Anti-TAU antibody and method of use

Abstract

To provide an additional therapeutic agent that targets pathological protein conformers known or suspected to cause neurodegenerative disorders.SOLUTION: The present invention pertains to an anti-Tau antibody and a use method thereof. In some embodiments, an antibody is disclosed which is an isolated antibody that binds to human Tau, the antibody binding to monomer-Tau, oligomer-Tau, non-phosphorylated Tau, and phosphorylated Tau. In some embodiments, the antibody binds to an epitope within amino acids 2-24 of mature human Tau.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 62 / 171,693, filed on 5 June 2015, which is incorporated herein by reference in its entirety for all purposes.

[0002] The present invention relates to an anti-Tau antibody and a method for using the same. [Background technology]

[0003] Neurofibrillary tangles and nerve fibrils (NTs) are major neuropathological features of Alzheimer's disease (AD). NTs are composed of post-translationally modified microtubule-associated Tau proteins, including phosphorylation, and develop through the aggregation of highly phosphorylated Tau conformers. AD shares this pathology with many neurodegenerative tauopathies, and in particular certain types of frontotemporal dementia (FTD). Tau proteins appear to be major players in cognitive decline in AD and related neurodegenerative tauopathies.

[0004] There are few therapeutic approaches that target the Tau protein, and these mainly consist of kinase inhibitors that are thought to increase Tau phosphorylation to pathological levels, and compounds that block cytoplasmic aggregation of highly phosphorylated Tau protein. These approaches suffer from various shortcomings in terms of specificity and efficacy. There is a need for additional therapeutic agents that target pathological protein conformers known or presumed to cause neurodegenerative disorders. [Overview of the project]

[0005] This disclosure provides an anti-Tau antibody and a method of using the same.

[0006] In some embodiments, an isolated antibody is provided that binds to human Tau, wherein the antibody binds to monomeric Tau, oligomeric Tau, unphosphorylated Tau, and phosphorylated Tau. In some embodiments, the antibody binds to an epitope between amino acids 2 and 24 of mature human Tau. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a human, humanized, or chimeric antibody. In some embodiments, the antibody is an antibody fragment that binds to human Tau. In some embodiments, human Tau contains the sequence of SEQ ID NO: 2.

[0007] In some embodiments, the antibody a) HVR-H1 containing an amino acid sequence selected from SEQ ID NOs: 12, 22, 282, 292, and 342; HVR-H2 containing an amino acid sequence selected from SEQ ID NOs: 13, 23, 283, 293, and 343; and HVR-H3 containing an amino acid sequence selected from SEQ ID NOs: 14, 24, 284, 294, and 344; or b) HVR-H1 containing an amino acid sequence selected from SEQ ID NOs. 72 and 302; HVR-H2 containing an amino acid sequence selected from SEQ ID NOs. 73 and 303; and HVR-H3 containing an amino acid sequence selected from SEQ ID NOs. 74 and 304; c) HVR-H1 containing the amino acid sequence of SEQ ID NO: 42; HVR-H2 containing the amino acid sequence of SEQ ID NO: 43; and HVR-H3 containing the amino acid sequence of SEQ ID NO: 44; d) HVR-H1 containing the amino acid sequence of SEQ ID NO: 62; HVR-H2 containing the amino acid sequence of SEQ ID NO: 63; and HVR-H3 containing the amino acid sequence of SEQ ID NO: 64; e) HVR-H1 containing the amino acid sequence of SEQ ID NO: 212; HVR-H2 containing the amino acid sequence of SEQ ID NO: 213; and HVR-H3 containing the amino acid sequence of SEQ ID NO: 214; f) HVR-H1 containing the amino acid sequence of SEQ ID NO: 32; HVR-H2 containing the amino acid sequence of SEQ ID NO: 33; and HVR-H3 containing the amino acid sequence of SEQ ID NO: 34; or g) Includes HVR-H1 containing the amino acid sequence of SEQ ID NO: 52; HVR-H2 containing the amino acid sequence of SEQ ID NO: 53; and HVR-H3 containing the amino acid sequence of SEQ ID NO: 54.

[0008] In some embodiments, the antibody a) HVR-L1 containing an amino acid sequence selected from SEQ ID NOs: 15, 25, 285, 295, 345, and 468-556; HVR-L2 containing an amino acid sequence selected from SEQ ID NOs: 16, 26, 286, 296, and 346; and HVR-L3 containing an amino acid sequence selected from SEQ ID NOs: 17, 27, 287, 297, and 347; b) HVR-L1 containing an amino acid sequence selected from SEQ ID NOs. 75 and 305; HVR-L2 containing an amino acid sequence selected from SEQ ID NOs. 76 and 306; and HVR-L3 containing an amino acid sequence selected from SEQ ID NOs. 77 and 307; c) HVR-L1 containing the amino acid sequence of SEQ ID NO: 45; HVR-L2 containing the amino acid sequence of SEQ ID NO: 46; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 47; d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 65; HVR-L2 containing the amino acid sequence of SEQ ID NO: 66; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 67; e) HVR-L1 containing the amino acid sequence of SEQ ID NO: 215; HVR-L2 containing the amino acid sequence of SEQ ID NO: 216; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 217 f) HVR-L1 containing the amino acid sequence of SEQ ID NO: 35; HVR-L2 containing the amino acid sequence of SEQ ID NO: 36; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 37; or g) Includes HVR-L1 containing the amino acid sequence of SEQ ID NO: 55; HVR-L2 containing the amino acid sequence of SEQ ID NO: 56; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 57.

[0009] In some embodiments, the antibody a) HVR-H1 containing an amino acid sequence selected from SEQ ID NOs: 12, 22, 282, 292, and 342; HVR-H2 containing an amino acid sequence selected from SEQ ID NOs: 13, 23, 283, 293, and 343; HVR-H3 containing an amino acid sequence selected from SEQ ID NOs: 14, 24, 284, 294, and 344; HVR-L1 containing an amino acid sequence selected from SEQ ID NOs: 15, 25, 285, 295, 345, and 468-556; HVR-L2 containing an amino acid sequence selected from SEQ ID NOs: 16, 26, 286, 296, and 346; and HVR-L3 containing an amino acid sequence selected from SEQ ID NOs: 17, 27, 287, 297, and 347; b) HVR-H1 containing an amino acid sequence selected from SEQ ID NOs. 72 and 302; HVR-H2 containing an amino acid sequence selected from SEQ ID NOs. 73 and 303; HVR-H3 containing an amino acid sequence selected from SEQ ID NOs. 74 and 304; HVR-L1 containing an amino acid sequence selected from SEQ ID NOs. 75 and 305; HVR-L2 containing an amino acid sequence selected from SEQ ID NOs. 76 and 306; and HVR-L3 containing an amino acid sequence selected from SEQ ID NOs. 77 and 307; c) HVR-H1 containing the amino acid sequence of SEQ ID NO: 42; HVR-H2 containing the amino acid sequence of SEQ ID NO: 43; HVR-H3 containing the amino acid sequence of SEQ ID NO: 44; HVR-L1 containing the amino acid sequence of SEQ ID NO: 45; HVR-L2 containing the amino acid sequence of SEQ ID NO: 46; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 47; d) HVR-H1 containing the amino acid sequence of SEQ ID NO: 62; HVR-H2 containing the amino acid sequence of SEQ ID NO: 63; HVR-H3 containing the amino acid sequence of SEQ ID NO: 64; HVR-L1 containing the amino acid sequence of SEQ ID NO: 65; HVR-L2 containing the amino acid sequence of SEQ ID NO: 66; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 67; e) HVR-H1 containing the amino acid sequence of SEQ ID NO: 212; HVR-H2 containing the amino acid sequence of SEQ ID NO: 213; HVR-H3 containing the amino acid sequence of SEQ ID NO: 214; HVR-L1 containing the amino acid sequence of SEQ ID NO: 215; HVR-L2 containing the amino acid sequence of SEQ ID NO: 216; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 217; f) HVR-H1 containing the amino acid sequence of SEQ ID NO: 32; HVR-H2 containing the amino acid sequence of SEQ ID NO: 33; HVR-H3 containing the amino acid sequence of SEQ ID NO: 34; HVR-L1 containing the amino acid sequence of SEQ ID NO: 35; HVR-L2 containing the amino acid sequence of SEQ ID NO: 36; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 37; or g) Includes HVR-H1 containing the amino acid sequence of SEQ ID NO: 52; HVR-H2 containing the amino acid sequence of SEQ ID NO: 53; HVR-H3 containing the amino acid sequence of SEQ ID NO: 54; HVR-L1 containing the amino acid sequence of SEQ ID NO: 55; HVR-L2 containing the amino acid sequence of SEQ ID NO: 56; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 57.

[0010] In some embodiments, the antibody a) Heavy chain variable region (VH) containing a sequence that is at least 95% identical to a sequence selected from sequence numbers 10, 20, 280, 290, and 340; b) A light chain variable region (VL) containing a sequence that is at least 95% identical to a sequence selected from sequence numbers 11, 21, 281, 291, and 341; c) VH as in (a) and VL as in (b); d) A heavy chain variable region (VH) containing a sequence that is at least 95% identical to a sequence selected from sequence numbers 70, 300, and 452-459; e) A light chain variable region (VL) containing at least 95% identical sequences to sequences selected from sequence numbers 71, 301, and 460-467; VH as in (d) and VL as in (e); g) Heavy chain variable region (VH) containing at least 95% identical sequence to sequence number 40; h) Light chain variable region (VL) containing at least 95% identical sequences to sequence number 41; i) VH as in (g) and VL as in (h); j) Heavy chain variable region (VH) containing at least 95% identical sequence to sequence number 60; k) Light chain variable region (VL) containing at least 95% identical sequence to sequence number 61; l)(j) VH and (k) VL; m) Heavy chain variable region (VH) containing at least 95% identical sequence to sequence number 210; n) Light chain variable region (VL) containing at least 95% identical sequences to sequence number 211; VH as found in (o)(m) and VL as found in (n); p) Heavy chain variable region (VH) containing at least 95% identical sequence to sequence number 30; q) A light chain variable region (VL) containing a sequence that is at least 95% identical to sequence number 31; VH as in (r)(p) and VL as in (q); s) Heavy chain variable region (VH) containing at least 95% identical sequence to sequence number 50; t) A light chain variable region (VL) containing a sequence that is at least 95% identical to sequence number 51; or This includes VH as shown in (u)(s) and VL as shown in (t).

[0011] In some embodiments, the antibody a) Heavy chain variable region (VH) containing sequences selected from sequence numbers 10, 20, 280, 290, and 340; b) Light chain variable region (VL) containing sequences selected from sequence numbers 11, 21, 281, 291, and 341; c) VH as in (a) and VL as in (b); d) Heavy chain variable region (VH) containing sequences selected from sequence numbers 70, 300, and 452-459; e) A light chain variable region (VL) containing sequences selected from sequence numbers 71, 301, and 460-467; VH as in (d) and VL as in (e); g) Heavy chain variable region (VH) containing the sequence of sequence number 40; h) Light chain variable region (VL) containing the sequence of sequence number 41; i) VH as in (g) and VL as in (h); j) Heavy chain variable region (VH) containing the sequence of sequence number 60; k) Light chain variable region (VL) containing the sequence of sequence number 61; l)(j) VH and (k) VL; m) Heavy chain variable region (VH) containing the sequence of sequence number 210; n) Light chain variable region (VL) containing the sequence of sequence number 211; VH as found in (o)(m) and VL as found in (n); p) Heavy chain variable region (VH) containing the sequence of sequence number 30; q) Light chain variable region (VL) containing the sequence of sequence number 31; VH as in (r)(p) and VL as in (q); s) Heavy chain variable region (VH) containing the sequence of sequence number 50; t) Light chain variable region (VL) containing the sequence of sequence number 51; or This includes VH as shown in (u)(s) and VL as shown in (t).

[0012] In some embodiments, the antibody comprises HVR-H1 containing the amino acid sequence of SEQ ID NO: 342; HVR-H2 containing the amino acid sequence of SEQ ID NO: 343; HVR-H3 containing the amino acid sequence of SEQ ID NO: 344; HVR-L1 containing the amino acid sequence of SEQ ID NO: 345; HVR-L2 containing the amino acid sequence of SEQ ID NO: 346; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 347.

[0013] In some embodiments, the antibody includes a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 340 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 341.

[0014] In some embodiments, the antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 348 or SEQ ID NO: 602, and a light chain containing the amino acid sequence of SEQ ID NO: 349.

[0015] In some embodiments, an isolated antibody that binds to human Tau is provided, comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 348 or SEQ ID NO: 602, and a light chain containing the amino acid sequence of SEQ ID NO: 349. In some embodiments, an isolated antibody that binds to human Tau is provided, comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 348, and a light chain containing the amino acid sequence of SEQ ID NO: 349. In some embodiments, an isolated antibody that binds to human Tau is provided, comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 602, and a light chain containing the amino acid sequence of SEQ ID NO: 349. In some embodiments, an isolated antibody that binds to human Tau is provided, comprising a heavy chain consisting of the amino acid sequence of SEQ ID NO: 348 or SEQ ID NO: 602, and a light chain consisting of the amino acid sequence of SEQ ID NO: 349. In some embodiments, an isolated antibody that binds to human Tau is provided, comprising a heavy chain consisting of the amino acid sequence of SEQ ID NO: 348, and a light chain consisting of the amino acid sequence of SEQ ID NO: 349. In some embodiments, an isolated antibody that binds to human Tau is provided, comprising a heavy chain consisting of the amino acid sequence of SEQ ID NO: 602, and a light chain consisting of the amino acid sequence of SEQ ID NO: 349.

[0016] In some embodiments, an isolated antibody that binds to human Tau is provided, which binds to an epitope in the amino acids 19-33, 19-42, 28-44, 37-51, 100-114, 109-123, 118-132, 154-168, 172-177, 217-231, or 397-411 of mature human Tau.

[0017] In some embodiments, the antibody a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 112; HVR-H2 containing the amino acid sequence of SEQ ID NO: 113; and HVR-H3 containing the amino acid sequence of SEQ ID NO: 114; b) HVR-H1 containing the amino acid sequence of SEQ ID NO: 132; HVR-H2 containing the amino acid sequence of SEQ ID NO: 133; and HVR-H3 containing the amino acid sequence of SEQ ID NO: 134; c) HVR-H1 containing the amino acid sequence of SEQ ID NO: 142; HVR-H2 containing the amino acid sequence of SEQ ID NO: 143; and HVR-H3 containing the amino acid sequence of SEQ ID NO: 144; d) HVR-H1 containing the amino acid sequence of SEQ ID NO: 152; HVR-H2 containing the amino acid sequence of SEQ ID NO: 153; and HVR-H3 containing the amino acid sequence of SEQ ID NO: 154; e) HVR-H1 containing the amino acid sequence of SEQ ID NO: 162; HVR-H2 containing the amino acid sequence of SEQ ID NO: 163; and HVR-H3 containing the amino acid sequence of SEQ ID NO: 164; f) HVR-H1 containing the amino acid sequence of SEQ ID NO: 252; HVR-H2 containing the amino acid sequence of SEQ ID NO: 253; and HVR-H3 containing the amino acid sequence of SEQ ID NO: 254; g) HVR-H1 containing the amino acid sequence of SEQ ID NO: 272; HVR-H2 containing the amino acid sequence of SEQ ID NO: 273; and HVR-H3 containing the amino acid sequence of SEQ ID NO: 274; h) HVR-H1 containing the amino acid sequence of SEQ ID NO: 102; HVR-H2 containing the amino acid sequence of SEQ ID NO: 103; and HVR-H3 containing the amino acid sequence of SEQ ID NO: 104; i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 172; HVR-H2 containing the amino acid sequence of SEQ ID NO: 173; and HVR-H3 containing the amino acid sequence of SEQ ID NO: 174; j) HVR-H1 containing the amino acid sequence of SEQ ID NO: 192; HVR-H2 containing the amino acid sequence of SEQ ID NO: 193; and HVR-H3 containing the amino acid sequence of SEQ ID NO: 194; k) HVR-H1 containing the amino acid sequence of SEQ ID NO: 242; HVR-H2 containing the amino acid sequence of SEQ ID NO: 243; and HVR-H3 containing the amino acid sequence of SEQ ID NO: 244; l) HVR-H1 containing an amino acid sequence selected from SEQ ID NOs. 82, 312, 322, and 332; HVR-H2 containing an amino acid sequence selected from SEQ ID NOs. 83, 313, 323, and 333; and HVR-H3 containing an amino acid sequence selected from SEQ ID NOs. 84, 314, 324, and 334; m) HVR-H1 containing the amino acid sequence of SEQ ID NO: 92; HVR-H2 containing the amino acid sequence of SEQ ID NO: 93; and HVR-H3 containing the amino acid sequence of SEQ ID NO: 94; n) HVR-H1 containing the amino acid sequence of SEQ ID NO: 122; HVR-H2 containing the amino acid sequence of SEQ ID NO: 123; and HVR-H3 containing the amino acid sequence of SEQ ID NO: 124; o) HVR-H1 containing the amino acid sequence of SEQ ID NO: 182; HVR-H2 containing the amino acid sequence of SEQ ID NO: 183; and HVR-H3 containing the amino acid sequence of SEQ ID NO: 184; p) HVR-H1 containing the amino acid sequence of SEQ ID NO: 202; HVR-H2 containing the amino acid sequence of SEQ ID NO: 203; and HVR-H3 containing the amino acid sequence of SEQ ID NO: 204; q) HVR-H1 containing the amino acid sequence of SEQ ID NO: 222; HVR-H2 containing the amino acid sequence of SEQ ID NO: 223; and HVR-H3 containing the amino acid sequence of SEQ ID NO: 224; r) HVR-H1 containing the amino acid sequence of SEQ ID NO: 232; HVR-H2 containing the amino acid sequence of SEQ ID NO: 233; and HVR-H3 containing the amino acid sequence of SEQ ID NO: 234; or s) Includes HVR-H1 containing the amino acid sequence of SEQ ID NO: 262; HVR-H2 containing the amino acid sequence of SEQ ID NO: 263; and HVR-H3 containing the amino acid sequence of SEQ ID NO: 264.

[0018] In some embodiments, the antibody a) HVR-L1 containing the amino acid sequence of SEQ ID NO: 115; HVR-L2 containing the amino acid sequence of SEQ ID NO: 116; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 117; b) HVR-L1 containing the amino acid sequence of SEQ ID NO: 135; HVR-L2 containing the amino acid sequence of SEQ ID NO: 136; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 137; c) HVR-L1 containing the amino acid sequence of SEQ ID NO: 145; HVR-L2 containing the amino acid sequence of SEQ ID NO: 146; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 147; d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 155; HVR-L2 containing the amino acid sequence of SEQ ID NO: 156; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 157; e) HVR-L1 containing the amino acid sequence of SEQ ID NO: 165; HVR-L2 containing the amino acid sequence of SEQ ID NO: 166; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 167; f) HVR-L1 containing the amino acid sequence of SEQ ID NO: 255; HVR-L2 containing the amino acid sequence of SEQ ID NO: 256; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 257; g) HVR-L1 containing the amino acid sequence of SEQ ID NO: 275; HVR-L2 containing the amino acid sequence of SEQ ID NO: 276; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 277; h) HVR-L1 containing the amino acid sequence of SEQ ID NO: 105; HVR-L2 containing the amino acid sequence of SEQ ID NO: 106; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 107; i) HVR-L1 containing the amino acid sequence of SEQ ID NO: 175; HVR-L2 containing the amino acid sequence of SEQ ID NO: 176; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 177; j) HVR-L1 containing the amino acid sequence of SEQ ID NO: 195; HVR-L2 containing the amino acid sequence of SEQ ID NO: 196; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 197; k) HVR-L1 containing the amino acid sequence of SEQ ID NO: 245; HVR-L2 containing the amino acid sequence of SEQ ID NO: 246; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 247; l) HVR-L1 containing an amino acid sequence selected from SEQ ID NOs. 85, 315, 325, and 335; HVR-L2 containing an amino acid sequence selected from SEQ ID NOs. 86, 316, 326, and 336; and HVR-L3 containing an amino acid sequence selected from SEQ ID NOs. 87, 317, 327, and 337; m) HVR-L1 containing the amino acid sequence of SEQ ID NO: 95; HVR-L2 containing the amino acid sequence of SEQ ID NO: 96; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 97; n) HVR-L1 containing the amino acid sequence of SEQ ID NO: 125; HVR-L2 containing the amino acid sequence of SEQ ID NO: 126; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 127; o) HVR-L1 containing the amino acid sequence of SEQ ID NO: 185; HVR-L2 containing the amino acid sequence of SEQ ID NO: 186; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 187; p) HVR-L1 containing the amino acid sequence of SEQ ID NO: 205; HVR-L2 containing the amino acid sequence of SEQ ID NO: 206; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 207; q) HVR-L1 containing the amino acid sequence of SEQ ID NO: 225; HVR-L2 containing the amino acid sequence of SEQ ID NO: 226; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 227; r) HVR-L1 containing the amino acid sequence of SEQ ID NO: 235; HVR-L2 containing the amino acid sequence of SEQ ID NO: 236; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 237; or s) Includes HVR-L1 containing the amino acid sequence of SEQ ID NO: 265; HVR-L2 containing the amino acid sequence of SEQ ID NO: 266; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 267.

[0019] In some embodiments, the antibody a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 112; HVR-H2 containing the amino acid sequence of SEQ ID NO: 113; HVR-H3 containing the amino acid sequence of SEQ ID NO: 114; HVR-L1 containing the amino acid sequence of SEQ ID NO: 115; HVR-L2 containing the amino acid sequence of SEQ ID NO: 116; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 117; b) HVR-H1 containing the amino acid sequence of SEQ ID NO: 132; HVR-H2 containing the amino acid sequence of SEQ ID NO: 133; HVR-H3 containing the amino acid sequence of SEQ ID NO: 134; HVR-L1 containing the amino acid sequence of SEQ ID NO: 135; HVR-L2 containing the amino acid sequence of SEQ ID NO: 136; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 137; c) HVR-H1 containing the amino acid sequence of SEQ ID NO: 142; HVR-H2 containing the amino acid sequence of SEQ ID NO: 143; HVR-H3 containing the amino acid sequence of SEQ ID NO: 144; HVR-L1 containing the amino acid sequence of SEQ ID NO: 145; HVR-L2 containing the amino acid sequence of SEQ ID NO: 146; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 147; d) HVR-H1 containing the amino acid sequence of SEQ ID NO: 152; HVR-H2 containing the amino acid sequence of SEQ ID NO: 153; HVR-H3 containing the amino acid sequence of SEQ ID NO: 154; HVR-L1 containing the amino acid sequence of SEQ ID NO: 155; HVR-L2 containing the amino acid sequence of SEQ ID NO: 156; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 157; e) HVR-H1 containing the amino acid sequence of SEQ ID NO: 162; HVR-H2 containing the amino acid sequence of SEQ ID NO: 163; HVR-H3 containing the amino acid sequence of SEQ ID NO: 164; HVR-L1 containing the amino acid sequence of SEQ ID NO: 165; HVR-L2 containing the amino acid sequence of SEQ ID NO: 166; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 167; f) HVR-H1 containing the amino acid sequence of SEQ ID NO: 252; HVR-H2 containing the amino acid sequence of SEQ ID NO: 253; HVR-H3 containing the amino acid sequence of SEQ ID NO: 254; HVR-L1 containing the amino acid sequence of SEQ ID NO: 255; HVR-L2 containing the amino acid sequence of SEQ ID NO: 256; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 257; or g) HVR-H1 containing the amino acid sequence of SEQ ID NO: 272; HVR-H2 containing the amino acid sequence of SEQ ID NO: 273; and HVR-H3 containing the amino acid sequence of SEQ ID NO: 274; HVR-L1 containing the amino acid sequence of SEQ ID NO: 275; HVR-L2 containing the amino acid sequence of SEQ ID NO: 276; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 277; h) HVR-H1 containing the amino acid sequence of SEQ ID NO: 102; HVR-H2 containing the amino acid sequence of SEQ ID NO: 103; HVR-H3 containing the amino acid sequence of SEQ ID NO: 104; HVR-L1 containing the amino acid sequence of SEQ ID NO: 105; HVR-L2 containing the amino acid sequence of SEQ ID NO: 106; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 107; i) HVR-H1 containing the amino acid sequence of SEQ ID NO: 172; HVR-H2 containing the amino acid sequence of SEQ ID NO: 173; HVR-H3 containing the amino acid sequence of SEQ ID NO: 174; HVR-L1 containing the amino acid sequence of SEQ ID NO: 175; HVR-L2 containing the amino acid sequence of SEQ ID NO: 176; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 177; j) HVR-H1 containing the amino acid sequence of SEQ ID NO: 192; HVR-H2 containing the amino acid sequence of SEQ ID NO: 193; HVR-H3 containing the amino acid sequence of SEQ ID NO: 194; HVR-L1 containing the amino acid sequence of SEQ ID NO: 195; HVR-L2 containing the amino acid sequence of SEQ ID NO: 196; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 197; or k) HVR-H1 containing the amino acid sequence of SEQ ID NO: 242; HVR-H2 containing the amino acid sequence of SEQ ID NO: 243; HVR-H3 containing the amino acid sequence of SEQ ID NO: 244; HVR-L1 containing the amino acid sequence of SEQ ID NO: 245; HVR-L2 containing the amino acid sequence of SEQ ID NO: 246; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 247; l) HVR-H1 containing an amino acid sequence selected from SEQ ID NOs. 82, 312, 322, and 332; HVR-H2 containing an amino acid sequence selected from SEQ ID NOs. 83, 313, 323, and 333; HVR-H3 containing an amino acid sequence selected from SEQ ID NOs. 84, 314, 324, and 334; HVR-L1 containing an amino acid sequence selected from SEQ ID NOs. 85, 315, 325, and 335; HVR-L2 containing an amino acid sequence selected from SEQ ID NOs. 86, 316, 326, and 336; and HVR-L3 containing an amino acid sequence selected from SEQ ID NOs. 87, 317, 327, and 337; m) HVR-H1 containing the amino acid sequence of SEQ ID NO: 92; HVR-H2 containing the amino acid sequence of SEQ ID NO: 93; HVR-H3 containing the amino acid sequence of SEQ ID NO: 94; HVR-L1 containing the amino acid sequence of SEQ ID NO: 95; HVR-L2 containing the amino acid sequence of SEQ ID NO: 96; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 97; n) HVR-H1 containing the amino acid sequence of SEQ ID NO: 122; HVR-H2 containing the amino acid sequence of SEQ ID NO: 123; HVR-H3 containing the amino acid sequence of SEQ ID NO: 124; HVR-L1 containing the amino acid sequence of SEQ ID NO: 125; HVR-L2 containing the amino acid sequence of SEQ ID NO: 126; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 127; o) HVR-H1 containing the amino acid sequence of SEQ ID NO: 182; HVR-H2 containing the amino acid sequence of SEQ ID NO: 183; HVR-H3 containing the amino acid sequence of SEQ ID NO: 184; HVR-L1 containing the amino acid sequence of SEQ ID NO: 185; HVR-L2 containing the amino acid sequence of SEQ ID NO: 186; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 187; p) HVR-H1 containing the amino acid sequence of SEQ ID NO: 202; HVR-H2 containing the amino acid sequence of SEQ ID NO: 203; HVR-H3 containing the amino acid sequence of SEQ ID NO: 204; HVR-L1 containing the amino acid sequence of SEQ ID NO: 205; HVR-L2 containing the amino acid sequence of SEQ ID NO: 206; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 207; q) HVR-H1 containing the amino acid sequence of SEQ ID NO: 222; HVR-H2 containing the amino acid sequence of SEQ ID NO: 223; HVR-H3 containing the amino acid sequence of SEQ ID NO: 224; HVR-L1 containing the amino acid sequence of SEQ ID NO: 225; HVR-L2 containing the amino acid sequence of SEQ ID NO: 226; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 227; r) HVR-H1 containing the amino acid sequence of SEQ ID NO: 232; HVR-H2 containing the amino acid sequence of SEQ ID NO: 233; HVR-H3 containing the amino acid sequence of SEQ ID NO: 234; HVR-L1 containing the amino acid sequence of SEQ ID NO: 235; HVR-L2 containing the amino acid sequence of SEQ ID NO: 236; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 237; or s) Includes HVR-H1 containing the amino acid sequence of SEQ ID NO: 262; HVR-H2 containing the amino acid sequence of SEQ ID NO: 263; HVR-H3 containing the amino acid sequence of SEQ ID NO: 264; HVR-L1 containing the amino acid sequence of SEQ ID NO: 265; HVR-L2 containing the amino acid sequence of SEQ ID NO: 266; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 267.

[0020] In some embodiments, the antibody a) Heavy chain variable region (VH) containing at least 95% identical sequence to sequence number 110; b) Light chain variable region (VL) containing at least 95% identical sequences to sequence number 111; c) VH as in (a) and VL as in (b); d) Heavy chain variable region (VH) containing a sequence that is at least 95% identical to sequence number 130; e) Light chain variable region (VL) containing at least 95% identical sequence to sequence number 131; VH as in (d) and VL as in (e); g) Heavy chain variable region (VH) containing at least 95% identical sequence to sequence number 140; h) Light chain variable region (VL) containing at least 95% identical sequences to sequence number 141; i) VH as in (g) and VL as in (h); j) Heavy chain variable region (VH) containing at least 95% identical sequences to sequence number 150; k) Light chain variable region (VL) containing at least 95% identical sequences to sequence number 151; l)(j) VH and (k) VL; m) Heavy chain variable region (VH) containing at least 95% identical sequence to sequence number 160; n) A light chain variable region (VL) containing at least 95% identical sequences to sequence number 161; or VH as found in (o)(m) and VL as found in (n); p) Heavy chain variable region (VH) containing at least 95% identical sequences to sequence number 250; q) A light chain variable region (VL) containing a sequence that is at least 95% identical to sequence number 251; VH as in (r)(p) and VL as in (q); s) Heavy chain variable region (VH) containing at least 95% identical sequence to sequence number 270; t) Light chain variable region (VL) containing a sequence at least 95% identical to sequence number 271; VH as in (u)(s) and VL as in (t); v) Heavy chain variable region (VH) containing at least 95% identical sequences to sequence number 100; w) Light chain variable region (VL) containing at least 95% identical sequences to sequence number 101; or VH as in (v) and VL as in (w); y) Heavy chain variable region (VH) containing a sequence at least 95% identical to sequence number 170; z) Light chain variable region (VL) containing at least 95% identical sequence to sequence number 171; VH as in aa)(y) and VL as in (z); bb) Heavy chain variable region (VH) containing a sequence at least 95% identical to sequence number 190; cc) Light chain variable region (VL) containing a sequence at least 95% identical to sequence number 191; VH as found in dd)(bb) and VL as found in (cc); ee) Heavy chain variable region (VH) containing at least 95% identical sequence to sequence number 240; ff) Light chain variable region (VL) containing a sequence that is at least 95% identical to sequence number 241; or VH as found in gg)(ee) and VL as found in (ff); hh) Heavy chain variable region (VH) containing a sequence that is at least 95% identical to sequences selected from sequence numbers 80, 310, 320, 330, and 446-451; ii) A light chain variable region (VL) containing at least 95% identical sequences to sequences selected from sequence numbers 81, 311, 321, 331, and 442-445; VH as found in (j)(hh) and VL as found in (ii); kk) Heavy chain variable region (VH) containing at least 95% identical sequence to sequence number 90; ll) Light chain variable region (VL) containing a sequence at least 95% identical to sequence number 91; VH as found in mm)(kk) and VL as found in (ll); nn) Heavy chain variable region (VH) containing a sequence at least 95% identical to sequence number 120; oo) A light chain variable region (VL) containing a sequence that is at least 95% identical to sequence number 121; VH as found in pp)(nn) and VL as found in (oo); qq) Heavy chain variable region (VH) containing at least 95% identical sequence to sequence number 180; rr) Light chain variable region (VL) containing a sequence at least 95% identical to sequence number 181; VH as found in ss)(qq) and VL as found in (rr); tt) Heavy chain variable region (VH) containing at least 95% identical sequence to sequence number 200; uu) Light chain variable region (VL) containing at least 95% identical sequence to sequence number 201; VH as found in vv)(tt) and VL as found in (uu); ww) Heavy chain variable region (VH) containing at least 95% identical sequences to sequence number 220; xx) A light chain variable region (VL) containing a sequence that is at least 95% identical to sequence number 221; VH as found in yy)(ww) and VL as found in (xx); zz) Heavy chain variable region (VH) containing at least 95% identical sequence to sequence number 230; aaa) Light chain variable region (VL) containing at least 95% identical sequence to sequence number 231; VH as found in bbb)(zz) and VL as found in (aaa); ccc) Heavy chain variable region (VH) containing at least 95% identical sequence to sequence number 260; ddd) Light chain variable region (VL) containing at least 95% identical sequence to sequence number 261; or This includes VH as found in eee)(ccc) and VL as found in (ddd).

[0021] In some embodiments, the antibody a) Heavy chain variable region (VH) containing the sequence of sequence number 110; b) Light chain variable region (VL) containing the sequence of sequence number 111; c) VH as in (a) and VL as in (b); d) Heavy chain variable region (VH) containing the sequence of sequence number 130; e) Light chain variable region (VL) containing the sequence of sequence number 131; VH as in (d) and VL as in (e); g) Heavy chain variable region (VH) containing the sequence of sequence number 140; h) Light chain variable region (VL) containing the sequence of sequence number 141; i) VH as in (g) and VL as in (h); j) Heavy chain variable region (VH) containing the sequence of sequence number 150; k) Light chain variable region (VL) containing the sequence of sequence number 151; l)(j) VH and (k) VL; m) Heavy chain variable region (VH) containing the sequence of sequence number 160; n) Light chain variable region (VL) containing the sequence of sequence number 161; or VH as found in (o)(m) and VL as found in (n); p) Heavy chain variable region (VH) containing the sequence of sequence number 250; q) Light chain variable region (VL) containing the sequence of sequence number 251; VH as in (r)(p) and VL as in (q); s) Heavy chain variable region (VH) containing the sequence of sequence number 270; t) Light chain variable region (VL) containing the sequence of sequence number 271; or VH as in (u)(s) and VL as in (t) v) Heavy chain variable region (VH) containing the sequence of sequence number 100; w) Light chain variable region (VL) containing the sequence of sequence number 101; or VH as in (v) and VL as in (w); y) Heavy chain variable region (VH) containing the sequence of sequence number 170; z) Light chain variable region (VL) containing the sequence of sequence number 171; VH as in aa)(y) and VL as in (z); bb) Heavy chain variable region (VH) containing the sequence of sequence number 190; cc) Light chain variable region (VL) containing the sequence of sequence number 191; VH as found in dd)(bb) and VL as found in (cc); ee) Heavy chain variable region (VH) containing the sequence of sequence number 240; ff) Light chain variable region (VL) containing the sequence of sequence number 241; VH as found in gg)(ee) and VL as found in (ff); hh) Heavy chain variable region (VH) containing sequences selected from sequence numbers 80, 310, 320, 330, and 446-451; ii) A light chain variable region (VL) containing sequences selected from sequence numbers 81, 311, 321, 331, and 442-445; VH as found in (j)(hh) and VL as found in (ii); kk) Heavy chain variable region (VH) containing the sequence of sequence number 90; ll) Light chain variable region (VL) containing the sequence of sequence number 91; VH as found in mm)(kk) and VL as found in (ll); nn) Heavy chain variable region (VH) containing the sequence of sequence number 120; oo) Light chain variable region (VL) containing the sequence of sequence number 121; VH as found in pp)(nn) and VL as found in (oo); qq) Heavy chain variable region (VH) containing the sequence of sequence number 180; rr) Light chain variable region (VL) containing the sequence of sequence number 181; VH as found in ss)(qq) and VL as found in (rr); tt) Heavy chain variable region (VH) containing the sequence of sequence number 200; uu) Light chain variable region (VL) containing the sequence of sequence number 201; VH as found in vv)(tt) and VL as found in (uu); ww) Heavy chain variable region (VH) containing the sequence of sequence number 220; xx) Light chain variable region (VL) containing the sequence of sequence number 221; VH as found in yy)(ww) and VL as found in (xx); zz) Heavy chain variable region (VH) containing the sequence of sequence number 230; aaa) Light chain variable region (VL) containing the sequence of sequence number 231; VH as found in bbb)(zz) and VL as found in (aaa); ccc) Heavy chain variable region (VH) containing the sequence of sequence number 260; ddd) Light chain variable region (VL) containing the sequence of sequence number 261; or This includes VH as found in eee)(ccc) and VL as found in (ddd).

[0022] In any of the embodiments described herein, the antibody may be an IgG1 or IgG4 antibody. In any of the embodiments described herein, the antibody may be an IgG4 antibody. In some such embodiments, the antibody contains the M252Y, S254T, and T256E mutations. In any of the embodiments described herein, the antibody may contain the S228P mutation. In any of the embodiments described herein, the antibody may contain the S228P, M252Y, S254T, and T256E mutations. In any of the embodiments described herein, the antibody may be an IgG4 antibody containing the S228P, M252Y, S254T, and T256E mutations. In some embodiments, the antibody is an antibody fragment. In any of the embodiments described herein, the antibody may be an IgG4 antibody containing the S228P, M252Y, S254T, and T256E mutations and lacking the C-terminal lysine (des-K) in the heavy chain constant region. The C-terminal lysine in the heavy chain constant region may be removed, for example, during antibody purification or by recombination of the nucleic acid encoding the antibody, so that the C-terminal lysine is not encoded.

[0023] In some embodiments, the isolated antibody conjugates to human Tau, wherein monomeric Tau, phosphorylated Tau, non-phosphorylated Tau, and oligomeric Tau each contain K100, 75, or 50. DAn antibody is provided that binds to it. In some embodiments, the antibody binds to cynomolgus monkey Tau (SEQ ID NO: 4).

[0024] In some embodiments, an isolated nucleic acid encoding an antibody described herein is provided. In some embodiments, a host cell comprising an isolated nucleic acid encoding an antibody described herein is provided. In some embodiments, a method for producing an antibody is provided, comprising culturing the host cell under conditions suitable for antibody production.

[0025] In some embodiments, an immune complex is provided comprising an isolated antibody described herein and a therapeutic agent. In some embodiments, a labeled antibody is provided comprising an antibody described herein and a detectable label.

[0026] In some embodiments, a pharmaceutical composition is provided comprising an isolated antibody described herein and a pharmaceutically acceptable carrier.

[0027] In some embodiments, a method for treating a Tau protein-related disease is provided, comprising administering an antibody described herein, or a pharmaceutical composition containing an antibody described herein, to an individual having a Tau protein-related disease. In some embodiments, the Tau protein-related disease is tauopathy. In some embodiments, the tauopathy is neurodegenerative tauopathy. In some embodiments, tauopathy is a disease that includes Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Creutzfeldt-Jakob disease, punch-drunk syndrome, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, Guam amyotrophic lateral sclerosis / parkinsonian dementia syndrome, non-Guam motor neuron disease with neurofibrillary tangles, argyrophilic granule dementia, corticobasal degeneration, diffuse neurofibrillary tangle disease with calcification, frontotemporal dementia, frontotemporal dementia linked to chromosome 17 and associated with Parkinsonian syndrome, Hallevorden-Spatz disease, multiple system atrophy, Niemann-Pick disease type C, and globus pallidus-pontonigra degeneration. The tauopathy is selected from degeneration, Pick's disease, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, neurofibrillary tangle dementia, post-encephalitis parkinson's disease, and myotonic dystrophy. In some embodiments, tauopathy is Alzheimer's disease or progressive supranuclear palsy.

[0028] In some embodiments, methods are provided for maintaining or increasing cognitive memory capacity in an individual, or for slowing memory loss, the methods comprising administering an antibody described herein, or a pharmaceutical composition containing an antibody described herein.

[0029] In some embodiments, methods are provided for reducing the levels of Tau protein, non-phosphorylated Tau protein, phosphorylated Tau protein, or hyperphosphorylated Tau protein in an individual, comprising administering an antibody described herein or a pharmaceutical composition containing an antibody described herein.

[0030] In some embodiments, the isolated antibodies described herein are provided for use as pharmaceuticals. In some embodiments, the isolated antibodies described herein are provided for use in the treatment of tauopathy in an individual. In some embodiments, tauopathy is neurodegenerative tauopathy. In some embodiments, tauopathy is Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Creutzfeldt-Jakob disease, punch-drunk syndrome, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, Guam amyotrophic lateral sclerosis / parkinsonian dementia syndrome, non-Guam motor neuron disease with neurofibrillary tangles, argyrophilic granule dementia The tauopathy is selected from corticobasal degeneration, diffuse neurofibrillary tangle disease with calcification, frontotemporal dementia, frontotemporal dementia linked to chromosome 17 and associated with Parkinsonian syndrome, Haller-Holden-Spats disease, multiple system atrophy, Niemann-Pick disease type C, globus pallidus-pontine-nigronitus degeneration, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, neurofibrillary tangle dementia, post-encephalitis-induced parkinsonism, and myotonic dystrophy. In some embodiments, the tauopathy is Alzheimer's disease or progressive supranuclear palsy.

[0031] In some embodiments, the isolated antibodies described herein are provided for use in maintaining or increasing cognitive memory capacity in an individual, or in slowing down memory loss. In some embodiments, the isolated antibodies described herein are provided for use in reducing levels of Tau protein, phosphorylated Tau protein, unphosphorylated Tau protein, or highly phosphorylated Tau protein in an individual.

[0032] In some embodiments, the use of antibodies described herein is provided for the production of pharmaceuticals for the treatment of Tau protein-related diseases in individuals. In some embodiments, Tau protein-related disease is tauopathy. In some embodiments, tauopathy is neurodegenerative tauopathy. In some embodiments, tauopathy is Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Creutzfeldt-Jakob disease, punch-drunk syndrome, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, Guam amyotrophic lateral sclerosis / parkinsonian dementia syndrome, non-Guam motor neuron disease with neurofibrillary tangles, argyrophilic granule dementia, The tauopathy is selected from corticobasal degeneration, diffuse neurofibrillary tangle disease with calcification, frontotemporal dementia, frontotemporal dementia linked to chromosome 17 and associated with Parkinsonian syndrome, Haller-Holden-Spats disease, multiple system atrophy, Niemann-Pick disease type C, globus pallidus-pontine-nigronitus degeneration, Pick's disease, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, neurofibrillary tangle dementia, post-encephalitis-induced parkinsonism, and myotonic dystrophy. In some embodiments, the tauopathy is Alzheimer's disease or progressive supranuclear palsy.

[0033] In some embodiments, the use of antibodies described herein is provided for the production of pharmaceuticals for maintaining or increasing cognitive memory capacity in an individual, or for slowing memory loss.

[0034] In some embodiments, a method is provided for detecting neurofibrillary tangles, neutrophils, or degenerated neurites, comprising contacting a sample with an antibody described herein. In some embodiments, the sample is a brain sample, a cerebrospinal fluid sample, or a blood sample.

[0035] In any of the embodiments described herein, the method or use may include administering the antibody described herein in combination with at least one additional therapy. Non-limiting examples of additional therapies include neurologics, corticosteroids, antibiotics, antivirals, and other therapeutic agents. Such other therapeutic agents include, but are not limited to, other anti-Tau antibodies, antibodies against amyloid-beta, antibodies against beta-secretase 1 ("BACE1"), and inhibitors of beta-secretase 1. [Brief explanation of the drawing]

[0036] [Figure 1A] The binding of antibodies to hyperphosphorylated tau (pTau) was compared to that of unphosphorylated tau using ELISA. The results are expressed in optical density (OD). [Figure 1B] The binding of antibodies to hyperphosphorylated tau (pTau) was compared to that of unphosphorylated tau using ELISA. The results are expressed in optical density (OD). [Figure 1C] The binding of antibodies to hyperphosphorylated tau (pTau) was compared to that of unphosphorylated tau using ELISA. The results are expressed in optical density (OD). [Figure 1D] The binding of antibodies to hyperphosphorylated tau (pTau) was compared to that of unphosphorylated tau using ELISA. The results are expressed in optical density (OD). [Figure 1E] The binding of antibodies to hyperphosphorylated tau (pTau) was compared to that of unphosphorylated tau using ELISA. The results are expressed in optical density (OD). [Figure 1F] The binding of antibodies to hyperphosphorylated tau (pTau) was compared to that of unphosphorylated tau using ELISA. The results are expressed in optical density (OD). [Figure 2A] Antibody binding to oligomeric Tau was evaluated using oligo and mono-Tau capture ELISA. Results are expressed in optical density (OD). [Figure 2B]Antibody binding to oligomeric Tau was evaluated using oligo and mono-Tau capture ELISA. Results are expressed in optical density (OD). [Figure 2C] Antibody binding to oligomeric Tau was evaluated using oligo and mono-Tau capture ELISA. Results are expressed in optical density (OD). [Figure 2D] Antibody binding to oligomeric Tau was evaluated using oligo and mono-Tau capture ELISA. Results are expressed in optical density (OD). [Figure 2E] Antibody binding to oligomeric Tau was evaluated using oligo and mono-Tau capture ELISA. Results are expressed in optical density (OD). [Figure 3] The three panTau antibodies tested showed binding to soluble Tau in brain lysates from Alzheimer's disease (AD) patients and compatible control donors using a Western blot (WB) assay. Protein extracts from AD and control brain lysates, as well as six isoforms of recombinant human Tau, were run on SDS-PAGE, and the membranes were blotted with the three panTau antibodies (37D3-H9, 94B2-C1, and 125B11-H3). Lanes containing AD samples were labeled AD18, AD24, and AD27, and lanes containing control samples were labeled C25 and C21. Lanes containing the six isoforms of recombinant human Tau were labeled as the hTau ladder. [Figure 4A] PanTau antibodies show binding to soluble Tau in brain lysates from AD and compatible control donors using Tau capture ELISA. Data for three panTau antibodies, 37D3-H9, 94B2-C1, and 125B11-H3, are presented. Results are expressed in optical density (OD), mean ± standard deviation, N=2. [Figure 4B]PanTau antibodies show binding to soluble Tau in brain lysates from AD and compatible control donors using Tau capture ELISA. Data for three panTau antibodies, 37D3-H9, 94B2-C1, and 125B11-H3, are presented. Results are expressed in optical density (OD), mean ± standard deviation, N=2. [Figure 4C] PanTau antibodies show binding to soluble Tau in brain lysates from AD and compatible control donors using Tau capture ELISA. Data for three panTau antibodies, 37D3-H9, 94B2-C1, and 125B11-H3, are presented. Results are expressed in optical density (OD), mean ± standard deviation, N=2. [Figure 5] A sensorgram showing 37D3-H9 covalently coupled to a human Tau monomer on the Biacore chip surface, as Fab (left panel) and IgG (right panel). A 1:1 coupling model is applied and shown as an overlay. The x-axis represents time (in seconds). The y-axis represents resonance units (RU). [Figure 6] Overlay sensograms showing the binding of hu37D3-H9.v5 samples (t=0 (left panel) and t=2 weeks (right panel)) to human Tau monomers of 3.1, 6.3, 12.5, 25, 25, 50, and 100 nM. A 1:1 binding model is applied and is shown in this figure. The x-axis represents time (in seconds). The y-axis represents resonance units (RU). [Figure 7] The binding of hu37D3-H9.v5 and hu37D3-H9.v5 N28D to the monomer Tau, individually (left panel shows hu37D3-H9.v5, middle panel shows hu37D3-H9.v5 N28D) and mixed in a 1:1 ratio (right panel). The x-axis represents time (in seconds). The y-axis represents resonance units (RU). [Figure 8]Affinity, stability index, and sequence of 90 37D3-H9 variants screened for potential stability improvement. For clarity, values ​​obtained for the unstressed control antibody (hu37D3-H9.v5 hIgG1), run at the start, intermediate, and end of each experiment, are shown in both sections of the table. [Figure 8A] Affinity, stability index, and sequence of 90 37D3-H9 variants screened for potential stability improvement. For clarity, values ​​obtained for the unstressed control antibody (hu37D3-H9.v5 hIgG1), run at the start, intermediate, and end of each experiment, are shown in both sections of the table. [Figure 8B] Affinity, stability index, and sequence of 90 37D3-H9 variants screened for potential stability improvement. For clarity, values ​​obtained for the unstressed control antibody (hu37D3-H9.v5 hIgG1), run at the start, intermediate, and end of each experiment, are shown in both sections of the table. [Figure 8C] Affinity, stability index, and sequence of 90 37D3-H9 variants screened for potential stability improvement. For clarity, values ​​obtained for the unstressed control antibody (hu37D3-H9.v5 hIgG1), run at the start, intermediate, and end of each experiment, are shown in both sections of the table. [Figure 8D] Affinity, stability index, and sequence of 90 37D3-H9 variants screened for potential stability improvement. For clarity, values ​​obtained for the unstressed control antibody (hu37D3-H9.v5 hIgG1), run at the start, intermediate, and end of each experiment, are shown in both sections of the table. [Figure 9]Structural model of the 37D3-H9 Fv region, showing the positions of light chain residues 28-33 (NGNTYF motif) and the relative positions of residues 28 and 33. Note that residue 33 was mutated in hu37D3.v28. A4-Leu are not near the unstable Asn-28 residue. The dotted line indicates the hydrogen bond between residue Asn-28 and residue Tyr-32. Figure generated using the MOE software package (Chemical Computing Group). [Figure 10] This shows the pharmacokinetics of the anti-Tau antibody 37D3-H9 in mice after a single 10 mg / kg intravenous or intraperitoneal injection. [Figure 11] The pharmacokinetics of hu37D3.v28.A4 hIgG4-S228P and hu37D3.v28.A4 hIgG4-S228P.YTE in cynomolgus monkeys after a single intravenous bolus injection at a dose of 1 mg / kg are shown. [Figure 12A] Binding of specific anti-Tau antibodies to Tau fragments. Shows binding of specific anti-Tau antibodies to Tau fragments 1-15, 10-24, 19-33, 28-42, 37-51, and 46-60. [Figure 12B] Binding of specific anti-Tau antibodies to Tau fragments. This shows the binding of antibody 37D3-H9 mIgG2a to Tau fragments 10-44, 10-24, 2-24, 2-34, and full-length Tau. [Figure 12C] Binding of specific anti-Tau antibodies to Tau fragments. This shows the binding of the antibody hu37D3-H9.v5 hIgG1 to Tau fragments 10-44, 10-24, 2-24, 2-34, and full-length Tau. [Figure 13A] Effector function on Tau toxicity in neuron-microglia cocultures. MAP2 fragmentation percentage in cocultures contacted with various antibodies and oligomeric Tau. [Figure 13B] Effector function of Tau toxicity in neuron-microglia co-cultures. Images of neurons (top panel) and neuron-microglia co-cultures (bottom panel) in contact with various antibodies and oligomeric Tau. [Figure 14] pTau212 / 214 levels in the hippocampus of mice administered anti-tau37D3-H9 WT IgG2a or anti-tau37D3-H9 DANG IgG2. [Figure 15] Comparison of human Tau sequences and cynomolgus monkey Tau sequences. The epitope of antibody 37D3-H9 is shown. [Figure 16] This shows the pharmacokinetics of the anti-Tau antibody 94B2-C1 in mice after a single intravenous or intraperitoneal injection of 10 mg / kg. [Figure 17] This shows the pharmacokinetics of the anti-Tau antibody 125B11-H3 in mice after a single intravenous or intraperitoneal injection of 10 mg / kg. [Figure 18] The alignment of the kappa-1 light chain variable regions in hu37D3-H9.v1, hu37D3-H9.v39, hu37D3-H9.v40, and hu37D3-H9.v41 is shown. [Figure 19A] The plasma antibody concentration (A) in cynomolgus monkeys after a single intravenous injection of the antibody indicated at 50 mg / kg is shown. [Figure 19B] The CSF antibody concentration in cynomolgus monkeys after a single intravenous injection of the antibody indicated at 50 mg / kg (B) is shown. [Figure 20] This shows the total plasma Tau concentration and plasma antibody concentration in cynomolgus monkeys after a single intravenous injection of the antibody indicated at 50 mg / kg. [Figure 21A] The antibody concentrations in various regions of the brain of cynomolgus monkeys, the mean antibody concentration in the brain (C), and the brain:plasma antibody concentration % (D) are shown 2 and 10 days after a single intravenous injection of 50 mg / kg of hu37D3.v28.A4 hIgG4-S228P(A) and hu37D3.v28.A4 hIgG4-S228P.YTE(B). [Figure 21B] The antibody concentrations in various regions of the brain of cynomolgus monkeys, the mean antibody concentration in the brain (C), and the brain:plasma antibody concentration % (D) are shown 2 and 10 days after a single intravenous injection of 50 mg / kg of hu37D3.v28.A4 hIgG4-S228P(A) and hu37D3.v28.A4 hIgG4-S228P.YTE(B). [Figure 21C] The antibody concentrations in various regions of the brain of cynomolgus monkeys, the mean antibody concentration in the brain (C), and the brain:plasma antibody concentration % (D) are shown 2 and 10 days after a single intravenous injection of 50 mg / kg of hu37D3.v28.A4 hIgG4-S228P(A) and hu37D3.v28.A4 hIgG4-S228P.YTE(B). [Figure 21D] The antibody concentrations in various regions of the brain of cynomolgus monkeys, the mean antibody concentration in the brain (C), and the brain:plasma antibody concentration % (D) are shown 2 and 10 days after a single intravenous injection of 50 mg / kg of hu37D3.v28.A4 hIgG4-S228P(A) and hu37D3.v28.A4 hIgG4-S228P.YTE(B). [Figure 22A] The concentration of the antibody in the brain of cynomolgus monkeys at various time points after a single intravenous injection of the indicated antibody at a dose of 50 mg / kg is plotted on a logarithmic scale. [Figure 22B] The concentration of the antibody in the brain of cynomolgus monkeys at various time points after a single intravenous injection of the indicated antibody at a dose of 50 mg / kg is plotted on a linear scale. [Figure 23A] This shows the antibody concentrations in the hippocampus of cynomolgus monkeys at various time points after a single intravenous injection of the antibody indicated at 50 mg / kg. [Figure 23B] This shows the antibody concentrations in the cerebellum of cynomolgus monkeys at various time points after a single intravenous injection of the antibody indicated at 50 mg / kg. [Figure 23C] This shows the antibody concentrations in the frontal cortex of cynomolgus monkeys at various time points after a single intravenous injection of the antibody indicated at 50 mg / kg. [Figure 23D] This shows the antibody concentrations in the CSF of cynomolgus monkeys at various time points after a single intravenous injection of the antibody indicated at 50 mg / kg. [Figure 23E] This shows the antibody concentrations in cynomolgus monkey plasma at various time points after a single intravenous injection of the antibody indicated at 50 mg / kg. [Figure 24A] This shows the mean plasma total Tau concentration over time in cynomolgus monkeys after a single intravenous injection of the antibody indicated at 50 mg / kg. [Figure 24B] This shows the time course of individual plasma total Tau concentrations in cynomolgus monkeys after a single intravenous injection of the antibody indicated at 50 mg / kg. [Modes for carrying out the invention]

[0037] I. Definition For the purposes of this specification, “acceptor human framework” is a framework comprising the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or human consensus framework, as defined below. An acceptor human framework “derived from” a human immunoglobulin framework or human consensus framework may comprise the same amino acid sequence, or it may comprise amino acid sequence variations. In some embodiments, the number of amino acid variations is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the sequence of the VL acceptor human framework is identical to the VL human immunoglobulin framework sequence or human consensus framework sequence.

[0038] "Affinity" refers to the sum of the non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects the 1:1 interaction between the members of a binding pair (e.g., an antibody and an antigen). The affinity of molecule X for its partner Y is generally expressed by the dissociation constant (K). D ) can be expressed by. Affinity can be measured by common methods known in the art, including the methods described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described below.

[0039] An "affinity-mature" antibody is an antibody that, compared to a parent antibody that does not undergo such changes, has one or more such changes within one or more hypervariable regions (HVRs), and such changes improve the antibody's affinity for an antigen.

[0040] The terms “anti-Tau antibody” and “antibody that binds to Tau” refer to an antibody that can bind to Tau with sufficient affinity to be useful as a diagnostic and / or therapeutic agent when the antibody targets Tau. In some embodiments, the degree to which an anti-Tau antibody binds to an unrelated non-Tau protein is less than about 10% of the antibody’s binding to Tau, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, an antibody that binds to Tau has a Tau-binding affinity of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (e.g., 10 -8 M or less, for example, 10 -8 M~10 -13 M, for example, 10 -9 M~10 -13 The dissociation constant (K) of M D ) has. In certain embodiments, anti-Tau antibodies bind to Tau epitopes that are conserved among Tau from different species. As used herein, the terms “anti-Tau antibody” and “antibody that binds to Tau” refer to antibodies that bind to monomeric Tau, oligomeric Tau, and / or phosphorylated Tau, unless otherwise specifically indicated. In some such embodiments, anti-Tau antibodies bind to monomeric Tau, oligomeric Tau, unphosphorylated Tau, and phosphorylated Tau in vitro with equivalent affinities, such as differing by only 50 times or less. In some embodiments, antibodies that bind to monomeric Tau, oligomeric Tau, unphosphorylated Tau, and phosphorylated Tau are called “pan-Tau antibodies”.

[0041] The term "antibody" is used most broadly herein and encompasses a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, insofar as they exhibit the desired antigen-binding activity.

[0042] The term "antibody fragment" refers to a molecule other than an intact antibody that contains a portion of an intact antibody and binds to an antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab’, Fab’-SH, F(ab’)2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments.

[0043] The "antibody that binds to the same epitope" as the reference antibody refers to an antibody that blocks the binding of the reference antibody to its antigen by 50% or more in a competitive assay, and conversely, a reference antibody that blocks the binding of an antibody to its antigen by 50% or more in a competitive assay. Exemplary competitive assays are provided herein.

[0044] The term "chimeric" antibody refers to an antibody in which a portion of the heavy chain and / or light chain is derived from a particular source or species, while the remaining portion of the heavy chain and / or light chain is derived from a different source or species.

[0045] The "class" of an antibody refers to the type of constant domain or constant region that its heavy chain possesses. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and some of these can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0046] As used herein, the term "cytotoxic agent" refers to a substance that inhibits or blocks cell function and / or causes cell death or destruction. Cytotoxic agents include radioisotopes (e.g., At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32Pb 212 Radioactive isotopes of Lu; chemotrephines or chemotherapy agents (e.g., methotrexate, adriamycin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other inserts); growth inhibitors; enzymes such as nucleases and their fragments; antibiotics; toxins such as small molecule toxins or enzymatic toxins of bacterial, fungal, plant or animal origin (including their fragments and / or variants); and various antitumor or anticancer agents listed below.

[0047] "Effector function" refers to the biological activity resulting from the Fc region of an antibody, which varies depending on the antibody isotype. Examples of antibody effector functions include C1q binding and complement-dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, downregulation of cell surface receptors (e.g., B cell receptors), and B cell activation.

[0048] The “effective dose” of a drug, for example, a pharmaceutical formulation, refers to the amount that is effective in achieving the desired therapeutic or prophylactic outcome over a period of time at the required dosage.

[0049] In this specification, the term “Fc region” is used to define the C-terminal region of an immunoglobulin heavy chain that includes at least a portion of the constant region. This term includes both the native sequence Fc region and mutant Fc regions. In some embodiments, the human IgG heavy chain Fc region extends from Cys226 or Pro230 to the carboxyl terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region follows the EU numbering scheme, also known as the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0050] "Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The variable domain FR generally consists of four FR domains: FR1, FR2, FR3, and FR4. Therefore, HVR and FR sequences generally appear in VH (or VL) in the following sequence: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0051] The terms “full-length antibody,” “intact antibody,” and “whole antibody” are used interchangeably herein to refer to antibodies having a structure substantially similar to that of a natural antibody or having a heavy chain containing an Fc region as defined herein.

[0052] The terms “host cell,” “host cell line,” and “host cell culture” are used interchangeably and refer to cells into which exogenous nucleic acids have been introduced, including the offspring of such cells. Host cells include “transformed organisms” and “transformed cells,” which include primary transformed cells and their offspring regardless of the number of passages. Offspring may contain mutations, although they are not entirely identical to the parent cells in terms of nucleic acid content. Mutant offspring having the same function or biological activity as those screened or selected from the originally transformed cells are included herein.

[0053] A "human antibody" is an antibody produced by a human or human cell, or derived from a non-human source that utilizes the human antibody repertoire, possessing an amino acid sequence that corresponds to another human antibody coding sequence. This definition of a human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues.

[0054] The term "variable region" or "variable domain" refers to a domain in the heavy or light chain of an antibody that is involved in the binding of the antibody to an antigen. The variable domains of the heavy and light chains (VH and VL, respectively) of natural antibodies generally have a similar structure, with each domain containing four conserved framework regions (FRs) and three hypervariable regions (HVRs). (e.g., Kindt et al., Kuby Immunology, 6) th See ed., WH Freeman and Co., page 91 (2007). A single VH domain or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, the VH domain or VL domain of an antibody that binds to an antigen can be used to isolate an antibody that binds to a specific antigen, and a library of complementary VL domains or VH domains can be screened, respectively. See, for example, Portolano et al., J. Immunol. 150:880-887 (1993) and Clarkson et al., Nature 352:624-628 (1991).

[0055] The "Human Consensus Framework" is a framework representing the most commonly occurring amino acid residues in the selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from subgroups of variable domain sequences. Generally, the sequence subgroups are those described in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), vols. 1-3. In some embodiments, for VL, the subgroup is subgroup Kappa I, as described by Kabat et al. (above). In some embodiments, for VH, the subgroup is subgroup III, as described by Kabat et al. (above).

[0056] A “humanized” antibody refers to a chimeric antibody containing amino acid residues derived from a non-human HVR and amino acid residues derived from a human FR. In certain embodiments, a humanized antibody contains substantially all of at least one, typically two, variable domains, with all or substantially all of its HVR (e.g., CDR) corresponding to that of a non-human antibody and all or substantially all of its FR corresponding to that of a human antibody. A humanized antibody may optionally contain at least a portion of the antibody constant region derived from a human antibody. The “humanized form” of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0057] As used herein, the terms “hypervariable region” or “HVR” refer to each region of an antibody variable domain that is hypervariable in the sequence (“complementarity-determining region” or “CDR”) and / or forms a structurally defined loop (“hypervariable loop”) and / or contains an antigen contact residue (“antigen contact”). Generally, an antibody contains six HVRs, three of which are located in VH (H1, H2, H3) and three in VL (L1, L2, L3). Examples of HVRs as used herein include: (a) Hypervariable loops formed at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)); (b) CDRs produced at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)); (c) Antigen contacts formed at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262:732-745 (1996)); and (d) Combinations of (a), (b), and / or (c) include HVR amino acid residues 46-56(L2), 47-56(L2), 48-56(L2), 49-56(L2), 26-35(H1), 26-35b(H1), 49-65(H2), 93-102(H3), and 94-102(H3).

[0058] Unless otherwise indicated, HVR residues and other residues within variable domains (e.g., FR residues) are numbered herein according to Kabat et al. (above).

[0059] An "immune complex" is an antibody that complexes with one or more heterologous molecules, including but not limited to cytotoxic drugs.

[0060] The “individual” or “subject” is a mammal. Mammals include, but are not limited to, livestock (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the individual or subject is a human.

[0061] "Isolated" antibodies are those that have been separated from their natural environment. In some embodiments, antibodies are purified to a purity of 95% or more than 99%, as determined by electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse-phase HPLC). For an overview of methods for evaluating antibody purity, see, for example, Flatman et al., J. Chromatogr. B848:79-87 (2007).

[0062] "Isolated" nucleic acids refer to nucleic acid molecules that have been separated from the components of their natural environment. Isolated nucleic acids usually contain nucleic acid molecules found within cells that contain nucleic acid molecules, but these nucleic acid molecules exist outside of chromosomes or at chromosomal locations different from their natural chromosomal locations.

[0063] "Isolated nucleic acid encoding an anti-Tau antibody" means one or more nucleic acid molecules encoding the antibody heavy chain and light chain (or fragments thereof), including such nucleic acid molecules(s) in a single vector or separate vectors, and such nucleic acid molecules(s) are located at one or more positions within a host cell.

[0064] As used herein, the term “monoclonal antibody” refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies constituting that population are identical and / or bind to the same epitope, except for hypothetical mutant antibodies containing naturally occurring mutations or those arising during the production of monoclonal antibody preparations, the latter generally present in small amounts. In contrast to polyclonal antibody preparations, which typically contain different antibodies directed to different determinants (epitopes), each monoclonal antibody in a monoclonal antibody preparation is directed to a single determinant on an antigen. Thus, the modifier “monoclonal” indicates the characteristic of an antibody obtained from a substantially homogeneous population of antibodies and is not to be interpreted as requiring the production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present invention can be produced by a variety of techniques, including, but not limited to, hybridoma methods, recombinant DNA methods, phage presentation methods, and methods utilizing transgenic animals containing all or part of a human immunoglobulin locus, and such methods and other exemplary methods for producing monoclonal antibodies are described herein.

[0065] A "naked antibody" refers to an antibody that is not complexed with a heterogeneous moiety (e.g., a cytotoxic moiety) or a radiolabel. Naked antibodies may be present in pharmaceutical formulations.

[0066] "Natural antibodies" refer to naturally occurring immune globulin molecules with various structures. For example, a natural IgG antibody is a heterotetrameric glycoprotein with approximately 150,000 daltons, composed of two identical light chains and two identical heavy chains linked by disulfide bonds. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain has a variable region (VL), also called a variable light domain or light chain variable domain, followed by a constant light (CL) domain. Based on the amino acid sequence of its constant domain, the light chains of an antibody can be assigned to one of two types called kappa (κ) and lambda (λ).

[0067] The term “packaging information” is used to refer to the instructions typically included in the packaging of a therapeutic product, which contain information about the indications, use, dosage, administration, combination therapies, contraindications, and / or warnings regarding the use of such therapeutic product.

[0068] The "amino acid sequence identity percentage (%)" for a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to amino acid residues in the reference polypeptide sequence, after the sequences have been aligned and gaps introduced as necessary to achieve the maximum sequence identity percentage, without considering any conservative substitutions as part of the sequence identity. Alignment for determining the amino acid sequence identity percentage can be achieved in various ways within the scope of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for sequence alignment, including any algorithm necessary to achieve the maximum alignment over the full length of the sequences being compared. However, for the purposes of this specification, the amino acid sequence identity % value is generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was written by Genentech, Inc., and its source code, along with user documentation, has been filed with the U.S. Copyright Office, Washington DC, 20559, and is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California, or can be compiled from source code. The ALIGN-2 program should be compiled for use with UNIX operating systems, including Digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not change.

[0069] In situations where ALIGN-2 is used for amino acid sequence comparison, the percentage of amino acid sequence identity of a given amino acid sequence A to, with, or relative to a given amino acid sequence B (or, a given amino acid sequence A that has or contains a certain percentage of amino acid sequence identity to, with, or relative to a given amino acid sequence B) is calculated as follows: 100 × fraction X / Y In the formula, X is the number of amino acid residues scored as a perfect match in the alignment of A and B by the sequence alignment program ALIGN-2, and Y is the total number of amino acid residues in B. It will be understood that if the length of amino acid sequence A is not equal to the length of amino acid sequence B, the amino acid sequence identity % of A to B will not be equal to the amino acid sequence identity % of B to A. Unless otherwise specifically stated, all amino acid sequence identity % values ​​used herein are obtained using the ALIGN-2 computer program as described in the preceding paragraph.

[0070] The term "pharmaceutical preparation" refers to a preparation in which the biological activity of the active ingredient contained therein is effective, and which does not contain any additional components that are unacceptably toxic to the person to whom the preparation is administered.

[0071] A "pharmaceutically acceptable carrier" refers to a component in a pharmaceutical preparation other than the active ingredient that is non-toxic to the target substance. Examples of pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0072] As used herein, the term “Tau” refers, unless otherwise indicated, to any native Tau protein of any vertebrate source, including primates (e.g., humans) and mammals such as rodents (e.g., mice and rats). The term encompasses “full-length” untreated Tau, as well as any form of Tau resulting from intracellular processing. The term also encompasses naturally occurring variants of Tau, such as splice variants or allele variants.

[0073] As used herein, the term "pTau" refers to Tau, which is phosphorylated by a protein kinase by the addition of a covalently bonded phosphate group to a serine, threonine, or tyrosine residue. In some embodiments, pTau is phosphorylated on a serine residue or a threonine residue. In some embodiments, pTau is phosphorylated on serine 409 and / or serine 404. In some embodiments, pTau is phosphorylated on serine 409.

[0074] As used herein, the terms “soluble Tau” or “soluble Tau protein” refer to a protein comprising both a fully solubilized Tau protein / peptide monomer, or a Tau-like peptide / protein, or a modified or cleaved Tau peptide / protein, or other derivatives of a Tau peptide / protein monomer, and a Tau protein oligomer. “Soluble Tau” specifically excludes neurofibrillary tangles (NFTs).

[0075] As used herein, the term “insoluble Tau” refers to multiple aggregated monomers of Tau peptides or proteins, Tau-like peptides / proteins, or modified or cleaved Tau peptides / proteins, or other derivatives of Tau peptides / proteins that form oligomeric or polymeric structures that are insoluble both in aqueous medium in vitro and in mammalian or human bodies (more specifically in the brain), but in particular to multiple aggregated monomers of Tau or modified or cleaved Tau peptides / proteins, or their derivatives, that are insoluble in mammalian or human bodies (more specifically in the brain). “Insoluble Tau” particularly includes neurofibrillary tangles (NFTs).

[0076] As used herein, the terms “Tau monomer” or “Tau monomer” refer to fully soluble Tau protein that does not have aggregated complexes in an aqueous medium.

[0077] As used herein, the terms “aggregated Tau,” “oligomeric Tau,” and “Tau oligomer” refer to multiple aggregated monomers of Tau peptides or proteins, or Tau-like peptides / proteins, or modified or cleaved Tau peptides / proteins, or other derivatives of Tau peptides / proteins that form oligomeric or polymer structures that are insoluble or soluble both in aqueous medium in vitro and in mammalian or human bodies (more specifically in the brain), but in particular, they refer to multiple aggregated monomers of Tau or modified or cleaved Tau peptides / proteins, or derivatives thereof, that are insoluble or soluble in mammalian or human bodies (more specifically in the brain).

[0078] The terms “pTau PHF,” “PHF,” and “paired helical fibrils” are used synonymously herein and refer to pairs of fibers that are wound in a helical pattern with a periodicity of 160 nm, visible on an electron microscope. The width varies between 10 and 22 nm. PHFs are the main structure in neurofibrillary tangles and nerve villous fibrils in Alzheimer's disease (AD). PHFs can also be found in some, though not all, degenerated neurites associated with senile plaques. The main component of PHFs is a hyperphosphorylated form of the microtubule-associated protein tau. PHFs can be composed in part of disulfide-bonded antiparallel hyperphosphorylated Tau proteins. PHF Tau can have its 20 amino acid residues at its C-terminus cleaved. The underlying mechanism of PHF formation is unknown, but hyperphosphorylation of Tau may release it from microtubules and increase the soluble pool of Tau in which PHFs can be formed within neurons.

[0079] As used herein, “treatment” (and its grammatical variations such as “to treat” or “to treat”) refers to a clinical intervention aimed at altering the natural course of the individual being treated, which may be performed for preventive purposes or during a clinicopathological process. Desired effects of treatment include, but are not limited to, prevention of disease onset or recurrence, symptom relief, reduction of any direct or indirect pathological consequences of the disease, prevention of metastasis, reduction of the rate of disease progression, recovery or remission of the condition, and remission or improvement of prognosis. In some embodiments, the antibodies of the present invention are used to delay the onset of the disease or slow the progression of the disease.

[0080] As used herein, the terms “early Alzheimer’s disease” or “early AD” (e.g., “a patient diagnosed with early AD” or “a patient suffering from early AD”) include patients with mild cognitive impairment due to AD, such as memory loss, and patients with AD biomarkers, such as amyloid-positive patients.

[0081] As used herein, the terms “mild Alzheimer’s disease” or “mild AD” (e.g., “a patient diagnosed with mild AD”) refer to a stage of AD characterized by an MMSE score of 20–26.

[0082] As used herein, the terms “mild to moderate Alzheimer’s disease” or “mild to moderate AD” (e.g., “a patient diagnosed with mild AD”) encompass both mild and moderate AD and are characterized by an MMSE score of 18–26.

[0083] As used herein, the terms “moderate Alzheimer’s disease” or “moderate AD” (e.g., “a patient diagnosed with moderate AD”) refer to a stage of AD characterized by an MMSE score of 18–19.

[0084] The term "MMSE" refers to a simplified intelligence assessment scale that provides scores between 1 and 30. See Folstein, et al., 1975, J. Psychiatr. Res. 12:189-98. Scores of 26 or less are generally considered to indicate deficits. The lower the numerical score on the MMSE, the greater the deficit or impairment of the test patient compared to another individual with a lower score. An increase in the MMSE score may indicate an improvement in the patient's condition, while a decrease in the MMSE score may indicate a worsening of the patient's condition.

[0085] As used herein, the term “vector” refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is bound. This term includes vectors as self-replicating nucleic acid structures, and vectors incorporated into the genome of a host cell into which they are introduced. Certain vectors can be directed towards the expression of the nucleic acid to which they are operably bound. Such vectors are referred to herein as “expression vectors.”

[0086] II. Compositions and Methods Antibodies that bind to Tau are provided. In some embodiments, the antibodies of the present invention bind to Tau, specifically monomeric Tau, oligomeric Tau, non-phosphorylated Tau, and phosphorylated Tau. In some embodiments, the antibodies of the present invention bind to epitopes within amino acids 2-24 of mature human Tau. In some embodiments, the antibodies of the present invention bind to epitopes within amino acids 2-24 of Tau, specifically monomeric Tau, oligomeric Tau, non-phosphorylated Tau, and phosphorylated Tau. In some embodiments, the antibodies bind to epitopes of human Tau having or consisting of the sequence AEPREQEFEVMEDHAGTYGLGDRK (SEQ ID NO: 2). In some embodiments, the antibodies bind to epitopes of cynomolgus monkey Tau having or consisting of the sequence AEPREQEFDVMEDHAGTYGLGDRK (SEQ ID NO: 4). In some embodiments, the antibody binds to an epitope of human Tau having or consisting of the sequence AEPRQEFEVMEDHAGTYGLGDRK (SEQ ID NO: 2), and to an epitope of cynomolgus monkey Tau having or consisting of the sequence AEPRQEFDVMEDHAGTYGLGDRK (SEQ ID NO: 4). In some embodiments, the antibody of the present invention binds to epitopes in amino acids 19-33, 19-42, 37-51, 100-114, 118-132, or 172-177 of mature human Tau. In some embodiments, the antibody of the present invention binds to epitopes in amino acids 19-33, 19-42, 37-51, 100-114, 118-132, or 172-177 of mature human Tau, and binds to monomeric Tau, oligomeric Tau, unphosphorylated Tau, and phosphorylated Tau.

[0087] The antibodies of the present invention are useful, for example, in the diagnosis or treatment of neurodegenerative diseases.

[0088] A. Exemplary anti-Tau antibody In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising an amino acid sequence selected from SEQ ID NOs: 12, 22, 282, 292, and 342; (b) HVR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 13, 23, 283, 293, and 343; (c) HVR-H3 comprising an amino acid sequence selected from SEQ ID NOs: 14, 24, 284, 294, and 344; (d) HVR-L1 comprising an amino acid sequence selected from SEQ ID NOs: 15, 25, 285, 295, 345, and 468-556; (e) HVR-L2 comprising an amino acid sequence selected from SEQ ID NOs: 16, 26, 286, 296, and 346; and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 17, 27, 287, 297, and 347.

[0089] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 342, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 343, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 344, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 345, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 346, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 347.

[0090] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising amino acid sequences selected from SEQ ID NOs: 72 and 302, (b) HVR-H2 comprising amino acid sequences selected from SEQ ID NOs: 73 and 303, (c) HVR-H3 comprising amino acid sequences selected from SEQ ID NOs: 74 and 304, (d) HVR-L1 comprising amino acid sequences selected from SEQ ID NOs: 75 and 305, (e) HVR-L2 comprising amino acid sequences selected from SEQ ID NOs: 76 and 306, and (f) HVR-L3 comprising amino acid sequences selected from SEQ ID NOs: 77 and 307.

[0091] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising an amino acid sequence selected from SEQ ID NOs. 82, 312, 322, and 332; (b) HVR-H2 comprising an amino acid sequence selected from SEQ ID NOs. 83, 313, 323, and 333; (c) HVR-H3 comprising an amino acid sequence selected from SEQ ID NOs. 84, 314, 324, and 334; (d) HVR-L1 comprising an amino acid sequence selected from SEQ ID NOs. 85, 315, 325, and 335; (e) HVR-L2 comprising an amino acid sequence selected from SEQ ID NOs. 86, 316, 326, and 336; and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NOs. 87, 317, 327, and 337.

[0092] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 32, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 33, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 34, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 35, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 36, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 37.

[0093] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 42, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 43, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 44, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 45, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 46, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 47.

[0094] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 52, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 53, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 54, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 55, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 56, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 57.

[0095] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 62, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 63, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 64, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 65, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 66, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 67.

[0096] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 72, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 73, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 74, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 75, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 76, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 77.

[0097] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 82, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 83, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 84, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 85, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 86, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 87.

[0098] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 92, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 93, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 94, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 95, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 96, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 97.

[0099] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 102, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 103, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 104, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 105, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 106, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 107.

[0100] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 112, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 113, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 114, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 115, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 116, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 117.

[0101] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 122, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 123, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 124, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 125, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 126, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 127.

[0102] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 132, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 133, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 134, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 135, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 136, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 137.

[0103] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 142, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 143, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 144, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 145, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 146, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 147.

[0104] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 152, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 153, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 154, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 155, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 156, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 157.

[0105] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 162, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 163, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 164, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 165, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 166, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 167.

[0106] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 172, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 173, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 174, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 175, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 176, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 177.

[0107] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 182, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 183, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 184, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 185, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 186, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 187.

[0108] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 192, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 193, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 194, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 195, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 196, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 197.

[0109] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 202, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 203, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 204, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 205, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 206, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 207.

[0110] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 212, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 213, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 214, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 215, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 216, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 217.

[0111] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 222, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 223, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 224, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 225, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 226, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 227.

[0112] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 232, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 233, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 234, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 235, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 236, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 237.

[0113] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 242, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 243, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 244, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 245, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 246, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 247.

[0114] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 252, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 253, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 254, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 255, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 256, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 257.

[0115] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 262, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 263, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 264, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 265, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 266, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 267.

[0116] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 272, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 273, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 274, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 275, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 276, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 277.

[0117] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 282, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 283, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 284, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 285, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 286, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 287.

[0118] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 292, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 293, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 294, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 295, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 296, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 297.

[0119] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 302, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 303, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 304, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 305, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 306, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 307.

[0120] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 312, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 313, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 314, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 315, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 316, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 317.

[0121] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 322, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 323, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 324, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 325, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 326, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 327.

[0122] In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 332, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 333, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 334, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 335, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 336, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 337.

[0123] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising an amino acid sequence selected from SEQ ID NOs: 12, 22, 282, 292, and 342; (b) HVR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 13, 23, 283, 293, and 343; and (c) HVR-H3 comprising an amino acid sequence selected from SEQ ID NOs: 14, 24, 284, 294, and 344.

[0124] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 having the amino acid sequence of SEQ ID NO: 342, (b) HVR-H2 having the amino acid sequence of SEQ ID NO: 343, and (c) HVR-H3 having the amino acid sequence of SEQ ID NO: 344. In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 having the amino acid sequence of SEQ ID NO: 342, (b) HVR-H2 having the amino acid sequence of SEQ ID NO: 343, and (c) HVR-H3 having the amino acid sequence of SEQ ID NO: 344.

[0125] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising amino acid sequences selected from SEQ ID NOs: 72 and 302, (b) HVR-H2 comprising amino acid sequences selected from SEQ ID NOs: 73 and 303, and (c) HVR-H3 comprising amino acid sequences selected from SEQ ID NOs: 74 and 304.

[0126] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising an amino acid sequence selected from SEQ ID NOs. 82, 312, 322, and 332, (b) HVR-H2 comprising an amino acid sequence selected from SEQ ID NOs. 83, 313, 323, and 333, and (c) HVR-H3 comprising an amino acid sequence selected from SEQ ID NOs. 84, 314, 324, and 334.

[0127] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 32, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 33, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 34.

[0128] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 42, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 43, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 44.

[0129] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 52, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 53, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 54.

[0130] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 62, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 63, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 64.

[0131] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 72, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 73, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 74.

[0132] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 82, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 83, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 84.

[0133] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 92, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 93, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 94.

[0134] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 102, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 103, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 104.

[0135] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 112, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 113, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 114.

[0136] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 122, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 123, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 124.

[0137] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 132, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 133, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 134.

[0138] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 142, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 143, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 144.

[0139] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 152, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 153, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 154.

[0140] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 162, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 163, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 164.

[0141] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 172, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 173, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 174.

[0142] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 182, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 183, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 184.

[0143] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 192, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 193, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 194.

[0144] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 202, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 203, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 204.

[0145] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 212, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 213, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 214.

[0146] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 222, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 223, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 224. In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 222, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 223, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 224.

[0147] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 232, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 233, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 234. In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 232, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 233, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 234.

[0148] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 242, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 243, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 244. In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 242, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 243, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 244.

[0149] In some embodiments, the anti-Tau antibody comprises at least one, two, or three hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 252, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 253, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 254. In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 252, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 253, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 254.

[0150] In some embodiments, the anti-Tau antibody comprises at least one, two, or three hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 262, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 263, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 264. In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 262, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 263, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 264.

[0151] In some embodiments, the anti-Tau antibody comprises at least one, two, or three hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 272, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 273, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 274. In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 272, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 273, and (c) HVR-H​​​In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 282, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 283, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 284.

[0153] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 292, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 293, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 294.

[0154] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 302, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 303, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 304.

[0155] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 312, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 313, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 314.

[0156] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 322, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 323, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 324.

[0157] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 332, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 333, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 334.

[0158] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising an amino acid sequence selected from SEQ ID NOs: 15, 25, 285, 295, 345, and 468-556, (b) HVR-L2 comprising an amino acid sequence selected from SEQ ID NOs: 16, 26, 286, 296, and 346, and (c) HVR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 17, 27, 287, 297, and 347. In some embodiments, the anti-Tau antibody comprises (a) HVR-L1 comprising an amino acid sequence selected from SEQ ID NOs. 15, 25, 285, 295, 345, and 468-556; (b) HVR-L2 comprising an amino acid sequence selected from SEQ ID NOs. 16, 26, 286, 296, and 346; and (c) HVR-L3 comprising an amino acid sequence selected from SEQ ID NOs. 17, 27, 287, 297, and 347.

[0159] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 345, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 346, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 347.

[0160] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising amino acid sequences selected from SEQ ID NOs: 75 and 305, (b) HVR-L2 comprising amino acid sequences selected from SEQ ID NOs: 76 and 306, and (c) HVR-L3 comprising amino acid sequences selected from SEQ ID NOs: 77 and 307.

[0161] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising an amino acid sequence selected from SEQ ID NOs. 85, 315, 325, and 335, (b) HVR-L2 comprising an amino acid sequence selected from SEQ ID NOs. 86, 316, 326, and 336, and (c) HVR-L3 comprising an amino acid sequence selected from SEQ ID NOs. 87, 317, 327, and 337.

[0162] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 35, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 36, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 37.

[0163] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 45, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 46, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 47.

[0164] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 55, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 56, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 57.

[0165] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 65, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 66, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 67.

[0166] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 75, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 76, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 77.

[0167] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 85, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 86, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 87.

[0168] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 95, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 96, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 97.

[0169] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 105, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 106, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 107. In some embodiments, the anti-Tau antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 105, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 106, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 107.

[0170] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 115, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 116, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 117. In some embodiments, the anti-Tau antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 115, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 116, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 117.

[0171] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 125, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 126, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 127. In some embodiments, the anti-Tau antibody comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 125, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 126, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 127.

[0172] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 135, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 136, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 137.

[0173] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 145, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 146, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 147.

[0174] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 155, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 156, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 157.

[0175] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 165, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 166, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 167.

[0176] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 175, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 176, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 177.

[0177] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 185, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 186, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 187.

[0178] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 195, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 196, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 197.

[0179] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 205, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 206, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 207.

[0180] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 215, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 216, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 217.

[0181] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 225, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 226, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 227.

[0182] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 235, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 236, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 237.

[0183] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 245, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 246, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 247.

[0184] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 255, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 256, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 257.

[0185] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 265, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 266, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 267.

[0186] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 275, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 276, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 277.

[0187] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 285, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 286, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 287.

[0188] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 295, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 296, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 297.

[0189] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 305, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 306, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 307.

[0190] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 315, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 316, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 317.

[0191] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 325, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 326, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 327.

[0192] In some embodiments, the anti-Tau antibody comprises at least one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 335, (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 336, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 337.

[0193] In some embodiments, the anti-Tau antibody includes (a) HVR-H1 comprising an amino acid sequence selected from SEQ ID NOs: 12, 22, 282, 292, and 342; (b) HVR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 13, 23, 283, 293, and 343; (c) HVR-H3 comprising an amino acid sequence selected from SEQ ID NOs: 14, 24, 284, 294, and 344; (d) HVR-L1 comprising an amino acid sequence selected from SEQ ID NOs: 15, 25, 285, 295, 345, and 468-556; (e) HVR-L2 comprising an amino acid sequence selected from SEQ ID NOs: 16, 26, 286, 296, and 346; and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 17, 27, 287, 297, and 347.

[0194] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 342, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 343, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 344, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 345, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 346, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 347.

[0195] In some embodiments, the anti-Tau antibody includes (a) HVR-H1 comprising an amino acid sequence selected from SEQ ID NOs. 72 and 302, (b) HVR-H2 comprising an amino acid sequence selected from SEQ ID NOs. 73 and 303, (c) HVR-H3 comprising an amino acid sequence selected from SEQ ID NOs. 74 and 304, (d) HVR-L1 comprising an amino acid sequence selected from SEQ ID NOs. 75 and 305, (e) HVR-L2 comprising an amino acid sequence selected from SEQ ID NOs. 76 and 306, and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NOs. 77 and 307.

[0196] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 comprising an amino acid sequence selected from SEQ ID NOs. 82, 312, 322, and 332; (b) HVR-H2 comprising an amino acid sequence selected from SEQ ID NOs. 83, 313, 323, and 333; (c) HVR-H3 comprising an amino acid sequence selected from SEQ ID NOs. 84, 314, 324, and 334; (d) HVR-L1 comprising an amino acid sequence selected from SEQ ID NOs. 85, 315, 325, and 335; (e) HVR-L2 comprising an amino acid sequence selected from SEQ ID NOs. 86, 316, 326, and 336; and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NOs. 87, 317, 327, and 337.

[0197] In some embodiments, the anti-Tau antibody includes (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 32, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 33, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 34, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 35, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 36, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 37.

[0198] In some embodiments, the anti-Tau antibody includes (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 42, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 43, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 44, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 45, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 46, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 47.

[0199] In some embodiments, the anti-Tau antibody includes (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 52, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 53, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 54, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 55, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 56, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 57.

[0200] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 62, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 63, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 64, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 65, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 66, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 67.

[0201] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 72, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 73, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 74, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 75, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 76, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 77.

[0202] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 82, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 83, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 84, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 85, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 86, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 87.

[0203] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 92, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 93, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 94, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 95, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 96, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 97.

[0204] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 102, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 103, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 104, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 105, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 106, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 107.

[0205] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 112, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 113, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 114, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 115, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 116, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 117.

[0206] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 122, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 123, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 124, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 125, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 126, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 127.

[0207] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 132, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 133, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 134, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 135, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 136, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 137.

[0208] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 142, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 143, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 144, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 145, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 146, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 147.

[0209] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 152, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 153, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 154, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 155, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 156, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 157.

[0210] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 162, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 163, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 164, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 165, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 166, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 167.

[0211] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 172, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 173, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 174, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 175, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 176, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 177.

[0212] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 182, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 183, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 184, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 185, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 186, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 187.

[0213] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 192, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 193, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 194, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 195, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 196, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 197.

[0214] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 202, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 203, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 204, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 205, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 206, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 207.

[0215] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 212, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 213, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 214, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 215, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 216, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 217.

[0216] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 222, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 223, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 224, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 225, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 226, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 227.

[0217] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 232, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 233, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 234, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 235, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 236, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 237.

[0218] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 242, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 243, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 244, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 245, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 246, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 247.

[0219] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 252, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 253, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 254, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 255, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 256, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 257.

[0220] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 262, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 263, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 264, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 265, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 266, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 267.

[0221] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 272, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 273, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 274, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 275, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 276, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 277.

[0222] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 282, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 283, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 284, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 285, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 286, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 287.

[0223] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 292, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 293, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 294, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 295, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 296, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 297.

[0224] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 302, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 303, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 304, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 305, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 306, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 307.

[0225] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 312, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 313, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 314, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 315, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 316, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 317.

[0226] In some embodiments, the anti-Tau antibody includes (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 322, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 323, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 324, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 325, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 326, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 327.

[0227] In some embodiments, the anti-Tau antibody comprises (a) HVR-H1 containing the amino acid sequence of SEQ ID NO: 332, (b) HVR-H2 containing the amino acid sequence of SEQ ID NO: 333, (c) HVR-H3 containing the amino acid sequence of SEQ ID NO: 334, (d) HVR-L1 containing the amino acid sequence of SEQ ID NO: 335, (e) HVR-L2 containing the amino acid sequence of SEQ ID NO: 336, and (f) HVR-L3 containing the amino acid sequence of SEQ ID NO: 337.

[0228] In any of the embodiments described above, the anti-Tau antibody is humanized. In some embodiments, the anti-Tau antibody comprises HVR as in any of the embodiments described above, and further comprises an acceptor human framework, such as a human immunoglobulin framework or a human consensus framework.

[0229] In another embodiment, the anti-Tau antibody contains a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NOs. 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, or 340. In certain embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to a reference sequence, but an anti-Tau antibody containing that sequence retains the ability to bind to Tau. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted within SEQ ID NOs: 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, or 340. In certain embodiments, substitutions, insertions, or deletions occur within the region outside the HVR (i.e., within the FR). Optionally, the anti-Tau antibody contains the VH sequence in SEQ ID NOs. 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, or 340, including post-translational modifications of that sequence.In a particular embodiment, VH is (a) HVR-H1 comprising the amino acid sequence of SEQ ID NOs: 12, 22, 32, 42, 52, 62, 72, 82, 92, 102, 112, 122, 132, 142, 152, 162, 172, 182, 192, 202, 212, 222, 232, 242, 252, 262, 272, 282, 292, 302, 312, 322, 332, or 342, (b) SEQ ID NOs: 13, 23, 33, 43, 53, 63, 73, 83, 93, 100, 113, 123, 133, 143, 153, 163, 173, 183, 193, 203, 213 (c) Contains one, two, or three HVRs selected from HVR-H2 containing the amino acid sequence 223, 233, 243, 253, 263, 273, 283, 293, 303, 313, 323, 333, or 343, and HVR-H3 containing the amino acid sequence 14, 24, 34, 44, 54, 64, 74, 84, 94, 104, 114, 124, 134, 144, 154, 164, 174, 184, 194, 204, 214, 224, 234, 244, 254, 264, 274, 284, 294, 304, 314, 324, 334, or 344.

[0230] In another embodiment, the anti-Tau antibody contains a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with respect to the amino acid sequence of SEQ ID NOs. 11, 21, 31, 41, 51, 61, 71, 81, 91, 101, 111, 121, 131, 141, 151, 161, 171, 181, 191, 201, 211, 221, 231, 241, 251, 261, 271, 281, 291, 301, 311, 321, 331, or 341. In certain embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions compared to a reference sequence, but an anti-Tau antibody containing that sequence retains the ability to bind to Tau. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted within SEQ ID NOs: 11, 21, 31, 41, 51, 61, 71, 81, 91, 101, 111, 121, 131, 141, 151, 161, 171, 181, 191, 201, 211, 221, 231, 241, 251, 261, 271, 281, 291, 301, 311, 321, 331, or 341. In certain embodiments, substitutions, insertions, or deletions occur within the region outside the HVR (i.e., within the FR). Optionally, the anti-Tau antibody contains the VL sequence in SEQ ID NOs. 11, 21, 31, 41, 51, 61, 71, 81, 91, 101, 111, 121, 131, 141, 151, 161, 171, 181, 191, 201, 211, 221, 231, 241, 251, 261, 271, 281, 291, 301, 311, 321, 331, or 341, including post-translational modifications of that sequence.In one particular embodiment, VL is (a) HVR-L1 containing the amino acid sequence of SEQ ID NOs: 15, 25, 35, 45, 55, 65, 75, 85, 95, 105, 115, 125, 135, 145, 155, 165, 175, 185, 195, 205, 215, 225, 235, 245, 255, 265, 275, 285, 295, 305, 315, 325, 335, or 345, (b) SEQ ID NOs: 16, 26, 36, 46, 56, 66, 76, 86, 96, 106, 116, 126, 136, 146, 156, 166, 176, 186, 196, 206, 216, 226, 236 (c) comprising one, two, or three HVRs selected from HVR-L2 having an amino acid sequence of 246, 266, 266, 276, 286, 296, 306, 316, 326, 336, or 346, and HVR-H3 having an amino acid sequence of HVR-L3 having an amino acid sequence of (c) 17, 27, 37, 47, 57, 67, 77, 87, 97, 107, 117, 127, 137, 147, 157, 167, 177, 187, 197, 207, 217, 227, 237, 247, 267, 277, 277, 287, 297, 307, 317, 327, 337, or 347.

[0231] In another embodiment, an anti-Tau antibody is provided, comprising a VH sequence as in any of the embodiments provided above, and a VL sequence as in any of the embodiments provided above. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 280 and SEQ ID NO: 281, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 290 and SEQ ID NO: 291, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 300 and SEQ ID NO: 301, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 310 and SEQ ID NO: 311, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 320 and SEQ ID NO: 321, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 330 and SEQ ID NO: 331, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 340 and SEQ ID NO: 341, respectively, including post-translational modifications of those sequences.

[0232] In some embodiments, an anti-Tau antibody is provided, comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 348 or SEQ ID NO: 602, and a light chain containing the amino acid sequence of SEQ ID NO: 349.

[0233] In a further embodiment, the present invention provides an antibody that binds to the same epitope as the anti-Tau antibody provided herein. For example, in a particular embodiment, an antibody is provided that binds to the same epitope as an antibody selected from 94B2-C1, 125B11-H3, 37D3-H9, and hu37D3-H9.v28.A4. In a particular embodiment, an antibody is provided that binds to an epitope in the Tau fragment consisting of amino acids 2-24 of SEQ ID NO: 2. In a particular embodiment, an antibody is provided that binds to an epitope in the Tau fragment consisting of amino acids 7-24 of SEQ ID NO: 2. In a particular embodiment, an antibody is provided that binds to an epitope in the Tau fragment consisting of amino acids 7-20 of SEQ ID NO: 2. In a particular embodiment, an antibody is provided that binds to an epitope in the Tau fragment consisting of amino acids 10-24 of SEQ ID NO: 2. In a particular embodiment, an antibody is provided that binds to an epitope in the Tau fragment consisting of amino acids 7-21 of SEQ ID NO: 2. In certain embodiments, an antibody is provided that binds to an epitope in the Tau fragment consisting of amino acids 8-22 of SEQ ID NO: 2. In certain embodiments, an antibody is provided that binds to an epitope in the Tau fragment consisting of amino acids 11-25 of SEQ ID NO: 2. In certain embodiments, an antibody is provided that binds to one or more of the following Tau fragments: 2-24, 7-24, 7-20, 10-24, 7-21, 8-22, and 11-25. In some embodiments, an antibody is provided that binds to a peptide having the sequence of SEQ ID NO: 593 but not to a peptide having the sequence of SEQ ID NO: 596 or SEQ ID NO: 597.

[0234] In a further embodiment of the present invention, the anti-Tau antibody according to any of the above embodiments is a monoclonal antibody comprising a chimeric, humanized, or human antibody. In one embodiment, the anti-Tau antibody is an antibody fragment, e.g., Fv, Fab, Fab', scFv, diabody, or F(ab')2 fragment. In another embodiment, the antibody is a full-length antibody, e.g., an intact IgG1 or IgG4 antibody, or another antibody class or isotype as defined herein.

[0235] In a further embodiment, an anti-Tau antibody according to any of the above embodiments may incorporate any of the features described in Sections 1 to 7 below, either individually or in combination.

[0236] 1. Antibody affinity In certain embodiments, the antibodies provided herein have a range of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (for example, 10 -8 M or less, for example, 10 -8 M~10 -13 M, for example, 10 -9 M~10 -13 The dissociation constant (K) of M D ) has.

[0237] In some embodiments, K D This is measured by radiolabeled antigen-binding assay (RIA). In some embodiments, the RIA is performed with the Fab version of the antibody of interest and its antigen. For example, the solution binding affinity of Fab to the antigen is measured by adding Fab to a minimum concentration in the presence of a series of titrations of the unlabeled antigen. 125 I) The antigen is measured by equilibrating with a labeled antigen and then capturing the bound antigen with a plate coated with anti-Fab antibody (see, e.g., Chen et al., J.Mol.Biol.293:865-881 (1999)). To establish conditions for the assay, MICROTITER® multiwell plates (Thermo Scientific) are coated overnight with 5 μg / ml of capture anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6), and then blocked with 2 wt / v bovine serum albumin in PBS at room temperature (approx. 23°C) for 2-5 hours. In a non-adsorbent plate (Nunc No. 269620), 100 pM or 26 pM [ 125Mix the [I]-antigen with serial dilutions of the target Fab (e.g., consistent with the evaluation of the anti-VEGF antibody Fab-12 in Presta et al., Cancer Res. 57:4593-4599 (1997)). Then incubate the target Fab overnight, but incubation can be extended for a longer period (e.g., about 65 hours) to ensure that equilibrium is reached. Then transfer the mixture to a capture plate for incubation at room temperature (e.g., 1 hour). Then remove the solution and wash the plate eight times with 0.1% polysorbate 20 (TWEEN-20®) in PBS. Once the plate is dry, add 150 μL / well of scintillant (MICROSCINT-20®, Packard) and count the plate on a TOPCOUNT® gamma counter (Packard) for 10 minutes. Select the concentration of each Fab that yields a maximum binding of 20% or less for use in the competitive binding assay.

[0238] According to another embodiment, K DThis is measured using a BIACORE® surface plasmon resonance assay. For example, an assay using BIACORE®-2000 or BIACORE®-3000 (BIAcore, Inc., Piscataway, NJ) is performed at approximately 10 resonance units (RUs) on an immobilized antigen CM5 chip at 25°C. In some embodiments, a carboxymethylated dextran biosensor chip (CM5, BIACORE, Inc.) is activated with N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) according to the supplier's instructions. The antigen is diluted to 5 μg / mL (approximately 0.2 μM) with 10 mM sodium acetate (pH 4.8) and then injected at a flow rate of 5 μL / min to obtain a coupled protein of approximately 10 resonance units (RUs). After antigen injection, 1 M ethanolamine is injected to block unreacted groups. For dynamic measurement, serially diluted 2-fold dilutions of Fab (0.78 nM to 500 nM) are injected at a flow rate of approximately 25 μL / min into PBS containing 0.05% polysorbate 20 (TWEEN-20®) surfactant (PBST) at 25°C. The association rate (k on ) and dissociation rate (k off The equilibrium dissociation constant (K) is calculated by simultaneously fitting the association sensorgram and dissociation sensorgram using a simple one-to-one Langmuir coupled model (BIACORE® Evaluation Software version 3.2). D ) to ratio k off / k on Calculate as follows. For example, see Chen et al., J.Mol.Biol.293:865-881(1999). The ON velocity obtained by the above surface plasmon resonance assay is 10 6 M -1 s -1If it exceeds this, the ON rate can be determined by using fluorescence quenching techniques to measure the increase or decrease in fluorescence emission intensity (excitation = 295 nm, emission = 340 nm, 16 nm band-passed) of 20 nM anti-antigen antibody (Fab form) (pH 7.2) in PBS at 25°C in the presence of increasing antigen concentrations, measured with a spectrophotometer such as a spectrophotometer with stopped flow (Aviv Instruments) or an 8000 series SLM-AMINCO™ spectrophotometer (ThermoSpectronic) with a stirred cuvette.

[0239] 2. Antibody fragment In certain embodiments, the antibodies provided herein are antibody fragments. These include, but are not limited to, Fab, Fab', Fab'-SH, F(ab')2, Fv, and scFv fragments, as well as other fragments described below. For an overview of specific antibody fragments, see Hudson et al. Nat. Med. 9:129-134 (2003). For an overview of scFv fragments, see, for example, Pluckthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994), as well as WO93 / 16185, and U.S. Patents 5,571,894 and 5,587,458. For a discussion of the Fab and F(ab')2 fragments, which contain salvage receptor-binding epitope residues and have increased in vivo half-lives, please refer to U.S. Patent No. 5,869,046.

[0240] A diabody is an antibody fragment having two antigen-binding sites, which may be bivalent or bispecific. See, for example, EP404,097, WO1993 / 01161, Hudson et al., Nat.Med.9:129-134(2003), and Hollinger et al., Proc.Natl.Acad.Sci.USA90:6444-6448(1993). Triabodies and tetrabodies are also described in Hudson et al., Nat.Med.9:129-134(2003).

[0241] A single-domain antibody is an antibody fragment containing all or part of the heavy chain variable domain or all or part of the light chain variable domain of an antibody. In certain embodiments, the single-domain antibody is a human single-domain antibody (see Domantis, Inc., Waltham, MA, e.g., U.S. Patent No. 6,248,516B1).

[0242] Antibody fragments can be prepared by a variety of techniques, including, but not limited to, protein digestion of intact antibodies and production by recombinant host cells (e.g., E. coli or phages), as described herein.

[0243] 3. Chimeric antibodies and human antibodies In certain embodiments, the antibodies provided herein are chimeric antibodies. Chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567 and in Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984). In one example, a chimeric antibody includes a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, e.g., a monkey) and a human constant region. In a further example, a chimeric antibody is a “class-switched” antibody in which the class or subclass has changed from the class or subclass of the parent antibody. Chimeric antibodies include their antigen-binding fragments.

[0244] In certain embodiments, a chimeric antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce its immunogenicity against humans while retaining the specificity and affinity of the parent non-human antibody. Generally, a humanized antibody contains one or more variable domains, whose HVR, e.g., CDR (or portions thereof), is derived from a non-human antibody, and whose FR (or portions thereof) is derived from a human antibody sequence. Optionally, the humanized antibody will also contain at least a portion of the human constant region. In some embodiments, several FR residues in the humanized antibody are replaced with corresponding residues derived from a non-human antibody (e.g., an antibody from which the HVR residues are derived) to restore or improve antibody specificity or affinity, for example.

[0245] Humanized antibodies and their production methods are outlined, for example, in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and also in, for example, Riechmann et al., Nature 332:323-329 (1988), Queen et al., Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989), U.S. Patent Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409, Kashmiri et al. Further details can be found in al., Methods36:25-34 (2005) (describes specificity-determining region (SDR) transplantation), Padlan, Mol.Immunol.28:489-498 (1991) (describes "resurfacing"), Dall'Acqua et al., Methods36:43-60 (2005) (describes "FR shuffling"), and Osbourn et al., Methods36:61-68 (2005) and Klimka et al., Br.J.Cancer,83:252-260 (2000) (describes the "inducible selection" approach to FR shuffling).

[0246] Human framework regions that can be used for humanization include framework regions selected using the "best fit" method (see, e.g., Sims et al. J.Immunol. 151:2296 (1993)), framework regions derived from consensus sequences of human antibodies of specific subgroups of light chain or heavy chain variable regions (e.g., Carter et al. Proc.Natl.Acad.Sci.USA, 89:4285 (1992) and Presta et al. J.Immunol., 151:2623 (1993)), human mature (somatically mutant) framework regions or human germline framework regions (e.g., Almagro and Fransson, Front.Biosci. 13:1619-1633 (2008)), and framework regions derived from screening of FR libraries (e.g., Baca et al., J.Biol.Chem. 272:10678-10684 (1997) and Rosok et al. Examples include, but are not limited to, al., J. Biol. Chem. 271:22611-22618 (1996).

[0247] 4. Human antibodies In certain embodiments, the antibodies provided herein are human antibodies. Human antibodies can be produced using a variety of techniques known in the art. Human antibodies are generally described in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-74 (2001) and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008).

[0248] Human antibodies can be prepared by administering an immunogen to transgenic animals modified to produce intact human antibodies or intact antibodies containing human variable regions in response to antigen administration. Such animals typically contain all or part of human immunoglobulin loci that either replace endogenous immunoglobulin loci, are extrachromosomal, or are randomly integrated into the animal's chromosomes. In such transgenic mice, endogenous immunoglobulin loci are generally inactivated. For an overview of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). See also, for example, U.S. Patent Nos. 6,075,181 and 6,150,584 describing XENOMOUSE® technology, U.S. Patent No. 5,770,429 describing HUMAB® technology, U.S. Patent No. 7,041,870 describing KM MOUSE® technology, and U.S. Patent Application Publication US2007 / 0061900 describing VELOCIMOUSE®. Human variable regions derived from intact antibodies produced by such animals can be further modified, for example, by combining them with different human constant regions.

[0249] Human antibodies can also be produced by hybridoma-based methods. Human myeloma and mouse-human heterozygous myeloma cell lines for producing human monoclonal antibodies have been described (see, for example, Kozbor J. Immunol., 133:3001 (1984), Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987), and Boerner et al., J. Immunol., 147:86 (1991)). Human antibodies produced by human B-cell hybridoma technology are also described in Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Additional methods include, for example, those described in U.S. Patent No. 7,189,826 (production of monoclonal human IgM antibody from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (human-human hybridomas). Human hybridoma technology (trioma technology) is also described in Vollmers and Brandlein, Histology and Histopathology, 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3):185-91 (2005).

[0250] Human antibodies can also be generated by isolating Fv clone variable domain sequences selected from human-derived phage presentation libraries. Such variable domain sequences can then be combined with desired human constant domains. Techniques for selecting human antibodies from antibody libraries are described below.

[0251] 5. Antibodies derived from libraries The antibodies of the present invention can be isolated by screening a combinatorial library for antibodies having desired activity(s). For example, various methods are known in the art for generating phage-presenting libraries and screening such libraries for antibodies having desired binding properties. Such methods are outlined, for example, in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001), and also in, for example, McCafferty et al., Nature 348:552-554, Clackson et al., Nature 352:624-628 (1991), Marks et al., J.Mol.Biol. 222:581-597 (1992), Marks and Bradbury, in Methods in Molecular Biology 248:161-175 (Lo, ed., Human Press, Totowa, NJ, 2003), Sidhu et al., J.Mol.Biol. 338(2):299-310 (2004); Lee et al. Further details are found in al., J.Mol.Biol.340(5):1073-1093(2004); Fellouse, Proc. Natl.Acad.Sci.USA101(34):12467-12472(2004), and Lee et al., J.Immunol.Methods284(1-2):119-132(2004).

[0252] In certain phage presentation methods, the VH and VL gene repertoires can be separately cloned by polymerase chain reaction (PCR), randomly recombined in a phage library, and then screened for antigen-binding phages, as described in Winter et al., Ann. Rev. Immunol., 12:433-455 (1994). The phages typically present antibody fragments as either single-stranded Fv(scFv) fragments or Fab fragments. Libraries derived from immunization sources provide high-affinity antibodies to immunogens without requiring hybridoma construction. Alternatively, as described by Griffiths et al., EMBO J, 12:725-734 (1993), naive repertoires can be cloned (e.g., from humans) to provide a single source of antibodies against a wide range of non-self and also self-antigens without any immunization. Finally, as described by Hoogenboom and Winter, J. Mol. Biol., 227:381-388 (1992), naive libraries can also be constructed synthetically by cloning an unrearranged V gene segment from stem cells, encoding a highly variable CDR3 region using PCR primers containing random sequences, and achieving rearrangement in vitro. Examples of patent publications describing human antibody phage libraries include U.S. Patent No. 5,750,373, as well as U.S. Patent Publications 2005 / 0079574, 2005 / 0119455, 2005 / 0266000, 2007 / 0117126, 2007 / 0160598, 2007 / 0237764, 2007 / 0292936, and 2009 / 0002360.

[0253] Antibodies or antibody fragments isolated from a human antibody library are considered human antibodies or human antibody fragments in this specification.

[0254] 6. Multispecific antibodies In certain embodiments, the antibodies provided herein are multispecific antibodies, for example, bispecific antibodies. A multispecific antibody is a monoclonal antibody having binding specificity to at least two different sites. In certain embodiments, one binding specificity is to Tau and the other is to any other antigen. In certain embodiments, one binding specificity is to Tau and the other is to amyloid beta. In certain embodiments, a bispecific antibody can bind to two different epitopes of Tau. A bispecific antibody can also be used to localize a cytotoxic agent to cells expressing Tau. A bispecific antibody may be prepared as a full-length antibody or as an antibody fragment.

[0255] Techniques for producing multispecific antibodies include, but are not limited to, the recombinant co-expression of two immunoglobulin heavy-light chain pairs with different specificities (see Milstein and Cuello, Nature 305:537 (1983), WO93 / 08829, and Traunecker et al., EMBO J.10:3655 (1991)), and the "knob-in-hole" operation (see, for example, U.S. Patent No. 5,731,168). Multispecific antibodies can also be produced by manipulating the electrostatic steering effect to create antibody Fc-heterodimer molecules (WO2009 / 089004A1), crosslinking two or more antibodies or fragments (see, e.g., U.S. Patent No. 4,676,980 and Brennan et al., Science, 229:81 (1985)), producing bispecific antibodies using leucine zippers (see, e.g., Kostelny et al., J.Immunol., 148(5):1547-1553 (1992)), producing bispecific antibody fragments using "diabody" technology (see, e.g., Hollinger et al., Proc.Natl.Acad.Sci.USA, 90:6444-6448 (1993)), and using single-stranded Fv(sFv) dimers (see, e.g., Gruber et al. It can also be prepared by preparing a triplicate antibody, as described in, for example, Tutt et al., J.Immunol., 152:5368 (1994), and Tutt et al., J.Immunol., 147:60 (1991).

[0256] Modified antibodies having three or more functional antigen-binding sites, including "octopus antibodies," are also included herein (see, for example, US2006 / 0025576A1).

[0257] The antibodies or fragments used herein also include “Dual Acting FAb” or “DAF” which include antigen-binding sites that bind to Tau and another different antigen (see, for example, US2008 / 0069820).

[0258] 7. Antibody variants In certain embodiments, amino acid sequence variants of antibodies provided herein are intended. For example, it may be desirable to improve the binding affinity and / or other biological properties of the antibody. Amino acid sequence variants of antibodies can be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from and / or insertions of residues in the amino acid sequence of the antibody, and / or substitutions thereof. Any combination of deletions, insertions, and substitutions can be performed to arrive at the final construct, provided that the final construct has the desired properties, such as antigen binding.

[0259] a) Substitution, insertion, and deletion variants In certain embodiments, antibody mutants having one or more amino acid substitutions are provided. Target sites for substitutional mutagenesis include HVR and FR. Conservative substitutions are shown in Table 1 under the heading "Preferred Substitutions." More substantial changes are provided in Table 1 under the heading "Exemplary Substitutions" and are further described below in relation to amino acid side chain classes. Amino acid substitutions are introduced into antibodies of interest, and the products can be screened for desired activities, such as retention / improvement of antigen binding, decreased immunogenicity, or improvement of ADCC or CDC. Table 1 TIFF0007835706000001.tif164170 Amino acids can be grouped according to their general side-chain properties. (1) Hydrophobic: norleucine, Met, Ala, Val, Leu, Ile; (2) Neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) Acidic: Asp, Glu; (4) Basicity: His, Lys, Arg; (5) Residues that affect chain orientation: Gly, Pro; (6) Aromatic: Trp, Tyr, Phe.

[0260] Non-conservative substitutions involve exchanging a member of one class for a member of another class.

[0261] Certain types of substitutional mutants involve substituting one or more hypervariable region residues of a parent antibody (e.g., a humanized antibody or a human antibody). Generally, the resulting mutant(s) selected for further study have modifications (e.g., improvements) to specific biological properties (e.g., increased affinity, decreased immunogenicity) compared to the parent antibody, and / or substantially retain certain biological properties of the parent antibody. An exemplary substitutional mutant is an affinity-mature antibody that can be conveniently generated using phage presentation-based affinity maturation techniques, such as those described herein. Briefly, one or more HVR residues are mutated, the mutant antibody is presented on a phage, and screened for specific biological activity (e.g., binding affinity).

[0262] Changes (e.g., substitutions) can be made to HVRs to improve, for example, antibody affinity. Such changes may be made to HVR "hot spots," i.e., residues encoded by codons that are frequently mutated during the somatic cell maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)) and / or residues that come into contact with the antigen, and the resulting mutant VH or VL is tested for binding affinity. Affinity maturation by constructing a secondary library and reselecting from it is described, for example, Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001)). In some embodiments of affinity maturation, diversity is introduced into the variable genes selected for maturation by one of various methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then constructed. Subsequently, this library is screened to identify any antibody variant with the desired affinity. Another way to introduce diversity involves an HVR-directed approach in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding can be specifically identified, for example, using alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3 are particularly often targeted.

[0263] In certain embodiments, substitutions, insertions, or deletions may occur within one or more HVRs, provided that such changes do not substantially reduce the antibody's ability to bind to the antigen. For example, conservative changes that do not substantially reduce binding affinity (e.g., conservative substitutions provided herein) may occur in an HVR. Such changes may, for example, be outside the antigen-contact residue within the HVR. In certain embodiments of the variant VH and VL sequences provided above, each HVR is either unchanged or contains one or fewer, two or fewer, or three or fewer amino acid substitutions.

[0264] A useful method for identifying antibody residues or regions that can be targeted for mutagenesis is called "alanine scanning mutagenesis," described by Cunningham and Wells (1989) Science, 244:1081-1085. In this method, residues or target residue groups (e.g., charged residues such as arg, asp, his, lys, and glu) are identified and it is determined whether substitution with neutral or charged amino acids (e.g., alanine or polyalanine) affects the antibody-antigen interaction. Further substitutions may be introduced at amino acid positions that exhibit functional sensitivity to the initial substitution. Alternatively, or in addition, the crystal structure of the antigen-antibody complex may be used to identify contact points between the antibody and antigen. Such contact residues and adjacent residues may be targeted as candidates for substitution or excluded. Mutagenesis can be screened to determine if they possess the desired properties.

[0265] Amino acid insertions include fusions of amino and / or carboxyl terminals in polypeptides ranging in length from 1 to 100 or more residues, as well as intrasequence insertions of single or multiple amino acid residues. An example of terminal insertion is an antibody with an N-terminal methionyl residue. Other insertion variants of antibody molecules include the fusion of the N-terminus or C-terminus of an antibody to an enzyme (e.g., for ADEPT) or polypeptide, which increases the serum half-life of the antibody.

[0266] b) Glycosylated variants In certain embodiments, the antibodies provided herein are modified to increase or decrease the degree to which the antibody is glycosylated. The addition or deletion of glycosylation sites to an antibody can be conveniently achieved by altering the amino acid sequence so that one or more glycosylation sites are created or removed.

[0267] If an antibody contains an Fc region, the carbohydrate bound to it may change. Natural antibodies produced by mammalian cells typically contain branched oligosaccharides, generally bound to Asn297 of the CH2 domain of the Fc region by an N-bond. See, for example, Wright et al. TIBTECH 15:26-32 (1997). Examples of oligosaccharides include various carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as fucose bound to the GlcNAc in the "stem" of the branched oligosaccharide structure. In some embodiments, modification of the oligosaccharide within the antibody of the present invention may be performed to produce antibody mutants with improved specific properties.

[0268] In some embodiments, antibody mutants are provided that have carbohydrate structures lacking fucose (directly or indirectly) bound to the Fc region. For example, the amount of fucose in such an antibody may be 1%–80%, 1%–65%, 5%–65%, or 20%–40%. The amount of fucose is determined by calculating the average amount of fucose in the glycans at Asn297 relative to the total of all sugar structures (e.g., complexes, hybrids, and high-mannose structures) bound to Asn297, measured, for example, by MALDI-TOF mass spectrometry as described in WO2008 / 077546. Asn297 refers to the asparagine residue located at approximately position 297 (Eu numbering of Fc region residues) within the Fc region, although Asn297 may also be located approximately ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to slight sequence variations within the antibody. Such fucosylated mutants may have improved ADCC function. For example, see U.S. Patent Publication No. US2003 / 0157108 (Presta, L.) and U.S. Patent Publication No. US2004 / 0093621 (Kyowa Hakko Kogyo Co., Ltd.). Examples of published data regarding "defucosation" or "fucose-deficient" antibody variants include US2003 / 0157108, WO2000 / 61739, WO2001 / 29246, US2003 / 0115614, US2002 / 0164328, US2004 / 0093621, US2004 / 0132140, US2004 / 0110704, US2004 / 0110282, US2004 / 0109865, WO2003 / 085119, WO2003 / 084570, WO2005 / 035586, WO2005 / 035778, WO2005 / 053742, WO2002 / 031140, and Okazaki et al. References include al. J. Mol. Biol. 336:1239-1249 (2004) and Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 (2004).Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells lacking protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); U.S. Patent Application No. US2003 / 0157108A1, Presta, L; and WO2004 / 056312A1, Adams et al., particularly Example 11), as well as knockout cell lines such as those containing the alpha-1,6-fucosyltransferase gene, FUT8, or knockout CHO cells (e.g., Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 (2004), Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006), and WO2003 / 085107).

[0269] For example, antibody mutants having a bifid oligosaccharide are provided, in which a branched oligosaccharide bound to the Fc region of the antibody is bifid by GlcNAc. Such antibody mutants may have reduced fucosylation and / or improved ADCC function. Examples of such antibody mutants are described, for example, in WO2003 / 011878 (Jean-Mairet et al.), U.S. Patent No. 6,602,684 (Umana et al.), and U.S.2005 / 0123546 (Umana et al.). Antibody mutants having at least one galactose residue in the oligosaccharide bound to the Fc region are also provided. Such antibody mutants may have improved CDC function. Such antibody variants are described, for example, in WO1997 / 30087 (Patel et al.), WO1998 / 58964 (Raju, S.), and WO1999 / 22764 (Raju, S.).

[0270] c) Fc region variant In certain embodiments, one or more amino acid modifications are introduced into the Fc region of an antibody provided herein, thereby generating an Fc region variant. The Fc region variant may include a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3, or IgG4 Fc region) containing amino acid modifications (e.g., substitutions) at one or more amino acid positions.

[0271] In certain embodiments, the present invention aims to create antibody mutants that, by possessing some, but not all, effector functions, are desirable candidates for applications where the in vivo half-life of the antibody is important, but certain effector functions (such as complement and ADCC) are unnecessary or harmful. In vitro and / or in vivo cytotoxicity assays can be performed to confirm the reduction / depletion of CDC and / or ADCC activity. For example, an Fc receptor (FcR) binding assay can be performed to confirm that the antibody lacks FcγR binding (and therefore is likely to lack ADCC activity) but retains FcRn binding ability. While NK cells, the primary cells that mediate ADCC, express only FcγRIII, monocytes express FcγRI, FcγRII, and FcγRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991). Non-limiting examples of in vitro assays for evaluating the ADCC activity of target molecules are described in U.S. Patent No. 5,500,362 (see, for example, Hellstrom, I. et al. Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I. et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985), and No. 5,821,337 (see Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-radioactive assay methods may be used (see, for example, the ACTI® non-radioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc., Mountain View, CA) and the CytoTox96® non-radioactive cytotoxicity assay (Promega, Madison, WI)). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells.Alternatively, or in addition, the ADCC activity of the target molecule can be evaluated in vivo in animal models, such as those disclosed in Clynes et al. Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). A C1q binding assay can also be performed to confirm that the antibody cannot bind to C1q and therefore lacks CDC activity. See, for example, the C1q and C3c binding ELISAs in WO2006 / 029879 and WO2005 / 100402. To evaluate complement activation, a CDC assay may be performed (see, for example, Gazzano-Santoro et al., J.Immunol.Methods202:163 (1996), Cragg, MS et al., Blood101:1045-1052 (2003), and Cragg, MS and MJ Glennie, Blood103:2738-2743 (2004)). FcRn binding and in vivo clearance / half-life determination can also be performed using methods known in the art (see, for example, Petkova, S B et al., Int'l.Immunol.18(12):1759-1769 (2006)).

[0272] Antibodies with reduced effector function include those having one or more substitutions among Fc region residues 238, 265, 269, 270, 297, 327, and 329 (U.S. Patent No. 6,737,056). Such Fc variants include the so-called "DANA" Fc variant having substitutions at alanine residues 265 and 297, and Fc variants having substitutions at two or more amino acid positions 265, 269, 270, 297, and 327 (U.S. Patent No. 7,332,581).

[0273] Specific antibody variants with improved or reduced binding to FcR are described. (See, for example, U.S. Patent No. 6,737,056, WO2004 / 056312, and Shields et al., J. Biol. Chem. 9(2):6591-6604(2001).)

[0274] In certain embodiments, the antibody mutant includes an Fc region having one or more amino acid substitutions that improve ADCC, for example, substitutions at positions 298, 333, and / or 334 (EU numbering of residues) of the Fc region.

[0275] In some embodiments, as described, for example, in U.S. Patent No. 6,194,551, WO99 / 51642, and Idusogie et al. J. Immunol. 164:4178-4184 (2000), the alteration occurs in the Fc region, resulting in altered (i.e., improved or reduced) C1q binding and / or complement-dependent cytotoxicity (CDC).

[0276] Antibodies with increased half-life and improved binding to the neonatal Fc receptor (FcRn), which are involved in the transfer of maternal IgG to the fetus, are described in US2005 / 0014934A1 (Hinton et al.). These antibodies contain an Fc region with one or more substitutions that improve binding to the FcRn in the Fc region. Such Fc variants include substitutions in one or more of the Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, ​​413, 424, or 434, for example, substitutions in Fc region residue 434 (U.S. Patent No. 7,371,826).

[0277] For other examples of Fc region variants, see also Duncan & Winter, Nature 322:738-40 (1988), U.S. Patent Nos. 5,648,260, 5,624,821, and WO94 / 29351.

[0278] d) Cysteine-modified antibody mutants In certain embodiments, it may be desirable to produce cysteine-modified antibodies, such as "thioMAb," in which one or more residues of the antibody are substituted with cysteine ​​residues. In certain embodiments, the substituted residues occur at the contactable sites of the antibody. By substituting these residues with cysteine, a reactive thiol group is thereby positioned at the contactable sites of the antibody, which can then be used to complex the antibody with other parts, such as the drug moiety or linker-drug moiety, to produce immunocomplexes as further described herein. In certain embodiments, one or more of the following residues may be substituted with cysteine: V205 (Kabat numbering) of the light chain, A118 (EU numbering) of the heavy chain, and S400 (EU numbering) of the heavy chain Fc region. Cysteine-modified antibodies may be produced, for example, as described in U.S. Patent No. 7,521,541.

[0279] e) Antibody derivative In certain embodiments, the antibodies provided herein may be further modified to include additional non-proteinoid moieties known and readily available in the art. Suitable moieties for antibody derivatization include, but are not limited to, water-soluble polymers. Non-limited examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol / propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene / maleic anhydride copolymers, polyamino acids (either homopolymers or random copolymers), and dextran or poly(n-vinylpyrrolidone) polyethylene glycol, propropylene glycol homopolymers, prolypropylene oxide / ethylene oxide copolymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may be advantageous in production due to its stability in water. The polymers can have any molecular weight and can be branched or unbranched. The number of polymers bound to the antibody can vary, and if two or more polymers are bound, they can be the same molecule or different molecules. In general, the number and / or types of polymers used in derivatization can be determined based on considerations including, but not limited to, the specific properties or functions of the antibody being improved, and whether the antibody derivative will be used in therapy under defined conditions.

[0280] In another embodiment, a complex of an antibody and a non-proteinaceous moiety is provided that can be selectively heated by exposure to radiation. In some embodiments, the non-proteinaceous moiety is a carbon nanotube (Kam et al., Proc. Natl. Acad. Sci. USA 102:11600-11605 (2005)). The radiation may be of any wavelength and may include, but is not limited to, wavelengths that do not harm normal cells, but heat the non-proteinaceous moiety to a temperature that kills cells proximal to the antibody-non-proteinaceous moiety.

[0281] B. Recombination method and composition Antibodies can be produced, for example, using recombinant methods and compositions described in U.S. Patent No. 4,816,567. In some embodiments, isolated nucleic acids encoding the anti-Tau antibody described herein are provided. Such nucleic acids may encode an amino acid sequence containing the VL of the antibody and / or an amino acid sequence containing the VH of the antibody (e.g., the light chain and / or heavy chain of the antibody). In a further embodiment, one or more vectors (e.g., expression vectors) containing such nucleic acids are provided. In a further embodiment, host cells containing such nucleic acids are provided. In such an embodiment, the host cells comprise (1) a vector comprising nucleic acids encoding an amino acid sequence containing the VL of the antibody and an amino acid sequence containing the VH of the antibody, or (2) a first vector comprising nucleic acids encoding an amino acid sequence containing the VL of the antibody and a second vector comprising nucleic acids encoding an amino acid sequence containing the VH of the antibody (e.g., transformed with them). In some embodiments, the host cells are eukaryotic, for example, Chinese hamster ovary (CHO) cells or lymphoid cells (e.g., Y0, NS0, Sp20 cells). In some embodiments, a method is provided for producing an anti-Tau antibody, comprising culturing host cells containing the nucleic acid encoding the antibody provided above under conditions suitable for antibody expression, and optionally recovering the antibody from the host cells (or host cell culture medium).

[0282] For recombinant production of anti-Tau antibodies, nucleic acids encoding the antibody, such as those described above, are isolated and inserted into one or more vectors for further cloning and / or expression in host cells. Such nucleic acids can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes capable of specifically binding to the genes encoding the heavy and light chains of the antibody).

[0283] Suitable host cells for cloning or expressing antibody-encoding vectors include prokaryotic or eukaryotic cells as described herein. For example, antibodies may be produced in bacteria, particularly when glycosylation and Fc effector function are not required. For the expression of antibody fragments and polypeptides in bacteria, see, for example, U.S. Patents 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol. 248 (BKCLo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254, which describes the expression of antibody fragments in E. coli.) After expression, the antibodies may be isolated from the bacterial cell paste in a soluble fraction and further purified.

[0284] In addition to prokaryotes, eukaryotic microorganisms such as filamentous fungi or yeasts are suitable cloning or expression hosts for antibody-encoding vectors, including fungal and yeast strains whose glycosylation pathways are "humanized," resulting in the production of antibodies with a partially or completely human glycosylation pattern. See Gerngross, Nat. Biotech. 22:1409-1414 (2004) and Li et al., Nat. Biotech. 24:210-215 (2006).

[0285] Host cells suitable for the expression of glycosylated antibodies can also be derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. In addition to insect cells, numerous baculovirus strains have been identified that can be used, in particular, for the transfection of armyworm cells.

[0286] Plant cell cultures can also be used as hosts. See, for example, U.S. Patents 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (which describe PLANTIBODIES® technology for antibody production in transgenic plants).

[0287] Vertebrate cells can also be used as hosts. For example, mammalian cell lines adapted to grow in suspension may be useful. Other examples of useful mammalian host cell lines include the SV40(COS-7) transformed monkey kidney CV1 cell line, human embryonic kidney cells (e.g., 293 or 293 cells described in Graham et al., J. Gen Virol. 36:59 (1977)), baby hamster kidney cells (BHK), mouse Sertoli cells (e.g., TM4 cells described in Mather, Biol. Reprod. 23:243-251 (1980)), monkey kidney cells (CV1), African green monkey kidney cells (VERO-76), human cervical cancer cells (HELA), canine kidney cells (MDCK), buffalo rat liver cells (BRL3A), human lung cells (W138), human liver cells (Hep G2), mouse mammary tumor cells (MMT060562), e.g., Mather et al., Annals These include TRI cells, MRC5 cells, and FS4 cells, as described in NYAcad.Sci.383:44-68(1982). Other useful mammalian host cell lines include DHFR -Examples include Chinese hamster ovary (CHO) cells, including CHO cells (Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)), as well as myeloma cell lines such as Y0, NS0, and Sp2 / 0. For an overview of specific mammalian host cell lines suitable for antibody production, see, for example, Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (BKCLo, ed., Humana Press, Totowa, NJ), pp. 255-268 (2003).

[0288] C. Assay The anti-Tau antibodies provided herein may be identified, screened, or characterized for their physical / chemical properties and / or biological activity by various assays known in the art.

[0289] 1. Binding assays and other assays In one embodiment, the antibody of the present invention is tested for its antigen-binding activity by known methods such as ELISA and Western blotting.

[0290] In another embodiment, a competitive assay can be used to identify antibodies that compete with the antibodies described herein for binding to Tau. In certain embodiments, such competing antibodies bind to the same epitope (e.g., a linear or conformational epitope) to which 94B2-C1, 125B11-H3, 37D3-H9, or hu37D3-H9.v28.A4 is bound. Detailed exemplary methods for mapping the epitopes to which antibodies bind are provided in Morris (1996) “Epitope Mapping Protocols,” in Methods in Molecular Biology vol. 66 (Humana Press, Totowa, NJ).

[0291] In one exemplary competitive assay, immobilized Tau (such as monomer Tau) is incubated in a solution containing a first labeled antibody that binds to Tau (e.g., any antibody described herein, such as hu37D3-H9.v28.A4) and a second unlabeled antibody to be tested for its ability to compete with the first antibody for binding to Tau. The second antibody may be present in the hybridoma supernatant. As a control, immobilized Tau is incubated in a solution containing the first labeled antibody but not the second unlabeled antibody. After incubation under conditions that allow the first antibody to bind to Tau, excess unbound antibody is removed and the amount of labeling associated with the immobilized Tau is measured. If the amount of labeling associated with the immobilized Tau is substantially reduced in the test sample compared to the control sample, it indicates that the second antibody is competing with the first antibody for binding to Tau. See Harlow and Lane (1988) Antibodies: A Laboratory Manual ch.14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY).

[0292] 2. Activity assay In one embodiment, an assay is provided for identifying an anti-Tau (e.g., pan-Tau) antibody having biological activity. Examples of biological activity include the binding of such an antibody to multiple forms of Tau (e.g., monomeric Tau, oligomeric Tau, non-phosphorylated Tau, and phosphorylated Tau), as well as the reduction of levels of Tau protein (e.g., paired helical fibrils containing total Tau, total soluble Tau, soluble non-phosphorylated Tau, soluble phosphorylated Tau, total insoluble Tau, insoluble non-phosphorylated Tau, insoluble phosphorylated Tau, hyperphosphorylated Tau, or hyperphosphorylated Tau in the brain, e.g., the cerebral cortex and / or hippocampus). Antibodies having such biological activity in vivo and / or in vitro are also provided.

[0293] In certain embodiments, the antibodies of the present invention are tested for such biological activity. For example, using an animal model of tauopathy, such as a Tau transgenic mouse (e.g., P301L), the binding of anti-Tau antibodies to brain sections, for example, to neurofibrillary tangles in the brain of transgenic mice, can be detected. Furthermore, an animal model of tauopathy, such as a Tau transgenic mouse (e.g., P301L), can be treated with an anti-Tau antibody, and using experimental techniques known in the art, it can be evaluated whether such treatment reduces the levels of Tau protein (e.g., total Tau, total soluble Tau, soluble phosphorylated Tau, soluble unphosphorylated Tau, total insoluble Tau, insoluble phosphorylated Tau, insoluble unphosphorylated Tau, hyperphosphorylated Tau, or paired helical fibrils containing hyperphosphorylated Tau) in the mouse brain (e.g., in the cerebral cortex and / or hippocampus).

[0294] D. Immune complex The present invention also provides an immune complex comprising the anti-Tau antibody of this specification, which is conjugated with one or more other therapeutic agents or radioisotopes.

[0295] In another embodiment, the immune complex comprises an antibody described herein, which complexes with a radioactive atom to form a radiocomplex. Various radioisotopes are available for the production of the radiocomplex. For example, At 211 , I 131 , I 125 , Y 90 Re 186 Re 188 Sm 153 , Bi 212 , P 32 Pb 212And radioactive isotopes of Lu are examples. When radioactive complexes are used for detection, they may include radioactive atoms for scintigraphy studies, such as tc99m or I123, or spin labels for nuclear magnetic resonance (NMR) imaging (also known as MRI), such as iodine-123, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese, or iron.

[0296] Antibody conjugates can be prepared using various bifunctional protein coupling agents such as N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), iminothiolane (IT), difunctional derivatives of imide esters (e.g., dimethylHCl adipiimidoate), active esters (e.g., disuccinimidyl suberate), aldehydes (e.g., glutaraldehyde), bis-azide compounds (e.g., bis(p-azidobenzoyl)hexanediamine), bis-diazonium derivatives (e.g., bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (e.g., toluene 2,6-diisocyanate), and bis-active fluorine compounds (e.g., 1,5-difluoro-2,4-dinitrobenzene). For example, lysine immunotoxins can be prepared as described in Vitetta et al., Science 238:1098 (1987). Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugating radionucleotides to antibodies. See WO94 / 11026. The linker may be a “cleavable linker” that facilitates the release of cytotoxic drugs within cells. For example, acid-unstable linkers, peptidase-sensitive linkers, photosensitive linkers, dimethyl linkers, or disulfide-containing linkers (Chari et al., Cancer Res. 52:127-131 (1992), U.S. Patent No. 5,208,020) may be used.

[0297] The immunoconjugates or ADCs described herein expressly intend to be prepared with crosslinking reagents including, but are not limited to, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, and sulfo-SMPB, as well as commercially available SVSB (succinimidyl-(4-vinylsulfone)benzoate) (e.g., from Pierce Biotechnology, Inc., Rockford, IL., USA).

[0298] E. Methods and compositions for diagnosis and detection In certain embodiments, any of the anti-Tau antibodies provided herein are useful for detecting the presence of Tau in a biological sample. As used herein, the term “detecting” includes quantitative or qualitative detection. In certain embodiments, the biological sample includes cells or tissue such as cerebrospinal fluid, brain cells or brain tissue (e.g., the cerebral cortex or hippocampus), or blood. In some embodiments, the biological sample is cerebrospinal fluid.

[0299] In some embodiments, anti-Tau antibodies are provided for use in diagnostic or detection methods. In a further embodiment, a method for detecting the presence of Tau in a biological sample is provided. In certain embodiments, the method comprises contacting a biological sample with the anti-Tau antibody described herein under conditions that allow binding of the anti-Tau antibody to Tau, and detecting whether a complex is formed between the anti-Tau antibody and Tau. Such a method may be an in vitro or in vivo method. Furthermore, the complex formed between the anti-Tau antibody and Tau in the test biological sample may be compared to the complex formed in a control biological sample (e.g., a biological sample from a healthy subject). The amount of the complex formed between the anti-Tau antibody and Tau in the test biological sample may also be quantified and compared to the amount of the complex formed in a control biological sample (e.g., a biological sample from a healthy subject), or the average amount of the complex known to form in healthy subjects.

[0300] In some embodiments, for example, if Tau is a biomarker for patient selection, an anti-Tau antibody is used to select subjects eligible for therapy with the anti-Tau antibody. For example, in some embodiments, an anti-Tau (e.g., pan-Tau) antibody is used to detect whether a subject has a Tau protein disease or disorder, or whether the subject is at high risk (predisposed) of a Tau protein disease or disorder.

[0301] Exemplary diseases or disorders that can be diagnosed using the antibodies of the present invention include Tau protein-related diseases or disorders, and diseases or disorders caused by or associated with neurofibrillary tangles or nerve villous fibers. In some embodiments, diseases or disorders that can be diagnosed using the antibodies of the present invention include Tau protein-related diseases or disorders that manifest as impairment or loss of cognitive function, including reasoning, situational judgment, cognitive memory, learning, and / or spatial navigation. In particular, diseases or disorders that can be diagnosed using the antibodies of the present invention include tauopathies such as neurodegenerative tauopathies. Exemplary diseases or disorders that can be diagnosed using the antibodies of the present invention include Alzheimer's disease, Creutzfeldt-Jakob disease, punch-drunk syndrome, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, Guam amyotrophic lateral sclerosis / Parkinson's disease dementia syndrome, non-Guam motor neuron disease with neurofibrillary tangles, argyrophilic grain dementia, and corticobasal degeneration. Examples of conditions that can be diagnosed using the antibodies of the present invention include, but are not limited to, diffuse neurofibrillary tangle disease with calcification, frontotemporal dementia, frontotemporal dementia linked to chromosome 17 and associated with Parkinsonian syndrome, Haller-Holden-Spats disease, multiple system atrophy, Niemann-Pick disease type C, globus pallidus-pontine-nigronitus degeneration, Pick's disease, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, neurofibrillary tangle dementia, post-encephalitis-induced parkinsonism, and myotonic dystrophy. In some embodiments, Alzheimer's disease (AD) is a disorder that can be diagnosed using the antibodies of the present invention.

[0302] In certain embodiments, labeled anti-Tau antibodies are provided. Labels include, but are not limited to, directly detectable labels or moieties (such as fluorescent labels, chromophore labels, electron-density labels, chemiluminescent labels, and radioactive labels), as well as moieties detected indirectly, for example, by enzymatic reactions or molecular interactions, such as enzymes or ligands. Exemplary labels include radioactive isotopes. 32 P, 14 C, 125 I,3 H, and 131 Examples of these include, but are not limited to, fluorophores such as rare earth chelates or fluorescein and its derivatives, rhodamine and its derivatives, dansyl, umbelliferone, luceriferases such as firefly luciferase and bacterial luciferase (U.S. Patent No. 4,737,456), luciferin, 2,3-dihydrophthalazinedione, horseradish peroxidase (HRP), alkaline phosphatase, β-galactosidase, glucoamylase, lysozyme, carbohydrate oxidases such as glucose oxidase, galactose oxidase, and glucose-6-phosphate dehydrogenase, enzymes that oxidize pigment precursors using hydrogen peroxide, such as HRP, lactoperoxidase, or heterocyclic oxidases such as uricase and xanthine oxidase coupled with microperoxidase, biotin / avidin, spin-labeled, bacteriophage-labeled, and stable free radicals.

[0303] F. Pharmaceutical preparations The pharmaceutical formulations of anti-Tau antibodies described herein are prepared in the form of lyophilized formulations or aqueous solutions by mixing such antibodies having a desired degree of purity with one or more pharmaceutically acceptable carriers, diluents, and / or excipients (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)). Pharmacochemically acceptable carriers, diluents, and excipients are generally non-toxic to the recipient at the dosages and concentrations used, and include sterile water, buffers (such as phosphoric acid, citrate, and other organic acids); antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzylammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol; butyl or benzyl alcohol; alkylparabens such as methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); and low molecular weight (less than approximately 10 residues) polypeptides. Examples of pharmaceutically acceptable carriers herein include, but are not limited to, proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein further include interstitial drug dispersants such as soluble neutrally active hyaluronidase glycoproteins (sHASEGP), e.g., human soluble PH-20 hyaluronidase glycoprotein such as rHuPH20 (HYLENEX®, Baxter International, Inc.). Specific exemplary sHASEGPs, including rHuPH20, and methods of use are described in U.S. Patent Publications 2005 / 0260186 and 2006 / 0104968.In one embodiment, sHASEGP is combined with one or more additional glycosaminoglycans, such as chondroitinase.

[0304] An example of a lyophilized antibody preparation is described in U.S. Patent No. 6,267,958. Aqueous antibody preparations include those described in U.S. Patent No. 6,171,586 and WO2006 / 044908, the latter of which contains a histidine-acetate buffer.

[0305] The formulations described herein may also contain two or more active ingredients, preferably having complementary activity that does not adversely affect one another, as required for the specific indication being treated. Such active ingredients are preferably present in combination in amounts effective for the intended purpose.

[0306] The active ingredient may be encapsulated in microcapsules prepared by coacervation techniques or interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, within colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or within macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

[0307] Sustained-release preparations can be prepared. A preferred example of a sustained-release preparation is a semipermeable matrix of a solid hydrophobic polymer containing an antibody, which may be in the form of a molded article, such as a film or microcapsule.

[0308] Preparations used for in vivo administration are generally sterile. Sterility can be easily achieved, for example, by filtration through a sterile filtration membrane.

[0309] G. Treatment methods and compositions Either the anti-Tau antibody or immune complex provided herein can be used in therapeutic methods.

[0310] In one embodiment, an anti-Tau antibody for use as a pharmaceutical is provided. In a further embodiment, an anti-Tau antibody for use in the treatment of a Tau protein-related disease or disorder is provided. In some embodiments, an anti-Tau antibody for use in the treatment of a disease or disorder caused by or associated with the formation of neurofibrillary tangles or nerve villous fissures is provided. In certain embodiments, an anti-Tau antibody for use in the treatment of a tauopathy such as neurodegenerative tauopathy is provided. Exemplary Tau protein-related diseases or disorders that can be treated with an anti-Tau antibody include Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Creutzfeldt-Jakob disease, punch-drunk syndrome, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, Guam amyotrophic lateral sclerosis / parkinsonian dementia syndrome, non-Guam motor neuron disease with neurofibrillary tangles, Examples of conditions that can be described include, but are not limited to, argyrophilic grain dementia, corticobasal degeneration, diffuse neurofibrillary tangle disease with calcification, frontotemporal dementia, frontotemporal dementia linked to chromosome 17 and associated with Parkinsonian syndrome, Haller-Holden-Spats disease, multiple system atrophy, Niemann-Pick disease type C, globus pallidus-pontine-nigronitus degeneration, Pick's disease, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, neurofibrillary tangle dementia, post-encephalitis-induced parkinsonism, and myotonic dystrophy. In some embodiments, anti-Tau antibodies for use in the treatment of Alzheimer's disease (AD) are disclosed herein. In some embodiments, anti-Tau antibodies for use in the treatment of moderate AD, mild to moderate AD, mild AD, early AD, or prodromal AD are provided herein. Furthermore, Tau protein-related diseases or disorders that can be treated with anti-Tau antibodies include diseases or disorders that manifest as impairment or loss of cognitive function, including reasoning, situational judgment, cognitive memory, learning, and / or spatial navigation. In certain embodiments, anti-Tau antibodies for use in therapeutic methods are provided.In certain embodiments, the present invention provides an anti-Tau antibody for use in a method of treating an individual having any one of the above-described Tau-related diseases or disorders, the method comprising administering an effective amount of the anti-Tau antibody to the individual. In such an embodiment, the method further comprises administering an effective amount of at least one additional therapeutic agent to the individual, such as, for example, the following.

[0311] In some embodiments, the antibodies of the present invention are used to treat individuals having MMSE scores between 20 and 30, between 20 and 26, between 24 and 30, between 21 and 26, between 22 and 26, between 22 and 28, between 23 and 26, between 24 and 26, or between 25 and 26. In some embodiments, the patient has an MMSE score between 22 and 26. As used herein, an MMSE score between two numbers includes the numbers at both ends of that range. For example, an MMSE score between 22 and 26 includes MMSE scores of 22 and 26.

[0312] In some embodiments, the antibodies of the present invention are used to treat individuals who are "tau-positive," for example, patients with brain tau deposits typical of Tau protein-related disorders, for example, patients with positive Tau PET scans.

[0313] In further embodiments, the present invention provides anti-Tau antibodies for use in reducing levels of Tau protein in an individual (e.g., total Tau, total soluble Tau, soluble phosphorylated Tau, total insoluble Tau, insoluble phosphorylated Tau, hyperphosphorylated Tau, or paired helical fibrils containing hyperphosphorylated Tau). For example, such reduction may occur in the brain (e.g., in the cerebral cortex and / or hippocampus). In some embodiments, the present invention provides anti-Tau antibodies for use in reducing levels of phosphorylated Tau. In some embodiments, the present invention provides anti-Tau antibodies for use in reducing levels of insoluble Tau (e.g., insoluble phosphorylated Tau). In some embodiments, the present invention provides anti-Tau antibodies for use in reducing levels of hyperphosphorylated Tau. In some embodiments, the present invention provides anti-Tau antibodies for use in reducing levels of paired helical fibrils (e.g., paired helical fibrils containing hyperphosphorylated Tau) in brain tissue (e.g., in the cerebral cortex and / or hippocampus). In certain embodiments, the present invention provides an anti-Tau antibody for use in a method for reducing the level of Tau protein (e.g., total Tau, total soluble Tau, soluble phosphorylated Tau, total insoluble Tau, insoluble phosphorylated Tau, hyperphosphorylated Tau, or paired helical fibrils containing hyperphosphorylated Tau) in the brain (e.g., in the cerebral cortex and / or hippocampus) of an individual, comprising administering an effective amount of anti-Tau antibody to the individual to reduce the level of Tau protein. The “individual” according to any of the above embodiments is a mammal, preferably a human.

[0314] In some embodiments, the present invention provides anti-Tau antibodies for use in regulating levels of Tau protein (e.g., paired helical fibrils containing total Tau, total soluble Tau, soluble phosphorylated Tau, total insoluble Tau, insoluble phosphorylated Tau, hyperphosphorylated Tau, or hyperphosphorylated Tau) in the brain of an individual (e.g., in the cerebral cortex and / or hippocampus).

[0315] In a further embodiment, the present invention provides the use of anti-Tau antibodies in the manufacture or preparation of pharmaceuticals. In some embodiments, the pharmaceuticals are for the treatment of Tau protein-related diseases or disorders. Tau protein-related diseases or disorders may be diseases or disorders caused by or associated with the formation of neurofibrillary tangles or nerve villous fibers. In certain embodiments, the pharmaceuticals are for the treatment of tauopathy, such as neurodegenerative tauopathy. In certain embodiments, the pharmaceuticals are for the treatment of Alzheimer's disease (AD), Creutzfeldt-Jakob disease, punch-drunk syndrome, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, Guam amyotrophic lateral sclerosis / Parkinson's disease dementia syndrome, non-Guam motor neuron disease with neurofibrillary tangles, argyrophilic grain dementia, corticobasal degeneration, diffuse nerve disease with calcification The pharmaceutical is for the treatment of diseases or disorders selected from the group consisting of transfibrillary tangle disease, frontotemporal dementia, frontotemporal dementia linked to chromosome 17 and associated with Parkinsonian syndrome, Haller-Holden-Spats disease, multiple system atrophy, Niemann-Pick disease type C, globus pallidus-pontine-nigronitus degeneration, Pick's disease, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, neurofibrillary tangle dementia, post-encephalitis-Parkinson's disease, and myotonic dystrophy. In some embodiments, the pharmaceutical is for the treatment of AD. In certain embodiments, the pharmaceutical is for the treatment of Tau-related diseases or disorders that manifest in impairment or loss of cognitive function, including reasoning, situational judgment, cognitive memory, learning, or spatial navigation. In a further embodiment, the pharmaceutical is for use in a method for treating any of the diseases listed above (e.g., tauopathies such as AD), which comprises administering an effective amount of the pharmaceutical to an individual having such a disease. In one such embodiment, the method further comprises administering an effective amount of at least one additional therapeutic agent to the individual, such as, for example, the one described below.

[0316] In a further embodiment, the pharmaceutical is for reducing levels of Tau protein (e.g., total Tau, total soluble Tau, soluble non-phosphorylated Tau, soluble phosphorylated Tau, total insoluble Tau, insoluble phosphorylated Tau, insoluble non-phosphorylated Tau, hyperphosphorylated Tau, or paired helical fibrils containing hyperphosphorylated Tau). For example, such a reduction of Tau protein may be observed in the brain of an individual (e.g., in the cerebral cortex and / or hippocampus) or in the cerebrospinal fluid. In some embodiments, the pharmaceutical is for reducing levels of paired helical fibrils. In a further embodiment, the pharmaceutical is for use in a method for reducing levels of Tau protein (e.g., total Tau, total soluble Tau, soluble phosphorylated Tau, total insoluble Tau, insoluble phosphorylated Tau, hyperphosphorylated Tau, or paired helical fibrils containing hyperphosphorylated Tau) in an individual, the method comprising administering an effective amount of the pharmaceutical to an individual to reduce levels of Tau protein. Any “individual” according to any of the above embodiments is a mammal, preferably a human.

[0317] In a further embodiment, the present invention provides a method for treating Tau protein-related diseases or disorders. Tau protein-related diseases or disorders that can be treated according to the method provided herein include diseases or disorders caused by or associated with the formation of neurofibrillary tangles or nerve villous fibers. In a particular embodiment, the present invention provides a method for treating tauopathy, such as neurodegenerative tauopathy. In a particular embodiment, the present invention provides a method for treating Alzheimer's disease, Creutzfeldt-Jakob disease, punch-drunk syndrome, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, Guam amyotrophic lateral sclerosis / Parkinson's disease dementia syndrome, non-Guam motor neuron disease with neurofibrillary tangles, argyrophilic grain dementia, corticobasal degeneration, and diffuse nerve damage with calcification. The present invention provides a method for treating a disease or disorder selected from the group consisting of neurofibrillary tangle disease, frontotemporal dementia, frontotemporal dementia linked to chromosome 17 and associated with Parkinsonian syndrome, Haller-Holden-Spats disease, multiple system atrophy, Niemann-Pick disease type C, globus pallidus-pontine-nigronitus degeneration, Pick's disease, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, neurofibrillary tangle dementia, post-encephalitis-Parkinson's disease, and myotonic dystrophy. In some embodiments, the present invention provides a method for treating Alzheimer's disease (AD). In certain embodiments, the present invention provides a method for treating Tau-related diseases or disorders that manifest in impairment or loss of cognitive function, including reasoning, situational judgment, cognitive memory, learning, or spatial navigation. In some embodiments, the method comprises administering an effective amount of anti-Tau antibody to an individual having the above-mentioned disease or disorder. In one such embodiment, the method further comprises administering an effective amount of at least one additional therapeutic agent to the individual, such as those described below. In some embodiments, the method comprises administering an effective amount of anti-Tau antibody to an individual having one of the diseases described herein. In such an embodiment, the method further comprises administering an effective amount of at least one additional therapeutic agent to the individual, as described below.Any "individual" following any of the above embodiments may be a human being.

[0318] In a further embodiment, the present invention provides a method for reducing the level of Tau protein (e.g., paired helical fibrils containing total Tau, total soluble Tau, soluble phosphorylated Tau, total insoluble Tau, insoluble phosphorylated Tau, hyperphosphorylated Tau, or hyperphosphorylated Tau) in an individual. For example, such a reduction in the level of Tau protein may be observed in the brain of an individual (e.g., the cerebral cortex and / or hippocampus) or in the cerebrospinal fluid. In some embodiments, the present invention provides a method for reducing the level of paired helical fibrils. In some embodiments, the method comprises administering an effective amount of anti-Tau antibody to an individual to reduce the level of Tau protein. In some embodiments, “individual” is a human.

[0319] In some embodiments, the present invention provides a method for alleviating one or more symptoms of a Tau protein-related disease or disorder, or a pharmaceutical product comprising an anti-Tau antibody for alleviating one or more symptoms of a Tau protein-related disease or disorder (any of the diseases or disorders described herein, e.g., AD). In some embodiments, the present invention provides a method for reducing the number or severity of one or more symptoms of a Tau protein-related disease or disorder, or a pharmaceutical product comprising an anti-Tau antibody for reducing the number or severity of one or more symptoms of a Tau protein-related disease or disorder (any of the diseases or disorders described herein, e.g., AD). In one particular embodiment, the symptom of a Tau protein-related disease or disorder is cognitive impairment. In one particular embodiment, the symptom of a Tau protein-related disease or disorder is learning and / or memory impairment. In one particular embodiment, the symptom of a Tau protein-related disease or disorder is long-term memory loss. In one particular embodiment, the symptom of a Tau protein-related disease or disorder is dementia. In some embodiments, symptoms of Tau protein-related disease or disorder include confusion, irritability, aggression, mood swings, or speech disorders. In some embodiments, symptoms of Tau protein-related disease or disorder include impairment or loss of one or more cognitive functions such as reasoning, situational judgment, cognitive memory, and / or learning. The methods provided herein include administering a certain amount (e.g., a therapeutically effective dose) of anti-Tau antibody to an individual (e.g., exhibiting one or more symptoms of Tau protein-related disease or disorder).

[0320] In certain embodiments, the present invention provides a method for maintaining or increasing cognitive memory capacity, or a method for slowing memory loss associated with Tau protein-related disease or disorder, or a pharmaceutical product comprising an anti-Tau antibody for maintaining or increasing cognitive memory capacity, or slowing memory loss associated with Tau protein-related disease or disorder (any of the diseases or disorders described herein, e.g., AD). The method provided herein comprises administering a certain amount (e.g., a therapeutically effective dose) of anti-Tau antibody to an individual (e.g., exhibiting one or more symptoms of memory loss or reduced memory capacity).

[0321] In some embodiments, the present invention provides a method for reducing the rate of progression of a Tau protein-related disease or disorder, or a pharmaceutical product comprising an anti-Tau antibody for reducing the rate of progression of a Tau protein-related disease or disorder (any of the diseases or disorders described herein, e.g., AD). The method provided herein comprises administering a certain amount (e.g., a therapeutically effective dose) of anti-Tau antibody to an individual (e.g., exhibiting one or more symptoms of a Tau protein-related disease or disorder).

[0322] In some embodiments, the present invention provides a method for preventing the development of a Tau protein-related disease or disorder, or a pharmaceutical product comprising an anti-Tau antibody for preventing the development of a Tau protein-related disease or disorder (any of the diseases or disorders described herein, e.g., AD). The method provided herein comprises administering a certain amount (e.g., a therapeutically effective dose) of anti-Tau antibody to an individual (e.g., at risk of a Tau protein-related disease or disorder).

[0323] In some embodiments, the present invention provides a method for delaying the onset of a Tau protein-related disease or disorder, or a pharmaceutical product comprising an anti-Tau antibody for delaying the onset of a Tau protein-related disease or disorder (any of the diseases or disorders described herein, e.g., AD). The method provided herein comprises administering a certain amount (e.g., a therapeutically effective dose) of anti-Tau antibody to an individual (e.g., exhibiting one or more symptoms of a Tau protein-related disease or disorder).

[0324] In a further embodiment, the present invention provides a pharmaceutical formulation comprising, for example, one of the anti-Tau antibodies provided herein for use in any of the therapeutic methods described above. In some embodiments, the pharmaceutical formulation comprises one of the anti-Tau antibodies provided herein and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical formulation comprises one of the anti-Tau antibodies provided herein and at least one additional therapeutic agent, for example, one described below.

[0325] The antibody of the present invention can be used alone or in combination with other agents in therapy. For example, the antibody of the present invention may be administered concurrently with at least one additional therapeutic agent.

[0326] For example, compositions according to the present invention may be administered in combination with other compositions, including additional therapeutic agents such as bioactive substances or compounds, such as known compounds used in the drug therapy of tauopathy and / or amyloidosis, and in a group of diseases and disorders associated with amyloid and amyloid-like proteins (such as amyloid-beta protein involved in Alzheimer's disease).

[0327] In general, other bioactive compounds may include neuronal transmission enhancers, psychotherapeutic agents, acetylcholinesterase inhibitors, calcium channel blockers, bioamines, benzodiazepine tranquilizers, acetylcholine synthesis, storage, or release enhancers, acetylcholine postsynaptic receptor agonists, monoamine oxidase A or B inhibitors, N-methyl-D-aspartate glutamate receptor antagonists, nonsteroidal anti-inflammatory drugs, antioxidants, serotonin receptor antagonists, or other therapeutic agents. In particular, bioactive compounds include compounds against oxidative stress, anti-apoptotic compounds, metal chelators, DNA repair inhibitors (such as pirenzepine and its metabolites), 3-amino-1-propanesulfonic acid (3APS), 1,3-propanedisulfonic acid (1,3PDS), secretase activators, beta- and gamma-secretase inhibitors, Tau proteins, anti-Tau antibodies (including, but not limited to, the antibodies disclosed in WO2012049570, WO2014028777, WO2014165271, WO2014100600, WO2015200806, US8980270, and US8980271), neurotransmitters, beta-sheet breakers, anti-inflammatory molecules, and "atypical antipsychotics" (e.g., clozapine, di). The invention may include a cholinesterase inhibitor (ChEI) (such as plasidone, risperidone, aripiprazole, or olanzapine), or a cholinesterase inhibitor (ChEI) (such as tacrine, rivastigmine, donepezil, and / or galantamine), as well as other drugs and nutritional supplements (e.g., vitamin B12, cysteine, acetylcholine precursors, lecithin, choline, ginkgo biloba, acyetyl-L-carnitine, idebenone, propentophilin, or xanthine derivatives), as well as a conjugated peptide according to the present invention (including antibodies, particularly monoclonal antibodies and their active fragments), and optionally at least one compound selected from pharmaceutically acceptable carriers and / or diluents and / or excipients, along with instructions for the treatment of a disease.

[0328] In some embodiments, the antibodies of the present invention may be administered in combination with neurolytic agents. Such neurolytic agents include beta-secretase, presenilin, amyloid precursor protein or its moiety, amyloid beta peptide or its oligomers or fibrillaries, cell death receptor 6 (DR6), receptor for advanced glycation end products (RAGE), parkin, and huntingtin; NMDA receptor antagonists (i.e., memantine), monoamine depletors (i.e., tetrabenazine); ergoloid mesylate; anticholinergic antiparkinsonian syndrome agents (i.e., procyclidine, diphenhydramine, trihexylphenidyl, benztropine, biperiden, and trihexyphenidyl); dopaminergic antiparkinsonian syndrome agents (i.e., entacapone, selegiline, pramipexole, bromocriptine, rotigotine, selegiline, ropinirole, rasagiline, apomorphine, carbidopa, levodopa, pergoli Examples of such substances include: dol, tolcapone, and amantadine; tetrabenazine; anti-inflammatory agents (including, but not limited to, nonsteroidal anti-inflammatory drugs (i.e., indomethicin and other compounds listed above)); hormones (i.e., estrogen, progesterone, and leuprolide); vitamins (i.e., folic acid and nicotinamide); dimebolin; homotaurine (i.e., 3-aminopropanesulfonic acid, 3APS); serotonin receptor activity modulators (i.e., xaliprodane); interferons, and antibodies or other binding molecules (including, but not limited to, small molecules, peptides, aptamers, or other protein binding agents) that specifically bind to targets selected from glucocorticoids or corticosteroids. The term "corticosteroid" includes, but is not limited to, fluticasone (including fluticasone propionate (FP)), beclomethasone, budesonide, ciclesonide, mometasone, flunisolide, betamethasone, and triamcinolone. "Inhalable corticosteroid" means a corticosteroid suitable for delivery by inhalation.Exemplary inhalable corticosteroids include fluticasone, beclomethasone propionate, budenoside, mometasone furoate, ciclesonide, flunisolide, and triamcinolone acetonide.

[0329] In some embodiments, one or more anti-amyloid beta (anti-Abeta) antibodies may be administered together with the anti-Tau antibodies provided herein. Non-limiting examples of such anti-Abeta antibodies include crenezumab, solanezumab, bapineozumab, aducanumab, gantenerumab, and BAN-2401 (Biogen, Eisai Co., Ltd.). In some embodiments, one or more beta-amyloid aggregation inhibitors may be administered together with the anti-Tau antibodies provided herein. Non-limiting exemplary beta-amyloid aggregation inhibitors include ELND-005 (also known as AZD-103 or siro-inositol), tramiprosate, and PTI-80 (Exebryl-1®, ProteoTech). In some embodiments, one or more BACE inhibitors may be administered together with the anti-Tau antibodies provided herein. Non-exclusive examples of such BACE inhibitors include E-2609 (Biogen, Eisai Co., Ltd.), AZD3293 (LY3314814, also known as AstraZeneca, Eli Lilly & Co.), MK-8931 (Verubecestat), and JNJ-54861911 (Janssen, Shionogi Pharma). In some embodiments, one or more Tau inhibitors may be administered together with the anti-Tau antibodies provided herein. Non-exclusive examples of such Tau inhibitors include methylthioninium, LMTX (leucomethylthioninium or Trx-0237, also known as TauRx Therapeutics Ltd.), Rember (trademark) (methylene blue or methylthioninium chloride [MTC], Trx-0014, TauRx Therapeutics Ltd.), PBT2 (Prana Biotechnology), and PTI-51-CH3 (TauPro (trademark), ProteoTech). In some embodiments, one or more other anti-Tau antibodies may be administered together with the anti-Tau antibodies provided herein.Other non-exclusive examples of such anti-Tau antibodies include BMS-986168 (Bristol-Myers Squibb) and C2N-8E12 (AbbVie, C2N Diagnostics, LLC). In some embodiments, a common misfolding inhibitor such as NPT088 (NeuroPhage Pharmaceuticals) may be administered together with the anti-Tau antibodies provided herein.

[0330] In some embodiments, compositions according to the present invention may comprise niacin or memantine, along with a chimeric antibody or humanized antibody according to the present invention, particularly monoclonal antibodies and their active fragments, and optionally a pharmaceutically acceptable carrier and / or diluent and / or excipient.

[0331] In some embodiments, compositions are provided, together with a chimeric antibody or humanized antibody according to the present invention, or an active fragment thereof, an "atypical antipsychotic" for the treatment of positive and negative psychotic symptoms (including hallucinations, delusions, thought disorders (manifested by significant thought scattering, digression, and erratic thinking), as well as bizarre or confused behavior, as well as anemia, flattened affect, emotional blunting, and withdrawal), such as clozapine, ziprasidone, risperidone, aripiprazole, or olanzapine, and optionally a pharmaceutically acceptable carrier and / or diluent and / or excipient.

[0332] In addition to the chimeric antibody or humanized antibody according to the present invention, other compounds that can be suitably used in the composition include therapeutic targets (pp. 36-39), alkanesulfonic acids and alkanol sulfates (pp. 39-51), cholinesterase inhibitors (pp. 51-56), NMDA receptor antagonists (pp. 56-58), estrogens (pp. 58-59), nonsteroidal anti-inflammatory drugs (pp. 60-61), antioxidants (pp. 61-62), peroxisome proliferator-activated receptor (PPAR) agonists (pp. 63-67), and cholesterol-lowering agents (pp. 68-75). This includes, for example, amyloid inhibitors (pp. 75-77), amyloid formation inhibitors (pp. 77-78), metal chelating agents (pp. 78-79), antipsychotics and antidepressants (pp. 80-82), nutritional supplements (pp. 83-89), and compounds that increase the availability of bioactive substances in the brain (see pp. 89-93), as well as prodrugs (pp. 93 and 94), as disclosed in WO2004 / 058258 (see pp. 16 and 17 in particular), and this document incorporates herein by reference the compounds referred to in particular on the pages indicated above.

[0333] Such combination therapies described above include combined administration (where two or more therapeutic agents are contained in the same or separate formulations) and separate administrations, in which case, administration of the antibody of the present invention may occur before, simultaneously with, and / or after the administration of the additional therapeutic agent(s). In some embodiments, the administration of the anti-Tau antibody and the administration of the additional therapeutic agent occur within about one month of each other, or within about one, two, or three weeks, or within about one, two, three, four, five, or six days.

[0334] The antibodies (and any additional therapeutic agents) of the present invention may be administered by any preferred means, including parenteral administration, intrapulmonary administration, intranasal administration, and, if desired for topical treatment, intralesional administration. Parenteral administration includes intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration. Dosage may be by any preferred route, for example, by injection, such as intravenous or subcutaneous injection, depending on whether the administration is short-term or chronic. Various dosing schedules, including but not limited to single doses, multiple doses at various time points, bolus administration, and pulse infusion, are contemplated herein.

[0335] The antibodies of the present invention will be formulated, administered, and given in a manner consistent with good medical practice. Factors to be considered in this context include the specific disorder being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the scheduling of administration, and other factors known to the physician. The antibodies are formulated, not necessarily but optionally, with one or more drugs currently used to prevent or treat the disorder in question. The effective amount of such other drugs depends on the amount of antibody present in the formulation, the type of disorder or treatment, and other factors considered above. These are generally used in the same dosages and routes of administration as described herein, or in about 1-99% of the dosages described herein, or in any dosage and route of administration as empirically / clinically determined to be appropriate.

[0336] For the prevention or treatment of disease, the appropriate dosage of the antibody of the present invention (when used alone or in combination with one or more other additional therapeutic agents) will depend on the type of disease being treated, the type of antibody, the severity and course of the disease, whether the antibody is administered for preventive or therapeutic purposes, previous therapies, the patient's medical history and response to the antibody, and the discretion of the attending physician. The antibody is preferably administered to the patient in a single dose or over a series of treatments. Depending on the type and severity of the disease, for example, whether by one or more separate doses or by continuous infusion, an initial candidate dose of antibody of about 1 μg / kg to 15 mg / kg (e.g., 0.1 mg / kg to 10 mg / kg) may be administered to the patient. A typical daily dose may range from about 1 μg / kg to 100 mg / kg or more, depending on the factors mentioned above. For repeated administrations over several days or more, depending on the condition, treatment will generally continue until the desired suppression of disease symptoms occurs. An exemplary dosage of the antibody would be in the range of approximately 0.05 mg / kg to approximately 10 mg / kg. Therefore, one or more doses of approximately 0.5 mg / kg, 2.0 mg / kg, 4.0 mg / kg, or 10 mg / kg (or any combination thereof) may be administered to the patient. Such doses may be administered intermittently, for example, weekly or every three weeks (for example, so that the patient receives approximately 2 to approximately 20 doses, or for example, approximately 6 doses of antibody). A higher initial loading dose, followed by one or more lower doses, may be administered. However, other dosage regimens may also be useful. The progress of this therapy is readily monitored by conventional techniques and assays.

[0337] It is understood that any of the above formulations or therapeutic methods may be carried out using the immune complex of the present invention, either in place of or in addition to the anti-Tau antibody.

[0338] H.Manufactured products In another embodiment of the present invention, a product is provided containing a material useful for the treatment, prevention and / or diagnosis of the above-mentioned disorders. The product comprises a container and a label or accompanying document on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, intravenous solution bags, etc. The container may be formed from a variety of materials such as glass or plastic. The container may hold a composition that is effective for the treatment, prevention and / or diagnosis of a pathological condition, either by itself or in combination with another composition, and may have a sterile access port (for example, the container may be an intravenous solution bag or a vial with a stopper that can be pierced by a subcutaneous needle). At least one active agent in the composition is the antibody of the present invention. The label or accompanying document indicates that the composition is used to treat a selected pathological condition. Furthermore, the product may comprise (a) a first container containing a composition comprising the antibody of the present invention, and (b) a second container containing a composition comprising a further cytotoxic agent or otherwise a therapeutic agent. The product of this embodiment of the present invention may further include a package insert indicating that the composition can be used to treat specific medical conditions. Alternatively, or in addition, the product may further include a second (or third) container containing a pharmaceutically acceptable buffer such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0339] It is understood that any of the above-mentioned products may contain the immune complex of the present invention in place of, or in addition to, the anti-Tau antibody.

[0340] Examples The following are examples of the methods and compositions of the present invention. It is understood that various other embodiments may be practiced, assuming the outline provided above.

[0341] Example 1: Production of Tau for immunization Generation of monomer-recombined Tau The recombinant human Tau construct, 2N4R isoform (amino acids 2-441), was fused to the N-terminal His tag to facilitate purification and characterization. See, for example, Figure 15. The fusion construct was cloned into the pET52b vector (Novagen) and expressed in E. coli. Cells were harvested and lysed overnight under denaturing conditions with 7M guanidium chloride and agitation at 4°C. Cell fragments were pelleted at 40,000 rpm for 1 hour. The recombinant His-tagged protein was isolated under denaturing conditions by nickel affinity chromatography (Ni Sepharose resin, GE Healthcare Life Sciences) followed by size exclusion chromatography (Superdex200 resin, GE Healthcare Life Sciences). Guanidium chloride was removed from the recovered protein by dialyzing to 20 mM MES, 50 mM NaCl, and 1 mM TCEP (pH 6.8). Subsequently, the His tag was removed using TEV protease, followed by final purification using cation exchange chromatography (Mono S column, GE Healthcare Life Sciences) to remove the cleaved His tag. The purification buffer contained 0.1 vol% Triton x-114 (v / v) to remove endotoxins. The purified protein was transferred to PBS containing 1 mM TCEP. Purity and monomeric state were analyzed by SDS-PAGE and SEC-MALLS. Identity was confirmed by mass spectrometry. Protein concentration was determined by 280 nm UV absorption. The final product was endotoxin-free (<0.5 EU / mg) as determined by a kinetic Limulus amebocyte lysate (LAL) assay.

[0342] Formation of phosphorylated Tau Phosphorylated Tau was generated using the Tau2-441 construct prepared using the method described above. The protein construct was phosphorylated using 0.5 μM PKA kinase (Life Technologies), which phosphorylates serine 409 in particular among other residues. The reaction mixture was incubated with 1 mM ATP and 5 mM MgCl2 at room temperature for 72 hours. Phosphorylation was confirmed by mass spectrometry. The kinase was removed using size exclusion chromatography (Superdex75, GE Healthcare Life Sciences). The purity, monomeric state, and endotoxin levels of the phosphorylated protein preparation were substantially analyzed as described above.

[0343] In vitro oligomerization of monomer Tau Oligomer Tau was generated using the monomer Tau2-441 construct. First, the monomer protein was exchanged for 20 mM N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES) and 25 mM NaCl (pH 7.4). Then, oligomerization was performed at 37°C for 3 days using 75 μM arachidonic acid (Cayman Chemicals) and 18 kDa heparin (Sigma Aldrich) at equimolar concentrations with the protein. Oligomerization was confirmed by thioflavin T fluorescence assay, dynamic light scattering (DLS), and analytical size exclusion chromatography. In some cases, oligomeric Tau is also called "oligoTau".

[0344] Example 2: Production of anti-Tau antibodies method Hybridoma Formation Nine-week-old female C57BL / 6JOlaHsd (C57BL / 6) and BALB / c OlaHsd (Balb / c) wild-type mice (Harlan, USA) were received. Six- and nine-week-old Tau knockout mice (B6.129-Mapttm1Hnd / J, The Jackson Laboratory, USA) were also received. Vaccination was started at 12-15 weeks of age. Mice were vaccinated with oligomerized human Tau. Prior to vaccination, oligo-Tau was mixed with one of the two adjuvants used in this study: 50% by volume of the Ribi Adjuvant System (Ribi, Sigma-Aldrich, Switzerland) or a combination of CpG single-stranded synthetic DNA oligodeoxynucleotide (CpG, Microsynth, Switzerland) and aluminum hydroxide (Al, Brenntag, Switzerland). Ribi is a 2% squalene oil-in-water emulsion containing monophosphoryl lipid A (isolated from Salmonella minnesota), synthetic trehalose dicolinomicolate (isolated from the code factor of Tubercle bacillus), 0.2% Tween-80, and water in squalene oil.

[0345] Except for groups D and G, which accepted a combination of intraperitoneal (ip) and heel joint administration, mice were vaccinated by subcutaneous injection (sc). Mice in group D received 50 μg of oligo-Tau intraperitoneally and 10 μg of oligo-Tau as an heel joint injection. Mice in group G received 8 μg of oligo-Tau intraperitoneally and 2 μg of oligo-Tau as an heel joint injection. See Table 2. For vaccines containing CpG and Al (CpG / Al) as adjuvants, each 200 μL injection contained 60 μg (30 nmol) of CpG, 1 mg of Al, and 50 μg of oligo-Tau. For all study groups, mice received injections on days 0, 14, 35, and 56. Mice used for myeloma fusion (Nanotools, Germany) were additionally vaccinated with a booster injection of oligo-Tau without adjuvant, administered three times daily (50 μg per intraperitoneal injection). Table 2. Mouse and vaccination protocols TIFF0007835706000002.tif100170

[0346] One day after the final of three booster injections, the mice were euthanized by blood loss, and their spleen cells were fused with myeloma cells to generate antibody-producing hybridomas.

[0347] Selection of hybridomas for subcloning For fusion, mice were divided into three groups for a total of 10 fusions (2 fusions in one group, 4 fusions in the second group, and 4 fusions in the third group), generating 299 hybridomas. Viable hybridomas were grown using serum-containing selective medium, and the best hybridomas were then selected for subcloning using the ELISA assay for full-length human Tau and oligo-Tau binding described below. After limiting dilution, the final hybridomas were grown in serum-free medium, and medium was collected from stable colonies for antibody screening and selection.

[0348] ELISA screening assay Serum-free supernatant was collected from stable hybridomas. The supernatant containing the target antibody was then screened by ELISA to characterize its properties, and antibodies were selected for further development. Using ELISA, binding to full-length human Tau (flTau, SignalChem, Canada), highly phosphorylated flTau (Genentech, USA), flTau oligomer vs. monomer preparations, and specific antibody Tau epitopes(s) were determined. Briefly, 96-well MaxiSorp ELISA plates (Nunc, Denmark) were coated with one of the targets shown in Table 3. Table 3. Targets used in the ELISA screening assay. TIFF0007835706000003.tif113170

[0349] Coating was performed overnight in phosphate-buffered saline (PBS) at 4°C. The plates were thoroughly washed with 0.05% Tween-20 / PBS and then blocked for 1 hour at 37°C with 1% bovine serum albumin (BSA) in 0.05% Tween-20 / PBS. Subsequently, the antibodies contained in the hybridoma supernatant were added at the indicated dilutions, incubated at 37°C for 2 hours, and then washed as previously described.

[0350] For direct ELISA, AP-complexed anti-mouse IgG secondary antibody (Jackson ImmunoResearch Laboratories, United Kingdom) was added to 0.05% Tween-20 / PBS at a dilution of 1 / 6000 for 2 hours at 37°C. After the final wash, the plates were incubated with p-nitrophenyl disodium phosphate hexahydrate (pNPP, Sigma-Aldrich, Switzerland) phosphatase substrate solution and read at 405 nm using an ELISA plate reader (Tecan, Switzerland). The results are expressed as optical density (OD).

[0351] For oligo-Tau and mono-Tau capture ELISA, antibodies contained in serum-free, sterile hybridoma supernatant were immobilized on anti-IgG coated plates at a 500-fold dilution. Oligo-Tau or mono-Tau was then incubated with site-specific biotin labeling using AVI tags. Target incubation was initiated at 5 μg / mL, followed by 8-fold or 16-fold dilutions. Streptavidin-HRP and ABTS substrates were used for signal quantification using a plate reader (Tecan, Switzerland). Results are expressed as OD.

[0352] Affinity estimation The affinity of unpurified antibodies in serum-free hybridoma supernatant was estimated by surface plasmon resonance using a Biacore T-100 instrument (GE Healthcare, United Kingdom). Antibodies were immobilized on anti-IgG biosensor chips, and flTau (SignalChem, Canada) was used as the target analyte. Dynamic analysis was performed using a 1:1 Langmuir fit model.

[0353] SDS-PAGE assay and Western blot assay The binding of selected panTau antibodies to Tau in the human brain was tested by Western blotting (WB) using brain lysates (Tissue Solutions, United Kingdom) from three AD donors and two non-AD control donors of the same age. The lysates were processed to obtain a detergent-free, soluble Tau fraction. The processed lysates were loaded onto 4-12% bis-tris gels (Novex, Life Technologies, Switzerland), transferred onto an Immobilon PVDF membrane, and blotted together with the antibody under test and IRDye800CW goat anti-mouse secondary antibody (Li-Cor, USA).

[0354] ELISA assay using human brain lysate To evaluate the binding of selected antibodies to undenatured human Tau in AD and control brain lysates, antibodies derived from hybridoma supernatant, or negative and positive control antibodies, were immobilized on the 96-well plates described above. Subsequently, Tau was captured in soluble human brain lysates (400 μg / mL protein, all from Tissue Solutions, United Kingdom) derived from AD subjects or same-age controls, and detection was performed using polyclonal rabbit panTau antibody (AbCam, United Kingdom), followed by Fc-γ fragment-specific anti-rabbit IgG-AP (Jackson ImmunoResearch, USA). Brain lysates derived from Tau knockout mice were used as negative sample controls. Plates were incubated with pNPP (Sigma-Aldrich) phosphatase substrate solution and read at 405 nm using an ELISA plate reader (Tecan, Switzerland). Results are expressed as optical density (OD).

[0355] Sequencing of antibody hybridomas Hybridoma cell lysates were supplied to Antitope (Antitope, United Kingdom) for variable region gene sequencing. Briefly, RT-PCR was performed using a degenerate primer pool of mouse signal sequences along with constant region primers for IgG variable heavy chain (VH), IgM VH, Ig kappa variable light chain (KVL), and Ig λ VL. Heavy chain V region mRNA was amplified using a set of six degenerate primer pools (HA~HF) specific to the VH signal sequence, along with either IgM or IgG specific constant region primers. Light chain V region mRNA was amplified using a set of eight signal sequence-specific degenerate primer pools (seven of the κ cluster (KA~KG) and one of the λ cluster (LA)), along with either κ or λ constant region primers. PCR products obtained from successful amplifications were purified, cloned into the 'TA' cloning vector (pGEM-T Easy, Promega), transformed into E. coli, and individual colonies were sequenced. The nucleotide and amino acid sequences of the antibody VH and VL regions were determined by sequencing 27 antibody hybridomas.

[0356] result Selection of hybridomas for subcloning Hybridomas generated from each of the three fusion cycles (a total of 299 hybridomas derived from 10 fusions) were first assayed for binding to flTau, and selected hybridomas were further assayed for binding to pTau and oligomerized Tau. The objective was to select antibodies that bind equally well to Tau and post-translational modified Tau (such as phosphorylated or oligomerized Tau). To this end, assays were performed on hybridomas to select the best panTau properties. To determine the antibody binding region and specific Tau epitopes, binding regions were determined using a library of 15-amino acid-length duplicated Tau peptides, first different Tau fragments, and then the entire 441-amino acid (aa) sequence of the longest human Tau isoform. To maximize binding to different post-translational modified forms of Tau and to all six different human Tau isoforms present in humans, groups of antibodies that bind to specific regions of Tau were intentionally avoided.

[0357] The triple fusion resulted in the generation of 133 subcloning stable hybridomas, which were screened for best panTau properties. A combination of different screening assays was used to narrow down the number of antibody hybridomas with favorable properties for panTau antibodies. Ninety hybridomas were assayed to compare flTau and pTau binding, and the results for 24 hybridomas are shown in Figures 1A–F. The initial screening was performed using Tau fragments to avoid selecting antibodies that bind to the region of Tau known to have highly phosphorylated residues in Alzheimer's disease (AD) and other tauopathy; therefore, most antibodies tested bound to both flTau and pTau with binding properties similar to those determined by this ELISA.

[0358] In some embodiments, it is desirable that the panTau antibody binds to both the monomeric and oligomeric forms of Tau without a strong preference for one over the other. A capture ELISA was set up to determine whether the antibody bound to both the monomeric and oligomeric forms of flTau. ELISA performed in capture mode preserves the oligomeric structure of pre-oligomerized Tau and the monomeric state of monoTau better than when performed as a direct ELISA in which the target is immobilized on the ELISA plate.

[0359] Each assay was performed by directly comparing the binding of the two forms of Tau with all 90 antibodies tested. Antibodies known to exhibit preferred binding to either oligo-Tau, or antibodies that do not distinguish between the two forms of Tau, were used as controls in each assay. Results for 18 hybridomas are shown in Figures 2A-E.

[0360] Epitope mapping is crucial for selecting antibodies with good panTau properties, as antibodies binding to regions with high density of potential pTau residues (Ser, Thr, and Tyr) may be avoided. Binding to all six isoforms of human Tau was also used as a selection criterion for panTau antibodies. The panTau epitopes of the initially selected antibodies were validated and determined with improved precision using a library of 49 peptides, each containing 15 amino acids (aa) extending to full-length human Tau (with 6 aa residue overlaps and a 9 aa offset). The residue count is based on the longest isoform of human Tau (441 aa). Binding vs. non-binding to all peptides was verified using unpurified antibodies at a high dilution of 1 / 10. Screening of antibodies from 112 hybridomas already selected by ELISA showed binding to 20 different Tau epitopes (Table 4). Table 4: Tau epitopes of antibodies TIFF0007835706000004.tif255170TIFF0007835706000005.tif153170

[0361] To measure affinity to flTau, 46 antibodies were measured using SPR on a Biacore instrument, and K D The following was determined. Biacore affinity measurements were performed by immobilizing antibodies on anti-IgG chips and using flTau as the target analyte. The results for 32 antibodies are shown in Table 5, and the antibodies were ranked based on their affinity for flTau. Of the antibodies whose affinity for flTau was measured, 22 antibodies had better affinity than 20 nM, and of these, 14 antibodies had K levels less than 5 nM. D It has an antibody 37D3-H9 with a K content of 1 nM. D It possessed (affinity). Table 5: Affinity to flTau TIFF0007835706000006.tif134170

[0362] To verify the binding of selected antibodies to all six human Tau isoforms, recombinant Tau ladders containing all six isoforms were run on SDS-PAGE, and Western blotting (WB) was performed using three selected Tau antibodies. All three panTau antibodies bound to all six Tau isoforms (Figure 3). In addition, brain homogenates from three AD individuals and two same-age controls were run concurrently for comparison. As expected, based on the mapped epitopes, all three antibodies tested in this assay showed binding to all six Tau isoforms. Differences observed in the banding patterns between human AD donors and control donors may represent greater phosphorylation and / or SDS-stable aggregation, which are expected to be present in AD targets.

[0363] Human Alzheimer's disease (AD) samples and control samples were further subjected to electrophoresis in a non-denaturing ELISA capture assay to verify binding to Tau in the human brain. Sample lysates treated with soluble Tau from two AD subjects and two non-AD control subjects of the same age were electrophoresed at eight dilutions, and three antibodies were tested (Figure 4A-C).

[0364] The antibody variable chain sequences were determined for 27 hybridomas (Antitope, United Kingdom). The protein sequences of specific heavy and light chain variable domains and hypervariable regions (HVRs) are shown in the sequence listing.

[0365] Example 3: Characterization of anti-Tau antibody Antibody heavy and light chains were constructed by gene synthesis and subcloning of the resulting DNA into mouse IgG2a (heavy chain) and mouse kappa (light chain) mammalian expression vectors. Antibodies were expressed in CHO cells and 293T cells by transient simultaneous transfection of heavy and light chain plasmids and purified using the affinity resin MabSelectSure (GE Healthcare Life Sciences). The purified recombinant antibodies were screened for binding to Tau monomer proteins on a Biacore T200 surface plasmon resonance instrument using a mouse IgG capture kit and Series S CM5 chip. The mIgG2a antibody, diluted in 10 mM HEPES (pH 7.4), 150 mM NaCl, and 0.05% Tween20 (electrophoresis buffer, HBSP), was subjected to a concentration of 1 μg / ml for 30 or 45 seconds using a flow rate of 10 μl / min (antibodies 26C1, 94B2-C1, 52F6-F11.v1, 52F6-F11.v2). Antibodies (11E10-B8, 55E7-F11, 125B11-H3, 123E9-A1, 30G1-B2, 66F5-A1, 89F4-A1, 93A8-D2, and 126F11-G11) were captured at a concentration of 0.1 μg / ml for 70 or 150 seconds (antibodies 19H6-F7, 3A4-H4, 54C1-H11, and 37D3-H9). At a flow rate of 30 μl / min, antibodies 26C1 and 94B2 were administered in concentrations of 16, 31, 63, 125, 125, 250, and 500 nM; antibodies 52F6-F11.v1 and 52F6-F11.v2 were administered in concentrations of 16, 31, 63, 125, 125, 250, 500, and 1000 nM; antibodies 11E10-B8, 55E7-F11, and 125B11-H3 were administered in concentrations of 6, 19, 56, 56, 167, and 500 nM; and antibodies 123E9-A1, 30G1-B2, and 66 The binding of Tau monomers in HBSP was monitored at 25°C using concentrations of 5, 16, 49, 148, 148, 444, 1333, and 4000 nM for F5-A1, 89F4-A1, 93A8-D2, and 126F11-G11; 0.4, 1.6, 6.3, 2.5, 100, and 400 nM for 19H6-F7; and 0.2, 0.8, 4, 4, 20, and 100 nM for 3A4-H4, 54C1-H11, and 37D3-H9.The association and dissociation times were monitored for 180–480 seconds and 300–600 seconds, respectively. Due to its high affinity (Table 6) and the absence of the NXS / T glycosylated motif in the CDR, antibody 37D3-H9 was selected for further analysis. Table 6. K of mouse antibodies against human Tau monomer D (nM). The data shown represents the results of a 1:1 combined model. TIFF0007835706000007.tif250170

[0366] 37D3-H9 exhibits binding activity when it binds to the Tau protein. Human monomer Tau protein was covalently coupled to a Biacore Series S CM5 chip using the Biacore Amine Coupling Kit (GE Life Sciences), resulting in immobilization at a level of approximately 128 RU. Direct binding of 37D3-H9 in both Fab and IgG forms was monitored using a single-cycle kinetics experiment format with association periods of 300 seconds each, and with antibody concentrations of 1, 2, 4, 8, and 16 nM (IgG) or 5, 10, 20, 40, and 80 nM (Fab). Dissociation was monitored for 7200 seconds (Fab) or 14400 seconds (IgG). Dissociation rates were calculated by fitting a 1:1 binding model to the data. The calculated dissociation rate for 37D3-H9 Fab was 5.0 × 10⁻⁶. -4 , and 37D3-H9 IgG is 1.1 × 10 -5 The difference was 45-fold. Figure 5 illustrates the difference in dissociation rates between Fab (left panel) and IgG (right panel), showing that 37D3-H9 IgG exhibits binding activity.

[0367] Example 4: Humanization of anti-Tau antibody The antibody 37D3-H9 was humanized by transplanting the antibody CDR and selected variable region framework residues onto the human antibody consensus framework (Dennis, MS (2010). CDR repair: A novel approach to antibody humanization. In Current Trends in Monoclonal Antibody Development and Manufacturing, SJ Shire, W. Gombotz, K. Bechtold-Peters and J. Andya, eds. (Springer, New York), pp. 9-28). Transplantation onto consensus VH3, Vκ2, and Vκ1 frameworks was evaluated. The heavy chain graft contained the mouse residue at position 49 (Kabat numbering system). The Vκ2 graft contained the mouse residues at positions 2 and 4 of the framework. The Vκ1 graft contained the mouse residues at positions 2, 4, and 43 of the framework. Humanized mutants were constructed by gene synthesis and subcloning into human IgG1 or IgG4 and kappa chain mammalian expression vectors. Antibodies were expressed in CHO cells by simultaneous transfection with heavy and light chain plasmids and purified using the affinity resin MabSelect Sure. Humanized mutants were screened for affinity to human Tau monomers using the Biacore Human IgG Capture Kit, Series S CM5 tip, and Biacore T200 instrument. Antibodies were diluted to 2 μg / ml and captured at 10 μl / min for 15 seconds. Association and dissociation of 100, 33, 11, and 3.7 nM human Tau monomers in 10 mM HEPES (pH 7.4), 150 mM NaCl, and 0.05% Tween20 (electrophoresis buffer, HBSP) were monitored at a flow rate of 30 μl / min for 180 seconds and 600 seconds, respectively. A 1:1 binding model was applied to the results (Table 7). Table 7: Affinity screening of humanized mutant forms of monomeric human Tau TIFF0007835706000008.tif176170

[0368] Surface plasmon resonance was used to further characterize the antibody variants hu37D3-H9.v1, hu37D3-H9.v2, hu37D3-H9.v5, and hu37D3-H9.v6 at additional antibody concentrations and longer association / dissociation times. These variants were analyzed at a wider range of human Tau monomer concentrations (1.2, 3.7, 11.1, 11.1, 33.3, 100 nM) and with increased association (300 seconds) and dissociation (1200 seconds) periods. A 1:1 binding model was applied to the results (Table 8). Table 8: Detailed analysis of the binding dynamics of selected mutants to human Tau by surface plasmon resonance. TIFF0007835706000009.tif68170

[0369] The YTE(M252Y / S254T / T256E) mutation was incorporated into a specific IgG4 antibody. Mutations in the neonatal (FcRn) binding domain of the Fc receptor, such as M252Y, S254T, and T256E(YTE), have been described as increasing FcRn binding and therefore extending the antibody's half-life. See U.S. Published Patent Application No. 2003 / 0190311 and Dall'Acqua et al., J. Biol. Chem. 281:23514-23524 (2006).

[0370] The antibody 125B11-H3 was humanized onto the VH3 and Vκ1 consensus frameworks. The heavy chain graft contained a mouse residue at position 78 (Kabat numbering). The Vκ1 graft contained mouse residues at positions 43 and 87 of the framework. The 113F5-F7 light chain was also humanized onto the Vκ1 framework, with additional mouse residues at positions 43 and 87 of the framework. The humanized mutant heavy chain (125B11) and light chains (125B11 and 113F5-F7) were co-transfected in multiple combinations and purified in the 96-well format described above. Subsequently, the humanized mutants were screened for affinity to human Tau monomers using the Biacore Human IgG Capture Kit, Series S CM5 chip, and Biacore T200 instrument. The antibody was diluted to 2 μg / ml and captured at 10 μl / min for 15 seconds. The association and dissociation of 0, 100, and 500 nM human Tau monomers in HBSP were monitored at a flow rate of 40 μl / min for 180 seconds and 300 seconds, respectively. A 1:1 binding model was applied to the results (Table 9). Table 9: Screening of 125B11-H3 and 113F5-F7 humanized mutants by surface plasmon resonance TIFF0007835706000010.tif109170 * Minimum binding to the Tau monomer. NT, not tested.

[0371] Based on affinity screening, mutant forms hu125B11.v17(HC3+LC1), hu125B11.v26(HC4+LC2), and hu125B11.v28(HC4+LC4) were selected for high-resolution kinetic analysis (Table 10). Antibody 94B2-C1 was humanized onto the VH1 and Vκ2 frameworks. The heavy chain grafts also included mouse residues at positions 28, 29, 67, 69, 71, and 73 (Kabat numbering). The Vκ2 grafts also included mouse residues at positions 2, 36, and 46 of the framework. Eight heavy chain and eight light chain combinations were expressed, purified, and screened by surface plasmon resonance (SPR) as described for 125B11 above. The results of the SPR screening are shown in Table 11. The mutant hu94B2.v105 (heavy chain mutant 94B2.HC1, light chain mutant 94B2.LC13) was selected for detailed SPR characterization (Table 11). Table 10: Dynamics data of selected humanized anti-Tau antibody variants Table 11: Screening of 94B2 humanized mutants by surface plasmon resonance. (TIFF0007835706000011.tif79170) TIFF0007835706000012.tif144170 * n=3 iterations average ¶ hu94B2.v105. § The minimum observed binding to the Tau monomer. NT, not tested.

[0372] Example 5: Stability analysis of humanized anti-Tau antibody Identification of chemical instability The antibody samples were subjected to thermal stress to mimic the stability of the product over its storage period. The samples were diluted to a concentration of 1 mg / ml by buffer exchange to 20 mM acetate buffer (pH 5.5) or phosphate buffer (pH 7.4). One ml sample was stressed at 40°C for two weeks, and the second sample was stored at -70°C as a control. Both samples were then digested using trypsin to produce peptides that could be analyzed using liquid chromatography-mass spectrometry (MS). For each peptide in the sample, retention time from LC, as well as high-resolution accurate mass and peptide ion fragmentation information (amino acid sequence information), were obtained by MS. Extracted ion chromatography (XIC) was performed for the target peptides (natural and modified peptide ions) from data sets within a ±10 ppm window, and the peaks were merged to determine their area. The relative percentage of modification for each sample was calculated by dividing (area of ​​modified peptide) by (area of ​​modified peptide + area of ​​native peptide) and multiplying by 100. These relative percentages were then compared between the control (t=0) sample and the stressed (t=2 weeks) sample. The percentages shown represent the stressed (t=2 weeks) value minus the control (t=0) value. Deamidation analysis of antibodies hu37D3-H9.v1 and hu37D3-H9.v5 was performed on sequence N within the light chain CDR-1. 28 G 29 N 30 (Kabat numbering) led to the observation that it is susceptible to deamidation. Deamidation N 28 G 29 N 30 The increase was found to be 16.5% in hu37D3-H9.v1 and 11% in hu37D3-H9.v5.

[0373] The effect of deamidation on antibodies that bind to antigens. N for affinity to human Tau 28 To evaluate the effects of deamidation, widely separated N 28It was desirable to obtain two samples that were in a deamidated state. Hu37D3-H9.v5 hIgG4.S228P was incubated at a concentration of 1 mg / ml in phosphate-buffered saline (pH 7.4) at 40°C for 2 weeks. Using LC-MS / MS, N 28 G 29 Deamidation of the motif was measured. Samples subjected to stress for t=2 weeks showed a 43.1% increase in deamidation compared to unstressed samples at t=0. Surface plasmon resonance (Biacore) using the GE Biacore Human IgG Capture Kit and Series S CM5 tip was used to analyze Tau binding in stressed and unstressed antibodies. hIgG was diluted to 2 μg / ml in 10 mM HEPES (pH 7.4), 150 mM NaCl, and 0.05% Tween20 (electrophoresis buffer, HBSP), and captured at a flow rate of 10 μl / min for 15 seconds (t0 sample) or 17 seconds (t2 sample). Using a flow rate of 30 μl / min, a 300-second association phase, and a 1800-second dissociation phase, kinetic data of human Tau monomers injected into HBSP at concentrations of 0, 3.1, 6.3, 12.5, 25, 25, 50, and 100 nM were collected. Between cycles, the surface was regenerated using a 30-second injection of 3 M magnesium chloride at 10 μl / min. A 1:1 binding model was fitted to the data using instrumental initial settings, including local fitting of the "RI" parameter. The results shown in Figure 6 and Table 12 indicate that in this experiment, the stressed antibody immobilized at a greater level than the unstressed antibody, although the magnitude of the Tau binding signal (represented by the magnitude of the parameter Rmax) was significantly lower. After normalizing the Rmax values ​​for the difference in capture levels, the stressed (t=2 weeks) sample appeared to exhibit approximately half the total Tau binding capacity of the unstressed sample (indicated by a 56% reduction in normalized Rmax). The calculated affinity appeared unchanged. In other words, this analysis shows the difference between the K of the sample at t=0 and the sample at t=2 weeks. D The difference was less than 2% (for t=0 and t=2 weeks, K D (=0.7nM). This result is consistent with samples from t=2 weeks containing a population of significantly reduced high-affinity antibodies. Table 12: Table 9: Relative bonding of stressed and unstressed hu37D3-H9.v5 samples to monomer Tau by surface plasmon resonance. TIFF0007835706000013.tif59170

[0374] Effect of deamidation on antibodies that bind to antigens and calculation of "normalized Rmax" Assuming that asparagine deamidation is expected to yield aspartic acid and isoaspartic acid products (Bischoff R. & Kolbe HVJ (1994). J. Chromat. 5, 662, p261-278), the affinity of human Tau monomer is N 28 D 28 The effects of substitution with the variant hu37D3-H9.v5 N28D were analyzed. Affinity was evaluated at 25°C using a Biacore T200 instrument, GE Biacore human IgG capture kit, and CM5 Series S tip. hIgG was diluted to 2 μg / ml in 10 mM HEPES (pH 7.4), 150 mM NaCl, and 0.05% Tween20 (electrophoresis buffer, HBSP) and captured at a flow rate of 10 μl / min for 22 seconds. Dynamic data of human Tau monomer injected into HBSP at concentrations of 0, 6.3, 12.5, 25, 25, 50, 100, 200, and 400 nM were collected using a flow rate of 30 μl / min, with a 300-second association phase and a 600-second dissociation phase. Between cycles, the surface was regenerated using a 30-second injection of 3 M magnesium chloride at 10 μl / min. A 1:1 coupled model was fitted to the data, and the affinity between hu37D3-H9.v5 and hu37D3-H9.v5.3 (also known herein as hu37D3-H9.v5 N28D) was calculated using dynamic analysis. The parameters used for the 1:1 fitting included instrumental initial settings for local fitting of the "RI" parameter. The results are shown in Figure 7 and Table 13.

[0375] The calculated K of the hu37D3-H9.v5 N28D variant DThis is 1.5 × 10⁶ of hu37D3-H9.v5 analyzed under the same conditions. -9 Compared to M (mean, intra-experimental determination with n=4), 160 × 10 -9 It was M. Therefore, N 28 D 28 The conversion to caused a more than 100-fold reduction in affinity. Assuming the relatively low affinity and relatively rapid dynamics of the hu37D3-H9.v5 N28D mutant, we proposed that N 28 Mutations and D 28 The kinetic analysis of mixtures with variants indicated that higher affinity populations dominate, and the presence of lower affinity variants may be reflected by a reduction in normalized Rmax. To verify this conclusion, the Tau-binding profiles of antibody variants hu37D3-H9.v5 and hu37D3-H9.v5 N28D were compared to the Tau-binding profiles of the two antibodies mixed together in equal amounts. Compared to hu37D3-H9.v5 alone, a 1:1 mixture of hu37D3-H9.v5 and hu37D3-H9.v5 N28D resulted in a 45% reduction in normalized Rmax (Table 13). The inventors concluded that changes in normalized Rmax under thermal stress may indicate a reduction in the population of high-affinity antibodies in the stressed sample. Therefore, the inventors determined that changes in normalized Rmax can be used to screen variants of hu37D3-H9 for improved stability. Table 13: Changes in normalized Rmax observed under thermal stress of hu37D3-H9.v5 and when mixed with the expected deamidation product hu37D3-H9.v5 N28D. TIFF0007835706000014.tif168170 * Normalized Rmax = Rmax(RU) / Ligand level(RU). Normalized Rmax for the reference antibody = 0.33 (mean of four intra-experimental decisions, standard deviation < 0.01).

[0376] Antibody optimization and selection Ninety 37D3-H9 variants were evaluated using Biacore, and their functional stability was compared with and without a two-week thermal stress period at 40°C. The variants were N 28 G 29 N 30 T 31 This included most single variants of the motif, double variants containing the G29A variant, double variants of Asn-28 and Tyr-32 that could functionally substitute them for hydrogen-bonding residues, and all possible rearrangements of residues 2, 4, 33, and 93 as either residues present in the original 37D3-H9 antibody or corresponding germline residue variants. Furthermore, mutations were tested in contexts where residue 1 was Asp or Glu, which did not affect the affinity or stability of the Asn-28 residue.

[0377] Antibodies were expressed by transient transfection of Expi293 cells in 96-well format and automated purification was performed on a Tecan freedom EVO200 liquid handling system with a 500 μL MCA96 head. Briefly, IgG in 1 mL of culture was captured using a tip column custom-packed with 20 μL of MabSelect SuRe resin (Glygen Corp & GE Healthcare). After washing with 1×PBS (pH 7.4), IgG was eluted into 160 μL of 50 mM phosphoric acid (pH 3) and neutralized with 12 μL of 20×PBS (pH 11). The MabSelect SuRe tip column was removed in 0.1 M NaOH and regenerated with 1×PBS (pH 7.4) for up to 15 consecutive uses. A Hamilton Star liquid handling robot was used to normalize the purified antibodies in 96-well format to 0.1 mg / ml. "Before stress" samples were maintained at approximately 4 °C and "after stress" samples were incubated in a PCR machine at 40 °C for 2 weeks. The functional stability of the "before stress" and "after stress" antibody preparations and the mutant form was compared by performing surface plasmon resonance kinetic experiments. Antibodies were evaluated using a human antibody capture CM5 Series S chip generated using a GE Biacore human IgG capture kit and a Biacore T200 instrument. Antibodies diluted up to 2 μg / ml were immobilized using an injection time of 15 seconds and a flow rate of 10 μl / min. Binding to Tau monomer at 0 nM, 26.5 nM and 265 nM at 25 °C was monitored during an association phase of 180 seconds followed by a dissociation phase of 300 seconds when using a flow rate of 40 μl / min. Samples were run in 10 mM HEPES (pH 7.4), 150 mM NaCl, 0.05% Tween 20 (HBSP) using a multiple cycle kinetic format. Data was analyzed using BIAevaluation software and fit to a 1:1 binding model. The resulting affinity (K DThe values ​​are shown in Figures 8A-D. The stability index was also calculated using the rationale that antibodies with impaired affinity (for example, due to deamidation of important residues) are expected to contribute equally to the IgG capture level ("ligand level") but less to the Tau binding measured, and that this is reflected in the experimentally derived Rmax value. To account for the change in the amount of each antibody captured, Rmax was normalized with respect to the antibody capture level ("ligand level," i.e., measured by the response units immobilized during antibody capture). Thus, the normalized Rmax is calculated as the experimental Rmax (unit = RU) derived by the "ligand level" (evaluation result representing the RUs captured during the hIgG capture step, unit = RU), and the stability index is calculated herein as normalized Rmax (after stress) divided by normalized Rmax (before stress).

[0378] The selected antibodies were expressed by transient transfection of CHO cells and purified. Subsequently, the antibodies were stressed at 1 mg / ml for 2 weeks, and deamidation analysis was performed by LC-MS / MS using RCM trypsin peptide mapping by DTT reduction, IAA capping, and pH 8.2 digestion. The results (Table 14) show that the mutant hu37D3-H9.v28.A4 was N 28 G 29 N 30 The motif demonstrated reduced susceptibility to deamidation. Since the residue is not located immediately adjacent to the Asn-28 residue (Figure 9), and it is unclear how the F33L mutation stabilizes Asn-28, the reduction in deamidation of hu37D3-H9.v28.A4 was unexpected. Table 14: hu37D3-H9.v28.A4 variant in deamidation stress tests Stability TIFF0007835706000015.tif115170

[0379] Example 6: Selection and Characterization of Humanized Anti-Tau Antibodies Antibody selection and characterization: Binding to human Tau protein The affinity of selected antibodies was evaluated at 25°C using a Biacore T200 instrument, GE Biacore Human IgG Capture Kit, and CM5 Series S tip. hIgG was diluted to 0.25 μg / ml in 10 mM HEPES (pH 7.4), 150 mM NaCl, and 0.05% Tween20 (electrophoresis buffer, HBSP) and captured at a flow rate of 10 μl / min for 150 seconds. Dynamic data of human Tau monomer injected in HBSP at concentrations of 0, 0.4, 1.2, 3.7, 11, 11, 33, and 100 nM were collected using a flow rate of 30 μl / min, with a 300-second association phase and a 600-second dissociation phase. Between cycles, the surface was regenerated using two consecutive 30-second injections of 3 M MgCl at 10 μl / min. The data were fitted to a 1:1 binding model (Table 15). Table 15: Dynamics data of selected humanized anti-Tau antibody variants TIFF0007835706000016.tif83170

[0380] Antibody characterization: Binding of the hIgG4.S228P.YTE format to human Tau protein Affinity was evaluated at 25°C using a Biacore T200 instrument, GE Biacore human FAb capture kit, and CM5 Series S tip. hIgG was diluted to 0.5 μg / ml in 10 mM HEPES (pH 7.4), 150 mM NaCl, and 0.05% Tween20 (electrophoresis buffer, HBSP), and captured at a flow rate of 10 μl / min for 180 seconds. Dynamic data of human Tau monomer injected into HBSP at concentrations of 0, 0.4, 1.2, 3.7, 11, 11, 33, and 100 nM were collected using a flow rate of 30 μl / min, a 300-second association phase, and a 600-second dissociation phase. Surface regeneration was performed between cycles using two consecutive 60-second injections of 10 mM glycine (pH 2.1). The data were fitted to a 1:1 binding model. Dynamic data are shown in Table 16. Table 16: Binding kinetics of hu37D3-H9.v28.A4 hIgG4.S228P.YTE to monomer human Tau by surface plasmon resonance. TIFF0007835706000017.tif45170

[0381] Antibody characterization: Binding to cynomolgus monkey Tau protein Affinity was evaluated at 25°C using a Biacore T200 instrument, GE Biacore human IgG capture kit, and CM5 Series S tip. hIgG was diluted to 2 μg / ml in 10 mM HEPES (pH 7.4), 150 mM NaCl, and 0.05% Tween20 (electrophoresis buffer, HBSP), and captured at a flow rate of 10 μl / min for 15 seconds. Dynamic data of human Tau monomer were collected from injections at a minimum of five different non-zero concentrations (one repeat concentration) between 1.2 and 100 nM. Dynamics were evaluated using a flow rate of 30 μl / min, with a 300-second association phase and a 600-second dissociation phase. Between cycles, a 30-second reinjection of 3 M magnesium chloride was performed at a flow rate of 10 μl / min. The results were fitted to a 1:1 binding model. Dynamic data are shown in Table 17. Table 17: Affinity of humanized anti-Tau antibodies against monomeric cynomolgus monkey Tau TIFF0007835706000018.tif115170

[0382] The humanized antibodies hu37D3.v28.A4 and hu37D3.v28.F1 also bind to phosphorylated Tau (pTau).

[0383] Example 7: Pharmacokinetics of anti-Tau antibody To evaluate the pharmacokinetics of anti-Tau37D3-H9 mIgG2a antibody in vivo, C57BL / 6 mice (conscious mice) were administered a single intravenous (IV) or intraperitoneal (IP) bolus infusion at a dose of 10 mg / kg. Plasma samples were collected at various time points up to 28 days post-dose to determine the anti-Tau antibody concentration.

[0384] The concentration of administered antibodies in mouse plasma was measured by standard ELISA using a mouse anti-muIgG2a antibody coating. Plasma samples were then added starting at a 1:100 dilution, followed by the addition of a mouse anti-muIgG2a-biotin conjugate, and subsequently, streptavidin conjugated with horseradish peroxidase for detection. The assay had a standard curve range of 1.56–200 ng / mL and a detection limit of 0.16 μg / mL. Results below this detection limit were reported as less than reportable (LTR).

[0385] Figure 10 shows the results of the pharmacokinetic analysis of anti-Tau37D3-H9 mIgG2a. Anti-Tau37D3-H9 mIgG2a showed similar exposure and clearance in wild-type C57BL / 6 mice as the isotype control antibody, with a clearance of 6.31 mL / day / kg.

[0386] To evaluate the pharmacokinetics of anti-Tau94B2-C1 mIgG2a and anti-tau125B11-H3 mIgG2a in vivo, conscious C57BL / 6 mice were administered a single intraperitoneal bolus of the antibody at a dose of 10 mg / kg. Plasma samples were collected at various time points up to 28 days post-dose to determine the anti-Tau antibody concentration.

[0387] The concentrations of administered antibodies in mouse plasma were measured by a standard ELISA using a mouse anti-muIgG2a antibody coat. Plasma samples were then added starting at a 1:100 dilution, followed by the addition of a mouse anti-muIgG2a-biotin conjugate, and subsequently, streptavidin conjugated with horseradish peroxidase for detection. The assay had a standard curve range of 0.78–100 ng / mL and a detection limit of 0.078 μg / mL. Concentrations were also measured by a specific ELISA using recombinant Tau as the coat. Plasma samples were then added starting at a 1:10 dilution, followed by the addition of goat anti-mIgG2a conjugated with horseradish peroxidase for detection. The assay had a standard curve range of 0.078–10 ng / mL and a detection limit of 0.0008 μg / mL. Results below this detection limit were reported as less than reportable (LTR).

[0388] The results of these experiments are shown in Figures 16 and 17. When concentrations were analyzed using a general assay, anti-Tau94B2 mIgG2a showed similar exposure and clearance in wild-type C57BL / 6 mice as isotype control antibodies. However, when concentrations were analyzed using a specific assay, lower exposure and faster clearance were observed. See Figure 16. The clearance determined by the general assay was 4.06 mL / day / kg, and the clearance determined by the specific assay was 7.53 mL / day / kg. These results suggest that antibodies may undergo in vivo changes over time that impair their ability to recognize their target. Anti-Tau125B11-H3 mIgG2a showed similar exposure and clearance in wild-type C57BL / 6 mice as isotype control antibodies, regardless of which assay produced the concentration. See Figure 17. The clearance determined by the general assay was 4.96 mL / day / kg, and the clearance determined by the specific assay was 4.90 mL / day / kg.

[0389] Table 18 shows the pharmacokinetic parameters of the anti-Tau antibodies 37D3-H9, 94B2-C1, and 125B11-H3 in mice. Table 18: Pharmacokinetic parameters of anti-Tau antibodies TIFF0007835706000019.tif71169

[0390] To evaluate the pharmacokinetics of hu37D3.v28.A4 hIgG4.S228P and hu37D3.v28.A4 hIgG4-S228P.YTE antibodies in vivo, cynomolgus monkeys (Macaca fascicularis) (conscious monkeys) were administered a single intravenous bolus infusion at a dose of 1 mg / kg. Plasma samples were collected at various time points up to 49 days post-dose to determine the anti-Tau antibody concentration.

[0391] The concentrations of administered antibodies in monkey plasma were measured using a standard ELISA coated with sheep anti-human IgG antibody. The assay was then terminated by adding goat anti-human IgG conjugated with horseradish peroxidase, starting with a 1:100 dilution of the plasma sample and ending with the addition of horseradish peroxidase. The assay had a standard curve range of 0.156–20 ng / mL and a detection limit of 0.02 μg / mL. Results below this detection limit were reported as less than reportable (LTR).

[0392] Figure 11 shows the results of pharmacokinetic analysis of hu37D3.v28.A4 hIgG4.S228P and hu37D3.v28.A4 hIgG4-S228P.YTE. In Figure 11, each data point in each set represents one animal, and the line represents the average of all animals in the antibody and assay groups. Table 19 shows the pharmacokinetic parameters of hu37D3.v28.A4 hIgG4.S228P and hu37D3.v28.A4 hIgG4-S228P.YTE in cynomolgus monkeys. Table 19: Pharmacokinetic parameters of hu37D3.v28.A4 hIgG4.S228P and hu37D3.v28.A4 hIgG4-S228P.YTE in cynomolgus monkeys TIFF0007835706000020.tif96170

[0393] Example 8: Further evaluation of the epitope characteristics of the anti-Tau antibody After comparing the binding of 37D3-H9 to biotin-labeled Tau monomers and biotin-labeled peptides (MAPT_10-24), the binding of 37D3-H9 to additional biotin-labeled peptides was also evaluated. 96-well microplates of Nunc maxisorp were coated with Neutravidin diluted to 2 μg / ml in 50 mM sodium carbonate buffer (pH 9.6) for over 12 hours at 4°C. All subsequent incubations were performed at room temperature. After coating, the plates were blocked with Superblock® (PBS) barrier buffer (Thermo Fisher Scientific) for 2 hours, followed by thorough washing with PBS and 0.05% polysorbate 20. Wells were then exposed to 1 μg / ml of biotin-labeled Tau peptide (Table 20) or biotin-labeled Tau monomer with an Avi tag for 1 hour, followed by washing as before. Peptides were synthesized using standard solid-phase Fmoc chemistry (see, e.g., Fmoc solid phase peptide synthesis: A practical approach; Chan, WC, White, PD, Eds.; Oxford University Press: New York, 2000). Antibodies 37D3-H9 mIgG2a and hu37D3-H9.v5 hIgG1, serially diluted from 500 nM to 50 pM in 90% Superblock® (PBS) barrier buffer, were conjugated to biotin-labeled Tau-coated wells for 90 minutes. The wells were washed as before, and the conjugated antibodies were detected with peroxidase-conjugated secondary antibodies (Invitrogen / Life Technologies) diluted 1 / 1000 in Superblock® barrier buffer (rabbit anti-mouse IgG or goat anti-human IgG (H+L), respectively). After 20 minutes, the wells were washed as before, and signals were generated on TMB Microwell2-Component Substrate (KPL). The reaction was stopped by adding 1M phosphoric acid, and the absorbance at 450 nM was measured using a SpectraMax M2 plate reader. Table 20: Peptide sequences TIFF0007835706000021.tif65169

[0394] The results of that experiment are shown in Figure 12. Figure 12A shows the binding of each antibody to the indicated peptide. In that experiment, both antibodies 37D3-H9 and 94B2-C1 showed strong binding to fragments 10-24, and antibody 94B2-C1 also showed strong binding to fragments 1-15. Antibodies 19F8-C11 and 123E9-A1 showed strong binding to fragments 19-33, while antibody 89F4-A1 showed strong binding to fragments 28-42 and 37-51. See Figure 12A. Both antibodies 37D3-H9 mIgG2a and hu37D3-H9.v5 hIgG1 showed strong binding to Tau fragments 2-24 and 2-34, and weak binding to fragments 10-24. See Figures 12B and 12C. These results suggest that the antibodies 37D3-H9 mIgG2a and hu37D3-H9.v5 hIgG1 bind to Tau epitopes within amino acids 2-24 of the mature protein.

[0395] In alanine scanning substitution experiments, mutations Y18A and L20A were found to inhibit the binding of mouse antibody 37D3-H9 to Tau fragments (fragments 2-21), suggesting that the antibody contacts these Tau residues. Using a series of 15-amino acid offset peptides, mouse antibody 37D3-H9 was found to bind to fragments 9-23 as well as fragments 10-24, and moderate binding to fragments 7-21, 8-22, and 11-25 was also observed.

[0396] Example 9: Cell-based characterization of 37D3-H9 humanized antibody method Primary hippocampal and microglia cultures, as well as hippocampal-microglia co-cultures Dissociated primary hippocampal neurons were prepared from wild-type C57BL / 6N mice during embryonic stage (16-17 days). Cells were plated at 25,000 cells / well onto 8-well chamber slides (Biocoat, 354688 Corning) coated with PDL / laminin. The plated cells were maintained in NbActiv4 (BrainBits), with half of the culture medium changed twice a week. Recombinant tau and antibodies were applied to the cultures after 18 cell divisions.

[0397] For microglia cultures, the cortex and hippocampus were dissociated from C57BL / 6N mice 1-2 days postnatally, and 225 mm 2 The cells were grown in a culture flask in 10% FBS in DMEM for 10–12 days. The culture flask was gently shaken to dissociate the microglia, and the cells in 10% FBS in DMEM were replated either on an 8-well chamber slide coated with PDL / laminin at 30,000 cells / well for imaging, or on an uncoated 48-well plate (3548, Corning) at 100,000 cells / well for cytokine assays. Four–five hours after plating, the cells were replaced with serum-free low-glucose DMEM, maintained overnight, and then treated with recombinant tau and antibody.

[0398] 225mm 2 A hippocampal-microglia coculture was prepared by replating microglia dissociated from a culture flask onto primary hippocampal neurons that had been cultured in vitro for 18 days in an 8-well slide chamber (12,500 microglia and 25,000 neurons per well). Four hours after microglia plating, the coculture was treated with recombinant tau and antibody.

[0399] In vitro treatment of recombinant tau and antibodies For hippocampal cultures or hippocampal-microglia co-cultures cultured for 18 days in vitro, recombinant human oligomer tau and antibody (500 nM each in a 1:1 ratio) or control were pre-incubated for 1 hour at 37°C in neuronal culture medium (hippocampal cultures cultured for 18 days in vitro: conditioned medium derived from fresh NbActiv4 (1:1)) before being added to the cells. The cells were incubated in the medium with the tau antibody mixture or control for 72 hours (hippocampal cultures) or 48 hours (hippocampal-microglia co-cultures). The cells were washed three times with PBS and then fixed.

[0400] For microglia cultures, recombinant human oligomer tau and antibodies or controls were pre-incubated for 1 hour at 37°C in low-glucose DMEM in the absence of serum, at 125 nM each (immunocytochemistry / imaging) or 250 nM each (cytokine assay), before being added to the cells. For immunocytochemistry / imaging, cells were incubated with the tau antibody mixture or control for 10 minutes, washed three times with PBS, and then fixed. For cytokine assay, cells were incubated with the tau antibody mixture or control for 24 hours, and the medium from each well was collected for the cytokine assay.

[0401] Immunocytochemistry, imaging techniques, and quantification Cells were fixed with 4% paraformaldehyde in PBS for 15 minutes and permeabilized with 0.1% Triton X-100 in PBS for 10 minutes. Using 10% donkey serum for blockade, cells were incubated overnight with primary antibodies at 4°C in PBS, and then incubated with Alexa-fluorophor-labeled secondary antibodies against appropriate species (Invitrogen) developed in donkeys. The primary antibodies used were anti-tau (DAKO) (rabbit anti-human Tau developed against the human Tau N-terminal region spanning amino acids 11-24), anti-MAP2 (ab5392, Abcam), and anti-Iba-1 (ab5076, Abcam). Slides were mounted with Prolong Gold DAPI (P36935, Invitrogen) and coverslip 1.

[0402] Confocal fluorescence imaging was performed using an LSM780 (Carl Zeiss, Inc.) with Zen2010 software (Carl Zeiss, Inc.). Five z-stack images at 0.98 μm intervals were collected for imaging of hippocampal cultures and hippocampal-microglia co-cultures using a Plan Apochromat 20× / 0.8M27 objective lens. For the MAP2 fragmentation assay, the z-projection of the maximum intensity of the image stack was generated and analyzed using Metamorph (Molecular Devices, Sunnyvale, CA). Noise was reduced using median filtering and nearest neighbor inverse superposition. Neurite growth module and subsequent morphological processing were used to analyze neurite and cell body lengths. Fragments smaller than 15 pixels (6.225 μm) were normalized to the total signal length to obtain a criterion for MAP2 fragmentation.

[0403] Microglia were imaged using an α-Plan Apochromat 100× / 1.46M27 objective lens. Intracellular recombinant tau uptake was quantified using Image J (1.43u, 64-bit, National Institutes of Health). The region of interest in cell area was manually plotted using the Iba-1 signal as a reference. Area and integrated intensity of tau immunoactivity in the region of interest were measured to obtain area-normalized tau immunoactivity. All analyses were performed blindly against experiment...

Claims

1. An isolated antibody that binds to human Tau, HVR-H1 containing the amino acid sequence of SEQ ID NO: 72; HVR-H2 containing the amino acid sequence of SEQ ID NO: 73; HVR-H3 containing the amino acid sequence of SEQ ID NO: 74; HVR-L1 containing the amino acid sequence of SEQ ID NO: 75; HVR-L2 containing the amino acid sequence of SEQ ID NO: 76; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 77 Isolated antibodies containing these antibodies.

2. a) A heavy chain variable region (VH) containing a sequence that is at least 95% identical to sequence number 70; b) A light chain variable region (VL) containing a sequence that is at least 95% identical to sequence number 71; or c) VH as in (a) and VL as in (b) The isolated antibody according to claim 1, comprising:

3. a) Heavy chain variable region (VH) containing the sequence of sequence number 70; b) A light chain variable region (VL) containing the sequence of sequence number 71; or c) VH as in (a) and VL as in (b) An isolated antibody according to claim 1 or 2, comprising:

4. An isolated antibody according to any one of claims 1 to 3, which is a monoclonal antibody.

5. An isolated antibody according to any one of claims 1 to 4, which is a humanized antibody or a chimeric antibody.

6. The isolated antibody according to any one of claims 1 to 5, wherein the human Tau comprises the sequence of SEQ ID NO:

2.

7. An isolated antibody according to any one of claims 1 to 6, which is an IgG1 or IgG4 antibody, and optionally an IgG4 antibody.

8. The isolated antibody according to claim 7, comprising the M252Y, S254T, T256E, and S228P mutations.

9. An isolated antibody according to any one of claims 1 to 8, which is an antibody fragment that binds to human Tau.

10. The monomer human Tau is bound with K₂D₀ of less than 10 nM, or full-length human Tau is bound with K₂D₀ of less than 5 nM. Ｄ An isolated antibody according to any one of claims 1 to 9, which is bound by [a specific mechanism].

11. An isolated nucleic acid encoding an isolated antibody according to any one of claims 1 to 10.

12. A host cell comprising the isolated nucleic acid described in claim 11.

13. A method for producing an antibody, comprising culturing the host cells described in claim 12 under conditions suitable for antibody production.

14. An immune complex comprising an isolated antibody according to any one of claims 1 to 10 and a second therapeutic agent.

15. A labeled antibody comprising an isolated antibody according to any one of claims 1 to 10 and a detectable label.

16. A pharmaceutical composition comprising an isolated antibody according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier.

17. A pharmaceutical agent for treating Tau protein-related disease, comprising an isolated antibody according to any one of claims 1 to 10.

18. The pharmaceutical product according to claim 17, wherein the Tau protein-related disease is tauopathy.

19. The pharmaceutical product according to claim 18, wherein the tauopathy is neurodegenerative tauopathy.

20. The aforementioned tauopathies include Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Creutzfeldt-Jakob disease, punch-drunk syndrome, Down syndrome, Gerstmann-Streussler-Scheinker disease, inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, Guam amyotrophic lateral sclerosis / parkinsonian dementia syndrome, non-Guam motor neuron disease with neurofibrillary tangles, argyrophilic granule dementia, corticobasal degeneration, diffuse neurofibrillary tangle disease with calcification, and frontotemporal type The pharmaceutical product according to claim 18 or 19, wherein the tauopathy is selected from dementia, frontotemporal dementia linked to chromosome 17 and associated with Parkinson's syndrome, Haller-Holden-Spats disease, multiple system atrophy, Niemann-Pick disease type C, globus pallidus-pontine-nigra degeneration, Pick's disease, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, neurofibrillary tangle dementia, post-encephalitis-Parkinson's disease, and myotonic dystrophy, and optionally, the tauopathy is Alzheimer's disease or progressive supranuclear palsy.

21. A pharmaceutical product comprising an isolated antibody according to any one of claims 1 to 10 for the purpose of maintaining or increasing cognitive memory capacity in an individual, or slowing memory loss; or for the purpose of reducing the levels of Tau protein, phosphorylated Tau protein, unphosphorylated Tau protein, or hyperphosphorylated Tau protein in an individual.

22. The pharmaceutical product according to any one of claims 17 to 21, wherein at least one additional therapy is administered, and the additional therapy is optionally selected from a neuroleptic, corticosteroid, antibiotic, antiviral, anti-Tau antibody, anti-amyloid-beta antibody, beta-amyloid aggregation inhibitor, anti-BACE1 antibody, BACE1 inhibitor, cholinesterase inhibitor (ChEI), N-methyl-D-aspartate (NMDA) receptor antagonist, and nutritional supplement.

23. a) The ChEI is tacrine, rivastigmine, donepezil, or galantamine, and the NMDA receptor antagonist is memantine; b) The anti-amyloid beta antibody is gantenerumab; c) The anti-amyloid beta antibody is crenezumab; or d) The pharmacopoeia according to claim 22, wherein at least one additional therapy is administered in combination with the pharmacopoeia, the additional therapy being gantenerumab.

24. A method for in vitro detection of neurofibrillary tangles, neutrophils, or degenerated neurites, comprising contacting a sample with an isolated antibody according to any one of claims 1 to 10.

25. The method according to claim 24, wherein the sample is a brain sample, a cerebrospinal fluid sample, or a blood sample.

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