHv4_L82cG (Sequence ID 111), hu9F5VHv4_L82cD (Sequence ID 112), hu9F5VHv4_L82P (Sequence ID 113), hu9F5VHv4_L80G (Sequence ID 114), hu9F5VHv4_L82K (Sequence ID 115), hu9F5VHv4_L82R (Sequence ID 116), hu9F5VHv4_L82E (Sequence ID 117), hu9F5VHv4_L82N (Sequence ID 118), hu9F5VHv4_Y79D (Sequence ID 1 19) It shows at least 90%, 95%, 96%, 97%, 98%, or 99% identity with hu9F5VHv4_Y79N (sequence number 120), hu9F5VHv4_Y79G (sequence number 121), hu9F5VHv5_M80E (sequence number 122), hu9F5VHv5_M80G (sequence number 123), hu9F5VHv4_L82cS (sequence number 124), hu9F5VHv4_Y79Q (sequence number 125), or hu9F5VHv4_S82aG (sequence number 126), and the humanized maturation light chain variable region is hu9F5VLv1 (sequence number 23), hu9F5VLv2 (sequence number 24), hu9F5VLv3 (sequence number 25), hu9F5VLv4 (sequence number 26), hu9F5VLv5 (sequence number 27), hu9F5VLv6 (sequence number 28), hu9F5VLv7 (sequence number 29), hu9F5VLv8 (sequence number 130), hu9F5VLv9 (sequence number 131), hu9F5VLv2_M51E (sequence number 61), hu9F5VLv2_M51D (sequence number 62), hu9F5VLv2_L27cD (sequence number 63), hu9F5VLv2_L27cG (sequence number 64),hu9F5VLv2_L27cS (SEQ ID NO: 65), hu9F5VLv2_L27cE (SEQ ID NO: 66), hu9F5VLv2_I30E (SEQ ID NO: 67), hu9F5VLv2_I30K (SEQ ID NO: 68), hu9F5VLv2_L27cT (SEQ ID NO: 69), hu9F5VLv2_L27cN (SEQ ID NO: 70), hu9F5VLv2_L27bD (SEQ ID NO: 71), hu9F5VLv2_I30G (SEQ ID NO: 72), hu9F5VLv2_L33N (SEQ ID NO: 73), hu9F5VLv2_L27cA (SEQ ID NO: 74), hu9F5VLv2 _L33T (sequence number 75), hu9F5VLv2_L33S (sequence number 76), hu9F5VLv2_L33R (sequence number 77), hu9F5VLv2_I30Q (sequence number 78), hu9F5VLv2_L27bT (sequence number 79), hu9F5VLv2_T31G (sequence number 80), hu9F5VLv2_L27bQ (sequence number 81), hu9F5VLv2_L33G (sequence number 82), hu9F5VLv2_L27cP (sequence number 83), hu9F5VLv2_V78R (sequence number 84), hu9F5VLv2_I75D (sequence number 85) hu9F5VLv2_V78D (sequence number 86), hu9F5VLv2_V78E (sequence number 87), hu9F5VLv2_V78P (sequence number 88), hu9F5VLv2_V78K (sequence number 89), hu9F5VLv2_R77D (sequence number 90), hu9F5VLv2_V78G (sequence number 91), hu9F5VLv2_S76P (sequence number 92), hu9F5VLv2_I75P (sequence number 93), hu9F5VLv2_I75Q (sequence number 94), hu9F5VLv2_I75G (sequence number 95), hu9F5VLv2_L73P (SEQ ID NO: 96), hu9F5VLv2_L73G (SEQ ID NO: 97), hu9F5VLv2_V78Q (SEQ ID NO: 98), hu9F5VLv2_S76G (SEQ ID NO: 99), hu9F5VLv2_L92D (SEQ ID NO: 100), hu9F5VLv2_Y86T (SEQ ID NO: 101), hu9F5VLv2_L92E (SEQ ID NO: 102), hu9F5VLv2_L92G (SEQ ID NO: 103), hu9F5VLv2_L92Q (SEQ ID NO: 104), hu9F5VLv2_L93G (SEQ ID NO: 105), hu9F5VLv2_V85G (SEQ ID NO: 106),hu9F5VLv2_L92T (sequence number 107), hu9F5VLv2_A89G (sequence number 108), hu9F5VLv8_DIM1 (sequence number 132), hu9F5VLv8_DIM2 (sequence number 133), hu9F5VLv8_DIM3 (sequence number 134), hu9F5VLv8_DIM4 (sequence number 135), hu9F5VLv8_DIM5 (sequence number 136), hu9F5VLv8_DIM6 (sequence number 137), hu9F5VLv8_DIM7 (sequence number 138), hu9F5VLv8_DIM8 (sequence number 139), hu9F5V Lv8_DIM9 (SEQ ID NO: 140), hu9F5VLv8_DIM10 (SEQ ID NO: 141), hu9F5VLv8_DIM11 (SEQ ID NO: 142), hu9F5VLv8_DIM12 (SEQ ID NO: 143), hu9F5VLv8_DIM13 (SEQ ID NO: 144), hu9F5VLv8_DIM14 (SEQ ID NO: 145), hu9F5VLv8_DIM15 (SEQ ID NO: 146), hu9F5VLv8_DIM16 (SEQ ID NO: 147), hu9F5VLv8_DIM17 (SEQ ID NO: 148), hu9F5VLv8_DIM18 (SEQ ID NO: 149), hu9 F5VLv8_DIM19 (SEQ ID NO: 150), hu9F5VLv8_DIM20 (SEQ ID NO: 151), hu9F5VLv8_DIM21 (SEQ ID NO: 152), hu9F5VLv8_DIM22 (SEQ ID NO: 153), hu9F5VLv8_DIM23 (SEQ ID NO: 154), hu9F5VLv8_DIM24 (SEQ ID NO: 155), hu9F5VLv8_DIM25 (SEQ ID NO: 156), hu9F5VLv8_DIM26 (SEQ ID NO: 157), hu9F5VLv8_DIM27 (SEQ ID NO: 158), hu9F5VLv8_DIM28 (SEQ ID NO: 159) hu9F5VLv8_DIM29 (sequence number 160), hu9F5VLv8_DIM30 (sequence number 161), hu9F5VLv9_DIM1 (sequence number 162), hu9F5VLv9_DIM2 (sequence number 163), hu9F5VLv9_DIM4 (sequence number 164), hu9F5VLv9_DIM5 (sequence number 165), hu9F5VLv9_DIM8 (sequence number 166), hu9F5VLv9_DIM10 (sequence number 167), hu9F5VLv9_DIM11 (sequence number 168), hu9F5VLv9_DIM13 (sequence number 169),This invention provides a variant of a 9F5 humanized antibody that exhibits at least 90%, 95%, 96%, 97%, 98%, or 99% identity with hu9F5VLv9_DIM19 (SEQ ID NO: 170) or hu9F5VLv9_DIM20 (SEQ ID NO: 171). In some such antibodies, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, or all 62 of the positions available for reverse mutation or other mutation in sequence numbers 15-22, 109-129, 23-29, 61-108, and 130-171 are similarly reverse-mutated or otherwise mutated. ,

[0519] In some humanized 9F5 antibodies, at least one of the following positions in the VH region is occupied by the indicated amino acids: H1 is occupied by E, H7 by T, H20 by I, H69 by M, H75 by T, H93 by T, H94 by T, and H109 by V. In some humanized 9F5 antibodies, positions H1, H17, H20, H69, H75, H94, and H109 are occupied by E, T, I, M, T, T, T, and V, respectively.

[0520] In some humanized 9F5 antibodies, at least one of the following positions in the VH region is occupied by the indicated amino acids: H66 is occupied by R, and H81 is occupied by E. In some humanized 9F5 antibodies, positions H66 and H81 are occupied by R and E, respectively.

[0521] In some humanized 9F5 antibodies, at least one of the following positions in the VH region is occupied by the indicated amino acids: H23 is occupied by I, and H83 is occupied by R. In some humanized 9F5 antibodies, positions H23 and H83 are occupied by K and R, respectively.

[0522] In some humanized 9F5 antibodies, at least one of the following positions in the VH region is occupied by the indicated amino acids: H43 is occupied by K, H51 by V, H76 by D, M80 by M, and H108 by L. In some humanized 9F5 antibodies, positions H43, H51, H76, H80, and H108 are occupied by K, V, D, M, and L, respectively.

[0523] In some humanized 9F5 antibodies, the H28 position in the VH region is occupied by a T cell.

[0524] In some humanized 9F5 antibodies, at least one of the following positions in the VH region is occupied by the indicated amino acids: H54 is occupied by D, and H56 is occupied by E. In some humanized 9F5 antibodies, positions H54 and H56 are occupied by D and E, respectively.

[0525] In some humanized 9F5 antibodies, position H40 in the VH region is occupied by A. In some humanized 9F5 antibodies, at least one of the following positions in the VH region is occupied by the indicated amino acid: H5 is occupied by V, H11 by V, H12 by K, H38 by R, and H42 by G.

[0526] In some humanized 9F5 antibodies, positions H5, H11, H12, H38, and H42 are occupied by V, V, K, R, and G, respectively.

[0527] In some humanized 9F5 antibodies, at least one of the following positions in the VH region is occupied by the indicated amino acid: H1 is occupied by Q or E, H5 by Q or V, H11 by L or V, H12 by V or K, H17 by S or T, H20 by L or I, H23 by T or K, H28 by N or T, H38 by K, R, or Q, H40 by R or A, H42 by E or G, H43 by Q or K, H48 by I or M, H51 by I or V, and H54 by N or D. H56 is occupied by D or E, H66 by K or R, H69 by I or M, H75 by S or T, H76 by N or D, H79 by Y, Q, D, N, or G, H80 by L, M, P, D, G, or E, H81 by Q or E, H82 by L, P, K, R, E, or N, H82a by S or G, H82c by L, G, D, or S, H83 by T or R, H93 by A or T, H94 by S or T, H108 by T or L, and H109 by L or V.

[0528] In some humanized 9F5 antibodies, such as hu9F5VHv2, the positions H1, H17, H20, H69, H75, H93, H94, and H109 in the VH region are occupied by E, T, I, M, T, T, T, and V, respectively. In some humanized 9F5 antibodies, such as hu9F5VHv3, the positions H1, H17, H20, H66, H69, H75, H81, H93, H94, and H109 in the VH region are occupied by E, T, I, R, M, T, E, T, T, and V, respectively. In some humanized 9F5 antibodies, such as hu9F5VHv4, the positions H1, H17, H20, H23, H28, H66, H69, H75, H81, H83, H93, H94, and H109 in the VH region are occupied by E, T, I, K, T, R, M, T, E, R, T, T, and V, respectively. In some humanized 9F5 antibodies, such as hu9F5VHv5, the positions H1, H17, H20, H23, H28, H43, H51, H54, H56, H66, H69, H75, H76, H80, H81, H83, H93, H94, H108, and H109 in the VH region are occupied by E, T, I, K, T, K, V, D, E, R, M, T, D, M, E, R, T, T, L, and V, respectively. In some humanized 9F5 antibodies, such as hu9F5VHv6, the positions H1, H17, H20, H23, H28, H40, H43, H48, H51, H54, H56, H66, H69, H75, H76, H80, H81, H83, H93, H94, H108, and H109 in the VH region are occupied by E, T, I, K, T, A, K, M, V, D, E, R, M, T, D, M, E, R, T, T, L, and V, respectively. In some humanized 9F5 antibodies, such as hu9F5VHv7, the positions H1, H5, H11, H12, H17, H20, H23, H38, H40, H42, H43, H51, H54, H56, H66, H69, H75, H76, H80, H81, H83, H93, H94, H108, and H109 in the VH region are occupied by E, V, V, K, T, I, K, R, A, G, K, V, D, E, R, M, T, D, M, E, R, T, T, L, and V, respectively.In some humanized 9F5 antibodies, such as hu9F5VHv8, the positions H1, H5, H11, H12, H17, H20, H23, H38, H40, H42, H43, H51, H66, H69, H75, H76, H80, H81, H83, H93, H94, H108, and H109 in the VH region are occupied by E, V, V, K, T, I, K, R, A, G, K, V, R, M, T, D, M, E, R, T, T, L, and V, respectively. In some humanized 9F5 antibodies, such as hu9F5VHv9, the positions H1, H5, H11, H12, H17, H20, H23, H38, H42, H43, H66, H69, H75, H80, H81, H83, H93, H94, H108, and H109 in the VH region are occupied by E, V, V, K, T, I, K, Q, G, K, R, M, T, M, E, R, T, T, L, and V, respectively. In some humanized 9F5 antibodies, the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 127.

[0529] In some humanized 9F5 antibodies, the positions H1, H5, H11, H12, H17, H20, H23, H38, H42, H43, H66, H69, H75, H80, H81, H83, H93, H94, H108, and H109 in the VH region are occupied by E, V, V, K, T, I, K, K, E, K, R, M, T, M, E, R, T, T, L, and V, respectively, in the case of hu9F5VHv10. In some humanized 9F5 antibodies, the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 128.

[0530] In some humanized 9F5 antibodies, the positions H1, H5, H11, H12, H17, H20, H23, H38, H42, H43, H66, H69, H75, H80, H81, H82c, H83, H93, H94, H108, and H109 in the VH region are occupied by E, V, V, K, T, I, K, K, E, K, R, M, T, M, E, G, R, T, T, L, and V, respectively, in the case of hu9F5VHv10_L82cG.

[0531] In some humanized 9F5 antibodies, at least one of the following positions in the VL region is occupied by the indicated amino acids: L7 is occupied by S, L8 by P, L15 by P, and L100 by Q. In some humanized 9F5 antibodies, positions L7, L8, L15, and L100 are occupied by S, P, P, and Q, respectively.

[0532] In some humanized 9F5 antibodies, position L66 in the VL region is occupied by G. In some humanized 9F5 antibodies, position L64 in the VL region is occupied by S.

[0533] In some humanized 9F5 antibodies, the L17 position in the VL region is occupied by E.

[0534] In some humanized 9F5 antibodies, at least one of the following positions in the VL region is occupied by the indicated amino acids: L11 is occupied by L, L51 by G, and L54 by R. In some humanized 9F5 antibodies, positions L11, L51, and L54 are occupied by L, G, and R, respectively.

[0535] In some humanized 9F5 antibodies, the L30 position in the VL region is occupied by Y.

[0536] In some humanized 9F5 antibodies, at least one of the following positions in the VL region is occupied by the listed amino acids: L3 is V or Q, L7 is A or S, L8 is A or P, L9 is F or L, L11 is N or L, L15 is L or P, L17 is T or E, L18 is S or P, L27b is L, D, T, or Q, L27c is L, D, G, S, E, T, N, A, P, or I, L30 is I, Y, E, K, G, or Q, L31 is T, N, or G, L33 is L, N, T, S, R, or G, L37 is L, Q, G, or I, and L39 is R or K, L51 is M, G, E, D, K, or I, L54 is L, R, G, or T, L60 is N or D, L64 is G or S, L66 is E or G, L73 is L, P, or G, L74 is R or K, L75 is I, D, P, Q, or G, L76 is S, P, or G, L77 is sequence number 146 or D, L78 is V, R, D, E, P, K, G, or Q, L85 is V or G, L86 is Y or T, L89 is A or G, L92 is L, D, E, G, Q, T, or I, L93 is E or G, and L100 is G or Q.

[0537] In some humanized 9F5 antibodies, such as hu9F5VLv1, positions L64 and L66 in the VL region are occupied by S and G, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv2, positions L7, L8, L15, L64, L66, and L100 in the VL region are occupied by S, P, P, S, G, and Q, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv3, positions L7, L8, L15, L17, L66, and L100 in the VL region are occupied by S, P, P, E, G, and Q, respectively.

[0538] In some humanized 9F5 antibodies, such as hu9F5VLv4, the positions L7, L8, L11, L15, L17, L51, L54, L66, and L100 in the VL region are occupied by S, P, L, P, E, G, R, G, and Q, respectively. In some humanized 9F5 antibodies, the light chain variable region contains one of the amino acid sequences of SEQ ID NOs. 133, 135-137, 142-144, 149, 158, 159, and 168. In some humanized 9F5 antibodies, the light chain variable region contains the amino acid sequence of SEQ ID NOs. 133. In some humanized 9F5 antibodies, the light chain variable region contains the amino acid sequence of SEQ ID NOs. 137. In some humanized 9F5 antibodies, the light chain variable region contains the amino acid sequence of SEQ ID NOs. 149. In some humanized 9F5 antibodies, the light chain variable region contains the amino acid sequence of SEQ ID NOs. 159.

[0539] In some humanized 9F5 antibodies, such as hu9F5VLv5, the VL region positions L7, L8, L11, L15, L17, L30, L51, L54, L66, and L100 are occupied by S, P, L, P, E, Y, G, R, G, and Q, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv6, the VL region positions L7, L8, L11, L15, L17, L30, L51, L54, and L100 are occupied by S, P, L, P, E, Y, G, R, and Q, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv7, the positions L7, L8, L9, L11, 15, L17, L18, L31, L39, L51, L54, L60, L66, L74, and L100 in the VL region are occupied by S, P, L, L, P, E, P, N, K, G, R, D, G, K, and Q, respectively.

[0540] In some humanized 9F5 antibodies, such as hu9F5VLv8, the VL region positions L7, L8, L11, L15, L17, L39, L64, L66, L74, and L100 are occupied by S, P, L, P, E, K, S, G, K, and Q, respectively. In some humanized 9F5 antibodies, the VL region position L3 is occupied by Q. In some humanized 9F5 antibodies, the VL region position L27c is occupied by D, G, I, L, or S, the VL region position L37 is occupied by G, I, L, or Q, the VL region position L51 is occupied by E, G, I, K, or M, the VL region position L54 is occupied by G, L, R, or T, and the VL region position L92 is occupied by G, I, or L. In some humanized 9F5 antibodies, position L27c in the VL region is occupied by D or S, position L37 in the VL region is occupied by G, L, or Q, position L51 in the VL region is occupied by G or K, position L54 in the VL region is occupied by R, and position L92 in the VL region is occupied by I.

[0541] In some humanized 9F5 antibodies, position L27c in the VL region is occupied by D, position L37 in the VL region is occupied by G, and position L51 in the VL region is occupied by G. In some humanized 9F5 antibodies, the heavy chain variable region has an amino acid sequence containing SEQ ID NO: 127, and the light chain variable region has an amino acid sequence containing SEQ ID NO: 149.

[0542] In some humanized 9F5 antibodies, position L27c in the VL region is occupied by D, position L37 in the VL region is occupied by Q, and position L51 in the VL region is occupied by G. In some humanized 9F5 antibodies, the heavy chain variable region has an amino acid sequence containing SEQ ID NO: 127, and the light chain variable region has an amino acid sequence containing SEQ ID NO: 137.

[0543] In some humanized 9F5 antibodies, position L27c in the VL region is occupied by S, position L37 in the VL region is occupied by L, and position L51 in the VL region is occupied by G. In some humanized 9F5 antibodies, the heavy chain variable region has an amino acid sequence containing SEQ ID NO: 127, and the light chain variable region has an amino acid sequence containing SEQ ID NO: 159.

[0544] In some humanized 9F5 antibodies, position L27c in the VL region is occupied by D, position L37 in the VL region is occupied by Q, and position L51 in the VL region is occupied by K. In some humanized 9F5 antibodies, the heavy chain variable region has an amino acid sequence containing SEQ ID NO: 127, and the light chain variable region has an amino acid sequence containing SEQ ID NO: 138.

[0545] In some humanized 9F5 antibodies, position L27c in the VL region is occupied by S, position L37 in the VL region is occupied by Q, and position L51 in the VL region is occupied by G. In some humanized 9F5 antibodies, the heavy chain variable region has an amino acid sequence containing SEQ ID NO: 127, and the light chain variable region has an amino acid sequence containing SEQ ID NO: 133.

[0546] In some humanized 9F5 antibodies, such as hu9F5VLv9, the VL region positions L7, L8, L11, L15, L17, L39, L60, L64, L66, L74, and L100 are occupied by S, P, L, P, E, K, D, S, G, K, and Q, respectively. In some humanized 9F5 antibodies, the VL region position L3 is occupied by Q.

[0547] In some humanized 9F5 antibodies, position L27c in the VL region is occupied by G or S, position L37 in the VL region is occupied by G, I, or Q, position L51 in the VL region is occupied by G, I, or K, position L54 in the VL region is occupied by Q or R, and position L92 in the VL region is occupied by G, I, or L. In some humanized 9F5 antibodies, position L27c in the VL region is occupied by G, position L37 in the VL region is occupied by G, position L51 in the VL region is occupied by G, and position L54 in the VL region is occupied by R. In some humanized 9F5 antibodies, position L92 in the VL region is occupied by I. In some humanized 9F5 antibodies, the heavy chain variable region has an amino acid sequence containing SEQ ID NO: 129, and the light chain variable region has an amino acid sequence containing SEQ ID NO: 168.

[0548] The light chain variable regions of any of the antibodies described above may be modified to further reduce immunogenicity. For example, in some humanized antibodies, position L27b of the VL region is occupied by D, T, or Q; position L27c of the VL region is occupied by D, G, S, E, T, N, A, I, or P; position L30 of the VL region is occupied by E, K, G, or Q; position L31 of the VL region is occupied by G; position L33 of the VL region is occupied by N, T, S, R, or G; position L37 of the VL region is occupied by Q, G, or I; position L51 of the VL region is occupied by E, D, G, K, or I; position L54 of the VL region is occupied by G, R, or T; position L60 of the VL region is occupied by D. L73 in the VL region is occupied by P or G; L75 in the VL region is occupied by D, P, Q, or G; L76 in the VL region is occupied by P or G; L77 in the VL region is occupied by D; L78 in the VL region is occupied by R, D, E, P, K, G, or Q; L85 in the VL region is occupied by G; L86 in the VL region is occupied by T; L89 in the VL region is occupied by G; L92 in the VL region is occupied by D, E, G, Q, I, or T; and / or L93 in the VL region is occupied by G (Kabat numbering).

[0549] In some humanized 9F5 antibodies, such as hu9F5VLv2_M51E, the position L51 in the VL region is occupied by E. In some humanized 9F5 antibodies, such as hu9F5VLv2_M51D, the position L51 in the VL region is occupied by D. In some humanized 9F5 antibodies, such as hu9F5VLv2_L27cD, the position L27c in the VL region is occupied by D. In some humanized 9F5 antibodies, such as hu9F5VLv2_L27cG, the position L27c in the VL region is occupied by G. In some humanized 9F5 antibodies, such as hu9F5VLv2_L27cS, the position L27c in the VL region is occupied by S. In some humanized 9F5 antibodies, such as hu9F5VLv2_L27cE, the position L27c in the VL region is occupied by E. In some humanized 9F5 antibodies, such as hu9F5VLv2_I30E, the position L30 in the VL region is occupied by E. In some humanized 9F5 antibodies, such as hu9F5VLv2_I30K, the position L30 in the VL region is occupied by K. In some humanized 9F5 antibodies, such as hu9F5VLv2_L27cT, the position L27c in the VL region is occupied by T. In some humanized 9F5 antibodies, such as hu9F5VLv2_L27cN, the position L27c in the VL region is occupied by N.

[0550] In some humanized 9F5 antibodies, such as hu9F5VLv2_L27bD, the position L27b in the VL region is occupied by D. In some humanized 9F5 antibodies, such as hu9F5VLv2_I30G, the position L30 in the VL region is occupied by G. In some humanized 9F5 antibodies, such as hu9F5VLv2_L33N, the position L33 in the VL region is occupied by N. In some humanized 9F5 antibodies, such as hu9F5VLv2_L27cA, the position L27c in the VL region is occupied by A. In some humanized 9F5 antibodies, such as hu9F5VLv2_L33T, the position L33 in the VL region is occupied by T. In some humanized 9F5 antibodies, such as hu9F5VLv2_L33S, the position L33 in the VL region is occupied by S. In some humanized 9F5 antibodies, such as hu9F5VLv2_L33R, the position L33 in the VL region is occupied by R. In some humanized 9F5 antibodies, such as hu9F5VLv2_I30Q, the position L30 in the VL region is occupied by Q. In some humanized 9F5 antibodies, such as hu9F5VLv2_L27bT, the position L27b in the VL region is occupied by T. In some humanized 9F5 antibodies, such as hu9F5VLv2_T31G, the position L31 in the VL region is occupied by G.

[0551] In some humanized 9F5 antibodies, such as hu9F5VLv2_L27bQ, the position L27b in the VL region is occupied by Q. In some humanized 9F5 antibodies, such as hu9F5VLv2_L33G, the position L33 in the VL region is occupied by G. In some humanized 9F5 antibodies, such as hu9F5VLv2_L27cP, the position L27c in the VL region is occupied by P. In some humanized 9F5 antibodies, such as hu9F5VLv2_V78R, the position L78 in the VL region is occupied by R. In some humanized 9F5 antibodies, such as hu9F5VLv2_I75D, the position L75 in the VL region is occupied by D. In some humanized 9F5 antibodies, such as hu9F5VLv2_V78D, the position L78 in the VL region is occupied by D. In some humanized 9F5 antibodies, such as hu9F5VLv2_V78E, the position L78 in the VL region is occupied by E. In some humanized 9F5 antibodies, such as hu9F5VLv2_V78P, the position L78 in the VL region is occupied by P. In some humanized 9F5 antibodies, such as hu9F5VLv2_V78K, the position L78 in the VL region is occupied by K. In some humanized 9F5 antibodies, such as hu9F5VLv2_R77D, the position L77 in the VL region is occupied by D.

[0552] In some humanized 9F5 antibodies, such as hu9F5VLv2_V78G, the L region position L78 is occupied by G. In some humanized 9F5 antibodies, such as hu9F5VLv2_S76P, the VL region position L76 is occupied by P. In some humanized 9F5 antibodies, such as hu9F5VLv2_I75P, the VL region position L75 is occupied by P. In some humanized 9F5 antibodies, such as hu9F5VLv2_I75Q, the VL region position L75 is occupied by Q. In some humanized 9F5 antibodies, such as hu9F5VLv2_I75G, the VL region position L75 is occupied by G. In some humanized 9F5 antibodies, such as hu9F5VLv2_L73P, the VL region position L73 is occupied by P. In some humanized 9F5 antibodies, such as hu9F5VLv2_L73G, the position L73 in the VL region is occupied by G. In some humanized 9F5 antibodies, such as hu9F5VLv2_V78Q, the position L78 in the VL region is occupied by Q. In some humanized 9F5 antibodies, such as hu9F5VLv2_S76G, the position L76 in the VL region is occupied by G. In some humanized 9F5 antibodies, such as hu9F5VLv2_L92D, the position L92 in the VL region is occupied by D.

[0553] In some humanized 9F5 antibodies, such as hu9F5VLv2_Y86T, the position L86 in the VL region is occupied by T. In some humanized 9F5 antibodies, such as hu9F5VLv2_L92E, the position L92 in the VL region is occupied by E. In some humanized 9F5 antibodies, such as hu9F5VLv2_L92G, the position L92 in the VL region is occupied by G. In some humanized 9F5 antibodies, such as hu9F5VLv2_L92Q, the position L92 in the VL region is occupied by Q. In some humanized 9F5 antibodies, such as hu9F5VLv2_L93G, the position L93 in the VL region is occupied by G. In some humanized 9F5 antibodies, such as hu9F5VLv2_V85G, the position L85 in the VL region is occupied by G. In some humanized 9F5 antibodies, such as hu9F5VLv2_L92T, the position L92 in the VL region is occupied by T. In some humanized 9F5 antibodies, such as hu9F5VLv2_A89G, the position L89 in the VL region is occupied by G.

[0554] In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L54G, and L92I, also known as hu9F5VLv8_DIM1, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, Q, G, G, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L54R, and L92I, also known as hu9F5VLv8_DIM2, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, Q, G, R, and I. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L54T, and L92I (also known as hu9F5VLv8_DIM3), the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, Q, G, T, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L54R, and L92G (also known as hu9F5VLv8_DIM4), the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, Q, G, R, and G, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cG, L37Q, M51G, L54R, and L92I, also known as hu9F5VLv8_DIM5, the positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, Q, G, R, and I, respectively.

[0555] In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cD, L37Q, M51G, L54R, and L92I, also known as hu9F5VLv8_DIM6, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, D, Q, G, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cD, L37Q, M51K, L54R, and L92I, also known as hu9F5VLv8_DIM7, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, D, Q, K, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cG, L37Q, M51K, L54R, and L92I, also known as hu9F5VLv8_DIM8, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, G, Q, K, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cG, L37Q, M51K, L54G, and L92I, also known as hu9F5VLv8_DIM9, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, G, Q, K, G, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cS, L37Q, M51K, L54G, and L92I, also known as hu9F5VLv8_DIM10, the positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, K, G, and I, respectively.

[0556] In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54R, and L92I, also known as hu9F5VLv8_DIM11, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, G, G, G, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54R, and L92G, also known as hu9F5VLv8_DIM12, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, G, G, G, R, and G, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cG, L37G, M51G, and L54R, also known as hu9F5VLv8_DIM13, the VL region positions L3, L27c, L37, L51, and L54 are occupied by Q, G, G, G, and R, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54T, and L92I, also known as hu9F5VLv8_DIM14, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, G, G, G, T, and I. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54T, and L92G, also known as hu9F5VLv8_DIM15, the positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, G, G, T, and G, respectively.

[0557] In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cG, L37G, M51G, and L54T, also known as hu9F5VLv8_DIM16, the VL region positions L3, L27c, L37, L51, and L54 are occupied by Q, G, G, G, and T, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cS, L37G, M51G, L54T, and L92I, also known as hu9F5VLv8_DIM17, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, G, G, T, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cD, L37G, M51G, L54R, and L92I, also known as hu9F5VLv8_DIM18, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, D, G, G, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cS, L37I, M51I, L54R, and L92I, also known as hu9F5VLv8_DIM19, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, I, I, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cS, L37Q, M51I, L54G, and L92I, also known as hu9F5VLv8_DIM20, the positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, I, G, and I, respectively.

[0558] In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cS, L37Q, M51I, and L54G (also known as hu9F5VLv8_DIM21), the VL region positions L3, L27c, L37, L51, and L54 are occupied by Q, S, Q, I, and G, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cS, L37Q, M51E, L54R, and L92I (also known as hu9F5VLv8_DIM22), the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, Q, E, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cG, L37Q, M51E, L54G, and L92I, also known as hu9F5VLv8_DIM23, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, G, Q, E, G, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cG, L37I, M51E, L54R, and L92I, also known as hu9F5VLv8_DIM24, the VL region positions L3, L27c, L37, L51, L54, and L92L are occupied by Q, G, I, E, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cG, L37I, M51E, L54R, and L92G, also known as hu9F5VLv8_DIM25, the positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, I, E, R, and G, respectively.

[0559] In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cI, L37I, M51E, and L54R, also known as hu9F5VLv8_DIM26, the VL region positions L3, L27c, L37, L51, and L54 are occupied by Q, I, I, E, and R, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L37Q, M51G, L54R, and L92I, also known as hu9F5VLv8_DIM27, the VL region positions L3, L37, L51, L54, and L92 are occupied by Q, Q, G, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cS, M51G, L54R, and L92I, also known as hu9F5VLv8_DIM28, the VL region positions L3, L27c, L51, L54, and L92 are occupied by Q, S, G, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cS, L37Q, L54R, and L92I, also known as hu9F5VLv8_DIM29, the VL region positions L3, L27c, L37, L54, and L92 are occupied by Q, S, Q, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cS, L37Q, M51G, and L92I, also known as hu9F5VLv8_DIM30, the positions L3, L27c, L37, L51, and L92 in the VL region are occupied by Q, S, Q, G, and I, respectively.

[0560] In some humanized 9F5 antibodies, such as hu9F5VLv9_V3Q, L27cS, L37Q, M51G, L54G, and L92I, also known as hu9F5VLv9_DIM1, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, Q, G, G, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv9_V3Q, L27cS, L37Q, M51G, L54R, and L92I, also known as hu9F5VLv9_DIM2, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, Q, G, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv9_V3Q, L27cS, L37Q, M51G, L54R, and L92G (also known as hu9F5VLv9_DIM4), the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, Q, G, R, and G, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv9_V3Q, L27cG, L37Q, M51G, L54R, and L92I (also known as hu9F5VLv9_DIM5), the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, G, Q, G, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv9_V3Q, L27cG, L37Q, M51K, L54R, and L92I, also known as hu9F5VLv9_DIM8, the positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, Q, K, R, and I, respectively.

[0561] In some humanized 9F5 antibodies, such as hu9F5VLv9_V3Q, L27cS, L37Q, M51K, L54G, and L92I, also known as hu9F5VLv9_DIM10, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, Q, K, G, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv9_V3Q, L27cG, L37G, M51G, L54R, and L92I, also known as hu9F5VLv9_DIM11, the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, G, G, G, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv9_V3Q, L27cG, L37G, M51G, and L54R (also known as hu9F5VLv9_DIM13), the VL region positions L3, L27c, L37, L51, and L54 are occupied by Q, G, G, G, and R, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv9_V3Q, L27cS, L37I, M51I, L54R, and L92I (also known as hu9F5VLv9_DIM19), the VL region positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, I, I, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv9_V3Q, L27cS, L37Q, M51I, L54G, and L92I, also known as hu9F5VLv9_DIM20, the positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, I, G, and I, respectively.

[0562] Furthermore, the heavy chain variable region of any of the antibodies described above may be modified to further reduce immunogenicity. For example, in some humanized antibodies, position H79 is occupied by D, N, G, or Q; position H80 is occupied by P, D, E, or G; position H82 is occupied by P, K, R, E, or N; position H82a is occupied by G; and / or position H82c is occupied by G, D, or S.

[0563] In some humanized 9F5 antibodies, position H80 is occupied by P, such as in hu9F5VHv4_L80P. In some humanized 9F5 antibodies, position H80 is occupied by D, such as in hu9F5VHv4_L80D. In some humanized 9F5 antibodies, position H82c is occupied by G, such as in hu9F5VHv4_L82cG and hu9F5VHv10_L82cG. In some humanized 9F5 antibodies, position H82c is occupied by D, such as in hu9F5VHv4_L82cD. In some humanized 9F5 antibodies, position H82 is occupied by P, such as in hu9F5VHv4_L82P. In some humanized 9F5 antibodies, position H80 is occupied by G, such as in hu9F5VHv4_L80G. In some humanized 9F5 antibodies, position H82 is occupied by K, such as hu9F5VHv4_L82K. In some humanized 9F5 antibodies, position H82 is occupied by R, such as hu9F5VHv4_L82R. In some humanized 9F5 antibodies, position H82 is occupied by E, such as hu9F5VHv4_L82E. In some humanized 9F5 antibodies, position H82 is occupied by N, such as hu9F5VHv4_L82N.

[0564] In some humanized 9F5 antibodies, position H79 is occupied by D, such as in hu9F5VHv4_Y79D. In some humanized 9F5 antibodies, position H79 is occupied by N, such as in hu9F5VHv4_Y79N. In some humanized 9F5 antibodies, position H79 is occupied by G, such as in hu9F5VHv4_Y79G. ​​In some humanized 9F5 antibodies, position H80 is occupied by E, such as in hu9F5VHv5_M80E. In some humanized 9F5 antibodies, position H80 is occupied by G, such as in hu9F5VHv5_M80G. In some humanized 9F5 antibodies, position H82c is occupied by S, such as in hu9F5VHv4_L82cS. In some humanized 9F5 antibodies, position H79 is occupied by Q, such as in hu9F5VHv4_Y79Q. In some humanized 9F5 antibodies, position H82a is occupied by G, such as in hu9F5VHv4_S82aG.

[0565] In some humanized 9F5 antibodies, the variable heavy chain has more than 85% identity to the human sequence. In some humanized 9F5 antibodies, the variable light chain has more than 85% identity to the human sequence. In some humanized 9F5 antibodies, the variable heavy chain and variable light chain each have more than 85% identity to the human germline sequence. In some humanized 9F5 antibodies, the three heavy chain CDRs are as defined by the Kabat / Chothia compound (sequences 8, 9, and 10, respectively), and the three light chain CDRs are as defined by the Kabat / Chothia compound (sequences 12, 13, and 14); however, position H28 is occupied by N or T, position H51 is occupied by I or V, position H54 is occupied by N or D, position H56 is occupied by D or E, position L27b is occupied by L, D, T, or Q, and position L27c is occupied by L, D, G, S, E, T, N, A, P, or I; position L30 is occupied by I, Y, E, K, G, or Q; position L31 is occupied by T, N, or G; position L33 is occupied by L, N, T, S, R, or G; position L51 is occupied by M, G, E, D, K, or I; position L54 is occupied by L, R, G, or T; position L89 is occupied by A or G; position L92 is occupied by L, D, E, G, Q, T, or I; and position L93 is occupied by E or G.

[0566] In some humanized 9F5 antibodies, the Kabat / Chothia compound CDR-H1 has an amino acid sequence containing SEQ ID NO: 50. In some humanized 9F5 antibodies, the Kabat CDR-H2 has an amino acid sequence containing SEQ ID NO: 51 or 52. In some humanized 9F5 antibodies, the Kabat CDR-L1 has an amino acid sequence containing SEQ ID NO: 53 or 54. In some humanized 9F5 antibodies, the Kabat CDR-L2 has an amino acid sequence containing SEQ ID NO: 55. In some humanized 9F5 antibodies, the Kabat CDR-L1 has an amino acid sequence selected from the group consisting of SEQ ID NOs: 172-193. In some humanized 9F5 antibodies, the Kabat CDR-L2 has an amino acid sequence selected from the group consisting of SEQ ID NOs: 194-205. In some humanized 9F5 antibodies, the Kabat CDR-L3 has an amino acid sequence selected from the group consisting of SEQ ID NOs: 206-213.

[0567] An example of a humanized antibody is the humanized form of mouse 10C12, denoted as Hu10C12.

[0568] The mouse antibody 10C12 contains a mature heavy chain variable region and a mature light chain variable region, each having an amino acid sequence containing SEQ ID NO: 7 and SEQ ID NO: 11, respectively. The present invention provides two illustrated humanized mature heavy chain variable regions: hu10C12VHv1 and hu10C12VHv2. Furthermore, the present invention provides two illustrated mature light chain variable regions: hu10C12VLv1 and hu10C12VLv2. Figures 7 and 8 show the alignment of the respective heavy chain variable regions and light chain variable regions of mouse 10C12 and various humanized antibodies.

[0569] For reasons including the possible effects on the conformation of the CDR and / or its binding to the antigen, interactions between the heavy and light chains, mediation of interactions with the constant region, being a site for desirable or undesirable post-translational modifications, being a residue that is rare at its position in the human variable region sequence, thus potentially immunogenic, reducing the likelihood of aggregation, and other reasons, the following nine variable region framework locations were considered candidate substitutions in two illustrated human mature light chain variable regions and two illustrated human mature light chain variable regions, as further detailed in the Examples: L64(G64S), L104(V104L), H1(Q1E), H24(V24A), H48(M48I), H67(V67A), H69(I69M), H93(A93T), and H94(R94T).

[0570] Here, as in other sections, the first mentioned residue is a residue of the humanized antibody formed by grafting a composite Chothia-Kabat CDR onto a human acceptor framework in the case of Kabat CDR or CDR-H1, and the second mentioned residue is a residue intended to replace that residue. Therefore, within the variable region framework, the first mentioned residue is human, and within the CDR, the first mentioned residue is mouse.

[0571] The illustrated antibodies include any rearrangement or combination of the illustrated mature heavy chain variable regions and mature light chain variable regions: hu10C12VHv1 / hu10C12VLv1, hu10C12VHv1 / hu10C12VLv2, hu10C12VHv2 / hu10C12VLv1, and hu10C12VHv2 / hu10C12VLv2.

[0572] The illustrated antibodies include any rearrangement or combination of either the illustrated mature light chain variable region hu10C12VLv1 (SEQ ID NO: 216) or hu10C12VLv2 (SEQ ID NO: 217) and either the illustrated mature heavy chain variable region hu10C12VHv1 (SEQ ID NO: 214) or hu10C12VHv2 (SEQ ID NO: 215).

[0573] The present invention provides variants of 10C12 humanized antibodies in which the humanized mature heavy chain variable region exhibits at least 90%, 95%, 96%, 97%, 98%, or 99% identity with hu10C12VHv1 (SEQ ID NO: 214) or hu10C12VHv2 (SEQ ID NO: 215), and the humanized mature light chain variable region exhibits at least 90%, 95%, 96%, 97%, 98%, or 99% identity with hu10C12VLv1 (SEQ ID NO: 216) or hu10C12VLv2 (SEQ ID NO: 217). Some such antibodies retain at least one, two, three, four, five, six, seven, eight, or all nine reverse mutations or other mutations in SEQ ID NOs. 214-215 and SEQ ID NOs. 216-217.

[0574] In some humanized 10C12 antibodies, at least one of the following positions in the VH region is occupied by the indicated amino acids: H24 is occupied by A, H48 by I, H67 by A, H69 by M, H93 by T, and H94 by T. In some humanized 10C12 antibodies, positions H24, H48, H67, H69, H93, and H94 are occupied by A, I, A, M, T, and T, respectively.

[0575] In some humanized 10C12 antibodies, at least one of the following positions in the VH region is occupied by the indicated amino acid: H1 is occupied by Q or E, H24 by A, H48 by I, H67 by A, H69 by M, H93 by T, and H94 by T.

[0576] In some humanized 10C12 antibodies, such as hu10C12VHv1, positions H24, H48, H67, H69, H93, and H94 are occupied by A, I, A, M, T, and T, respectively. In some humanized 10C12 antibodies, such as hu10C12VHv2, positions H1, H24, H48, H67, H69, H93, and H94 are occupied by E, A, I, A, M, T, and T, respectively.

[0577] In some humanized 10C12 antibodies, position L64 in the VL region is occupied by S.

[0578] In some humanized 10C12 antibodies, at least one of the following positions in the VL region is occupied by the indicated amino acid: L64 is S, and L104 is V or L.

[0579] In some humanized 10C12 antibodies, positions L64 and L104 in the VL region are occupied by S, such as in hu10C12VLv1. In some humanized 10C12 antibodies, such as hu10C12VLv2, positions L64 and L104 in the VL region are occupied by S and L, respectively.

[0580] In some humanized 10C12 antibodies, the variable heavy chain exhibits more than 85% identity to the human sequence. In some humanized 10C12 antibodies, the variable light chain exhibits more than 85% identity to the human sequence. In some humanized 10C12 antibodies, the variable heavy chain and variable light chain each exhibit more than 85% identity to the human germline sequence. In some humanized 10C12 antibodies, the three heavy chain CDRs are as defined by the Kabat / Chothia compound (SEQ ID NOs: 8, 9, and 10), and the three light chain CDRs are as defined by the Kabat / Chothia compound (SEQ ID NOs: 12, 13, and 14).

[0581] An example of a humanized antibody is the humanized form of the mouse 12C4 antibody, denoted as Hu12C4.

[0582] The mouse antibody 12C4 contains a mature heavy chain variable region and a mature light chain variable region having amino acid sequences including SEQ ID NO: 219 and SEQ ID NO: 11, respectively. The present invention provides two illustrated humanized mature heavy chain variable regions: hu12C4VHv1 and hu12C4VHv2. Furthermore, the present invention provides two illustrated mature light chain variable regions: hu12C4VLv1 and hu12C4VLv2. Figures 9 and 10 show the alignment of the heavy chain variable region and light chain variable region of mouse 12C4 and various humanized antibodies, respectively.

[0583] For reasons including the possible effects on the conformation of the CDR and / or its binding to the antigen, interactions between the heavy and light chains, mediation of interactions with the constant region, being a site for desirable or undesirable post-translational modifications, being a residue that is rare at its position in the human variable region sequence, thus potentially immunogenic, the possibility of aggregation, and other reasons, the following six variable region framework locations were considered candidate substitutions in two illustrated human mature light chain variable regions and two illustrated human mature light chain variable regions, as further detailed in the Examples: L64(G64S), L104(V104L), H1(Q1E), H48(M48I), H93(A93T), and H94(R94T).

[0584] Here, as in other sections, the first mentioned residue is a residue of the humanized antibody formed by grafting a composite Chothia-Kabat CDR onto a human acceptor framework in the case of Kabat CDR or CDR-H1, and the second mentioned residue is a residue intended to replace that residue. Therefore, within the variable region framework, the first mentioned residue is human, and within the CDR, the first mentioned residue is mouse.

[0585] The exemplified antibodies include any rearrangement or combination of the exemplified mature heavy chain variable regions and mature light chain variable regions: hu12C4VHv1 / hu12C4VLv1, hu12C4VHv1 / hu12C4VLv2, hu12C4VHv2 / hu12C4VLv1, and hu12C4VHv2 / hu12C4VLv2.

[0586] The illustrated antibodies include a rearrangement or combination of either the illustrated mature light chain variable region hu12C4VLv1 (SEQ ID NO: 223) or hu12C4VLv2 (SEQ ID NO: 224) and either the illustrated mature heavy chain variable region hu12C4VHv1 (SEQ ID NO: 221) or hu12C4VHv2 (SEQ ID NO: 222).

[0587] The present invention provides variants of 12C4 humanized antibodies in which the humanized mature heavy chain variable region exhibits at least 90%, 95%, 96%, 97%, 98%, or 99% identity with hu12C4VHv1 (SEQ ID NO: 221) or hu12C4VHv2 (SEQ ID NO: 222), and the humanized mature light chain variable region exhibits at least 90%, 95%, 96%, 97%, 98%, or 99% identity with hu12C4VLv1 (SEQ ID NO: 223) or hu12C4VLv2 (SEQ ID NO: 224). Some such antibodies retain at least one, two, three, four, five, or all of the reverse mutations or other mutations in SEQ ID NOs. 221-222 and SEQ ID NOs. 223-224.

[0588] In some humanized 12C4 antibodies, at least one of the following positions in the VH region is occupied by the indicated amino acid: H1 is occupied by Q or E, H48 by M or I, H93 by A or T, and H94 by R or T.

[0589] In some humanized 12C4 antibodies, such as hu12C4VHv2, the positions H1, H48, H93, and H94 in the VH region are occupied by E, I, T, and T, respectively.

[0590] In some humanized 12C4 antibodies, at least one of the following positions in the VL region is occupied by the indicated amino acid: L64 is G or S, and L104 is V or L.

[0591] In some humanized 12C4 antibodies, such as hu12C4VLv2, the positions L64 and L104 in the VL region are occupied by S and L, respectively.

[0592] In some humanized 12C4 antibodies, the variable heavy chain exhibits more than 85% identity to the human sequence. In some humanized 12C4 antibodies, the variable light chain exhibits more than 85% identity to the human sequence. In some humanized 12C4 antibodies, the variable heavy chain and variable light chain each exhibit more than 85% identity to the human germline sequence. In some humanized 12C4 antibodies, the three heavy chain CDRs are as defined by the Kabat / Chothia compound (SEQ ID NOs. 8, 220, and 10), and the three light chain CDRs are as defined by the eKabat / Chothia compound (SEQ ID NOs. 12, 13, and 14).

[0593] The exemplary humanized antibody is a humanized form of mouse 17C12, denoted as Hu17C12.

[0594] The mouse antibody 17C12 contains a mature heavy chain variable region and a mature light chain variable region having amino acid sequences including SEQ ID NOs. 225 and 228, respectively. The present invention provides two illustrated humanized mature heavy chain variable regions: hu17C12VHv and hu17C12VHv2. Furthermore, the present invention provides two illustrated mature light chain variable regions: hu17C12VLv1 and hu17C12VLv2. Figures 11 and 12 show the alignment of the heavy chain variable region and light chain variable region of mouse 17C12 and various humanized antibodies, respectively.

[0595] For reasons such as the possible effects on the three-dimensional structure of the CDR and / or its binding to the antigen, the interaction between the heavy and light chains, the mediation of interactions with the constant region, the presence of desirable or undesirable post-translational modifications, the presence of residues that are rare at that position in the human variable region sequence, thus potentially immunogenic, the possibility of aggregation, and other reasons, the position of the following 13 variable region frameworks is further considered in the examples. As detailed, two exemplified human mature light chain variable regions and two exemplified human mature light chain variable regions were considered candidate substitutions: L2(I2V), L36(Y36L), L43(P43S), H1(Q1E), H2(V2I), H24(V24A), H48(M48I), H67(V67A), H69(I69M), H93(A93T), H94(R94T), H108(T108L), and H113(R113S).

[0596] Here, as in other sections, the first mentioned residue is a residue of the humanized antibody formed by grafting a composite Chothia-Kabat CDR onto a human acceptor framework in the case of Kabat CDR or CDR-H1, and the second mentioned residue is a residue intended to replace that residue. Therefore, within the variable region framework, the first mentioned residue is human, and within the CDR, the first mentioned residue is mouse.

[0597] The exemplified antibodies include any rearrangement or combination of the exemplified mature heavy chain variable regions and mature light chain variable regions: hu17C12VHv1 / hu17C12VLv1, hu17C12VHv1 / hu17C12VLv2, hu17C12VHv2 / hu17C12VLv1, and hu17C12VHv2 / hu17C12VLv2.

[0598] The illustrated antibodies include any rearrangement or combination of either the illustrated mature light chain variable region hu17C12VLv1 (SEQ ID NO: 234) or hu17C12VLv2 (SEQ ID NO: 235) and either the illustrated mature heavy chain variable region hu17C12VHv1 (SEQ ID NO: 232) or hu17C12VHv2 (SEQ ID NO: 233).

[0599] The present invention provides variants of 17C12 humanized antibodies in which the humanized mature heavy chain variable region exhibits at least 90%, 95%, 96%, 97%, 98%, or 99% identity with hu17C12VHv1 (SEQ ID NO: 232) or hu17C12VHv2 (SEQ ID NO: 233), and the humanized mature light chain variable region exhibits at least 90%, 95%, 96%, 97%, 98%, or 99% identity with hu17C12VLv1 (SEQ ID NO: 234) or hu17C12VLv2 (SEQ ID NO: 235). In some such antibodies, at least one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or all thirteen reverse mutations or other mutations are retained in SEQ ID NOs. 232-233 and SEQ ID NOs. 234-235.

[0600] In some humanized 17C12 antibodies, at least one of the following positions in the VH region is occupied by the indicated amino acids: H2 is occupied by I, H24 by A, H48 by I, H67 by A, H69 by M, H93 by T, and H94 by T. In some humanized 17C12 antibodies, positions H2, H24, H48, H67, H69, H93, and H94 are occupied by E, A, I, A, M, T, and T, respectively.

[0601] In some humanized 17C12 antibodies, at least one of the following positions in the VH region is occupied by the indicated amino acid: H1 is occupied by Q or E, H2 by I, H24 by A, H48 by I, H67 by A, H69 by M, H93 by T, H94 by T, H108 by T or L, and H113 by R or S.

[0602] In some humanized 17C12 antibodies, such as hu17C12VHv1, the positions H2, H24, H48, H67, H69, H93, and H94 in the VH region are occupied by E, A, I, A, M, T, and T, respectively. In some humanized 17C12 antibodies, such as hu17C12VHv2, the positions H1, H2, H24, H48, H67, H69, H93, H94, H108, and H113 in the VH region are occupied by E, I, A, I, A, M, T, T, L, and S, respectively.

[0603] In some humanized 17C12 antibodies, at least one of the following positions in the VL region is occupied by the indicated amino acid: L2 is occupied by V, and L36 is occupied by L. In some humanized 17C12 antibodies, positions L2 and L36 are occupied by V and L, respectively.

[0604] In some humanized 17C12 antibodies, at least one of the following positions in the VL region is occupied by the indicated amino acid: L2 is V, L36 is L, and L43 is P or S.

[0605] In some humanized 17C12 antibodies, such as hu17C12VLv1, positions L2 and L36 in the VL region are occupied by V and L, respectively. In some humanized 17C12 antibodies, such as hu17C12VLv2, positions L2, L36, and L43 in the VL region are occupied by V, L, and S, respectively.

[0606] In some humanized 17C12 antibodies, the variable heavy chain exhibits more than 85% identity to the human sequence. In some humanized 17C12 antibodies, the variable...

Claims

1. A humanized antibody or antigen-binding antibody fragment that binds to human tau, It comprises a humanized mature heavy chain variable region containing three heavy chain CDRs of the mouse antibody, and a humanized mature light chain variable region containing three light chain CDRs of the mouse antibody, The mouse antibody is characterized by a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region having the amino acid sequence of SEQ ID NO:

11. The humanized mature heavy chain variable region has an amino acid sequence that is at least 90% identical to any one of SEQ ID NOs: 15-20 and SEQ ID NOs: 109-129, and the humanized mature light chain variable region has an amino acid sequence that is at least 90% identical to any one of SEQ ID NOs: 23-29, SEQ ID NOs: 61-108, and SEQ ID NOs: 130-171. (i) Kabat positions H1, H5, H11, H12, H17, H20, H23, H38, H42, H43, H66, H69, H75, H80, H81, H83, H93, H94, H108, and H109 are occupied by E, V, V, K, T, I, K, Q, G, K, R, M, T, M, E, R, T, T, L, and V, respectively, or Kabat positions H1, H5, H11, H12, H17, H20, H23, H38, H42, H43, H66, H69, H75, H80, H81, H83, H93, H94, H108, and H109 are occupied by E, V, V, K, T, I, K, K, E, K, R, M, T, M, E, R, T, T, L, and V, respectively, and / or (ii) Kabat positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, Q, G, R, and I, respectively. Kabat positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, Q, G, T, and I, respectively. Kabat positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, G, Q, G, R, and I, respectively. Kabat positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, D, Q, G, R, and I, respectively. Kabat positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, D, Q, K, R, and I, respectively. Kabat positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, G, Q, K, R, and I, respectively. Kabat positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, G, G, G, R, and I, respectively. Kabat positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, G, G, G, R, and G, respectively. Kabat positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, G, G, G, T, and I, respectively. Kabat positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, G, G, T, and I, respectively. Kabat positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, D, G, G, R, and I, respectively. Kabat positions L3, L37, L51, L54, and L92 are occupied by Q, Q, G, R, and I, respectively. Kabat positions L3, L27c, L51, L54, and L92 are occupied by Q, S, G, R, and I, respectively. Kabat positions L3, L27c, L37, L54, and L92 are occupied by Q, S, Q, R, and I, respectively, or Kabat positions L3, L27c, L37, L51, and L92 are occupied by Q, S, Q, G, and I, respectively. Humanized antibody or antigen-binding antibody fragment.

2. The humanized antibody or antigen-binding antibody fragment according to Claim 1, wherein Kabat positions H1, H5, H11, H12, H17, H20, H23, H38, H42, H43, H66, H69, H75, H80, H81, H83, H93, H94, H108, and H109 are occupied by E, V, V, K, T, I, K, Q, G, K, R, M, T, M, E, R, T, T, L, and V, respectively.

3. The humanized antibody or antigen-binding antibody fragment according to Claim 1, wherein Kabat positions H1, H5, H11, H12, H17, H20, H23, H38, H42, H43, H66, H69, H75, H80, H81, H83, H93, H94, H108, and H109 are occupied by E, V, V, K, T, I, K, K, E, K, R, M, T, M, E, R, T, T, L, and V, respectively.

4. The humanized antibody or antigen-binding antibody fragment according to any one of claims 1 to 3, wherein the Kabat positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, Q, G, R, and I, respectively.

5. The humanized antibody or antigen-binding antibody fragment according to any one of claims 1 to 3, wherein the Kabat positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, Q, G, T, and I, respectively.

6. The humanized antibody or antigen-binding antibody fragment according to any one of claims 1 to 3, wherein the Kabat positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, G, Q, G, R, and I, respectively.

7. The humanized antibody or antigen-binding antibody fragment according to any one of claims 1 to 3, wherein the Kabat positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, D, Q, G, R, and I, respectively.

8. The humanized antibody or antigen-binding antibody fragment according to any one of claims 1 to 3, wherein the Kabat positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, D, Q, K, R, and I, respectively.

9. The humanized antibody or antigen-binding antibody fragment according to any one of claims 1 to 3, wherein the Kabat positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, G, Q, K, R, and I, respectively.

10. The humanized antibody or antigen-binding antibody fragment according to any one of claims 1 to 3, wherein the Kabat positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, G, G, G, R, and I, respectively.

11. The humanized antibody or antigen-binding antibody fragment according to any one of claims 1 to 3, wherein the Kabat positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, G, G, G, R, and G, respectively.

12. The humanized antibody or antigen-binding antibody fragment according to any one of claims 1 to 3, wherein the Kabat positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, G, G, G, T, and I, respectively.

13. The humanized antibody or antigen-binding antibody fragment according to any one of claims 1 to 3, wherein the Kabat positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, S, G, G, T, and I, respectively.

14. The humanized antibody or antigen-binding antibody fragment according to any one of claims 1 to 3, wherein the Kabat positions L3, L27c, L37, L51, L54, and L92 are occupied by Q, D, G, G, R, and I, respectively.

15. The humanized antibody or antigen-binding antibody fragment according to any one of claims 1 to 3, wherein the Kabat positions L3, L37, L51, L54, and L92 are occupied by Q, Q, G, R, and I, respectively.

16. The humanized antibody or antigen-binding antibody fragment according to any one of claims 1 to 3, wherein the Kabat positions L3, L27c, L51, L54, and L92 are occupied by Q, S, G, R, and I, respectively.

17. The humanized antibody or antigen-binding antibody fragment according to any one of claims 1 to 3, wherein the Kabat positions L3, L27c, L37, L54, and L92 are occupied by Q, S, Q, R, and I, respectively.

18. The humanized antibody or antigen-binding antibody fragment according to any one of claims 1 to 3, wherein the Kabat positions L3, L27c, L37, L51, and L92 are occupied by Q, S, Q, G, and I, respectively.

19. A humanized antibody or antigen-binding antibody fragment according to any one of claims 1 to 18, wherein the humanized antibody is the humanized antibody according to any one of claims 1 to 18.

20. A humanized antibody or antigen-binding antibody fragment according to any one of claims 1 to 18, which is a humanized antigen-binding antibody fragment.

21. The humanized antibody or antigen-binding antibody fragment according to claim 19, wherein the humanized antibody has the isotype of human IgG1.

22. The humanized antibody or antigen-binding antibody fragment according to any one of claims 1 to 19 and 21, wherein the mature light chain variable region is fused to the light chain constant region, and the mature heavy chain variable region is fused to the heavy chain constant region.

23. The humanized antibody or antigen-binding antibody fragment according to claim 22, wherein the heavy chain constant region is a mutant of the natural human heavy chain constant region having reduced binding to the Fcγ receptor compared to the natural human heavy chain constant region.

24. The humanized antibody or antigen-binding antibody fragment according to claim 19, wherein the humanized antibody has a human IgG2 or IgG4 isotype.

25. A pharmaceutical composition comprising a humanized antibody or antigen-binding antibody fragment according to any one of claims 1 to 24 and a pharmaceutically acceptable carrier.

26. A nucleic acid encoding the heavy chain and light chain of a humanized antibody according to any one of claims 1 to 19 and 21 to 24.

27. ​​The pharmaceutical composition according to claim 25 for use in a method for inhibiting or reducing tau aggregation in subjects having or at risk of developing tau-mediated amyloidosis.

28. The pharmaceutical composition according to claim 25 for use in a method for treating or preventing tau-related diseases in a subject.

29. The tau-related disease is Alzheimer's disease, Down syndrome, mild cognitive impairment, primary age-related tauopathy, post-encephalitis parkinsonism, post-traumatic dementia or boxer's dementia, Pick's disease, Niemann-Pick disease type C, supranuclear palsy, frontotemporal dementia, frontotemporal lobar degeneration, argyrophilic granulopathy, GGT (globular glial tauopathy), Guam amyotrophic lateral sclerosis / parkinsonian dementia complex, corticobasal degeneration (CBD), Lewy body dementia, Lewy body variant of Alzheimer's disease (LBVAD), chronic traumatic encephalopathy (CTE), GGT (globular glial A pharmaceutical composition for use according to claim 28, which is tauopathy, Parkinson's disease, or progressive supranuclear palsy (PSP).

30. The pharmaceutical composition according to claim 25 for use in a method for detecting tau protein deposition in subjects having or at risk of a disease related to tau aggregation or deposition.

Images