HK1249531B - Anti-tau antibodies and methods of use - Google Patents

Description

Anti-TAU antibodies and methods of use

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 62/171,693, filed June 5, 2015, which is incorporated herein by reference in its entirety for any purpose.

Field of the Invention

The present invention relates to anti-Tau antibodies and methods of using the same.

Background of the Invention

Neurofibrillary tangles and neurofibrillary tangles (NTs) are the main neuropathological hallmarks of Alzheimer's disease (AD). NTs are composed of microtubule-associated Tau proteins that have undergone post-translational modifications (including phosphorylation) and develop through the aggregation of hyperphosphorylated Tau conformers. AD shares this pathology with many neurodegenerative tauopathies, particularly certain types of frontotemporal dementia (FTD). Tau protein appears to be a major player in cognitive loss in AD and related neurodegenerative tauopathies.

Therapeutic approaches targeting tau are few and primarily include inhibitors of kinases that are thought to increase tau phosphorylation to pathological levels and compounds that block cytoplasmic aggregation of hyperphosphorylated tau. These approaches suffer from various specificity and efficacy shortcomings. Additional therapeutic agents targeting pathological protein conformers known or suspected to contribute to neurodegenerative disorders are needed.

Summary of the Invention

The present invention provides anti-Tau antibodies and methods of using the same.

In some embodiments, isolated antibodies that bind to human Tau are provided, wherein the antibodies bind to monomeric Tau, oligomeric Tau, non-phosphorylated Tau, and phosphorylated Tau. In some embodiments, the antibodies bind to an epitope within amino acids 2 to 24 of mature human Tau. In some embodiments, the antibodies are monoclonal antibodies. In some embodiments, the antibodies are human, humanized, or chimeric antibodies. In some embodiments, the antibodies are antibody fragments that bind to human Tau. In some embodiments, the human Tau comprises the sequence of SEQ ID NO: 2.

In some embodiments, the antibody comprises:

a) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 12, 22, 282, 292, and 342; an HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 13, 23, 283, 293, and 343; and an HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 14, 24, 284, 294, and 344; or

b) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 72 and 302; HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 73 and 303; and HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 74 and 304;

c) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 42; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 43; and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 44;

d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 62; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 63; and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 64;

e) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 212; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 213; and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 214;

f) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 32; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 33; and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 34; or

g) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 52; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 53; and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 54.

In some embodiments, the antibody comprises:

a) an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 15, 25, 285, 295, 345, and 468 to 556; an HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 16, 26, 286, 296, and 346; and an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 17, 27, 287, 297, and 347;

b) an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 75 and 305; an HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 76 and 306; and an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 77 and 307;

c) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 45; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 46; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 47;

d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 65; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 66; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 67;

e) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 215; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 216; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 217;

f) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 35; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 36; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 37; or

g) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 55; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 56; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 57.

In some embodiments, the antibody comprises:

a) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 12, 22, 282, 292, and 342; an HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 13, 23, 283, 293, and 343; an HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 14, 24, 284, 294, and 344; an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 15, 25, 285, 295, 345, and 468 to 556; an HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 16, 26, 286, 296, and 346; and an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 17, 27, 287, 297, and 347;

b) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 72 and 302; an HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 73 and 303; an HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 74 and 304; an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 75 and 305; an HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 76 and 306; and an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 77 and 307;

c) HVR-H1 comprising the amino acid sequence of SEQ ID NO:42; HVR-H2 comprising the amino acid sequence of SEQ ID NO:43; HVR-H3 comprising the amino acid sequence of SEQ ID NO:44; HVR-L1 comprising the amino acid sequence of SEQ ID NO:45; HVR-L2 comprising the amino acid sequence of SEQ ID NO:46; and HVR-L3 comprising the amino acid sequence of SEQ ID NO:47;

d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 62; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 63; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 64; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 65; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 66; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 67;

e) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 212; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 213; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 214; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 215; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 216; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 217;

f) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 32; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 33; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 34; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 35; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 36; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 37; or

g) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 52; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 53; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 54; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 55; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 56; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 57.

In some embodiments, the antibody comprises:

a) a heavy chain variable region (VH) comprising a sequence that is at least 95% identical to a sequence selected from the group consisting of SEQ ID NOs: 10, 20, 280, 290, and 340;

b) a light chain variable region (VL) comprising a sequence that is at least 95% identical to a sequence selected from the group consisting of SEQ ID NOs: 11, 21, 281, 291, and 341;

c) VH as in (a) and VL as in (b);

d) a heavy chain variable region (VH) comprising a sequence that is at least 95% identical to a sequence selected from the group consisting of SEQ ID NOs: 70, 300, and 452 to 459;

e) a light chain variable region (VL) comprising a sequence that is at least 95% identical to a sequence selected from the group consisting of SEQ ID NOs: 71, 301, and 460 to 467;

f) VH as in (d) and VL as in (e);

g) a heavy chain variable region (VH) comprising a sequence at least 95% identical to SEQ ID NO: 40;

h) a light chain variable region (VL) comprising a sequence at least 95% identical to SEQ ID NO: 41;

i) VH as in (g) and VL as in (h);

j) a heavy chain variable region (VH) comprising a sequence at least 95% identical to SEQ ID NO: 60;

k) a light chain variable region (VL) comprising a sequence at least 95% identical to SEQ ID NO: 61;

1) VH as in (j) and VL as in (k);

m) a heavy chain variable region (VH) comprising a sequence at least 95% identical to SEQ ID NO: 210;

n) a light chain variable region (VL) comprising a sequence at least 95% identical to SEQ ID NO: 211;

o) VH as in (m) and VL as in (n);

p) a heavy chain variable region (VH) comprising a sequence at least 95% identical to SEQ ID NO: 30;

q) a light chain variable region (VL) comprising a sequence at least 95% identical to SEQ ID NO: 31;

r) VH as in (p) and VL as in (q);

s) a heavy chain variable region (VH) comprising a sequence at least 95% identical to SEQ ID NO: 50;

t) a light chain variable region (VL) comprising a sequence at least 95% identical to SEQ ID NO: 51; or

u) VH as in (s) and VL as in (t).

In some embodiments, the antibody comprises:

a) a heavy chain variable region (VH) comprising a sequence selected from the group consisting of SEQ ID NOs: 10, 20, 280, 290, and 340;

b) a light chain variable region (VL) comprising a sequence selected from the group consisting of SEQ ID NOs: 11, 21, 281, 291, and 341;

c) VH as in (a) and VL as in (b);

d) a heavy chain variable region (VH) comprising a sequence selected from the group consisting of SEQ ID NOs: 70, 300, and 452 to 459;

e) a light chain variable region (VL) comprising a sequence selected from the group consisting of SEQ ID NOs: 71, 301, and 460 to 467;

f) VH as in (d) and VL as in (e);

g) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 40;

h) a light chain variable region (VL) comprising the sequence of SEQ ID NO: 41;

i) VH as in (g) and VL as in (h);

j) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 60;

k) a light chain variable region (VL) comprising the sequence of SEQ ID NO: 61;

l) VH as in (j) and VL as in (k);

m) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 210;

n) a light chain variable region (VL) comprising the sequence of SEQ ID NO: 211;

o) VH as in (m) and VL as in (n);

p) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30;

q) a light chain variable region (VL) comprising the sequence of SEQ ID NO: 31;

r) VH as in (p) and VL as in (q);

s) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 50;

t) a light chain variable region (VL) comprising the sequence of SEQ ID NO: 51; or

u) VH as in (s) and VL as in (t).

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

In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:340 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:341.

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

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

In some embodiments, isolated antibodies that bind to human Tau are provided, wherein the antibody binds to an epitope within amino acids 19 to 33, 19 to 42, 28 to 44, 37 to 51, 100 to 114, 109 to 123, 118 to 132, 154 to 168, 172 to 177, 217 to 231, or 397 to 411 of mature human Tau.

In some embodiments, the antibody comprises:

a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 112; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 113; and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 114;

b) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 132; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 133; and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 134;

c) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 142; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 143; and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 144;

d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 152; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 153; and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 154;

e) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 162; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 163; and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 164;

f) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 252; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 253; and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 254;

g) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 272; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 273; and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 274;

h) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 102; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 103; and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 104;

i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 172; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 173; and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 174;

j) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 192; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 193; and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 194;

k) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 242; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 243; and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 244;

l) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 82, 312, 322, and 332; an HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 83, 313, 323, and 333; and an HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 84, 314, 324, and 334;

m) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 92; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 93; and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 94;

n) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 122; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 123; and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 124;

o) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 182; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 183; and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 184;

p) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 202; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 203; and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 204;

q) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 222; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 223; and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 224;

r) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 232; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 233; and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 234; or

s) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 262; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 263; and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 264.

In some embodiments, the antibody comprises:

a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 115; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 116; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 117;

b) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 135; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 136; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 137;

c) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 145; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 146; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 147;

d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 155; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 156; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 157;

e) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 165; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 166; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 167;

f) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 255; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 256; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 257;

g) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 275; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 276; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 277;

h) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 105; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 106; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 107;

i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 175; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 176; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 177;

j) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 195; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 196; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 197;

k) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 245; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 246; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 247;

l) an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 85, 315, 325, and 335; an HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 86, 316, 326, and 336; and an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 87, 317, 327, and 337;

m) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 95; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 96; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 97;

n) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 125; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 126; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 127;

o) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 185; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 186; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 187;

p) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 205; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 206; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 207;

q) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 225; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 226; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 227;

r) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 235; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 236; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 237; or

s) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 265; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 266; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 267.

In some embodiments, the antibody comprises:

a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 112; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 113; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 114; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 115; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 116; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 117;

b) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 132; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 133; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 134; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 135; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 136; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 137;

c) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 142; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 143; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 144; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 145; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 146; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 147;

d) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 152; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 153; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 154; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 155; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 156; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 157;

e) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 162; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 163; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 164; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 165; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 166; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 167;

f) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 252; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 253; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 254; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 255; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 256; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 257; or

g) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 272; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 273; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 274; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 275; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 276; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 277;

h) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 102; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 103; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 104; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 105; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 106; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 107;

i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 172; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 173; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 174; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 175; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 176; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 177;

j) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 192; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 193; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 194; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 195; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 196; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 197; or

k) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 242; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 243; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 244; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 245; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 246; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 247;

l) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 82, 312, 322, and 332; an HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 83, 313, 323, and 333; an HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 84, 314, 324, and 334; an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 85, 315, 325, and 335; an HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 86, 316, 326, and 336; and an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 87, 317, 327, and 337;

m) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 92; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 93; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 94; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 95; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 96; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 97;

n) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 122; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 123; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 124; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 125; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 126; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 127;

o) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 182; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 183; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 184; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 185; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 186; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 187;

p) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 202; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 203; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 204; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 205; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 206; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 207;

q) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 222; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 223; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 224; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 225; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 226; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 227;

r) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 232; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 233; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 234; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 235; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 236; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 237; or

s) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 262; HVR-H2 comprising the amino acid sequence of SEQ ID NO: 263; HVR-H3 comprising the amino acid sequence of SEQ ID NO: 264; HVR-L1 comprising the amino acid sequence of SEQ ID NO: 265; HVR-L2 comprising the amino acid sequence of SEQ ID NO: 266; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 267.

In some embodiments, the antibody comprises:

a) a heavy chain variable region (VH) comprising a sequence at least 95% identical to SEQ ID NO: 110;

b) a light chain variable region (VL) comprising a sequence at least 95% identical to SEQ ID NO: 111;

c) VH as in (a) and VL as in (b);

d) a heavy chain variable region (VH) comprising a sequence at least 95% identical to SEQ ID NO: 130;

e) a light chain variable region (VL) comprising a sequence at least 95% identical to SEQ ID NO: 131;

f) VH as in (d) and VL as in (e);

g) a heavy chain variable region (VH) comprising a sequence at least 95% identical to SEQ ID NO: 140;

h) a light chain variable region (VL) comprising a sequence at least 95% identical to SEQ ID NO: 141;

i) VH as in (g) and VL as in (h);

j) a heavy chain variable region (VH) comprising a sequence at least 95% identical to SEQ ID NO: 150;

k) a light chain variable region (VL) comprising a sequence at least 95% identical to SEQ ID NO: 151;

l) VH as in (j) and VL as in (k);

m) a heavy chain variable region (VH) comprising a sequence at least 95% identical to SEQ ID NO: 160;

n) a light chain variable region (VL) comprising a sequence at least 95% identical to SEQ ID NO: 161; or

o) VH as in (m) and VL as in (n);

p) a heavy chain variable region (VH) comprising a sequence at least 95% identical to SEQ ID NO: 250;

q) a light chain variable region (VL) comprising a sequence at least 95% identical to SEQ ID NO: 251;

r) VH as in (p) and VL as in (q);

s) a heavy chain variable region (VH) comprising a sequence at least 95% identical to SEQ ID NO: 270;

t) a light chain variable region (VL) comprising a sequence at least 95% identical to SEQ ID NO: 271;

u) VH as in (s) and VL as in (t);

v) a heavy chain variable region (VH) comprising a sequence at least 95% identical to SEQ ID NO: 100;

w) a light chain variable region (VL) comprising a sequence at least 95% identical to SEQ ID NO: 101; or

x) VH as in (v) and VL as in (w);

y) a heavy chain variable region (VH) comprising a sequence at least 95% identical to SEQ ID NO: 170;

z) a light chain variable region (VL) comprising a sequence at least 95% identical to SEQ ID NO: 171;

aa) VH as in (y) and VL as in (z);

bb) a heavy chain variable region (VH) comprising a sequence at least 95% identical to SEQ ID NO: 190;

cc) a light chain variable region (VL) comprising a sequence at least 95% identical to SEQ ID NO: 191;

dd) VH as in (bb) and VL as in (cc);

ee) a heavy chain variable region (VH) comprising a sequence at least 95% identical to SEQ ID NO: 240;

ff) a light chain variable region (VL) comprising a sequence at least 95% identical to SEQ ID NO: 241; or

gg) VH as in (ee) and VL as in (ff);

hh) a heavy chain variable region (VH) comprising a sequence that is at least 95% identical to a sequence selected from the group consisting of SEQ ID NOs: 80, 310, 320, 330, and 446 to 451;

ii) a light chain variable region (VL) comprising a sequence that is at least 95% identical to a sequence selected from the group consisting of SEQ ID NOs: 81, 311, 321, 331, and 442 to 445;

jj) VH as in (hh) and VL as in (ii);

kk) a heavy chain variable region (VH) comprising a sequence at least 95% identical to SEQ ID NO: 90;

11) a light chain variable region (VL) comprising a sequence at least 95% identical to SEQ ID NO: 91;

mm) VH as in (kk) and VL as in (ll);

nn) a heavy chain variable region (VH) comprising a sequence at least 95% identical to SEQ ID NO: 120;

oo) a light chain variable region (VL) comprising a sequence at least 95% identical to SEQ ID NO: 121;

pp) VH as in (nn) and VL as in (oo);

qq) a heavy chain variable region (VH) comprising a sequence at least 95% identical to SEQ ID NO: 180;

rr) a light chain variable region (VL) comprising a sequence at least 95% identical to SEQ ID NO: 181;

ss) VH as in (qq) and VL as in (rr);

tt) a heavy chain variable region (VH) comprising a sequence at least 95% identical to SEQ ID NO: 200;

uu) a light chain variable region (VL) comprising a sequence at least 95% identical to SEQ ID NO: 201;

vv) VH as in (tt) and VL as in (uu);

ww) a heavy chain variable region (VH) comprising a sequence at least 95% identical to SEQ ID NO: 220;

xx) a light chain variable region (VL) comprising a sequence at least 95% identical to SEQ ID NO: 221;

yy) VH as in (ww) and VL as in (xx);

zz) a heavy chain variable region (VH) comprising a sequence at least 95% identical to SEQ ID NO: 230;

aaa) a light chain variable region (VL) comprising a sequence at least 95% identical to SEQ ID NO: 231;

bbb) VH as in (zz) and VL as in (aaa);

ccc) a heavy chain variable region (VH) comprising a sequence at least 95% identical to SEQ ID NO: 260;

ddd) a light chain variable region (VL) comprising a sequence at least 95% identical to SEQ ID NO: 261; or

eee) VH as in (ccc) and VL as in (ddd).

In some embodiments, the antibody comprises:

a) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 110;

b) a light chain variable region (VL) comprising the sequence of SEQ ID NO: 111;

c) VH as in (a) and VL as in (b);

d) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 130;

e) a light chain variable region (VL) comprising the sequence of SEQ ID NO: 131;

f) VH as in (d) and VL as in (e);

g) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 140;

h) a light chain variable region (VL) comprising the sequence of SEQ ID NO: 141;

i) VH as in (g) and VL as in (h);

j) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 150;

k) a light chain variable region (VL) comprising the sequence of SEQ ID NO: 151;

l) VH as in (j) and VL as in (k);

m) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 160;

n) a light chain variable region (VL) comprising the sequence of SEQ ID NO: 161; or

o) VH as in (m) and VL as in (n);

p) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 250;

q) a light chain variable region (VL) comprising the sequence of SEQ ID NO: 251;

r) VH as in (p) and VL as in (q);

s) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 270;

t) a light chain variable region (VL) comprising the sequence of SEQ ID NO: 271; or

u) VH as in (s) and VL as in (t)

v) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 100;

w) a light chain variable region (VL) comprising the sequence of SEQ ID NO: 101; or

x) VH as in (v) and VL as in (w);

y) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 170;

z) a light chain variable region (VL) comprising the sequence of SEQ ID NO: 171;

aa) VH as in (y) and VL as in (z);

bb) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 190;

cc) a light chain variable region (VL) comprising the sequence of SEQ ID NO: 191;

dd) VH as in (bb) and VL as in (cc);

ee) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 240;

ff) a light chain variable region (VL) comprising the sequence of SEQ ID NO: 241;

gg) VH as in (ee) and VL as in (ff);

hh) a heavy chain variable region (VH) comprising a sequence selected from the group consisting of SEQ ID NOs: 80, 310, 320, 330, and 446 to 451;

ii) a light chain variable region (VL) comprising a sequence selected from the group consisting of SEQ ID NOs: 81, 311, 321, 331, and 442 to 445;

jj) VH as in (hh) and VL as in (ii);

kk) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 90;

11) a light chain variable region (VL) comprising the sequence of SEQ ID NO: 91;

mm) VH as in (kk) and VL as in (ll);

nn) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 120;

oo) a light chain variable region (VL) comprising the sequence of SEQ ID NO: 121;

pp) VH as in (nn) and VL as in (oo);

qq) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 180;

rr) a light chain variable region (VL) comprising the sequence of SEQ ID NO: 181;

ss) VH as in (qq) and VL as in (rr);

tt) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 200;

uu) a light chain variable region (VL) comprising the sequence of SEQ ID NO: 201;

vv) VH as in (tt) and VL as in (uu);

ww) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 220;

xx) a light chain variable region (VL) comprising the sequence of SEQ ID NO: 221;

yy) VH as in (ww) and VL as in (xx);

zz) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 230;

aaa) a light chain variable region (VL) comprising the sequence of SEQ ID NO: 231;

bbb) VH as in (zz) and VL as in (aaa);

ccc) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 260;

ddd) a light chain variable region (VL) comprising the sequence of SEQ ID NO: 261; or

eee) VH as in (ccc) and VL as in (ddd).

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 comprises M252Y, S254T, and T256E mutations. In any of the embodiments described herein, the antibody may comprise an S228P mutation. In any of the embodiments described herein, the antibody may comprise S228P, M252Y, S254T, and T256E mutations. In any of the embodiments described herein, the antibody may be an IgG4 antibody comprising 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 comprising S228P, M252Y, S254T, and T256E mutations and lacking the C-terminal lysine (des-K) of the heavy chain constant region. The C-terminal lysine of the heavy chain constant region can be removed, for example, during purification of the antibody, or by recombinantly engineering the nucleic acid encoding the antibody such that the C-terminal lysine is not encoded.

In some embodiments, an isolated antibody that binds human Tau is provided, wherein the antibody binds to each of monomeric Tau, phosphorylated Tau, non-phosphorylated Tau, and oligomeric Tau with a _K of less than 100 nM, less than 75 nM, or less than 50 nM. In some embodiments, the antibody binds to cynomolgus monkey Tau (SEQ ID NO: 4).

In some embodiments, an isolated nucleic acid is provided, wherein the isolated nucleic acid encodes an antibody described herein. In some embodiments, a host cell is provided, wherein the host cell comprises an isolated nucleic acid encoding an antibody described herein. In some embodiments, a method of producing an antibody is provided, comprising culturing the host cell under conditions suitable for producing the antibody.

In some embodiments, an immunoconjugate is provided, wherein the immunoconjugate comprises 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.

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

In some embodiments, a method for treating a Tau protein-related disease is provided, comprising administering an antibody as described herein or a pharmaceutical composition comprising an antibody as described herein to an individual suffering from a Tau protein-related disease. In some embodiments, the Tau protein-related disease is a tauopathy. In some embodiments, the tauopathy is a neurodegenerative tauopathy. In some embodiments, the tauopathy is selected from the group consisting of Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Creutzfeldt-Jacob disease, dementia pugilistica, Down's syndrome, Gerstmann-Scheinker disease, inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam, non-Guam motor neuron disease with neurofibrillary tangles, argyrophilic grain dementia, corticobasal degeneration, diffuse neurofibrillary tangles with calcifications, frontotemporal dementia, frontotemporal dementia with parkinsonism linked to chromosome 17, Hallevorden-Spatz disease, and tauopathies. In some embodiments, the tauopathy is Alzheimer's disease or progressive supranuclear palsy.

In some embodiments, a method of maintaining or improving cognitive memory ability or slowing memory loss in an individual is provided, comprising administering an antibody described herein or a pharmaceutical composition comprising an antibody described herein.

In some embodiments, a method of reducing the level of Tau protein, non-phosphorylated Tau protein, phosphorylated Tau protein, or hyperphosphorylated Tau protein in a subject is provided, comprising administering an antibody described herein or a pharmaceutical composition comprising an antibody described herein.

In some embodiments, the isolated antibodies described herein are provided for use as medicaments. In some embodiments, the isolated antibodies described herein are provided for use in treating tauopathy in an individual. In some embodiments, tauopathy is a neurodegenerative tauopathy. In some embodiments, tauopathy is selected from Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Creutzfeldt-Jakob disease, dementia pugilistica, Down syndrome, Gerstner syndrome, inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis/Guam Parkinsonism-dementia complex, non-Guam motor neuron disease with neurofibrillary tangles, argyrophilic grain dementia, corticobasal degeneration , diffuse neurofibrillary tangles with calcifications, frontotemporal dementia, frontotemporal dementia with parkinsonism linked to chromosome 17, Hallervorden-Spatz disease, multiple system atrophy, Niemann-Pick disease type C, pallidoponto-nigral degeneration, Pick's disease, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, tangle-only dementia, postencephalitic parkinsonism, and myotonic dystrophy. In some embodiments, the tauopathy is Alzheimer's disease or progressive supranuclear palsy.

In some embodiments, the isolated antibodies described herein are provided for use in maintaining or improving cognitive memory abilities or slowing down memory loss in an individual. In some embodiments, the isolated antibodies described herein are provided for use in reducing the level of Tau protein, phosphorylated Tau protein, non-phosphorylated Tau protein, or hyperphosphorylated Tau protein in an individual.

In some embodiments, the use of the antibodies described herein is provided for the manufacture of a medicament for treating a Tau protein-related disease in an individual. In some embodiments, the Tau protein-related disease is a tauopathy. In some embodiments, the tauopathy is a neurodegenerative tauopathy. In some embodiments, the tauopathy is selected from Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Creutzfeldt-Jakob disease, dementia pugilistica, Down syndrome, Gerstner syndrome, inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis/Guam Parkinson's syndrome-dementia complex, non-Guam motor neuron disease with neurofibrillary tangles, argyrophilic granular dementia, corticobasal degeneration , diffuse neurofibrillary tangles with calcifications, frontotemporal dementia, frontotemporal dementia with parkinsonism linked to chromosome 17, Hallervorden-Spatz disease, multiple system atrophy, Niemann-Pick disease type C, pallidoponto-nigral degeneration, Pick's disease, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, tangle-only dementia, postencephalitic parkinsonism, and myotonic dystrophy. In some embodiments, the tauopathy is Alzheimer's disease or progressive supranuclear palsy.

In some embodiments, use of the antibodies described herein is provided for the manufacture of a medicament for maintaining or improving cognitive memory ability or slowing memory loss in an individual.

In some embodiments, a method of detecting neurofibrillary tangles, neuropil threads, or dystrophic neuritis is provided, 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.

In any of the embodiments described herein, the methods or uses may comprise administering an antibody described herein in combination with at least one additional therapy. Non-limiting examples of additional therapies include neuroleptics, corticosteroids, antibiotics, antivirals, and other therapeutic agents. Such other therapeutic agents include, but are not limited to, other anti-Tau antibodies, antibodies to amyloid-β, antibodies to β-secretase 1 ("BACE1"), and inhibitors of β-secretase 1.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1A-F. Antibody binding to hyperphosphorylated Tau (pTau) was compared to binding to non-phosphorylated Tau using ELISA. Results are expressed as optical density (O.D.).

Figure 2A-E. Antibody binding to oligomeric Tau was assessed using oligo-Tau and single-Tau capture ELISAs. Results are expressed as optical density (O.D.).

Figure 3. Using Western blot (WB) assay, the three pan-Tau antibodies tested showed that they bind to soluble Tau in brain lysates from Alzheimer's disease (AD) and matched control donors. Protein extracts from AD and control brain lysates and six recombinant human Tau isoforms were run on SDS-PAGE and membranes blotted with three pan-Tau antibodies (37D3-H9, 94B2-C1, and 125B11-H3). Lanes with AD samples are labeled AD18, AD24, and AD27, and lanes with control samples are labeled C25 and C21. Lanes run with six recombinant human Tau isoforms are labeled hTau sequence ladder.

Figure 4A-C. Pan-Tau antibodies were shown to bind to soluble Tau in brain lysates from AD and matched control donors using a Tau capture ELISA. Data are shown for three pan-Tau antibodies: 37D3-H9, 94B2-C1, and 125B11-H3. Results are presented as optical density (O.D.), mean ± SD, N = 2.

Figure 5. Sensorgrams showing 37D3-H9 binding to human Tau monomers covalently coupled to the surface of a Biacore chip in Fab format (left panel) and IgG format (right panel). A 1:1 binding model was applied and the images are shown as an overlay. The x-axis indicates time (unit = seconds). The y-axis indicates resonance units (RU).

Figure 6. Overlay sensorgrams showing binding of hu37D3-H9.v5 sample to 3.1, 6.3, 12.5, 25, 25, 50, and 100 nM human Tau monomer at t = 0 (left panel) and t = 2 weeks (right panel). A 1:1 binding model was applied and is also shown in this figure. The x-axis indicates time (unit = seconds). The y-axis indicates resonance units (RU).

Figure 7. Binding of hu37D3-H9.v5 and hu37D3-H9.v5 N28D to monomeric Tau (left panel shows hu37D3-H9.v5 and middle panel shows hu37D3-H9.v5 N28D) and a 1:1 mixture (right panel). The x-axis indicates time (unit = seconds). The y-axis indicates resonance units (RU).

Figure 8A-D. Affinity, stability index, and sequence of 90 37D3-H9 variants screened for potential improved stability. For clarity, values obtained using an unstressed control antibody (hu37D3-H9.v5 hIgG1) run at the beginning, middle, and end of each experiment are shown in both parts of the table.

FIG9 . Structural model of the 37D3-H9 Fv region showing the location of light chain residues 28 to 33 (NGNTYF motif) and the relative positions of residues 28 and 33. Note that residue 33, which was mutated to Leu in hu37D3.v28.A4, is not adjacent to the labile Asn-28 residue. The dotted line shows the hydrogen bond between residues Asn-28 and Tyr-32. The figure was generated using the MOE software package (Chemical Computing Group).

FIG10 shows the pharmacokinetics of anti-Tau antibody 37D3-H9 in mice following a single 10 mg/kg intravenous or intraperitoneal injection.

Figure 11 shows the pharmacokinetics of hu37D3.v28.A4 hIgG4-S228P and hu37D3.v28.A4 hIgG4-S228P.YTE in cynomolgus monkeys following a single IV bolus injection at a dose of 1 mg/kg.

Figure 12A-C. Binding of certain anti-tau antibodies to tau fragments. (A) Binding of certain anti-tau antibodies to tau fragments 1-15, 10-24, 19-33, 28-42, 37-51, and 46-60 is shown. (B) Binding of antibody 37D3-H9 mIgG2a to tau fragments 10-44, 10-24, 2-24, 2-34, and full-length tau. (C) Binding of antibody hu37D3-H9.v5 hIgG1 to tau fragments 10-44, 10-24, 2-24, 2-34, and full-length tau.

Figure 13A-B. Impact of effector function on Tau toxicity in neuron-microglia co-cultures. (A) Percentage of MAP2 fragmentation in co-cultures exposed to various antibodies and oligomeric Tau. (B) Images of neurons (top panel) and neuron-microglia co-cultures (bottom panel) exposed to various antibodies and oligomeric Tau.

Figure 14. pTau212/214 levels in the hippocampus of mice administered anti-tau 37D3-H9 WT IgG2a or anti-tau 37D3-H9 DANG IgG2.

Figure 15. Comparison of human and cynomolgus monkey Tau sequences. Epitopes for antibody 37D3-H9 are indicated.

FIG16 shows the pharmacokinetics of anti-Tau antibody 94B2-C1 in mice following a single 10 mg/kg intravenous or intraperitoneal injection.

FIG17 shows the pharmacokinetics of anti-Tau antibody 125B11-H3 in mice following a single 10 mg/kg intravenous or intraperitoneal injection.

Figure 18 shows an alignment of the kappa 1 light chain variable regions of hu37D3-H9.v1, hu37D3-H9.v39, hu37D3-H9.v40, and hu37D3-H9.v41.

19A-B show plasma antibody concentrations (A) and CSF antibody concentrations (B) in cynomolgus monkeys following a single IV injection of the indicated antibodies at 50 mg/kg.

FIG20 shows plasma total Tau concentrations and plasma antibody concentrations in cynomolgus monkeys following a single IV injection of the indicated antibodies at 50 mg/kg.

Figures 21A-D show the antibody concentration in various regions of the cynomolgus monkey brain 2 and 10 days after a single IV injection of hu37D3.v28.A4 hIgG4-S228P (A) and hu37D3.v28.A4 hIgG4-S228P.YTE (B) at 50 mg/kg; the mean antibody concentration in the brain (C); and the % brain:plasma antibody concentration (D).

22A-B show antibody concentrations in cynomolgus monkey brains at various time points following a single IV injection of the indicated antibodies at 50 mg/kg, plotted on logarithmic (A) and linear (B) scales.

23A-E show antibody concentrations in the hippocampus (A), cerebellum (B), frontal cortex (C), CSF (D), and plasma (E) of cynomolgus monkeys at various time points following a single IV injection of the indicated antibodies at 50 mg/kg.

24A-B show mean (A) and individual (B) plasma total Tau concentrations over time in cynomolgus monkeys following a single IV injection of the indicated antibodies at 50 mg/kg.

DETAILED DESCRIPTION

I. Definition

For the purposes herein, an "acceptor human framework" is a framework comprising an 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 a human consensus framework as defined below. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence of a human immunoglobulin framework or a human consensus framework, or it may contain amino acid sequence changes. In some embodiments, the number of amino acid changes 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 a VL human immunoglobulin framework sequence or a human consensus framework sequence.

"Affinity" refers to the strength of the sum of 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 a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y can generally be represented by a dissociation constant ( _KD ). Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described below.

An "affinity matured" antibody is one that has one or more alterations in one or more hypervariable regions (HVRs) which improve the affinity of the antibody for antigen, compared to a parent antibody that does not possess such alterations.

The terms "anti-Tau antibody" and "antibody that binds to Tau" refer to an antibody that can bind to Tau with sufficient affinity so that the antibody is useful as a diagnostic and/or therapeutic agent targeting Tau. In some embodiments, the extent of binding of the anti-Tau antibody to unrelated, non-Tau proteins is less than about 10% of the binding of the antibody to Tau, as measured by, for example, radioimmunoassay (RIA). In certain embodiments, the dissociation constant ( _KD ) of the antibody that binds to Tau is ≤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, e.g., ^10-8 M to ^10-13 M, e.g., ^10-9 M to ^10-13 M). In certain embodiments, the anti-Tau antibody binds to an epitope of Tau that is conserved among Tau from different species. Unless otherwise specifically indicated, 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. In some such embodiments, the anti-Tau antibody binds to monomeric Tau, oligomeric Tau, non-phosphorylated Tau, and phosphorylated Tau with similar affinities, such as with affinities that differ by no more than 50-fold from one another. In some embodiments, antibodies that bind to monomeric Tau, oligomeric Tau, non-phosphorylated Tau, and phosphorylated Tau are referred to as "pan-Tau antibodies."

The term "antibody" is used herein in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired antigen-binding activity.

"Antibody fragments" refer to molecules other than intact antibodies that comprise a portion of an intact antibody that binds to the 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.

An "antibody that binds to the same epitope as a reference antibody" is an antibody that blocks binding of the reference antibody to its antigen by 50% or more in a competition assay, and conversely, the reference antibody blocks binding of the antibody to its antigen by 50% or more in a competition assay. An exemplary competition assay is provided herein.

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

The "class" of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these classes can be further divided into subclasses (isotypes), such as IgG ₁ , IgG ₂ , IgG ₃ , IgG ₄ , IgA ₁ , and IgA ₂ . The heavy chain constant domains corresponding to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

As used herein, the term "cytotoxic agent" refers to a substance that inhibits or interferes with cell function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At ²¹¹ , I ¹³¹ , I ¹²⁵ , Y ⁹⁰ , Re ¹⁸⁶ , Re ¹⁸⁸ , Sm ¹⁵³ , Bi ²¹² , P ³² , Pb ²¹² and radioactive isotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, adriamicin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof, such as nucleolytic enzymes; antibiotics; toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof; and various anti-tumor or anti-cancer agents disclosed below.

"Effector functions" refer to those biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: Clq 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.

An "effective amount" of an agent (eg, a pharmaceutical formulation) refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.

The term "Fc region" herein is used to define the C-terminal region of an immunoglobulin heavy chain containing at least a portion of a constant region. The term includes native sequence Fc regions and variant Fc regions. In some embodiments, the human IgG heavy chain Fc region extends from Cys226 or from Pro230 to the carboxyl terminus of the heavy chain. However, the C-terminal lysine (Lys447) in the Fc region may or may not be present. Unless otherwise indicated herein, the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also referred to as the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

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

The terms "full length antibody," "intact antibody," and "whole antibody" are used interchangeably herein and refer to an antibody that has a structure substantially similar to a native antibody structure or has heavy chains that contain an Fc region as defined herein.

The terms "host cell," "host cell strain," and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells," which include the primary transformed cell and progeny derived therefrom (regardless of the number of passages). The nucleic acid content of the progeny may not be exactly the same as that of the parent cell, but may contain mutations. Mutant progeny having the same function or biological activity as that screened or selected for the original transformed cell are included herein.

A "human antibody" is an antibody whose amino acid sequence corresponds to that of an antibody produced by a human or human cell, or derived from a non-human source that utilizes a human antibody repertoire or other human antibody encoding sequences. This definition of a human antibody specifically excludes humanized antibodies comprising non-human antigen-binding residues.

The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to an antigen. The variable domains of the heavy and light chains (VH and VL, respectively) of a native antibody generally have a similar structure, with each domain comprising four conserved framework regions (FRs) and three hypervariable regions (HVRs). (See, e.g., Kindt et al., Kuby Immunology, 6th ed., W.H. Freeman and Co., p. 91 (2007).) A single VH or VL domain may be sufficient to confer antigen-binding specificity. In addition, antibodies that bind to a particular antigen can be isolated using VH or VL domains from antibodies that bind to that antigen to screen for libraries of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150: 880-887 (1993); Clarkson et al., Nature 352: 624-628 (1991).

"Human consensus framework" is a framework that represents the most frequently occurring amino acid residues in a selected human immunoglobulin VL or VH framework sequence. In general, the human immunoglobulin VL or VH sequence is selected from a subset of variable domain sequences. In general, the sequence subset is a subset such as that described in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), Volumes 1-3. In some embodiments, for VL, the subset is a subset such as that described in Kabat et al., supra, subgroup κI. In some embodiments, for VH, the subset is a subset such as that described in Kabat et al., supra, subgroup III.

A "humanized" antibody refers to a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid residues from human FRs. In certain embodiments, a humanized antibody will comprise substantially all of at least one and typically two variable domains, wherein all or substantially all of the HVRs (e.g., CDRs) correspond to the HVRs of a non-human antibody, and all or substantially all of the FRs correspond to the FRs of a human antibody. A humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody (e.g., a non-human antibody) refers to an antibody that has undergone humanization.

As used herein, the term "hypervariable region" or "HVR" refers to each of the regions of an antibody variable domain that are hypervariable in sequence ("complementarity determining regions" or "CDRs") and/or form structurally well-defined loops ("hypervariable loops") and/or contain antigen-contacting residues ("antigen contacts"). Generally, antibodies comprise six HVRs: three in VH (H1, H2, H3) and three in VL (L1, L2, L3). Exemplary HVRs herein include:

(a) Hypervariable loops occurring 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 occurring 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) antigenic contacts occurring 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) A combination of (a), (b) and/or (c), comprising 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).

Unless otherwise indicated, HVR residues and other residues in the variable domain (eg, FR residues) are numbered herein according to Kabat et al., supra.

An "immunoconjugate" is an antibody conjugated to one or more heterologous molecules, including but not limited to, a cytotoxic agent.

An "individual" or "subject" is a mammal. Mammals include, but are not limited to, domestic animals (e.g., cows, 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.

An "isolated" antibody is one that has been separated from the components of its natural environment. In some embodiments, the antibody is purified to a purity greater than 95% or 99% as determined by, for example, electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse phase HPLC). For a review of methods for assessing antibody purity, see, for example, Flatman et al., J. Chromatogr. B 848:79-87 (2007).

An "isolated" nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. An isolated nucleic acid includes a nucleic acid molecule contained in cells that ordinarily contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.

"Isolated nucleic acid encoding an anti-Tau antibody" refers to one or more nucleic acid molecules encoding the antibody heavy and light chains (or fragments thereof), including such nucleic acid molecules in a single vector or separate vectors and such nucleic acid molecules present at one or more locations in a host cell.

As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, that is, except for possible variant antibodies (e.g., antibodies containing naturally occurring mutations or mutations that occur during the production of monoclonal antibody preparations, such variants generally existing in small amounts), the individual antibodies constituting the population are identical and/or bind to the same epitope. Compared to polyclonal antibody preparations that typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on the antigen. Therefore, the modifier "monoclonal" indicates that the characteristic of the antibody is obtained from a substantially homogeneous antibody population and should not be interpreted as requiring the antibody to be produced by any particular method. For example, the monoclonal antibodies used in accordance with the present invention can be made by a variety of techniques, including but not limited to hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for making the monoclonal antibodies described herein.

A "naked antibody" is an antibody that is not conjugated to a heterologous moiety (eg, a cytotoxic moiety) or a radiolabel. Naked antibodies can be presented in the form of pharmaceutical formulations.

"Native antibodies" refer to naturally occurring immunoglobulin molecules with different structures. For example, native IgG antibodies are heterotetrameric glycoproteins of approximately 150,000 daltons, consisting of two identical light chains and two identical heavy chains bonded by disulfide bonds. From N-terminus to C-terminus, each heavy chain has a variable region (VH), also referred to as a variable heavy chain domain or a heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, from N-terminus to C-terminus, each light chain has a variable region (VL), also referred to as a variable light chain domain or a light chain variable domain, followed by a constant light chain (CL) domain. The light chains of antibodies can be classified into one of two types, referred to as κ and λ, based on the amino acid sequence of their constant domains.

The term "package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and/or warnings concerning the use of such therapeutic products.

"Percentage (%) of amino acid sequence identity relative to a reference polypeptide sequence is defined as the percentage of amino acid residues in the candidate sequence that are identical to the amino acid residues in the reference polypeptide sequence, after aligning the reference polypeptide sequence with the candidate sequence and, if necessary, introducing gaps to achieve maximum sequence identity, and without considering conservative substitutions as part of sequence identity. Alignment for purposes of determining percentage of amino acid sequence identity can be achieved in various ways within the skill 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 aligning sequences, including any algorithm required for achieving maximum alignment within the full length of the compared sequences. However, for purposes herein, amino acid sequence identity % values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was created by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington, D.C., 20559, where it 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 written from the source code. The ALIGN-2 program has been written 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 vary.

In the case of amino acid sequence comparison using ALIGN-2, the % amino acid sequence identity of a given amino acid sequence A relative to, with, or against a given amino acid sequence B (or, it can be expressed as a given amino acid sequence A having or comprising a certain % amino acid sequence identity with a given amino acid sequence B) is calculated as follows:

100 multiplied by the fraction X/Y

wherein X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in the program's alignment of A and B, and wherein Y is the total number of amino acid residues in B. It will be understood that where 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 specifically stated otherwise, all % amino acid sequence identity values used herein are obtained using the ALIGN-2 computer program as described immediately above.

The term "pharmaceutical formulation" refers to a preparation that is in a form that permits the biological activity of the active ingredient contained therein to be effectively exerted, and does not contain additional components that are unacceptably toxic to a subject to which the preparation would be administered.

"Pharmaceutically acceptable carrier" refers to a component of a pharmaceutical preparation other than the active ingredient that is non-toxic to the subject. Pharmaceutically acceptable carriers include (but are not limited to) buffers, excipients, stabilizers or preservatives.

Unless otherwise indicated, as used herein, the term "Tau" refers to any native Tau protein from any vertebrate source, including mammals, such as primates (e.g., humans) and rodents (e.g., mice and rats). The term encompasses "full-length" unprocessed Tau as well as any form of Tau produced by processing in the cell. The term also encompasses naturally occurring Tau variants, such as splice variants or allelic variants.

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

As used herein, the term "soluble Tau" or "soluble Tau protein" refers to a protein consisting of fully soluble Tau protein/peptide monomers or Tau-like peptides/proteins, or modified or truncated Tau peptides/proteins or other derivatives of Tau peptide/protein monomers and Tau protein oligomers. "Soluble Tau" specifically excludes neurofibrillary tangles (NFTs).

As used herein, the term "insoluble Tau" refers to a plurality of aggregated Tau peptide or protein monomers, or Tau-like peptides/proteins, or modified or truncated Tau peptides/proteins, or other derivatives of Tau peptides/proteins, which form oligomeric or polymeric structures that are insoluble in aqueous media in vitro and in vivo in mammals or humans (more particularly in the brain); but in particular, it refers to a plurality of aggregated Tau monomers or modified or truncated Tau peptides/proteins, or derivatives thereof, which are insoluble in mammals or humans (more particularly in the brain), respectively. In particular, "insoluble Tau" includes neurofibrillary tangles (NFTs).

As used herein, the term "monomeric Tau" or "Tau monomer" refers to Tau protein that is completely soluble in aqueous media without aggregated complexes.

As used herein, the terms "aggregated Tau," "oligomeric Tau," and "Tau oligomer" refer to a plurality of aggregated Tau peptide or protein monomers, or Tau-like peptides/proteins, or modified or truncated Tau peptides/proteins, or other derivatives of Tau peptides/proteins, which form oligomeric or polymeric structures that are insoluble or soluble in aqueous media in vitro and in vivo in mammals or humans (more particularly in the brain); but in particular, they refer to a plurality of aggregated Tau monomers or modified or truncated Tau peptides/proteins, or derivatives thereof, which are insoluble or soluble, respectively, in mammals or humans (more particularly in the brain).

The terms "pTau PHF," "PHF," and "paired helical filaments" are used synonymously herein and refer to pairs of filaments periodically wound into a helix of 160 nm visible on electron microscopy. The width varies between 10 and 22 nm. PHF is the predominant structure in neurofibrillary tangles and neuropil threads of Alzheimer's disease (AD). PHF can also be found in some, but not all, dystrophic neurites associated with neuritic plaques. The major component of PHF is a hyperphosphorylated form of the microtubule-associated protein tau. PHF can be composed, in part, of antiparallel, hyperphosphorylated Tau proteins linked by disulfide bonds. PHF Tau can have its C-terminal 20 amino acid residues truncated. The underlying mechanism of PHF formation is uncertain, but hyperphosphorylation of Tau can cause it to dissociate from microtubules, thereby increasing the pool of soluble Tau from which PHF can form inside neurons.

As used herein, "treatment" (and grammatical variations thereof, such as "treat" or "treating") refers to clinical intervention to attempt to alter the natural course of a disease in the individual being treated, and can be performed to achieve prevention or during the course of clinical pathology. Desirable therapeutic effects include, but are not limited to, preventing the onset or recurrence of disease, alleviating symptoms, alleviating any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, ameliorating or palliating the condition of the disease, and alleviating or improving prognosis. In some embodiments, the antibodies of the invention are used to delay disease development or slow disease progression.

As used herein, the term "early Alzheimer's disease" or "early AD" (e.g., "a patient diagnosed with early AD" or "a patient suffering from early AD") includes patients with mild cognitive impairment (such as memory impairment) attributed to AD and patients with AD biomarkers, e.g., amyloid-positive patients.

The term "mild Alzheimer's disease" or "mild AD" (eg, "a patient diagnosed with mild AD") as used herein refers to a stage of AD characterized by an MMSE score of 20-26.

The term "mild to moderate Alzheimer's disease" or "mild to moderate AD" as used herein encompasses both mild and moderate AD and is characterized by an MMSE score of 18-26.

As used herein, the term "moderate Alzheimer's disease" or "moderate AD" (eg, "a patient diagnosed with moderate AD") refers to a stage of AD characterized by an MMSE score of 18-19.

The term "MMSE" refers to the Mini Mental State Examination, which provides a score between 1 and 30. See Folstein et al., 1975, J. Psychiatr. Res. 12: 189-98. Scores of 26 and below are generally considered to indicate impairment. The lower the numerical score on the MMSE, the greater the impairment or disorder of the patient being tested relative to another individual with a lower score. An increase in the MMSE score can indicate an improvement in the patient's condition, while a decrease in the MMSE score can indicate a worsening of the patient's condition.

As used herein, the term "vector" refers to a nucleic acid molecule that is capable of propagating another nucleic acid molecule to which it is linked. The term includes vectors that are self-replicating nucleic acid structures as well as vectors that are incorporated into the genome of a host cell into which they have been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operably linked. Such vectors are referred to herein as "expression vectors."

II. Compositions and Methods

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

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

A. Exemplary anti-Tau antibodies

In some embodiments, the anti-Tau antibody comprises at least one, two, three, four, five, or six HVRs selected from the group consisting of: (a) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 12, 22, 282, 292, and 342; (b) an HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 13, 23, 283, 293, and 343; (c) an HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 14, 24, 284, 294, and 344; (d) an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 15, 25, 285, 295, 345, and 468 to 556; (e) an HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 16, 26, 286, 296, and 346; and (f) an HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: HVR-L3 of the amino acid sequence of NO: 17, 27, 287, 297 and 347.

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.

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

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

In some embodiments, an anti-Tau antibody comprises (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 342; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 343; and (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 344. In some embodiments, an anti-Tau antibody comprises at least one, two, or three HVRs selected from: (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 342; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 343; and (c) an HVR-H3 comprising 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 the group consisting of: (a) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 72 and 302; (b) an HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 73 and 303; and (c) an HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 74 and 304. In some embodiments, the anti-Tau antibody comprises (a) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 72 and 302; (b) an HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 73 and 303; and (c) an HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 74 and 304.

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

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. In some embodiments, the anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, an 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. In some embodiments, an anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, an 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. In some embodiments, an anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

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.

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.

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.

In some embodiments, an 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: 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, an 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.

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: 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.

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: 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-H3 comprising the amino acid sequence of SEQ ID NO: 274.

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. In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, an 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. In some embodiments, an anti-Tau antibody comprises (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.

In some embodiments, an 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. In some embodiments, an anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, an 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. In some embodiments, an anti-Tau antibody comprises (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.

In some embodiments, an 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. In some embodiments, an anti-Tau antibody comprises (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.

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

In some embodiments, an 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. In some embodiments, an anti-Tau antibody comprises (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.

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

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

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. In some embodiments, the anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, an 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, an 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.

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.

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.

In some embodiments, an 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. In some embodiments, an anti-Tau antibody comprises (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.

In some embodiments, an 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. In some embodiments, an anti-Tau antibody comprises (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.

In some embodiments, an 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. In some embodiments, an anti-Tau antibody comprises (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.

In some embodiments, an 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. In some embodiments, an anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, an 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. In some embodiments, an anti-Tau antibody comprises (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.

In some embodiments, an 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. In some embodiments, an anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, an 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. In some embodiments, an anti-Tau antibody comprises (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.

In some embodiments, an 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. In some embodiments, an anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, an 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. In some embodiments, an anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, an 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. In some embodiments, an anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, an 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. In some embodiments, an anti-Tau antibody comprises (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.

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. In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, an 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. In some embodiments, an anti-Tau antibody comprises (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.

In some embodiments, an 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. In some embodiments, an anti-Tau antibody comprises (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.

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

In some embodiments, the anti-Tau antibody comprises (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.

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

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

In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, the anti-Tau antibody comprises (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.

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; (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.

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; (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.

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; (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.

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; (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.

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; (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.

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; (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.

In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, the anti-Tau antibody comprises (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.

In some embodiments, the anti-Tau antibody comprises (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.

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

In another aspect, the anti-Tau antibody comprises a heavy chain variable domain (VH) sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 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 relative to a reference sequence contains substitutions (e.g., conservative substitutions), insertions, or deletions, but an anti-Tau antibody comprising such a sequence retains the ability to bind to Tau. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in SEQ ID NO: 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, the substitution, insertion, or deletion occurs in a region outside of the HVR (i.e., in the FR). Optionally, the anti-Tau antibody comprises a VH sequence in SEQ ID NO: 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 said sequence. In a specific embodiment, VH comprises one, two or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 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) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 1 NO: 13, 23, 33, 43, 53, 63, 73, 83, 93, 100, 113, 123, 133, 143, 153, 163, 173, 183, 193, 203, 213, 223, 233, 243, 253, 263, 273, 283, 293, 303, 313, 323, 333 or 343, and (c) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 13, 23, 33, 43, 53, 63, 73, 83, 93, 100, 113, 123, 133, 143, 153, 163, 173, 183, 193, 203, 213, 223, 233, 243, 253, 263, 273, 283, 293 HVR-H3 of the amino acid sequence of NO: 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.

In another aspect, the anti-Tau antibody comprises a light chain variable domain (VL) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 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 relative to a reference sequence contains substitutions (e.g., conservative substitutions), insertions or deletions, but an anti-Tau antibody comprising said sequence retains the ability to bind to Tau. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 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, the substitution, insertion, or deletion occurs in a region outside of the HVR (i.e., in the FR). Optionally, the anti-Tau antibody comprises a VL sequence in SEQ ID NO: 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 said sequence. In a specific embodiment, VL comprises one, two, or three HVRs selected from: (a) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 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) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: NO: 16, 26, 36, 46, 56, 66, 76, 86, 96, 106, 116, 126, 136, 146, 156, 166, 176, 186, 196, 206, 216, 226, 236, 246, 266, 266, 276, 286, 296, 306, 316, 326, 336 or 346, and (c) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16, 26, 36, 46, 56, 66, 76, 86, 196, 206, 216, 226, 236, 246, HVR-L3 having an amino acid sequence of NO: 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.

In another aspect, an anti-Tau antibody is provided, wherein the antibody comprises a VH as in any of the embodiments provided above and a VL 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 antibodies comprise 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 antibodies comprise the VH and VL sequences in SEQ ID NO: 340 and SEQ ID NO: 341, respectively, including post-translational modifications of those sequences.

In some embodiments, an anti-Tau antibody is provided, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 348 or SEQ ID NO: 602 and a light chain comprising the amino acid sequence of SEQ ID NO: 349. In some embodiments, an anti-Tau antibody is provided, wherein the antibody comprises 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 another aspect, the present invention provides an antibody that binds to the same epitope as an anti-Tau antibody provided herein. For example, in certain embodiments, 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 certain embodiments, an antibody is provided that binds to an epitope within a Tau fragment consisting of amino acids 2-24 of SEQ ID NO: 2. In certain embodiments, an antibody is provided that binds to an epitope within a Tau fragment consisting of amino acids 7-24 of SEQ ID NO: 2. In certain embodiments, an antibody is provided that binds to an epitope within a Tau fragment consisting of amino acids 7-20 of SEQ ID NO: 2. In certain embodiments, an antibody is provided that binds to an epitope within a Tau fragment consisting of amino acids 10-24 of SEQ ID NO: 2. In certain embodiments, an antibody is provided that binds to an epitope within a Tau fragment consisting of amino acids 7-21 of SEQ ID NO: 2. In certain embodiments, antibodies are provided that bind to an epitope within a Tau fragment consisting of amino acids 8-22 of SEQ ID NO: 2. In certain embodiments, antibodies are provided that bind to an epitope within a Tau fragment consisting of amino acids 11-25 of SEQ ID NO: 2. In certain embodiments, antibodies are provided that bind to one or more or all of the following Tau fragments: 2-24, 7-24, 7-20, 10-24, 7-21, 8-22, and 11-25. In some embodiments, antibodies are provided that bind 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.

In another aspect of the invention, the anti-Tau antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric antibody, a humanized antibody, or a human antibody. In one embodiment, the anti-Tau antibody is an antibody fragment, such as an Fv, Fab, Fab', scFv, a diabody, or a F(ab') ₂ fragment. In another embodiment, the antibody is a full-length antibody, such as a complete IgG1 or IgG4 antibody, or other antibody classes or isotypes as defined herein.

In another aspect, the anti-Tau antibody according to any of the above embodiments may incorporate any of the features, singly or in combination, as described in Sections 1 to 7 below.

1. Antibody affinity

In certain embodiments, the dissociation constant ( _KD ) of an antibody provided herein is ≤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, e.g., 10 ^{"8 M} to 10 ^"13 M, e.g., 10 ^"9 M to 10 ^"13 M).

In some embodiments, _KD is measured by a radiolabeled antigen binding assay (RIA). In some embodiments, the RIA is performed with a Fab version of the antibody of interest and its antigen. For example, the solution binding affinity of a Fab for an antigen is measured by equilibrating the Fab with a minimal concentration of ( ¹²⁵ I)-labeled antigen in the presence of a titration series of unlabeled antigen, followed by capturing the bound antigen with a culture plate coated with an anti-Fab antibody (see, e.g., Chen et al., J. Mol. Biol. 293:865-881 (1999)). To establish assay conditions, multiwell culture plates (ThermoScientific) were 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% (w/v) bovine serum albumin in PBS for two to five hours at room temperature (approximately 23° C.). In a non-adsorbent culture plate (Nunc #269620), 100 pM or 26 pM [ ^125I ] antigen is mixed with a serial dilution of the target Fab (e.g., consistent with the evaluation of the anti-VEGF antibody Fab-12, Presta et al., Cancer Res. 57:4593-4599 (1997)). The target Fab is then incubated overnight; however, the incubation can be continued for a longer period of time (e.g., 65 hours) to ensure that equilibrium is reached. Thereafter, the mixture is transferred to a capture culture plate for incubation at room temperature (e.g., for one hour). The solution is then removed and the culture plate is washed eight times with PBS containing 0.1% polysorbate 20. When the culture plate has dried, 150 μl/well of scintillant (MICROSCINT-20 ^™ ; Packard) is added and the culture plate is counted for 10 minutes on a TOPCOUNT ^™ gamma counter (Packard). Concentrations of each Fab that provide less than or equal to 20% of maximal binding are selected for competitive binding assays.

According to another embodiment, _KD is measured using surface plasmon resonance. For example, the assay is performed using a BIAcore-2000 or -3000 (BIAcore, Inc., Piscataway, NJ) at 25°C with an immobilized antigen CM5 chip at approximately 10 resonance units (RU). 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. 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 approximately 10 resonance units (RU) of coupled protein. Following antigen injection, 1 M ethanolamine is injected to block unreacted groups. For kinetic measurements, two-fold serial dilutions of Fab (0.78 nM to 500 nM) in PBS containing 0.05% polysorbate 20 (TWEEN-20 ^™ ) surfactant (PBST) were injected at 25°C at a flow rate of approximately 25 μl/min. Association rates ( _kon ) and dissociation rates ( _koff ) were calculated by simultaneous fitting of the association and dissociation sensorgrams using a simple one-to-one Langmuir binding model (Evaluation software version 3.2). The equilibrium dissociation constant ( _KD ) was calculated as the ratio _koff / _kon . See, e.g., Chen et al., J. Mol. Biol. 293:865-881 (1999). If the association rate determined by surface plasmon resonance analysis described above exceeds 10 ⁶ M ^-1 s ^-1 , the association rate can be determined by using a fluorescence quenching technique that measures the increase or decrease in fluorescence emission intensity (excitation = 295 nm; emission = 340 nm, 16 ^nm bandpass) of 20 nM anti-antigen antibody (Fab form) in PBS (pH 7.2) at 25°C in the presence of increasing concentrations of antigen as measured in a spectrometer such as a stop-flow equipped spectrophotometer with a stirred cell (Aviv Instruments) or an 8000-series SLM-AMINCO™ spectrophotometer (ThermoSpectronic).

2. Antibody fragments

In certain embodiments, the antibodies provided herein are antibody fragments. Antibody fragments include, but are not limited to, Fab, Fab', Fab'-SH, F(ab') ₂ , Fv, and scFv fragments, and other fragments described below. For a review of certain antibody fragments, see Hudson et al., Nat. Med. 9: 129-134 (2003). For a review of scFv fragments, see, for example, Pluckthün, The Pharmacology of Monoclonal Antibodies, Vol. 113, Rosenburg and Moore, eds. (Springer-Verlag, New York), pp. 269-315 (1994); see also WO 93/16185; and U.S. Pat. Nos. 5,571,894 and 5,587,458. For a discussion of Fab and F(ab') ₂ fragments comprising salvage receptor binding epitope residues and having extended in vivo half-lives, see U.S. Pat. No. 5,869,046.

Diabodies are antibody fragments with two antigen-binding sites, which can be bivalent or bispecific. See, for example, EP 404,097; WO 1993/01161; Hudson et al., Nat. Med. 9:129-134 (2003); and Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al., Nat. Med. 9:129-134 (2003).

Single-domain antibodies are antibody fragments that contain all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In certain embodiments, a single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, MA; see, e.g., U.S. Patent No. 6,248,516 Bl).

Antibody fragments can be made by a variety of techniques, including, but not limited to, proteolytic digestion of intact antibodies and production by recombinant host cells (eg, E. coli or phage), as described herein.

3. Chimeric and humanized antibodies

In certain embodiments, the antibodies provided herein are chimeric antibodies. Certain chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81: 6851-6855 (1984). In one embodiment, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate (such as a monkey)) and a human constant region. In another embodiment, a chimeric antibody is a "class-switched" antibody, in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.

In certain embodiments, chimeric antibodies are humanized antibodies. Typically, non-human antibodies are humanized to reduce immunogenicity to people while retaining the specificity and affinity of the parent non-human antibody. In general, humanized antibodies include one or more variable domains, wherein HVR, such as CDR (or a portion thereof) are derived from non-human antibodies, and FR (or a portion thereof) are derived from human antibody sequences. Humanized antibodies optionally also include at least a portion of a human constant region. In some embodiments, some FR residues in humanized antibodies are replaced with corresponding residues from non-human antibodies (e.g., antibodies from which HVR residues are derived) to, for example, restore or improve antibody specificity or affinity.

Humanized antibodies and methods for making them are reviewed, for example, in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and further described, for example, in Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989); U.S. Pat. Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describing specificity determining region (SDR) grafting); Padlan, Mol. Immunol. 28:489-498 (1991) (describing “resurfacing”); Dall'Acqua et al., Methods 36:43-60 (2005) (describing “FR shuffling”); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describing the “guided selection” method of FR shuffling).

Human framework regions that can be used for humanization include, but are not limited to, framework regions selected using the "best-fit" method (see, e.g., Sims et al., J. Immunol. 151: 2296 (1993)); framework regions derived from the consensus sequence of human antibodies having a particular subgroup of light or heavy chain variable regions (see, e.g., Carter et al., Proc. Natl. Acad. Sci. USA, 89: 4285 (1992); and Presta et al., J. Immunol., 151: 2 623 (1993)); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)); and framework regions derived from screening FR libraries (see, e.g., Baca et al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996)).

4. Human Antibodies

In certain embodiments, the antibodies provided herein are human antibodies. Various techniques known in the art can be used to generate human antibodies. 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).

Human antibodies can be prepared by administering immunogens to transgenic animals that have been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge. Such animals typically contain all or part of the human immunoglobulin loci, which replace the endogenous immunoglobulin loci, or are present extrachromosomally or randomly integrated into the animal chromosomes. In such transgenic mice, the endogenous immunoglobulin loci are generally inactivated. For a review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23: 1117-1125 (2005). See also, for example, U.S. Patents 6,075,181 and 6,150,584 describing XENOMOUSE ^™ technology; U.S. Patent 5,770,429 describing technology; U.S. Patent 7,041,870 describing KM technology; and U.S. Patent Application Publication No. US2007/0061900 describing technology. The human variable regions of intact antibodies produced by such animals can be further modified, for example, by combining with different human constant regions.

Human antibodies can also be made by hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies have been described. (See, e.g., 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 Boemer et al., J. Immunol., 147:86 (1991).) Human antibodies produced via human B-cell hybridoma technology are also described in Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Other methods include, for example, those described in U.S. Pat. No. 7,189,826 (describing the production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (describing 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).

Human antibodies can also be produced by isolating Fv pure line variable domain sequences selected from human phage display libraries. Such variable domain sequences can then be combined with desired human constant domains. The following describes techniques for selecting human antibodies from antibody libraries.

5. Library-derived antibodies

The antibodies of the present invention can be isolated by screening combinatorial libraries for antibodies having the desired activity or activities. For example, a variety of methods are known in the art for generating phage display libraries and screening such libraries for antibodies having the desired binding characteristics. Such methods are reviewed, for example, in Hoogenboom et al., Methods in Molecular Biology 178: 1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001), and further described, for example, in 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, 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., J. Mol. Biol. 340(5):1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101(34):12467-12472 (2004); and Lee et al., J. Immunol. Methods 284(1-2):119-132 (2004).

In certain phage display methods, repertoires of VH and VL genes are cloned separately by polymerase chain reaction (PCR) and randomly recombined in phage libraries, which can then be screened for antigen binding phage as described in Winter et al., Ann. Rev. Immunol. 12: 433-455 (1994). Phage typically display antibody fragments in the form of single-chain Fv (scFv) fragments or Fab fragments. Libraries from immune sources provide high-affinity antibodies against the immunogen without the need to construct hybridomas. Alternatively, the original repertoire (e.g., from humans) can be cloned to provide a single source of antibodies against a wide variety of non-self antigens as well as self antigens without the need for any immunization, as described in Griffiths et al., EMBO J, 12: 725-734 (1993). Finally, primary libraries can also be made synthetically by cloning unrearranged V gene segments from stem cells and using PCR primers containing random sequences to encode the hypervariable CDR3 regions and to achieve in vitro rearrangement, as described by Hoogenboom and Winter, J. Mol. Biol., 227: 381-388 (1992). Patent publications describing human antibody phage libraries include, for example, U.S. Patent No. 5,750,373 and U.S. Patent Publication Nos. 2005/0079574, 2005/0119455, 2005/0266000, 2007/0117126, 2007/0160598, 2007/0237764, 2007/0292936, and 2009/0002360.

Antibodies or antibody fragments isolated from human antibody libraries are considered human antibodies or human antibody fragments herein.

6. Multispecific Antibodies

In certain embodiments, the antibodies provided herein are multispecific antibodies, such as bispecific antibodies. Multispecific antibodies are monoclonal antibodies that have binding specificity for at least two different sites. In certain embodiments, one of the binding specificities is for Tau and the other is for any other antigen. In certain embodiments, one of the binding specificities is for Tau and the other is for amyloid beta. In certain embodiments, bispecific antibodies can bind to two different epitopes of Tau. Bispecific antibodies can also be used to localize cytotoxic agents on cells expressing Tau. Bispecific antibodies can be prepared in the form of full-length antibodies or antibody fragments.

Techniques for making multispecific antibodies include, but are not limited to, recombinant co-expression of two immunoglobulin heavy chain-light chain pairs with different specificities (see Milstein and Cuello, Nature 305:537 (1983)), WO 93/08829, and Traunecker et al., EMBO J. 10:3655 (1991)), and "knob-in-hole" engineering (see, e.g., U.S. Pat. No. 5,731,168). Multispecific antibodies can also be made by engineering electrostatic director effects for making antibody Fc-heterodimeric molecules (WO 93/08829). 2009/089004A1); cross-linking two or more antibodies or fragments (see, e.g., U.S. Patent No. 4,676,980 and Brennan et al., Science, 229:81 (1985)); using leucine zippers to produce bispecific antibodies (see, e.g., Kostelny et al., J. Immunol., 148(5):1547-1553 (1992)); using "double-chain" antibodies for making bispecific antibody fragments. and preparation of trispecific antibodies as described in, for example, Tutt et al., J. Immunol. 147:60 (1991).

Also included herein are engineered antibodies with three or more functional antigen binding sites, including "Octopus antibodies" (see, eg, US 2006/0025576A1).

The antibodies or fragments herein also include "dual-acting FAbs" or "DAFs," which comprise antigen binding sites that bind to Tau as well as another, different antigen (see, eg, US 2008/0069820).

7. Antibody variants

In certain embodiments, the amino acid sequence variants of the antibody provided herein are encompassed. For example, the binding affinity and/or other biological properties of the improved antibody may need to be improved. The amino acid sequence variants of the antibody can be prepared by introducing suitable modifications into the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, the disappearance and/or insertion and/or replacement of the residue in the amino acid sequence of the antibody. Any combination of disappearance, insertion and replacement can be carried out to obtain the final construct, with the limiting condition that the final construct has the desired characteristics, for example, antigen binding.

a) Substitution, insertion and deletion variants

In certain embodiments, antibody variants having one or more amino acid substitutions are provided. Target sites for substitution-type mutagenesis include HVRs and FRs. 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 with reference to amino acid side chain classes. Amino acid substitutions can be introduced into the target antibody, and the product can be screened for desired activity, such as retained/improved antigen binding, reduced immunogenicity, or improved ADCC or CDC.

Table 1

Amino acids can be grouped according to shared side chain properties:

(1) Hydrophobicity: norleucine, Met, Ala, Val, Leu, Ile;

(2) Neutral hydrophilicity: Cys, Ser, Thr, Asn, Gln;

(3) Acidic: Asp, Glu;

(4) Basic: His, Lys, Arg;

(5) Residues that affect chain orientation: Gly, Pro;

(6) Aromatic: Trp, Tyr, Phe.

Non-conservative substitutions will necessarily entail exchanging a member of one of these classes for another class.

One type of substitution variant involves replacing one or more hypervariable region residues of a parent antibody (e.g., a humanized antibody or a human antibody). In general, the resulting variant selected for further study will have modifications (e.g., improvements) in certain biological properties relative to the parent antibody (e.g., increased affinity, reduced immunogenicity) and/or will substantially retain certain biological properties of the parent antibody. An exemplary substitution variant is an affinity matured antibody, which can be conveniently produced, for example, using affinity maturation techniques based on phage display (such as those described herein). In short, one or more HVR residues are mutated, and the variant antibodies are displayed on phage and screened for a specific biological activity (e.g., binding affinity).

Changes (e.g., substitutions) can be made in HVRs to, for example, improve antibody affinity. Such changes can be made in HVR "hot spots" (i.e., residues encoded by codons that undergo high frequency mutations during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207: 179-196 (2008)), and/or residues that contact the antigen), where the resulting variant VH or VL is tested for binding affinity. Affinity maturation by constructing and reselecting from secondary libraries has been described in Hoogenboom et al., Methods in Molecular Biology 178: 1-37 (O'Brien et al., eds., Human Press, Totowa, NJ, (2001)). In some embodiments of affinity maturation, diversity is introduced into the variable genes selected for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then generated. This library is then screened to identify any antibody variants with the desired affinity. Another approach to introduce diversity involves the 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. In particular, CDR-H3 and CDR-L3 are often targeted.

In certain embodiments, substitutions, insertions or deletions may occur within one or more HVRs, as long as such changes do not substantially reduce the ability of the antibody to bind to the antigen. For example, conservative changes that do not substantially reduce binding affinity (e.g., conservative substitutions as provided herein) may be made in the HVRs. Such changes may, for example, be made outside of residues that contact the antigen in the HVRs. In certain embodiments of the variant VH and VL sequences provided above, each HVR is unchanged or contains no more than one, two, or three amino acid substitutions.

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

Amino acid sequence insertions include amino- and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing one hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include antibodies with an N-terminal methionyl residue. Other insertional variants of the antibody molecule include fusions of the N- or C-terminus of the antibody to an enzyme (e.g., for ADEPT) or a polypeptide that increases the serum half-life of the antibody.

b) Glycosylation variants

In certain embodiments, the antibodies provided herein are altered to increase or decrease the degree of antibody glycosylation. Adding glycosylation sites to an antibody or deleting glycosylation sites from an antibody can be conveniently achieved by altering the amino acid sequence to create or remove one or more glycosylation sites.

In the case where the antibody comprises an Fc region, the carbohydrate attached thereto can be changed. Native antibodies produced by mammalian cells typically contain branched biantennary oligosaccharides, which are generally attached to Asn297 of the CH2 domain of the Fc region via an N-bond. See, for example, Wright et al. TIBTECH 15: 26-32 (1997). Oligosaccharides can include various carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as trehalose attached to the GlcNAc in the "backbone" of the biantennary oligosaccharide structure. In some embodiments, the oligosaccharides in the antibodies of the present invention can be modified to produce antibody variants with certain improved properties.

In some embodiments, antibody variants are provided that lack carbohydrate structures that are attached (directly or indirectly) to the Fc region. For example, the amount of trehalose in such antibodies may be 1% to 80%, 1% to 65%, 5% to 65%, or 20% to 40%. The amount of trehalose is determined by calculating the average amount of trehalose at Asn297 within the sugar chain relative to the sum of all sugar structures (e.g., complex, hybrid, and high mannose structures) attached to Asn 297 as measured by MALDI-TOF mass spectrometry, as described, for example, in WO 2008/077546. Asn297 refers to the asparagine residue located at approximately position 297 in the Fc region (Eu numbering of Fc region residues); however, due to minor sequence variations in antibodies, Asn297 may also be located approximately ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300. Such trehalose variants may have improved ADCC function. See, e.g., U.S. Patent Publication Nos. US 2003/0157108 (Presta, L.); US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications on "defucosylated" or "fucosylated" antibody variants include: US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614; US 2002/0164328; US 2004/0093621; US 2004/0132140; US 2004/0110704; US 2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO 2005/035586; WO 2005/035778; WO2005/053742; WO2002/031140; Okazaki et al. J. Mol. Biol. 336: 1239-1249 (2004); 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. US 2003/0157108 A1, Presta, L; and WO 2004/056312 A1, Adams et al., particularly Example 11), and gene knockout cell lines, such as α-1,6-fucosyltransferase gene (FUT8) gene knockout CHO cells (see, e.g., Yamane-Ohnuki et al., Biotech. Bioeng. 87: 614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4): 680-688 (2006); and WO 2003/085107).

Antibody variants further have oligosaccharides that are cut into two parts, for example, biantennary oligosaccharides attached to the Fc region of the antibody are cut into two parts by GlcNAc. Such antibody variants may have reduced fucosylation and/or improved ADCC function. Examples of such antibody variants are described in, for example, WO 2003/011878 (Jean-Mairet et al.); U.S. Patent No. 6,602,684 (Umana et al.); and US 2005/0123546 (Umana et al.). Antibody variants in which at least one galactose residue in the oligosaccharide is attached to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described in, for example, WO 1997/30087 (Patel et al.); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.).

c) Fc region variants

In certain embodiments, one or more amino acid modifications can be introduced into the Fc region of an antibody provided herein, thereby generating an Fc region variant. An Fc region variant can comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3, or IgG4 Fc region) comprising an amino acid modification (e.g., substitution) at one or more amino acid positions.

In certain embodiments, the present invention encompasses antibody variants with some, but not all, effector functions, making the antibodies desirable candidates for applications where in vivo antibody half-life is critical, while certain effector functions (such as complement and ADCC) are unnecessary or deleterious. In vitro and/or in vivo cytotoxicity assays can be performed to confirm reduction/depletion of CDC and/or ADCC activity. For example, Fc receptor (FcR) binding assays can be performed to ensure that the antibody lacks FcγR binding (and therefore may lack ADCC activity), but retains FcRn binding ability. NK cells, the primary cells used to mediate ADCC, express only FcγRIII, while monocytes express FcγRI, FcγRII, and FcγRIII. The expression of FcRs 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 ADCC activity of target molecules are described in U.S. Pat. Nos. 5,500,362 (see, e.g., 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 5,821,337 (see, e.g., Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-radioactive assays can be employed (see, e.g., ACTI ^™ Non-Radioactive Cytotoxicity Assay for Flow Cytometry (Cell Technology, Inc. Mountain View, CA); and CytoTox Non-Radioactive Cytotoxicity Assay (Promega, Madison, WI)). Suitable effector cells for such assays include peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells. Alternatively or additionally, ADCC activity of the target molecule can be assessed in vivo, for example, in an animal model such as that disclosed in Clynes et al., Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). C1q binding assays can also be performed to confirm that the antibody cannot bind to C1q and therefore lacks CDC activity. See, for example, C1q and C3c binding ELISAs in WO 2006/029879 and WO 2005/100402. To assess complement activation, a CDC assay can be performed (see, e.g., Gazzano-Santoro et al., J. Immunol. Methods 202: 163 (1996); Cragg, MS et al., Blood 101: 1045-1052 (2003); and Cragg, MS and MJ Glennie, Blood 103: 2738-2743 (2004)). FcRn binding and in vivo clearance/half-life assays can also be performed using methods known in the art (see, e.g., Petkova, SB et al., Int'l. Immunol. 18(12): 1759-1769 (2006)).

Antibodies with reduced effector function include those with substitutions of one or more of Fc region residues 238, 265, 269, 270, 297, 327, and 329 ( U.S. Pat. No. 6,737,056 ). Such Fc mutants include Fc mutants with substitutions of two or more of amino acid positions 265, 269, 270, 297, and 327, including the so-called "DANA" Fc mutant in which residues 265 and 297 are substituted with alanine ( U.S. Pat. No. 7,332,581 ).

Certain antibody variants with improved or diminished binding to FcRs are described (see, e.g., U.S. Patent No. 6,737,056; WO 2004/056312 and Shields et al., J. Biol. Chem. 9(2): 6591-6604 (2001)).

In certain embodiments, the antibody variant comprises an Fc region with one or more amino acid substitutions that improve ADCC, such as substitutions at positions 298, 333, and/or 334 of the Fc region (EU numbering of residues).

In some embodiments, alterations are made in the Fc region that result in altered (i.e., improved or reduced) C1q binding and/or complement-dependent cytotoxicity (CDC), e.g., as described in U.S. Patent No. 6,194,551, WO 99/51642, and Idusogie et al. J. Immunol. 164:4178-4184 (2000).

Antibodies with increased half-life and improved binding to the neonatal Fc receptor (FcRn), which is responsible for the transfer of maternal IgG to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)), are described in US 2005/0014934 A1 (Hinton et al.). These antibodies comprise an Fc region having one or more substitutions therein that improve binding of the Fc region to FcRn. Such Fc variants include those having substitutions at one or more of the following 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, e.g., substitution of Fc region residue 434 ( U.S. Pat. No. 7,371,826 ).

For other examples of Fc region variants, see also Duncan and Winter, Nature 322:738-40 (1988); U.S. Patent No. 5,648,260; U.S. Patent No. 5,624,821; and WO 94/29351.

d) Cysteine-engineered antibody variants

In certain embodiments, it may be desirable to produce antibodies engineered with cysteine, such as "thioMAbs," in which one or more residues of an antibody are substituted with cysteine residues. In a specific embodiment, the substituted residues are present at accessible sites of the antibody. By replacing those residues with cysteine, reactive thiol groups are located at accessible sites of the antibody and can be used to bind the antibody to other moieties (such as drug moieties or linker-drug moieties) to produce immunoconjugates as further described herein. In certain embodiments, any 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-engineered antibodies can be produced as described, for example, in U.S. Patent No. 7,521,541.

e) Antibody derivatives

In certain embodiments, the antibodies provided herein may be further modified to contain additional non-proteinaceous moieties known in the art and readily available. Suitable moieties for antibody derivatization include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol/propylene glycol copolymers, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene/maleic anhydride copolymers, polycyanoacetic acid (homopolymer or random copolymer) and dextran or poly(n-vinyl pyrrolidone) polyethylene glycol, polypropylene glycol homopolymer, polyoxypropylene/ethylene oxide copolymers, polyoxyethylene polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water. The polymer may have any molecular weight and may be branched or unbranched. The number of polymers attached to the antibody can vary, and if more than one polymer is attached, they can be the same or different molecules. In general, the number and/or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the specific properties or functions of the antibody to be modified, whether the antibody derivative will be used for therapy under a specific condition, and the like.

In another embodiment, a conjugate of an antibody with a non-protein moiety that can be selectively heated by exposure to radiation is provided. In some embodiments, the non-protein moiety is a carbon nanotube (Kam et al., Proc. Natl. Acad. Sci. USA 102: 11600-11605 (2005)). The radiation can be of any wavelength and includes, but is not limited to, a wavelength that does not damage normal cells but heats the non-protein moiety to a temperature that kills cells proximal to the antibody-non-protein moiety.

B. Recombinant Methods and Compositions

Antibodies can be produced using, for example, recombinant methods and compositions as described in U.S. Patent No. 4,816,567. In some embodiments, an isolated nucleic acid encoding an anti-Tau antibody described herein is provided. Such nucleic acids may encode an amino acid sequence comprising the VL of the antibody and/or an amino acid sequence comprising the VH of the antibody (e.g., a light chain and/or a heavy chain of the antibody). In another embodiment, one or more vectors (e.g., expression vectors) comprising such nucleic acids are provided. In another embodiment, a host cell comprising such nucleic acids is provided. In one such embodiment, the host cell comprises (e.g., has been transformed as follows): (1) a vector comprising a nucleic acid encoding an amino acid sequence comprising the VL of the antibody and an amino acid sequence comprising the VH of the antibody; or (2) a first vector comprising a nucleic acid encoding an amino acid sequence comprising the VL of the antibody and a second vector comprising a nucleic acid encoding an amino acid sequence comprising the VH of the antibody. In some embodiments, the host cell is a eukaryotic cell, such as a Chinese hamster ovary (CHO) cell or a lymphocyte (e.g., a Y0, NS0, Sp20 cell). In some embodiments, a method of making an anti-Tau antibody is provided, wherein the method comprises culturing a host cell comprising a nucleic acid encoding the antibody as provided above under conditions suitable for expression of the antibody, and optionally recovering the antibody from the host cell (or host cell culture medium).

For recombinant production of anti-Tau antibodies, nucleic acids encoding antibodies, 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 genes encoding the heavy and light chains of the antibody).

Host cells suitable for cloning or expressing vectors encoding antibodies include prokaryotic or eukaryotic cells described herein. For example, antibodies can be produced in bacteria, especially when glycosylation and Fc effector functions are not required. For expression of antibody fragments and polypeptides in bacteria, see, for example, U.S. Patents Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254, which describes expression of antibody fragments in E. coli.) After expression, the antibody can be separated from the bacterial cell paste in a soluble fraction and can be further purified.

In addition to prokaryotes, eukaryotic microorganisms such as filamentous fungi or yeast are suitable cloning or expression hosts for antibody-encoding vectors, including fungi and yeast strains whose glycosylation pathways have been "humanized" so that the antibodies produced have a partially or fully human glycosylation pattern. See Gerngross, Nat. Biotech. 22: 1409-1414 (2004) and Li et al., Nat. Biotech. 24: 210-215 (2006).

Suitable host cells for expressing glycosylated antibodies also come from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Numerous baculovirus strains have been identified that can be used in conjunction with insect cells, particularly for transfecting Spodoptera frugiperda cells.

Plant cell cultures can also be used as hosts. See, for example, U.S. Patent Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (describing PLANTIBODIES ^™ technology for producing antibodies in transgenic plants).

Vertebrate cells can also be used as hosts. For example, mammalian cell lines adapted for growth in suspension may be suitable. Other examples of suitable mammalian host cell lines are monkey kidney CV1 cells transformed with SV40 (COS-7); human embryonic kidney cell lines (such as 293 or 293 cells as described, for example, in Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK); mouse Sertoli cells (such as TM4 cells as described, for example, in Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK); buffalo rat liver cells (BRL 3A); human lung cells (W138); human hepatocytes (Hep G2); mouse mammary tumor (MMT 060562); as described, for example, in Mather et al., Annals of TRI cells described in N.Y. Acad. Sci. 383:44-68 (1982); MRC 5 cells; and FS4 cells. Other suitable mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR-CHO cells (Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)); and myeloma cell lines such as Y0, NS0, and Sp2/0. For a review of certain mammalian host cell lines suitable for antibody production, see, for example, Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, NJ), pp. 255-268 (2003).

C. Determination

The anti-Tau antibodies provided herein can be identified, screened, or characterized for their physical/chemical properties and/or biological activities by various assays known in the art.

1. Binding Assays and Other Assays

In one aspect, the antibodies of the invention are tested for antigen binding activity, e.g., by known methods such as ELISA, Western blotting, and the like.

In another aspect, competition assays 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) as that bound by 94B2-C1, 125B11-H3, 37D3-H9, or hu37D3-H9.v28.A4. Detailed exemplary methods for mapping epitopes bound by antibodies are provided in Morris (1996) "Epitope Mapping Protocols," in Methods in Molecular Biology, Vol. 66 (Humana Press, Totowa, NJ).

In an exemplary competition assay, immobilized Tau (such as monomeric Tau) is incubated in a solution comprising a first labeled antibody (e.g., any of the antibodies described herein, such as hu37D3-H9.v28.A4) that binds to Tau and a second unlabeled antibody being 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 comprising the first labeled antibody but without the second unlabeled antibody. Following incubation under conditions permissive for binding of the first antibody to Tau, excess unbound antibody is removed, and the amount of label associated with the immobilized Tau is measured. If the amount of label associated with immobilized Tau in the test sample is substantially reduced relative to that in 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, Chapter 14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY).

2. Activity Assay

In one aspect, an assay for identifying anti-Tau (e.g., pan-Tau) antibodies with biological activity is provided. Biological activity may include, for example, binding of such antibodies to various forms of Tau (e.g., monomeric Tau, oligomeric Tau, non-phosphorylated Tau, and phosphorylated Tau) and reducing the level of Tau protein (e.g., in the brain, such as total Tau in the cerebral cortex and/or hippocampus, total soluble Tau, soluble non-phosphorylated Tau, soluble phosphorylated Tau, total insoluble Tau, insoluble non-phosphorylated Tau, insoluble phosphorylated Tau, hyperphosphorylated Tau, or paired helical filaments containing hyperphosphorylated Tau). Antibodies with such biological activity in vivo and/or in vitro are also provided.

In certain embodiments, the present invention is tested for such biological activity of the antibody. For example, the animal model of tau disease, such as Tau transgenic mice (such as P301L) can be used to detect the combination of anti-Tau antibodies and brain slices, and for example with the combination of neurofibrillary tangles in the transgenic mouse brain. In addition, the animal model of tau disease, such as Tau transgenic mice (such as P301L) can be processed with anti-Tau antibodies, and known experimental techniques in the art can be used to assess whether such treatment reduces the level of Tau protein (such as total Tau, total soluble Tau, soluble phosphorylated Tau, soluble non-phosphorylated Tau, total insoluble Tau, insoluble phosphorylated Tau, insoluble non-phosphorylated Tau, superphosphorylated Tau or paired helical filaments containing superphosphorylated Tau) in the mouse brain.

D. Immunoconjugates

The present invention also provides immunoconjugates comprising an anti-Tau antibody described herein in combination with one or more other therapeutic agents or radioisotopes.

In another embodiment, the immunoconjugate comprises an antibody as described herein that is bound to a radioactive atom to form a radioconjugate. A variety of radioisotopes are available for use in producing radioconjugates. Examples include At ²¹¹ , I ¹³¹ , I ¹²⁵ , Y ⁹⁰ , Re ¹⁸⁶ , Re ¹⁸⁸ , Sm ¹⁵³ , Bi ²¹² , P ³² , Pb ²¹² and radioisotopes of Lu. When the radioconjugate is used for detection, it may comprise a radioactive atom for scintigraphic studies, such as tc99m or 1123; or a spin label for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, mri), such as iodine-123, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese or iron.

Conjugates of antibodies can be made using a variety of bifunctional protein coupling agents, such as N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP), succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl diimidoadipate hydrochloride), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis(p-azidobenzoyl)hexanediamine), bis-diazonium derivatives (such as bis(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin 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 WO 94/11026. The linker can be a "cleavable linker" that facilitates release of the cytotoxic drug in the cell. For example, an acid-labile linker, a peptidase-sensitive linker, a photolabile linker, a dimethyl linker, or a linker containing a disulfide bond can be used (Chari et al., Cancer Res. 52:127-131 (1992); U.S. Pat. No. 5,208,020).

The immunoconjugates or ADCs herein specifically encompass, but are not limited to, such conjugates prepared with cross-linking reagents including, but 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, and SVSB (succinimidyl-(4-vinylsulfone)benzoate), which are commercially available (e.g., from Pierce Biotechnology, Inc., Rockford, IL., U.S.A.).

E. Methods and compositions for diagnosis and detection

In certain embodiments, any of the anti-Tau antibodies provided herein are suitable for detecting the presence of Tau in a biological sample. As used herein, the term "detection" encompasses quantitative or qualitative detection. In certain embodiments, the biological sample comprises cells or tissues, such as cerebrospinal fluid, brain cells or tissues (e.g., cerebral cortex or hippocampus), or blood. In some embodiments, the biological sample is cerebrospinal fluid.

In some embodiments, an anti-Tau antibody for use in a diagnostic or detection method is provided. On the other hand, a method for detecting the presence of Tau in a biological sample is provided. In certain embodiments, the method comprises contacting the biological sample with an anti-Tau antibody as described herein under conditions that allow the anti-Tau antibody to bind to Tau, and detecting whether a complex is formed between the anti-Tau antibody and Tau. Such methods may be in vitro or in vivo methods. In addition, the complex formed between the anti-Tau antibody and Tau in the test biological sample can be compared with the complex formed in a control biological sample (e.g., a biological sample from one or more healthy subjects). The amount of the complex formed between the anti-Tau antibody and Tau in the test biological sample can also be quantified and compared with the amount of the complex formed in the control biological sample (e.g., a biological sample from one or more healthy subjects) or with the average amount of the complex known to be formed in healthy subjects.

In some embodiments, anti-Tau antibodies are used to select subjects suitable for treatment with anti-Tau antibodies, e.g., where Tau is a biomarker for patient selection. For example, in some embodiments, anti-Tau (e.g., pan-Tau) antibodies are used to detect whether a subject has a Tau disease or disorder, or whether a subject has a high risk (or predisposition) for a Tau disease or disorder.

Exemplary diseases or conditions that can be diagnosed using the antibodies of the present invention include Tau protein-related diseases or conditions, and diseases or conditions caused by or associated with the formation of neurofibrillary tangles or neurofibrillary nets. In some embodiments, diseases or conditions that can be diagnosed using the antibodies of the present invention include Tau protein-related diseases or conditions that appear in the impairment or loss of cognitive function, including inference, situational judgment, memory ability, learning and/or special navigation. Specifically, diseases or conditions that can be diagnosed using the antibodies of the present invention include tau diseases, such as neurodegenerative tau diseases. Exemplary diseases or disorders that can be diagnosed using the antibodies of the invention include, but are not limited to, Alzheimer's disease, Creutzfeldt-Jakob disease, dementia pugilistica, Down syndrome, Gross-Schönlein disease, inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis/Guam parkinsonism-dementia complex, non-Guam motor neuron disease with neurofibrillary tangles, argyrophilic grain dementia, corticobasal degeneration, diffuse neurofibrillary tangles with calcifications, frontotemporal dementia, frontotemporal dementia with parkinsonism linked to chromosome 17, Hallervorden-Spatz disease, multiple system atrophy, Niemann-Pick disease type C, pallidopontinunivous degeneration, Pick's disease, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, tangle-only dementia, postencephalitic parkinsonism, and myotonic dystrophy. In some embodiments, the disorder that can be diagnosed using the antibodies of the invention is Alzheimer's disease (AD).

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-dense labels, chemiluminescent labels, and radioactive labels), as well as moieties that are indirectly detected, for example, via an enzymatic reaction or molecular interaction (such as an enzyme or ligand). Exemplary labels include, but are not limited to, radioisotopes ³² P, ¹⁴ C, ¹²⁵ I, ³ H, and ¹³¹ I; 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. Pat. 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; heterocyclic oxidases such as uricase and xanthine oxidase coupled to an enzyme that oxidizes the dye precursor with hydrogen peroxide, such as HRP, lactoperoxidase, or microperoxidase; biotin/avidin; spin labels; phage labels; stable free radicals, and the like.

F. Pharmaceutical Preparations

Pharmaceutical formulations of anti-Tau antibodies as described herein are prepared by mixing such antibodies of the desired purity with one or more optionally selected pharmaceutically acceptable carriers, diluents and/or excipients in the form of a lyophilized formulation or an aqueous solution (Remington's Pharmaceutical Sciences 16th edition, Osol, A. ed. (1980)). Pharmaceutically acceptable carriers, diluents and excipients are generally non-toxic to recipients at the dosages and concentrations employed and include, but are not limited to: sterile water; buffers such as phosphates, citrates and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexahydroxyquaternium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 1 0 residues) polypeptides; 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 dextrins; 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 neutral active hyaluronidase glycoprotein (sHASEGP), for example, human soluble PH-20 hyaluronidase glycoprotein, such as rHuPH20 (Baxter International, Inc.). Certain exemplary sHASEGPs (including rHuPH20) and methods of use are described in U.S. Patent Publication Nos. 2005/0260186 and 2006/0104968. In one aspect, the sHASEGP is combined with one or more additional glycosaminoglycanases, such as chondroitinases.

Exemplary lyophilized antibody formulations are described in US Patent No. 6,267,958. Aqueous antibody formulations include those described in US Patent No. 6,171,586 and WO 2006/044908, the formulation described in WO 2006/044908 including a histidine-acetate buffer.

The formulations herein may also contain more than one active ingredient necessary for the specific indication being treated, preferably those with complementary activities that do not adversely affect each other. Such active ingredients are suitably present in combination in amounts effective for the intended purpose.

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

Sustained-release preparations can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, eg, films, or microcapsules.

Formulations for in vivo administration are generally sterile. Sterility can be readily accomplished, for example, by filtration through sterile filtration membranes.

G. Methods of Treatment and Compositions

Any of the anti-tau antibodies provided herein can be used in therapeutic methods.

In one aspect, an anti-Tau antibody is provided for use as a medicament. In other aspects, an anti-Tau antibody is provided for use in treating a Tau protein-related disease or condition. In some embodiments, an anti-Tau antibody is provided for use in treating a disease or condition caused by or associated with the formation of neurofibrillary tangles or neurofibrillary meshwork. In a specific embodiment, an anti-Tau antibody is provided for use in treating tauopathy, such as neurodegenerative tauopathy. Exemplary Tau protein-related diseases or conditions that can be treated with anti-tau antibodies include, but are not limited to, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Creutzfeldt-Jakob disease, dementia pugilistica, Down syndrome, Gerstner syndrome, inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis/Guam Parkinson's syndrome-dementia complex, non-Guam motor neuron disease with neurofibrillary tangles, argyrophilic granular dementia , corticobasal degeneration, diffuse neurofibrillary tangles with calcification, frontotemporal dementia, frontotemporal dementia with parkinsonism linked to chromosome 17, Hallerwarden-Spatz disease, multiple system atrophy, Niemann-Pick disease type C, pallidopontinioglancholic degeneration, Pick's disease, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, tangle-only dementia, postencephalitic parkinsonism, and myotonic dystrophy. In some embodiments, provided herein are anti-Tau antibodies for the treatment of Alzheimer's disease (AD). In some embodiments, provided herein are anti-Tau antibodies for the treatment of moderate AD, mild to moderate AD, mild AD, early AD, or prodromal AD. In addition, Tau protein-related diseases or conditions that can be treated with anti-Tau antibodies include diseases or conditions that manifest in impairment or loss of cognitive function, such as reasoning, situational judgment, memory, learning, and/or specialized navigation. In certain embodiments, an anti-Tau antibody for use in a method of treatment is provided. In certain embodiments, the present invention provides an anti-Tau antibody for use in a method of treating an individual suffering from any of the Tau-related diseases or conditions described above, the method comprising administering to the individual an effective amount of the anti-Tau antibody. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, such as described below.

In some embodiments, the antibodies of the invention are used to treat individuals with an MMSE score 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's MMSE score is between 22 and 26. As used herein, an MMSE score between two values includes the values at each end of the range. For example, an MMSE score between 22 and 26 includes MMSE scores of 22 and 26.

In some embodiments, antibodies of the invention are used to treat 'tau positive' individuals, eg, patients with brain tau deposits typical of Tau protein-related disorders, eg, patients with positive Tau PET scans.

In other embodiments, the present invention provides an anti-Tau antibody for reducing the level of Tau protein (total Tau, total soluble Tau, soluble phosphorylated Tau, total insoluble Tau, insoluble phosphorylated Tau, hyperphosphorylated Tau, or paired helical filaments containing hyperphosphorylated Tau) in a subject. 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 an anti-Tau antibody for reducing the level of phosphorylated Tau. In some embodiments, the present invention provides an anti-Tau antibody for reducing the level of insoluble Tau (e.g., insoluble phosphorylated Tau). In some embodiments, the present invention provides an anti-Tau antibody for reducing the level of hyperphosphorylated Tau. In some embodiments, the present invention provides an anti-Tau antibody for reducing the level of paired helical filaments (e.g., paired helical filaments 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 filaments containing hyperphosphorylated Tau) in the brain of an individual (e.g., in the cerebral cortex and/or hippocampus), the method comprising administering to the individual an effective amount of the anti-Tau antibody to reduce the level of Tau protein. The "individual" according to any of the above embodiments is a mammal, preferably a human.

In some embodiments, the present invention provides an anti-Tau antibody for use in modulating 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 filaments containing hyperphosphorylated Tau) in the brain (e.g., in the cerebral cortex and/or hippocampus) of a subject.

On the other hand, the present invention provides the use of anti-Tau antibodies for the manufacture or preparation of medicaments. In some embodiments, the medicament is used to treat 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 neurofibrillary meshwork. In specific embodiments, the medicament is used to treat tau diseases, such as neurodegenerative tau diseases. In specific embodiments, the medicament is used to treat a disease or disorder selected from the group consisting of: Alzheimer's disease (AD), Creutzfeldt-Jakob disease, dementia pugilistica, Down syndrome, Gross-Schönlein syndrome, inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis/Guam Parkinson's syndrome-dementia complex, non-Guam motor neuron disease with neurofibrillary tangles, argyrophilic granular dementia, cortical basal degeneration, and other neurodegenerative diseases. In some embodiments, the medicament is used to treat AD. In certain embodiments, the medicament is used to treat Tau-related diseases or disorders that appear in the disorder or loss of cognitive function, such as reasoning, situational judgment, memory ability, learning or special navigation. In another embodiment, the medicament is used to treat one of the diseases listed above (e.g., tauopathy, such as AD), comprising administering an effective amount of the medicament to an individual suffering from such a disease. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, eg, as described below.

In another embodiment, the agent is used to reduce the level 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 filaments containing hyperphosphorylated Tau). For example, such a reduction in Tau protein can be observed in the brain (e.g., cerebral cortex and/or hippocampus) or cerebrospinal fluid of the individual. In some embodiments, the agent is used to reduce the level of paired helical filaments. In another embodiment, the agent is used 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 filaments containing hyperphosphorylated Tau) in an individual, the method comprising administering to the individual an effective amount of the agent to reduce the level of Tau protein. The "individual" according to any of the above embodiments is a mammal, preferably a human.

On the other hand, the present invention provides a method for treating a Tau protein-related disease or condition. Tau protein-related diseases or conditions that can be treated according to the methods provided herein include diseases or conditions caused by or associated with the formation of neurofibrillary tangles or neurofibrillary tangles. In a specific embodiment, the present invention provides a method for treating tauopathy, such as a neurodegenerative tauopathy. In a specific embodiment, the present invention provides a method for treating a disease or condition selected from the group consisting of: Alzheimer's disease, Creutzfeldt-Jakob disease, dementia pugilistica, Down syndrome, Gross-Schönlein disease, inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis/Guam parkinsonism-dementia complex, non-Guam motor neuron disease with neurofibrillary tangles, argyrophilic grain dementia, corticobasal degeneration, diffuse neurofibrillary tangles with calcifications, frontotemporal dementia, frontotemporal dementia with parkinsonism linked to chromosome 17, Hallevorden-Spatz disease, multiple system atrophy, Niemann-Pick disease type C, pallidopontinioglanological degeneration, Pick's disease, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, tangle-only dementia, postencephalitic parkinsonism, and myotonic dystrophy. In some embodiments, the present invention provides a method for treating Alzheimer's disease (AD). In specific embodiments, the present invention provides a method for treating Tau-related diseases or disorders manifested in impairment or loss of cognitive function, such as reasoning, situational judgment, memory ability, learning, or special navigation. In some embodiments, the method includes administering an effective amount of an anti-Tau antibody to an individual suffering from any of the diseases or disorders described above. In one such embodiment, the method further includes administering an effective amount of at least one additional therapeutic agent, such as described below, to the individual. In some embodiments, the method includes administering an effective amount of an anti-Tau antibody to an individual suffering from one of the diseases described herein. In one such embodiment, the method further includes administering an effective amount of at least one additional therapeutic agent, such as described below, to the individual. According to any of the above embodiments, an "individual" may be a human.

In another aspect, the present invention provides 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 filaments containing hyperphosphorylated Tau) in an individual. For example, such a reduction in Tau protein levels can be observed in the brain (e.g., cerebral cortex and/or hippocampus) or cerebrospinal fluid of an individual. In some embodiments, the present invention provides a method for reducing the level of paired helical filaments. In some embodiments, the method comprises administering to the individual an effective amount of an anti-Tau antibody to reduce the level of Tau protein. In some embodiments, an "individual" is a human.

In some aspects, the present invention provides a method for alleviating one or more symptoms of a Tau protein-related disease or condition; or an anti-Tau antibody or an agent comprising an anti-Tau antibody for alleviating one or more symptoms of a Tau protein-related disease or condition (such as any of the diseases or conditions described herein, e.g., AD). In some aspects, the present invention provides a method for reducing the number of symptoms of a Tau protein-related disease or condition or reducing the severity of one or more symptoms thereof; or an anti-Tau antibody or an agent comprising an anti-Tau antibody for reducing the number of symptoms of a Tau protein-related disease or condition (such as any of the diseases or conditions described herein, e.g., AD) or reducing the severity of one or more symptoms thereof. In a specific embodiment, the symptom of a Tau protein-related disease or condition is cognitive impairment. In a specific embodiment, the symptom of a Tau protein-related disease or condition is learning and/or memory impairment. In a specific embodiment, the symptom of a Tau protein-related disease or condition is long-term memory loss. In a specific embodiment, the symptom of a Tau protein-related disease or condition is dementia. In some embodiments, the symptom of a Tau protein-related disease or condition is confusion, irritability, aggression, mood swings, or language disorders. In some embodiments, the symptoms of a Tau protein-related disease or disorder are impairment or loss of one or more cognitive functions, such as reasoning, situational judgment, memory, and/or learning. The methods provided herein include administering an amount (e.g., a therapeutically effective amount) of an anti-Tau antibody to an individual (e.g., who exhibits one or more symptoms of a Tau protein-related disease or disorder).

In a specific aspect, the present invention provides a method for maintaining or increasing cognitive memory ability or for slowing down memory loss associated with a Tau protein-related disease or disorder; or an anti-Tau antibody or an agent comprising an anti-Tau antibody for maintaining or increasing cognitive memory ability or for slowing down memory loss associated with a Tau protein-related disease or disorder (such as any of the diseases or disorders described herein, e.g., AD). The methods provided herein include administering an amount (e.g., a therapeutically effective amount) of an anti-Tau antibody to an individual (e.g., who exhibits one or more symptoms of memory loss or reduced memory ability).

In some aspects, the present invention provides a method for reducing the rate of progression of a Tau protein-related disease or disorder; or an anti-Tau antibody or an agent comprising an anti-Tau antibody for reducing the rate of progression of a Tau protein-related disease or disorder (such as any of the diseases or disorders described herein, e.g., AD). The methods provided herein include administering an amount (e.g., a therapeutically effective amount) of an anti-Tau antibody to an individual (e.g., who exhibits one or more symptoms of a Tau protein-related disease or disorder).

In some aspects, the present invention provides a method for preventing the development of a Tau protein-related disease or condition; or an anti-Tau antibody or an agent comprising an anti-Tau antibody for preventing the development of a Tau protein-related disease or condition (such as any of the diseases or conditions described herein, e.g., AD). The methods provided herein include administering an amount (e.g., a therapeutically effective amount) of an anti-Tau antibody to an individual (e.g., a risk factor for a Tau protein-related disease or condition).

In some aspects, the present invention provides a method for delaying the development of a Tau protein-related disease or condition; or an anti-Tau antibody or an agent comprising an anti-Tau antibody for delaying the development of a Tau protein-related disease or condition (such as any of the diseases or conditions described herein, e.g., AD). The methods provided herein include administering an amount (e.g., a therapeutically effective amount) of an anti-Tau antibody to an individual (e.g., who exhibits one or more symptoms of a Tau protein-related disease or condition).

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

The antibodies of the present invention can be used alone or in combination with other agents in therapy. For example, the antibodies of the present invention can be co-administered with at least one additional therapeutic agent.

For example, compositions according to the present invention may be administered in combination with other compositions comprising additional therapeutic agents, such as biologically active substances or compounds, such as known compounds used in the medical treatment of tauopathies and/or amyloidosis (a group of diseases and disorders associated with amyloid or amyloid-like proteins, such as amyloid β protein, involved in Alzheimer's disease).

In general, other biologically active compounds may include enhancers of neuronal transmission; psychotropic drugs; acetylcholinesterase inhibitors; calcium channel blockers; biogenic amines; benzodiazepine sedatives; enhancers of acetylcholine synthesis, storage, or release; acetylcholine postsynaptic receptor agonists; monoamine oxidase-A or -B inhibitors; N-methyl-D-aspartate glutamate receptor antagonists; nonsteroidal anti-inflammatory drugs; antioxidants; serotonin agonist receptor antagonists or other therapeutic agents. In particular, the biologically active agent or compound may comprise at least one compound selected from the group consisting of compounds directed against oxidative stress, anti-apoptotic compounds, metal chelators, DNA repair inhibitors (such as pirenzepine and metabolites), 3-amino-1-propanesulfonic acid (3APS), 1,3-propanedisulfonate (1,3PDS), secretase activators, β- and γ-secretase inhibitors, tau protein, anti-Tau antibodies (including but not limited to those disclosed in WO2012049570, WO2014028777, WO2014165271, WO2014100600, WO2015200806, US8980270 and US8980271), neurotransmitters, beta-sheet blockers, breakers), anti-inflammatory molecules, "atypical antipsychotics" (such as clozapine, ziprasidone, risperidone, aripiprazole or olanzapine) or cholinesterase inhibitors (ChEI) (such as tacrine, rivastigmine, donepezil and/or galantamine) and other drugs and nutritional supplements (such as vitamin B12, cysteine, acetylcholine precursors, lecithin, choline, Ginkgo biloba, acetyl-L-carnitine, idebenone, propentofylline or xanthine derivatives), together with the binding peptides according to the present invention (including antibodies, especially monoclonal antibodies and active fragments thereof), and optionally containing a pharmaceutically acceptable carrier and/or diluent and/or excipient, and instructions for use in the treatment of the disease.

In some embodiments, the antibodies of the present invention can be administered in combination with neurological drugs. Such neurological drugs include, but are not limited to, antibodies or other binding molecules (including, but not limited to, small molecules, peptides, aptamers, or other protein binders) that specifically bind to a target selected from the group consisting of: beta secretase, presenilin, amyloid precursor protein or a portion thereof, amyloid beta peptide or an oligomer or fibril thereof, death receptor 6 (DR6), receptor for advanced glycation end products (RAGE), parkin, and huntingtin; NMDA receptor antagonists (i.e., memantine), monoamine depleting agents (i.e., tetrabenazine); ergoloid dihydroergotamine (e.g., ergoloid methylsulfonyltransferase); mesylate; anticholinergic antiparkinsonian agents (i.e., procyclidine, diphenhydramine, trihexylphenidyl, benztropine, biperiden, and trihexyphenidyl); dopamine agonist antiparkinsonian agents (i.e., entacapone, selegiline, pramipexole) , bromocriptine, rotigotine, selegiline, ropinirole, rasagiline, apomorphine, carbidopa, levodopa, pergolide, tolcapone, and amantadine); tetrabenazine; anti-inflammatory agents (including but not limited to nonsteroidal anti-inflammatory drugs (i.e., indomethacin); omethicin and other compounds listed above); hormones (i.e., estrogen, progesterone, and leuprolide); vitamins (i.e., folate and nicotinamide); dimebolin; homotaurine (i.e., 3-aminopropane sulfonic acid; 3APS); serotonin receptor activity modulators (i.e., xaliproden); interferons and glucocorticoids or corticosteroids. The term "corticosteroid" includes, but is not limited to, fluticasone (including fluticasone propionate (FP) ), beclometasone, budesonide, ciclesonide, mometasone, flunisolide, betamethasone, and triamcinolone. "Inhalable corticosteroid" means a corticosteroid suitable for delivery by inhalation. Exemplary inhalable corticosteroids are fluticasone, beclometasone dipropionate, butenide, mometasone furoate, ciclesonide, flunisolide, and triamcinolone acetonide.

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

In some embodiments, the composition according to the present invention may comprise nicotinic acid or memantine together with a chimeric antibody or a humanized antibody according to the present invention (including antibodies, particularly monoclonal antibodies and active fragments thereof), and optionally a pharmaceutically acceptable carrier and/or diluent and/or excipient.

In some embodiments, a composition is provided comprising an "atypical antipsychotic" (such as clozapine, ziprasidone, risperidone, aripiprazole or olanzapine) together with a chimeric antibody or humanized antibody according to the present invention or an active fragment thereof, and optionally comprising a pharmaceutically acceptable carrier and/or diluent and/or excipient, wherein the atypical antipsychotic is used to treat positive and negative psychotic symptoms, including hallucinations, delusions, thought disorders (manifested by significant incoherence, derailment, digression) and bizarre or disorganized behavior, as well as anhedonia, apathy, dullness and social withdrawal.

In addition to the chimeric or humanized antibodies according to the invention, other compounds that may be suitably used in the composition are, for example, those disclosed in WO 2004/058258 (see especially pages 16 and 17), including therapeutic drug targets (pages 36-39), alkanesulfonic acids and alkanolsulfonic acids (pages 39-51), cholinesterase inhibitors (pages 51-56), NMDA receptor antagonists (pages 56-58), estrogens (pages 58-59), nonsteroidal anti-inflammatory drugs (pages 60-61), antioxidants (pages 61-62), peroxisome proliferator-activated receptor (PPAR) agonists (pages 63-67), cholesterol Alcohol lowering agents (pp. 68-75), amyloid inhibitors (pp. 75-77), amyloid formation inhibitors (pp. 77-78), metal chelators (pp. 78-79), antipsychotics and antidepressants (pp. 80-82), nutritional supplements (pp. 83-89) and compounds that increase the availability of biologically active substances in the brain (see pp. 89-93) and prodrugs (pp. 93 and 94), which documents are incorporated herein by reference, but in particular the compounds mentioned on the pages indicated above.

Such combination therapies mentioned above encompass combined administration (wherein two or more therapeutic agents are included in the same formulation or separate formulations) and separate administration, in which case administration of the antibodies of the invention may be performed before, simultaneously with, and/or after administration of one or more additional therapeutic agents. In some embodiments, administration of the anti-Tau antibody and administration of the additional therapeutic agent are performed within about one month of each other, or within about one, two, two, or three weeks, or within about one, two, three, four, five, or six days.

The antibodies of the present invention (and any additional therapeutic agents) can be administered by any suitable means, including parenteral, intrapulmonary and intranasal administration, and, if necessary, for local treatment, including intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration. Administration can be by any suitable route (e.g., by injection, such as intravenous or subcutaneous injection), which depends in part on whether the administration is short-term or long-term. Various administration schedules are contemplated herein, including, but not limited to, single administration or multiple administrations over various time points, rapid administration, and pulsed infusion.

The antibodies of the present invention will be formulated, administered and used in a manner consistent with good medical practice. Factors considered in this case include the specific condition being treated, the specific mammal being treated, the clinical condition of individual patients, the cause of the condition, the site of delivery of the agent, the method of administration, the administration time course and other factors known to medical practitioners. Antibodies are not necessary, but are optionally formulated together with one or more medicaments currently used to prevent or treat the above-mentioned conditions. The effective amount of such other agents depends on the amount of the antibody present in the preparation, the type of condition or treatment and other factors discussed above. These agents are generally used in the same dosage as described herein and with the administration route as described herein, or with about 1% to 99% of the dosage described herein, or with any dosage and any approach determined to be appropriate empirically/clinically.

For the prevention or treatment of disease, the appropriate dose 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 to be treated, the type of antibody, the severity and course of the disease, whether to administer the antibody for prevention or treatment purposes, previous therapy, the patient's clinical history and the reaction to the antibody and the judgment of the attending physician. The antibody is appropriately administered to the patient at one time or over a series of treatments. Depending on the type and severity of the disease, whether, for example, administered alone or multiple times or by continuous infusion, about 1 μg/kg to 15 mg/kg (e.g., 0.1 mg/kg-10 mg/kg) of the antibody may be an initial candidate dose for administration to the patient. A typical daily dose may be in the range of about 1 μg/kg to 100 mg/kg or greater than 100 mg/kg, depending on the factors mentioned above. For repeated administration over several days or longer, depending on the condition, treatment will generally be continued until the desired degree of inhibition of disease symptoms occurs. An exemplary dose of the antibody will be in the range of about 0.05 mg/kg to about 10 mg/kg. Thus, one or more doses of about 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 (e.g., so that the patient receives about two to about twenty, or for example, about six, doses of the antibody). An initial higher loading dose may be administered, followed by one or more lower doses. However, other dosing regimens may be applicable. The progress of this therapy is easily monitored by conventional techniques and assays.

It should be understood that any of the above-described formulations or treatment methods can be performed using the immunoconjugates of the present invention instead of or in addition to anti-Tau antibodies.

H. Products

In another aspect of the present invention, an article containing materials suitable for treating, preventing and/or diagnosing the conditions described above is provided. The article comprises a container and a label or package insert on or accompanying the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, and the like. The container can be formed from a variety of materials (such as glass or plastic). The container holds a composition alone or in combination with another composition that is effective for treating, preventing and/or diagnosing the condition, and may have a sterile access port (for example, the container may be an intravenous solution bag or vial with a stopper pierceable by a hypodermic needle). At least one active agent in the composition is an antibody of the present invention. The label or package insert indicates that the composition is used to treat the selected condition. In addition, the article may comprise (a) a first container containing a composition, wherein the composition comprises an antibody of the present invention; and (b) a second container containing a composition, wherein the composition comprises another cytotoxic agent or other therapeutic agent. The article in this embodiment of the invention may further include a package insert indicating that the composition can be used to treat a specific condition. Alternatively or additionally, the article of manufacture may further comprise a second (or third) container comprising 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.

It will be understood that any of the above-described preparations may include an immunoconjugate of the present invention in place of or in addition to an anti-Tau antibody.

III. Examples

The following are examples of methods and compositions of the present invention. It is understood that various other embodiments may be practiced, given the general description provided above.

Example 1: Generation of Tau for Immunization

Generation of monomeric recombinant Tau

The recombinant human Tau construct, 2N4R isoform (amino acids 2-441), was fused to an N-terminal His tag for ease of purification and characterization. See, for example, FIG15 . The fusion construct was cloned into the pET52b vector (Novagen) and expressed in E. coli. The cells were harvested and lysed using 7M guanidinium chloride under denaturing conditions at 4° C. with stirring. The cell fragments were pelleted at 40,000 rpm for 1 hour. The recombinant His-tagged protein was isolated by nickel affinity chromatography (Ni Sepharose excel affinity resin, GE Healthcare Life Sciences) followed by size exclusion chromatography (Superdex 200 resin, GE Healthcare Life Sciences) under denaturing conditions. The guanidinium chloride was removed by dialysis of the recovered protein into 20 mM MES, 50 mM NaCl, and 1 mM TCEP at pH 6.8. The His tag was subsequently removed using TEV protease, followed by final purification using cation exchange chromatography (Mono S column, GE Healthcare LifeSciences) to remove the cleaved His tag. The purification buffer contained 0.1% Triton X-114 (v/v) to remove endotoxins. The purified protein was exchanged into PBS with 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 UV absorption at 280 nm. The final product was endotoxin-free (<0.5 EU/mg) as determined by the kinetic Limulus Amebocyte Lysate (LAL) assay.

Producing phosphorylated Tau

Phosphorylated Tau was generated using the Tau2-441 construct prepared by the method described above. The protein construct was phosphorylated using 0.5 μM PKA kinase (Life Technologies), which phosphorylates serine 409 among other residues. The reaction mixture was incubated with 1 mM ATP, 5 mM _MgCl2 at room temperature for 72 hours. Phosphorylation was confirmed by mass spectrometry. Kinase was removed using size exclusion chromatography (Superdex 75, GE Healthcare Life Sciences). The purity, monomeric state, and endotoxin level of the phosphorylated protein preparation were analyzed essentially as described above.

In vitro oligomerization of monomeric Tau

Oligomeric Tau was produced using a monomeric Tau2-441 construct. The monomeric protein was first replaced with 20 mM N, N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), 25 mM NaCl (pH 7.4), followed by oligomerization at 37°C for 3 days using 75 μM arachidonic acid (Cayman Chemicals) and 18 kDa heparin (Sigma Aldrich) at an equimolar concentration to the protein. Oligomerization was confirmed by thioflavin T fluorescence, dynamic light scattering (DLS), and analytical size exclusion chromatography. In some cases, oligomeric Tau is referred to as "oligoTau".

Example 2: Generation of Anti-Tau Antibodies

method

Hybridoma production

Nine-week-old female C57BL/6O1aHsd (C57BL/6) and BALB/c O1aHsd (Balb/c) wild-type mice were obtained (Harlan, USA). Tau knockout mice (B6.129-MapttmlHnd/J; The Jackson Laboratory, USA) were obtained at 6 and 9 weeks of age. Vaccination began at 12 to 15 weeks of age. Mice were vaccinated with oligomeric human tau. Prior to vaccination, oligotau was mixed with one of the two adjuvants used in this study: 50% v/v Ribi adjuvant system (Ribi; Sigma-Aldrich, Switzerland) or a combination of CpG single-stranded synthetic DNA oligodeoxynucleotides (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) and synthetic trehalose dibacterium mycolate (isolated from the cord factor of Tubercle bacillus) in squalene oil, 0.2% Tween-80, and water.

Mice were vaccinated by subcutaneous injection (s.c.), except for Groups D and G, which received a combination of intraperitoneal (i.p.) and paw administration. Mice in Group D received 50 μg of oligo Tau i.p. and 10 μg of oligo Tau via paw injection. Mice in Group G received 8 μg of oligo Tau i.p. and 2 μg of oligo Tau via paw injection. See Table 2.

For vaccination with CpG and Al (CpG/Al) as adjuvant, each 200 μL injection contained 60 μg (30 nmol) CpG, 1 mg Al, and 50 μg oligo Tau. For all study groups, mice were injected on days 0, 14, 35, and 56. Mice used for myeloma fusion (Nanotools, Germany) were additionally vaccinated with three daily booster injections of unadjuvanted oligo Tau (50 μg per i.p. injection).

Table 2. Mice and vaccination regimen

One day after the last of three booster injections, mice were bled and sacrificed, and spleen cells were fused with myeloma cells to generate antibody-producing hybridomas.

Selection of hybridomas for subcloning

For fusion, mice were divided into three groups for a total of 10 fusions (2 fusions in one group, four fusions in the second group, and four fusions in the third group), resulting in 299 hybridomas. Live hybridomas were grown using serum-containing selection medium, and then the best hybridomas for subcloning were selected using ELISA assays for full-length human Tau and oligoTau binding as described below. After limiting dilution, the final hybridomas were then grown in serum-free medium, and culture medium was collected from stable colonies for antibody screening and selection.

ELISA screening assay

Serum-free supernatants were collected from stable hybridomas. The supernatants containing the target antibodies were then screened by ELISA assay to characterize the antibody properties and select antibodies for further development. The ELISA assay was used to determine the following: binding to full-length human Tau (flTau; SignalChem, Canada), binding to hyperphosphorylated flTau (Genentech, USA), binding to oligomeric versus monomeric preparations of flTau, and binding to certain antibody Tau epitopes. Briefly, 96-well MaxiSorp ELISA plates (Nunc, Denmark) were coated with one of the targets shown in Table 3.

Table 3. Targets used in ELISA screening assays.

Coating was performed overnight in phosphate-buffered saline (PBS) at 4°C. Plates were washed extensively with 0.05% Tween-20/PBS and then blocked with 1% bovine serum albumin (BSA) in 0.05% Tween-20/PBS for 1 hour at 37°C. Antibodies contained in hybridoma supernatants were then added at the indicated dilutions and incubated at 37°C for 2 hours, after which the plates were washed as previously described.

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

For oligo- and mono-Tau capture ELISAs, antibodies contained in serum-free sterile hybridoma supernatants were immobilized on anti-IgG-coated plates at a 500-fold dilution, followed by incubation with oligo- or mono-Tau, both of which were site-specifically biotinylated via an AVI tag. Target incubation began at 5 μg/mL and was subsequently diluted 8- or 16-fold. Streptavidin-HRP and ABTS substrates were used for signal quantification in a plate reader (Tecan, Switzerland). Results are expressed as O.D.

Affinity estimation

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

SDS-PAGE and western blot assay

The binding of selected pan-Tau antibodies to Tau in human brain was tested in Western blotting (WB) using brain lysates from three AD donors and two age-matched non-AD control donors (Tissue Solutions, United Kingdom). 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) and transferred to Immobilon PVDF membranes and blotted with the tested antibodies and IRDye 800CW goat anti-mouse secondary antibodies (Li-Cor, USA).

ELISA assay using human brain lysate

To evaluate the binding of selected antibodies to undenatured human Tau in AD and control brain lysates, antibodies from hybridoma supernatants or negative and positive control antibodies were immobilized on 96-well culture plates as described above. Tau was then captured in soluble human brain lysates (400 μg/mL protein; both from TissueSolutions, United Kingdom) from AD or age-matched control subjects and detected using a polyclonal rabbit pan-Tau antibody (AbCam, United Kingdom) followed by Fc-γ fragment-specific anti-rabbit IgG-AP (Jackson ImmunoResearch, USA). Brain lysates from Tau knockout mice were used as negative sample controls. The plates were incubated with pNPP (Sigma-Aldrich) phosphatase substrate solution and read at 405 nm using an ELISA plate reader (Tecan, Switzerland). The results are expressed as optical density (O.D.).

Sequencing of antibody hybridomas

Hybridoma cell lysates were provided to Antitope (Antitope, United Kingdom) for variable region gene sequencing. Briefly, RT-PCR was performed using a degenerate primer pool for the murine signal sequence along with constant region primers for each of the IgG variable heavy chain (VH), IgM VH chain, Igκ variable light chain (KVL), and Igλ VL chain. Heavy chain V region mRNA was amplified using a set of six degenerate primer pools (HA to HF) specific for the VH signal sequence along with 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 for the κ cluster (KA to KG) and one for the λ cluster (LA)) along with 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 using sequences from 27 antibody hybridomas.

result

Selection of hybridomas for subcloning

Hybridomas generated from each of the three rounds of fusion (a total of 299 hybridomas derived from ten fusions) were initially assayed for binding to flTau, and selected hybridomas were additionally assayed for binding to pTau and oligomeric Tau. The goal was to select antibodies that bound equally well to Tau and post-translationally modified Tau (such as phosphorylated or oligomeric Tau). To this end, hybridomas were assayed to select for optimal pan-Tau properties. To determine the antibody binding region and specific Tau epitope, different Tau fragments were first used, and then a 15-mer overlapping Tau peptide library spanning the entire 441 amino acid (aa) sequence of the longest human Tau isoform was used to determine the binding region. A panel of antibodies that bound to a predetermined Tau region was intentionally avoided in order to maximize binding to different post-translationally modified forms of Tau and to all six different human Tau isoforms present in humans.

The three fusion series resulted in 133 subcloned stable hybridomas that were screened for optimal pan-Tau properties. A combination of different screening assays was used to reduce the number of antibody hybridomas with preferred properties for pan-Tau antibodies. To compare flTau and pTau binding, 90 hybridomas were assayed, of which the results for 24 hybridomas are shown in Figures 1A-F. Since the initial screening was performed using Tau fragments to avoid selecting antibodies that bind to regions of Tau known to have a high density of residues phosphorylated in Alzheimer's disease (AD) and other tauopathies, most of the antibodies tested bound to flTau and pTau with similar binding properties as determined by this ELISA.

In some embodiments, it is desirable for a pan-Tau antibody to bind to both monomeric and oligomeric forms of Tau without a strong preference for one or the other. A capture ELISA is set up to determine whether the antibody binds to both monomeric and oligomeric forms of flTau. ELISAs run in capture mode better preserve the oligomeric conformation of pre-oligomeric Tau and the monomeric state of single Tau compared to when run in a direct ELISA format (where the target is immobilized on an ELISA plate).

Each assay was performed by directly comparing the binding of the two Tau forms to all 90 antibodies tested. Antibodies known to preferentially bind to either oligoTau or to not discriminate between the two Tau forms were used as controls in each assay. The results for 18 hybridomas are shown in Figures 2A-E.

Mapping the epitope is crucial for selecting antibodies with good pan-Tau properties because antibodies that bind to regions with a high density of potential pTau residues (Ser, Thr, and Tyr) can be avoided. Binding to all six isoforms of human Tau was also used as a selection criterion for pan-Tau antibodies. The pan-Tau epitopes of the initially selected antibodies were validated and determined with improved accuracy using a library of 49 peptides, each with 15 amino acids (aa) across the full length of human Tau, with 6 aa residues overlapping and 9 aa offsets. Residue numbering is based on the longest isoform of human Tau (441 aa). In contrast to the absence of binding to all peptides, unpurified antibodies were used at a higher 1/10 dilution to verify binding. Screening of antibodies from 112 hybridomas previously selected by ELISA indicated binding to 20 different Tau epitopes (Table 4).

Table 4: Tau epitopes targeted by antibodies

For affinity measurements for flTau, 46 antibodies were measured using SPR on a Biacore instrument, with K _values determined. Biacore affinity measurements were performed by immobilizing the antibodies on an anti-IgG chip and using flTau as the target analyte. The results for 32 antibodies are shown in Table 5, where the antibodies are categorized based on their affinity for flTau. Of the antibodies whose affinity for flTau was measured, 22 had an affinity better than 20 nM, 14 had a _K below 5 nM, and antibody 37D3-H9 had a _K of 1 nM.

Table 5: Affinity for flTau

To verify the binding of the selected antibodies to all six isoforms of human Tau, SDS-PAGE was run with a recombinant Tau ladder containing all six isoforms, and Western blotting (WB) was performed using the three selected Tau antibodies. All three pan-Tau antibodies bound to all six Tau isoforms (Figure 3). In addition, brain homogenates from three AD and two age-matched controls were run simultaneously for comparison. As expected and based on the located epitopes, all three antibodies tested in this assay showed binding to all six Tau isoforms. The differences observed in the banding patterns between human AD and control donors may indicate greater phosphorylation and/or SDS-stabilized Tau aggregates expected to be present in AD subjects.

Human Alzheimer's disease (AD) and control samples were also run in a native ELISA capture assay to validate binding to Tau in human brain. The three antibodies were tested by running sample lysates processed against soluble Tau from two AD and two non-AD age-matched control subjects at 8-fold dilutions (Figures 4A-C).

The antibody variable chain sequences of 27 hybridomas were determined (Antitope, United Kingdom).The protein sequences of certain heavy and light chain variable domains and hypervariable regions (HVRs) are shown in the Sequence Listing.

Example 3: Characterization of Anti-Tau Antibodies

The antibody heavy and light chains were constructed by gene synthesis and subcloning the resulting DNA into murine IgG2a (heavy chain) and murine kappa (light chain) mammalian expression vectors. Antibodies were expressed in CHO or 293T cells by transient co-transfection of heavy and light chain plasmids and purified using affinity resin MabSelectSure (GE Healthcare Life Sciences). Purified recombinant antibodies were screened for binding to Tau monomer protein using a mouse IgG capture kit and S series CM5 chips on a Biacore T200 surface plasmon resonance instrument. A concentration of 1 μg/ml was captured using a flow rate of 10 μl/min in the form of mIgG2a diluted in 10 mM HEPES (pH 7.4), 150 mM NaCl, 0.05% Tween 20 (running buffer, HBSP) for 30 or 45 seconds (antibodies 26C1, 94B2-C1, 52F6-F11.v1, 52F6-F11.v2, 11E10-B8, 55E7-F11, 125B11-H3, 123E9-A1, 30G1-B2, 66F5-A1, 89F4-A1, 93A8-D2 and 126F11-G11), or capturing antibodies at a concentration of 0.1 μg/ml for 70 or 150 seconds (antibodies 19H6-F7, 3A4-H4, 54C1-H11 and 37D3-H9). Binding of Tau monomers in HBSP was monitored at 25°C using a flow rate of 30 μl/min and the following concentrations: 16, 31, 63, 125, 125, 250, and 500 nM for antibodies 26C1 and 94B2; 16, 31, 63, 125, 125, 250, 500, and 1000 nM for antibodies 52F6-F11.v1 and 52F6-F11.v2; and 6, 19, 56, 56, 63, 125, 125, 250, 500, and 1000 nM for antibodies 11E10-B8, 55E7-F11, and 125B11-H3. , 167 and 500 nM; for antibodies 123E9-A1, 30G1-B2, 66F5-A1, 89F4-A1, 93A8-D2 and 126F11-G11.5, 16, 49, 148, 148, 444, 1333 and 4000 nM; for 19H6-F7, 0.4, 1.6, 6.3, 2.5, 100 and 400 nM; and for 3A4-H4, 54C1-H11 and 37D3-H9, 0.2, 0.8, 4, 4, 20 and 100 nM. The association and dissociation times were monitored for 180-480 seconds and 300-600 seconds, respectively. Antibody 37D3-H9 was selected for further analysis due to high affinity (Table 6) and the absence of NXS/T glycosylation motifs in the CDRs.

Table 6: _KD (nM) of murine antibodies to human Tau monomer. Data shown represent the output of a 1:1 binding model.

37D3-H9 exhibits affinity when binding to Tau protein

Human monomeric Tau protein was covalently coupled to a Biacore S series CM5 chip using a Biacore amine coupling kit (GE Life Sciences) so that it was immobilized at a level of approximately 128 RU. Direct binding of 37D3-H9 in Fab and IgG form was monitored using a single-cycle kinetic experimental mode, with five association time periods of 300 s each and 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). The dissociation rate values were calculated using a 1:1 binding model fit to the data. The calculated dissociation rate was 5.0 × 10 ^-4 for 37D3-H9 Fab and 1.1 × 10 ^-5 for 37D3-H9 IgG, a 45-fold difference. Figure 5 illustrates the difference in dissociation rates for Fab (left panel) and IgG (right panel), indicating that 37D3-H9 IgG exhibits avidity.

Example 4: Humanization of anti-Tau antibodies

Antibody 37D3-H9 was humanized by grafting antibody CDRs and selected variable region framework residues onto a human antibody consensus framework (Dennis, M.S. (2010). CDR repair: A novel approach to antibody humanization. Current Trends in Monoclonal Antibody Development and Manufacturing, S.J. Shire, W. Gombotz, K. Bechtold-Peters and J. Andya, eds. (Springer, New York), pp. 9-28). Grafts onto consensus VH3, Vκ2, and Vκ1 frameworks were evaluated. The heavy chain graft included a murine residue at position 49 (Kabat numbering system). The Vκ2 graft included murine residues in framework positions 2 and 4. The Vκ1 graft included murine residues in framework positions 2, 4, and 43. Humanized variants were constructed by gene synthesis and subcloning into human IgG1 or IgG4 and κ chain mammalian expression vectors. The antibodies were expressed by co-transfecting heavy and light chain plasmids into CHO cells and purified using the affinity resin MabSelect Sure. Humanized variants were screened for affinity to human Tau monomers using a Biacore human IgG capture kit, an S series CM5 chip, and a Biacore T200 instrument. The antibodies were diluted to 2 μg/ml and captured for 15 seconds at 10 μl/min. At a flow rate of 30 μl/min, the association and dissociation of 100, 33, 11, and 3.7 nM human Tau monomers in 10 mM HEPES (pH 7.4), 150 mM NaCl, 0.05% Tween 20 (operating buffer, HBSP) were monitored 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 variants against monomeric human Tau

Antibody variants hu37D3-H9.v1, hu37D3-H9.v2, hu37D3-H9.v5, and hu37D3-H9.v6 were further characterized by surface plasmon resonance at other antibody concentrations and longer association/dissociation times. These variants were analyzed using a wider range of human Tau monomer concentrations (1.2, 3.7, 11.1, 11.1, 33.3, 100 nM) and increased association (300 seconds) and dissociation (1200 seconds) time periods. A 1:1 binding model was applied to the results (Table 8).

Table 8: Detailed analysis of the binding kinetics of selected variants to human Tau by surface plasmon resonance

The YTE (M252Y/S254T/T256E) mutation was incorporated into certain IgG4 antibodies. Neonatal Fc receptor (FcRn) binding domain mutations such as M252Y, S254T, and T256E (YTE) have been described to increase FcRn binding and thus increase antibody half-life. See U.S. Published Patent Application No. 2003/0190311 and Dall'Acqua et al., J. Biol. Chem. 281: 23514-23524 (2006).

Antibody 125B11-H3 was humanized onto a VH3 and Vκ1 consensus framework. The heavy chain graft included a murine residue at position 78 (Kabat numbering system). The Vκ1 graft included murine residues in framework positions 43 and 87. The light chain of 113F5-F7 was also humanized onto a Vκ1 framework, which has additional murine residues at framework positions 43 and 87. The humanized variant heavy chain (125B11) and light chain (125B11 and 113F5-F7) were co-transfected in a variety of combinations and purified as described above in a 96-well plate format. The humanized variants were then screened for affinity to human Tau monomers using a Biacore human IgG capture kit, an S series CM5 chip, and a Biacore T200 instrument. The antibodies were diluted to 2 μg/ml and captured for 15 seconds at 10 μl/min. The association and dissociation of 0, 100 and 500 nM human Tau monomers in HBSP were monitored for 180 s and 300 s, respectively, at a flow rate of 40 μl/min. A 1:1 binding model was applied to the results (Table 9).

Table 9: Screening of 125B11-H3 and 113F5-F7 humanized variants by surface plasmon resonance

*Minimal binding to Tau monomers

NT, not tested.

Variants hu125B11.v17 (HC3 + LC1), hu125B11.v26 (HC4 + LC2), and hu125B11.v28 (HC4 + LC4) were selected for high-resolution kinetic analysis based on affinity screening (Table 10). Antibody 94B2-C1 was humanized onto the VH1 and Vκ2 frameworks. The heavy chain graft also included murine residues at positions 28, 29, 67, 69, 71, and 73 (Kabat numbering system). The Vκ2 graft also included murine residues at framework positions 2, 36, and 46. A combination of eight heavy chains and eight light chains was expressed, as described above for 125B11, and purified and screened by surface plasmon resonance (SPR). The results of the SPR screening are shown in Table 11. Variant hu94B2.v105 (heavy chain variant 94B2.HC1, light chain variant 94B2.LC13) was selected for detailed SPR characterization (Table 11).

Table 10: Kinetic data of selected humanized anti-Tau antibody variants

Table 11: Screening of 94B2 humanized variants by surface plasmon resonance

*n=mean of 3 replicates.

hu94B2.v105.

^§Minimal binding to Tau monomers was observed.

NT, not tested.

Example 5: Stability Analysis of Humanized Anti-Tau Antibodies

Identifying chemical instabilities

Antibody samples were subjected to heat stress to simulate the stability during the product shelf life. The sample buffer was replaced with 20mM acetate buffer (pH 5.5) or phosphate buffer (pH 7.4), and diluted to a concentration of 1mg/ml. 1ml samples were subjected to stress for 2 weeks at 40°C, and a second sample was stored at -70°C as a control. Subsequently, both samples were digested using trypsin to produce peptides, and liquid chromatography (LC)-mass spectrometry (MS) analysis was used to analyze the peptides. For each peptide in the sample, retention time (from LC) and high-resolution accurate mass and peptide ion fragmentation information (amino acid sequence information) were obtained in MS. Under a window of ± 10ppm, according to data sets, the extracted ion chromatograms (XICs) of the target peptides (native and modified peptide ions) were obtained and the peaks were integrated to determine the area. The relative percentage of each sample was calculated by multiplying (the area of modified peptides) by (the area of modified peptides plus the area of native peptides) by 100. These relative percentages were then compared between control (t = 0) and stressed (t = 2 weeks) samples. The percentages shown represent the stress (t = 2 weeks) values minus the control (t = 0) values. Deamidation analysis of antibodies hu37D3-H9.v1 and hu37D3-H9.v5 resulted in the observation that the sequence N ²⁸ G ²⁹ N ³⁰ (Kabat numbering) within the light chain CDR-1 was susceptible to deamidation. The increase in deamidation N ²⁸ G ²⁹ N ³⁰ was found to be 16.5% for hu37D3-H9.v1 and 11% for hu37D3-H9.v5.

Effect of deamidation on antibody-antigen binding

To assess the effect of ^N28 deamidation on affinity for human Tau, two samples with widely spaced ^N28 deamidation states were obtained. Hu37D3-H9.v5hIgG4.S228P was incubated at 40°C for two weeks at a concentration of 1 mg/ml in phosphate-buffered saline (pH 7.4). Deamidation of ^{the N28G29} motif was measured using LC-MS/MS. Deamidation increased by 43.1% in the sample stressed at t=2 weeks relative to the unstressed sample at t=0. Tau binding of stressed and unstressed antibodies was analyzed by surface plasmon resonance (Biacore) using the GE Biacore Human IgG Capture Kit and an S-series CM5 chip. hIgG was diluted to 2 μg/ml in 10 mM HEPES (pH 7.4), 150 mM NaCl, 0.05% Tween 20 (running buffer, HBSP) and captured for 15 seconds (t0 sample) or 17 seconds (t2 sample) at a flow rate of 10 μl/min. Kinetic data were collected for human Tau monomer injected at concentrations of 0, 3.1, 6.3, 12.5, 25, 25, 50, and 100 nM in HBSP using a flow rate of 30 μl/min, a 300-second association phase, and an 1800-second dissociation phase. Between cycles, the surface was regenerated using a 30-second injection of 3 M magnesium chloride at 10 μl/min. Data were fitted to a 1:1 binding model using instrument default parameters (including local fitting of the "RI" parameter). The results shown in Figure 6 and Table 12 demonstrate that, although the stressed antibodies were immobilized at higher levels than the unstressed antibodies in this experiment, the magnitude of the Tau binding signal (as indicated by the magnitude of the parameter Rmax) was significantly lower. After normalizing the Rmax values for differences in capture levels, the stressed (t = 2 weeks) samples appeared to exhibit approximately half the total Tau binding capacity of the unstressed samples (indicated by a 56% decrease in normalized Rmax). The calculated affinity appeared unchanged: in this analysis, the _KD difference between the t = 0 and t = 2 week samples was less than 2% ( _KD = 0.7 nM for both t = 0 and t = 2 weeks). The results are consistent, with the t = 2 week sample containing a significantly reduced population of high-affinity antibodies.

Table 12: Relative binding of stressed and unstressed hu37D3-H9.v5 samples to monomeric Tau by surface plasmon resonance

Effect of deamidation on antibody-antigen binding and calculation of "normalized Rmax"

Given that asparagine deamidation is expected to produce aspartate and isoaspartate products (Bischoff R. and Kolbe HVJ (1994). J. Chromat. 5, 662, pp. 261-278), the effect of replacing ^N28 with ^D28 (variant hu37D3-H9.v5N28D) on affinity for human Tau monomer was analyzed. Affinity was assessed at 25°C using a Biacore T200 instrument, the GE Biacore Human IgG Capture Kit, and a CM5S series chip. hIgG was diluted to 2 μg/ml in 10 mM HEPES (pH 7.4), 150 mM NaCl, 0.05% Tween 20 (running buffer, HBSP) and captured for 22 seconds at a flow rate of 10 μl/min. Kinetic data were collected for human Tau monomers injected at concentrations of 0, 6.3, 12.5, 25, 25, 50, 100, 200, and 400 nM in HBSP using a flow rate of 30 μl/min, a 300-second association phase, and a 600-second dissociation phase. Between cycles, the surface was regenerated using a 30-second injection of 3M magnesium chloride at 10 μl/min. The data were fitted with a 1:1 binding model, and the affinities of hu37D3-H9.v5 and hu37D3-H9.v5.3 (also referred to herein as hu37D3-H9.v5N28D) were calculated using kinetic analysis. Parameters used for the 1:1 fit included the instrument default parameters for a local fit of the "RI" parameter. The results are shown in Figure 7 and Table 13.

The calculated _KD value for the hu37D3-H9.v5 N28D variant was 160 × ^10-9 M, compared to a calculated _KD value of 1.5 × ^10-9 M (mean, n = 4 assays) for hu37D3-H9.v5 analyzed under the same conditions. Thus, the conversion of ^N28 to ^D28 resulted in a >100-fold decrease in affinity. Given the relatively low affinity and relatively fast kinetics of the hu37D3-H9.v5 N28D variant, we hypothesized that kinetic analysis of a mixture of ^N28 and ^D28 variants would be dominated by the higher affinity population, and the presence of the lower affinity variant would be reflected by a decrease in the normalized Rmax. To test this hypothesis, the Tau binding profiles of the antibody variants hu37D3-H9.v5 and hu37D3-H9.v5 N28D were compared to the Tau binding profiles of equal amounts of these two antibodies mixed together. A 1:1 mixture of hu37D3-H9.v5 and hu37D3-H9.v5 N28D resulted in a 45% decrease in normalized Rmax compared to hu37D3-H9.v5 alone (Table 13). We conclude that changes in normalized Rmax after heat stress can indicate a decrease in the high-affinity antibody population in the stressed sample. We infer that changes in normalized Rmax can therefore be used to screen for variants of hu37D3-H9 with improved stability.

Table 13: Changes in normalized Rmax observed after heat stress of hu37D3-H9.v5 and after mixing hu37D3-H9.v5 with the expected deamidated product hu37D3-H9.v5 N28D

*Normalized Rmax = Rmax (RU) / ligand level (RU). Normalized Rmax of reference antibody = 0.33 (mean value determined in four experiments, standard deviation < 0.01).

Antibody optimization and selection

90 37D3-H9 variants were evaluated by Biacore to compare their functional stability under conditions with or without a two-week ⁴⁰ °C heat stress period. Variants included most single mutations of the ^N28G29N30T31 motif, double mutants containing the ^G29A mutation, ^double mutations of Asn-28 and Tyr-32 (functionally replacing these groups with hydrogen-bonding residues), and all possible permutations of residues 2, 4, 33, and 93 (as present in the original 37D3-H9 antibody or the corresponding germline residue variants). In addition, mutations were tested where residue 1 was Asp or Glu, which did not affect the affinity or stability of the Asn-28 residue.

Antibodies were expressed by transient transfection of Expi293 cells in 96-well plates and automatically purified on a Tecan freedom EVO 200 liquid handling system with a 500 μL MCA96 head. Briefly, IgG in 1 mL of culture was captured using a custom top column (Glygen Corp & GE Healthcare) filled with 20 μL of MabSelect SuRe resin. 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 top column was stripped in 0.1 M NaOH and regenerated with 1× PBS (pH 7.4) for up to 15 consecutive uses. Purified antibodies in 96-well plates were standardized to 0.1 mg/ml using a Hamilton Star liquid handling robot. "Pre-stress" samples were kept at approximately 4°C, and "post-stress" samples were incubated at 40°C for two weeks in a PCR machine. The functional stability of the variants was compared by running surface plasmon resonance kinetics experiments using "pre-stress" and "post-stress" antibody preparations. Antibodies were evaluated using a human antibody capture CM5 S-series chip generated with the GE Biacore IgG Capture Kit and a Biacore T200 instrument. Antibodies diluted to 2 μg/ml were immobilized using a 15-second injection time and a flow rate of 10 μl/min. Binding to 0 nM, 26.5 nM, and 265 nM Tau monomers was monitored at 25°C using a flow rate of 40 μl/min for an 180-second association phase, followed by a 300-second dissociation phase. Samples were run in 10 mM HEPES (pH 7.4), 150 mM NaCl, 0.05% Tween 20 (HBSP) using multi-cycle kinetic mode. Data were analyzed using BIAevaluation software and fitted to a 1:1 binding model. The resulting affinity ( _KD ) values are shown in Figures 8A-D. A stability index was also calculated using the following rationale: antibodies with impaired affinity (due to, for example, deamidation of key residues) are expected to contribute equally to the IgG capture level ("ligand level") but less to the measured Tau binding, and this will be reflected in the experimentally derived Rmax values. To account for variations in the amount of each antibody captured, Rmax was normalized to the antibody capture level (as measured by "ligand level," the response units immobilized during antibody capture). Therefore, normalized Rmax was calculated as the experimental Rmax value (unit = RU) divided by the "ligand level" (the estimated output representing the RU captured during the hIgG capture step, unit = RU), and the stability index was calculated here as normalized Rmax (after stress) divided by normalized Rmax (before stress).

The selected antibodies were expressed by transient transfection of CHO cells and purified. Subsequently, the antibodies were stressed for two weeks at 1 mg/ml using RCM tryptic peptide mapping, DTT reduction, IAA blocking, and pH 8.2 digestion, and deamidation was analyzed by LC-MS/MS. ^The results (Table 14) demonstrate that the variant hu37D3-H9.v28.A4 has reduced sensitivity to deamidation at ^{the N28G29N30} motif. The reduced deamidation of hu37D3-H9.v28.A4 was unexpected because the residue was not mapped in the immediate vicinity of the Asn-28 residue (Figure 9), and it is unclear how the F33L mutation can stabilize Asn-28.

Table 14: Stability of hu37D3-H9.v28.A4 variants to deamidation in stress tests

Example 6: Selection and Characterization of Humanized Anti-Tau Antibodies

Antibody Selection and Characterization: Binding to Human Tau Protein

The affinity of the selected antibodies was assessed at 25°C using a Biacore T200 instrument, the GE Biacore Human IgG Capture Kit, and a CM5 S-series chip. hIgG was diluted to 0.25 μg/ml in 10 mM HEPES (pH 7.4), 150 mM NaCl, 0.05% Tween 20 (running buffer, HBSP) and captured for 150 seconds at a flow rate of 10 μl/min. Kinetic data were collected for human Tau monomer injected at concentrations of 0, 0.4, 1.2, 3.7, 11, 11, 33, and 100 nM in HBSP using a flow rate of 30 μl/min, a 300-second association phase, and a 600-second dissociation phase. Between cycles, the surface was regenerated using two sequential 30-second injections of 3 M magnesium chloride at 10 μl/min. Data were fit to a 1:1 binding model (Table 15).

Table 15: Kinetic data of selected humanized anti-Tau antibody variants

Antibody Characterization: Binding to Human Tau Protein in the hIgG4.S228P.YTE Format

Affinity was assessed at 25°C using a Biacore T200 instrument, the GE Biacore Human FAb Capture Kit, and a CM5 S-series chip. hIgG was diluted to 0.5 μg/ml in 10 mM HEPES (pH 7.4), 150 mM NaCl, 0.05% Tween 20 (running buffer, HBSP) and captured for 180 seconds at a flow rate of 10 μl/min. Kinetic data were collected for human Tau monomers injected at concentrations of 0, 0.4, 1.2, 3.7, 11, 11, 33, and 100 nM in HBSP using a flow rate of 30 μl/min, a 300-second association phase, and a 600-second dissociation phase. Between cycles, the surface was regenerated using two sequential 60-second injections of 10 mM glycine (pH 2.1). Data were fit to a 1:1 binding model. Kinetic data are shown in Table 16.

Table 16: Binding kinetics of hu37D3-H9.v28.A4 hIgG4.S228P.YTE to monomeric human Tau by surface plasmon resonance

Antibody Characterization: Binding to Cynomolgus Monkey Tau Protein

Affinity was assessed at 25°C using a Biacore T200 instrument, GE Biacore human IgG capture kit, and CM5 S series chips. hIgG was diluted to 2 μg/ml in 10 mM HEPES (pH 7.4), 150 mM NaCl, 0.05% Tween 20 (running buffer, HBSP) and captured for 15 seconds at a flow rate of 10 μl/min. Kinetic data for human Tau monomers injected at a minimum of five different non-zero concentrations between 1.2 and 100 nM (with one replicate) were collected. Kinetics were assessed using a flow rate of 30 μl/min, a 300-second association phase, and a 600-second dissociation phase. Between each cycle, a 30-second regeneration injection of 3M magnesium chloride was performed at a flow rate of 10 μl/min. The results were fitted to a 1:1 binding model. The kinetic data are shown in Table 17.

Table 17: Affinity of humanized anti-Tau antibodies for monomeric cynomolgus monkey Tau

Humanized antibodies hu37D3.v28.A4 and hu37D3.v28.F1 also bind to phosphorylated Tau (pTau).

Example 7: Pharmacokinetics of Anti-Tau Antibodies

To evaluate the in vivo pharmacokinetics of the anti-Tau 37D3-H9 mIgG2a antibody, conscious mice were administered a single intravenous (IV) or intraperitoneal (IP) bolus injection of 10 mg/kg to C57BL/6 mice. Plasma samples were collected at various time points up to 28 days after dosing to determine the anti-Tau antibody concentration.

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

Figure 10 shows the results of pharmacokinetic analysis of anti-Tau 37D3-H9 mIgG2a. The exposure and clearance of anti-Tau 37D3-H9 mIgG2a in wild-type C57BL/6 mice were similar to those of the isotype control antibody, with a clearance of 6.31 mL/day/kg.

To evaluate the in vivo pharmacokinetics of anti-Tau 94B2-C1 mIgG2a and anti-tau 125B11-H3 mIgG2a, conscious C57BL/6 mice were administered a single IP bolus injection of the antibodies at a dose of 10 mg/kg. Plasma samples were collected at various time points up to 28 days after dosing to determine anti-Tau antibody concentrations.

The concentration of the administered antibody in mouse plasma was measured using a universal ELISA as follows: using a mouse anti-muIgG2a antibody coating, followed by the addition of plasma samples starting at a 1:100 dilution, and ending with the addition of mouse anti-muIgG2a-biotin conjugate and then streptavidin conjugated to horseradish peroxidase for detection. The standard curve for this assay ranged from 0.78 to 100 ng/mL, and the limit of detection was 0.078 μg/mL. The concentration was also measured using a specific ELISA as follows: using recombinant Tau as a coating, followed by the addition of plasma samples starting at a 1:10 dilution, and ending with the addition of goat anti-mIgG2a conjugated to horseradish peroxidase for detection. The standard curve for this assay ranged from 0.078 to 10 ng/mL, and the limit of detection was 0.0008 μg/mL. Results below this limit of detection were reported as less than reportable (LTR).

The results of those experiments are shown in Figures 16 and 17. When the universal assay was used to analyze concentrations, the exposure and clearance of anti-Tau 94B2mIgG2a in wild-type C57BL/6 mice were similar to those of the isotype control antibody, but when the specific assay was used to analyze concentrations, its exposure was lower and clearance was faster. See Figure 16. The clearance determined by the universal assay was 4.06 mL/day/kg, and the clearance determined by the specific assay was 7.53 mL/day/kg. These results indicate that antibodies can undergo changes in vivo over time that impair their ability to recognize their targets. Regardless of the assay used to generate the concentrations, the exposure and clearance of anti-Tau125B11-H3 mIgG2a in wild-type C57BL/6 mice were similar to those of the isotype control antibody. See Figure 17. The clearance determined by the universal assay was 4.96 mL/day/kg, and the clearance determined by the specific assay was 4.90 mL/day/kg.

Table 18 shows the pharmacokinetic parameters of anti-Tau antibodies 37D3-H9, 94B2-C1, and 125B11-H3 in mice.

Table 18: Pharmacokinetic parameters of anti-Tau antibodies

To evaluate the in vivo pharmacokinetics of hu37D3.v28.A4 hIgG4.S228P and hu37D3.v28.A4 hIgG4-S228P.YTE antibodies, conscious monkeys were administered a single IV bolus injection of 1 mg/kg. Plasma samples were collected at various time points up to 49 days after dosing to determine anti-Tau antibody concentrations.

The concentration of the administered antibody in monkey plasma was measured using a universal ELISA as follows: a sheep anti-human IgG antibody coating was used, followed by the addition of plasma samples starting at a 1:100 dilution and ending with the addition of goat anti-human IgG conjugated to horseradish peroxidase for detection. The standard curve for this assay ranged from 0.156 to 20 ng/mL, and the limit of detection was 0.02 μg/mL. Results below this limit of detection were reported as less than reportable (LTR).

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 represents one animal, and the line represents the mean 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

Example 8: Further epitope characterization of anti-Tau antibodies

After comparing 37D3-H9 with biotinylated Tau monomers and biotinylated peptides (MAPT_10-24), the binding of 37D3-H9 to other biotinylated peptides was also assessed. Nunc maxisorp 96-well microwell culture plates were coated with neutravidin diluted to 2 μg/ml in 50mM sodium carbonate buffer (pH 9.6) at 4 ° C and kept for >12 hours. All subsequent cultivations were carried out at room temperature. After coating, the culture plates were blocked for two hours with Superblock ^™ (PBS) blocking buffer (Thermo Fisher Scientific), followed by thorough cleaning with PBS, 0.05% polysorbate 20. The wells were then exposed to 1 μg/ml of biotinylated Tau peptide (Table 20) or Avi tag biotinylated Tau monomers for one hour and cleaned as before. Each peptide was 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-H9mIgG2a and hu37D3-H9.v5 hIgG1, serially diluted from 500 nM to 50 pM in 90% Superblock ^™ (PBS) blocking buffer, were bound to wells coated with biotinylated Tau for 90 min. The wells were washed as before, and bound antibodies were detected with a 1/1000 dilution of a peroxidase-conjugated secondary antibody (Invitrogen/Life Technologies) in Superblock ^™ blocking buffer (rabbit anti-mouse IgG or goat anti-human IgG (H+L), respectively). After 20 min, the wells were washed as before, and signal was generated using TMB Microwell Two-Component Substrate (KPL). The reaction was stopped by adding 1 M phosphoric acid and the absorbance at 450 nm was measured using a SpectraMax M2 plate reader.

Table 20: Peptide sequences

The results of this experiment are shown in Figure 12. Figure 12A shows the binding of each of the indicated antibodies to the indicated peptides. Antibodies 37D3-H9 and 94B2-C1 both showed strong binding to fragment 10-24 in this experiment, and antibody 94B2-C1 also showed strong binding to fragment 1-15. Antibodies 19F8-C11 and 123E9-A1 showed strong binding to fragment 19-33, while antibody 89F4-A1 showed strong binding to fragments 28-42 and 37-51. See Figure 12A. Antibodies 37D3-H9 mIgG2a and hu37D3-H9.v5hIgG1 both showed strong binding to Tau fragments 2-24 and 2-34, and weaker binding to fragment 10-24. See Figures 12B and 12C. These results indicate that antibodies 37D3-H9 mIgG2a and hu37D3-H9.v5 hIgG1 bind to an epitope within amino acids 2-24 of the mature protein in Tau.

In an alanine scanning substitution experiment, mutations Y18A and L20A were found to abolish binding of murine antibody 37D3-H9 to Tau fragments (fragment 2-21), indicating that the antibody contacts these Tau residues. Using a series of 15-mer offset peptides, murine antibody 37D3-H9 was found to exhibit similar binding to fragments 9-23 as to fragments 10-24, and also exhibited moderate binding to fragments 7-21, 8-22, and 11-25.

Example 9: Cell-based characterization of 37D3-H9 humanized antibody

method

Primary hippocampal and microglial cell cultures and hippocampal-microglial co-cultures

Dissociated primary hippocampal neurons were prepared from embryonic day 16-17 wild-type C57BL/6N mice. Cells were plated at 25,000 cells/well on 8-well chamber slides coated with PDL/laminin (Biocoat, 354688 Corning). Cells were plated and maintained in NbActiv4 (BrainBits), with half the medium replaced twice weekly. Recombinant Tau and antibodies were administered to the cultures at 18 cell divisions.

For microglial cell culture, the cortex and hippocampus of postnatal day 1-2 C57BL/6N mice were dissociated and grown in DMEM containing 10% FBS for 10-12 days in ^225mm2 culture flasks. The culture flasks were gently shaken to dissociate the microglial cells, and the cells in DMEM containing 10% FBS were re-plated on 8-well chamber slides coated with PDL/laminin at 30,000 cells/well for imaging or on uncoated 48-well culture plates (3548, Corning) at 100,000 cells/well for cytokine determination. 4-5 hours after plating, the cells were switched to serum-free low-glucose DMEM and kept overnight before being treated with recombinant Tau and antibodies.

Hippocampal-microglial co-cultures were prepared by replating microglial cells dissociated from 225 ^mm2 culture flasks onto 18DIV primary hippocampal neurons in 8-well glass slide chambers (12,500 microglial cells and 25,000 neurons per well). Four hours after microglial cell plating, the co-cultures were treated with recombinant Tau and antibodies.

In vitro treatment of recombinant tau and antibodies

For 18DIV hippocampal cultures or hippocampal-microglial co-cultures, recombinant human oligomeric tau and antibodies (500 nM each at a 1:1 ratio) or controls were pre-incubated in neuronal culture medium (conditioned medium from 18DIV hippocampal cultures: fresh NbActiv4 at 1:1) for 1 hour at 37°C before adding them to the cells. Cells were incubated in culture with the tau antibody mixture or controls for 72 hours (hippocampal cultures) or 48 hours (hippocampal-microglial co-cultures) in culture medium. Cells were washed three times with PBS and then fixed.

For microglial cell culture, recombinant human oligomeric tau and antibodies or controls were pre-incubated at 125 nM each (immunocytochemistry/imaging) or 250 nM each (cytokine assay) in low glucose DMEM in the absence of serum for 1 hour at 37°C and then added to the cells. For immunocytochemistry/imaging, cells were incubated with tau antibody mixture or control for 10 min and washed three times with PBS before fixation. For cytokine assay, cells were incubated with tau antibody mixture or control for 24 hours, and the culture medium of each well was collected for cytokine assay.

Immunocytochemistry, imaging, and quantification

Cells were fixed with 4% paraformaldehyde in PBS for 15 min and permeabilized with 0.1% Triton X-100 in PBS for 10 min. Blocking was performed using 10% donkey serum, and cells were incubated overnight at 4°C with primary antibodies in PBS, followed by incubation with Alexa fluorophore-labeled secondary antibodies (Invitrogen) directed against appropriate substances produced in donkeys. The primary antibodies used were anti-tau (DAKO), rabbit anti-human Tau developed against the N-terminal region of human Tau 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 coverslips No. 1.

Confocal fluorescence imaging was performed using LSM780 (Carl Zeiss, Inc.) using Zen 2010 software (Carl Zeiss, Inc.). For imaging of hippocampal cultures and hippocampal-microglial co-cultures, 5 z stack images with an interval of 0.98 μm were collected using a Plan Apochromat 20×/0.8 M27 objective. For MAP2 fragmentation determination, maximum intensity z projections were generated for image stacks and analyzed using Metamorph (Molecular Devices, Sunnyvale, CA). A median filter and nearest neighbor deconvolution were used to reduce noise. Neurite and cell body lengths were analyzed using the neurite outgrowth module followed by morphological processing. Fragments less than 15 pixels (6.225 μm) were normalized to the total signal length to obtain measurements of MAP2 fragmentation.

Microglial cells were imaged using an α-plan apochromat 100×/1.46M27 objective. Quantification of recombinant tau uptake in cells was performed using Image J (1.43u, 64-bit, National Institutes of Health). ROIs of cellular regions were manually drawn using Iba-1 signal as a reference. The area and integrated intensity of tau immunoreactivity within the ROI were measured to obtain tau immunoreactivity normalized to area. All analyses were performed without knowledge of experimental conditions.

result

The results of the experiment are shown in Figure 13. As shown in Figure 13A, antibodies with full effector function did not protect against Tau toxicity in neuron-microglia co-cultures. Figure 13B shows images of neuron-microglia co-cultures contacted with oligomeric Tau and antibodies (bottom panel). Antibodies lacking effector function, 37D3-H9 hIgG4 and hu37D3-H9 hIgG1 (N297G), protected against Tau toxicity, while 37D3-H9 hIgG1 did not.

Example 10: Dose-dependent reduction of tauopathies in Tau Tg mice administered 37D3-H9 IgG2a or 37D3-H9 IgG2a DANG

Transgenic mice expressing human Tau P301L under the Thy1 promoter (Tau P301L-Tg) were maintained on a C57BL/6N (Charles River) background. Tau P301L-Tg and wild-type littermates were assigned to treatment groups and administered weekly intraperitoneally (i.p.) with 30 mg/kg IgG2a control (anti-gp120); 3, 10, or 30 mg/kg anti-tau 37D3-H9 WT IgG2a; and 3, 10, or 30 mg/kg anti-tau 37D3-H9 DANG IgG2a. DANG refers to the D265A/N297G mutation in IgG2a, which abolishes effector function. All antibody dosing solutions were prepared at a concentration of 10 mg/ml in 10 mM histidine (pH 5.8), 6% sucrose, and 0.02% Tween 20. Treatment began at 13 weeks of age. The mice in the in vivo study were male and staggered into three groups. In addition, three untreated TauP301L-Tg mice were harvested at 3 months of age to determine baseline lesion levels at the start of treatment.

To collect tissue, mice were anesthetized with 2.5% tribromoethanol (0.5 ml per 25 g body weight) and perfused transcardially with PBS. The brain was collected and cut into two parts. The right hemisphere was fixed in 4% paraformaldehyde overnight at 4°C, then transferred to phosphate buffered saline and processed for immunohistochemistry. The left hemisphere was cut into smaller pieces on ice and then frozen at -80°C for biochemical analysis. Tail clips were obtained from all mice to confirm genotype.

Hemibrains were multiply embedded in gelatin matrix using blocks (NeuroScience Associates, Knoxville, TN) and sectioned coronally at 25 μm thickness. Within each block, brain position was randomized with respect to genotype and treatment. Free-floating sections of individual mouse hemibrains or blocks were stained as previously described (Le Pichon et al., 2013, PLoS One, 8(4): e62342), but washed in PBS instead of Tris-buffered saline and incubated with primary antibodies at 4°C instead of room temperature. The primary antibody was rabbit anti-pTau212/214 (generated in-house; 0.01 μg/ml). To avoid high background staining, in the case of subtype-specific mouse primary antibodies, we used the corresponding subtype-specific secondary antibody (e.g., biotinylated anti-mouse IgG3, Bethyl A90-111B).

Immunohistochemical staining slides were imaged using a Leica SCN400 (Leica Microsystems; Buffalo Grove, IL) full slide scanning system at 200× magnification with a resolution of 0.5 μm/pixel. Target regions (ROIs) were manually drawn at the hippocampal level of 4 matches per animal, and the amount of staining in these ROIs was quantified in an automated manner using the two endpoints described below. All image analyses were performed without knowing the genotype and treatment group. For positive pixel area analysis of IHC staining quantification, digital images of antibody-labeled brain sections were analyzed as previously described (LePichon et al., 2013). The percentage of stained area was calculated by standardizing the total positive pixels relative to the total ROI pixel area. For positive pixel areas only, the Beer-Lambert law was used, and absorbance = -log (transmitted light intensity/incident light intensity) was used to calculate the integrated intensity.

The results of the experiments are shown in Figure 14. Administration of anti-tau 37D3-H9 WT IgG2a or anti-tau 37D3-H9 DANG IgG2a resulted in a dose-dependent reduction of pTau212/214 in the hippocampus.

Example 11: Humanized 37D3-H9κ1 variant

Humanized antibodies based on hu37D3-H9.v1 with a kappa 1 light chain were generated and tested for N ²⁸ stability. An alignment of the light chain variable regions of the three variants tested with hu37D3-H9.v1 is shown in Figure 18. The three variants differ from each other in the light chain variable region: hu37D3.v39 contains the mutation F33L, hu37D3.v40 contains the mutation G29T, and hu37D3.v41 contains the mutation N30Q.

Antibody samples were subjected to heat stress as follows. The sample buffer was replaced with 20mM acetic acid histidine acetate, 240mM sucrose (pH 5.5), and diluted to a concentration of 1mg/ml. 1ml sample was subjected to stress for 2 weeks at 40°C, and a second sample was stored at -70°C as a control. Subsequently, two samples were digested using trypsin to produce peptides, and liquid chromatography (LC)-mass spectrometry (MS) analysis was used to analyze the peptides. For each peptide in the sample, retention time (from LC) and high-resolution accurate mass and peptide ion fragmentation information (amino acid sequence information) were obtained in MS. Under the window of ± 10ppm, according to data set, the extracted ion chromatogram (XIC) of target peptide (native and modified peptide ion) was obtained and peak was integrated to measure area. The relative percentage of each sample was calculated by multiplying (the area of modified peptide) divided by (the area of modified peptide plus the area of native peptide) by 100. These relative percentages were then compared between the control (t=0) samples and the stressed (t=2 weeks) samples. The percentages shown represent the stressed (t=2 weeks) values minus the control (t=0) values. The results are shown in Table 21. The results demonstrate that the F33L mutation effectively reduces deamidation in the κ1 humanized light chain.

Table 21 - Stability of hu37D3-H9.v1 variants in stress testing against deamidation.

The affinity of the humanized antibody variants was measured at 25°C using a Biacore T200 instrument, a GE Biacore human FAb capture kit, and a CM5 S series chip. The antibodies were diluted to 1 μg/ml in HBSP (10 mM HEPES (pH 7.4), 150 mM NaCl, 0.05% Tween 20) and captured for 180 seconds at a flow rate of 10 μl/min. Kinetic data for human Tau monomers injected at 1.2, 3.7, 11, 33, and 100 nM in HBSP were collected using a single-cycle kinetic method and a flow rate of 30 μl/min. Tau monomers at each concentration were injected for a period of 3 minutes, and dissociation was monitored for ten minutes. Between each cycle, the surface was regenerated with two sequential one-minute injections of 10 mM glycine (pH 2.1). The data were fitted to a 1:1 binding model using BIAEvaluation software. Each antibody was analyzed twice within the experiment; the data in Table 22 are shown as mean ± range.

Table 22: Affinity of hu37D3-H9.v1 variants for monomeric Tau

Example 12: Pharmacokinetics and Pharmacodynamics of hu37D3.v28.A4 hIgG4-S228P and hu37D3.v28.A4 hIgG4-S228P.YTE in Cynomolgus Monkeys

To evaluate the in vivo pharmacokinetics and pharmacodynamics of the hu37D3.v28.A4 hIgG4.S228P and hu37D3.v28.A4 hIgG4-S228P.YTE antibodies, a single IV bolus injection was administered to five conscious cynomolgus monkeys (Macaca fascicularis) per group at a dose of 50 mg/kg in the first phase. Anti-gD hIgG4 was used as a control, also at a dose of 50 mg/kg. Plasma and CSF samples were collected at various time points up to 35 days after dosing to determine anti-Tau antibody concentrations. Following the final sample collection, the animals were allowed to recover for 63-64 days before initiating the second phase. In the second phase, 15 animals from the first phase plus 3 additional animals were divided into two groups; the first group (n=9) was administered with the antibody hu37D3.v28.A4 hIgG4.S228P, and the second group (n=9) was administered with the antibody hu37D3.v28.A4 hIgG4-S228P.YTE (both at 50 mg/kg). Brains of 4 or 5 animals per group were harvested on days 2 and 10 after dosing.

Human IgG4 antibodies in cynomolgus monkey plasma, CSF, and brain homogenates (described below) were measured by ELISA using a sheep anti-human IgG monkey-adsorbed antibody coating followed by the addition of plasma samples starting at a 1:100 dilution, CSF samples starting at a 1:20 dilution, or brain homogenate samples starting at a 1:10 dilution, and ending with the addition of a goat anti-human IgG antibody conjugated to horseradish peroxidase that was monkey-adsorbed for detection. 3,3',5,5'-tetramethylbenzidine was used for color development and 1M phosphoric acid was used for neutralization. Samples were read at 450/620 nm. The standard curve range for this assay was 0.156-20 ng/mL, and the detection limits were 0.02 μg/mL for plasma, 0.003 μg/mL for CSF, and 0.002 μg/mL for brain homogenate. Results below this concentration were reported as less than reportable (LTR).

The results of the pharmacokinetic analysis are shown in Figures 19A (plasma) and 19B (CSF) and Tables 23 and 24. Animals suspected of being positive for anti-therapeutic antibodies (ATA+) were excluded from the analysis. These data show that the introduction of the YTE mutation in the Fc region of hu37D3.v28.A4hIgG4.S228P slowed peripheral and CSF clearance of the antibody by approximately two-fold.

Table 23: Mean (±SD) Plasma Clearance and _Cmax Estimates Following a Single IV Bolus Dose

Table 24: Mean (±SD) CSF _Cmax Estimates Following a Single IV Bolus

Brain antibody concentrations were determined on days 2 and 10 post-injection as follows. Brain tissue was weighed and then homogenized in phosphate-buffered saline containing 1% NP-40 and cOmplete ^™ Mini EDTA-free protease inhibitor cocktail tablets. The homogenized brain samples were then rotated at 4°C for 1 hour, followed by 20 minutes at 14,000 rpm. The supernatant was isolated for brain antibody measurement by ELISA as described above. The results of this experiment are shown in Figures 21A-D. The concentration of antibody hu37D3.v28.A4 hIgG4-S228P.YTE in the brain and the brain:plasma concentration ratio of antibody hu37D3.v28.A4 hIgG4-S228P.YTE tended to be higher than that of antibody hu37D3.v28.A4 hIgG4.S228P.

Pharmacodynamic responses in plasma were also determined. Total Tau concentrations in _K2EDTA plasma were determined using an electrochemiluminescence (ECL) immunoassay (Roche Professional Diagnostics (RPD), Penzberg, Germany). The immunoassay was validated for quantification of total Tau in human CSF, and because of the similarity between human and cynomolgus monkey Tau, the immunoassay was deemed acceptable for measurement of cynomolgus monkey Tau in CSF and plasma. The assay captured and detected amino acids 159-224 of human and cynomolgus monkey Tau (a region present in all known isoforms), regardless of phosphorylation state. The lower limit of detection (LDL) of the assay was 1.01 pg/mL. The assay tolerated 15.0 mg/mL hu37D3.v28.A4 hIgG4-S228P.YTE.

The results of the pharmacodynamic analysis are shown in Figure 20. After excluding animals suspected of being ATA+ and another animal with a missing baseline value, there were 3 animals in each group. Unexpectedly, within the first day of dosing, plasma Tau levels increased to a greater extent in animals treated with the YTE variants than in those treated with the non-YTE variants. Furthermore, since the PK between the variants was similar at early time points, this result could not be predicted by the pharmacokinetic response (Figure 20). A more robust response was maintained throughout the sampling duration in animals treated with the YTE variants.

Example 13: Pharmacokinetics and pharmacodynamics of hu37D3.v28.A4 hIgG4-S228P.YTE in cynomolgus monkey brain

To evaluate antibody pharmacokinetics in the brain, twelve conscious cynomolgus monkeys (Macaca fascicularis) in each group were administered a single IV bolus injection of hu37D3.v28.A4 hIgG4-S228P.YTE at a dose of 50 mg/kg. Anti-gD hIgG4 was used as a control, also at a dose of 50 mg/kg. At various time points up to 42 days after dosing, plasma samples were collected to determine anti-Tau antibody concentrations. In addition, at various time points up to 42 days, two monkeys were sacrificed and brain and CSF antibody concentrations were determined.

Antibody concentrations were determined essentially as described in Example 12.

Figures 22A-B show antibody concentrations in cynomolgus monkey brain at various time points post-dose plotted on logarithmic (A) and linear (B) scales.Table 25 shows brain concentration parameters.

Table 25: Mean (±SD) Brain PK Parameter Estimates Following a Single IV Bolus

The hu37D3.v28.A4 hIgG4-S228P.YTE antibody displayed increased brain concentrations at the final time point compared to anti-gD.

Antibody concentrations were also determined in various brain regions, including the hippocampus, cerebellum, and frontal cortex. Figures 23A-C and Tables 26 to 28 show the results of this analysis.

Table 26: Mean Hippocampal PK Parameter Estimates Following a Single IV Bolus

Table 27: Mean Cerebellar PK Parameter Estimates Following a Single IV Bolus

Table 28: Mean Frontal Cortical PK Parameter Estimates Following a Single IV Bolus

The results of this experiment demonstrate exposure of various regions of the brain to the antibody hu37D3.v28.A4 hIgG4-S228P.YTE following a single IV injection. Overall exposure in the brain was comparable between the two groups, however, similar to observations in plasma, at the final time point, antibody concentrations in the brain increased approximately two-fold in animals given the antibody hu37D3.v28.A4 hIgG4-S228P.YTE compared to those given anti-gD. See Figure 23. These results suggest that higher trough (final) concentrations are maintained in the brain following administration of the YTE antibody.

Antibody concentrations in CSF and plasma were also determined over time. Figures 23D (CSF) and 23E (plasma) and Tables 29 and 30 show the results of this analysis.

Table 29: Mean CSF PK Parameter Estimates Following a Single IV Bolus

Table 30: Mean Plasma PK Parameter Estimates Following a Single IV Bolus

Again, similar to the plasma and brain pharmacokinetics, antibody concentrations in CSF and plasma increased approximately two-fold at the final time point in animals given antibody hu37D3.v28.A4 hIgG4-S228P.YTE compared to anti-gD. See Figure 23.

The plasma pharmacodynamics of antibody hu37D3.v28.A4 hIgG4-S228P.YTE and a control antibody were assessed following a single IV 50 mg/kg dose using plasma samples collected from cynomolgus monkeys. Plasma Tau was quantified using the immunoassay described in Example 12.

The results of the pharmacodynamic analysis are shown in Figures 24A-B. Figure 24A shows the mean total plasma Tau concentration normalized to baseline. Figure 24B shows the total plasma Tau concentration of individual monkeys in the study normalized to baseline. Similar to the results observed in Example 12, administration of the antibody hu37D3.v28.A4 hIgG4-S228P.YTE resulted in significantly increased plasma Tau levels. While not intending to be bound by any particular theory, these data suggest that hu37D3.v28.A4 hIgG4-S228P.YTE binds to Tau in the brain and, as a result, Tau is cleared from the brain to the periphery. These results are consistent with target engagement of hu37D3.v28.A4 hIgG4-S228P.YTE in the brain.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, the illustration and example should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific literature cited herein are expressly incorporated by reference in their entirety.

Sequence Listing

Sequence Listing

<110> AC IMMUNE SA

GENENTECH, INC.

ADOLFSSON, Oskar

AYALON, Gai

HOTZEL, Isidro

DICARA, Danielle

<120> Anti-TAU antibodies and methods of use

<130> 01147-0006-00PCT

<140> PCT/US16/35409

<141> 2016-06-02

<150> US 62/171,693

<151> 2015-06-05

<160> 602

<170> PatentIn Version 3.5

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<223> Synthesis: 37D3-H9 heavy chain variable region (VH)

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<220>

<223> Synthesis: 37D3-H9 light chain variable region (VL)

<400> 11

Asp Asp Leu Leu Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Phe Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser Leu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 12

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 37D3-H9 HVR-H1

<400> 12

Ser Tyr Gly Met Ser

1 5

<210> 13

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 37D3-H9 HVR-H2

<400> 13

Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val Lys

1 5 10 15

Gly

<210> 14

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 37D3-H9 HVR-H3

<400> 14

Ser Tyr Ser Gly Ala Met Asp Tyr

1 5

<210> 15

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 37D3-H9 HVR-L1

<400> 15

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 16

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 37D3-H9 HVR-L2

<400> 16

Lys Val Ser Asn Arg Phe Ser

1 5

<210> 17

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 37D3-H9 HVR-L3

<400> 17

Phe Gln Gly Ser Leu Val Pro Trp Thr

1 5

<210> 18

<400> 18

000

<210> 19

<400> 19

000

<210> 20

<211> 117

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 37D3-H9b heavy chain variable region (VH)

<400> 20

Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Ala Lys Pro Gly Gly

1 5 10 15

Ser Leu Lys Leu Ser Cys Thr Ala Ser Gly Leu Ile Phe Arg Ser Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu Glu Trp Val

35 40 45

Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser

100 105 110

Val Thr Val Ser Ser

115

<210> 21

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 37D3-H9b light chain variable region (VL)

<400> 21

Glu Asp Leu Leu Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Phe Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser Leu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 22

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 37D3-H9b HVR-H1

<400> 22

Ser Tyr Gly Met Ser

1 5

<210> 23

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 37D3-H9b HVR-H2

<400> 23

Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val Lys

1 5 10 15

Gly

<210> 24

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 37D3-H9b HVR-H3

<400> 24

Ser Tyr Ser Gly Ala Met Asp Tyr

1 5

<210> 25

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 37D3-H9b HVR-L1

<400> 25

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 26

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 37D3-H9b HVR-L2

<400> 26

Lys Val Ser Asn Arg Phe Ser

1 5

<210> 27

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 37D3-H9b HVR-L3

<400> 27

Phe Gln Gly Ser Leu Val Pro Trp Thr

1 5

<210> 28

<400> 28

000

<210> 29

<400> 29

000

<210> 30

<211> 117

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 11E10-B8 heavy chain variable region (VH)

<400> 30

Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu Glu Trp Val

35 40 45

Ala Thr Ile Ser Gly Gly Gly Ser Tyr Thr Tyr Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Val Ser Tyr Asp Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser

100 105 110

Val Thr Val Ser Ser

115

<210> 31

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 11E10-B8 light chain variable region (VL)

<400> 31

Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Leu Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 32

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 11E10-B8 HVR-H1

<400> 32

Ser Tyr Gly Met Ser

1 5

<210> 33

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 11E10-B8 HVR-H2

<400> 33

Thr Ile Ser Gly Gly Gly Ser Tyr Thr Tyr Tyr Pro Asp Ser Val Lys

1 5 10 15

Gly

<210> 34

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 11E10-B8 HVR-H3

<400> 34

Ser Tyr Asp Gly Ala Met Asp Tyr

1 5

<210> 35

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 11E10-B8 HVR-L1

<400> 35

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 36

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 11E10-B8 HVR-L2

<400> 36

Lys Val Ser Asn Arg Phe Ser

1 5

<210> 37

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 11E10-B8 HVR-L3

<400> 37

Phe Gln Gly Ser His Val Pro Trp Thr

1 5

<210> 38

<400> 38

000

<210> 39

<400> 39

000

<210> 40

<211> 117

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 54C1-H11 and 61E7-C4 heavy chain variable regions (VH)

<400> 40

Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Lys Val Ser Cys Val Ala Ser Gly Phe Thr Phe Arg Ser Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu Asp Trp Val

35 40 45

Ala Thr Ile Ser Ser Gly Gly Asn Tyr Thr Tyr Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Ser Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser

100 105 110

Val Thr Val Ser Ser

115

<210> 41

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 54C1-H11 and 61E7-C4 light chain variable regions (VL)

<400> 41

Asp Thr Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Thr Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 42

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 54C1-H11 and 61E7-C4 HVR-H1

<400> 42

Ser Tyr Gly Met Ser

1 5

<210> 43

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 54C1-H11 and 61E7-C4 HVR-H2

<400> 43

Thr Ile Ser Ser Gly Gly Asn Tyr Thr Tyr Tyr Pro Asp Ser Val Lys

1 5 10 15

Gly

<210> 44

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 54C1-H11 and 61E7-C4 HVR-H3

<400> 44

Ser Tyr Ser Gly Ala Met Asp Tyr

1 5

<210> 45

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 54C1-H11 and 61E7-C4 HVR-L1

<400> 45

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 46

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 54C1-H11 and 61E7-C4 HVR-L2

<400> 46

Thr Val Ser Asn Arg Phe Ser

1 5

<210> 47

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 54C1-H11 and 61E7-C4 HVR-L3

<400> 47

Phe Gln Gly Ser His Val Pro Trp Thr

1 5

<210> 48

<400> 48

000

<210> 49

<400> 49

000

<210> 50

<211> 117

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 3A4-H4 heavy chain variable region (VH)

<400> 50

Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu Glu Trp Val

35 40 45

Ala Thr Ile Ser Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Phe Cys

85 90 95

Ala Thr Ser Tyr Asp Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser

100 105 110

Val Thr Val Ser Ser

115

<210> 51

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 3A4-H4 light chain variable region (VL)

<400> 51

Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly

85 90 95

Thr Leu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 52

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 3A4-H4 HVR-H1

<400> 52

Ser Tyr Gly Met Ser

1 5

<210> 53

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 3A4-H4 HVR-H2

<400> 53

Thr Ile Ser Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val Lys

1 5 10 15

Gly

<210> 54

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 3A4-H4 HVR-H3

<400> 54

Ser Tyr Asp Gly Ala Met Asp Tyr

1 5

<210> 55

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 3A4-H4 HVR-L1

<400> 55

Arg Ser Ser Gln Asn Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 56

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 3A4-H4 HVR-L2

<400> 56

Lys Val Ser Asn Arg Phe Ser

1 5

<210> 57

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 3A4-H4 HVR-L3

<400> 57

Phe Gln Gly Thr Leu Val Pro Trp Thr

1 5

<210> 58

<400> 58

000

<210> 59

<400> 59

000

<210> 60

<211> 117

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 19H6-F7 heavy chain variable region (VH)

<400> 60

Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu Glu Trp Val

35 40 45

Ala Thr Ile Ser Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Pro Ser Tyr Asp Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser

100 105 110

Val Thr Val Ser Ser

115

<210> 61

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 19H6-F7 light chain variable region (VL)

<400> 61

Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser Leu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 62

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 19H6-F7 HVR-H1

<400> 62

Ser Tyr Gly Met Ser

1 5

<210> 63

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 19H6-F7 HVR-H2

<400> 63

Thr Ile Ser Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val Lys

1 5 10 15

Gly

<210> 64

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 19H6-F7 HVR-H3

<400> 64

Ser Tyr Asp Gly Ala Met Asp Tyr

1 5

<210> 65

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 19H6-F7 HVR-L1

<400> 65

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 66

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 19H6-F7 HVR-L2

<400> 66

Lys Val Ser Asn Arg Phe Ser

1 5

<210> 67

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 19H6-F7 HVR-L3

<400> 67

Phe Gln Gly Ser Leu Val Pro Trp Thr

1 5

<210> 68

<400> 68

000

<210> 69

<400> 69

000

<210> 70

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 94B2-C1 heavy chain variable region (VH)

<400> 70

Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Met Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Leu Thr Gly Tyr

20 25 30

Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Asn Leu Glu Trp Ile

35 40 45

Gly Leu Ile Ser Pro Tyr Asn Gly Val Thr Ser Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Asn Thr Ala Tyr

65 70 75 80

Met Glu Leu Leu Ser Leu Thr Phe Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Gly Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

100 105 110

Ala

<210> 71

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 94B2-C1 light chain variable region (VL)

<400> 71

Asp Val Val Met Thr Gln Thr Pro Leu Thr Leu Ser Val Thr Ile Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser

35 40 45

Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro

50 55 60

Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Trp Gln Gly

85 90 95

Thr His Phe Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 72

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 94B2-C1 HVR-H1

<400> 72

Gly Tyr Thr Met Asn

1 5

<210> 73

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 94B2-C1 HVR-H2

<400> 73

Leu Ile Ser Pro Tyr Asn Gly Val Thr Ser Tyr Asn Gln Lys Phe Lys

1 5 10 15

Gly

<210> 74

<211> 4

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 94B2-C1 HVR-H3

<400> 74

Gln Gly Ala Tyr

1

<210> 75

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 94B2-C1 HVR-L1

<400> 75

Lys Ser Ser Gln Ser Leu Leu Asp Ser Asp Gly Lys Thr Tyr Leu Asn

1 5 10 15

<210> 76

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 94B2-C1 HVR-L2

<400> 76

Leu Val Ser Lys Leu Asp Ser

1 5

<210> 77

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 94B2-C1 HVR-L3

<400> 77

Trp Gln Gly Thr His Phe Pro Trp Thr

1 5

<210> 78

<400> 78

000

<210> 79

<400> 79

000

<210> 80

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 125B11-H3 heavy chain variable region (VH)

<400> 80

Glu Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Met Lys Leu Ser Cys Val Ala Ser Arg Phe Ile Phe Ser Asn Tyr

20 25 30

Trp Met Asn Trp Val Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Val

35 40 45

Ala Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ser

65 70 75 80

Val Tyr Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Thr Gly Ile Tyr

85 90 95

Tyr Cys Thr Gly Gly Thr Thr Tyr Trp Gly Gln Gly Thr Thr Leu Thr

100 105 110

Val Ser Ser

115

<210> 81

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 125B11-H3 light chain variable region (VL)

<400> 81

Asp Ile Val Met Thr Gln Ser Gln Lys Phe Leu Ser Thr Ser Val Gly

1 5 10 15

Asp Arg Val Asn Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Gly Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Ile Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly

50 55 60

Asn Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asp Met Gln Ser

65 70 75 80

Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Phe Arg Thr Tyr Pro Tyr

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 82

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 125B11-H3 HVR-H1

<400> 82

Asn Tyr Trp Met Asn

1 5

<210> 83

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 125B11-H3 HVR-H2

<400> 83

Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu Ser

1 5 10 15

Val Lys Gly

<210> 84

<211> 4

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 125B11-H3 HVR-H3

<400> 84

Gly Thr Thr Tyr

1

<210> 85

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 125B11-H3 HVR-L1

<400> 85

Lys Ala Ser Gln Asn Val Gly Thr Ala Val Ala

1 5 10

<210> 86

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 125B11-H3 HVR-L2

<400> 86

Ser Ala Ser Ile Arg Tyr Thr

1 5

<210> 87

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 125B11-H3 HVR-L3

<400> 87

Gln Gln Phe Arg Thr Tyr Pro Tyr Thr

1 5

<210> 88

<400> 88

000

<210> 89

<400> 89

000

<210> 90

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 113F5-F7 heavy chain variable region (VH)

<400> 90

Glu Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Met Arg Leu Ser Cys Val Ala Ser Glu Phe Thr Phe Ser Asn Tyr

20 25 30

Trp Met Asn Trp Ile Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Val

35 40 45

Ala Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Ala Ser Asn Phe Ser

65 70 75 80

Val Tyr Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Thr Gly Ile Tyr

85 90 95

Tyr Cys Thr Gly Gly Thr Ser Tyr Trp Gly Gln Gly Thr Thr Leu Thr

100 105 110

Val Ser Ser

115

<210> 91

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 113F5-F7 light chain variable region (VL)

<400> 91

Asp Ile Val Met Thr Gln Ser Gln Lys Ile Met Ser Thr Ser Val Gly

1 5 10 15

Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Arg Pro Gly His Ser Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Arg Arg Phe Ser Gly Val Pro Asp Arg Phe Thr Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ile Asn Val Gln Ser

65 70 75 80

Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Phe Ser Thr Tyr Pro Tyr

85 90 95

Thr Phe Gly Val Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 92

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 113F5-F7 HVR-H1

<400> 92

Asn Tyr Trp Met Asn

1 5

<210> 93

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 113F5-F7 HVR-H2

<400> 93

Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu Ser

1 5 10 15

Val Lys Gly

<210> 94

<211> 4

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 113F5-F7 HVR-H3

<400> 94

Gly Thr Ser Tyr

1

<210> 95

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 113F5-F7 HVR-L1

<400> 95

Lys Ala Ser Gln Asn Val Gly Thr Ala Val Ala

1 5 10

<210> 96

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 113F5-F7 HVR-L2

<400> 96

Ser Ala Ser Arg Arg Phe Ser

1 5

<210> 97

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 113F5-F7 HVR-L3

<400> 97

Gln Gln Phe Ser Thr Tyr Pro Tyr Thr

1 5

<210> 98

<400> 98

000

<210> 99

<400> 99

000

<210> 100

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 26C1-B11 heavy chain variable region (VH)

<400> 100

Glu Val His Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Ser Gly Ala

1 5 10 15

Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Tyr

20 25 30

Tyr Met Tyr Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile

35 40 45

Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Phe Pro Lys Phe

50 55 60

Gln Gly Lys Ala Thr Met Thr Ala Asp Thr Ser Ser Lys Thr Ala Tyr

65 70 75 80

Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Asn Ala Trp Arg Ala Arg Ala Thr Asn Ser Ala Leu Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 101

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 26C1-B11 light chain variable region (VL)

<400> 101

Asp Val Val Met Thr Gln Thr Pro Leu Thr Leu Ser Val Thr Ile Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Arg Arg Pro Gly Gln Ser

35 40 45

Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro

50 55 60

Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Trp Gln Gly

85 90 95

Thr His Phe Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 102

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 26C1-B11 HVR-H1

<400> 102

Asp Tyr Tyr Met Tyr

1 5

<210> 103

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 26C1-B11 HVR-H2

<400> 103

Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Phe Pro Lys Phe Gln

1 5 10 15

Gly

<210> 104

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 26C1-B11 HVR-H3

<400> 104

Trp Arg Ala Arg Ala Thr Asn Ser Ala Leu Asp Tyr

1 5 10

<210> 105

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 26C1-B11 HVR-L1

<400> 105

Lys Ser Ser Gln Ser Leu Leu Asp Ser Asp Gly Lys Thr Tyr Leu Asn

1 5 10 15

<210> 106

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 26C1-B11 HVR-L2

<400> 106

Leu Val Ser Lys Leu Asp Ser

1 5

<210> 107

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 26C1-B11 HVR-L3

<400> 107

Trp Gln Gly Thr His Phe Pro Trp Thr

1 5

<210> 108

<400> 108

000

<210> 109

<400> 109

000

<210> 110

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 26C1-C8 heavy chain variable region (VH)

<400> 110

Glu Val His Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Ser Gly Ala

1 5 10 15

Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Tyr

20 25 30

Tyr Met Tyr Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile

35 40 45

Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Phe Pro Lys Phe

50 55 60

Gln Gly Lys Ala Thr Met Thr Ala Asp Thr Ser Ser Lys Thr Ala Tyr

65 70 75 80

Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Asn Ala Trp Arg Ala Arg Ala Thr Asn Ser Ala Leu Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 111

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 26C1-C8 light chain variable region (VL)

<400> 111

Asp Val Val Met Thr Gln Thr Pro Leu Thr Leu Ser Val Thr Ile Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Arg Arg Pro Gly Gln Ser

35 40 45

Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro

50 55 60

Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Trp Gln Gly

85 90 95

Thr His Phe Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 112

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 26C1-C8 HVR-H1

<400> 112

Asp Tyr Tyr Met Tyr

1 5

<210> 113

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 26C1-C8 HVR-H2

<400> 113

Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Phe Pro Lys Phe Gln

1 5 10 15

Gly

<210> 114

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 26C1-C8 HVR-H3

<400> 114

Trp Arg Ala Arg Ala Thr Asn Ser Ala Leu Asp Tyr

1 5 10

<210> 115

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 26C1-C8 HVR-L1

<400> 115

Lys Ser Ser Gln Ser Leu Leu Asp Ser Asp Gly Lys Thr Tyr Leu Asn

1 5 10 15

<210> 116

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 26C1-C8 HVR-L2

<400> 116

Leu Val Ser Lys Leu Asp Ser

1 5

<210> 117

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 26C1-C8 HVR-L3

<400> 117

Trp Gln Gly Thr His Phe Pro Trp Thr

1 5

<210> 118

<400> 118

000

<210> 119

<400> 119

000

<210> 120

<211> 117

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 30G1-B2 heavy chain variable region (VH)

<400> 120

Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala

1 5 10 15

Ser Val Thr Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Glu Met Tyr Trp Val Lys Gln Thr Pro Val His Gly Leu Glu Trp Ile

35 40 45

Gly Ala Ile Asp Pro Glu Thr Gly Asp Thr Ala Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Asn Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ile Arg Gln Tyr Gly Asn Trp Phe Pro Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ala

115

<210> 121

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 30G1-B2 light chain variable region (VL)

<400> 121

Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ala

20 25 30

Asn Gly Asn Thr Tyr Leu His Trp Phe Leu Gln Lys Pro Gly Leu Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Gly Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Thr Arg Leu Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser

85 90 95

Thr His Val Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 122

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 30G1-B2 HVR-H1

<400> 122

Asp Tyr Glu Met Tyr

1 5

<210> 123

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 30G1-B2 HVR-H2

<400> 123

Ala Ile Asp Pro Glu Thr Gly Asp Thr Ala Tyr Asn Gln Lys Phe Lys

1 5 10 15

Gly

<210> 124

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 30G1-B2 HVR-H3

<400> 124

Gln Tyr Gly Asn Trp Phe Pro Tyr

1 5

<210> 125

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 30G1-B2 HVR-L1

<400> 125

Arg Ser Ser Gln Ser Leu Val His Ala Asn Gly Asn Thr Tyr Leu His

1 5 10 15

<210> 126

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 30G1-B2 HVR-L2

<400> 126

Lys Val Ser Asn Arg Phe Ser

1 5

<210> 127

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 30G1-B2 HVR-L3

<400> 127

Ser Gln Ser Thr His Val Pro Phe Thr

1 5

<210> 128

<400> 128

000

<210> 129

<400> 129

000

<210> 130

<211> 114

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 66F5-A1 heavy chain variable region (VH)

<400> 130

Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala

1 5 10 15

Ser Val Thr Leu Ser Cys Lys Ala Ser Gly Tyr Tyr Thr Phe Ile Asp Tyr

20 25 30

Glu Met Asn Trp Val Lys Gln Thr Pro Val His Gly Leu Glu Trp Ile

35 40 45

Gly Ala Ile Asp Pro Glu Asn Gly Gly Thr Ala Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Lys Ala Ile Val Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ser Gly Pro His Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val

100 105 110

Ser Ser

<210> 131

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 66F5-A1 light chain variable region (VL)

<400> 131

Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ala Met Ser Val Gly

1 5 10 15

Gln Lys Val Thr Met Ser Cys Lys Ser Ser Ser Gln Ser Leu Leu Asn Ser

20 25 30

Ser Thr Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Ser Pro Lys Leu Leu Val Tyr Phe Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ile Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln

85 90 95

His Tyr Ser Thr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile

100 105 110

Lys

<210> 132

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 66F5-A1 HVR-H1

<400> 132

Asp Tyr Glu Met Asn

1 5

<210> 133

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 66F5-A1 HVR-H2

<400> 133

Ala Ile Asp Pro Glu Asn Gly Gly Thr Ala Tyr Asn Gln Lys Phe Lys

1 5 10 15

Gly

<210> 134

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 66F5-A1 HVR-H3

<400> 134

Pro His Phe Asp Tyr

1 5

<210> 135

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 66F5-A1 HVR-L1

<400> 135

Lys Ser Ser Gln Ser Leu Leu Asn Ser Ser Thr Gln Lys Asn Tyr Leu

1 5 10 15

Ala

<210> 136

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 66F5-A1 HVR-L2

<400> 136

Phe Ala Ser Thr Arg Glu Ser

1 5

<210> 137

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 66F5-A1 HVR-L3

<400> 137

Gln Gln His Tyr Ser Thr Pro Tyr Thr

1 5

<210> 138

<400> 138

000

<210> 139

<400> 139

000

<210> 140

<211> 119

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 123E9-A1 heavy chain variable region (VH)

<400> 140

Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Tyr Met Lys Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile

35 40 45

Gly Asp Ile Asp Pro Asn Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Ala Gly Phe Gly Asp Ser Phe Ser Phe Trp Gly Leu Gly

100 105 110

Thr Leu Val Thr Val Ser Ala

115

<210> 141

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 123E9-A1 light chain variable region (VL)

<400> 141

Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Phe Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser His Val Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 142

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 123E9-A1 HVR-H1

<400> 142

Asp Tyr Tyr Met Lys

1 5

<210> 143

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 123E9-A1 HVR-H2

<400> 143

Asp Ile Asp Pro Asn Asn Gly Gly Thr Ser Tyr Asn Gln Lys Phe Lys

1 5 10 15

Gly

<210> 144

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 123E9-A1 HVR-H3

<400> 144

Ser Ala Gly Phe Gly Asp Ser Phe Ser Phe

1 5 10

<210> 145

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 123E9-A1 HVR-L1

<400> 145

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 146

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 123E9-A1 HVR-L2

<400> 146

Lys Val Ser Asn Arg Phe Ser

1 5

<210> 147

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 123E9-A1 HVR-L3

<400> 147

Phe Gln Gly Ser His Val Pro Pro Thr

1 5

<210> 148

<400> 148

000

<210> 149

<400> 149

000

<210> 150

<211> 119

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 15C6-A7 heavy chain variable region (VH)

<400> 150

Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Met Met Thr Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Tyr Met Lys Trp Val Lys Gln Ser Asn Gly Lys Ser Leu Glu Trp Ile

35 40 45

Gly Asp Leu Asp Pro Tyr Thr Gly Gly Ala Asn Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met His Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Arg Gly Tyr Gly Asp Ser Phe Ala Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ala

115

<210> 151

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 15C6-A7 light chain variable region (VL)

<400> 151

Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Phe Gln Gly

85 90 95

Ser His Val Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 152

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 15C6-A7 HVR-H1

<400> 152

Asp Tyr Tyr Met Lys

1 5

<210> 153

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 15C6-A7 HVR-H2

<400> 153

Asp Leu Asp Pro Tyr Thr Gly Gly Ala Asn Tyr Asn Gln Lys Phe Lys

1 5 10 15

Gly

<210> 154

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 15C6-A7 HVR-H3

<400> 154

Ser Arg Gly Tyr Gly Asp Ser Phe Ala Tyr

1 5 10

<210> 155

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 15C6-A7 HVR-L1

<400> 155

Arg Ser Ser Gln Asn Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 156

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 15C6-A7 HVR-L2

<400> 156

Lys Val Ser Asn Arg Phe Ser

1 5

<210> 157

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 15C6-A7 HVR-L3

<400> 157

Phe Gln Gly Ser His Val Pro Pro Thr

1 5

<210> 158

<400> 158

000

<210> 159

<400> 159

000

<210> 160

<211> 119

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 19F8-B1 heavy chain variable region (VH)

<400> 160

Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Tyr Met Lys Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile

35 40 45

Gly Asp Leu Asn Pro Asn Asn Gly Gly Thr Leu Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Gln Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Phe Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Ala Gly Tyr Gly Asp Ser Phe Ala Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ala

115

<210> 161

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 19F8-B1 light chain variable region (VL)

<400> 161

Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Ile Tyr Phe Cys Phe Gln Gly

85 90 95

Ser His Val Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 162

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 19F8-B1 HVR-H1

<400> 162

Asp Tyr Tyr Met Lys

1 5

<210> 163

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 19F8-B1 HVR-H2

<400> 163

Asp Leu Asn Pro Asn Asn Gly Gly Thr Leu Tyr Asn Gln Lys Phe Lys

1 5 10 15

Gly

<210> 164

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 19F8-B1 HVR-H3

<400> 164

Ser Ala Gly Tyr Gly Asp Ser Phe Ala Tyr

1 5 10

<210> 165

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 19F8-B1 HVR-L1

<400> 165

Arg Ser Ser Gln Asn Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 166

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 19F8-B1 HVR-L2

<400> 166

Lys Val Ser Asn Arg Phe Ser

1 5

<210> 167

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 19F8-B1 HVR-L3

<400> 167

Phe Gln Gly Ser His Val Pro Pro Thr

1 5

<210> 168

<400> 168

000

<210> 169

<400> 169

000

<210> 170

<211> 119

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 24A11-D5 heavy chain variable region (VH)

<400> 170

Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Tyr Met Lys Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile

35 40 45

Gly Asp Leu Asn Pro Lys Asn Gly Gly Ile Ile Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Gln Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Phe Tyr Cys

85 90 95

Ala Arg Ser Gly Gly Tyr Gly Asp Ser Phe Ala Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ala

115

<210> 171

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 24A11-D5 light chain variable region (VL)

<400> 171

Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Ile Tyr Phe Cys Phe Gln Gly

85 90 95

Ser His Val Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 172

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 24A11-D5 HVR-H1

<400> 172

Asp Tyr Tyr Met Lys

1 5

<210> 173

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 24A11-D5 HVR-H2

<400> 173

Asp Leu Asn Pro Lys Asn Gly Gly Ile Ile Tyr Asn Gln Lys Phe Lys

1 5 10 15

Gly

<210> 174

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 24A11-D5 HVR-H3

<400> 174

Ser Gly Gly Tyr Gly Asp Ser Phe Ala Tyr

1 5 10

<210> 175

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 24A11-D5 HVR-L1

<400> 175

Arg Ser Ser Gln Asn Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 176

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 24A11-D5 HVR-L2

<400> 176

Lys Val Ser Asn Arg Phe Ser

1 5

<210> 177

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 24A11-D5 HVR-L3

<400> 177

Phe Gln Gly Ser His Val Pro Pro Thr

1 5

<210> 178

<400> 178

000

<210> 179

<400> 179

000

<210> 180

<211> 114

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 126F11-G11 heavy chain variable region (VH)

<400> 180

Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala

1 5 10 15

Ser Val Lys Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Lys Asp Asp

20 25 30

Tyr Met His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile

35 40 45

Gly Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Ala Ser Lys Phe

50 55 60

Gln Gly Lys Ala Thr Ile Thr Thr Asp Thr Ser Ser Asn Thr Ala Tyr

65 70 75 80

Leu Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Leu Asp Phe Ala Tyr Gly Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val

100 105 110

Ser Ser

<210> 181

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 126F11-G11 light chain variable region (VL)

<400> 181

Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser His Val Pro Pro Ala Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 182

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 126F11-G11 HVR-H1

<400> 182

Asp Asp Tyr Met His

1 5

<210> 183

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 126F11-G11 HVR-H2

<400> 183

Trp Ile Asp Pro Glu Asn Gly Asp Thr Glu Tyr Ala Ser Lys Phe Gln

1 5 10 15

Gly

<210> 184

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 126F11-G11 HVR-H3

<400> 184

Phe Ala Tyr Gly Tyr

1 5

<210> 185

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 126F11-G11 HVR-L1

<400> 185

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 186

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 126F11-G11 HVR-L2

<400> 186

Lys Val Ser Asn Arg Phe Ser

1 5

<210> 187

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 126F11-G11 HVR-L3

<400> 187

Phe Gln Gly Ser His Val Pro Pro Ala

1 5

<210> 188

<400> 188

000

<210> 189

<400> 189

000

<210> 190

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 89F4-A1 heavy chain variable region (VH)

<400> 190

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly

1 5 10 15

Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Ala Tyr Phe Ala Asp

50 55 60

Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Thr Met

65 70 75 80

Leu Tyr Leu Gln Met Asn Asn Leu Lys Ser Glu Asp Thr Ala Met Tyr

85 90 95

Tyr Cys Val Ser Gly Gly Asn Tyr Val Pro Phe Ala Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ala

115 120

<210> 191

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 89F4-A1 light chain variable region (VL)

<400> 191

Asn Ile Met Met Thr Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly

1 5 10 15

Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Val Phe Tyr Ser

20 25 30

Ser Glu Gln Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Ser Pro Lys Leu Leu Ile Ser Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Val Gln Gly Glu Asp Leu Ala Val Tyr Tyr Cys His Gln

85 90 95

Tyr Leu Ser Ser Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 192

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 89F4-A1 HVR-H1

<400> 192

Thr Tyr Ala Met Asn

1 5

<210> 193

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 89F4-A1 HVR-H2

<400> 193

Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Ala Tyr Phe Ala Asp Ser

1 5 10 15

Val Lys Asp

<210> 194

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 89F4-A1 HVR-H3

<400> 194

Gly Gly Asn Tyr Val Pro Phe Ala Tyr

1 5

<210> 195

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 89F4-A1 HVR-L1

<400> 195

Lys Ser Ser Gln Ser Val Phe Tyr Ser Ser Glu Gln Arg Asn Tyr Leu

1 5 10 15

Ala

<210> 196

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 89F4-A1 HVR-L2

<400> 196

Trp Ala Ser Thr Arg Glu Ser

1 5

<210> 197

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 89F4-A1 HVR-L3

<400> 197

His Gln Tyr Leu Ser Ser Phe Thr

1 5

<210> 198

<400> 198

000

<210> 199

<400> 199

000

<210> 200

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 93A8-D2 heavy chain variable region (VH)

<400> 200

Glu Val Gln Leu Gln Gln Ser Gly Pro Val Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Tyr Val Asn Trp Val Lys Gln Ser His Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Leu Ile Asn Pro Asn Asn Gly Arg Thr Ser Tyr Asn Gln Asn Phe

50 55 60

Asn Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Phe

65 70 75 80

Met Asp Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Glu Gly Gly Thr Gly Tyr Trp Gly Gln Gly Thr Thr Leu Ser

100 105 110

Val Ser Ser

115

<210> 201

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 93A8-D2 light chain variable region (VL)

<400> 201

Asp Val Val Met Thr Gln Thr Pro Leu Thr Leu Ser Val Thr Ile Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Arg Pro Gly Gln Ser

35 40 45

Pro Arg Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro

50 55 60

Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Ala Ala Glu Asp Leu Gly Val Tyr Tyr Cys Trp Gln Gly

85 90 95

Thr His Phe Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 202

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 93A8-D2 HVR-H1

<400> 202

Asp Tyr Tyr Val Asn

1 5

<210> 203

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 93A8-D2 HVR-H2

<400> 203

Leu Ile Asn Pro Asn Asn Gly Arg Thr Ser Tyr Asn Gln Asn Phe Asn

1 5 10 15

Asp

<210> 204

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 93A8-D2 HVR-H3

<400> 204

Glu Gly Gly Thr Gly Tyr

1 5

<210> 205

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 93A8-D2 HVR-L1

<400> 205

Lys Ser Ser Gln Ser Leu Leu Asp Ser Asp Gly Lys Thr Tyr Leu Asn

1 5 10 15

<210> 206

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 93A8-D2 HVR-L2

<400> 206

Leu Val Ser Lys Leu Asp Ser

1 5

<210> 207

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 93A8-D2 HVR-L3

<400> 207

Trp Gln Gly Thr His Phe Pro Arg Thr

1 5

<210> 208

<400> 208

000

<210> 209

<400> 209

000

<210> 210

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 14F5-D9 heavy chain variable region (VH)

<400> 210

Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Thr Ser Gly Phe Thr Phe Ser Asp Phe

20 25 30

Tyr Met Glu Trp Val Arg Gln Ser Pro Gly Lys Arg Leu Glu Trp Ile

35 40 45

Ala Ala Ser Lys Asn Lys Ala Asn Asp Tyr Thr Thr Glu Tyr Asn Ala

50 55 60

Ser Val Lys Asp Arg Phe Phe Val Ser Arg Asp Thr Ser Gln Ser Ile

65 70 75 80

Leu Tyr Leu Gln Met Asn Ala Leu Arg Ala Glu Asp Thr Ala Ile Tyr

85 90 95

Tyr Cys Ala Arg Asp Ala Leu Gly Thr Val Phe Ala Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ala

115 120

<210> 211

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 14F5-D9 light chain variable region (VL)

<400> 211

Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Phe Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser

85 90 95

Thr Leu Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105 110

<210> 212

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 14F5-D9 HVR-H1

<400> 212

Asp Phe Tyr Met Glu

1 5

<210> 213

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 14F5-D9 HVR-H2

<400> 213

Ala Ser Lys Asn Lys Ala Asn Asp Tyr Thr Thr Glu Tyr Asn Ala Ser

1 5 10 15

Val Lys Asp

<210> 214

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 14F5-D9 HVR-H3

<400> 214

Asp Ala Leu Gly Thr Val Phe Ala Tyr

1 5

<210> 215

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 14F5-D9 HVR-L1

<400> 215

Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His

1 5 10 15

<210> 216

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 14F5-D9 HVR-L2

<400> 216

Lys Val Phe Asn Arg Phe Ser

1 5

<210> 217

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 14F5-D9 HVR-L3

<400> 217

Ser Gln Ser Thr Leu Val Pro Leu Thr

1 5

<210> 218

<400> 218

000

<210> 219

<400> 219

000

<210> 220

<211> 122

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 73H6-B8 heavy chain variable region (VH)

<400> 220

Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln

1 5 10 15

Ser Leu Ser Ile Thr Cys Thr Ile Ser Gly Phe Ser Leu Thr Ser Tyr

20 25 30

Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu

35 40 45

Val Val Ile Trp Ser Asp Gly Ser Thr Thr Tyr Asn Ser Ala Leu Lys

50 55 60

Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu

65 70 75 80

Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala

85 90 95

Arg Gln Gly Gly Phe Ile Thr Thr Ala Tyr Tyr Ala Met Asp Tyr Trp

100 105 110

Gly Gln Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 221

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 73H6-B8 light chain variable region (VL)

<400> 221

Asp Ile Val Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly

1 5 10 15

Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser

20 25 30

Arg Thr Arg Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Lys Gln

85 90 95

Ser Tyr Asn Leu Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 222

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 73H6-B8 HVR-H1

<400> 222

Ser Tyr Gly Val His

1 5

<210> 223

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 73H6-B8 HVR-H2

<400> 223

Val Ile Trp Ser Asp Gly Ser Thr Thr Tyr Asn Ser Ala Leu Lys Ser

1 5 10 15

<210> 224

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 73H6-B8 HVR-H3

<400> 224

Gln Gly Gly Phe Ile Thr Thr Ala Tyr Tyr Ala Met Asp Tyr

1 5 10

<210> 225

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 73H6-B8 HVR-L1

<400> 225

Lys Ser Ser Gln Ser Leu Leu Asn Ser Arg Thr Arg Lys Asn Tyr Leu

1 5 10 15

Ala

<210> 226

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 73H6-B8 HVR-L2

<400> 226

Trp Ala Ser Thr Arg Glu Ser

1 5

<210> 227

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 73H6-B8 HVR-L3

<400> 227

Lys Gln Ser Tyr Asn Leu Tyr Thr

1 5

<210> 228

<400> 228

000

<210> 229

<400> 229

000

<210> 230

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 22G7-C9 heavy chain variable region (VH)

<400> 230

Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu

1 5 10 15

Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Cys

20 25 30

Ser Ile His Trp Val Lys Gln Ala Pro Gly Glu Gly Leu Lys Trp Met

35 40 45

Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Ser Tyr Ala Asp Asp Phe

50 55 60

Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Phe

65 70 75 80

Leu Gln Ile Asn Asn Leu Lys Ser Glu Asp Thr Ala Ser Tyr Phe Cys

85 90 95

Gly Thr Ala Tyr Tyr Arg Tyr Asp Gly Ala Leu Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 231

<211> 111

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 22G7-C9 light chain variable region (VL)

<400> 231

Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Gln Ser Val Ser Thr Ser

20 25 30

Ser Tyr Ser Tyr Met His Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Glu Ser Gly Val Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His

65 70 75 80

Pro Val Glu Glu Glu Asp Thr Ala Thr Tyr Tyr Cys Gln His Ser Trp

85 90 95

Glu Leu Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 232

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 22G7-C9 HVR-H1

<400> 232

Asp Cys Ser Ile His

1 5

<210> 233

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 22G7-C9 HVR-H2

<400> 233

Trp Ile Asn Thr Glu Thr Gly Glu Pro Ser Tyr Ala Asp Asp Phe Lys

1 5 10 15

Gly

<210> 234

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 22G7-C9 HVR-H3

<400> 234

Ala Tyr Tyr Arg Tyr Asp Gly Ala Leu Asp Tyr

1 5 10

<210> 235

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 22G7-C9 HVR-L1

<400> 235

Arg Ala Ser Gln Ser Val Ser Thr Ser Ser Tyr Ser Tyr Met His

1 5 10 15

<210> 236

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 22G7-C9 HVR-L2

<400> 236

Tyr Ala Ser Asn Leu Glu Ser

1 5

<210> 237

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 22G7-C9 HVR-L3

<400> 237

Gln His Ser Trp Glu Leu Pro Trp Thr

1 5

<210> 238

<400> 238

000

<210> 239

<400> 239

000

<210> 240

<211> 116

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 7A11-C12 heavy chain variable region (VH)

<400> 240

Gln Ile Gln Leu Val Gln Ser Gly Pro Asp Leu Lys Lys Pro Gly Glu

1 5 10 15

Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met

35 40 45

Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr Tyr Ala Glu Glu Phe

50 55 60

Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr

65 70 75 80

Leu Gln Ile Asp Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Gly Thr Val Ser Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ala

115

<210> 241

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 7A11-C12 light chain variable region (VL)

<400> 241

Asp Val Val Met Ser Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp His Ala Ser Ile Ser Cys Arg Ser Ser Gln Asn Leu Val His Ser

20 25 30

Asp Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe Cys Ser Gln Ser

85 90 95

Thr His Val Ile Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 242

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 7A11-C12 HVR-H1

<400> 242

Asn Tyr Gly Met Asn

1 5

<210> 243

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 7A11-C12 HVR-H2

<400> 243

Trp Ile Asn Thr Asn Thr Gly Glu Pro Thr Tyr Ala Glu Glu Phe Lys

1 5 10 15

Gly

<210> 244

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 7A11-C12 HVR-H3

<400> 244

Gly Thr Val Ser Phe Pro Tyr

1 5

<210> 245

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 7A11-C12 HVR-L1

<400> 245

Arg Ser Ser Gln Asn Leu Val His Ser Asp Gly Asn Thr Tyr Leu His

1 5 10 15

<210> 246

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 7A11-C12 HVR-L2

<400> 246

Lys Val Ser Asn Arg Phe Ser

1 5

<210> 247

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 7A11-C12 HVR-L3

<400> 247

Ser Gln Ser Thr His Val Ile Phe Thr

1 5

<210> 248

<400> 248

000

<210> 249

<400> 249

000

<210> 250

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 12A10-E8 heavy chain variable region (VH)

<400> 250

Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu

1 5 10 15

Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met

35 40 45

Gly Trp Ile Asn Met Tyr Thr Gly Glu Pro Thr Tyr Gly Asp Asp Phe

50 55 60

Lys Gly Arg Phe Val Phe Ser Leu Glu Thr Ser Val Ser Thr Val Tyr

65 70 75 80

Leu Gln Ile Asn Asn Leu Lys Lys Glu Asp Thr Ala Thr Phe Phe Cys

85 90 95

Ala Arg Gly Gly Arg Pro Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr

100 105 110

Val Ser Ser

115

<210> 251

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 12A10-E8 light chain variable region (VL)

<400> 251

Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly

1 5 10 15

Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Phe Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Asn Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Leu Gln Gly

85 90 95

Ser His Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 252

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 12A10-E8 HVR-H1

<400> 252

Asn Tyr Gly Met Asn

1 5

<210> 253

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 12A10-E8 HVR-H2

<400> 253

Trp Ile Asn Met Tyr Thr Gly Glu Pro Thr Tyr Gly Asp Asp Phe Lys

1 5 10 15

Gly

<210> 254

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 12A10-E8 HVR-H3

<400> 254

Gly Gly Arg Pro Asp Tyr

1 5

<210> 255

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 12A10-E8 HVR-L1

<400> 255

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 256

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 1 2A10-E8 HVR-L2

<400> 256

Lys Val Phe Asn Arg Phe Ser

1 5

<210> 257

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 12A10-E8 HVR-L3

<400> 257

Leu Gln Gly Ser His Val Pro Tyr Thr

1 5

<210> 258

<400> 258

000

<210> 259

<400> 259

000

<210> 260

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 55E7-F11 heavy chain variable region (VH)

<400> 260

Glu Val Lys Leu Glu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Met Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr

20 25 30

Trp Met Asn Trp Val Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Val

35 40 45

Ala Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ser

65 70 75 80

Val Tyr Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Thr Gly Ile Tyr

85 90 95

Tyr Cys Ala Gly Tyr Phe Tyr Gly Gly Tyr Phe Asp Val Trp Gly Thr

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 261

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 55E7-F11 light chain variable region (VL)

<400> 261

Glu Leu Val Leu Thr Gln Ser Pro Thr Thr Met Ala Ala Ser Pro Gly

1 5 10 15

Lys Lys Ile Thr Ile Thr Cys Ser Ala Ser Ser Ser Ile Ser Ser Asn

20 25 30

Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Phe Ser Pro Lys Leu Leu

35 40 45

Ile Tyr Arg Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Gly Thr Met Glu

65 70 75 80

Ala Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Gly Ser Ser Leu Pro

85 90 95

Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 262

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 55E7-F11 HVR-H1

<400> 262

Asn Tyr Trp Met Asn

1 5

<210> 263

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 55E7-F11 HVR-H2

<400> 263

Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu Ser

1 5 10 15

Val Lys Gly

<210> 264

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 55E7-F11 HVR-H3

<400> 264

Tyr Phe Tyr Gly Gly Tyr Phe Asp Val

1 5

<210> 265

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 55E7-F11 HVR-L1

<400> 265

Ser Ala Ser Ser Ser Ile Ser Ser Asn Tyr Leu His

1 5 10

<210> 266

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 55E7-F11 HVR-L2

<400> 266

Arg Thr Ser Asn Leu Ala Ser

1 5

<210> 267

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 55E7-F11 HVR-L3

<400> 267

Gln Gln Gly Ser Ser Leu Pro Phe Thr

1 5

<210> 268

<400> 268

000

<210> 269

<400> 269

000

<210> 270

<211> 117

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 52F6-F11 heavy chain variable region (VH)

<400> 270

Gln Val Gln Leu Gln Gln Ser Gly Thr Glu Leu Ala Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr His Tyr

20 25 30

Trp Met His Trp Ile Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Tyr Pro Thr Asn Asp Tyr Thr Lys Tyr Asn Gln Asn Phe

50 55 60

Arg Asp Lys Ala Thr Leu Thr Ala Asp Glu Ser Ser Asn Ser Ala Tyr

65 70 75 80

Met Gln Leu Asn Ser Leu Thr Tyr Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ala Gly Asn Arg Val Phe Asp Phe Trp Gly Gln Gly Thr Thr

100 105 110

Leu Thr Val Ser Ser

115

<210> 271

<211> 109

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 52F6-F11 light chain variable region (VL)

<400> 271

Gln Ala Val Val Thr Gln Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu

1 5 10 15

Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Ser

20 25 30

Asn Phe Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly

35 40 45

Leu Ile Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala

65 70 75 80

Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Ser Asn

85 90 95

Leu Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 272

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 52F6-F11 HVR-H1

<400> 272

His Tyr Trp Met His

1 5

<210> 273

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 52F6-F11 HVR-H2

<400> 273

Tyr Ile Tyr Pro Thr Asn Asp Tyr Thr Lys Tyr Asn Gln Asn Phe Arg

1 5 10 15

Asp

<210> 274

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 52F6-F11 HVR-H3

<400> 274

Ala Gly Asn Arg Val Phe Asp Phe

1 5

<210> 275

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 52F6-F11 HVR-L1

<400> 275

Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Phe Ala Asn

1 5 10

<210> 276

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 52F6-F11 HVR-L2

<400> 276

Gly Thr Asn Asn Arg Ala Pro

1 5

<210> 277

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: 52F6-F11 HVR-L3

<400> 277

Ala Leu Trp Tyr Ser Asn Leu Trp Val

1 5

<210> 278

<400> 278

000

<210> 279

<400> 279

000

<210> 280

<211> 117

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v1 heavy chain variable region (VH)

<400> 280

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 281

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v1 light chain variable region (VL)

<400> 281

Glu Asp Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Ser Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Phe Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile

65 70 75 80

Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser Leu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 282

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v1 HVR-H1

<400> 282

Ser Tyr Gly Met Ser

1 5

<210> 283

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v1 HVR-H2

<400> 283

Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val Lys

1 5 10 15

Gly

<210> 284

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v1 HVR-H3

<400> 284

Ser Tyr Ser Gly Ala Met Asp Tyr

1 5

<210> 285

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v1 HVR-L1

<400> 285

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 286

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v1 HVR-L2

<400> 286

Lys Val Ser Asn Arg Phe Ser

1 5

<210> 287

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v1 HVR-L3

<400> 287

Phe Gln Gly Ser Leu Val Pro Trp Thr

1 5

<210> 288

<211> 447

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v1 IgG1 heavy chain

<400> 288

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu

115 120 125

Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys

130 135 140

Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser

145 150 155 160

Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser

165 170 175

Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser

180 185 190

Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn

195 200 205

Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His

210 215 220

Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val

225 230 235 240

Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr

245 250 255

Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu

260 265 270

Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys

275 280 285

Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser

290 295 300

Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys

305 310 315 320

Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile

325 330 335

Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro

340 345 350

Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu

355 360 365

Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn

370 375 380

Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser

385 390 395 400

Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg

405 410 415

Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu

420 425 430

His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 289

<211> 219

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v1 IgG1 light chain

<400> 289

Glu Asp Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Ser Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Phe Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile

65 70 75 80

Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser Leu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

115 120 125

Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe

130 135 140

Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln

145 150 155 160

Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser

165 170 175

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu

180 185 190

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser

195 200 205

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 290

<211> 117

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v5 heavy chain variable region (VH)

<400> 290

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 291

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v5 light chain variable region (VL)

<400> 291

Glu Asp Val Leu Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Phe Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser Leu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 292

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v5 HVR-H1

<400> 292

Ser Tyr Gly Met Ser

1 5

<210> 293

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v5 HVR-H2

<400> 293

Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val Lys

1 5 10 15

Gly

<210> 294

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v5 HVR-H3

<400> 294

Ser Tyr Ser Gly Ala Met Asp Tyr

1 5

<210> 295

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v5 HVR-L1

<400> 295

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 296

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v5 HVR-L2

<400> 296

Lys Val Ser Asn Arg Phe Ser

1 5

<210> 297

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v5 HVR-L3

<400> 297

Phe Gln Gly Ser Leu Val Pro Trp Thr

1 5

<210> 298

<400> 298

000

<210> 299

<400> 299

000

<210> 300

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu94B2.v105 heavy chain variable region (VH)

<400> 300

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Leu Thr Gly Tyr

20 25 30

Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Leu Ile Ser Pro Tyr Asn Gly Val Thr Ser Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Arg Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Gly Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

100 105 110

Ser

<210> 301

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu94B2.v105 light chain variable region (VL)

<400> 301

Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly

85 90 95

Thr His Phe Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 302

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu94B2.v105 HVR-H1

<400> 302

Gly Tyr Thr Met Asn

1 5

<210> 303

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu94B2.v105 HVR-H2

<400> 303

Leu Ile Ser Pro Tyr Asn Gly Val Thr Ser Tyr Asn Gln Lys Phe Lys

1 5 10 15

Gly

<210> 304

<211> 4

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu94B2.v105 HVR-H3

<400> 304

Gln Gly Ala Tyr

1

<210> 305

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu94B2.v105 HVR-L1

<400> 305

Lys Ser Ser Gln Ser Leu Leu Asp Ser Asp Gly Lys Thr Tyr Leu Asn

1 5 10 15

<210> 306

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu94B2.v105 HVR-L2

<400> 306

Leu Val Ser Lys Leu Asp Ser

1 5

<210> 307

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu94B2.v105 HVR-L3

<400> 307

Trp Gln Gly Thr His Phe Pro Trp Thr

1 5

<210> 308

<400> 308

000

<210> 309

<400> 309

000

<210> 310

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11.v17 heavy chain variable region (VH)

<400> 310

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Ile Phe Ser Asn Tyr

20 25 30

Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Thr Gly Gly Thr Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 311

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11.v17 light chain variable region (VH)

<400> 311

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Ile Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Phe Arg Thr Tyr Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 312

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11.v17 HVR-H1

<400> 312

Asn Tyr Trp Met Asn

1 5

<210> 313

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11.v17 HVR-H2

<400> 313

Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu Ser

1 5 10 15

Val Lys Gly

<210> 314

<211> 4

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11.v17 HVR-H3

<400> 314

Gly Thr Thr Tyr

1

<210> 315

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11.v17 HVR-L1

<400> 315

Lys Ala Ser Gln Asn Val Gly Thr Ala Val Ala

1 5 10

<210> 316

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11.v17 HVR-L2

<400> 316

Ser Ala Ser Ile Arg Tyr Thr

1 5

<210> 317

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11.v17 HVR-L3

<400> 317

Gln Gln Phe Arg Thr Tyr Pro Tyr Thr

1 5

<210> 318

<400> 318

000

<210> 319

<400> 319

000

<210> 320

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11.v26 heavy chain variable region (VH)

<400> 320

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Ile Phe Ser Asn Tyr

20 25 30

Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Thr Gly Gly Thr Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 321

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11.v26 light chain variable region (VH)

<400> 321

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Ile Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Phe Arg Thr Tyr Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 322

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11.v26 HVR-H1

<400> 322

Asn Tyr Trp Met Asn

1 5

<210> 323

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11.v26 HVR-H2

<400> 323

Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu Ser

1 5 10 15

Val Lys Gly

<210> 324

<211> 4

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11.v26 HVR-H3

<400> 324

Gly Thr Thr Tyr

1

<210> 325

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11.v26 HVR-L1

<400> 325

Lys Ala Ser Gln Asn Val Gly Thr Ala Val Ala

1 5 10

<210> 326

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11.v26 HVR-L2

<400> 326

Ser Ala Ser Ile Arg Tyr Thr

1 5

<210> 327

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11.v26 HVR-L3

<400> 327

Gln Gln Phe Arg Thr Tyr Pro Tyr Thr

1 5

<210> 328

<400> 328

000

<210> 329

<400> 329

000

<210> 330

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11.v28 heavy chain variable region (VH)

<400> 330

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Ile Phe Ser Asn Tyr

20 25 30

Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Thr Gly Gly Thr Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 331

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11.v28 light chain variable region (VH)

<400> 331

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Ile Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Arg Thr Tyr Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 332

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11.v28 HVR-H1

<400> 332

Asn Tyr Trp Met Asn

1 5

<210> 333

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11.v28 HVR-H2

<400> 333

Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu Ser

1 5 10 15

Val Lys Gly

<210> 334

<211> 4

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11.v28 HVR-H3

<400> 334

Gly Thr Thr Tyr

1

<210> 335

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11.v28 HVR-L1

<400> 335

Lys Ala Ser Gln Asn Val Gly Thr Ala Val Ala

1 5 10

<210> 336

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11.v28 HVR-L2

<400> 336

Ser Ala Ser Ile Arg Tyr Thr

1 5

<210> 337

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11.v28 HVR-L3

<400> 337

Gln Gln Phe Arg Thr Tyr Pro Tyr Thr

1 5

<210> 338

<400> 338

000

<210> 339

<400> 339

000

<210> 340

<211> 117

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v28.A4 heavy chain variable region (VH)

<400> 340

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 341

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v28.A4 light chain variable region (VL)

<400> 341

Asp Asp Val Leu Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser Leu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 342

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v28.A4 HVR-H1

<400> 342

Ser Tyr Gly Met Ser

1 5

<210> 343

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v28.A4 HVR-H2

<400> 343

Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val Lys

1 5 10 15

Gly

<210> 344

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v28.A4 HVR-H3

<400> 344

Ser Tyr Ser Gly Ala Met Asp Tyr

1 5

<210> 345

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v28.A4 HVR-L1

<400> 345

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 346

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v28.A4 HVR-L2

<400> 346

Lys Val Ser Asn Arg Phe Ser

1 5

<210> 347

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v28.A4 HVR-L3

<400> 347

Phe Gln Gly Ser Leu Val Pro Trp Thr

1 5

<210> 348

<211> 444

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v28.A4 IgG4-S228P.YTE heavy chain

<400> 348

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu

115 120 125

Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys

130 135 140

Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser

145 150 155 160

Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser

165 170 175

Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser

180 185 190

Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn

195 200 205

Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro

210 215 220

Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe

225 230 235 240

Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val

245 250 255

Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe

260 265 270

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro

275 280 285

Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

290 295 300

Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val

305 310 315 320

Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala

325 330 335

Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln

340 345 350

Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

355 360 365

Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro

370 375 380

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser

385 390 395 400

Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu

405 410 415

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His

420 425 430

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 349

<211> 219

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v28.A4 IgG4-S228P.YTE light chain

<400> 349

Asp Asp Val Leu Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser Leu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

115 120 125

Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe

130 135 140

Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln

145 150 155 160

Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser

165 170 175

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu

180 185 190

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser

195 200 205

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 350

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Unstressed control (average, n=9)

<400> 350

Glu Asp Leu His Ser Asn Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 351

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v5

<400> 351

Glu Asp Leu His Ser Asn Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 352

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v5.1

<400> 352

Glu Asp Leu His Ser Asn Ala Asn Thr Tyr Phe Leu

1 5 10

<210> 353

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v5.2

<400> 353

Glu Asp Leu His Ser Ser Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 354

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v5.3

<400> 354

Glu Asp Leu His Ser Asp Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 355

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v5.4

<400> 355

Glu Asp Leu His Ser Gln Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 356

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v5.5

<400> 356

Glu Asp Leu His Ser Glu Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 357

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v5.6

<400> 357

Glu Asp Leu His Ser Ala Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 358

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v5.7

<400> 358

Glu Asp Leu His Ser Asn Gly Asp Thr Tyr Phe Leu

1 5 10

<210> 359

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v5.8

<400> 359

Glu Asp Leu His Ser Asn Gly Gln Thr Tyr Phe Leu

1 5 10

<210> 360

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v5.9

<400> 360

Glu Asp Leu His Ser Asn Gly Glu Thr Tyr Phe Leu

1 5 10

<210> 361

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v5.10

<400> 361

Glu Asp Leu His Ser Asn Gly Ala Thr Tyr Phe Leu

1 5 10

<210> 362

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v5.11

<400> 362

Glu Asp Leu His Ser Asn Gly Ser Thr Tyr Phe Leu

1 5 10

<210> 363

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28

<400> 363

Asp Asp Leu His Ser Asn Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 364

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.A2

<400> 364

Asp Asp Leu His Ser Asn Gly Asn Thr Tyr Phe His

1 5 10

<210> 365

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.A4

<400> 365

Asp Asp Leu His Ser Asn Gly Asn Thr Tyr Leu Leu

1 5 10

<210> 366

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.A6

<400> 366

Asp Asp Leu His Ser Asn Gly Asn Thr Tyr Leu His

1 5 10

<210> 367

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.A8

<400> 367

Asp Asp Met His Ser Asn Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 368

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.A10

<400> 368

Asp Asp Met His Ser Asn Gly Asn Thr Tyr Phe His

1 5 10

<210> 369

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.A12

<400> 369

Asp Asp Met His Ser Asn Gly Asn Thr Tyr Leu Leu

1 5 10

<210> 370

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.A14

<400> 370

Asp Asp Met His Ser Asn Gly Asn Thr Tyr Leu His

1 5 10

<210> 371

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.A16

<400> 371

Asp Val Leu His Ser Asn Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 372

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.A18

<400> 372

Asp Val Leu His Ser Asn Gly Asn Thr Tyr Phe His

1 5 10

<210> 373

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.A20

<400> 373

Asp Val Leu His Ser Asn Gly Asn Thr Tyr Leu Leu

1 5 10

<210> 374

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.A22

<400> 374

Asp Val Leu His Ser Asn Gly Asn Thr Tyr Leu His

1 5 10

<210> 375

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.A24

<400> 375

Asp Val Met His Ser Asn Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 376

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.A26

<400> 376

Asp Val Met His Ser Asn Gly Asn Thr Tyr Phe His

1 5 10

<210> 377

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.A28

<400> 377

Asp Val Met His Ser Asn Gly Asn Thr Tyr Leu Leu

1 5 10

<210> 378

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.A30

<400> 378

Asp Val Met His Ser Asn Gly Asn Thr Tyr Leu His

1 5 10

<210> 379

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.B1

<400> 379

Asp Asp Leu His Ser Ile Gly Asn Thr Phe Phe Leu

1 5 10

<210> 380

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.B2

<400> 380

Asp Asp Leu His Ser Met Gly Asn Thr Phe Phe Leu

1 5 10

<210> 381

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.B3

<400> 381

Asp Asp Leu His Ser Gln Gly Asn Thr Trp Phe Leu

1 5 10

<210> 382

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.B4

<400> 382

Asp Asp Leu His Ser Gln Gly Asn Thr His Phe Leu

1 5 10

<210> 383

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.B6

<400> 383

Asp Asp Leu His Ser Asp Gly Asn Thr Arg Phe Leu

1 5 10

<210> 384

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.B7

<400> 384

Asp Asp Leu His Ser Asp Gly Asn Thr Lys Phe Leu

1 5 10

<210> 385

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.B8

<400> 385

Asp Asp Leu His Ser Glu Gly Asn Thr Arg Phe Leu

1 5 10

<210> 386

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.C1

<400> 386

Asp Asp Leu His Ser Asn Asn Asn Thr Tyr Phe Leu

1 5 10

<210> 387

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.C2

<400> 387

Asp Asp Leu His Ser Asn Asp Asn Thr Tyr Phe Leu

1 5 10

<210> 388

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.D1

<400> 388

Asp Asp Leu His Ala Asn Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 389

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Unstressed control (average, n=9)

<400> 389

Glu Asp Leu His Ser Asn Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 390

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.E1

<400> 390

Asp Asp Leu Asn Ser Asn Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 391

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.E2

<400> 391

Asp Asp Leu Gln Ser Asn Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 392

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.E3

<400> 392

Asp Asp Leu Asp Ser Asp Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 393

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.F1

<400> 393

Asp Asp Leu His Ser Asn Thr Asn Thr Tyr Phe Leu

1 5 10

<210> 394

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.F2

<400> 394

Asp Asp Leu His Thr Asn Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 395

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.F3

<400> 395

Asp Asp Leu His Thr Asn Ala Asn Thr Tyr Phe Leu

1 5 10

<210> 396

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.51

<400> 396

Glu Asp Leu His Ser His Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 397

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.52

<400> 397

Glu Asp Leu His Ser Lys Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 398

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.53

<400> 398

Glu Asp Leu His Ser Arg Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 399

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.54

<400> 399

Glu Asp Leu His Ser Leu Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 400

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.55

<400> 400

Asp Asp Leu His Ser Asn Gln Asn Thr Tyr Phe Leu

1 5 10

<210> 401

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.56

<400> 401

Asp Asp Leu His Ser Asn Tyr Asn Thr Tyr Tyr Phe Leu

1 5 10

<210> 402

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v28.57

<400> 402

Asp Asp Leu His Ser Asn Phe Asn Thr Tyr Phe Leu

1 5 10

<210> 403

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v29.1

<400> 403

Glu Asp Leu His Ser Asn Gly Asp Thr Tyr Phe Leu

1 5 10

<210> 404

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v29.2

<400> 404

Glu Asp Leu His Ser Asn Gly Gln Thr Tyr Phe Leu

1 5 10

<210> 405

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v29.3

<400> 405

Glu Asp Leu His Ser Asn Gly Glu Thr Tyr Phe Leu

1 5 10

<210> 406

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v29.4

<400> 406

Glu Asp Leu His Ser Asn Gly Ala Thr Tyr Phe Leu

1 5 10

<210> 407

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v29.5

<400> 407

Glu Asp Leu His Ser Asn Gly His Thr Tyr Phe Leu

1 5 10

<210> 408

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v29.6

<400> 408

Glu Asp Leu His Ser Asn Gly Lys Thr Tyr Phe Leu

1 5 10

<210> 409

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v29.7

<400> 409

Glu Asp Leu His Ser Asn Gly Leu Thr Tyr Phe Leu

1 5 10

<210> 410

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v29.8

<400> 410

Glu Asp Leu His Ser Asn Ala Asp Thr Tyr Phe Leu

1 5 10

<210> 411

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v29.9

<400> 411

Glu Asp Leu His Ser Asn Ala Gln Thr Tyr Phe Leu

1 5 10

<210> 412

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v29.10

<400> 412

Glu Asp Leu His Ser Asn Ala Glu Thr Tyr Phe Leu

1 5 10

<210> 413

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v29.11

<400> 413

Glu Asp Leu His Ser Asn Ala Ala Thr Tyr Phe Leu

1 5 10

<210> 414

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v29.12

<400> 414

Glu Asp Leu His Ser Asn Ala His Thr Tyr Phe Leu

1 5 10

<210> 415

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v29.13

<400> 415

Glu Asp Leu His Ser Asn Ala Lys Thr Tyr Phe Leu

1 5 10

<210> 416

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3.v29.14

<400> 416

Glu Asp Leu His Ser Asn Ala Leu Thr Tyr Phe Leu

1 5 10

<210> 417

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v30.1

<400> 417

Asp Asp Leu His Ser Gly Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 418

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v30.2

<400> 418

Asp Asp Leu His Ser Thr Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 419

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v30.3

<400> 419

Asp Asp Leu His Ser Val Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 420

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v30.4

<400> 420

Asp Asp Leu His Ser Leu Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 421

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v30.5

<400> 421

Asp Asp Leu His Ser Ile Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 422

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v30.6

<400> 422

Asp Asp Leu His Ser Pro Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 423

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v30.7

<400> 423

Asp Asp Leu His Ser Phe Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 424

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v30.8

<400> 424

Asp Asp Leu His Ser Tyr Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 425

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v30.9

<400> 425

Asp Asp Leu His Ser His Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 426

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v30.10

<400> 426

Asp Asp Leu His Ser Lys Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 427

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v30.11

<400> 427

Asp Asp Leu His Ser Arg Gly Asn Thr Tyr Phe Leu

1 5 10

<210> 428

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v31.1

<400> 428

Asp Asp Leu His Ser Asn Ala Gly Thr Tyr Phe Leu

1 5 10

<210> 429

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v31.2

<400> 429

Asp Asp Leu His Ser Asn Ala Val Thr Tyr Phe Leu

1 5 10

<210> 430

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v31.3

<400> 430

Asp Asp Leu His Ser Asn Ala Ile Thr Tyr Phe Leu

1 5 10

<210> 431

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v31.4

<400> 431

Asp Asp Leu His Ser Asn Ala Pro Thr Tyr Phe Leu

1 5 10

<210> 432

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v31.5

<400> 432

Asp Asp Leu His Ser Asn Ala Phe Thr Tyr Phe Leu

1 5 10

<210> 433

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v31.6

<400> 433

Asp Asp Leu His Ser Asn Ala Tyr Thr Tyr Phe Leu

1 5 10

<210> 434

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v31.7

<400> 434

Asp Asp Leu His Ser Asn Ala Arg Thr Tyr Phe Leu

1 5 10

<210> 435

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v31.8

<400> 435

Asp Asp Leu His Ser Asn Ala Asn Val Tyr Phe Leu

1 5 10

<210> 436

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v31.9

<400> 436

Asp Asp Leu His Ser Asn Ala Asn Ile Tyr Phe Leu

1 5 10

<210> 437

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v31.10

<400> 437

Asp Asp Leu His Ser Asn Ala Asn Pro Tyr Phe Leu

1 5 10

<210> 438

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v31.11

<400> 438

Asp Asp Leu His Ser Asn Ala Asn Phe Tyr Phe Leu

1 5 10

<210> 439

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v31.12

<400> 439

Asp Asp Leu His Ser Asn Ala Asn Tyr Tyr Phe Leu

1 5 10

<210> 440

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v31.13

<400> 440

Asp Asp Leu His Ser Asn Ala Asn Asn Tyr Phe Leu

1 5 10

<210> 441

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu37D3-H9.v31.14

<400> 441

Asp Asp Leu His Ser Asn Ala Asn Arg Tyr Phe Leu

1 5 10

<210> 442

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11-H3.LC1

<400> 442

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Ile Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Phe Arg Thr Tyr Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 443

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11-H3.LC2

<400> 443

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Ile Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Phe Arg Thr Tyr Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 444

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11-H3.LC3

<400> 444

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Ile Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Arg Thr Tyr Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 445

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11-H3.LC4

<400> 445

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Ile Arg Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Arg Thr Tyr Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 446

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11-H3.HC1

<400> 446

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Ile Phe Ser Asn Tyr

20 25 30

Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Thr Gly Gly Thr Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 447

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11-H3.HC2

<400> 447

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Ile Phe Ser Asn Tyr

20 25 30

Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

65 70 75 80

Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Thr Gly Gly Thr Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 448

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11-H3.HC3

<400> 448

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Ile Phe Ser Asn Tyr

20 25 30

Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Thr Gly Gly Thr Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 449

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11-H3.HC4

<400> 449

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Ile Phe Ser Asn Tyr

20 25 30

Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Thr Gly Gly Thr Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 450

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11-H3.HC5

<400> 450

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Ile Phe Ser Asn Tyr

20 25 30

Tyr Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Thr Gly Gly Thr Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 451

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu125B11-H3.HC6

<400> 451

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Arg Phe Ile Phe Ser Asn Tyr

20 25 30

Phe Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Gln Ile Arg Leu Lys Ser Asp Asn Tyr Ala Thr His Tyr Ala Glu

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr

65 70 75 80

Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Thr Gly Gly Thr Thr Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 452

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu94B2.HC1

<400> 452

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Leu Thr Gly Tyr

20 25 30

Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Leu Ile Ser Pro Tyr Asn Gly Val Thr Ser Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Arg Ala Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Gly Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

100 105 110

Ser

<210> 453

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu94B2.HC2

<400> 453

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Leu Thr Gly Tyr

20 25 30

Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Leu Ile Ser Pro Tyr Asn Gly Val Thr Ser Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Arg Val Thr Leu Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Gly Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

100 105 110

Ser

<210> 454

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu94B2.HC3

<400> 454

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Leu Thr Gly Tyr

20 25 30

Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Leu Ile Ser Pro Tyr Asn Gly Val Thr Ser Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Arg Ala Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Gly Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

100 105 110

Ser

<210> 455

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu94B2.HC4

<400> 455

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Leu Thr Gly Tyr

20 25 30

Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Leu Ile Ser Pro Tyr Asn Gly Val Thr Ser Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Arg Ala Thr Leu Thr Arg Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Gly Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

100 105 110

Ser

<210> 456

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu94B2.HC5

<400> 456

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Leu Thr Gly Tyr

20 25 30

Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Leu Ile Ser Pro Tyr Asn Gly Val Thr Ser Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Arg Ala Thr Leu Thr Val Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Gly Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

100 105 110

Ser

<210> 457

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu94B2.HC6

<400> 457

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Leu Thr Gly Tyr

20 25 30

Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Leu Ile Ser Pro Tyr Asn Gly Val Thr Ser Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Arg Val Thr Ile Thr Val Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Gly Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

100 105 110

Ser

<210> 458

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu94B2.HC7

<400> 458

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Leu Thr Gly Tyr

20 25 30

Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Leu Ile Ser Pro Tyr Asn Gly Val Thr Ser Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Arg Val Thr Ile Thr Arg Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Gly Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

100 105 110

Ser

<210> 459

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu94B2.HC8

<400> 459

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Leu Thr Gly Tyr

20 25 30

Thr Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Leu Ile Ser Pro Tyr Asn Gly Val Thr Ser Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Arg Val Thr Ile Thr Val Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gln Gly Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

100 105 110

Ser

<210> 460

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu94B2.LC9

<400> 460

Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly

85 90 95

Thr His Phe Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 461

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu94B2.LC10

<400> 461

Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly

85 90 95

Thr His Phe Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 462

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu94B2.LC11

<400> 462

Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Asp Gly Lys Thr Tyr Leu Asn Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly

85 90 95

Thr His Phe Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 463

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu94B2.LC12

<400> 463

Asp Val Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Asp Gly Lys Thr Tyr Leu Asn Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly

85 90 95

Thr His Phe Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 464

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu94B2.LC13

<400> 464

Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly

85 90 95

Thr His Phe Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 465

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu94B2.LC14

<400> 465

Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Asp Gly Lys Thr Tyr Leu Asn Trp Leu Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly

85 90 95

Thr His Phe Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 466

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu94B2.LC15

<400> 466

Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Asp Gly Lys Thr Tyr Leu Asn Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly

85 90 95

Thr His Phe Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 467

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu94B2.LC16

<400> 467

Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser

20 25 30

Asp Gly Lys Thr Tyr Leu Asn Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Trp Gln Gly

85 90 95

Thr His Phe Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 468

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v5.1 HVR-L1

<400> 468

Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Asn Thr Tyr Phe Glu

1 5 10 15

<210> 469

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v5.2 HVR-L1

<400> 469

Arg Ser Ser Gln Ser Ile Val His Ser Ser Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 470

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v5.3 HVR-L1

<400> 470

Arg Ser Ser Gln Ser Ile Val His Ser Asp Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 471

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v5.4 HVR-L1

<400> 471

Arg Ser Ser Gln Ser Ile Val His Ser Gln Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 472

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v5.5 HVR-L1

<400> 472

Arg Ser Ser Gln Ser Ile Val His Ser Glu Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 473

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v5.6 HVR-L1

<400> 473

Arg Ser Ser Gln Ser Ile Val His Ser Ala Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 474

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v5.7 HVR-L1

<400> 474

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asp Thr Tyr Phe Glu

1 5 10 15

<210> 475

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v5.8 HVR-L1

<400> 475

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Gln Thr Tyr Phe Glu

1 5 10 15

<210> 476

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v5.9 HVR-L1

<400> 476

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Glu Thr Tyr Phe Glu

1 5 10 15

<210> 477

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v5.10 HVR-L1

<400> 477

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Ala Thr Tyr Phe Glu

1 5 10 15

<210> 478

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v5.11 HVR-L1

<400> 478

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Ser Thr Tyr Phe Glu

1 5 10 15

<210> 479

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28 HVR-L1

<400> 479

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 480

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.A2 HVR-L1

<400> 480

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 481

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.A4 HVR-L1

<400> 481

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 482

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.A6 HVR-L1

<400> 482

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 483

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.A8 HVR-L1

<400> 483

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 484

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.A10 HVR-L1

<400> 484

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 485

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.A12 HVR-L1

<400> 485

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 486

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.A14 HVR-L1

<400> 486

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 487

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.A16 HVR-L1

<400> 487

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 488

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.A18 HVR-L1

<400> 488

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 489

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.A20 HVR-L1

<400> 489

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 490

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.A22 HVR-L1

<400> 490

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 491

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.A24 HVR-L1

<400> 491

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 492

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.A26 HVR-L1

<400> 492

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 493

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.A28 HVR-L1

<400> 493

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 494

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.A30 HVR-L1

<400> 494

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 495

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.B1 HVR-L1

<400> 495

Arg Ser Ser Gln Ser Ile Val His Ser Ile Gly Asn Thr Phe Phe Glu

1 5 10 15

<210> 496

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.B2 HVR-L1

<400> 496

Arg Ser Ser Gln Ser Ile Val His Ser Met Gly Asn Thr Phe Phe Glu

1 5 10 15

<210> 497

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.B3 HVR-L1

<400> 497

Arg Ser Ser Gln Ser Ile Val His Ser Gln Gly Asn Thr Trp Phe Glu

1 5 10 15

<210> 498

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.B4 HVR-L1

<400> 498

Arg Ser Ser Gln Ser Ile Val His Ser Gln Gly Asn Thr His Phe Glu

1 5 10 15

<210> 499

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.B6 HVR-L1

<400> 499

Arg Ser Ser Gln Ser Ile Val His Ser Asp Gly Asn Thr Arg Phe Glu

1 5 10 15

<210> 500

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.B7 HVR-L1

<400> 500

Arg Ser Ser Gln Ser Ile Val His Ser Asp Gly Asn Thr Lys Phe Glu

1 5 10 15

<210> 501

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.B8 HVR-L1

<400> 501

Arg Ser Ser Gln Ser Ile Val His Ser Glu Gly Asn Thr Arg Phe Glu

1 5 10 15

<210> 502

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.C1 HVR-L1

<400> 502

Arg Ser Ser Gln Ser Ile Val His Ser Asn Asn Asn Thr Tyr Phe Glu

1 5 10 15

<210> 503

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.C2 HVR-L1

<400> 503

Arg Ser Ser Gln Ser Ile Val His Ser Asn Asp Asn Thr Tyr Phe Glu

1 5 10 15

<210> 504

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.D1 HVR-L1

<400> 504

Arg Ser Ser Gln Ser Ile Val His Ala Asn Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 505

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.E1 HVR-L1

<400> 505

Arg Ser Ser Gln Ser Ile Val Asn Ser Asn Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 506

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.E2 HVR-L1

<400> 506

Arg Ser Ser Gln Ser Ile Val Gln Ser Asn Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 507

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.E3 HVR-L1

<400> 507

Arg Ser Ser Gln Ser Ile Val Asp Ser Asp Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 508

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.F1 HVR-L1

<400> 508

Arg Ser Ser Gln Ser Ile Val His Ser Asn Thr Asn Thr Tyr Phe Glu

1 5 10 15

<210> 509

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.F2 HVR-L1

<400> 509

Arg Ser Ser Gln Ser Ile Val His Thr Asn Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 510

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.F3 HVR-L1

<400> 510

Arg Ser Ser Gln Ser Ile Val His Thr Asn Ala Asn Thr Tyr Phe Glu

1 5 10 15

<210> 511

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.51 HVR-L1

<400> 511

Arg Ser Ser Gln Ser Ile Val His Ser His Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 512

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.52 HVR-L1

<400> 512

Arg Ser Ser Gln Ser Ile Val His Ser Lys Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 513

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.53 HVR-L1

<400> 513

Arg Ser Ser Gln Ser Ile Val His Ser Arg Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 514

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.54 HVR-L1

<400> 514

Arg Ser Ser Gln Ser Ile Val His Ser Leu Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 515

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.55 HVR-L1

<400> 515

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gln Asn Thr Tyr Phe Glu

1 5 10 15

<210> 516

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.56 HVR-L1

<400> 516

Arg Ser Ser Gln Ser Ile Val His Ser Asn Tyr Asn Thr Tyr Phe Glu

1 5 10 15

<210> 517

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v28.57 HVR-L1

<400> 517

Arg Ser Ser Gln Ser Ile Val His Ser Asn Phe Asn Thr Tyr Phe Glu

1 5 10 15

<210> 518

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v29.1 HVR-L1

<400> 518

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asp Thr Tyr Phe Glu

1 5 10 15

<210> 519

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v29.2 HVR-L1

<400> 519

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Gln Thr Tyr Phe Glu

1 5 10 15

<210> 520

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v29.3 HVR-L1

<400> 520

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Glu Thr Tyr Phe Glu

1 5 10 15

<210> 521

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v29.4 HVR-L1

<400> 521

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Ala Thr Tyr Phe Glu

1 5 10 15

<210> 522

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v29.5 HVR-L1

<400> 522

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly His Thr Tyr Phe Glu

1 5 10 15

<210> 523

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v29.6 HVR-L1

<400> 523

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Lys Thr Tyr Phe Glu

1 5 10 15

<210> 524

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v29.7 HVR-L1

<400> 524

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Leu Thr Tyr Phe Glu

1 5 10 15

<210> 525

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v29.8 HVR-L1

<400> 525

Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Asp Thr Tyr Phe Glu

1 5 10 15

<210> 526

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v29.9 HVR-L1

<400> 526

Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Gln Thr Tyr Phe Glu

1 5 10 15

<210> 527

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v29.10 HVR-L1

<400> 527

Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Glu Thr Tyr Phe Glu

1 5 10 15

<210> 528

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v29.11 HVR-L1

<400> 528

Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Ala Thr Tyr Phe Glu

1 5 10 15

<210> 529

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v29.12 HVR-L1

<400> 529

Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala His Thr Tyr Phe Glu

1 5 10 15

<210> 530

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v29.13 HVR-L1

<400> 530

Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Lys Thr Tyr Phe Glu

1 5 10 15

<210> 531

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v29.14 HVR-L1

<400> 531

Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Leu Thr Tyr Phe Glu

1 5 10 15

<210> 532

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v30.1 HVR-L1

<400> 532

Arg Ser Ser Gln Ser Ile Val His Ser Gly Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 533

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v30.2 HVR-L1

<400> 533

Arg Ser Ser Gln Ser Ile Val His Ser Thr Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 534

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v30.3 HVR-L1

<400> 534

Arg Ser Ser Gln Ser Ile Val His Ser Val Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 535

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v30.4 HVR-L1

<400> 535

Arg Ser Ser Gln Ser Ile Val His Ser Leu Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 536

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v30.5 HVR-L1

<400> 536

Arg Ser Ser Gln Ser Ile Val His Ser Ile Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 537

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v30.6 HVR-L1

<400> 537

Arg Ser Ser Gln Ser Ile Val His Ser Pro Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 538

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v30.7 HVR-L1

<400> 538

Arg Ser Ser Gln Ser Ile Val His Ser Phe Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 539

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v30.8 HVR-L1

<400> 539

Arg Ser Ser Gln Ser Ile Val His Ser Tyr Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 540

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v30.9 HVR-L1

<400> 540

Arg Ser Ser Gln Ser Ile Val His Ser His Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 541

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v30.10 HVR-L1

<400> 541

Arg Ser Ser Gln Ser Ile Val His Ser Lys Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 542

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v30.11 HVR-L1

<400> 542

Arg Ser Ser Gln Ser Ile Val His Ser Arg Gly Asn Thr Tyr Phe Glu

1 5 10 15

<210> 543

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v31.1 HVR-L1

<400> 543

Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Gly Thr Tyr Phe Glu

1 5 10 15

<210> 544

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v31.2 HVR-L1

<400> 544

Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Val Thr Tyr Phe Glu

1 5 10 15

<210> 545

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v31.3 HVR-L1

<400> 545

Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Ile Thr Tyr Phe Glu

1 5 10 15

<210> 546

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v31.4 HVR-L1

<400> 546

Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Pro Thr Tyr Phe Glu

1 5 10 15

<210> 547

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v31.5 HVR-L1

<400> 547

Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Phe Thr Tyr Phe Glu

1 5 10 15

<210> 548

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v31.6 HVR-L1

<400> 548

Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Tyr Thr Tyr Phe Glu

1 5 10 15

<210> 549

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v31.7 HVR-L1

<400> 549

Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Arg Thr Tyr Phe Glu

1 5 10 15

<210> 550

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v31.8 HVR-L1

<400> 550

Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Asn Val Tyr Phe Glu

1 5 10 15

<210> 551

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v31.9 HVR-L1

<400> 551

Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Asn Ile Tyr Phe Glu

1 5 10 15

<210> 552

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v31.10 HVR-L1

<400> 552

Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Asn Pro Tyr Phe Glu

1 5 10 15

<210> 553

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v31.11 HVR-L1

<400> 553

Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Asn Phe Tyr Phe Glu

1 5 10 15

<210> 554

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v31.12 HVR-L1

<400> 554

Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Asn Tyr Tyr Phe Glu

1 5 10 15

<210> 555

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v31.13 HVR-L1

<400> 555

Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Asn Asn Tyr Phe Glu

1 5 10 15

<210> 556

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v31.14 HVR-L1

<400> 556

Arg Ser Ser Gln Ser Ile Val His Ser Asn Ala Asn Arg Tyr Phe Glu

1 5 10 15

<210> 557

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Human Tau 7-24 peptide

<400> 557

Glu Phe Glu Val Met Glu Asp His Ala Gly Thr Tyr Gly Leu Gly Asp

1 5 10 15

Arg Lys

<210> 558

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Human Tau 7-20 peptide

<400> 558

Glu Phe Glu Val Met Glu Asp His Ala Gly Thr Tyr Gly Leu

1 5 10

<210> 559

<400> 559

000

<210> 560

<211> 117

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v39 heavy chain variable region (VH)

<400> 560

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 561

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v39 light chain variable region (VL)

<400> 561

Glu Asp Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Ser Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile

65 70 75 80

Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser Leu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 562

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v39 HVR-H1

<400> 562

Ser Tyr Gly Met Ser

1 5

<210> 563

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v39 HVR-H2

<400> 563

Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val Lys

1 5 10 15

Gly

<210> 564

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v39 HVR-H3

<400> 564

Ser Tyr Ser Gly Ala Met Asp Tyr

1 5

<210> 565

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v39 HVR-L1

<400> 565

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu

1 5 10 15

<210> 566

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v39 HVR-L2

<400> 566

Lys Val Ser Asn Arg Phe Ser

1 5

<210> 567

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v39 HVR-L3

<400> 567

Phe Gln Gly Ser Leu Val Pro Trp Thr

1 5

<210> 568

<211> 444

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v39 IgG4-S228P.YTE heavy chain

<400> 568

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu

115 120 125

Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys

130 135 140

Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser

145 150 155 160

Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser

165 170 175

Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser

180 185 190

Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn

195 200 205

Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro

210 215 220

Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe

225 230 235 240

Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val

245 250 255

Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe

260 265 270

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro

275 280 285

Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

290 295 300

Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val

305 310 315 320

Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala

325 330 335

Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln

340 345 350

Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

355 360 365

Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro

370 375 380

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser

385 390 395 400

Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu

405 410 415

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His

420 425 430

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 569

<211> 219

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v39 IgG4-S228P.YTE light chain

<400> 569

Glu Asp Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Ser Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile

65 70 75 80

Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser Leu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

115 120 125

Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe

130 135 140

Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln

145 150 155 160

Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser

165 170 175

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu

180 185 190

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser

195 200 205

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 570

<211> 117

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v40 heavy chain variable region (VH)

<400> 570

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 571

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v40 light chain variable region (VL)

<400> 571

Glu Asp Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Ser Ile Val His Ser

20 25 30

Asn Thr Asn Thr Tyr Phe Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile

65 70 75 80

Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser Leu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 572

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v40 HVR-H1

<400> 572

Ser Tyr Gly Met Ser

1 5

<210> 573

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v40 HVR-H2

<400> 573

Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val Lys

1 5 10 15

Gly

<210> 574

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v40 HVR-H3

<400> 574

Ser Tyr Ser Gly Ala Met Asp Tyr

1 5

<210> 575

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v40 HVR-L1

<400> 575

Arg Ser Ser Gln Ser Ile Val His Ser Asn Thr Asn Thr Tyr Phe Glu

1 5 10 15

<210> 576

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v40 HVR-L2

<400> 576

Lys Val Ser Asn Arg Phe Ser

1 5

<210> 577

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v40 HVR-L3

<400> 577

Phe Gln Gly Ser Leu Val Pro Trp Thr

1 5

<210> 578

<211> 444

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v40 IgG4-S228P.YTE heavy chain

<400> 578

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu

115 120 125

Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys

130 135 140

Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser

145 150 155 160

Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser

165 170 175

Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser

180 185 190

Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn

195 200 205

Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro

210 215 220

Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe

225 230 235 240

Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val

245 250 255

Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe

260 265 270

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro

275 280 285

Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

290 295 300

Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val

305 310 315 320

Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala

325 330 335

Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln

340 345 350

Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

355 360 365

Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro

370 375 380

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser

385 390 395 400

Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu

405 410 415

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His

420 425 430

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 579

<211> 219

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v40 IgG4-S228P.YTE light chain

<400> 579

Glu Asp Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Ser Ile Val His Ser

20 25 30

Asn Thr Asn Thr Tyr Phe Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile

65 70 75 80

Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser Leu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

115 120 125

Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe

130 135 140

Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln

145 150 155 160

Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser

165 170 175

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu

180 185 190

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser

195 200 205

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 580

<211> 117

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v41 heavy chain variable region (VH)

<400> 580

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 581

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v41 light chain variable region (VL)

<400> 581

Glu Asp Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Ser Ile Val His Ser

20 25 30

Asn Gly Gln Thr Tyr Phe Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile

65 70 75 80

Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser Leu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 582

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v41 HVR-H1

<400> 582

Ser Tyr Gly Met Ser

1 5

<210> 583

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v41 HVR-H2

<400> 583

Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val Lys

1 5 10 15

Gly

<210> 584

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v41 HVR-H3

<400> 584

Ser Tyr Ser Gly Ala Met Asp Tyr

1 5

<210> 585

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v41 HVR-L1

<400> 585

Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Gln Thr Tyr Phe Glu

1 5 10 15

<210> 586

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v41 HVR-L2

<400> 586

Lys Val Ser Asn Arg Phe Ser

1 5

<210> 587

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v41 HVR-L3

<400> 587

Phe Gln Gly Ser Leu Val Pro Trp Thr

1 5

<210> 588

<211> 444

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v41 IgG4-S228P.YTE heavy chain

<400> 588

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu

115 120 125

Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys

130 135 140

Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser

145 150 155 160

Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser

165 170 175

Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser

180 185 190

Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn

195 200 205

Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro

210 215 220

Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe

225 230 235 240

Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val

245 250 255

Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe

260 265 270

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro

275 280 285

Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

290 295 300

Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val

305 310 315 320

Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala

325 330 335

Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln

340 345 350

Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

355 360 365

Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro

370 375 380

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser

385 390 395 400

Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu

405 410 415

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His

420 425 430

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 589

<211> 219

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3.v41 IgG4-S228P.YTE light chain

<400> 589

Glu Asp Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Ser Ile Val His Ser

20 25 30

Asn Gly Gln Thr Tyr Phe Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile

65 70 75 80

Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser Leu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

115 120 125

Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe

130 135 140

Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln

145 150 155 160

Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser

165 170 175

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu

180 185 190

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser

195 200 205

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 590

<211> 444

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v1 IgG4 heavy chain

<400> 590

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu

115 120 125

Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys

130 135 140

Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser

145 150 155 160

Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser

165 170 175

Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser

180 185 190

Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn

195 200 205

Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro

210 215 220

Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe

225 230 235 240

Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val

245 250 255

Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe

260 265 270

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro

275 280 285

Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

290 295 300

Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val

305 310 315 320

Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala

325 330 335

Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln

340 345 350

Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

355 360 365

Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro

370 375 380

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser

385 390 395 400

Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu

405 410 415

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His

420 425 430

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys

435 440

<210> 591

<211> 219

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v1 IgG4 light chain

<400> 591

Glu Asp Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Ser Ile Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Phe Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ser

35 40 45

Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile

65 70 75 80

Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly

85 90 95

Ser Leu Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105 110

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

115 120 125

Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe

130 135 140

Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln

145 150 155 160

Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser

165 170 175

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu

180 185 190

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser

195 200 205

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 592

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: MAPT (10-24)

<400> 592

Val Met Glu Asp His Ala Gly Thr Tyr Gly Leu Gly Asp Arg Lys

1 5 10 15

<210> 593

<211> 23

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: MAPT (2-24)

<400> 593

Ala Glu Pro Arg Gln Glu Phe Glu Val Met Glu Asp His Ala Gly Thr

1 5 10 15

Tyr Gly Leu Gly Asp Arg Lys

20

<210> 594

<211> 33

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: MAPT (2-34)

<400> 594

Ala Glu Pro Arg Gln Glu Phe Glu Val Met Glu Asp His Ala Gly Thr

1 5 10 15

Tyr Gly Leu Gly Asp Arg Lys Asp Gln Gly Gly Tyr Thr Met His Gln

20 25 30

Asp

<210> 595

<211> 35

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: MAPT (10-44)

<400> 595

Val Met Glu Asp His Ala Gly Thr Tyr Gly Leu Gly Asp Arg Lys Asp

1 5 10 15

Gln Gly Gly Tyr Thr Met His Gln Asp Gln Glu Gly Asp Thr Asp Ala

20 25 30

Gly Leu Lys

35

<210> 596

<211> 23

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: MAPT(2-24)Y18A

<400> 596

Ala Glu Pro Arg Gln Glu Phe Glu Val Met Glu Asp His Ala Gly Thr

1 5 10 15

Ala Gly Leu Gly Asp Arg Lys

20

<210> 597

<211> 23

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: MAPT(2-24)L20A

<400> 597

Ala Glu Pro Arg Gln Glu Phe Glu Val Met Glu Asp His Ala Gly Thr

1 5 10 15

Tyr Gly Ala Gly Asp Arg Lys

20

<210> 598

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu113F5-F7.LC1

<400> 598

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Arg Arg Phe Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Phe Ser Thr Tyr Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 599

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu113F5-F7.LC2

<400> 599

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Arg Arg Phe Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Phe Ser Thr Tyr Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 600

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu113F5-F7.LC3

<400> 600

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Arg Arg Phe Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Thr Tyr Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 601

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: hu113F5-F7.LC4

<400> 601

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Arg Arg Phe Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Ser Thr Tyr Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 602

<211> 443

<212> PRT

<213> Artificial sequence

<220>

<223> Synthesis: Hu37D3-H9.v28.A4 IgG4-S228P.YTE des-K heavy chain

<400> 602

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ile Phe Arg Ser Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Thr Ile Asn Ser Gly Gly Thr Tyr Thr Tyr Tyr Pro Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Asn Ser Tyr Ser Gly Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu

115 120 125

Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys

130 135 140

Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser

145 150 155 160

Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser

165 170 175

Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser

180 185 190

Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn

195 200 205

Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro

210 215 220

Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe

225 230 235 240

Pro Pro Lys Pro Lys Asp Thr Leu Tyr Ile Thr Arg Glu Pro Glu Val

245 250 255

Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe

260 265 270

Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro

275 280 285

Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr

290 295 300

Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val

305 310 315 320

Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala

325 330 335

Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln

340 345 350

Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly

355 360 365

Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro

370 375 380

Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser

385 390 395 400

Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu

405 410 415

Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His

420 425 430

Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly

435 440

Claims (32)

1. An isolated antibody bound to human Tau, wherein the antibody is bound to monomeric Tau, oligomeric Tau, non-phosphorylated Tau, and phosphorylated Tau, wherein the antibody comprises: a) HVR-H1 as shown in the amino acid sequence of SEQ ID NO:342; HVR-H2 as shown in the amino acid sequence of SEQ ID NO:343; HVR-H3 as shown in the amino acid sequence of SEQ ID NO:344; HVR-L1 as shown in the amino acid sequences selected from SEQ ID NO:345, 15, 468 to 478, 495 to 517, 522 to 534, 536 to 539 and 543 to 556; HVR-L2 as shown in the amino acid sequence of SEQ ID NO:346; and HVR-L3 as shown in the amino acid sequence of SEQ ID NO:347; b) HVR-H1 as shown in the amino acid sequence of SEQ ID NO:42; HVR-H2 as shown in the amino acid sequence of SEQ ID NO:43; HVR-H3 as shown in the amino acid sequence of SEQ ID NO:44; HVR-L1 as shown in the amino acid sequence of SEQ ID NO:45; HVR-L2 as shown in the amino acid sequence of SEQ ID NO:46; and HVR-L3 as shown in the amino acid sequence of SEQ ID NO:47; c) HVR-H1 as shown in the amino acid sequence of SEQ ID NO:62; HVR-H2 as shown in the amino acid sequence of SEQ ID NO:63; HVR-H3 as shown in the amino acid sequence of SEQ ID NO:64; HVR-L1 as shown in the amino acid sequence of SEQ ID NO:65; HVR-L2 as shown in the amino acid sequence of SEQ ID NO:66; and HVR-L3 as shown in the amino acid sequence of SEQ ID NO:67; d) HVR-H1 as shown in the amino acid sequence of SEQ ID NO:32; HVR-H2 as shown in the amino acid sequence of SEQ ID NO:33; HVR-H3 as shown in the amino acid sequence of SEQ ID NO:34; HVR-L1 as shown in the amino acid sequence of SEQ ID NO:35; HVR-L2 as shown in the amino acid sequence of SEQ ID NO:36; and HVR-L3 as shown in the amino acid sequence of SEQ ID NO:37; or e) HVR-H1 as shown in the amino acid sequence of SEQ ID NO:52; HVR-H2 as shown in the amino acid sequence of SEQ ID NO:53; HVR-H3 as shown in the amino acid sequence of SEQ ID NO:54; HVR-L1 as shown in the amino acid sequence of SEQ ID NO:55; HVR-L2 as shown in the amino acid sequence of SEQ ID NO:56; and HVR-L3 as shown in the amino acid sequence of SEQ ID NO:57. 2. The isolated antibody of claim 1, wherein the antibody comprises: a) A heavy chain variable region (VH) containing a sequence having at least 95% identity with a sequence selected from SEQ ID NO:340, 10 and 20; b) A light chain variable region (VL) comprising a sequence having at least 95% identity with a sequence selected from SEQ ID NO:341, 11, 21, 281, 291, 561, 571 and 581; c) VH in (a) and VL in (b); d) A heavy chain variable region (VH) containing a sequence having at least 95% identity with SEQ ID NO:40; e) A light chain variable region (VL) containing a sequence having at least 95% identity with SEQ ID NO:41; f) VH in (d) and VL in (e); g) A heavy chain variable region (VH) containing a sequence having at least 95% identity with SEQ ID NO:60; h) A light chain variable region (VL) containing a sequence having at least 95% identity with SEQ ID NO:61; i) VH in (g) and VL in (h); j) A heavy chain variable region (VH) containing a sequence having at least 95% identity with SEQ ID NO:30; k) A light chain variable region (VL) containing a sequence having at least 95% identity with SEQ ID NO:31; l) VH in (j) and VL in (k); m) contains a heavy chain variable region (VH) that has at least 95% identity with the sequence of SEQ ID NO:50; n) A light chain variable region (VL) containing a sequence having at least 95% identity with SEQ ID NO:51; or o) VH in (m) and VL in (n). 3. The isolated antibody of claim 1, wherein the antibody comprises: a) A heavy chain variable region (VH) comprising sequences selected from SEQ ID NO:340, 10, 20, 280, 290, 560, 570 and 580; b) A light chain variable region (VL) comprising sequences selected from SEQ ID NO:341, 11, 21, 281, 291, 561, 571 and 581; c) VH in (a) and VL in (b); d) The heavy chain variable region (VH) containing the sequence of SEQ ID NO:40; e) The light chain variable region (VL) containing the sequence of SEQ ID NO:41; f) VH in (d) and VL in (e); g) Heavy chain variable region (VH) containing the sequence of SEQ ID NO:60; h) The light chain variable region (VL) containing the sequence of SEQ ID NO:61; i) VH in (g) and VL in (h); j) The heavy chain variable region (VH) containing the sequence of SEQ ID NO:30; k) The light chain variable region (VL) containing the sequence of SEQ ID NO:31; l) VH in (j) and VL in (k); m) The heavy chain variable region (VH) containing the sequence of SEQ ID NO:50; n) The light chain variable region (VL) containing the sequence of SEQ ID NO:51; or o) VH in (m) and VL in (n). 4. The isolated antibody of claim 1, wherein the antibody comprises HVR-H1 as shown in the amino acid sequence of SEQ ID NO:342; HVR-H2 as shown in the amino acid sequence of SEQ ID NO:343; HVR-H3 as shown in the amino acid sequence of SEQ ID NO:344; HVR-L1 as shown in the amino acid sequence of SEQ ID NO:345; HVR-L2 as shown in the amino acid sequence of SEQ ID NO:346; and HVR-L3 as shown in the amino acid sequence of SEQ ID NO:347. 5. The isolated antibody of claim 1, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:340 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:341. 6. The isolated antibody of claim 1, wherein the antibody comprises: a) a heavy chain comprising an amino acid sequence having at least 95%, at least 97%, or at least 99% identity with the sequence of SEQ ID NO:348 or SEQ ID NO:602, and a light chain comprising an amino acid sequence having at least 95%, at least 97%, or at least 99% identity with the sequence of SEQ ID NO:349; or b) Heavy chains containing the amino acid sequence of SEQ ID NO:348 or SEQ ID NO:602 and light chains containing the amino acid sequence of SEQ ID NO:349. 7. An isolated antibody bound to human Tau, wherein the antibody comprises a heavy chain comprising an amino acid sequence comprising SEQ ID NO:348 or SEQ ID NO:602 and a light chain comprising an amino acid sequence comprising SEQ ID NO:349. 8. An isolated antibody bound to human Tau, wherein the antibody comprises 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. 9. The isolated antibody according to any one of claims 1 to 5, wherein the antibody is an IgG1 or IgG4 antibody. 10. The isolated antibody of claim 9, wherein the antibody is an IgG4 antibody. 11. The isolated antibody of claim 10, wherein the antibody comprises M252Y, S254T and T256E mutations. 12. The isolated antibody of claim 11, wherein the antibody contains the S228P mutation. 13. The isolated antibody as described in any one of claims 1 to 5, wherein it is an antibody fragment. 14. The isolated antibody according to any one of claims 1 to 8, wherein the antibody binds to each of the monomers Tau, phosphorylated Tau, non-phosphorylated Tau, and oligomeric Tau at a _KD concentration of less than 100 nM, less than 75 nM, or less than 50 nM. 15. The isolated antibody according to any one of claims 1 to 8, which binds to cynomolgus monkey Tau at SEQ ID NO:4. 16. An isolated nucleic acid encoding an antibody as described in any one of claims 1 to 15. 17. A host cell comprising the nucleic acid as described in claim 16. 18. A method for producing an antibody, comprising culturing a host cell as described in claim 17 under conditions suitable for producing the antibody. 19. An immunoconjugate comprising the isolated antibody and the second therapeutic agent as described in any one of claims 1 to 15. 20. A labeled antibody comprising the antibody as claimed in any one of claims 1 to 15 and a detectable label. 21. A pharmaceutical composition comprising the isolated antibody as described in any one of claims 1 to 15 and a pharmaceutically acceptable carrier. 22. Use of the antibody of any one of claims 1 to 15 or the pharmaceutical composition of claim 21 to manufacture an agent for treating Tau protein-related diseases in an individual. 23. The use as described in claim 22, wherein the Tau protein-related disease is a tau protein disease. 24. The use as described in claim 23, wherein the tau proteinosis is a neurodegenerative tau proteinosis. 25. The use as described in claim 23, wherein the tau protein disease is selected from Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Creutzfeldt-Jakob disease (CJD), boxer's dementia, Down syndrome, Gerschner's syndrome, inclusion body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury, ALS/Guam Parkinson's syndrome-dementia relapse, non-Guam motor neuron disease with neurofibrillary tangles, argyrophilic granular dementia, cortical atherosclerosis, etc. Basal ganglia degeneration, diffuse neurofibrillary tangles with calcification, frontotemporal dementia, frontotemporal dementia linked to chromosome 17 with Parkinson's syndrome, Hallewarden-Scholes disease, multiple systemic atrophy, Niemann-Pick disease type C, globus pallidus-pontine-substantia nigra degeneration, Pick's disease, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, tangles-only dementia, post-encephalitis Parkinson's syndrome, and myotonic dystrophy. 26. The use as described in claim 23, wherein the tau protein disease is Alzheimer's disease or progressive supranuclear palsy. 27. Use of the antibody of any one of claims 1 to 15 or the pharmaceutical composition of claim 21 to manufacture a medicament for maintaining or improving cognitive memory or slowing memory loss in an individual with a Tau protein-related disease. 28. Use of the antibody of any one of claims 1 to 15 or the pharmaceutical composition of claim 21 to manufacture an agent for reducing the level of Tau protein, non-phosphorylated Tau protein, phosphorylated Tau protein or hyperphosphorylated Tau protein in an individual. 29. The use as claimed in any one of claims 22 to 28, wherein the agent is to be administered in conjunction with at least one additional therapy. 30. The use as described in claim 29, wherein the additional therapy is selected from neuropharmaceuticals, corticosteroids, antibiotics, antiviral agents, anti-Tau antibodies, Tau inhibitors, anti-amyloid β antibodies, β-amyloid aggregation inhibitors, anti-BACE1 antibodies, and BACE1 inhibitors. 31. Use of the antibody as described in any one of claims 1 to 15 or the labeled antibody as described in claim 20 to manufacture a reagent for detecting neurofibrillary tangles, nerve fiber networks, or dystrophic neuritis in samples from an individual. 32. The use as described in claim 31, wherein the sample is a brain sample, a cerebrospinal fluid sample, or a blood sample.