Antibodies recognizing 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-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 62 / 803,334, filed February 8, 2019, U.S. Provisional Patent Application No. 62 / 813,124, filed March 3, 2019, and U.S. Provisional Patent Application No. 62 / 855,434, filed May 31, 2019, each of which is incorporated by reference in its entirety for all purposes.

[0002] A reference to a sequence list The sequence listing in file 2020_02_07_542496WO_SEQLST.txt is 3560 kb, 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 phosphorylated forms (see, e.g., 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 non-phosphorylated forms) and phosphotau (p-tau, i.e., phosphorylated tau) are released by the brain in response to neuronal 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, which, along with plaques, are a hallmark of Alzheimer's disease. These tangles consist of abnormal fibrils measuring 10 nm in diameter, arranged in a paired helix with a regular period of 80 nm. Tau in neurofibrillary tangles is abnormally phosphorylated (hyperphosphorylated), with phosphate groups attached to specific sites on the molecule. In Alzheimer's disease, significant involvement of neurofibrillary tangles is observed in layer II neurons of the entorhinal cortex, the CA1 and subiculum regions of the hippocampus, the amygdala, and deeper layers of the neocortex (layers III, V, and superficial layer VI). Hyperphosphorylated tau has also been reported to interfere with microtubule assembly, which may promote the breakdown of neuronal networks.

[0005] Tau inclusions are part of the defining neuropathology of several neurodegenerative diseases, including Alzheimer's disease, frontotemporal lobar degeneration, progressive supranuclear palsy, and Pick's disease. Summary of the Invention

[0006] In one aspect, 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 comprising SEQ ID NO: 10. In some such antibodies, the heavy chain CDR-H1 has an amino acid sequence comprising SEQ ID NO: 8. In some such antibodies, the light chain CDRs CDR-L1, CDR-L2, and CDR-L3 have amino acid sequences comprising SEQ ID NOs: 12, 13, and 14, respectively. In some such antibodies, the heavy chain CDR-H1 has an amino acid sequence comprising SEQ ID NO: 8. Some such antibodies bind to the same epitope on human tau as 9F5.

[0007] Some such antibodies comprise the three light chain CDRs and three heavy chain CDRs of monoclonal antibody 9F5, a murine antibody characterized by a heavy chain variable region having an amino acid sequence comprising SEQ ID NO:7 and a light chain variable region having an amino acid sequence comprising 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 combination, except that N or T may occupy position H28, I or V may occupy position H51, N or D may occupy position H54, and D or E may occupy position H56 (SEQ ID NOs: 8, 9, and 10, respectively); and the three light chain CDRs, CDR-L1, CDR-L2, and CDR-L3, are as defined by the Kabat / Chothia combination, except that N or T may occupy position H28, I or V may occupy position H51, N or D may occupy position H54, and D or E may occupy position H56 (SEQ ID NOs: 8, 9, and 10, respectively). and L92 and L93 are as defined by the Kabat / Chothia complex, except that 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 (SEQ ID NOs: 12, 13, and 14, respectively).

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

[0010] Some antibodies are 9F5 or chimeric, veneered, or humanized forms thereof. In some antibodies, the variable heavy chain has 85% or more identity to a human sequence. In some antibodies, the variable light chain has 85% or more identity to a human sequence. In some antibodies, the variable heavy chain and variable light chain each have 85% or more identity to a 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 murine antibody characterized by a mature heavy chain variable region of SEQ ID NO: 7 and a mature light chain variable region of SEQ ID NO: 11. Some antibodies comprise a humanized mature heavy chain variable region comprising the three heavy chain CDRs of 9F5 and a humanized mature light chain variable region comprising the three light chain CDRs of 9F5. In some antibodies, the CDRs are defined CDRs selected from the group consisting of Kabat, Chothia, Kabat / Chothia combined, AbM, and Contact.

[0012] In some antibodies, the humanized mature heavy chain variable region comprises the three Kabat / Chothia composite heavy chain CDRs of 9F5 (SEQ ID NOs:8-10), and the humanized mature light chain variable region comprises the three Kabat / Chothia composite light chain CDRs of 9F5 (SEQ ID NOs:12-14). In some antibodies, the humanized mature heavy chain variable region comprises the three Kabat heavy chain CDRs of 9F5 (SEQ ID NOs:40, 9, and 10), and the humanized mature light chain variable region comprises the three Kabat light chain CDRs of 9F5 (SEQ ID NOs:12-14). In some antibodies, the humanized mature heavy chain variable region comprises the three Chothia heavy chain CDRs of 9F5 (SEQ ID NOs:41, 42, and 10), and the humanized mature light chain variable region comprises the three Chothia light chain CDRs of 9F5 (SEQ ID NOs:12-14). In some antibodies, the humanized mature heavy chain variable region comprises the three AbM heavy chain CDRs of 9F5 (SEQ ID NO:8, SEQ ID NO:43, and SEQ ID NO:10), and the humanized mature light chain variable region comprises the three AbM light chain CDRs of 9F5 (SEQ ID NO:12-14). In some antibodies, the humanized mature heavy chain variable region comprises the three Contact heavy chain CDRs of 9F5 (SEQ ID NO:44-46), and the humanized mature light chain variable region comprises the three Contact light chain CDRs of 9F5 (SEQ ID NO:47-49).

[0013] For example, the antibody is a humanized antibody, a veneered antibody, or a chimeric antibody.

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

[0015] 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 E, H17 is occupied by T, H20 is occupied by I, H69 is occupied by M, H75 is occupied by T, H93 is occupied by T, H94 is occupied by T, and H109 is occupied 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 is occupied by V, H76 is occupied by D, M80 is occupied by M, and H108 is occupied 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, position H28 of the VH region is occupied by a 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, position H40 of the VH region is occupied by an 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 is occupied by V, H12 is occupied by K, H38 is occupied by R, and H42 is occupied 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 indicated amino acid: H1 is occupied by Q or E, H5 is occupied by Q or V, H11 is occupied by L or V, H12 is occupied by V or K, H17 is occupied by S or T, H20 is occupied by L or I, H23 is occupied by T or K, H28 is occupied by N or T, H38 is occupied by K, R, or Q, H40 is occupied by R or A, H42 is occupied by E or G, H43 is occupied by Q or K, H48 is occupied by I or M, H51 is occupied by I or V, H54 is occupied by N or D, and 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, 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, 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, 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, positions H1, H17, H20, H23, H28, H43, H51, H54, H56, H66, H69, H75, H76, H80, H81, H83, H93, H94, H108, and H109 of 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, positions H1, H17, H20, H23, H28, H40, H43, H48, H51, H54, H56, H66, H69, H75, H76, H80, H81, H83, H93, H94, H108, and H109 of 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, 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 of 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, 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 of 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, positions H1, H5, H11, H12, H17, H20, H23, H38, H42, H43, H66, H69, H75, H80, H81, H83, H93, H94, H108, and H109 of 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 comprises the amino acid sequence of SEQ ID NO: 127.

[0026] In some antibodies, positions H1, H5, H11, H12, H17, H20, H23, H38, H42, H43, H66, H69, H75, H80, H81, H83, H93, H94, H108, and H109 of 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 comprises the amino acid sequence of SEQ ID NO: 128.

[0027] In some antibodies, positions H1, H5, H11, H12, H17, H20, H23, H38, H42, H43, H66, H69, H75, H80, H81, H82c, H83, H93, H94, H108, and H109 of 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 is occupied by P, L15 is occupied by P, and L100 is occupied 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 of the VL region is occupied by G. In some antibodies, position L64 of the VL region is occupied by S.

[0032] In some antibodies, position L17 of 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 of 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 indicated amino acid: 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 or or K, 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 comprises the amino acid sequence of any of SEQ ID NOs: 133, 135-137, 142-144, 149, 158, 159, and 168. In some antibodies, the light chain variable region comprises the amino acid sequence of SEQ ID NO: 133. In some antibodies, the light chain variable region comprises the amino acid sequence of SEQ ID NO: 137. In some antibodies, the light chain variable region comprises the amino acid sequence of SEQ ID NO: 149. In some antibodies, the light chain variable region comprises the amino acid sequence of SEQ ID NO: 159.

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

[0038] In some antibodies, positions L7, L8, L11, L15, L17, L39, L60, L64, L66, L74, and L100 in the VL region are occupied by S, P, L, P, E, K, N, S, G, K, and Q, respectively. In some antibodies, position L3 in the VL region is occupied by Q. In some antibodies, position L27c in the VL region is occupied by D, G, I, L, or S, position L37 in the VL region is occupied by G, I, L, or Q, position L51 in the VL region is occupied by E, G, I, K, or M, position L54 in the VL region is occupied by G, L, R, or T, and position L92 in the VL region 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 of the VL region is occupied by D, position L37 of the VL region is occupied by G, and position L51 of the VL region is occupied by G. In some antibodies, the heavy chain variable region has an amino acid sequence comprising SEQ ID NO: 127, and the light chain variable region has an amino acid sequence comprising SEQ ID NO: 149.

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

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

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

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

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

[0045] In some antibodies, position L27c of the VL region is occupied by G, position L37 of the VL region is occupied by G, position L51 of the VL region is occupied by G, and position L54 of the VL region is occupied by R. In some antibodies, position L92 of the VL region is occupied by I. In some antibodies, the heavy chain variable region has an amino acid sequence comprising SEQ ID NO: 129, and the light chain variable region has an amino acid sequence comprising 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 provided in 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 provided in 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 provided in 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, positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, G, G, and I, respectively. In some antibodies, positions L3Q, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, G, R, and I. In some antibodies, positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, G, T, and I, respectively. In some antibodies, positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, G, R, and G, respectively. In some antibodies, positions L3, L27c, L37, L51, L54, and L92 of the VL region are occupied by Q, G, Q, G, R, and I, respectively.

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

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

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

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

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

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

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

[0059] Some antibodies comprise a mature heavy chain variable region having an amino acid sequence at least 95% identical to any one of SEQ ID NOs: 15 to 22 and 109 to 129, and a mature light chain variable region having an amino acid sequence at least 95% identical to any one of SEQ ID NOs: 23 to 29, 61 to 108, and 130 to 171. Some antibodies comprise a mature heavy chain variable region having an amino acid sequence at least 98% identical to any one of SEQ ID NOs: 15 to 22 and 109 to 129, and a mature light chain variable region having an amino acid sequence at least 98% identical to any one of SEQ ID NOs: 23 to 29, 61 to 108, and 130 to 171. In some antibodies, the mature heavy chain variable region has the amino acid sequence of any one of SEQ ID NOs: 15 to 22 and 109 to 129, and the mature light chain variable region has the amino acid sequence of any one of SEQ ID NOs: 23 to 29, 61 to 108, and 130 to 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 comprise the three light chain CDRs and three heavy chain CDRs of monoclonal antibody 10C12, a murine antibody characterized by a heavy chain variable region having an amino acid sequence comprising SEQ ID NO:7 and a light chain variable region having an amino acid sequence comprising SEQ ID NO:11.

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

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

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

[0076] In some antibodies, the humanized mature heavy chain variable region comprises the three Kabat / Chothia composite heavy chain CDRs of 10C12 (SEQ ID NOs:8-10), and the humanized mature light chain variable region comprises the three Kabat / Chothia composite light chain CDRs of 10C12 (SEQ ID NOs:12-14). In some antibodies, the humanized mature heavy chain variable region comprises the three Kabat heavy chain CDRs of 10C12 (SEQ ID NOs:40, 9, and 10), and the humanized mature light chain variable region comprises the three Kabat light chain CDRs of 10C12 (SEQ ID NOs:12-14). In some antibodies, the humanized mature heavy chain variable region comprises the three Chothia heavy chain CDRs of 10C12 (SEQ ID NOs:41, 42, and 10), and the humanized mature light chain variable region comprises the three Chothia light chain CDRs of 10C12 (SEQ ID NOs:12-14). In some antibodies, the humanized mature heavy chain variable region comprises the three AbM heavy chain CDRs of 10C12 (SEQ ID NO:8, SEQ ID NO:43, and SEQ ID NO:10), and the humanized mature light chain variable region comprises the three AbM light chain CDRs of 10C12 (SEQ ID NO:12-14). In some antibodies, the humanized mature heavy chain variable region comprises the three Contact heavy chain CDRs of 10C12 (SEQ ID NO:44-46), and the humanized mature light chain variable region comprises the three Contact light chain CDRs of 10C12 (SEQ ID NO:47-49).

[0077] For example, the antibody can be a humanized antibody, a veneered antibody, or a chimeric antibody.

[0078] Some such antibodies comprise a humanized mature heavy chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs: 214-215, and a humanized mature light chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs: 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 is occupied by I, H67 is occupied by A, H69 is occupied by M, H93 is occupied by T, and H94 is occupied 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 is occupied by A, H48 is occupied by I, H67 is occupied by A, H69 is occupied by M, H93 is occupied by T, and H94 is occupied 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 an 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 comprise a mature heavy chain variable region having an amino acid sequence at least 95% identical to any one of SEQ ID NOs: 214 to 215, and a mature light chain variable region having an amino acid sequence at least 95% identical to any one of SEQ ID NOs: 216 to 217. Some antibodies comprise a mature heavy chain variable region having an amino acid sequence at least 98% identical to any one of SEQ ID NOs: 214 to 215, and a mature light chain variable region having an amino acid sequence at least 98% identical to any one of SEQ ID NOs: 216 to 217. In some antibodies, the mature heavy chain variable region has the amino acid sequence of any one of SEQ ID NOs: 214 to 215, and the mature light chain variable region has the amino acid sequence of any one of SEQ ID NOs: 216 to 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 comprise the three light chain CDRs and three heavy chain CDRs of monoclonal antibody 12C4, a murine antibody characterized by a heavy chain variable region having an amino acid sequence comprising SEQ ID NO: 219 and a light chain variable region having an amino acid sequence comprising SEQ ID NO: 11.

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

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

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

[0090] In some antibodies, the humanized mature heavy chain variable region comprises the three Kabat / Chothia composite heavy chain CDRs of 12C4 (SEQ ID NOs:8, 220, and 10), and the humanized mature light chain variable region comprises the three Kabat / Chothia composite light chain CDRs of 12C4 (SEQ ID NOs:12-14). In some antibodies, the humanized mature heavy chain variable region comprises the three Kabat heavy chain CDRs of 12C4 (SEQ ID NOs:40, 220, and 10), and the humanized mature light chain variable region comprises the three Kabat light chain CDRs of 12C4. In some antibodies, the humanized mature heavy chain variable region comprises the three Chothia heavy chain CDRs of 12C4 (SEQ ID NOs:41, 42, and 10), and the humanized mature light chain variable region comprises the three Chothia light chain CDRs of 12C4 (SEQ ID NOs:12-14). In some antibodies, the humanized mature heavy chain variable region comprises the three AbM heavy chain CDRs of 12C4 (SEQ ID NO:8, SEQ ID NO:257, and SEQ ID NO:10), and the humanized mature light chain variable region comprises the three AbM light chain CDRs of 12C4 (SEQ ID NOs:12-14). In some antibodies, the humanized mature heavy chain variable region comprises the three Contact heavy chain CDRs of 12C4 (SEQ ID NOs:44, 258, and 46), and the humanized mature light chain variable region comprises the three Contact light chain CDRs of 12C4 (SEQ ID NOs:47-49).

[0091] For example, the antibody can be a humanized antibody, a veneered antibody, or a chimeric antibody.

[0092] Some such antibodies comprise a humanized mature heavy chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs: 221-222, and a humanized mature light chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs: 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 is occupied by M or I, H93 is occupied by A or T, and H94 is occupied 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 positions are occupied by the indicated amino acids: L64 is G or S, and L104 is V or L. In some antibodies, VL region positions L64 and L104 are occupied by S and L, respectively.

[0095] Some antibodies comprise a mature heavy chain variable region having an amino acid sequence at least 95% identical to any one of SEQ ID NOs: 221 to 222, and a mature light chain variable region having an amino acid sequence at least 95% identical to any one of SEQ ID NOs: 223 to 224. Some antibodies comprise a mature heavy chain variable region having an amino acid sequence at least 98% identical to any one of SEQ ID NOs: 221 to 222, and a mature light chain variable region having an amino acid sequence at least 98% identical to any one of SEQ ID NOs: 223 to 224. In some antibodies, the mature heavy chain variable region has the amino acid sequence of any one of SEQ ID NOs: 221 to 222, and the mature light chain variable region has the amino acid sequence of any one of SEQ ID NOs: 223 to 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 comprise the three light chain CDRs and three heavy chain CDRs of monoclonal antibody 17C12, a murine antibody characterized by a heavy chain variable region having an amino acid sequence comprising SEQ ID NO: 225 and a light chain variable region having an amino acid sequence comprising SEQ ID NO: 228.

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

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

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

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

[0102] For example, the antibody can be a humanized antibody, a veneered antibody, or a chimeric antibody.

[0103] Some such antibodies comprise a humanized mature heavy chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs: 232-233, and a humanized mature light chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs: 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 is occupied by A, H48 is occupied by I, H67 is occupied by A, H69 is occupied by M, H93 is occupied by T, and H94 is occupied 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 is occupied by I, H24 is occupied by A, H48 is occupied by I, H67 is occupied by A, H69 is occupied by M, H93 is occupied by T, H94 is occupied by T, H108 is occupied by T or L, and H113 is occupied by R or S. In some antibodies, VH region positions H2, H24, H48, H67, H69, H93, and H94 are occupied by E, A, I, A, M, T, and T, respectively. In some antibodies, positions H1, H2, H24, H48, H67, H69, H93, H94, H108, and H113 of 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 36 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 comprise a mature heavy chain variable region having an amino acid sequence at least 95% identical to any one of SEQ ID NOs: 232 to 233, and a mature light chain variable region having an amino acid sequence at least 95% identical to any one of SEQ ID NOs: 234 to 235. Some antibodies comprise a mature heavy chain variable region having an amino acid sequence at least 98% identical to any one of SEQ ID NOs: 232 to 233, and a mature light chain variable region having an amino acid sequence at least 98% identical to any one of SEQ ID NOs: 234 to 235. In some antibodies, the mature heavy chain variable region has the amino acid sequence of any one of SEQ ID NOs: 232 to 233, and the mature light chain variable region has the amino acid sequence of any one of SEQ ID NOs: 234 to 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 comprise the three light chain CDRs and three heavy chain CDRs of monoclonal antibody 14H3, a murine antibody characterized by a heavy chain variable region having an amino acid sequence comprising SEQ ID NO: 240 and a light chain variable region having an amino acid sequence comprising 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 composite (SEQ ID NOs: 241, 242, and 243, respectively), except that G or S can occupy position H35B, and the three light chain CDRs, CDR-L1, CDR-L2, and CDR-L3, are as defined by the Kabat / Chothia composite (SEQ ID NOs: 245, 246, and 247, respectively). In some antibodies, CDR-H1 has an amino acid sequence comprising SEQ ID NO: 277.

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

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

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

[0115] For example, the antibody can be a humanized antibody, a veneered antibody, or a chimeric antibody.

[0116] Some such antibodies comprise a humanized mature heavy chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs: 248-249, and a humanized mature light chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs: 250-251.

[0117] In some antibodies, position H35B in the VH region is occupied by an 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 is occupied by M or L, and H113 is occupied by L or S. In some antibodies, position H35B in the VH region is occupied by S. In some antibodies, 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 comprise a mature heavy chain variable region having an amino acid sequence at least 95% identical to any one of SEQ ID NOs: 248 to 249, and a mature light chain variable region having an amino acid sequence at least 95% identical to any one of SEQ ID NOs: 250 to 251. Some antibodies comprise a mature heavy chain variable region having an amino acid sequence at least 98% identical to any one of SEQ ID NOs: 248 to 249, and a mature light chain variable region having an amino acid sequence at least 98% identical to any one of SEQ ID NOs: 250 to 251. In some antibodies, the mature heavy chain variable region has the amino acid sequence of any one of SEQ ID NOs: 248 to 249, and the mature light chain variable region has the amino acid sequence of any one of SEQ ID NOs: 250 to 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, the antibody can be a chimeric antibody, e.g., the antibody can be a veneered antibody.

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

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

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

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

[0128] In another aspect, the present invention provides vectors comprising nucleic acids encoding mature heavy and light chain variable regions operably linked to one or more control sequences that affect the expression of any of the antibodies disclosed herein in mammalian cells, recombinant expression vectors comprising the nucleic acids, host cells transformed with the recombinant expression vectors, and host cells transformed with the nucleic acids. 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, the one or more control sequences comprise 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 and light chain variable regions. In some vectors, the nucleic acid is codon-optimized for expression in a host cell. In some vectors, the one or more control sequences comprise a eukaryotic promoter. In some vectors, the nucleic acid further encodes a selectable gene.

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

[0130] In yet another aspect, the invention provides a first vector and a second vector comprising nucleic acids encoding a mature heavy chain variable region and a mature light chain variable region, respectively, each operably linked to one or more control sequences for affecting the expression in a mammalian cell of any of the antibodies disclosed herein, and a host cell comprising the nucleic acids. In some first and second vectors, the nucleic acid further encodes 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, respectively.

[0131] In yet another aspect, the invention provides a method of expressing an antibody in a mammalian cell, comprising the step of expressing said antibody by incorporating any of the nucleic acids disclosed herein into the genome of a transgenic animal.

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

[0133] Also provided are methods for producing humanized, chimeric, or veneered antibodies, such as humanized, chimeric, or veneered forms of 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3. In such methods, cells transformed with nucleic acids encoding the antibody heavy and light chains are cultured so that the cells secrete the antibody, which can then be purified from the cell culture medium.

[0134] A cell line producing any of the antibodies disclosed herein can be produced by introducing into cells a vector encoding the antibody heavy and light chains and a selectable marker, growing the cells under conditions to select for cells with increased vector copy number, isolating a single cell from the selected cells, and depositing the cloned cells from the selected single cell based on antibody yield.

[0135] Some cells can grow under selective conditions and are at least 100 mg / L / 10 6 Cell lines can be screened for that naturally express and secrete the antibody at 1000 cells / 24 h. Single cells can be isolated from the selected cells. Cells cloned from the single cells can then be deposited. Single cells can be selected based on desirable properties, such as antibody yield. Exemplary cell lines are those that express 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3.

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

[0137] Also provided are methods of treating or effecting prevention of a tau-associated disease in a subject, comprising administering an effective regimen of an antibody disclosed herein to treat or effect prevention of the disease. Examples of such diseases include Alzheimer's disease, Down's syndrome, mild cognitive impairment, primary age-related tauopathy, postencephalitic parkinsonism, posttraumatic dementia or dementia pugilistica, Pick's disease, Niemann-Pick type C disease, supranuclear palsy, frontotemporal dementia, frontotemporal lobar degeneration, argyrophilic grain disease, globular glial tauopathy (GGT), Guam amyotrophic lateral sclerosis / Parkinsonism-dementia complex, corticobasal degeneration (CBD), dementia with Lewy bodies, Lewy body variant of Alzheimer's disease (LBVAD), chronic traumatic encephalopathy (CTE), globular glial tauopathy (GGT), Parkinson's disease, or progressive supranuclear palsy (PSP). In some methods, the tau-related disease is Alzheimer's disease. In some methods, the patient is a carrier of ApoE4.

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

[0139] Also provided is a method of inducing phagocytosis of tau, comprising inducing phagocytosis of tau by administering an effective regime of the antibodies disclosed herein.

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

[0141] Also provided is a method of inhibiting the formation of tau fibrillar tangles, comprising administering an effective regimen of the antibodies disclosed herein.

[0142] The present invention also provides a method for detecting tau protein precipitates in a subject having or at risk for a disease associated with tau aggregation or precipitation, comprising administering to the subject an antibody disclosed herein and detecting the antibody bound to tau in the subject. Examples of such diseases are Alzheimer's disease, Down's syndrome, mild cognitive impairment, primary age-related tauopathy, postencephalitic parkinsonism, post-traumatic dementia or dementia pugilistica, Pick's disease, Niemann-Pick type C disease, supranuclear palsy, frontotemporal dementia, frontotemporal lobar degeneration, argyrophilic grain disease, globular glial tauopathy (GGT), Guam amyotrophic lateral sclerosis / Parkinsonism-dementia complex, corticobasal degeneration (CBD), dementia with Lewy bodies, Lewy body variant of Alzheimer's disease (LBVAD), chronic traumatic encephalopathy (CTE), globular glial tauopathy (GGT), Parkinson's disease, or progressive supranuclear palsy (PSP). In some embodiments, the antibody is administered into the subject's body by intravenous injection. In some embodiments, the antibody is administered directly to the brain by intravenous injection or by drilling a hole in the subject's 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 associated with tau aggregation or precipitation, comprising the steps of measuring a first level of tau protein precipitates in the subject prior to treatment by administering an antibody disclosed herein to the subject, detecting a first amount of the antibody bound to tau in the subject, administering the treatment to the subject, measuring a second level of tau protein precipitates 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 precipitates 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 associated with tau aggregation or precipitation, comprising the steps of measuring a first level of tau protein precipitates in the subject before treatment by administering an antibody disclosed herein to the subject, detecting a first amount of the antibody bound to tau in the subject, administering the treatment to the subject, measuring a second level of tau protein precipitates in the subject after treatment by administering the antibody to the subject, and detecting the second amount of antibody bound to tau in the subject, wherein no change in the level of tau protein precipitates or a small increase in tau protein precipitates 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 residues (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 residues QIVYKP (SEQ ID NO: 57). The present invention also provides an isolated monoclonal antibody that specifically binds to a peptide consisting of residues EIVYKSP (SEQ ID NO: 58). The present invention also provides an isolated monoclonal antibody that specifically binds to a peptide consisting of residues 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 at an epitope comprising at least one residue from 307 to 312 of SEQ ID NO: 1. Some such antibodies bind to an epitope from 307 to 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 at an epitope comprising at least one residue from 391 to 397 of SEQ ID NO: 1. Some such antibodies bind to an epitope from 391 to 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 at an epitope comprising at least one residue from 391 to 396 of SEQ ID NO: 1. Some such antibodies bind to an epitope from 391 to 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 at an epitope comprising at least one residue from 307 to 312 of SEQ ID NO: 1 and at least one residue from 391 to 397 of SEQ ID NO: 1. The present invention also provides isolated monoclonal antibodies that specifically bind to a polypeptide of SEQ ID NO: 1 at an epitope comprising at least one residue from among residues 307-312 of SEQ ID NO: 1 and at least one residue from among residues 391-396 of SEQ ID NO: 1.

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

[0148] The present invention also provides methods for producing antibodies that specifically bind to an epitope comprising (Q / E)IVYK(S / P) (SEQ ID NO: 56), comprising immunizing an animal with tau or a fragment thereof and screening for antibodies that specifically bind to the epitope. In some such methods, the animal is immunized with 383 amino acid human tau (4R0N). In some such methods, the human tau comprises a P301S mutation. In some such methods, the human tau is recombinant and N-terminally His-tagged.

[0149] In some such methods, screening is performed against 15 amino acid peptides that contain QIVYKP (SEQ ID NO: 57), EIVYKSP (SEQ ID NO: 58), EIVYKS (SEQ ID NO: 277), or any other consensus motif represented by (Q / E)IVYK(S / P) (SEQ ID NO: 56). In some such methods, the peptide comprises QIVYKP (SEQ ID NO: 57), or EIVYKSP (SEQ ID NO: 58), or EIVYKS (SEQ ID NO: 277).

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

[0151] [Figure 1A] FIG. 1A depicts an 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 murine 9F5 antibody (SEQ ID NO: 7) and the heavy chain variable regions of humanized versions of the 9F5 antibody (hu9F5VHv1, hu9F5VHv2, hu9F5VHv3, hu9F5VHv4, hu9F5VHv5, hu9F5VHv6, hu9F5VHv7, and hu9F5VHv8). hu9F5VHv1 is SEQ ID NO: 15, hu9F5VHv2 is SEQ ID NO: 16, hu9F5VHv3 is SEQ ID NO: 17, hu9F5VHv4 is SEQ ID NO: 18, hu9F5VHv5 is SEQ ID NO: 19, hu9F5VHv6 is SEQ ID NO: 20, hu9F5VHv7 is SEQ ID NO: 21, and hu9F5VHv8 is SEQ ID NO: 22. The CDRs of the mouse 9F5 VH are in bold, as defined by the Kabat / Chothia composite. [Figure 1B] FIG. 1B depicts an 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 murine 9F5 antibody (SEQ ID NO: 7) and the heavy chain variable regions of humanized versions of the 9F5 antibody (hu9F5VHv1, hu9F5VHv2, hu9F5VHv3, hu9F5VHv4, hu9F5VHv5, hu9F5VHv6, hu9F5VHv7, and hu9F5VHv8). hu9F5VHv1 is SEQ ID NO: 15, hu9F5VHv2 is SEQ ID NO: 16, hu9F5VHv3 is SEQ ID NO: 17, hu9F5VHv4 is SEQ ID NO: 18, hu9F5VHv5 is SEQ ID NO: 19, hu9F5VHv6 is SEQ ID NO: 20, hu9F5VHv7 is SEQ ID NO: 21, and hu9F5VHv8 is SEQ ID NO: 22. The CDRs of the mouse 9F5 VH are in bold, as defined by the Kabat / Chothia composite. [Figure 2A]Figure 2A depicts an alignment of the human germline light chain variable region sequence IGKV2-28*01&_IGKJ2*01 (IGKV2-28*01_IGKJ2*01; SEQ ID NO: 37), human acceptor CAB51297-VL_huFrwk (CAB51297_L; SEQ ID NO: 35), and human acceptor 1911357B-VL_huFRwk (1911357B_L; SEQ ID NO: 36) with the light chain variable region of the murine 9F5 antibody (SEQ ID NO: 11) and the light chain variable regions of humanized versions of the 9F5 antibody (hu9F5VLv1, hu9F5VLv2, hu9F5VLv3, hu9F5VLv4, hu9F5VLv5, hu9F5VLv6, and hu9F5VLv7). hu9F5VLv1 is SEQ ID NO: 23, hu9F5VLv2 is SEQ ID NO: 24, hu9F5VLv3 is SEQ ID NO: 25, hu9F5VLv4 is SEQ ID NO: 26, hu9F5VLv5 is SEQ ID NO: 27, hu9F5VLv6 is SEQ ID NO: 28, and hu9F5VLv7 is SEQ ID NO: 29. The CDRs of mouse 9F5 VL are in bold, as defined by Kabat. [Figure 2B] Figure 2B depicts an alignment of the human germline light chain variable region sequence IGKV2-28*01&_IGKJ2*01 (IGKV2-28*01_IGKJ2*01; SEQ ID NO: 37), human acceptor CAB51297-VL_huFrwk (CAB51297_L; SEQ ID NO: 35), and human acceptor 1911357B-VL_huFRwk (1911357B_L; SEQ ID NO: 36) with the light chain variable region of the murine 9F5 antibody (SEQ ID NO: 11) and the light chain variable regions of humanized versions of the 9F5 antibody (hu9F5VLv1, hu9F5VLv2, hu9F5VLv3, hu9F5VLv4, hu9F5VLv5, hu9F5VLv6, and hu9F5VLv7). hu9F5VLv1 is SEQ ID NO: 23, hu9F5VLv2 is SEQ ID NO: 24, hu9F5VLv3 is SEQ ID NO: 25, hu9F5VLv4 is SEQ ID NO: 26, hu9F5VLv5 is SEQ ID NO: 27, hu9F5VLv6 is SEQ ID NO: 28, and hu9F5VLv7 is SEQ ID NO: 29. The CDRs of mouse 9F5 VL are in bold, as defined by Kabat. [Figure 3] FIG. 3 depicts the results of an assay demonstrating that the murine 9F5 antibody blocks tau internalization into neurons. [Figure 4A] Figure 4A depicts 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 murine 9F5 antibody (SEQ ID NO: 7) and the heavy chain variable regions of humanized versions of the 9F5 antibody (hu9F5VHv1, hu9F5VHv2, hu9F5VHv3, hu9F5VHv4, hu9F5VHv5, hu9F5VHv6, hu9F5VHv7, hu9F5VHv8, hu9F5VHv9, and hu9F5VHv10). hu9F5VHv1 is SEQ ID NO: 15, hu9F5VHv2 is SEQ ID NO: 16, hu9F5VHv3 is SEQ ID NO: 17, hu9F5VHv4 is SEQ ID NO: 18, hu9F5VHv5 is SEQ ID NO: 19, hu9F5VHv6 is SEQ ID NO: 20, hu9F5VHv7 is SEQ ID NO: 21, hu9F5VHv8 is SEQ ID NO: 22, hu9F5VHv9 is SEQ ID NO: 127, and hu9F5VHv10 is SEQ ID NO: 128. The CDRs of mouse 9F5 VH are in bold, as defined by Kabat / Chothia composite. Residues identical to those in mouse 9F5 VH are indicated by "". [Figure 4B]Figure 4B depicts an 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 murine 9F5 antibody (SEQ ID NO: 7) and the heavy chain variable regions of humanized versions of the 9F5 antibody (hu9F5VHv1, hu9F5VHv2, hu9F5VHv3, hu9F5VHv4, hu9F5VHv5, hu9F5VHv6, hu9F5VHv7, hu9F5VHv8, hu9F5VHv9, and hu9F5VHv10). hu9F5VHv1 is SEQ ID NO: 15, hu9F5VHv2 is SEQ ID NO: 16, hu9F5VHv3 is SEQ ID NO: 17, hu9F5VHv4 is SEQ ID NO: 18, hu9F5VHv5 is SEQ ID NO: 19, hu9F5VHv6 is SEQ ID NO: 20, hu9F5VHv7 is SEQ ID NO: 21, hu9F5VHv8 is SEQ ID NO: 22, hu9F5VHv9 is SEQ ID NO: 127, and hu9F5VHv10 is SEQ ID NO: 128. The CDRs of mouse 9F5 VH are in bold, as defined by Kabat / Chothia composite. Residues identical to those in mouse 9F5 VH are indicated by "". [Figure 5A]FIG. 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; SEQ ID NO: 36). 36) with the light chain variable region of the murine 9F5 antibody (SEQ ID NO: 11) and the light chain variable regions of humanized versions of the 9F5 antibody (hu9F5VLv1, hu9F5VLv2, hu9F5VLv3, hu9F5VLv4, hu9F5VLv5, hu9F5VLv6, hu9F5VLv7, hu9F5VLv8, and hu9F5VLv9). hu9F5VLv1 is SEQ ID NO: 23, hu9F5VLv2 is SEQ ID NO: 24, hu9F5VLv3 is SEQ ID NO: 25, hu9F5VLv4 is SEQ ID NO: 26, hu9F5VLv5 is SEQ ID NO: 27, hu9F5VLv6 is SEQ ID NO: 28, hu9F5VLv7 is SEQ ID NO: 2, hu9F5VLv8 is SEQ ID NO: 130, and hu9F5VLv9 is SEQ ID NO: 131. The CDRs of mouse 9F5 VL are in bold as defined by Kabt. Residues identical to those in mouse 9F5 VL are indicated by "". [Figure 5B]FIG. 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; SEQ ID NO: 36). 36) with the light chain variable region of the murine 9F5 antibody (SEQ ID NO: 11) and the light chain variable regions of humanized versions of the 9F5 antibody (hu9F5VLv1, hu9F5VLv2, hu9F5VLv3, hu9F5VLv4, hu9F5VLv5, hu9F5VLv6, hu9F5VLv7, hu9F5VLv8, and hu9F5VLv9). hu9F5VLv1 is SEQ ID NO: 23, hu9F5VLv2 is SEQ ID NO: 24, hu9F5VLv3 is SEQ ID NO: 25, hu9F5VLv4 is SEQ ID NO: 26, hu9F5VLv5 is SEQ ID NO: 27, hu9F5VLv6 is SEQ ID NO: 28, hu9F5VLv7 is SEQ ID NO: 2, hu9F5VLv8 is SEQ ID NO: 130, and hu9F5VLv9 is SEQ ID NO: 131. The CDRs of mouse 9F5 VL are in bold as defined by Kabt. Residues identical to those in mouse 9F5 VL are indicated 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 (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), hu9F5VLv9_DIM1 (SEQ ID NO: 162), hu9F5VLv9_DIM2 (SEQ ID NO: 163), hu9F5VLv9_DIM4 (SEQ ID NO: 164), h u9F5VLv9_DIM5 (SEQ ID NO: 165), hu9F5VLv9_DIM8 (SEQ ID NO: 166), hu9F5VLv9_DIM10 (SEQ ID NO: 167), hu9F5VLv9_DIM11 (SEQ ID NO: 168), hu9F5VLv9_DIM13 (SEQ ID NO: 169), hu9F5VLv9_DIM19 (SEQ ID NO: 170), hu9F5VLv9_DIM20 (SEQ ID NO: 171), hu9F5VLv8_DIM27 (SEQ ID NO: 158), hu9F5VLv8_DIM28 (SEQ ID NO: 159), hu9F5VLv8_DIM29 (SEQ ID NO: 160),

[0033] Figure 1 shows an alignment of the light chain variable region of hu9F5VLv8 with hu9F5VLv8_DIM30 (SEQ ID NO: 161). The CDRs of hu9F5VLv8 are 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 (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), hu9F5VLv9_DIM1 (SEQ ID NO: 162), hu9F5VLv9_DIM2 (SEQ ID NO: 163), hu9F5VLv9_DIM4 (SEQ ID NO: 164), h u9F5VLv9_DIM5 (SEQ ID NO: 165), hu9F5VLv9_DIM8 (SEQ ID NO: 166), hu9F5VLv9_DIM10 (SEQ ID NO: 167), hu9F5VLv9_DIM11 (SEQ ID NO: 168), hu9F5VLv9_DIM13 (SEQ ID NO: 169), hu9F5VLv9_DIM19 (SEQ ID NO: 170), hu9F5VLv9_DIM20 (SEQ ID NO: 171), hu9F5VLv8_DIM27 (SEQ ID NO: 158), hu9F5VLv8_DIM28 (SEQ ID NO: 159), hu9F5VLv8_DIM29 (SEQ ID NO: 160),

[0033] Figure 1 shows an alignment of the light chain variable region of hu9F5VLv8 with hu9F5VLv8_DIM30 (SEQ ID NO: 161). The CDRs of hu9F5VLv8 are 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 (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), hu9F5VLv9_DIM1 (SEQ ID NO: 162), hu9F5VLv9_DIM2 (SEQ ID NO: 163), hu9F5VLv9_DIM4 (SEQ ID NO: 164), h u9F5VLv9_DIM5 (SEQ ID NO: 165), hu9F5VLv9_DIM8 (SEQ ID NO: 166), hu9F5VLv9_DIM10 (SEQ ID NO: 167), hu9F5VLv9_DIM11 (SEQ ID NO: 168), hu9F5VLv9_DIM13 (SEQ ID NO: 169), hu9F5VLv9_DIM19 (SEQ ID NO: 170), hu9F5VLv9_DIM20 (SEQ ID NO: 171), hu9F5VLv8_DIM27 (SEQ ID NO: 158), hu9F5VLv8_DIM28 (SEQ ID NO: 159), hu9F5VLv8_DIM29 (SEQ ID NO: 160),

[0033] Figure 1 shows an alignment of the light chain variable region of hu9F5VLv8 with hu9F5VLv8_DIM30 (SEQ ID NO: 161). The CDRs of hu9F5VLv8 are in bold, as defined by Kabat. [Figure 7] Figure 7 depicts an alignment of the heavy chain variable region of the murine 10C12 antibody (SEQ ID NO: 7, labeled m10C12 VH in Figure 7) and the heavy chain variable regions of humanized versions of the 10C12 antibody (hu10C12VHv1 and hu10C12VHv2) with 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). hu10C12VHv1 is SEQ ID NO: 214, and hu10C12VHv2 is SEQ ID NO: 215. The CDRs of the murine 10C12 VH are in bold, as defined by the Kabat / Chothia composite. [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 murine 10C12 (SEQ ID NO: 11) and the light chain variable regions of humanized versions of the 10C12 antibody (hu10C12VLv1 and hu10C12VLv2). hu10C12VLv1 is SEQ ID NO: 216, and hu10C12VLv2 is SEQ ID NO: 217. The CDRs of murine 10C12 VL are 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 murine 12C4 antibody (SEQ ID NO: 219) and the heavy chain variable regions of humanized versions of the 12C4 antibody (hu12C4VHv1 and hu12C4VHv2). hu12C4VHv1 is SEQ ID NO: 221, and hu12C4VHv2 is SEQ ID NO: 222. The CDRs of the murine 12C4 VH are in bold, as defined by the Kabat / Chothia composite. [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 human acceptor CAB51297 (SEQ ID NO: 35) with the light chain variable region of the murine 12C4 antibody (SEQ ID NO: 11) and the light chain variable region of a humanized version of the 12C4 antibody (hu12C4VLv1 and huvVLv2). hu12C4VLv1 is SEQ ID NO: 223, and hu12C4VLv2 is SEQ ID NO: 224. The CDRs of the murine 12C4 VL are 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 murine 17C12 antibody (SEQ ID NO: 225) and the heavy chain variable regions of humanized versions of the 17C12 antibody (hu17C12VHv1 and hu17C12VHv2). hu17C12VHv1 is SEQ ID NO: 232, and hu17C12VHv2 is SEQ ID NO: 233. The CDRs of the murine 17C12 VH are in bold, as defined by the Kabat / Chothia composite. [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 human acceptor QDO16713 VL (SEQ ID NO: 238) with the light chain variable region of the murine 17C12 antibody (SEQ ID NO: 228) and the light chain variable region of a humanized version of the 17C12 antibody (hu17C12VLv1 and hu17C12VLv2). hu17C12VLv1 is SEQ ID NO: 234, and hu17C12VLv2 is SEQ ID NO: 235. The CDRs of the murine 17C12 VL are in bold, as defined by Kabat. [Figure 13]Figure 13 shows the alignment of the heavy chain variable region of the murine 14H3 antibody (SEQ ID NO: 240) and the heavy chain variable region of a humanized version of the 14H3 antibody (hu14H3VHv1 and hu14H3VHv2) with the human germline heavy chain variable region sequences IGHV2-70*04 & IGHJ4*01 (SEQ ID NO: 254) and the human acceptor heavy chain variable region sequence QDJ57937VH hFrwk (SEQ ID NO: 253). hu14H3VHv1 is SEQ ID NO: 248, and hu14H3VHv2 is SEQ ID NO: 249. The CDRs of the murine 14H3 VH are in bold, as defined by the Kabat / Chothia composite. [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 human acceptor ABC66914VL_hFwrk (SEQ ID NO: 256) with the light chain variable region of the murine 14H3 antibody (SEQ ID NO: 244) and the light chain variable regions of humanized versions of the 14H3 antibody (hu14H3VLv1 and hu14H3VLv2). hu14H3VLv1 is SEQ ID NO: 250, and hu14H3VLv2 is SEQ ID NO: 251. The CDRs of the murine 14H3 VL are in bold, as defined by Kabat. [Figure 15] FIG. 15 depicts the results of an assay showing that the mouse 10C12, 12C4, 2D11, 17C12, 14H3, and 9F5 antibodies block the internalization of tau into neurons. [Figure 16] FIG. 16 depicts the results of an assay demonstrating that mouse 10C12, 12C4, 2D11, and 9F5 antibodies prevent tau toxicity in primary neurons (neuronal viability). [Figure 17] FIG. 17 depicts the results of an assay (LDH release) showing that mouse 10C12, 12C4, 2D11, and 9F5 antibodies prevent tau toxicity in primary neurons. [Figure 18]FIG. 18 depicts the results of a Western blot assay showing that the mouse 10C12 antibody, the mouse 12C4 antibody, the mouse 2D11 antibody, the mouse 17C12 antibody, the mouse 14H3 antibody, and the mouse 9F5 antibody detect tau in samples derived from the brains of Alzheimer's disease patients. [Figure 19] FIG. 19 shows the results of immunoprecipitation assays using mouse 10C12, 12C4, 2D11, 17C12, 14H3, and 9F5 antibodies, as well as samples derived from the brains of patients with Alzheimer's disease. [Figure 20] FIG. 20 depicts the results of an assay to determine the ability of 9F5 humanized variants to resist aggregation induced by agitation stress. [Figure 21] FIG. 21 depicts the results of an assay to measure the ability of 9F5 humanized variants to withstand exposure to low pH. [Figure 22] FIG. 22 depicts the results of an assay to measure the propensity of 9F5 humanized variants to aggregate under simulated high concentration conditions. [Figure 23A] FIG. 23A depicts the results of an immunohistochemistry assay using a control, mouse 2D11, mouse 9F5, mouse 12C4, mouse 14H3, and mouse 17C12. [Figure 23B] FIG. 23B depicts the results of an immunohistochemistry assay using a control, mouse 2D11, mouse 9F5, mouse 12C4, mouse 14H3, and mouse 17C12. [Figure 23C] FIG. 23C depicts the results of an immunohistochemistry assay using a control, mouse 2D11, mouse 9F5, mouse 12C4, mouse 14H3, and mouse 17C12. [Figure 23D] FIG. 23D depicts the results of an immunohistochemistry assay using a control, mouse 2D11, mouse 9F5, mouse 12C4, mouse 14H3, and mouse 17C12. [Figure 23E] FIG. 23E depicts the results of an immunohistochemistry assay using a control, mouse 2D11, mouse 9F5, mouse 12C4, mouse 14H3, and mouse 17C12. [Figure 23F] FIG. 23F depicts the results of an immunohistochemistry assay 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 region of the murine 9F5 antibody (SEQ ID NO: 7), the murine 10C12 antibody (SEQ ID NO: 7), the murine 2D11 antibody (SEQ ID NO: 7), the murine 12C4 antibody (SEQ ID NO: 219), the murine 14H3 antibody (SEQ ID NO: 240), and the murine 17C12 antibody (SEQ ID NO: 225). The CDRs of the murine 9F5 VH are in bold, as defined by the Kabat / Chothia composite. [Figure 25] Figure 25 shows the alignment of the light chain variable region of the murine 9F5 antibody (SEQ ID NO: 11), the murine 10C12 antibody (SEQ ID NO: 11), the murine 2D11 antibody (SEQ ID NO: 11), the murine 12C4 antibody (SEQ ID NO: 11), the murine 14H3 antibody (SEQ ID NO: 244), and the murine 17C12 antibody (SEQ ID NO: 228). The CDRs of the murine 9F5 VL are in bold, as defined by Kabat. DETAILED DESCRIPTION OF THE INVENTION

[0152] A brief description of arrays SEQ ID NO: 1 represents the amino acid sequence of a human tau isoform (Swiss-Prot P10636-8).

[0153] SEQ ID NO: 2 represents the amino acid sequence of a human tau isoform (Swiss-Prot P10636-7).

[0154] SEQ ID NO: 3 represents the amino acid sequence of a human tau isoform (Swiss-Prot P10636-6), (4R0N human tau).

[0155] SEQ ID NO: 4 represents the amino acid sequence of a human tau isoform (Swiss-Prot P10636-5).

[0156] SEQ ID NO: 5 represents the amino acid sequence of a human tau isoform (Swiss-Prot P10636-4).

[0157] SEQ ID NO: 6 represents the amino acid sequence of a human tau isoform (Swiss-Prot P10636-2).

[0158] SEQ ID NO: 7 represents the amino acid sequence of the heavy chain variable region of the murine 9F5 antibody.

[0159] SEQ ID NO: 8 represents the amino acid sequence of the composite Kabat / Chothia CDR-H1 of the murine 9F5 antibody.

[0160] SEQ ID NO: 9 represents the amino acid sequence of the Kabat CDR-H2 of the murine 9F5 antibody.

[0161] SEQ ID NO: 10 represents the amino acid sequence of the Kabat CDR-H3 of the murine 9F5 antibody.

[0162] SEQ ID NO: 11 represents the amino acid sequence of the light chain variable region of the murine 9F5 antibody.

[0163] SEQ ID NO: 12 represents the amino acid sequence of the Kabat CDR-L1 of the murine 9F5 antibody.

[0164] SEQ ID NO: 13 represents the amino acid sequence of the Kabat CDR-L2 of the murine 9F5 antibody.

[0165] SEQ ID NO: 14 represents the amino acid sequence of the Kabat CDR-L3 of the murine 9F5 antibody.

[0166] SEQ ID NO: 15 represents the amino acid sequence of the humanized heavy chain variable region hu9F5VHv1.

[0167] SEQ ID NO: 16 represents the amino acid sequence of the humanized heavy chain variable region hu9F5VHv2.

[0168] SEQ ID NO: 17 represents the amino acid sequence of the humanized heavy chain variable region hu9F5VHv3.

[0169] SEQ ID NO: 18 represents the amino acid sequence of the humanized heavy chain variable region hu9F5VHv4.

[0170] SEQ ID NO: 19 represents the amino acid sequence of the humanized heavy chain variable region hu9F5VHv5.

[0171] SEQ ID NO: 20 represents the amino acid sequence of the humanized heavy chain variable region hu9F5VHv6.

[0172] SEQ ID NO: 21 represents the amino acid sequence of the humanized heavy chain variable region hu9F5VHv7.

[0173] SEQ ID NO: 22 represents the amino acid sequence of the humanized heavy chain variable region hu9F5VHv8.

[0174] SEQ ID NO: 23 represents the amino acid sequence of the humanized light chain variable region hu9F5VLv1.

[0175] SEQ ID NO: 24 represents the amino acid sequence of the humanized light chain variable region hu9F5VLv2.

[0176] SEQ ID NO: 25 represents the amino acid sequence of the humanized light chain variable region hu9F5VLv3.

[0177] SEQ ID NO: 26 represents the amino acid sequence of the humanized light chain variable region hu9F5VLv4.

[0178] SEQ ID NO: 27 represents the amino acid sequence of the humanized light chain variable region hu9F5VLv5 of the humanized 9F5 antibody.

[0179] SEQ ID NO: 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 shows 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 * This represents the amino acid sequence of 01.

[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 * This represents the amino acid sequence of 01.

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

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

[0191] SEQ ID NO: 40 represents the amino acid sequence of the Kabat CDR-H1 of the murine 9F5 antibody.

[0192] SEQ ID NO: 41 represents the amino acid sequence of the Chothia CDR-H1 of the murine 9F5 antibody.

[0193] SEQ ID NO: 42 represents the amino acid sequence of the Chothia CDR-H2 of the murine 9F5 antibody.

[0194] SEQ ID NO: 43 represents the amino acid sequence of AbM CDR-H2 of the murine 9F5 antibody.

[0195] SEQ ID NO: 44 represents the amino acid sequence of Contact CDR-H1 of the mouse 9F5 antibody.

[0196] SEQ ID NO: 45 represents the amino acid sequence of Contact CDR-H2 of the mouse 9F5 antibody.

[0197] SEQ ID NO: 46 represents the amino acid sequence of Contact CDR-H3 of the mouse 9F5 antibody.

[0198] SEQ ID NO: 47 represents the amino acid sequence of Contact CDR-L1 of the mouse 9F5 antibody.

[0199] SEQ ID NO: 48 represents the amino acid sequence of Contact CDR-L2 of the mouse 9F5 antibody.

[0200] SEQ ID NO: 49 represents the amino acid sequence of Contact CDR-L3 of the mouse 9F5 antibody.

[0201] SEQ ID NO: 50 represents the amino acid sequence of another Kabat / Chothia composite CDR-H1 of the humanized 9F5 antibody (present in hu9F5VHv4, hu9F5VHv5, and hu9F5VHv6).

[0202] SEQ ID NO: 51 represents the amino acid sequence of another Kabat CDR-H2 of the humanized 9F5 antibody (present in hu9F5VHv5, hu9F5VHv6, and hu9F5VHv7).

[0203] SEQ ID NO: 52 represents the amino acid sequence of another Kabat CDR-H2 of the humanized 9F5 antibody (present in hu9F5VHv8).

[0204] SEQ ID NO: 53 represents the amino acid sequence of another Kabat CDR-L1 of the humanized 9F5 antibody (present in hu9F5VLv5 and hu9F5VLv6).

[0205] SEQ ID NO: 54 represents the amino acid sequence of another Kabat CDR-L1 (present in hu9F5VLv7) of the humanized 9F5 antibody

[0206] SEQ ID NO: 55 identifies another Kabat CDR-L2 of the humanized 9F5 antibody (hu9F5VLv4, hu9F5VLv5, hu9F5VLv6, hu9F5VLv7, hu9F5VLv8_DIM2, hu9F5VLv8_DIM4, hu9F5VLv8_DIM5, hu9F5VLv8_DIM6, hu9F5VLv8_DIM11, hu9F5VLv8_DIM12, hu9F5VLv8 hu9F5VLv9_DIM13, hu9F5VLv8_DIM18, hu9F5VLv8_DIM27, hu9F5VLv8_DIM28, hu9F5VLv9_DIM2, hu9F5VLv9_DIM4, hu9F5VLv9_DIM5, hu9F5VLv9_DIM11, and hu9F5VLv9_DIM13).

[0207] SEQ ID NO: 56 represents the amino acid sequence of the epitope of antibody 9F5.

[0208] SEQ ID NO: 57 represents the amino acid sequence of the consensus motif of the peptide to which antibody 9F5 binds.

[0209] SEQ ID NO: 58 represents the amino acid sequence of the consensus motif of the peptide to which antibody 9F5 binds.

[0210] SEQ ID NO: 59 represents the amino acid sequence of the linker.

[0211] SEQ ID NO: 60 represents the amino acid sequence of the HA control peptide.

[0212] SEQ ID NO: 61 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_M51E).

[0213] SEQ ID NO: 62 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_M51D).

[0214] SEQ ID NO: 63 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27cD).

[0215] SEQ ID NO: 64 represents the amino acid sequence of the variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27cG).

[0216] SEQ ID NO: 65 represents the amino acid sequence of the variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27cS).

[0217] SEQ ID NO: 66 represents the amino acid sequence of the variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27cE).

[0218] SEQ ID NO: 67 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_I30E).

[0219] SEQ ID NO: 68 represents the amino acid sequence of the variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_I30K).

[0220] SEQ ID NO: 69 represents the amino acid sequence of the variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27cT).

[0221] SEQ ID NO: 70 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27cN).

[0222] SEQ ID NO: 71 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27bD).

[0223] SEQ ID NO: 72 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_I30G).

[0224] SEQ ID NO: 73 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L33N).

[0225] SEQ ID NO: 74 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27cA).

[0226] SEQ ID NO: 75 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L33T).

[0227] SEQ ID NO: 76 represents the amino acid sequence of the variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L33S).

[0228] SEQ ID NO: 77 represents the amino acid sequence of the variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L33R).

[0229] SEQ ID NO: 78 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_I30Q).

[0230] SEQ ID NO: 79 represents the amino acid sequence of the variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27bT).

[0231] SEQ ID NO: 80 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_T31G).

[0232] SEQ ID NO: 81 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27bQ).

[0233] SEQ ID NO: 82 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L33G).

[0234] SEQ ID NO: 83 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27cP).

[0235] SEQ ID NO: 84 represents the amino acid sequence of the variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_V78R).

[0236] SEQ ID NO: 85 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_I75D).

[0237] SEQ ID NO: 86 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_V78D).

[0238] SEQ ID NO: 87 represents the amino acid sequence of the variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_V78E).

[0239] SEQ ID NO: 88 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_V78P).

[0240] SEQ ID NO: 89 represents the amino acid sequence of the variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_V78K).

[0241] SEQ ID NO: 90 represents the amino acid sequence of the variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_R77D).

[0242] SEQ ID NO: 91 represents the amino acid sequence of the variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_V78G).

[0243] SEQ ID NO: 92 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_S76P).

[0244] SEQ ID NO: 93 represents the amino acid sequence of the variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_I75P).

[0245] SEQ ID NO: 94 represents the amino acid sequence of the variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_I75Q).

[0246] SEQ ID NO: 95 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_I75G).

[0247] SEQ ID NO: 96 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L73P).

[0248] SEQ ID NO: 97 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L73G).

[0249] SEQ ID NO: 98 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_V78Q).

[0250] SEQ ID NO: 99 represents the amino acid sequence of the variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_S76G).

[0251] SEQ ID NO: 100 represents the amino acid sequence of the variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L92D).

[0252] SEQ ID NO: 101 represents the amino acid sequence of the variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_Y86T).

[0253] SEQ ID NO: 102 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L92E).

[0254] SEQ ID NO: 103 represents the amino acid sequence of the variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L92G).

[0255] SEQ ID NO: 104 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L92Q).

[0256] SEQ ID NO: 105 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L93G).

[0257] SEQ ID NO: 106 represents the amino acid sequence of the variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_V85G).

[0258] SEQ ID NO: 107 represents the amino acid sequence of the variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L92T).

[0259] SEQ ID NO: 108 represents the amino acid sequence of a variant of the hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_A89G).

[0260] SEQ ID NO: 109 represents the amino acid sequence of a variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L80P).

[0261] SEQ ID NO: 110 represents the amino acid sequence of a variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L80D).

[0262] SEQ ID NO: 111 represents the amino acid sequence of the variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L82cG).

[0263] SEQ ID NO: 112 represents the amino acid sequence of a variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L82cD).

[0264] SEQ ID NO: 113 represents the amino acid sequence of a variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L82P).

[0265] SEQ ID NO: 114 represents the amino acid sequence of a variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L80G).

[0266] SEQ ID NO: 115 represents the amino acid sequence of a variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L82K).

[0267] SEQ ID NO: 116 represents the amino acid sequence of the variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L82R).

[0268] SEQ ID NO: 117 represents the amino acid sequence of a variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L82E).

[0269] SEQ ID NO: 118 represents the amino acid sequence of a variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L82N).

[0270] SEQ ID NO: 119 represents the amino acid sequence of a variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_Y79D).

[0271] SEQ ID NO: 120 represents the amino acid sequence of the variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_Y79N).

[0272] SEQ ID NO: 121 represents the amino acid sequence of the variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_Y79G).

[0273] SEQ ID NO: 122 represents the amino acid sequence of the variant of the hu9F5VHv5 heavy chain variable region (also known as hu9F5VHv5_M80E).

[0274] SEQ ID NO: 123 represents the amino acid sequence of the variant of the hu9F5VHv5 heavy chain variable region (also known as hu9F5VHv5_M80G).

[0275] SEQ ID NO: 124 represents the amino acid sequence of a variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L82cS).

[0276] SEQ ID NO: 125 represents the amino acid sequence of the variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_Y79Q).

[0277] SEQ ID NO: 126 represents the amino acid sequence of a variant of the hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_S82aG).

[0278] SEQ ID NO: 127 represents the amino acid sequence of the heavy chain variable region hu9F5VHv9.

[0279] SEQ ID NO: 128 represents the amino acid sequence of the heavy chain variable region hu9F5VHv10 (also known as hu9F5VHv9_Q38K_G42E).

[0280] SEQ ID NO: 129 represents the amino acid sequence of the heavy chain variable region hu9F5VHv10_L82cG.

[0281] SEQ ID NO: 130 represents the amino acid sequence of the light chain variable region hu9F5VLv8.

[0282] SEQ ID NO: 131 represents the amino acid sequence of the light chain variable region hu9F5VLv9 (also known as hu9F5VLv8_N60D).

[0283] SEQ ID NO: 132 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L54G, L92I, also known as hu9F5VLv8_DIM1).

[0284] SEQ ID NO: 133 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L54R, L92I, also known as hu9F5VLv8_DIM2).

[0285] SEQ ID NO: 134 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L54T, L92I, also known as hu9F5VLv8_DIM3).

[0286] SEQ ID NO: 135 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L54R, L92G, also known as hu9F5VLv8_DIM4).

[0287] SEQ ID NO: 136 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cG, L37Q, M51G, L54R, L92I, also known as hu9F5VLv8_DIM5).

[0288] SEQ ID NO: 137 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cD, L37Q, M51G, L54R, L92I, also known as hu9F5VLv8_DIM6).

[0289] SEQ ID NO: 138 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cD, L37Q, M51K, L54R, L92I, also known as hu9F5VLv8_DIM7).

[0290] SEQ ID NO: 139 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cG, L37Q, M51K, L54R, L92I, also known as hu9F5VLv8_DIM8).

[0291] SEQ ID NO: 140 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cG, L37Q, M51K, L54G, L92I, also known as hu9F5VLv8_DIM9).

[0292] SEQ ID NO: 141 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cS, L37Q, M51K, L54G, L92I, also known as hu9F5VLv8_DIM10).

[0293] SEQ ID NO: 142 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54R, L92I, also known as hu9F5VLv8_DIM11).

[0294] SEQ ID NO: 143 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54R, L92G, also known as hu9F5VLv8_DIM12).

[0295] SEQ ID NO: 144 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54R, also known as hu9F5VLv8_DIM13).

[0296] SEQ ID NO: 145 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54T, L92I, also known as hu9F5VLv8_DIM14).

[0297] SEQ ID NO: 146 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54T, L92G, also known as hu9F5VLv8_DIM15).

[0298] SEQ ID NO: 147 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54T, also known as hu9F5VLv8_DIM16).

[0299] SEQ ID NO: 148 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cS, L37G, M51G, L54T, L92I, also known as hu9F5VLv8_DIM17).

[0300] SEQ ID NO: 149 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cD, L37G, M51G, L54R, L92I, also known as hu9F5VLv8_DIM18).

[0301] SEQ ID NO: 150 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cS, L37I, M51I, L54R, L92I, also known as hu9F5VLv8_DIM19).

[0302] SEQ ID NO: 151 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cS, L37Q, M51I, L54G, L92I, also known as hu9F5VLv8_DIM20).

[0303] SEQ ID NO: 152 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cS, L37Q, M51I, L54G, also known as hu9F5VLv8_DIM21).

[0304] SEQ ID NO: 153 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cS, L37Q, M51E, L54R, L92I, also known as hu9F5VLv8_DIM22).

[0305] SEQ ID NO: 154 Variant of Hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cG, L37Q, M51E, L54G, L92I, also known as hu9F5VLv8_DIM23).

[0306] SEQ ID NO: 155 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cG, L37I, M51E, L54R, L92I, also known as hu9F5VLv8_DIM24).

[0307] SEQ ID NO: 156 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cG, L37I, M51E, L54R, L92G, also known as hu9F5VLv8_DIM25).

[0308] SEQ ID NO: 157 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cI, L37I, M51E, L54R, also known as hu9F5VLv8_DIM26).

[0309] SEQ ID NO: 158 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L37Q, M51G, L54R, L92I, also known as hu9F5VLv8_DIM27).

[0310] SEQ ID NO: 159 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cS, M51G, L54R, L92I, also known as hu9F5VLv8_DIM28).

[0311] SEQ ID NO: 160 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cS, L37Q, L54R, L92I, also known as hu9F5VLv8_DIM29).

[0312] SEQ ID NO: 161 represents the amino acid sequence of a variant of the hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L92I, also known as hu9F5VLv8_DIM30).

[0313] SEQ ID NO: 162 represents the amino acid sequence of a variant of the hu9F5VLv9 light chain variable region (hu9F5VLv9_V3Q, L27cS, L37Q, M51G, L54G, L92I, also known as hu9F5VLv9_DIM1).

[0314] SEQ ID NO: 163 represents the amino acid sequence of a variant of the hu9F5VLv9 light chain variable region (hu9F5VLv9_V3Q, L27cS, L37Q, M51G, L54R, L92I, also known as hu9F5VLv9_DIM2).

[0315] SEQ ID NO: 164 represents the amino acid sequence of a variant of the hu9F5VLv9 light chain variable region (hu9F5VLv9_V3Q, L27cS, L37Q, M51G, L54R, L92G, also known as hu9F5VLv9_DIM4).

[0316] SEQ ID NO: 165 represents the amino acid sequence of a variant of the hu9F5VLv9 light chain variable region (hu9F5VLv9_V3Q, L27cG, L37Q, M51G, L54R, L92I, also known as hu9F5VLv9_DIM5).

[0317] SEQ ID NO: 166 represents the amino acid sequence of a variant of the hu9F5VLv9 light chain variable region (hu9F5VLv9_V3Q, L27cG, L37Q, M51K, L54R, L92I, also known as hu9F5VLv9_DIM8).

[0318] SEQ ID NO: 167 represents the amino acid sequence of a variant of the hu9F5VLv9 light chain variable region (hu9F5VLv9_V3Q, L27cS, L37Q, M51K, L54G, L92I, also known as hu9F5VLv9_DIM10).

[0319] SEQ ID NO: 168 represents the amino acid sequence of a variant of the hu9F5VLv9 light chain variable region (hu9F5VLv9_V3Q, L27cG, L37G, M51G, L54R, L92I, also known as hu9F5VLv9_DIM11).

[0320] SEQ ID NO: 169 represents the amino acid sequence of a variant of the hu9F5VLv9 light chain variable region (hu9F5VLv9_V3Q, L27cG, L37G, M51G, L54R, also known as hu9F5VLv9_DIM13).

[0321] SEQ ID NO: 170 represents the amino acid sequence of a variant of the hu9F5VLv9 light chain variable region (hu9F5VLv9_V3Q, L27cS, L37I, M51I, L54R, L92I, also known as hu9F5VLv9_DIM19).

[0322] SEQ ID NO: 171 represents the amino acid sequence of a variant of the hu9F5VLv9 light chain variable region (hu9F5VLv9_V3Q, L27cS, L37Q, M51I, L54G, L92I, also known as hu9F5VLv9_DIM20).

[0323] SEQ ID NO: 172 represents the amino acid sequence of another Kabat CDR-L1 of the humanized 9F5 antibody (present in hu9F5VLv2_L27bD).

[0324] SEQ ID NO: 173 represents the amino acid sequence of another Kabat CDR-L1 of the humanized 9F5 antibody (present in hu9F5VLv2_L27bT).

[0325] SEQ ID NO: 174 represents the amino acid sequence of another Kabat CDR-L1 of the humanized 9F5 antibody (present in hu9F5VLv2_L27bQ).

[0326] SEQ ID NO: 175 represents the amino acid sequence of another Kabat CDR-L1 of the humanized 9F5 antibody (present in hu9F5VLv2_L27cD, hu9F5VLv8_DIM6, hu9F5VLv8_DIM7, and hu9F5VLv8_DIM18).

[0327] SEQ ID NO: 176 identifies another Kabat CDR-L1 of the humanized 9F5 antibody (hu9F5VLv2_L27cG, hu9F5VLv8_DIM5, hu9F5VLv8_DIM8, hu9F5VLv8_DIM9, hu9F5VLv8_DIM11, hu9F5VLv8_DIM12, hu9F5VLv8_DIM13, hu9F5VLv8_DIM14, hu9F5VLv8_DIM 15, hu9F5VLv8_DIM16, hu9F5VLv8_DIM23, hu9F5VLv8_DIM24, hu9F5VLv8_DIM25, hu9F5VLv9_DIM5, hu9F5VLv9_DIM8, hu9F5VLv9_DIM11, and hu9F5VLv9_DIM13).

[0328] SEQ ID NO: 177 is another Kabat AAC sequence for the humanized 9F5 antibody. 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) is shown.

[0329] SEQ ID NO: 178 represents the amino acid sequence of another Kabat CDR-L1 of the humanized 9F5 antibody (present in hu9F5VLv2_L27cE).

[0330] SEQ ID NO: 179 represents the amino acid sequence of another Kabat CDR-L1 of the humanized 9F5 antibody (present in hu9F5VLv2_L27cT).

[0331] SEQ ID NO: 180 represents the amino acid sequence of another Kabat CDR-L1 of the humanized 9F5 antibody (present in hu9F5VLv2_L27cN).

[0332] SEQ ID NO: 181 represents the amino acid sequence of another Kabat CDR-L1 of the humanized 9F5 antibody (present in hu9F5VLv2_L27cA).

[0333] SEQ ID NO: 182 represents the amino acid sequence of another Kabat CDR-L1 of the humanized 9F5 antibody (present in hu9F5VLv2_L27cP).

[0334] SEQ ID NO: 183 represents the amino acid sequence of another Kabat CDR-L1 of the humanized 9F5 antibody (present in hu9F5VLv8_DIM26).

[0335] SEQ ID NO: 184 represents the amino acid sequence of another Kabat CDR-L1 of the humanized 9F5 antibody (present in hu9F5VLv2_I30E).

[0336] SEQ ID NO: 185 represents the amino acid sequence of another Kabat CDR-L1 of the humanized 9F5 antibody (present in hu9F5VLv2_I30K).

[0337] SEQ ID NO: 186 represents the amino acid sequence of another Kabat CDR-L1 of the humanized 9F5 antibody (present in hu9F5VLv2_I30G).

[0338] SEQ ID NO: 187 represents the amino acid sequence of another Kabat CDR-L1 of the humanized 9F5 antibody (present in hu9F5VLv2_I30Q).

[0339] SEQ ID NO: 188 represents the amino acid sequence of another Kabat CDR-L1 of the humanized 9F5 antibody (present in hu9F5VLv2_T31G).

[0340] SEQ ID NO: 189 represents the amino acid sequence of another Kabat CDR-L1 of the humanized 9F5 antibody (present in hu9F5VLv2_L33N).

[0341] SEQ ID NO: 190 represents the amino acid sequence of another Kabat CDR-L1 of the humanized 9F5 antibody (present in hu9F5VLv2_L33T).

[0342] SEQ ID NO: 191 represents the amino acid sequence of another Kabat CDR-L1 of the humanized 9F5 antibody (present in hu9F5VLv2_L33S).

[0343] SEQ ID NO: 192 represents the amino acid sequence of another Kabat CDR-L1 of the humanized 9F5 antibody (present in hu9F5VLv2_L33R).

[0344] SEQ ID NO: 193 represents the amino acid sequence of another Kabat CDR-L1 of the humanized 9F5 antibody (present in hu9F5VLv2_L33G).

[0345] SEQ ID NO: 194 represents the amino acid sequence of another Kabat CDR-L2 of the humanized 9F5 antibody (present in hu9F5VLv2_M51E).

[0346] SEQ ID NO: 195 represents the amino acid sequence of another Kabat CDR-L2 of the humanized 9F5 antibody (present in hu9F5VLv2_M51D).

[0347] SEQ ID NO: 196 represents the amino acid sequence of another Kabat CDR-L2 of the humanized 9F5 antibody (present in hu9F5VLv8_DIM30).

[0348] SEQ ID NO: 197 represents the amino acid sequence of another Kabat CDR-L2 of the humanized 9F5 antibody (present in hu9F5VLv8_DIM29).

[0349] SEQ ID NO: 198 represents the amino acid sequence of another Kabat CDR-L2 of the humanized 9F5 antibody (present in hu9F5VLv8_DIM1 and hu9F5VLv9_DIM1).

[0350] SEQ ID NO: 199 represents the amino acid sequence of another Kabat CDR-L2 of the humanized 9F5 antibody (present in hu9F5VLv8_DIM3, hu9F5VLv8_DIM14, hu9F5VLv8_DIM15, hu9F5VLv8_DIM16, and hu9F5VLv8_DIM17).

[0351] SEQ ID NO: 200 represents the amino acid sequence of another Kabat CDR-L2 of the humanized 9F5 antibody (present in hu9F5VLv8_DIM7, hu9F5VLv8_DIM8, and hu9F5VLv9_DIM8).

[0352] SEQ ID NO: 201 represents the amino acid sequence of another Kabat CDR-L2 of the humanized 9F5 antibody (present in hu9F5VLv8_DIM9, hu9F5VLv8_DIM10, and hu9F5VLv9_DIM10).

[0353] SEQ ID NO: 202 represents the amino acid sequence of another Kabat CDR-L2 of the humanized 9F5 antibody (present in hu9F5VLv8_DIM19, and hu9F5VLv9_DIM19).

[0354] SEQ ID NO: 203 represents the amino acid sequence of another Kabat CDR-L2 of the humanized 9F5 antibody (present in hu9F5VLv8_DIM20, hu9F5VLv8_DIM21, and hu9F5VLv9_DIM20).

[0355] SEQ ID NO: 204 represents the amino acid sequence of another Kabat CDR-L2 of the humanized 9F5 antibody (present in hu9F5VLv8_DIM22, hu9F5VLv8_DIM24, hu9F5VLv8_DIM25, and hu9F5VLv8_DIM26).

[0356] SEQ ID NO: 205 represents the amino acid sequence of another Kabat CDR-L2 of the humanized 9F5 antibody (present in hu9F5VLv8_DIM23).

[0357] SEQ ID NO: 206 represents the amino acid sequence of another Kabat CDR-L3 of the humanized 9F5 antibody (present in hu9F5VLv2_A89G).

[0358] SEQ ID NO: 207 represents the amino acid sequence of another Kabat CDR-L3 of the humanized 9F5 antibody (present in hu9F5VLv2_L92D).

[0359] SEQ ID NO: 208 represents the amino acid sequence of another Kabat CDR-L3 of the humanized 9F5 antibody (present in hu9F5VLv2_L92E).

[0360] SEQ ID NO: 209 represents the amino acid sequence of another Kabat CDR-L3 of the humanized 9F5 antibody (present in hu9F5VLv8_DIM4, hu9F5VLv8_DIM12, hu9F5VLv8_DIM15, hu9F5VLv8_DIM25, and hu9F5VLv9_DIM4).

[0361] SEQ ID NO: 210 represents the amino acid sequence of another Kabat CDR-L3 of the humanized 9F5 antibody (present in hu9F5VLv2_L92Q).

[0362] SEQ ID NO: 211 represents the amino acid sequence of another Kabat CDR-L3 of the humanized 9F5 antibody (present in hu9F5VLv2_L92T).

[0363] SEQ ID NO: 212 identifies another Kabat CDR-L3 of 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, hu9F5VLv8_DIM20, hu9F5VLv8_DIM11, hu9F5VLv8_DIM12, hu9F5VLv8_DIM13, hu9F5VLv8_DIM14, hu9F5VLv8_DIM15, hu9F5VLv8_DIM16, hu9F5VLv8_DIM17, hu9F5VLv8_DIM18, hu9F5VLv8_DIM19, hu9F5VLv8_DIM20, hu9F5VLv8_DIM18, hu9F5VLv8_DIM19, hu9F5VLv8_DIM21, hu9F5VLv8_DIM22, hu9F5VLv8_DIM23, hu9F5VLv8_DIM24, hu9F5VLv8_DIM25, hu9F5VLv8_DIM2 These represent the amino acid sequences of hu9F5VLv9_DIM1, hu9F5VLv9_DIM2, hu9F5VLv8_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] SEQ ID NO: 213 represents the amino acid sequence of another Kabat CDR-L3 of the humanized 9F5 antibody (present in hu9F5VLv2_L93G).

[0365] SEQ ID NO: 214 represents the amino acid sequence of the humanized heavy chain variable region hu10C12VHv1.

[0366] SEQ ID NO: 215 represents the amino acid sequence of the humanized heavy chain variable region hu10C12VHv2.

[0367] SEQ ID NO: 216 represents the amino acid sequence of the humanized light chain variable region hu10C12VLv1.

[0368] SEQ ID NO: 217 represents the amino acid sequence of the humanized light chain variable region hu10C12VLv2.

[0369] SEQ ID NO: 218 represents the amino acid sequence of the heavy chain variable region acceptor CAC20421-VH_huFrwk.

[0370] SEQ ID NO: 219 represents the amino acid sequence of the heavy chain variable region of the murine 12C4 antibody.

[0371] SEQ ID NO: 220 represents the amino acid sequence of the Kabat CDR-H2 of the murine 12C4 antibody.

[0372] SEQ ID NO: 221 represents the amino acid sequence of the humanized heavy chain variable region hu12C4VHv1.

[0373] SEQ ID NO: 222 represents the amino acid sequence of the humanized heavy chain variable region hu12C4VHv2.

[0374] SEQ ID NO: 223 represents the amino acid sequence of the humanized light chain variable region hu12C4VLv1.

[0375] SEQ ID NO: 224 represents the amino acid sequence of the humanized light chain variable region hu12C4VLv2.

[0376] SEQ ID NO: 225 represents the amino acid sequence of the heavy chain variable region of the murine 17C12 antibody.

[0377] SEQ ID NO: 226 represents the amino acid sequence of the composite Kabat / Chothia CDR H1 of the murine 17C12 antibody.

[0378] SEQ ID NO: 227 represents the amino acid sequence of the Kabat CDR H2 of the murine 17C12 antibody.

[0379] SEQ ID NO: 228 represents the amino acid sequence of the light chain variable region of the murine 17C12 antibody.

[0380] SEQ ID NO: 229 represents the amino acid sequence of the Kabat CDR-L1 of the murine 17C12 antibody.

[0381] SEQ ID NO: 230 represents the amino acid sequence of the Kabat CDR-L2 of the murine 17C12 antibody.

[0382] SEQ ID NO: 231 represents the amino acid sequence of the Kabat CDR-L3 of the murine 17C12 antibody.

[0383] SEQ ID NO: 232 represents the amino acid sequence of the humanized heavy chain variable region hu17C12VHv1.

[0384] SEQ ID NO: 233 represents the amino acid sequence of the humanized heavy chain variable region hu17C12VHv2.

[0385] SEQ ID NO: 234 represents the amino acid sequence of the humanized light chain variable region hu17C12VLv1.

[0386] SEQ ID NO: 235 represents the amino acid sequence of the humanized light chain variable region hu17C12VLv2.

[0387] SEQ ID NO: 236 shows the amino acid sequence of the heavy chain variable region structural model 3PP3-VH_mSt.

[0388] SEQ ID NO: 237 shows the amino acid sequence of the light chain variable region structural model 3PP3-VL_mSt.

[0389] SEQ ID NO: 238 represents the amino acid sequence of the light chain variable region acceptor QDO16713-VL_huFrwk.

[0390] SEQ ID NO: 239 is the light chain variable region germline sequence IGKV2-29 * 02 & IGKJ4 * This represents the amino acid sequence of 01.

[0391] SEQ ID NO: 240 represents the amino acid sequence of the heavy chain variable region of the murine 14H3 antibody.

[0392] SEQ ID NO: 241 represents the amino acid sequence of the composite Kabat / Chothia CDR H1 of the murine 14H3 antibody.

[0393] SEQ ID NO: 242 represents the amino acid sequence of the Kabat CDR H2 of the murine 14H3 antibody.

[0394] SEQ ID NO: 243 represents the amino acid sequence of the Kabat CDR H3 of the murine 14H3 antibody.

[0395] SEQ ID NO: 244 represents the amino acid sequence of the light chain variable region of the murine 14H3 antibody.

[0396] SEQ ID NO: 245 represents the amino acid sequence of Kabat CDR L1 of the murine 14H3 antibody.

[0397] SEQ ID NO: 246 represents the amino acid sequence of the Kabat CDR L2 of the murine 14H3 antibody.

[0398] SEQ ID NO: 247 represents the amino acid sequence of the Kabat CDR L3 of the murine 14H3 antibody.

[0399] SEQ ID NO: 248 represents the amino acid sequence of the humanized heavy chain variable region hu14H3VHv1.

[0400] SEQ ID NO: 249 represents the amino acid sequence of the humanized heavy chain variable region hu14H3VHv2.

[0401] SEQ ID NO: 250 represents the amino acid sequence of the humanized light chain variable region hu14H3VLv1.

[0402] SEQ ID NO: 251 represents the amino acid sequence of the humanized light chain variable region hu14H3VLv2.

[0403] SEQ ID NO: 252 shows the amino acid sequence of the heavy chain variable region structural model 2VQ1-VH_mSt.

[0404] SEQ ID NO: 253 represents the amino acid sequence of the heavy chain variable region acceptor QDJ57937-VH_huFrwk.

[0405] SEQ ID NO: 254 is the heavy chain variable region germline sequence IGHV1-70 * 04 & IGHJ4 * This represents the amino acid sequence of 01.

[0406] SEQ ID NO: 255 represents the amino acid sequence of the light chain variable region structural model 2VQ1-VL_mSt.

[0407] SEQ ID NO: 256 represents the amino acid sequence of the light chain variable region acceptor ABC66914-VL_huFrwk.

[0408] SEQ ID NO: 257 represents the amino acid sequence of AbM CDR-H2 of the murine 12C4 antibody.

[0409] SEQ ID NO: 258 represents the amino acid sequence of Contact CDR-H2 of the mouse 12C4 antibody.

[0410] SEQ ID NO: 259 represents the amino acid sequence of the Chothia CDR-H1 of the murine 17C12 antibody.

[0411] SEQ ID NO: 260 represents the amino acid sequence of AbM CDR-H2 of the murine 17C12 antibody.

[0412] SEQ ID NO: 261 represents the amino acid sequence of Contact CDR-H2 of the mouse 17C12 antibody.

[0413] SEQ ID NO: 262 represents the amino acid sequence of Contact CDR-L1 of the mouse 17C12 antibody.

[0414] SEQ ID NO: 263 represents the amino acid sequence of Contact CDR-L2 of the mouse 17C12 antibody.

[0415] SEQ ID NO: 264 represents the amino acid sequence of Contact CDR-L3 of the mouse 17C12 antibody.

[0416] SEQ ID NO: 265 represents the amino acid sequence of the Kabat CDR-H1 of the murine 14H3 antibody.

[0417] SEQ ID NO: 266 represents the amino acid sequence of the Chothia CDR-H1 of the murine 14H3 antibody.

[0418] SEQ ID NO: 267 represents the amino acid sequence of the Chothia CDR-H2 of the murine 14H3 antibody.

[0419] SEQ ID NO: 268 represents the amino acid sequence of AbM CDR-H2 of the murine 14H3 antibody.

[0420] SEQ ID NO: 269 represents the amino acid sequence of Contact CDR-H1 of the mouse 14H3 antibody.

[0421] SEQ ID NO: 270 represents the amino acid sequence of Contact CDR-H2 of the mouse 14H3 antibody.

[0422] SEQ ID NO: 271 represents the amino acid sequence of Contact CDR-H3 of mouse 14H3 antibody.

[0423] SEQ ID NO: 272 represents the amino acid sequence of Contact CDR-L1 of mouse 14H3 antibody.

[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 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] definition Monoclonal antibodies or other biological entities are usually provided in isolated form. This means that the antibody or other biological entity is usually at least 50% (w / w) pure, free from interfering proteins and other contaminants resulting from its production or purification, although this does not exclude the possibility that the monoclonal antibody may be combined with an excess of a pharmaceutically acceptable carrier or other vehicle intended to facilitate its use. Optionally, the monoclonal antibody is at least 60% (w / w), 70% (w / w), 80% (w / w), 90% (w / w), 95% (w / w), or 99% (w / w) pure free from interfering proteins and contaminants resulting from its production or purification. Often, an isolated monoclonal antibody or other biological entity is the predominant macromolecular species remaining after its purification.

[0430] 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 Specific binding refers to the affinity and / or avidity of an antibody to one or more targets. Specific binding is detectably significant in magnitude and comparable to nonspecific binding occurring to at least one unrelated target. Specific binding can be the result of the formation of bonds between specific functional groups or specific spatial matches (e.g., lock and key), whereas nonspecific binding is usually the result of van der Waals forces. However, specific binding does not necessarily imply that an antibody binds to one and only one target.

[0431] The basic antibody structural unit is a tetramer of subunits. Each tetramer contains two identical pairs of polypeptide chains, each pair having one "light" chain (approximately 25 kDa) and one "heavy" chain (approximately 50-70 kDa). The amino-terminal portion of each chain contains a variable region of approximately 100-110 or more amino acids primarily responsible for antigen recognition. This variable region is initially expressed linked to a cleavable signal peptide. The variable region without the signal peptide is sometimes referred to as a mature variable region. Thus, for example, a light chain mature variable region refers to the light chain variable region without the light chain signal peptide. The carboxy-terminus of each chain defines a constant region primarily responsible for effector function.

[0432] Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, and define the antibody's isotype as IgG, IgM, IgA, IgD, and IgE, respectively. Within light and heavy chains, the variable and constant regions are joined by a "J" region of about 12 or more amino acids, with the heavy chain also including a "D" region of about 10 more amino acids. See generally, Fundamental Immunology, Paul, W., ed., 2nd ed. Raven Press, NY, 1989, Ch. 7 (incorporated by reference in its entirety for all purposes).

[0433] An immunoglobulin light or heavy chain variable region (also referred to herein as a "light chain variable domain" ("VL domain") or a "heavy chain variable domain" ("VH domain"), respectively) consists of a "framework" region interrupted by three "complementarity-determining regions" or "CDRs." The framework regions act to align the CDRs for specific binding to an antigen epitope. The CDRs contain the amino acid residues of an antibody primarily responsible for antigen binding. From the amino to carboxyl termini, VL and VH domains comprise the following framework regions (FRs) and CDR regions: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. CDR1, 2, and 3 of a VL domain are also referred to herein as CDR-L1, CDR-L2, and CDR-L3, respectively; CDR1, 2, and 3 of a VH domain are also referred to herein as CDR-H1, CDR-H2, and CDR-H3, respectively. Where the present 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, and thus the present application should also be understood to disclose VL sequences without a C-terminal R.

[0434] The amino acid assignments for each VL and VH domain follow one of the conventional CDR definitions, including the Kabat definition (Kabat, Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, MD, 1987 and 1991)), the Chothia definition (Chothia & Lesk, J. Mol. Biol. 196:901-917, 1987; Chothia et al., Nature 342:878-883, 1989), the Chothia-Kabat CDR combination, in which CDR-H1 is a combination of the Chothia and Kabat CDRs, and the Oxford Examples include the AbM definition used by antibody modeling software from Molecular; and the contact definition from Martin et al. (bioinfo.org.uk / abs) (see Table 1). Kabat provides a widely used numbering scheme (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 according to a particular 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 that other residues that fall within other conventional CDR definitions but are outside the scope of the specified definition may also be present. For example, an antibody containing a CDR defined by Kabat includes, among other possibilities, an antibody in which the CDR contains Kabat CDR residues but no other CDR residues, and an antibody in which the CDR H1 is a composite Chothia-Kabat CDR H1 and the other CDRs contain Kabat CDR residues but no additional CDR residues according to other definitions. [Table 1]

[0435] The term "antibody" includes intact antibodies and binding fragments thereof. Fragments, typically containing separate heavy and light chains, Fab, Fab', F(ab')2, F(ab)c, Dabs, nanobodies, and Fv, compete with the intact antibody from which they were derived for specific binding to a target. Fragments can be produced by recombinant DNA techniques or by enzymatic or chemical separation of intact immunoglobulins. The term "antibody" also includes bispecific and / or humanized antibodies. Bispecific or bifunctional antibodies are artificial hybrid antibodies having two different heavy / light chain pairs and two different binding sites (see, e.g., 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 chain / light chain pairs include a humanized 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3 heavy chain / light chain pair and a heavy chain / light chain pair specific for a different epitope on tau other than that bound by 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3.

[0436] In some bispecific antibodies, one heavy chain / light chain pair is a humanized 9F5 antibody, a humanized 10C12 antibody, a humanized 2D11 antibody, a humanized 12C4 antibody, a humanized 17C12 antibody, or a humanized 14H3 antibody, which are further disclosed below, and the other heavy chain / light chain pair is derived from an antibody that binds to a receptor expressed at the blood-brain barrier, such as an insulin receptor, an insulin-like growth factor (IGF) receptor, a leptin receptor, a lipoprotein receptor, or a transferrin receptor (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 engineering the bispecific antibody to reduce its affinity for blood-brain barrier receptors, which results in broader distribution in the brain (see, e.g., Atwal et al., Sci. Trans. Med. 3, 84ra43, 2011; Yu et al., Sci. Trans. Med. 3, 84ra44, 2011).

[0437] Also exemplary bispecific antibodies include: (1) dual variable domain antibodies (DVD-Ig), in which 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™) Molecule, In: Antibody Engineering, Springer Berlin Heidelberg (2010)); (2) Tandabs, which are fusions of two single-chain diabodies resulting in tetravalent bispecific antibodies with two binding sites for each target antigen; (3) flexibodies, which are combinations of diabodies and scFvs resulting in multivalent molecules; and (4) so-called "dock and dock" antibodies based on the "D / D domain (dimerization and docking domain)" of protein kinase A, which, when applied to Fabs, can result in trivalent bispecific binding proteins consisting of two identical Fab fragments bound to different Fab fragments. or (5) so-called Scorpion molecules, which comprise, for example, two scFvs fused to either end of a human Fc region. Examples of platforms useful for the preparation of bispecific antibodies include BiTE (Micromet), DART (MacroGenics), Fcab and Mab2 (F-star), Fc-engineered IgG1 (Xencor), or DuoBody (based on Fab arm exchange, Genmab).

[0438] The term "epitope" refers to a site on an antigen to which an antibody binds. Epitopes can be formed from contiguous or non-contiguous amino acids juxtaposed by tertiary folding of one or more proteins. Epitopes formed from contiguous amino acids (also known as linear epitopes) typically remain after exposure to denaturing solvents, whereas epitopes formed by tertiary folding (conformational epitopes) typically are lost after treatment with denaturing solvents. An epitope comprises at least three, usually at least five or eight to ten amino acids in a unique spatial conformation. Methods for determining the spatial conformation of an epitope 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 simple immunoassays that demonstrate the ability of one antibody to compete with the binding of another antibody to a target antigen. An antibody's epitope can also be defined by X-ray crystallography of the antibody bound to its antigen to identify the exact residues. Alternatively, two antibodies have the same epitope if all amino acid mutations in the antigen that reduce or eliminate binding of one antibody also reduce or eliminate binding of the other. Two antibodies have overlapping epitopes if some amino acid mutations that reduce or eliminate binding of one antibody also reduce or eliminate binding of the other.

[0440] Competition between antibodies is determined by an assay in which the antibody under test 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 an excess of the test antibody (e.g., at least 2-fold, 5-fold, 10-fold, 20-fold, or 100-fold) inhibits binding of the reference antibody by at least 50%, as measured in a competitive binding assay. Some test antibodies inhibit 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 adjacent epitopes that are sufficiently close to the epitope bound by the reference antibody due to steric hindrance that occurs.

[0441] The term "pharmaceutically acceptable" means the carrier, diluent, excipient or adjuvant must be compatible with the other ingredients of the formulation and not substantially deleterious to the recipient thereof.

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

[0443] An individual is at high risk for a disease if the subject has at least one known risk factor (genetic factors, biochemical factors, familial, and situational exposures) that places the individual with the risk factor at a statistically significantly higher risk of developing the disease than individuals without the risk factor.

[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 samples can be organs, organelles, tissues, tissue sections, body fluids, peripheral blood, plasma, serum, cells, molecules such as proteins and peptides, and any parts or combinations derived therefrom. The term biological sample can also encompass all materials derived from processing the sample. Derived materials can include cells or their passages. Processing of a biological sample can include one or more of filtration, distillation, extraction, concentration, fixation, inactivation of interfering components, etc.

[0445] The term "control sample" refers to a biological sample that is not known or suspected to contain a region affected by a tau-related disease, or at least not known or suspected to contain a disease region of a given type. A control sample may be obtained from an individual not affected by a tau-related disease. Alternatively, a control sample may be obtained from a patient affected by a tau-related disease. Such a biological sample may be obtained simultaneously with a biological sample suspected of containing a tau-related disease, or in a different context. Both the biological sample and the control sample may be obtained from the same tissue. Preferably, the control sample consists of an essentially or grossly normal, healthy region and can be used for comparison with a biological sample suspected of containing a region affected by a tau-related disease. Preferably, the tissue of the control sample is of the same type as the tissue of the biological sample. Preferably, cells suspected of being affected by a tau-related disease in the biological sample arise from the same cell type (e.g., neurons or glia) as the cell type in the control sample.

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

[0447] The term "symptom" refers to subjective evidence of disease, such as a change in gait, as perceived by the subject. "Sign" refers to objective evidence of disease observed by a physician.

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

[0449] For the purpose of classifying amino acid substitutions as conservative or non-conservative, 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 that affect chain orientation): gly, pro; and Group VI (aromatic side chains): trp, tyr, phe. Conservative substitutions involve substitutions between amino acids of the same class. Non-conservative substitutions constitute exchanging a member of one of these classes for another.

[0450] Percentage sequence identity is determined for maximally aligned antibody sequences according to the Kabat numbering convention. After alignment, when a region of an antibody of interest (e.g., the entire mature variable region of a heavy or light chain) is compared to the same region of a reference antibody, the percentage sequence identity between the region of the antibody of interest and the reference antibody is the number of positions occupied by the same amino acid in the subject and reference antibodies, divided by the total number of aligned positions in the two regions, not accounting for gaps, multiplied by 100 to convert to a percentage.

[0451] A composition or method "comprising or including" one or more recited elements may include other elements not specifically recited. For example, a composition "comprising" an antibody may include the antibody alone or the antibody in combination with other components.

[0452] The representation of a range of values ​​includes every integer within or defining that range, and every subrange defined by an integer within that range.

[0453] Unless otherwise clear from the context, the term "about" includes de minimis values, such as values ​​within the standard error of measurement (e.g., SEM) of the stated value.

[0454] Statistical significance means p≦0.05.

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

[0456] Detailed Description I. General Provisions The present invention provides antibodies that bind to tau. Some antibodies specifically bind to an epitope within (Q / E)IVYK(S / P) (SEQ ID NO: 56). Some antibodies specifically bind to a peptide containing the amino acid sequence QIVYKP (SEQ ID NO: 57, corresponding to residues 307-312 of the tau isoform of SEQ ID NO: 1). Some antibodies specifically bind to a peptide containing the amino acid sequence EIVYKSP (SEQ ID NO: 58, corresponding to residues 391-397 of the tau isoform of SEQ ID NO: 1). These antibodies differ from 3D6 and other antibodies, which are characterized by binding to the microtubule-binding region (MTBR) of human tau, in that they contain an additional epitope near the C-terminus of tau. The specificity of the additional C-terminus provides the basis for linking these antibodies to an increasing number of pathology-associated conformational forms of tau. Some antibodies specifically bind to a peptide containing the amino acid sequence EIVYKS (SEQ ID NO: 277, corresponding to residues 391-396 of the tau isoform of 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 slow the progression of tau-related pathologies and associated symptoms. While understanding the mechanism is not necessary for the practice of the present invention, reduced toxicity may occur as a result of antibodies stabilizing non-toxic conformations, inhibiting intercellular or intracellular transmission of pathogenic tau forms, blocking tau phosphorylation, preventing tau binding to cells, or inducing proteolytic cleavage of tau, inducing phagocytosis of tau, or preventing tau from inter- or intramolecularly aggregating or 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 toxicity / increased cellular uptake and / or clearance. Large aggregates of tau molecules may exhibit reduced uptake into neuronal cells. Some antibodies of the invention, by bivalent binding to tau, bring other tau molecules into closer proximity, encouraging their aggregation into tau aggregates that are too large to be internalized within neurons. Furthermore, Fc-mediated phagocytosis requires several tau-binding antibodies to be brought into closer proximity.Large aggregates of tau molecules may have many anti-tau antibodies bound to them, providing the clusters necessary for Fc-mediated phagocytosis by macrophages. The antibodies of the invention or agents that induce such antibodies may be used in methods to treat or affect the prevention of Alzheimer's disease and other diseases associated with tau.

[0457] II.Target molecule Unless otherwise clear from the context, 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, glycosylation, 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, the first met residue of which is truncated. Residues are numbered according to the 441 isoform. Thus, for example, reference to phosphorylation at position 404 refers to position 404 in the 441 isoform, or the corresponding position in 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] JPEG2025029046000004.jpg178162

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

[0459] Tau can be phosphorylated at 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 otherwise clear from the context, reference to tau or a fragment thereof includes the naturally occurring human amino acid sequence, including its isoforms, mutants, and allelic 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 an epitope formed by amino acids from either or both of two regions of tau that share the common core motif of IVYK (SEQ ID NO: 276). These regions are defined by residues 307-312 and 391-397 or 391-396 of SEQ ID NO: 1, respectively. Thus, an antibody containing one binding site for tau, such as an scFv, can specifically bind to tau at an epitope formed by amino acids within either of these regions individually, or it can specifically bind to a hybrid epitope formed by amino acids from both of these regions. An antibody containing two binding sites for tau can also simultaneously bind to epitopes within the ranges 307-312 and 391-397, or within the range 391-396, from its two binding sites. The epitopes can be on the same or different tau molecules. Some antibodies of the present invention specifically bind to a peptide consisting of residues 307-312 of tau, i.e., residues QIVYKP (SEQ ID NO: 57). Some antibodies of the present invention specifically bind to a peptide consisting of residues 391-397 of tau, i.e., residues EIVYKSP (SEQ ID NO: 58). Some antibodies of the present invention specifically bind to a peptide consisting of residues 391-396 of tau, i.e., EIVYKS (SEQ ID NO: 277). Some antibodies of the present invention specifically bind to a peptide consisting of the consensus motif (Q / E)IVYK(S / P) (SEQ ID NO: 56). These antibodies can be obtained by immunization with tau polypeptide purified from natural sources or expressed recombinantly. Antibodies can be screened for binding to unphosphorylated forms of tau and forms in which one or more phosphorylation-prone residues are phosphorylated. The present invention also provides antibodies that bind to the same epitope 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 competes with the reference antibody, shares one or more of its functional properties, such as inhibiting tau internalization into neuronal cells, and optionally possesses such properties to the same extent, or to a greater extent than the reference antibody, within experimental error.

[0462] The present invention provides antibodies that compete with 9F5 for binding to tau and reduce tau-induced toxicity in neurons. The present invention provides antibodies that compete with 9F5 for binding to tau and have increased resistance to agitation stress. Exemplary 9F5 humanized antibodies that compete with 9F5 for binding to tau and have increased resistance to agitation stress are 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 binding to tau and have increased resistance to low pH stress. Exemplary 9F5 humanized antibodies that compete with 9F5 for binding to tau and have increased resistance to low pH stress are 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 binding to tau, have increased resistance to agitation stress, and have increased resistance to low pH stress include DIM2 [hu9F5VHv9 / hu9F5VLv8_DIM2 SEQ ID NO: 127 / SEQ ID NO: 133], DIM6 [hu9F5VHv9 / hu9F5VLv8_DIM6 SEQ ID NO: 127 / SEQ ID NO: 137], DIM7 [hu9F5VHv9 / hu9F5VLv8_DIM7 SEQ ID NO: 127 / SEQ ID NO: 138], DIM8 [hu9F5VHv9 / hu9F5VLv8_DIM8 SEQ ID NO: 127 / SEQ ID NO: 139], DIM13 [hu9F5VHv9 / hu9F5VLv8_DIM13 SEQ ID NO: 127 / SEQ ID NO: 144], DIM18 [hu9F5VHv9 / hu9F5VLv8_DIM18 SEQ ID NO: 127 / SEQ ID NO: 149], DIM28 [hu9F5VHv9 / hu9F5VLv8_DIM28 SEQ ID NO: 127 / SEQ ID NO: 159], and DIM30 [hu9F5VHv9 / hu9F5VLv8_DIM30 SEQ ID NO: 127 / SEQ ID NO: 161].

[0463] The present invention provides antibodies that compete with 9F5 for binding to tau and have 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 combined with the original leucine at position L27c (DIM27), also known as hu9F5VHv9 / hu9F5VLv8_DIM27 SEQ ID NO: 127 / SEQ ID NO: 158.

[0464] The above-mentioned antibodies can be produced de novo by immunizing with a tau peptide comprising or consisting of the amino acid sequence 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), or by immunizing with a full-length tau peptide or a fragment thereof containing the residues and screening for specific binding to peptides containing the residues. Preferably, such tau peptides are conjugated to a heterologous conjugate molecule that helps elicit an antibody response against the peptide. Conjugation can be direct or via a spacer peptide or amino acid. Cysteine ​​is used as a spacer amino acid because its free sulfhydryl group facilitates attachment of a carrier molecule. Polyglycine linkers (e.g., 2-6 glycines) with or without a cysteine ​​residue between the glycine and the peptide can also be used. Carrier molecules act to provide T cell epitopes that help elicit an antibody response to the peptide. Several carriers are commonly used, notably keyhole limpet hemocyanin (KLH), ovalbumin, and bovine serum albumin (BSA). Peptide spacers can be added to peptide immunogens as part of solid-phase peptide synthesis. Carriers are usually added by chemical cross-linking.Some examples of chemical cross-linkers that can be used include cross-N-maleimido-6-aminocaproyl ester or m-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS) (see, 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). (1998)). When present, the carrier and spacer may be attached to either end of the immunogen.

[0465] Peptides, including optional spacers and carriers, can be used to immunize experimental animals or B cells, as described in more detail below. Hybridoma supernatants can be tested for binding to tau peptides comprising or consisting of the amino acid sequence 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), and / or phosphorylated and nonphosphorylated forms of tau, e.g., the full-length isoform of tau having position 404 in the phosphorylated form. The peptides can be conjugated to a carrier or other tag to facilitate screening assays. In this case, the carrier or tag is selectively different from the spacer and carrier molecule combination used in immunization to exclude antibodies specific for 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 clear from the context, reference to 9F5 should be understood to refer to any of the murine, chimeric, veneered, and humanized forms of this antibody. The antibody has been deposited under [DEPOSIT NUMBER]. This antibody specifically binds to a peptide comprising or consisting of the amino acid sequence QIVYKP (SEQ ID NO: 57), a peptide comprising or consisting of the amino acid sequence EIVYKSP (SEQ ID NO: 58), or a peptide comprising or consisting of the amino acid sequence (Q / E)IVYK(S / P) (SEQ ID NO: 56). The Kabat / Chothia composite CDRs of the heavy chain of 9F5 are designated SEQ ID NOs: 8, 9, and 10, respectively, and the Kabat / Chothia composite CDRs of the light chain of 9F5 are designated SEQ ID NOs: 12, 13, and 14, respectively.

[0467] Additional 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 mature variable heavy and light chain regions (after cleavage of the signal peptide) characterized by SEQ ID NO:7 and SEQ ID NO:11, respectively. Unless otherwise clear from the context, reference to 10C12 should be understood to refer to any of the murine, chimeric, veneered, and humanized forms of this antibody. 10C12 has been deposited under [deposit number]. 10C12 is further characterized by its ability to bind to both non-pathological and pathological forms and conformations of tau, as well as misfolded / aggregated forms of tau. 10C12 is associated with structural properties such as tau fibrillar tangles and degenerated neurites in tissues from Alzheimer's disease, and precipitates monomeric and aggregated tau from Alzheimer's disease extracts.

[0468] 2D11 has mature variable heavy and light chain regions (after cleavage of the signal peptide) characterized by SEQ ID NO:7 and SEQ ID NO:11, respectively. Unless otherwise clear from the context, reference to 2D11 should be understood to refer to any of the murine, chimeric, veneered, and humanized forms of this antibody. 2D11 has been deposited under [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 misfolded / aggregated forms of tau. 2D11 is associated with structural properties, such as tau fibrillar tangles and degenerated neurites, in Alzheimer's disease-derived tissues, and precipitates monomeric and aggregated tau from Alzheimer's disease extracts.

[0469] 12C4 has mature variable heavy and light chain regions (after cleavage of the signal peptide) characterized by SEQ ID NO:219 and SEQ ID NO:11, respectively. Unless otherwise clear from the context, reference to 12C4 should be understood to refer to any of the murine, chimeric, veneered, and humanized forms of this antibody. 12C4 has been deposited under [deposit number]. 12C4 is further characterized by its ability to bind to both non-pathological and pathological forms and conformations of tau, as well as misfolded / aggregated forms of tau. 12C4 is associated with structural properties, such as tau fibrillar tangles and degenerated neurites, in Alzheimer's disease-derived tissues, and precipitates monomeric and aggregated tau from Alzheimer's disease extracts.

[0470] 17C12 has mature variable heavy and light chain regions (after cleavage of the signal peptide) characterized by SEQ ID NO:225 and SEQ ID NO:228, respectively. Unless otherwise clear from the context, reference to 17C12 should be understood to refer to any of the murine, chimeric, veneered, and humanized forms of this antibody. 17C12 has been deposited under [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 misfolded / aggregated forms of tau.

[0471] 14H3 has mature variable heavy and light chain regions (after cleavage of the signal peptide) characterized by SEQ ID NOS: 240 and 244, respectively. Unless otherwise clear from the context, reference to 14H3 should be understood to refer to any of the murine, chimeric, veneered, and humanized forms of this antibody. 14H3 has been deposited under [deposit number]. 14H3 is further characterized by its ability to bind to both non-pathological and pathological forms and conformations of tau, as well as misfolded / aggregated forms of tau. 14H3 has been associated with structural properties such as tau fibrillar tangles and degenerated neurites in tissues derived from Alzheimer's disease.

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

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

[0474] Some antibodies of the present invention bind to the same or overlapping epitope as antibodies designated 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3. The sequences of the mature heavy and light chain variable regions of 9F5 are set forth as SEQ ID NOs:7 and 11, respectively. The sequences of the mature heavy and light chain variable regions of 10C12 are set forth as SEQ ID NOs:7 and 11, respectively. The sequences of the mature heavy and light chain variable regions of 2D11 are set forth as SEQ ID NOs:7 and 11, respectively. The sequences of the mature heavy and light chain variable regions of 12C4 are set forth as SEQ ID NOs:219 and 11, respectively. The sequences of the mature heavy and light chain variable regions of 17C12 are set forth as SEQ ID NOs:225 and 228, respectively. The sequences of the mature heavy and light chain variable regions of 14H3 are set forth as SEQ ID NOs:240 and 244, respectively. Other antibodies having such binding specificity can be produced by immunizing mice with tau or a portion thereof comprising a desired epitope (e.g., a tau peptide comprising or consisting of the amino acid sequence QIVYKP (SEQ ID NO: 57), a tau peptide comprising or consisting of the amino acid sequence EIVYKSP (SEQ ID NO: 58), a tau peptide comprising or consisting of the amino acid sequence EIVYKS (SEQ ID NO: 277), or a tau peptide comprising or consisting of the amino acid sequence (Q / E)IVYK(S / P) (SEQ ID NO: 56)), and screening the resulting antibodies for binding to tau, optionally in competition with antibodies having the variable regions of murine 9F5 (IgG1 / κ), 10C12 (IgG2a / κ), 2D11 (IgG2a / κ), 12C4 (IgG2a / κ), 17C12 (IgG2a / κ), or 14H3 (IgG2a / κ). Fragments of tau containing the desired epitope may be conjugated to a carrier and / or combined with an adjuvant to help elicit an antibody response against the fragment. Such antibodies may be screened for differential binding to tau or its fragments compared to mutants of specified residues.Screening against such mutants allows for more precisely defining binding specificity, thereby identifying antibodies whose binding is inhibited by mutagenesis of specific residues, possibly sharing the functional properties of other exemplified antibodies. The mutations can be systematic substitutions with alanine (or serine, if alanine is already present), one residue at a time or at more widely spaced intervals, across the target or across a section of it where the epitope is known to remain. If the same set of mutations significantly reduces binding of two antibodies, then the two antibodies bind to the same epitope.

[0475] Antibodies having the binding specificity of a selected murine antibody (e.g., 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3) can also be produced using variants of the phage display method. See Winter, International Patent Publication No. 92 / 20791. This method is particularly suitable for producing human antibodies. In this method, the heavy or light chain variable region of a selected murine antibody is used as the starting material. For example, if a light chain variable region is selected as the starting material, a phage library is constructed in which members display the same light chain variable region (i.e., the murine starting material) and different heavy chain variable regions. The heavy chain variable region can be obtained, for example, from a library of rearranged human heavy chain variable regions. Phages (e.g., at least 10 8 , preferably at least 10 9 M -1 ) are selected. The heavy chain variable region from this phage then serves as starting material for constructing a further phage library, in which 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. The light chain variable region may be obtained from a library of rearranged human variable light chain regions. Again, phage that show strong specific binding to tau or a fragment thereof are selected. The resulting antibodies typically have the same or similar epitope specificity as the murine starting material.

[0476] The Kabat / Chothia composite CDRs of the heavy chain of 9F5 are represented by SEQ ID NOs: 8 to 10, respectively, and the Kabat / Chothia composite CDRs of the light chain of 9F5 are represented by SEQ ID NOs: 12 to 14, respectively.

[0477] The Kabat / Chothia composite CDRs of the heavy chain of 10C12 are represented by SEQ ID NOs: 8 to 10, respectively, and the Kabat / Chothia composite CDRs of the light chain of 10C12 are represented by SEQ ID NOs: 12 to 14, respectively.

[0478] The Kabat / Chothia composite CDRs of the heavy chain of 2D11 are represented by SEQ ID NOs: 8 to 10, respectively, and the Kabat / Chothia composite CDRs of the light chain of 2D11 are represented by SEQ ID NOs: 12 to 14, respectively.

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

[0480] The composite Kabat / Chothia CDRs of the heavy chain of 12C4 are represented as SEQ ID NOs: 8, 220, and 10, respectively, and the Kabat CDRs of the light chain of 12C4 are represented as SEQ ID NOs: 12-14, respectively.

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

[0482] The Kabat / Chothia composite CDRs of the heavy chain of 17C12 are represented as SEQ ID NOS: 226, 227, and 10, respectively, and the Kabat CDRs of the light chain of 17C12 are represented as SEQ ID NOS: 229-231, respectively.

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

[0484] The Kabat / Chothia composite CDRs of the heavy chain of 14H3 are represented as SEQ ID NOs: 241 to 243, respectively, and the Kabat CDRs of the light chain of 14H3 are represented as SEQ ID NOs: 245 to 247, respectively.

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

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

[0487] The present invention also provides antibodies having some or all (e.g., three, four, five, and six) 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. An antibody may comprise both a heavy chain and a light chain. A CDR is substantially derived from the corresponding 9F5 CDR if it contains no more than 4, 3, 2, or 1 substitutions, insertions, or deletions, except that CDR-H2 (as defined by Kabat) may have no more than 6, 5, 4, 3, 2, or 1 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 the mature light chain variable region, may retain their functional properties, and / or may differ from 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3 by a small number of functionally minor amino acid substitutions (e.g., conservative substitutions), deletions, or insertions.

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

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

[0490] B. Non-human antibodies Production of other non-human antibodies, e.g., mouse, guinea pig, primate, rabbit, or rat antibodies, against tau, or a fragment thereof (e.g., a peptide comprising 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)) can be achieved, for example, by immunizing the animal with tau or a fragment thereof. See Harlow & Lane, Antibodies, A Laboratory Manual (CSHP NY, 1988) (incorporated by reference for all purposes). Optionally, the immunogen can be 383-amino acid human tau (4R0N). Optionally, the immunogen can be human tau containing the P301S mutation. Optionally, the immunogen can be recombinantly N-terminally His-tagged human tau. Optionally, animals are immunized with a tau fragment containing a peptide represented by (Q / E)IVYK(S / P) (SEQ ID NO: 56) conjugated 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 can be administered fused to or otherwise complexed with a carrier protein. Optionally, the immunogen can be administered with an adjuvant. Several types of adjuvants can be used, as described below. Complete Freund's adjuvant, followed by incomplete adjuvant, can be used to immunize laboratory animals. Rabbits or guinea pigs are usually used to generate polyclonal antibodies. Mice are usually used to generate monoclonal antibodies. Antibodies are screened for specific binding to tau or an epitope 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 can be performed against 15 amino acid peptides containing QIVYKP (SEQ ID NO:57), EIVYKSP (SEQ ID NO:58), EIVYKS (SEQ ID NO:277), or any other consensus motif represented by (Q / E)IVYK(S / P) (SEQ ID NO:56). Optionally, the peptides include QIVYKP (SEQ ID NO:57), EIVYKSP (SEQ ID NO:58), or EIVYKS (SEQ ID NO:277). Such screening can be accomplished by determining antibody binding to a collection of tau variants, such as tau variants containing or consisting of amino acid residues 307-312, or 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 can be assessed, for example, by Western blot, FACS, or ELISA.

[0491] C. Humanized Antibodies Humanized antibodies are genetically engineered antibodies in which CDRs from a non-human "donor" antibody are grafted into the sequences of a human "acceptor" antibody (see, e.g., U.S. Pat. Nos. 5,530,101 and 5,585,089 (Queen); U.S. Pat. Nos. 5,225,539 (Winter); 6,407,213 (Carter); 5,859,205 (Adair); and 6,881,557 (Foote)). The sequences of the acceptor antibody can be, for example, the sequences of a mature human antibody, a composite of such sequences, a consensus sequence of human antibody sequences, or a sequence of a germline region. Thus, a humanized antibody is an antibody having at least three, four, five, or all of the CDRs, completely or substantially, derived from the donor antibody, and variable region framework sequences and constant regions, if present, completely or substantially, derived from human antibody sequences. Similarly, a humanized heavy chain has at least one, two, and usually all three CDRs completely or substantially derived from the heavy chain of a donor antibody, and heavy chain variable region framework sequences and heavy chain constant regions, if present, substantially derived from human heavy chain variable region framework and constant region sequences. Similarly, a humanized light chain has at least one, two, and usually all three CDRs completely or substantially derived from the light chain of a donor antibody, and light chain variable region framework sequences and light chain constant regions, if present, substantially derived from human light chain variable region framework and constant region sequences. Other than nanobodies and dAbs, humanized antibodies include humanized heavy chains and humanized light chains. The CDRs of a humanized antibody are derived from substantially the corresponding CDRs in a non-human antibody if at least 85%, 90%, 95%, or 100% of the corresponding residues (defined by any conventional definition, but preferably by Kabat) are identical between each CDR. The framework sequences of the variable region of an antibody chain or the constant region of an antibody chain are substantially derived from the framework sequences of a human variable region or human constant region, respectively, if at least 85%, 90%, 95%, or 100% of the corresponding residues as defined by Kabat are identical.For a humanized antibody to be classified as humanized under the 2014 World Health Organization (WHO) International Nonproprietary Name (INN) definition, the antibody must have at least 85% identity to the human germline antibody sequence (i.e., prior to somatic mutations). A mixed antibody is one in which one antibody chain (e.g., the heavy chain) conforms to a threshold, but the other chain (e.g., the light chain) does not. If neither chain conforms to the threshold, even though the variable framework regions in both chains are substantially human with some mouse backmutations, the antibody is classified as chimeric. 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 at http: / / www.who.int / medicines / services / inn / BioRev2014.pdf) (incorporated herein by reference). For the avoidance of doubt, the term "humanized," as used herein, is not intended to be limited to the 2014 WHO INN definition of a humanized antibody. Some humanized antibodies provided herein have at least 85% sequence identity with human germline sequences, and some humanized antibodies provided herein have less than 85% sequence identity with human germline sequences. Some heavy chains of the humanized antibodies provided herein have about 60-100% sequence identity with human germline sequences, e.g., about 60%-69%, 70%-79%, 80%-84%, or 85%-89% sequence identity.Some heavy chains fall below the 2014 WHO INN definition, e.g., have about 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, or 82%, 83%, or 84% sequence identity to human germline sequences, while other heavy chains meet the 2014 WHO INN definition, have about 85%, 86%, 87%, 88%, 89% or more sequence identity to human germline sequences. Some light chains of the humanized antibodies provided herein have about 60% to 100% sequence identity to human germline sequences, e.g., within the range of about 80% to 84% or 85% to 89% sequence identity. Some light chains fall below the 2014 WHO INN definition, e.g., having about 81%, 82%, 83%, or 84% sequence identity to human germline sequences, while other light chains meet the 2014 WHO INN definition, having about 85%, 86%, 87%, 88%, 89%, or more sequence identity to human germline sequences. Some humanized antibodies provided herein that are "chimeric" under the 2014 WHO INN definition have a heavy chain that is less than 85% identical to human germline sequences paired with a light chain that is less than 85% identical to human germline sequences. For example, some humanized antibodies provided herein that have a heavy chain that is less than 85% identical to human germline sequences paired with a light chain that is less than 85% identical to human germline sequences, or vice versa, are "mixed" under the 2014 WHO INN definition. Some humanized antibodies provided herein meet the 2014 WHO INN definition of "humanized" and have a heavy chain having at least 85% sequence identity to a human germline sequence paired with a light chain having at least 85% sequence identity to a human germline sequence. Exemplary 12C4 antibodies that meet the 2014 WHO INN definition of "humanized" include antibodies having a mature heavy chain having the amino acid sequence of SEQ ID NO:221 or SEQ ID NO:222 paired with a mature light chain sequence having the amino acid sequence of SEQ ID NO:223 or SEQ ID NO:224.Exemplary 14H3 antibodies that meet the 2014 WHO INN definition of "humanized" include antibodies having a mature heavy chain having the amino acid sequence of SEQ ID NO: 248 or SEQ ID NO: 249 paired with a mature light chain sequence having the amino acid sequence of SEQ ID NO: 251 or SEQ ID NO: 252. Some humanized antibodies provided herein meet the 2014 WHO INN definition of "mixed." Exemplary 9F5 antibodies that meet the 2014 WHO INN definition of "mixed" include antibodies having a mature heavy chain having the amino acid sequence of any of SEQ ID NOs: 15-22 and 127-128 paired with a mature light chain sequence having the amino acid sequence of any of SEQ ID NOs: 26-29 and 130-131. Exemplary 10C12 antibodies that meet the 2014 WHO INN definition of "mixed" include antibodies having a mature heavy chain having the amino acid sequence of SEQ ID NO: 214 or SEQ ID NO: 215 paired with a mature light chain sequence having the amino acid sequence of SEQ ID NO: 216 or 217. Exemplary 17C12 antibodies that meet the 2014 WHO INN definition of "mixed" include antibodies 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 sequence having the amino acid sequence of SEQ ID NO: 235. Further humanized 9F5 antibodies of the invention include antibodies having a mature heavy chain having the amino acid sequence of any of SEQ ID NOs: 15-22 and 127-128 paired with a mature light chain having the amino acid sequence of any of SEQ ID NOs: 23-25. Further humanized 17C12 antibodies of the invention include antibodies 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 as defined by Kabat) from a murine antibody, although they can also be made with fewer than all CDRs (e.g., at least three, four, or five CDRs) from a murine antibody (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] In some antibodies, only a portion of the CDR, called the SDR, i.e., a subset of CDR residues required for binding, is required to maintain binding of the humanized antibody. CDR residues that do not contact the antigen and are not in the SDR can be identified from regions of the Kabat CDR other than the Chothia hypervariable loops (Chothia, J. Mol. Biol. 196:901, 1987), by molecular modeling and / or experience, or based on previous testing as described in Gonzales et al., Mol. Immunol. 41:863, 2004 (e.g., residues H60-H65 of CDR H2 are often not required). In such humanized antibodies, where one or more donor CDR residues are absent or the entire donor CDR is omitted, the amino acid residues occupying those positions can be the amino acids occupying the corresponding positions (according to Kabat numbering) in the acceptor antibody sequence. The number of substitutions of acceptor donor amino acids in such included CDRs reflects a balance of competing considerations. Such substitutions are potentially advantageous in reducing the number of murine amino acids in the humanized antibody and, as a result, reducing potential immunogenicity, and / or in order to meet the WHO INN definition of "humanization." However, substitutions may also result in changes in affinity, and significant reductions in affinity are preferably avoided. The substitution positions within the CDRs and the substituted amino acids may also be empirically selected.

[0494] The sequence of the human acceptor antibody can optionally be selected from many known human antibodies to provide a high degree of sequence identity (e.g., 65-85% identity) between the framework of the human acceptor sequence variable region 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 experimental error), e.g., binding affinity for human tau and inhibition of tau internalization into neurons, as described in the Examples, as the murine antibodies from which they are derived. For example, some humanized and chimeric antibodies have binding affinities within a factor of 3, 2, or 1 of the murine antibodies from which they are derived, or affinities that are indistinguishable within experimental error. Some humanized and chimeric antibodies inhibit tau internalization into neurons as described in the Examples within a factor of 3, 2, or 1 of the murine antibodies from which they are derived, or inhibit the same as the murine antibodies from which they are derived, within experimental error.

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

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

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

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

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

[0500] If more than one human acceptor antibody sequence is selected, a composite or hybrid of these acceptors can be used, and the amino acids used at different positions in the humanized light and heavy chain variable regions can be taken from any of the human acceptor antibody sequences used. For example, the human mature heavy chain variable region of AAN16432-VH_huFrwk (SEQ ID NO: 31) and humanized 48G7 Fab with PDB accession code 2RCS-VH_huFrwk (SEQ ID NO: 32) were used as hybrid acceptor sequences for humanization of the 9F5 mature heavy chain variable region. Examples of positions where the two acceptors differ are 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). A humanized version of the 9F5 heavy chain variable region may include any of the 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 of 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 positions where these two acceptors differ are positions 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). A humanized version of the 9F5 light chain variable region can include any of the amino acids at any of these positions. * 01 & IGKJ2 * 01 (SEQ ID NO: 37) was also used as the acceptor sequence for humanization of the 9F5 mature light chain variable region.

[0501] Specific amino acids from the framework residues of the human variable region may be selected for substitution based on their potential effect on CDR conformation and / or antigen binding, which may be determined by modeling, testing the characteristics of the amino acid at a particular position, or by experimentally observing the effect of substituting or mutagenesing specific amino acids.

[0502] For example, if an amino acid differs between a residue in the murine variable region framework and a residue in the selected human variable region framework, the amino acid in the human framework may be: (1) Direct non-covalent binding to the antigen or (2) adjacent to or within the CDR region, as defined by Chothia but not Kabat; (3) interact with the CDR region in some other way (e.g., within about 6 Å of the CDR region) (e.g., identified by modeling the light or heavy chain on the resolved structure of a homologous known immunoglobulin chain); or (4) Residues involved in the VL-VH interface If it is reasonably predicted that this will occur, amino acids from the equivalent framework from the mouse antibody may be substituted.

[0503] In one embodiment, humanized sequences are generated using QuikChange site-directed mutagenesis, a two-step PCR protocol that allows for the introduction of multiple mutations, deletions, and insertions [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 alternatively as canonical and veneer residues. Framework residues that help define the conformation of the CDR loop are sometimes referred to as 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 conformation of the antigen-binding loop and play a role in fine-tuning the fit of the antibody to the antigen are sometimes referred to as veneer 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 in the acceptor human framework that are rare in human immunoglobulins at that position. These amino acids can be substituted with amino acids from the equivalent position in the mouse donor antibody 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 glutamic acid (E) to minimize the possibility of conversion to pyroglutamic acid [Y. Diana Liu, et al., 2011, J. Biol. Chem., 286: 11211-11217]. Conversion of glutamic acid (E) to pyroglutamic acid (pE) is slower than conversion from glutamine (Q). Due to the loss of a primary amine in the conversion of glutamine to pE, the antibody becomes more acidic. Incomplete conversion leads to antibody heterogeneity, which can be observed as multiple peaks using charge-based analytical methods. Differences in heterogeneity may represent loss of process control. Exemplary 9F5 humanized heavy chain variable regions with N-terminal glutamine to glutamate substitutions are SEQ ID NO:16 (hu9F5VHv2), SEQ ID NO:17 (hu9F5VHv3), SEQ ID NO:18 (hu9F5VHv4), SEQ ID NO:19 (hu9F5VHv5), SEQ ID NO:20 (hu9F5VHv6), SEQ ID NO:21 (hu9F5VHv7), SEQ ID NO:22 (hu9F5VHv8), SEQ ID NO: 109 (hu9F5VHv4_L80P), SEQ ID NO: 110 (hu9F5VHv4_L80D), SEQ ID NO: 111 (hu9F5VHv4_L82cG), SEQ ID NO: 112 (hu9F5VHv4_L82cD), SEQ ID NO: 113 (hu9F5VHv4_L82P), SEQ ID NO: 114 (hu9F5VHv4_L80G), SEQ ID NO: 115 (hu9F5VHv4_L82K ), SEQ ID NO: 116 (hu9F5VHv4_L82R), SEQ ID NO: 117 (hu9F5VHv4_L82E), SEQ ID NO: 118 (hu9F5VHv4_L82N), SEQ ID NO: 119 (hu9F5VHv4_Y79D), SEQ ID NO: 120 (hu9F5VHv4_Y79N), SEQ ID NO: 121 (hu9F5VHv4_Y79G), SEQ ID NO: 122 (hu9F5VHv5_M80E ), SEQ ID NO: 123 (hu9F5VHv5_M80G), SEQ ID NO: 124 (hu9F5VHv4_L82cS), SEQ ID NO: 125 (hu9F5VHv4_Y79Q), SEQ ID NO: 126 (hu9F5VHv4_S82aG), SEQ ID NO: 127 (hu9F5VHv9), SEQ ID NO: 128 (hu9F5VHv10), SEQ ID NO: 129 (hu9F5VHv10_L82cG).An exemplary 10C12 humanized heavy chain variable region with an N-terminal glutamine to glutamate substitution is SEQ ID NO: 215 (hu10C12VHv2). An exemplary 12C4 humanized heavy chain variable region with an N-terminal glutamine to glutamate substitution is SEQ ID NO: 222 (hu12C4VHv2). An exemplary 17C12 humanized heavy chain variable region with an N-terminal glutamine to glutamate substitution is SEQ ID NO: 233 (hu17C12VHv2).

[0507] Exemplary humanized antibodies include the humanized form of murine 9F5, designated Hu9F5.

[0508] Murine antibody 9F5 comprises a mature heavy chain variable region and a mature light chain variable region having amino acid sequences comprising SEQ ID NO: 7 and SEQ ID NO: 11, respectively. The present invention provides 29 exemplified 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 (SEQ ID NO: 116), hu9F5VHv4_L82E (SEQ ID NO: 117), hu9F5VHv4_L82N (SEQ ID NO: 118), hu9F5VHv4_Y79D (SEQ ID NO: 119), hu9F5VHv4_Y79N (SEQ ID NO: 120), hu9F5VHv4_Y79G (SEQ ID NO: 121), hu9F5VHv5_M80E (SEQ ID NO: 122), h Provided are u9F5VHv5_M80G (SEQ ID NO: 123), hu9F5VHv4_L82cS (SEQ ID NO: 124), hu9F5VHv4_Y79Q (SEQ ID NO: 125), hu9F5VHv4_S82aG (SEQ ID NO: 126), hu9F5VHv9 (SEQ ID NO: 127), hu9F5VHv10 (SEQ ID NO: 128), and hu9F5VHv10_L82cG (SEQ ID NO: 129). The present invention further provides 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 (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_L33N (SEQ ID NO: 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 (SEQ ID NO: 85), hu9F5VLv2_V78D (SEQ ID NO: 86), hu9F5VLv2_V78E (SEQ ID NO: 87), hu9F5VLv2_V78P (SEQ ID NO: 88), hu9F5VLv2_V78K (SEQ ID NO: 89), hu9F5VLv2_R77D (SEQ ID NO: 90), hu9F5VLv2_V78G (SEQ ID NO: 91), hu9F5VLv2_S76P (SEQ ID NO: 92), hu9F5VLv2_I75P (SEQ ID NO: 93), hu9F5VLv2_I75Q (SEQ ID NO: 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 (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), hu9F5V Lv8_DIM8 (SEQ ID NO: 139), hu9F5VLv8_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), 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 (SEQ ID NO: 159), hu9F5VLv8_DIM29 (SEQ ID NO: 160), hu9F5VLv8_DIM30 (SEQ ID NO: 161), hu9F5VLv9_DIM1 (SEQ ID NO: 162), hu9F5VLv9_DIM2 (SEQ ID NO: 163), hu9F5VLv9_DIM4 (SEQ ID NO: 164), hu9F5VLv9_DIM5 (SEQ ID NO: 165), hu9F5VLv9_DIM8) (SEQ ID NO: 166), hu9F5VLv9_DIM10 (SEQ ID NO: 167), hu9F5VLv9_DIM11 (SEQ ID NO: 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 alignments of the heavy chain variable regions of murine 9F5 and various humanized antibodies. Figures 2A-2B and 5A-5B show alignments of the light chain variable regions of murine 9F5 and various humanized antibodies. Figures 6A-6C show alignments of the light chain variable regions of humanized variant hu9F5VLv8 and various humanized antibodies.

[0509] The following 48 variable region framework positions were selected for inclusion in the 95 illustrated human mature light chain variants, as further detailed in the Examples, for reasons such as possible effects on CDR conformation and / or binding to antigen, interactions between heavy and light chains, mediating interactions with the constant region, being sites of desirable or undesirable post-translational modifications, being residues that are rare at that position in human variable region sequences and therefore potentially immunogenic, reducing the likelihood of aggregation, and other reasons: The variable regions and 29 exemplified substitutions in the human mature light chain variable region were considered: 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), L76 (I76D, I76P, I76Q, I76G), L77 (I77D, I77P, I77Q, I77G), L78 (I78D, I78P, I78G), L79 (I79D, I79P, I79Q, I79G), L80 (I79D, I79S, I79S), L81 (I79D, I79S, I79S), L82 (I79K), L83 (I79K, I79S), L84 (I79K), L85 (I79K, I79K), L86 (I79K, I79K), L87 (I79K, I79K), L88 (I79K, I79K), L89 (I79K, I79K), L90 (I79K, I79K), L91 (I79K, I79K), L92 (I79K, I79K), L93 (I79K, I79K), L94 (I79K, I79K), L95 (I79K, I79K), L96 (I79 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 variable region CDR positions were considered as candidates for substitution in 95 exemplified human mature light chain variable regions and 29 exemplified 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, In some humanized 9F5 antibodies, the Kabat / Chothia composite CDR-H1 has an amino acid sequence comprising SEQ ID NO:50. In some humanized 9F5 antibodies, the Kabat / Chothia composite CDR-H1 has an amino acid sequence comprising SEQ ID NO: 50, and the Kabat CDR-H2 has an amino acid sequence comprising SEQ ID NO: 51. In some humanized 9F5 antibodies, the Kabat CDR-H2 has an amino acid sequence comprising SEQ ID NO: 51. In some humanized 9F5 antibodies, the Kabat CDR-H2 has an amino acid sequence comprising SEQ ID NO: 52. In some humanized 9F5 antibodies, the Kabat CDR-L2 has an amino acid sequence comprising SEQ ID NO: 55. In some humanized 9F5 antibodies, the Kabat CDR-L1 has an amino acid sequence comprising SEQ ID NO: 53, and the Kabat CDR-L2 has an amino acid sequence comprising SEQ ID NO: 55. In some humanized 9F5 antibodies, the Kabat CDR-L1 has an amino acid sequence comprising SEQ ID NO: 54, and the Kabat CDR-L2 has an amino acid sequence comprising SEQ ID NO: 55. In some humanized 9F5 antibodies, the Kabat CDR-L1 has an amino acid sequence comprising a 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 comprising a 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 comprising a sequence selected from the group consisting of SEQ ID NOs: 206-213.

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

[0511] The exemplified antibodies may be any permutation or combination of the exemplified mature heavy chain variable regions and mature light chain variable regions: hu9F5VHv1 / hu9F5VLv1, hu9F5VHv1 / hu9F5VLv2, hu9F5VHv1 / hu9F5VLv3, hu9F5VHv1 / hu9F5VLv4, hu9F5VLv1 / hu9F5VLv5, hu9F5VHv1 / hu9F5VLv6, hu9F5VHv1 / hu9F5VLv7, hu9F5VHv2 / hu9F5VLv1, hu9F5VHv2 / hu9F5VLv2, hu9F5VHv2 ...2 / hu9F5VLv4, 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,Including hu9F5VHv7 / hu9F5VLv6, hu9F5VHv7 / hu9F5VLv7, hu9F5VHv8 / hu9F5VLv1, hu9F5VHv8 / hu9F5VLv2, hu9F5VHv8 / hu9F5VLv3, hu9F5VHv8 / hu9F5VLv4, hu9F5VLv8 / hu9F5VLv5, hu9F5VHv8 / hu9F5VLv6, hu9F5VHv8 / hu9F5VLv7.

[0512] Exemplary antibodies include the 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_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_L33N (SEQ ID NO: 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), hu9F5VL v2_V78R (SEQ ID NO: 84), hu9F5VLv2_I75D (SEQ ID NO: 85), hu9F5VLv2_V78D (SEQ ID NO: 86), hu9F5VLv2_V78E (SEQ ID NO: 87), hu9F5VLv2_V78P (SEQ ID NO: 88), hu9F5VLv2_V78K (SEQ ID NO: 89), hu9F5VLv2_R77D (SEQ ID NO: 90), hu9F5VLv2_V78G (SEQ ID NO: 91), hu9F5VLv2_S76P (SEQ ID NO: 92), hu9F5VLv2_I75P (SEQ ID NO: 93), hu9F5VLv2_I75Q (SEQ ID NO: 94),hu9F5VLv2_I75G (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 (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 (SEQ ID NO: 139), hu9F5VLv8_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), 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 (SEQ ID NO: 159), hu9F5VLv8_DIM29 (SEQ ID NO: 160), hu9F5VLv8_DIM30 (SEQ ID NO: 161), hu9F5VLv9_DIM1 (SEQ ID NO: 162), hu9F5VLv9_DIM2 (SEQ ID NO: 163), hu9F5VLv9_DIM4 (SEQ ID NO: 164), hu9F5VLv9_DIM5 (SEQ ID NO: 165), hu9F5VLv9_DIM8 (SEQ ID NO: 166), hu9F5VLv9_DIM10 (SEQ ID NO: 167), hu9F5VLv9_DIM11 (SEQ ID NO: 168), 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), hu9F5VLv9_DIM13 (SEQ ID NO: 169), hu9F5VLv9_DIM19 (SEQ ID NO: 170), and hu9F5VLv9_DIM20 (SEQ ID NO: 171). No. 22), hu9F5VHv9 (SEQ ID NO: 127), hu9F5VHv10 (SEQ ID NO: 128), hu9F5VHv10_L82cG (SEQ ID NO: 129), 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 (SEQ ID NO: 116), hu9F5VHv4_L82E (SEQ ID NO: 117), hu9F5VHv4_L82N (SEQ ID NO: 118), hu9F5VHv4_Y79D (SEQ ID NO: 119), hu9F5VHv4_Y79N (SEQ ID NO: 120), hu9F5VHv4_Y79G (SEQ ID NO: 121), hu9F5VHv5_M80E (SEQ ID NO: 122), hu9F5VHv5_M80G (SEQ ID NO: 123), hu9F5VHv4_L82cS (SEQ ID NO: 124), hu9F5VHv4_Y79Q (SEQ ID NO: 125),and hu9F5VHv4_S82aG (SEQ ID NO: 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 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 antibodies 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 provides antibodies 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 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 antibodies 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 provides antibodies 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 antibodies 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 provides antibodies 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 antibodies 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 provides antibodies 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 antibodies 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 provides antibodies 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 humanized mature heavy chain variable regions selected from the group consisting of 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), hu9F5VHv9 (SEQ ID NO: 127), hu9F5VHv10 (SEQ ID NO: 128), hu9F5VHv10_L82cG (SEQ ID NO: 129), hu9F5VHv4_L80P (SEQ ID NO: 130), and hu9F5VHv5_L82cG (SEQ ID NO: 131). 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 (SEQ ID NO: 116), hu9F5VHv4_L82E (SEQ ID NO: 117), hu9F5VHv4_L82N (SEQ ID NO: 118), hu9F5VHv4_Y79D (SEQ ID NO: 119), 19), hu9F5VHv4_Y79N (SEQ ID NO: 120), hu9F5VHv4_Y79G (SEQ ID NO: 121), hu9F5VHv5_M80E (SEQ ID NO: 122), hu9F5VHv5_M80G (SEQ ID NO: 123), hu9F5VHv4_L82cS (SEQ ID NO: 124), hu9F5VHv4_Y79Q (SEQ ID NO: 125), or hu9F5VHv4_S82aG (SEQ ID NO: 126), and the humanized mature light chain variable region is hu9F5VLv1 (SEQ ID NO: 127), hu9F5VHv4_Y79N (SEQ ID NO: 120), hu9F5VHv4_Y79G (SEQ ID NO: 121), hu9F5VHv5_M80E (SEQ ID NO: 122), hu9F5VHv5_M80G (SEQ ID NO: 123), hu9F5VHv4_L82cS (SEQ ID NO: 124), hu9F5VHv4_Y79Q (SEQ ID NO: 125), or hu9F5VHv4_S82aG (SEQ ID NO: 126). 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 (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_L33N (SEQ ID NO: 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 (SEQ ID NO: 85) , hu9F5VLv2_V78D (SEQ ID NO: 86), hu9F5VLv2_V78E (SEQ ID NO: 87), hu9F5VLv2_V78P (SEQ ID NO: 88), hu9F5VLv2_V78K (SEQ ID NO: 89), hu9F5VLv2_R77D (SEQ ID NO: 90), hu9F5VLv2_V78G (SEQ ID NO: 91), hu9F5VLv2_S76P (SEQ ID NO: 92), hu9F5VLv2_I75P (SEQ ID NO: 93), hu9F5VLv2_I75Q (SEQ ID NO: 94), hu9F5VLv2_I75G (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 (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 (SEQ ID NO: 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 (SEQ ID NO: 160), hu9F5VLv8_DIM30 (SEQ ID NO: 161), hu9F5VLv9_DIM1 (SEQ ID NO: 162), hu9F5VLv9_DIM2 (SEQ ID NO: 163), hu9F5VLv9_DIM4 (SEQ ID NO: 164), hu9F5VLv9_DIM5 (SEQ ID NO: 165), hu9F5VLv9_DIM8 (SEQ ID NO: 166), hu9F5VLv9_DIM10 (SEQ ID NO: 167), hu9F5VLv9_DIM11 (SEQ ID NO: 168), hu9F5VLv9_DIM13 (SEQ ID NO: 169),Variants of the 9F5 humanized antibody are provided that exhibit at least 90%, 95%, 96%, 97%, 98%, or 99% identity to 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 subject to backmutation or other mutation in SEQ ID NOs: 15-22, 109-129, SEQ ID NOs: 23-29, SEQ ID NOs: 61-108, and SEQ ID NOs: 130-171 have similarly been backmutated 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 acid: H1 is occupied by E, H7 is occupied by T, H20 is occupied by I, H69 is occupied by M, H75 is occupied by T, H93 is occupied by T, H94 is occupied by T, and H109 is occupied 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 acid: 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 acid: 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 acid: H43 is occupied by K, H51 is occupied by V, H76 is occupied by D, M80 is occupied by M, and H108 is occupied 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, position H28 of the VH region is occupied by a T.

[0524] In some humanized 9F5 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 humanized 9F5 antibodies, positions H54 and H56 are occupied by D and E, respectively.

[0525] In some humanized 9F5 antibodies, position H40 of 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 is occupied by V, H12 is occupied by K, H38 is occupied by R, and H42 is occupied 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 is occupied by Q or V, H11 is occupied by L or V, H12 is occupied by V or K, H17 is occupied by S or T, H20 is occupied by L or I, H23 is occupied by T or K, H28 is occupied by N or T, H38 is occupied by K, R, or Q, H40 is occupied by R or A, H42 is occupied by E or G, H43 is occupied by Q or K, H48 is occupied by I or M, H51 is occupied by I or V, and H54 is occupied by N or D. H56 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.

[0528] In some humanized 9F5 antibodies, such as hu9F5VHv2, positions H1, H17, H20, H69, H75, H93, H94, and H109 of the VH region are occupied by E, T, I, M, T, T, T, and V, respectively. In some humanized 9F5 antibodies, such as hu9F5VHv3, positions H1, H17, H20, H66, H69, H75, H81, H93, H94, and H109 of 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, positions H1, H17, H20, H23, H28, H66, H69, H75, H81, H83, H93, H94, and H109 of 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, positions H1, H17, H20, H23, H28, H43, H51, H54, H56, H66, H69, H75, H76, H80, H81, H83, H93, H94, H108, and H109 of 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, positions H1, H17, H20, H23, H28, H40, H43, H48, H51, H54, H56, H66, H69, H75, H76, H80, H81, H83, H93, H94, H108, and H109 of 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, 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 of 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, 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 of 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, positions H1, H5, H11, H12, H17, H20, H23, H38, H42, H43, H66, H69, H75, H80, H81, H83, H93, H94, H108, and H109 of 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 comprises the amino acid sequence of SEQ ID NO: 127.

[0529] In some humanized 9F5 antibodies, positions H1, H5, H11, H12, H17, H20, H23, H38, H42, H43, H66, H69, H75, H80, H81, H83, H93, H94, H108, and H109 of 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, such as in hu9F5VHv10. In some humanized 9F5 antibodies, the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 128.

[0530] In some humanized 9F5 antibodies, 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, such as in 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 acid: L7 is occupied by S, L8 is occupied by P, L15 is occupied by P, and L100 is occupied 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 of the VL region is occupied by G. In some humanized 9F5 antibodies, position L64 of the VL region is occupied by S.

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

[0534] In some humanized 9F5 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. In some humanized 9F5 antibodies, positions L11, L51, and L54 are occupied by L, G, and R, respectively.

[0535] In some humanized 9F5 antibodies, position L30 of 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 indicated amino acid: 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 SEQ ID NO: 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 in hu9F5VLv1, positions L64 and L66 in the VL region are occupied by S and G, respectively. In some humanized 9F5 antibodies, such as in 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 in 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, 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 comprises the amino acid sequence of any of SEQ ID NOs: 133, 135-137, 142-144, 149, 158, 159, and 168. In some humanized 9F5 antibodies, the light chain variable region comprises the amino acid sequence of SEQ ID NO: 133. In some humanized 9F5 antibodies, the light chain variable region comprises the amino acid sequence of SEQ ID NO: 137. In some humanized 9F5 antibodies, the light chain variable region comprises the amino acid sequence of SEQ ID NO: 149. In some humanized 9F5 antibodies, the light chain variable region comprises the amino acid sequence of SEQ ID NO: 159.

[0539] In some humanized 9F5 antibodies, such as hu9F5VLv5, positions L7, L8, L11, L15, L17, L30, L51, L54, L66, and L100 in the VL region are occupied by S, P, L, P, E, Y, G, R, G, and Q, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv6, positions L7, L8, L11, L15, L17, L30, L51, L54, and L100 in the VL region are occupied by S, P, L, P, E, Y, G, R, and Q, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv7, 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, positions L7, L8, L11, L15, L17, L39, L64, L66, L74, and L100 in the VL region are occupied by S, P, L, P, E, K, S, G, K, and Q, respectively. In some humanized 9F5 antibodies, position L3 in the VL region is occupied by Q. In some humanized 9F5 antibodies, position L27c in the VL region is occupied by D, G, I, L, or S, position L37 in the VL region is occupied by G, I, L, or Q, position L51 in the VL region is occupied by E, G, I, K, or M, position L54 in the VL region is occupied by G, L, R, or T, and position L92 in the VL region is occupied by G, I, or L. In some humanized 9F5 antibodies, position L27c of the VL region is occupied by D or S, position L37 of the VL region is occupied by G, L, or Q, position L51 of the VL region is occupied by G or K, position L54 of the VL region is occupied by R, and position L92 of the VL region is occupied by I.

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

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

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

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

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

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

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

[0548] The light chain variable region of any of the above-described antibodies can 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; and position L60 of the VL region is occupied by D. position L73 in the VL region is occupied by P or G; position L75 in the VL region is occupied by D, P, Q, or G; position L76 in the VL region is occupied by P or G; position L77 in the VL region is occupied by D; position L78 in the VL region is occupied by R, D, E, P, K, G, or Q; position L85 in the VL region is occupied by G; position L86 in the VL region is occupied by T; position L89 in the VL region is occupied by G; position L92 in the VL region is occupied by D, E, G, Q, I, or T; and / or position L93 in the VL region is occupied by G (Kabat numbering).

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

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

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

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

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

[0554] In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L54G, L92I, also known as hu9F5VLv8_DIM1, positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, G, G, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L54R, L92I, also known as hu9F5VLv8_DIM2, positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, G, R, and I. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L54T, L92I, also known as hu9F5VLv8_DIM3, positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, G, T, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L54R, L92G, also known as hu9F5VLv8_DIM4, positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, G, R, and G, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cG, L37Q, M51G, L54R, L92I, also known as hu9F5VLv8_DIM5, 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, L92I, also known as hu9F5VLv8_DIM6, positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, D, Q, G, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cD, L37Q, M51K, L54R, L92I, also known as hu9F5VLv8_DIM7, positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, D, Q, K, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cG, L37Q, M51K, L54R, L92I, also known as hu9F5VLv8_DIM8, positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, Q, K, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cG, L37Q, M51K, L54G, L92I, also known as hu9F5VLv8_DIM9, positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, Q, K, G, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cS, L37Q, M51K, L54G, L92I, also known as hu9F5VLv8_DIM10, 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, L92I, also known as hu9F5VLv8_DIM11, positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, G, G, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54R, L92G, also known as hu9F5VLv8_DIM12, positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, G, G, R, and G, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54R, also known as hu9F5VLv8_DIM13, positions L3, L27c, L37, L51, and L54 in the VL region are occupied by Q, G, G, G, and R, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54T, L92I, also known as hu9F5VLv8_DIM14, positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, G, G, T, and I. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54T, L92G, also known as hu9F5VLv8_DIM15, 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, L54T, also known as hu9F5VLv8_DIM16, positions L3, L27c, L37, L51, and L54 in the VL region are occupied by Q, G, G, G, and T, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cS, L37G, M51G, L54T, L92I, also known as hu9F5VLv8_DIM17, positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, G, G, T, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cD, L37G, M51G, L54R, L92I, also known as hu9F5VLv8_DIM18, positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, D, G, G, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cS, L37I, M51I, L54R, L92I, also known as hu9F5VLv8_DIM19, positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, I, I, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cS, L37Q, M51I, L54G, L92I, also known as hu9F5VLv8_DIM20, 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, L54G, also known as hu9F5VLv8_DIM21, positions L3, L27c, L37, L51, and L54 in the VL region are occupied by Q, S, Q, I, and G, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cS, L37Q, M51E, L54R, L92I, also known as hu9F5VLv8_DIM22, positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, E, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cG, L37Q, M51E, L54G, L92I, also known as hu9F5VLv8_DIM23, 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, L92I, also known as hu9F5VLv8_DIM24, 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, L92G, also known as hu9F5VLv8_DIM25, 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, L54R, also known as hu9F5VLv8_DIM26, positions L3, L27c, L37, L51, and L54 in the VL region are occupied by Q, I, I, E, and R, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L37Q, M51G, L54R, L92I, also known as hu9F5VLv8_DIM27, positions L3, L37, L51, L54, and L92 in the VL region are occupied by Q, Q, G, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cS, M51G, L54R, L92I, also known as hu9F5VLv8_DIM28, positions L3, L27c, L51, L54, and L92 in the VL region are occupied by Q, S, G, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cS, L37Q, L54R, L92I, also known as hu9F5VLv8_DIM29, positions L3, L27c, L37, L54, and L92 in the VL region are occupied by Q, S, Q, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L92I, also known as hu9F5VLv8_DIM30, 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, L92I, also known as hu9F5VLv9_DIM1, positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, G, G, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv9_V3Q, L27cS, L37Q, M51G, L54R, L92I, also known as hu9F5VLv9_DIM2, positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, G, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv9_V3Q, L27cS, L37Q, M51G, L54R, L92G, also known as hu9F5VLv9_DIM4, positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, G, R, and G, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv9_V3Q, L27cG, L37Q, M51G, L54R, L92I, also known as hu9F5VLv9_DIM5, positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, Q, G, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv9_V3Q, L27cG, L37Q, M51K, L54R, L92I, also known as hu9F5VLv9_DIM8, 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, L92I, also known as hu9F5VLv9_DIM10, positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, K, G, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv9_V3Q, L27cG, L37G, M51G, L54R, L92I, also known as hu9F5VLv9_DIM11, positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, G, G, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv9_V3Q, L27cG, L37G, M51G, L54R, also known as hu9F5VLv9_DIM13, positions L3, L27c, L37, L51, and L54 in the VL region are occupied by Q, G, G, G, and R, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv9_V3Q, L27cS, L37I, M51I, L54R, L92I, also known as hu9F5VLv9_DIM19, positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, I, I, R, and I, respectively. In some humanized 9F5 antibodies, such as hu9F5VLv9_V3Q, L27cS, L37Q, M51I, L54G, L92I, also known as hu9F5VLv9_DIM20, positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, I, G, and I, respectively.

[0562] The heavy chain variable region of any of the above-described antibodies may also 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 in hu9F5VHv4_L82K. In some humanized 9F5 antibodies, position H82 is occupied by R, such as in hu9F5VHv4_L82R. In some humanized 9F5 antibodies, position H82 is occupied by E, such as in hu9F5VHv4_L82E. In some humanized 9F5 antibodies, position H82 is occupied by N, such as in 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 85% or more identity to human sequences. In some humanized 9F5 antibodies, the variable light chain has 85% or more identity to human sequences. In some humanized 9F5 antibodies, the variable heavy chain and variable light chain each have 85% or more identity to human germline sequences. In some humanized 9F5 antibodies, the three heavy chain CDRs are as defined by a Kabat / Chothia combination (SEQ ID NOs: 8, 9, and 10, respectively), and the three light chain CDRs are as defined by a Kabat / Chothia combination (SEQ ID NOs: 12, 13, and 14), except that 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, T, or Q. 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 composite CDR-H1 has an amino acid sequence comprising SEQ ID NO: 50. In some humanized 9F5 antibodies, the Kabat CDR-H2 has an amino acid sequence comprising SEQ ID NO: 51 or SEQ ID NO: 52. In some humanized 9F5 antibodies, the Kabat CDR-L1 has an amino acid sequence comprising SEQ ID NO: 53 or SEQ ID NO: 54. In some humanized 9F5 antibodies, the Kabat CDR-L2 has an amino acid sequence comprising 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] Exemplary humanized antibodies include the humanized form of murine 10C12, designated Hu10C12.

[0568] Murine antibody 10C12 comprises a mature heavy chain variable region and a mature light chain variable region having amino acid sequences comprising SEQ ID NO:7 and SEQ ID NO:11, respectively. The present invention provides two exemplary humanized mature heavy chain variable regions: hu10C12VHv1 and hu10C12VHv2. The present invention also provides two exemplary mature light chain variable regions: hu10C12VLv1 and hu10C12VLv2. Figures 7 and 8 show alignments of the heavy and light chain variable regions, respectively, of murine 10C12 and various humanized antibodies.

[0569] The following nine variable region framework positions were considered candidates for substitution in two exemplified human mature light chain variable regions and two exemplified human mature light chain variable regions, as further detailed in the Examples, for reasons such as possible effects on CDR conformation and / or binding to antigen, interactions between the heavy and light chains, mediating interactions with the constant region, being sites of desirable or undesirable post-translational modifications, being rare residues at that position in human variable region sequences and therefore potentially immunogenic, reducing the likelihood of aggregation, and other reasons: L64 (G64S), L104 (V104L), H1 (Q1E), H24 (V24A), H48 (M48I), H67 (V67A), H69 (I69M), H93 (A93T), and H94 (R94T).

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

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

[0572] The exemplified antibodies include any of the exemplified mature light chain variable regions hu10C12VLv1 (SEQ ID NO: 216) and hu10C12VLv2 (SEQ ID NO: 217) permutations or combinations of any of the exemplified mature heavy chain variable regions hu10C12VHv1 (SEQ ID NO: 214) and hu10C12VHv2 (SEQ ID NO: 215).

[0573] The present invention provides variants of the 10C12 humanized antibody in which the humanized mature heavy chain variable region exhibits at least 90%, 95%, 96%, 97%, 98%, or 99% identity to 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 to 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 of the backmutations 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 acid: H24 is occupied by A, H48 is occupied by I, H67 is occupied by A, H69 is occupied by M, H93 is occupied by T, and H94 is occupied 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 is occupied by A, H48 is occupied by I, H67 is occupied by A, H69 is occupied by M, H93 is occupied by T, and H94 is occupied 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 of the VL region is occupied by an 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, positions L64 and L104 in the VL region are occupied by S and L, respectively, such as in hu10C12VLv2.

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

[0581] Exemplary humanized antibodies include a humanized form of the murine 12C4 antibody, designated Hu12C4.

[0582] Murine antibody 12C4 comprises a mature heavy chain variable region and a mature light chain variable region having amino acid sequences comprising SEQ ID NO:219 and SEQ ID NO:11, respectively. The present invention provides two exemplary humanized mature heavy chain variable regions: hu12C4VHv1 and hu12C4VHv2. The present invention also provides two exemplary mature light chain variable regions: hu12C4VLv1 and hu12C4VLv2. Figures 9 and 10 show alignments of the heavy and light chain variable regions, respectively, of murine 12C4 and various humanized antibodies.

[0583] For reasons such as possible effects on CDR conformation and / or binding to antigen, interactions between the heavy and light chains, mediating interactions with the constant region, being sites of desirable or undesirable post-translational modifications, being a rare residue at that position in human variable region sequences and therefore potentially immunogenic, gaining potential for aggregation, and other reasons, the following six variable region framework positions were considered candidates for substitution in two exemplified human mature light chain variable regions and two exemplified 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 elsewhere, the first mentioned residue is the residue of the humanized antibody formed by grafting the Kabat CDR, or in the case of CDR-H1, the composite Chothia-Kabat CDR, onto a human acceptor framework, and the second mentioned residue is the residue proposed to replace that residue. Thus, within the variable region framework, the first mentioned residue is human, and within the CDRs, the first mentioned residue is murine.

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

[0586] The exemplified antibodies include any permutation or combination of the exemplified mature light chain variable regions hu12C4VLv1 (SEQ ID NO: 223) and hu12C4VLv2 (SEQ ID NO: 224) with any of the exemplified mature heavy chain variable regions hu12C4VHv1 (SEQ ID NO: 221) and hu12C4VHv2 (SEQ ID NO: 222).

[0587] The present invention provides variants of the 12C4 humanized antibody in which the humanized mature heavy chain variable region exhibits at least 90%, 95%, 96%, 97%, 98%, or 99% identity to 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 to hu12C4VLv1 (SEQ ID NO: 223) or hu12C4VLv2 (SEQ ID NO: 224). Some such antibodies retain at least one, two, three, four, five, or all six of the backmutations 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 is occupied by M or I, H93 is occupied by A or T, and H94 is occupied by R or T.

[0589] In some humanized 12C4 antibodies, such as hu12C4VHv2, positions H1, H48, H93, and H94 of 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; L104 is V or L;

[0591] In some humanized 12C4 antibodies, such as hu12C4VLv2, 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 has 85% or more identity to human sequences. In some humanized 12C4 antibodies, the variable light chain has 85% or more identity to human sequences. In some humanized 12C4 antibodies, the variable heavy chain and variable light chain each have 85% or more identity to human germline sequences. In some humanized 12C4 antibodies, the three heavy chain CDRs are as defined by the Kabat / Chothia combination (SEQ ID NOs: 8, 220, and 10), and the three light chain CDRs are as defined by the eKabat / Chothia combination (SEQ ID NOs: 12, 13, and 14).

[0593] An exemplary humanized antibody is a humanized form of murine 17C12, designated Hu17C12.

[0594] Murine antibody 17C12 comprises a mature heavy chain variable region and a mature light chain variable region having amino acid sequences comprising SEQ ID NOs: 225 and 228, respectively. The present invention provides two exemplary humanized mature heavy chain variable regions: hu17C12VHv and hu17C12VHv2. The present invention also provides two exemplary mature light chain variable regions: hu17C12VLv1 and hu17C12VLv2. Figures 11 and 12 show alignments of the heavy and light chain variable regions, respectively, of murine 17C12 and various humanized antibodies.

[0595] The following 13 variable region framework positions are further illustrated in the Examples for reasons such as their possible influence on CDR conformation and / or binding to antigen, interactions between heavy and light chains, mediating interactions with the constant region, being sites of desirable or undesirable post-translational modifications, being rare residues at that position in human variable region sequences and therefore potentially immunogenic, resulting in potential for aggregation, and other reasons: As detailed, two exemplary human mature light chain variable regions and two exemplary human mature light chain variable regions were considered as candidates for substitution: 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 elsewhere, the first mentioned residue is the residue of the humanized antibody formed by grafting the Kabat CDR, or in the case of CDR-H1, the composite Chothia-Kabat CDR, onto a human acceptor framework, and the second mentioned residue is the residue proposed to replace that residue. Thus, within the variable region framework, the first mentioned residue is human, and within the CDRs, the first mentioned residue is murine.

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

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

[0599] The present invention provides variants of the 17C12 humanized antibody in which the humanized mature heavy chain variable region exhibits at least 90%, 95%, 96%, 97%, 98%, or 99% identity to 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 to 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 of the backmutations or other mutations in SEQ ID NOs: 232-233 and SEQ ID NOs: 234-235 are retained.

[0600] In some humanized 17C12 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 is occupied by A, H48 is occupied by I, H67 is occupied by A, H69 is occupied by M, H93 is occupied by T, and H94 is occupied 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 is occupied by I, H24 is occupied by A, H48 is occupied by I, H67 is occupied by A, H69 is occupied by M, H93 is occupied by T, H94 is occupied by T, H108 is occupied by T or L, and H113 is occupied by R or S.

[0602] In some humanized 17C12 antibodies, such as hu17C12VHv1, 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, 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 36 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 has 85% or more identity to human sequences. In some humanized 17C12 antibodies, the variable light chain has 85% or more identity to human sequences. In some humanized 17C12 antibodies, the variable heavy chain and variable light chain each have 85% or more identity to human germline sequences. In some humanized 9F5 antibodies, the three heavy chain CDRs are as defined by a Kabat / Chothia composite (SEQ ID NOs: 226, 227, and 10), and the three light chain CDRs are as defined by a Kabat / Chothia composite (SEQ ID NOs: 229-231).

[0607] An exemplary humanized antibody is a humanized form of murine 14H3, designated Hu14H3.

[0608] Murine antibody 14H3 comprises a mature heavy chain variable region and a mature light chain variable region having amino acid sequences comprising SEQ ID NO:240 and SEQ ID NO:244, respectively. The present invention provides two exemplary humanized mature heavy chain variable regions: hu14H3VHv1 and hu14H3VHv2. The present invention also provides two exemplary mature light chain variable regions: hu14H3VLv1 and hu14H3VLv2. Figures 13 and 14 show alignments of the heavy and light chain variable regions, respectively, of murine 14H3 and various humanized antibodies.

[0609] For reasons such as possible effects on CDR conformation and / or binding to antigen, interactions between the heavy and light chains, mediating interactions with the constant region, being sites of desirable or undesirable post-translational modifications, being rare residues at that position in human variable region sequences and therefore potentially immunogenic, gaining potential for aggregation, and other reasons, the following eight variable region framework positions were considered candidates for substitution in two exemplified human mature light chain variable regions and two exemplified human mature light chain variable regions, as further detailed in the Examples: L2 (I2V), L7 (T7S), L37 (L37Q), L87 (Y87F), L100 (G100Q), L104 (V104L), H108 (M108L), and H113 (L113S). The following variable region CDR positions were considered as candidates for substitution in two exemplified human mature heavy chain variable regions, as further detailed in the Examp...

Claims

1. An isolated monoclonal antibody that competes with antibody 9F5 for binding to human tau.

2. The antibody of claim 1, wherein the heavy chain CDR-H3 has an amino acid sequence comprising SEQ ID NO:

10.

3. The antibody of claim 1, wherein the heavy chain CDR-H1 has an amino acid sequence comprising SEQ ID NO:

8.

4. The antibody of claim 2, wherein the light chain CDRs CDR-L1, CDR-L2, and CDR-L3 have amino acid sequences comprising SEQ ID NOs: 12, 13, and 14, respectively.

5. The antibody of claim 4, wherein the heavy chain CDR-H1 has an amino acid sequence comprising SEQ ID NO:

8.

6. The antibody of claim 1 , which binds to the same epitope on human tau as 9F5.

7. The antibody of claim 1, comprising the three light chain CDRs and three heavy chain CDRs of monoclonal antibody 9F5, a murine antibody characterized by a heavy chain variable region having an amino acid sequence comprising SEQ ID NO:7 and a light chain variable region having an amino acid sequence comprising SEQ ID NO:

11.

8. The three heavy chain CDRs, CDR-H1, CDR-H2, and CDR-H3, are as defined by the Kabat / Chothia combination, except that N or T may occupy position H28, I or V may occupy position H51, N or D may occupy position H54, and D or E may occupy position H56 (SEQ ID NOs: 8, 9, and 10, respectively); and the three light chain CDRs, CDR-L1, CDR-L2, and CDR-L3, are as defined by the Kabat / Chothia combination, except that N or T may occupy position H28, I or V may occupy position H51, N or D may occupy position H54, and D or E may occupy position H56 (SEQ ID NOs: 8, 9, and 10, respectively).

8. The antibody of claim 7, as defined by the Kabat / Chothia complex, except that M, 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 (SEQ ID NOs: 12, 13, and 14, respectively).

9. The antibody of claim 8, wherein CDR-H1 has an amino acid sequence comprising SEQ ID NO:

50.

10. The antibody of claim 8, wherein CDR-H2 has an amino acid sequence comprising SEQ ID NO:

51.

11. The antibody of claim 8, wherein CDR-H2 has an amino acid sequence comprising SEQ ID NO:

52.

12. The antibody of claim 8, wherein CDR-L1 has an amino acid sequence comprising any one of SEQ ID NO:53, SEQ ID NO:54, and SEQ ID NO:172-193.

13. The antibody of claim 8, wherein CDR-L2 has an amino acid sequence comprising any one of SEQ ID NO:55, SEQ ID NO:194 to SEQ ID NO:

205.

14. The antibody of claim 8, wherein CDR-L3 has an amino acid sequence comprising any one of SEQ ID NOs: 206 to 213.

15. The antibody of claim 8, wherein CDR-H1 has an amino acid sequence comprising SEQ ID NO:50 and CDR-H2 has an amino acid sequence comprising SEQ ID NO:

51.

16. The antibody of claim 8, wherein CDR-L1 has an amino acid sequence comprising SEQ ID NO:53 and CDR-L2 has an amino acid sequence comprising SEQ ID NO:

55.

17. The antibody of claim 8, wherein CDR-L1 has an amino acid sequence comprising SEQ ID NO:54 and CDR-L2 has an amino acid sequence comprising SEQ ID NO:

55.

18. 2. The antibody of any one of the preceding claims, which is a humanized antibody.

19. 19. The humanized antibody of claim 18, wherein the humanized mature heavy chain variable region comprises the three Kabat heavy chain CDRs of 9F5 (SEQ ID NO:40, SEQ ID NO:9, and SEQ ID NO:10) and the humanized mature light chain variable region comprises the three Kabat light chain CDRs of 9F5 (SEQ ID NO:12-14).

20. The humanized antibody of any one of claims 1 to 19, comprising a humanized mature heavy chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs: 15-22 and 109-129, and a humanized mature light chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs: 23-29, 61-108, and 130-171.

21. 21. The humanized antibody of claim 20, wherein 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 is occupied by Q or V, H11 is occupied by L or V, H12 is occupied by V or K, H17 is occupied by S or T, H20 is occupied by L or I, H23 is occupied by T or K, H28 is occupied by N or T, H38 is occupied by K, R, or Q, H40 is occupied by R or A, H42 is occupied by E or G, H43 is occupied by Q or K, H48 is occupied by I or M, H51 is occupied by I or V, and H54 is occupied by N or D. H56 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.

22. 22. The humanized antibody of claim 21, wherein the positions H1, H5, H11, H12, H17, H20, H23, H38, H42, H43, H66, H69, H75, H80, H81, H83, H93, H94, H108, and H109 provided 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.

23. 23. The humanized antibody of claim 22, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:

127.

24. 22. The humanized antibody of claim 21, wherein the positions H1, H5, H11, H12, H17, H20, H23, H38, H42, H43, H66, H69, H75, H80, H81, H83, H93, H94, H108, and H109 provided 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.

25. 25. The humanized antibody of claim 24, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:

128.

26. 21. The humanized antibody of claim 20, wherein at least one of the following positions in the VL region is occupied by the indicated amino acid: 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 L3 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.

27. 22. The humanized antibody of claim 21, wherein the positions L3Q, L27c, L37, L51, L54, and L92 provided in the VL region are occupied by Q, S, Q, G, R, and I.

28. 22. The humanized antibody of claim 21, wherein positions L3, L27c, L37, L51, L54, and L92 provided in the VL region are occupied by Q, S, Q, G, T, and I, respectively.

29. 22. The humanized antibody of claim 21, wherein positions L3, L27c, L37, L51, L54, and L92 provided in the VL region are occupied by Q, G, Q, G, R, and I, respectively.

30. 22. The humanized antibody of claim 21, wherein the positions L3, L27c, L37, L51, L54, and L92 provided in the VL region are occupied by Q, D, Q, G, R, and I, respectively.

31. 22. The humanized antibody of claim 21, wherein the positions L3, L27c, L37, L51, L54, and L92 provided in the VL region are occupied by Q, D, Q, K, R, and I, respectively.

32. 22. The humanized antibody of claim 21, wherein the positions L3, L27c, L37, L51, L54, and L92 provided in the VL region are occupied by Q, G, Q, K, R, and I, respectively.

33. 22. The humanized antibody of claim 21, wherein positions L3, L27c, L37, L51, L54, and L92 provided in the VL region are occupied by Q, G, G, G, R, and I, respectively.

34. 22. The humanized antibody of claim 21, wherein positions L3, L27c, L37, L51, L54, and L92 provided in the VL region are occupied by Q, G, G, G, R, and G, respectively.

35. 22. The humanized antibody of claim 21, wherein the positions L3, L27c, L37, L51, L54, and L92 provided in the VL region are occupied by Q, G, G, G, T, and I.

36. 22. The humanized antibody of claim 21, wherein the positions L3, L27c, L37, L51, L54, and L92 provided in the VL region are occupied by Q, S, G, G, T, and I, respectively.

37. 22. The humanized antibody of claim 21, wherein positions L3, L27c, L37, L51, L54, and L92 provided in the VL region are occupied by Q, D, G, G, R, and I, respectively.

38. 22. The humanized antibody of claim 21, wherein positions L3, L37, L51, L54, and L92 provided in the VL region are occupied by Q, Q, G, R, and I, respectively.

39. 22. The humanized antibody of claim 21, wherein the positions L3, L27c, L51, L54, and L92 provided in the VL region are occupied by Q, S, G, R, and I, respectively.

40. 22. The humanized antibody of claim 21, wherein the positions L3, L27c, L37, L54, and L92 provided in the VL region are occupied by Q, S, Q, R, and I, respectively.

41. 22. The humanized antibody of claim 21, wherein the positions L3, L27c, L37, L51, and L92 provided in the VL region are occupied by Q, S, Q, G, and I, respectively.

42. 22. The humanized antibody of claim 21, wherein positions L3, L27c, L37, L51, L54, and L92 provided in the VL region are occupied by Q, G, G, G, R, and I, respectively.

43. 21. The humanized antibody of claim 20, wherein the mature heavy chain variable region has the amino acid sequence of any one of SEQ ID NOs: 15-22 and 109-129, and the mature light chain variable region has the amino acid sequence of any one of SEQ ID NOs: 23-29, 61-108, and 130-171.

44. 44. The humanized antibody of claim 43, wherein 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.

45. The humanized antibody of claim 437, wherein 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.

46. 44. The humanized antibody of claim 43, wherein 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.

47. 44. The humanized antibody of claim 43, wherein 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.

48. 44. The humanized antibody of claim 43, wherein 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.

49. 44. The humanized antibody of claim 43, wherein 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.

50. 44. The humanized antibody of claim 43, wherein 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.

51. 44. The humanized antibody of claim 43, wherein 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.

52. 45. The humanized antibody of claim 44, wherein 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.

53. 44. The humanized antibody of claim 43, wherein 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.

54. 44. The humanized antibody of claim 43, wherein 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.

55. 44. The humanized antibody of claim 43, wherein 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.

56. 44. The humanized antibody of claim 43, wherein 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.

57. 44. The humanized antibody of claim 43, wherein 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.

58. 44. The humanized antibody of claim 43, wherein 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.

59. 44. The humanized antibody of claim 43, wherein 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.

60. The antibody of claim 1, comprising the three light chain CDRs and three heavy chain CDRs of monoclonal antibody 10C12, a murine antibody characterized by a heavy chain variable region having an amino acid sequence comprising SEQ ID NO:7 and a light chain variable region having an amino acid sequence comprising SEQ ID NO:

11.

61. 61. The antibody of claim 60, which is a humanized antibody.

62. 62. The humanized antibody of claim 61, wherein the humanized mature heavy chain variable region comprises the three Kabat heavy chain CDRs of 10C12 (SEQ ID NO:40, SEQ ID NO:9, and SEQ ID NO:10) and the humanized mature light chain variable region comprises the three light chain CDRs of 10C12 (SEQ ID NO:12-14).

63. 63. The humanized antibody of any one of claims 60 to 62, comprising a humanized mature heavy chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs: 214 to 215, and a humanized mature variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs: 216 to 217.

64. The humanized antibody of claim 63, wherein 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 is occupied by A, H48 is occupied by I, H67 is occupied by A, H69 is occupied by M, H93 is occupied by T, and H94 is occupied by T.

65. 65. The humanized antibody of claim 64, wherein the provided positions H1, H24, H48, H67, H69, H93, and H94 are occupied by E, A, I, A, M, T, and T, respectively.

66. The humanized antibody of claim 63, wherein 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.

67. 67. The humanized antibody of claim 66, wherein positions L64 and L104 of the VL region are occupied by S and L, respectively.

68. 64. The humanized antibody of claim 63, wherein the mature heavy chain variable region has the amino acid sequence of any one of SEQ ID NOs: 214-215, and the mature light chain variable region has the amino acid sequence of any one of SEQ ID NOs: 216-217.

69. The antibody of claim 5, comprising the three light chain CDRs and three heavy chain CDRs of monoclonal antibody 12C4, a murine antibody characterized by a heavy chain variable region having an amino acid sequence comprising SEQ ID NO:219 and a light chain variable region having an amino acid sequence comprising SEQ ID NO:

11.

70. 70. The antibody of claim 69, which is a humanized antibody.

71. 71. The humanized antibody of claim 70, wherein the humanized mature heavy chain variable region comprises the three Kabat heavy chain CDRs of 12C4 (SEQ ID NO:40, SEQ ID NO:220, and SEQ ID NO:10) and the humanized mature light chain variable region comprises the three Kabat light chain CDRs of 12C4 (SEQ ID NO:12-14).

72. 72. The humanized antibody of any one of claims 69 to 71, comprising a humanized mature heavy chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs: 221 to 222, and a humanized mature light chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs: 223 to 224.

73. The humanized antibody of claim 72, wherein 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 is occupied by M or I, H93 is occupied by A or T, and H94 is occupied by R or T.

74. 74. The humanized antibody of claim 73, wherein the positions H1, H48, H93, and H94 provided in the VH region are occupied by E, I, T, and T, respectively.

75. The humanized antibody of claim 72, wherein the VL region positions are occupied by the indicated amino acids: L64 is G or S and L104 is V or L.

76. 76. The humanized antibody of claim 75, wherein positions L64 and L104 provided in the VL region are occupied by S and L, respectively.

77. 73. The humanized antibody of claim 72, wherein the mature heavy chain variable region has the amino acid sequence of any one of SEQ ID NOs: 221-222, and the mature light chain variable region has the amino acid sequence of any one of SEQ ID NOs: 223-224.

78. The antibody of claim 2, comprising the three light chain CDRs and three heavy chain CDRs of monoclonal antibody 17C12, a murine antibody characterized by a heavy chain variable region having an amino acid sequence comprising SEQ ID NO:225 and a light chain variable region having an amino acid sequence comprising SEQ ID NO:

228.

79. The antibody of claim 78, which is a humanized antibody.

80. 80. The humanized antibody of claim 79, wherein the humanized mature heavy chain variable region comprises the three Kabat heavy chain CDRs of 17C12 (SEQ ID NO:40, SEQ ID NO:227, and SEQ ID NO:10) and the humanized mature light chain variable region comprises the three Kabat light chain CDRs of 17C12 (SEQ ID NO:229-231).

81. 81. The humanized antibody of any one of claims 78 to 80, comprising a humanized mature heavy chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs: 232 to 233, and a humanized mature light chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs: 234 to 235.

82. The humanized antibody of claim 81, wherein 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 is occupied by I, H24 is occupied by A, H48 is occupied by I, H67 is occupied by A, H69 is occupied by M, H93 is occupied by T, H94 is occupied by T, H108 is occupied by T or L, and H113 is occupied by R or S.

83. 83. The humanized antibody of claim 82, wherein the positions H1, H2, H24, H48, H67, H69, H93, H94, H108, and H113 provided in the VH region are occupied by E, I, A, I, A, M, T, T, L, and S, respectively.

84. The humanized antibody of claim 81, wherein 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.

85. 85. The humanized antibody of claim 84, wherein positions L2, L36, and L43 provided in the VL region are occupied by V, L, and S, respectively.

86. The antibody of claim 81, wherein the mature heavy chain variable region has the amino acid sequence of any one of SEQ ID NOs: 232-233, and the mature light chain variable region has the amino acid sequence of any one of SEQ ID NOs: 234-235.

87. The antibody of claim 1, comprising the three light chain CDRs and the three heavy chain CDRs of monoclonal antibody 14H3, a murine antibody characterized by a heavy chain variable region having an amino acid sequence comprising SEQ ID NO:240 and a light chain variable region having an amino acid sequence comprising SEQ ID NO:

244.

88. 88. The antibody of claim 87, wherein the three heavy chain CDRs, CDR-H1, CDR-H2, and CDR-H3, are as defined by the Kabat / Chothia composite, except that G or S may occupy position H35B (SEQ ID NOs: 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 composite (SEQ ID NOs: 245, 246, and 247, respectively).

89. The antibody of claim 88, wherein CDR-H1 has an amino acid sequence comprising SEQ ID NO:

277.

90. The antibody of any one of claims 87 to 89, which is a humanized antibody.

91. 91. The humanized antibody of claim 90, wherein the humanized mature heavy chain variable region comprises the three Kabat heavy chain CDRs of 14H3 (SEQ ID NO:265, SEQ ID NO:242, and SEQ ID NO:243) and the humanized mature light chain variable region comprises the three Kabat light chain CDRs of 14H3 (SEQ ID NO:245-247).

92. 92. The humanized antibody of any one of claims 87 to 91, comprising a humanized mature heavy chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs: 248 to 249, and a humanized mature light chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs: 250 to 251.

93. The humanized antibody of claim 92, wherein at least one of the following positions in the VH region is occupied by the indicated amino acid: H35B is occupied by S, H108 is occupied by M or L, and H113 is occupied by L or S.

94. 94. The humanized antibody of claim 93, wherein the positions H35B, H108, and H113 provided in the VH region are occupied by S, L, and S, respectively.

95. The humanized antibody of claim 92, wherein 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.

96. 96. The humanized antibody of claim 95, wherein positions L2, L7, L37, L87, L100, and L104 provided in the VL region are occupied by V, S, Q, F, Q, and L, respectively.

97. 93. The humanized antibody of claim 92, wherein the mature heavy chain variable region has the amino acid sequence of any one of SEQ ID NOs: 248-249, and the mature light chain variable region has the amino acid sequence of any one of SEQ ID NOs: 250-251.

98. The antibody of any one of claims 1 to 97, which is an intact antibody.

99. 98. The antibody of any one of claims 1 to 97, which is a binding fragment.

100. 2. The antibody of any one of the preceding claims, having an isotype of human IgG1.

101. 100. The humanized antibody of any one of claims 18-59, 61-68, 70-77, 79-86, and 90-100, wherein the mature light chain variable region is fused to a light chain constant region and the mature heavy chain variable region is fused to a heavy chain constant region.

102. The humanized antibody of claim 101, wherein the heavy chain constant region is a mutated version of a native human heavy chain constant region that has reduced binding to Fcγ receptors compared to the native human heavy chain constant region.

103. The antibody according to any one of claims 1 to 99 and 101 to 102, wherein the isotype is human IgG2 or IgG4.

104. A pharmaceutical composition comprising an antibody as defined in any one of claims 1 to 103 and a pharma- ceutically acceptable carrier.

105. A nucleic acid encoding the heavy and / or light chain of an antibody according to any one of claims 1 to 104.

106. 1. A method for humanizing a murine antibody, comprising the steps of: (a) selecting one or more acceptor antibodies; (b) identifying the amino acid residues of the murine antibody that are retained; (c) synthesizing a nucleic acid encoding a humanized heavy chain comprising the CDRs of the heavy chain of the murine antibody and a nucleic acid encoding a humanized light chain comprising the CDRs of the light chain of the murine antibody; (d) expressing the nucleic acid in a host cell to produce the humanized antibody. Including, the murine antibody is 9F5, characterized by a mature heavy chain variable region of SEQ ID NO: 7 and a mature light chain variable region of SEQ ID NO: 11; the murine antibody is 10C12, characterized by a mature heavy chain variable region of SEQ ID NO:7 and a mature light chain variable region of SEQ ID NO:11; the murine antibody is 2D11, characterized by a mature heavy chain variable region of SEQ ID NO:7 and a mature light chain variable region of SEQ ID NO:11; the murine antibody is 12C4, characterized by a mature heavy chain variable region of SEQ ID NO: 219 and a mature light chain variable region of SEQ ID NO: 11; the murine antibody is 17C12, characterized by a mature heavy chain variable region of SEQ ID NO: 225 and a mature light chain variable region of SEQ ID NO: 228; The murine antibody is 14H3, characterized by a mature heavy chain variable region of SEQ ID NO: 240 and a mature light chain variable region of SEQ ID NO: 244; method.

107. A method of inhibiting or reducing tau aggregation in a subject having or at risk of developing tau-mediated amyloidosis, comprising the step of inhibiting or reducing tau aggregation in said subject by administering to said subject an effective regime of an antibody described in any one of claims 1 to 104.

108. 106. A method of treating or preventing a tau-associated disease in a subject, comprising the step of treating or preventing said disease by administering an effective regime of an antibody as defined in any one of claims 1 to 104.

109. The tau-related disease is Alzheimer's disease, Down's syndrome, mild cognitive impairment, primary age-related tauopathy, postencephalitic parkinsonism, posttraumatic dementia or dementia pugilistica, Pick's disease, Niemann-Pick type C disease, supranuclear palsy, frontotemporal dementia, frontotemporal lobar degeneration, argyrophilic grain disease, GGT (globular glial tauopathy), Guam amyotrophic lateral sclerosis / Parkinsonism 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).

110. 110. The method of claim 109, wherein the tau-related disease is Alzheimer's disease.

111. 105. A method for detecting tau protein deposits in a subject having or at risk of a disease associated with tau aggregation or precipitation, comprising administering to the subject an antibody as defined in any one of claims 1 to 104, and detecting said antibody bound to tau in said subject.

112. An isolated monoclonal antibody which specifically binds to a peptide consisting of the residues (Q / E)IVYK(S / P) (SEQ ID NO:56).

113. An isolated monoclonal antibody that specifically binds to a peptide consisting of the residues QIVYKP (SEQ ID NO:57).

114. An isolated monoclonal antibody that specifically binds to a peptide consisting of the residues EIVYKSP (SEQ ID NO:58).

115. An isolated monoclonal antibody that specifically binds to a peptide consisting of the residues EIVYKS (SEQ ID NO:277).

116. A method of treating or preventing a tau-related disease in a subject, comprising administering an immunogen comprising a tau peptide of up to 20 consecutive amino acids of SEQ ID NO: 1 to which antibody 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3 specifically binds, wherein the peptide induces the formation of antibodies in the subject that specifically bind to tau.

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