IP Library › Granted Patent US 11,702,467
Granted Patent B2
US 11,702,467 · App. 17/355,529 · Granted Jul 18, 2023

High affinity antibodies targeting tau phosphorylated at serine 413

Inventors: Jeanne E. Baker (Redwood City, CA); Sophie Parmentier Batteur (Haverford, PA); Ming-Tang Chen (Dover, MA); Alan C. Cheng (San Francisco, CA); Chung-Ming Hsieh (Newton, MA); Carl Mieczkowski (Hercules, CA); Sokreine Suon (King of Prussia, PA)
Assignee: Merck Sharp & Dohme LLC
C07K16/18A61K45/06A61P25/00A61K2039/505
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Quick Facts
Patent No.
US 11,702,467
App. No.
17/355,529
Granted
Jul 18, 2023
Kind
B2
Abstract

Provided herein are high affinity antibodies or antigen binding fragments thereof that specifically bind to human tau-pS413. Also provided are compositions, kits, methods, and uses involving such antibodies or antigen binding fragments thereof.

Claims (199)

1. An antibody or antigen binding fragment thereof that binds to tau-pS413, comprising:

(a) a heavy chain variable region complementarity determining region 1 (VH-CDR1) comprising the amino acid sequence of SEQ ID NO:41; a heavy chain variable region complementarity determining region 2 (VH-CDR2) comprising the amino acid sequence of SEQ ID NO:42; and a heavy chain variable region complementarity determining region 3 (VH-CDR3) comprising the amino acid sequence of SEQ ID NO:43; and

a light chain variable region complementarity determining region 1 (VL-CDR1) comprising the amino acid sequence of SEQ ID NO:29; a light chain variable region complementarity determining region 2 (VL-CDR2) comprising the amino acid sequence of SEQ ID NO:30; and a light chain variable region complementarity determining region 3 (VL-CDR3) comprising the amino acid sequence of SEQ ID NO:31;

(b) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:41; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:42; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:43; and

a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35;

(c) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:41; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:42; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:43; and

a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:37; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:38; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:39;

(d) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:41; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:42; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:43; and

a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:25; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:26; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:27;

(e) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:41; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:42; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:43; and

a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:17; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:18; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:19;

(f) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:45; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:46; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:47; and

a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:29; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:30; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:31;

(g) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:45; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:46; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:47; and

a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35;

(h) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:45; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:46; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:47; and

a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:37; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:38; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:39;

(i) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:45; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:46; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:47; and

a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:25; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:26; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:27;

(j) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:45; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:46; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:47; and

a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:17; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:18; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:19;

(k) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:49; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:50; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:51; and

a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:29; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:30; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:31;

(l) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:49; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:50; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:51; and

a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35;

(m) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:49; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:50; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:51; and

a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:37; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:38; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:39;

(n) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:49; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:50; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:51; and

a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:25; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:26; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:27;

(o) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:49; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:50; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:51; and

a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:17; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:18; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:19;

(p) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; and

a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:29; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:30; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:31;

(q) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; and

a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35;

(r) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; and

a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:37; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:38; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:39;

(s) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; and

a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:25; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:26; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:27;

(t) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; and

a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:17; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:18; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:19;

(u) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:21; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:22; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:23; and

a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:29; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:30; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:31;

(v) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:21; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:22; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:23; and

a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35;

(w) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:21; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:22; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:23; and

a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:37; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:38; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:39;

(x) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:86; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:87; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:88; and

a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:83; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:84; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:85;

(y) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:92; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:93; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:94; and

a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:89; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:90; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:91;

(z) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:98; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:99; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:100; and

a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:95; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:96; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:97;

(aa) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:104; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:105; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:106; and

a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:101; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:102; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:103;

(bb) a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO:44; and

a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO:32;

(cc) a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:44; and

a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36;

(dd) a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:44; and

a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:40;

(ee) a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:44; and

a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:28;

(ff) a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:44; and

a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:20;

(gg) a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:48; and

a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:32;

(hh) a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:48; and

a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36;

(ii) a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:48; and

a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:40;

(jj) a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:48; and

a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:28;

(kk) a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:48; and

a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:20;

(ll) a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:52; and

a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:32;

(mm) a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:52; and

a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36;

(nn) a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:52; and

a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:40;

(oo) a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:52; and

a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:28;

(pp) a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:52; and

a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:20;

(qq) a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56; and

a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:32;

(rr) a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56; and

a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36;

(ss) a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56; and

a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:40;

(tt) a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56; and

a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:28;

(uu) a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56; and

a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:20;

(vv) a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:24; and

a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:32;

(ww) a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:24; and

a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36; or

(xx) a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:24; and

a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:40.

2. The antibody or antigen-binding fragment of claim 1 , comprising:

(a) a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:44, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:32;

(b) a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:44, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:36;

(c) a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:44, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:40;

(d) a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:44, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:28;

(e) a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:44, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:20;

(f) a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:48, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:32;

(g) a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:48, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:36;

(h) a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:48, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:40;

(i) a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:48, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:28;

(j) a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:48, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:20;

(k) a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:52, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:32;

(l) a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:52, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:36;

(m) a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:52, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:40;

(n) a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:52, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:28;

(o) a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:52, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:20;

(p) a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:56, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:32;

(q) a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:56, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:36;

(r) a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:56, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:40;

(s) a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:56, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:28;

(t) a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:56, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:20;

(u) a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:24, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:32;

(v) a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:24, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:36; or

(w) a VH having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:24, and a VL having at least 90% amino acid sequence identity to the amino acid sequence of SEQ ID NO:40.

3. The antibody or antigen binding fragment thereof of claim 1 , comprising:

(a) a VH having the amino acid sequence of SEQ ID NO:44, and a VL having the amino acid sequence of SEQ ID NO:32;

(b) a VH having the amino acid sequence of SEQ ID NO:44, and a VL having the amino acid sequence of SEQ ID NO:36;

(c) a VH having the amino acid sequence of SEQ ID NO:44, and a VL having the amino acid sequence of SEQ ID NO:40;

(d) a VH having the amino acid sequence of SEQ ID NO:44, and a VL having the amino acid sequence of SEQ ID NO:28;

(e) a VH having the amino acid sequence of SEQ ID NO:44, and a VL having the amino acid sequence of SEQ ID NO:20;

(f) a VH having the amino acid sequence of SEQ ID NO:48, and a VL having the amino acid sequence of SEQ ID NO:32;

(g) a VH having the amino acid sequence of SEQ ID NO:48, and a VL having the amino acid sequence of SEQ ID NO:36;

(h) a VH having the amino acid sequence of SEQ ID NO:48, and a VL having the amino acid sequence of SEQ ID NO:40;

(i) a VH having the amino acid sequence of SEQ ID NO:48, and a VL having the amino acid sequence of SEQ ID NO:28;

(j) a VH having the amino acid sequence of SEQ ID NO:48, and a VL having the amino acid sequence of SEQ ID NO:20;

(k) a VH having the amino acid sequence of SEQ ID NO:52, and a VL having the amino acid sequence of SEQ ID NO:32;

(l) a VH having the amino acid sequence of SEQ ID NO:52, and a VL having the amino acid sequence of SEQ ID NO:36;

(m) a VH having the amino acid sequence of SEQ ID NO:52, and a VL having the amino acid sequence of SEQ ID NO:40;

(n) a VH having the amino acid sequence of SEQ ID NO:52, and a VL having the amino acid sequence of SEQ ID NO:28;

(o) a VH having the amino acid sequence of SEQ ID NO:52, and a VL having the amino acid sequence of SEQ ID NO:20;

(p) a VH having the amino acid sequence of SEQ ID NO:56, and a VL having the amino acid sequence of SEQ ID NO:32;

(q) a VH having the amino acid sequence of SEQ ID NO:56, and a VL having the amino acid sequence of SEQ ID NO:36;

(r) a VH having the amino acid sequence of SEQ ID NO:56, and a VL having the amino acid sequence of SEQ ID NO:40;

(s) a VH having the amino acid sequence of SEQ ID NO:56, and a VL having the amino acid sequence of SEQ ID NO:28;

(t) a VH having the amino acid sequence of SEQ ID NO:56, and a VL having the amino acid sequence of SEQ ID NO:20;

(u) a VH having the amino acid sequence of SEQ ID NO:24, and a VL having the amino acid sequence of SEQ ID NO:32;

(v) a VH having the amino acid sequence of SEQ ID NO:24, and a VL having the amino acid sequence of SEQ ID NO:36; or

(w) a VH having the amino acid sequence of SEQ ID NO:24, and a VL having the amino acid sequence of SEQ ID NO:40.

4. The antibody or antigen-binding fragment of claim 3 , further comprising:

(a) a heavy chain constant region having the amino acid sequence of SEQ ID NO:59, 60, 61, 62, 63, 64, 65, 66, 67, or 68; and

(b) a light chain constant region having the amino acid sequence of SEQ ID NO:57 or 58.

5. An antibody or antigen binding fragment thereof that binds to tau-pS413, comprising

(a) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; and

a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35; or

(b) a VH-CDR1, a VH-CDR2, and a VH-CDR3 of a VH comprising the amino acid sequence of SEQ ID NO:56; and a VL-CDR1, a VL-CDR2, and a VL-CDR3 of a VL comprising the amino acid sequence of SEQ ID NO:36.

6. An antibody or antigen binding fragment thereof that binds to tau-pS413, comprising a VH comprising the amino acid sequence of SEQ ID NO:56 and a VL comprising the amino acid sequence of SEQ ID NO:36.

7. The antibody of claim 5 , comprising:

(a) a light chain comprising the amino acid sequence of SEQ ID NO:71 and a heavy chain comprising the amino acid sequence of SEQ ID NO:72;

(b) a light chain comprising the amino acid sequence of SEQ ID NO:73 and a heavy chain comprising the amino acid sequence of SEQ ID NO:74; or

(c) a light chain comprising the amino acid sequence of SEQ ID NO:75 and a heavy chain comprising the amino acid sequence of SEQ ID NO:76.

8. The antibody or antigen binding fragment thereof of claim 1 , having an equilibrium dissociation constant (KD) of 1×10 −8 M or less for tau-pS413.

9. The antibody or antigen binding fragment thereof of claim 8 , having an KD of 2×10 −9 M or less for tau-pS413.

10. The antibody or antigen binding fragment thereof of claim 9 , wherein the KD is measured by Biacore with the antibody or antigen binding fragment thereof being immobilized.

11. An isolated nucleic acid, encoding:

(a) the VH of the antibody or antigen binding fragment thereof of claim 3 ;

(b) the VL of the antibody or antigen binding fragment thereof of claim 3 ; or

(c) the VH and the VL of the antibody or antigen binding fragment thereof of claim 3 .

12. An expression vector comprising the isolated nucleic acid of claim 11 .

13. A host cell comprising the expression vector of claim 12 .

14. A method of producing an antibody or antigen binding fragment thereof, comprising:

(a) culturing the host cell of claim 13 under conditions wherein the antibody or antigen binding fragment thereof is expressed; and

(b) harvesting the antibody or antigen binding fragment thereof.

15. A composition comprising the antibody or antigen binding fragment thereof of claim 1 , and a pharmaceutically acceptable carrier.

16. A method of treating tauopathy in a subject, comprising administering to the subject an effective amount of the antibody or antigen binding fragment thereof of claim 1 .

17. The method of claim 16 , wherein the tauopathy is Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, Pick's disease, argyrophilic grain dementia (argyrophilic grain disease), multiple system tauopathy with presenile dementia (MSTD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), dementia with neurofibrillary tangles, diffuse neurofibrillary tangle with calcification (DNTC), white matter tauopathy with globular glial inclusions (WMT-GGI), frontotemporal lobar degeneration with tau pathology (FTLD-tau), Economo's encephalitis sequela, subacute sclerosing panencephalitis, or boxer's encephalopathy.

18. A method of decreasing the amount of tau-pS413 in the brain of a subject in need thereof, the method comprising administering to the subject an effective amount of the antibody or antigen binding fragment thereof of claim 1 .

19. The method of claim 17 , further comprising administering to the subject an additional agent.

20. The method of claim 19 , wherein the additional agent is selected from the group consisting of a cholinesterase inhibitor, an NMDA receptor antagonist, an amyloid beta peptide aggregation inhibitor, an antioxidant, a gamma-secretase modulator, a nerve growth factor (NGF) mimic, a PPARy agonist, an HMS-CoA reductase inhibitor, a statin, an ampakine, a calcium channel blocker, a GABA receptor antagonist, a glycogen synthase kinase inhibitor, an intravenous immunoglobulin, a muscarinic receptor agonist, a nicotinic receptor modulator, an active or passive amyloid beta peptide for immunization, a phosphodiesterase inhibitor, a serotonin receptor antagonist, an anti-amyloid beta peptide antibody, a growth hormone, a neurotrophic factor, a brain-derived neurotrophic factor (BDNF), a nerve growth factor (NGF), a neurotrophin-4/5, a fibroblast growth factor, neurotrophin (NT)-3, erythropoietin (EPO), hepatocyte growth factor (HGF), epidermal growth factor (EGF), transforming growth factor (TGF)-aplha, TGF-beta, vascular endothelial growth factor (VEGF), an interleukin-1 receptor antagonist (IL-lra), a ciliary neurotrophic factor (CNTF), a glial-derived neurotrophic factor (GDNF), neurturin, platelet-derived growth factor (PDGF), heregulin, neuregulin, artemin, persephin, an interleukin, glial cell line derived neurotrophic factor (GFR), granulocyte-colony stimulating factor (CSF), granulocyte-macrophage-CSF, a netrin, cardiotrophin-1, leukemia inhibitory factor (LIF), midkine, pleiotrophin, a bone morphogenetic protein (BMP), a saposin, a semaphoring, stem cell factor (SCF), and a different anti-tau antibody, or a combination thereof.

21. A monoclonal antibody that binds to tau-pS413, comprising

(a) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:53; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:54; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:55; and

(b) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:33; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:34; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:35.

22. The monoclonal antibody of claim 21 that comprises a VH comprising the amino acid sequence of SEQ ID NO:56 and a VL comprising the amino acid sequence of SEQ ID NO:36.

23. An antibody that binds to tau-pS413, comprising a light chain comprising the amino acid sequence of SEQ ID NO:73 and a heavy chain comprising the amino acid sequence of SEQ ID NO:74.

24. A composition comprising the monoclonal antibody of claim 21 and a pharmaceutically acceptable carrier.

25. A composition comprising the monoclonal antibody of claim 22 and a pharmaceutically acceptable carrier.

26. A method of treating tauopathy in a subject, comprising administering to the subject an effective amount of the monoclonal antibody of 21, wherein the tauopathy is Alzheimer's disease.

27. A method of decreasing the amount of tau-pS413 in the brain of a subject in need thereof, the method comprising administering to the subject an effective amount of the monoclonal antibody of claim 21 .

28. The method of claim 20 , wherein the cholinesterase inhibitor is selected from the group consisting of donepezil, galantamine, rivastigmine, and tacrine.

29. The method of claim 20 , wherein the NMDA receptor antagonist is memantine.

30. An isolated nucleic acid encoding:

(a) a light chain comprising the amino acid sequence of SEQ ID NO:73;

(b) a heavy chain comprising the amino acid sequence of SEQ ID NO:74; or

(c) a light chain comprising the amino acid sequence of SEQ ID NO:73 and a heavy chain comprising the amino acid sequence of SEQ ID NO:74.

31. An expression vector comprising the isolated nucleic acid of claim 30 .

32. A host cell comprising the expression vector of claim 31 .

33. A method of producing an antibody or antigen binding fragment thereof, comprising:

(a) culturing the host cell of claim 32 under conditions wherein the antibody or antigen binding fragment thereof is expressed; and

(b) harvesting the antibody or antigen binding fragment thereof.

Assignments (2)
MERGER Recorded Aug 8, 2022
From: MERCK SHARP & DOHME CORP.
To: MERCK SHARP & DOHME LLC
Reel/Frame 061102/0145 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 2, 2021
From: BAKER, JEANNE E.; PARMENTIER BATTEUR, SOPHIE; CHEN, MING-TANG; CHENG, ALAN C.; HSIEH, CHUNG-MING; MIECZKOWSKI, CARL; SUON, SOKREINE
To: MERCK SHARP & DOHME CORP.
Reel/Frame 058711/0715 →