Tigit-binding agents and uses thereof

Patent metadata

Field	Value
Publication number	US-2016376365-A1
Application number	US-201615167166-A
Country	US
Kind code	A1
Filing date	May 27, 2016
Priority date	May 28, 2015
Publication date	Dec 29, 2016
Grant date	—

Abstract

Agents that specifically bind TIGIT are disclosed. The TIGIT-binding agents may include polypeptides, antibodies, and/or bispecific agents. Also disclosed are methods of using the agents for enhancing the immune response and/or treatment of diseases such as cancer.

First claim

1 - 242 . (canceled)

243 . An isolated antibody that specifically binds the extracellular domain of TIGIT, which comprises:
(a) a heavy chain CDR1 comprising GSSLSSSYMS (SEQ ID NO:7), a heavy chain CDR2 comprising IIGSNGNTYYANWAKG (SEQ ID NO:8), and a heavy chain CDR3 comprising GGYRTSGMDP (SEQ ID NO:9), and a light chain CDR1 comprising QASQSISSYLNW (SEQ ID NO:10), a light chain CDR2 comprising DALKLAS (SEQ ID NO:11), and a light chain CDR3 comprising QQEHSVGNVDN (SEQ ID NO:12); (b) a heavy chain CDR1 comprising GFSLSSSYMS (SEQ ID NO: 13), a heavy chain CDR2 comprising IIGSNGNTYYANWAKG (SQ ID NO:8), and a heavy chain CDR3 comprising GGYRTSGMDP (SEQ ID NO:9); and a light chain CDR1 comprising QASQNIYSDLAW (SEQ ID NO:81), a light chain CDR2 comprising RASTLAS (SEQ ID NO:15), and a light chain CDR3 comprising QQEHLVAWIYN (SEQ ID NO:16); or (c) a heavy chain CDR1 comprising TSDYAWN (SEQ ID NO:57), a heavy chain CDR2 comprising YISYSGSTSYNPSLRS (SEQ ID NO:58), and a heavy chain CDR3 comprising ARRQVGLGFAY (SEQ ID NO:59), and a light chain CDR1 comprising KASQDVSTAVA (SEQ ID NO:60), a light chain CDR2 comprising SASYRYT (SEQ ID NO:61), and a light chain CDR3 comprising QQHYSTP (SEQ ID NO:62).

244 . The antibody of claim 243 , which comprises:
(a) a heavy chain variable region having at least 90% sequence identity to SEQ ID NO:17 and a light chain variable region having at least 90% sequence identity to SEQ ID NO:18; (b) a heavy chain variable region having at least 90% sequence identity to SEQ ID NO:19 and a light chain variable region having at least 90% sequence identity to SEQ ID NO:20; (c) a heavy chain variable region having at least 90% sequence identity to SEQ ID NO:32 and a light chain variable region having at least 90% sequence identity to SEQ ID NO:20; (d) a heavy chain variable region having at least 95% sequence identity to SEQ ID NO:63 and a light chain variable region having at least 95% sequence identity to SEQ ID NO:64; or (e) a heavy chain variable region having at least 95% sequence identity to SEQ ID NO:67 and a light chain variable region having at least 95% sequence identity to SEQ ID NO:68.

245 . The antibody of claim 243 , which is a monoclonal antibody, a humanized antibody, a human antibody, a chimeric antibody, a bispecific antibody, an IgG1 antibody, an IgG2 antibody, an IgG4 antibody, or an antibody fragment comprising an antigen binding site.

246 . The antibody of claim 243 , which comprises:
(a) a heavy chain amino acid sequence of SEQ ID NO:26 and a light chain amino acid sequence of SEQ ID NO:28; (b) a heavy chain amino acid sequence of SEQ ID NO:27 and a light chain amino acid sequence of SEQ ID NO:28; (c) a heavy chain amino acid sequence of SEQ ID NO:29 and a light chain amino acid sequence of SEQ II) NO:30; (d) a heavy chain amino acid sequence of SEQ ID NO:34 and a light chain amino acid sequence of SEQ ID NO:30; (e) a heavy chain amino acid sequence of SEQ ID NO:56 and a light chain amino acid sequence of SEQ ID NO:30; or (f) a heavy chain amino acid sequence of SEQ ID NO:70 and a light chain amino acid sequence of SEQ ID NO:72.

247 . An antibody comprising:
(a) the heavy chain variable region encoded by the plasmid deposited with ATCC as PTA-122180 and the light chain variable region encoded by the plasmid deposited with ATCC as PTA-122181; or (b) the heavy chain variable region encoded by the plasmid deposited with ATCC as PTA-122346 and the light chain variable region encoded by the plasmid deposited with ATCC as PTA-122347.

248 . An isolated antibody that competes with an antibody of claim 243 for specific binding to TIGIT.

249 . An isolated antibody that binds the same epitope on TIGIT as an antibody of claim 243 .

250 . An isolated antibody that binds an epitope on TIGIT that overlaps with the epitope on TIGIT bound by an antibody of claim 243 .

251 . The antibody of claim 243 , which:
(a) inhibits binding of TIGIT to poliovirus receptor (PVR); (b) inhibits or blocks the interaction between TIGIT and PVR; (c) inhibits TIGIT signaling; (d) inhibits TIGIT activation; (e) inhibits phosphorylation of TIGIT; and/or (f) decreases cell surface expression of TIGIT.

252 . The antibody of claim 243 , which induces and/or enhances an immune response.

253 . The antibody of claim 252 , wherein the immune response is directed to a tumor or tumor cell.

254 . The antibody of claim 243 , which:
(a) increases cell-mediated immunity; (b) increases T-cell activity; (c) increases cytolytic T-cell (CTL) activity; (d) increases natural killer (NK) cell activity; (e) increases IL-2 production and/or the number of IL-2-producing cells; (f) increases IFN-gamma production and/or the number of IFN-gamma-producing cells; (g) increases a Th1-type immune response; (h) decreases IL-4 production and/or the number of IL-4-producing cells; (i) decreases IL-10 and/or the number of IL-10-producing cells; (j) decreases a Th2-type immune response; (k) inhibits and/or decreases the suppressive activity of regulatory T-cells (Tregs); and/or (l) inhibits and/or decreases the suppressive activity of myeloid-derived suppressor cells (MDSCs).

255 . An isolated antibody that specifically binds human TIGIT, wherein the antibody binds an epitope comprising:
(a) amino acids within SEQ II) NO:79; (b) amino acids within SEQ ID NO:80; (c) amino acids within SEQ ID NO:79 and SEQ ID NO:80; (d) amino acids Q62 and I109 of SEQ ID NO:4; (e) amino acids Q62 and T119 of SEQ ID NO:4; (f) amino acids Q64 and I109 of SEQ ID NO:4; (g) amino acids Q64 and T119 of SEQ ID NO:4; (h) amino acids Q62, Q64, and I109 of SEQ ID NO:4; (i) amino acids Q62, Q64, and T119 of SEQ ID NO:4; (j) amino acids Q62, I109, and TI 19 of SEQ ID NO:4; (k) amino acids Q64, I109, and TI 19 of SEQ ID NO:4; or (l) amino acids Q62, Q64, I109, and T119 of SEQ ID NO:4.

256 . The antibody of claim 255 , wherein the antibody binds an epitope comprising at least one of amino acids N58, E60, Q62, Q64, L65, F107, I109, H111, T117, T119, and G120 of SEQ ID NO:4.

257 . A cell comprising or producing an antibody of claim 243 .

258 . A pharmaceutical composition comprising an antibody of claim 243 and a pharmaceutically acceptable carrier.

259 . An isolated polynucleotide molecule comprising a polynucleotide that encodes an antibody of claim 243 .

260 . An isolated polynucleotide comprising a polynucleotide sequence selected from the group consisting of: SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, and SEQ ID NO:84.

261 . A vector comprising the polynucleotide of claim 259 .

262 . A polypeptide comprising a sequence selected from the group consisting of: SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:55, SEQ ID NO:56, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:82, and SEQ ID NO:83.

263 . A heterodimeric agent comprising an antibody of claim 243 .

264 . A bispecific agent comprising:
a) a first arm that specifically binds TIGIT, and b) a second arm, wherein the first arm comprises an antibody of claim 243 .

265 . A method of inducing, activating, promoting, increasing, enhancing,

Assignees

• Oncomed Pharm Inc

Inventors

• Gurney Austin L
• Xie Ming-Hong

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/04

  Immunostimulants · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• C07K16/2803 Primary

  against the immunoglobulin superfamily · CPC title

• C07K2317/94

  Stability, e.g. half-life, pH, temperature or enzyme-resistance · CPC title