Tight-binding agents and uses thereof

1. An isolated antibody that specifically binds the extracellular domain of TIGIT, which comprises:

(a) a heavy chain CDR1 comprising GSSLSSSYMS (SEQ II) 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 (SEQ ID NO:8), and a heavy chain CDR3 comprising GGYRTSGMDP (SEQ 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).

2. The antibody of claim 1 , 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.

3. The antibody of claim 1 , which is a monoclonal antibody, a humanized 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.

4. The antibody of claim 1 , 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 ID 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.

5. The antibody of claim 1 , 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.

6. The antibody of claim 1 , which induces and/or enhances an immune response.

7. The antibody of claim 6 , wherein the immune response is directed to a tumor or tumor cell.

8. The antibody of claim 1 , which:

(a) increases cell-mediated immunity;

(b) increases T-cell activity;

(c) increases cytolytic (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 production 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).

9. A heterodimeric agent comprising an antibody of claim 1 .

10. 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 1 .

11. A pharmaceutical composition comprising an antibody of claim 1 and a pharmaceutically acceptable carrier.

12. 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.

13. A cell comprising or producing an antibody of claim 1 .

14. An isolated polynucleotide molecule comprising a polynucleotide that encodes an antibody of claim 1 .

15. 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.

16. A vector comprising the polynucleotide of claim 14 .

17. 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: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.