received by the International Bureau on 18 July 2014 (18.07.2014)

1. An isolated polypeptide comprising a poliovirus receptor (PVR) variant, wherein the PVR variant comprises one or more amino acid substitutions as compared to wild-type PVR, and wherein the PVR variant specifically binds the extracellular domain of human TIGIT and does not bind or binds weakly to the extracellular domain of human CD226.

2. The polypeptide of claim 1, which also binds the extracellular domain of human CD96.

3. The polypeptide of claim 1 or claim 2, wherein the one or more amino acid substitutions comprise substitutions in one or more amino acids:

(a) corresponding to amino acids 40-143 of wild-type PVR (SEQ ID NO: l);

(b) corresponding to amino acids 60-90 and/or amino acids 125-133 of wild-type PVR (SEQ ID NO:l);

(c) corresponding to amino acids 65, 67, 72, 73, 74, 81 , 82, 84, and 85 of wild-type PVR (SEQ ID NO: l);

(d) corresponding to amino acid 72 of wild-type PVR (SEQ ID NO.T);

(e) corresponding to amino acid 82 of wild-type PVR (SEQ ID NO: 1); or

(f) corresponding to amino acid 72 and amino acid 82 of wild-type PVR (SEQ ID NO: 1).

4. The polypeptide of claim 1 or claim 2, wherein the PVR variant comprises an amino acid sequence selected from the group consisting of: SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO:20, and SEQ ID NO:21.

5. The polypeptide of any one of claims 1 to 4, which is a soluble receptor.

6. The polypeptide of any one of claims 1 to 5, wherein the PVR variant is linked to a non- PVR polypeptide.

7. The polypeptide claim 6, wherein the non-PVR polypeptide comprises a human Fc region.

AMENDED SHEET (ARTICLE 19)

84

8. The polypeptide of any one of claims 1 to 7, which is monovalent or a heterodimeric protein.

9. The polypeptide of claim 8, wherein the heterodimeric protein comprises a second polypeptide comprising an immune response stimulating agent.

10. The polypeptide of any one of claims 1 to 9, 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) is an antagonist of TIGIT-mediated signaling;

(f) is an antagonist of CD96-mediated signaling;

(g) inhibits TIGIT signaling;

(h) inhibits CD96 signaling;

(i) increases CD226 signaling;

(j) inhibits or blocks the interaction between PVR and TIGIT;

(k) inhibits or blocks the interaction between PVR and TIGIT and the interaction between PVR and CD96;

(1) does not inhibit the interaction between PVR and CD226;

(m) inhibits or blocks the interaction between PVR and TIGIT and the interaction between PVR and CD96, and does not inhibit the interaction between PVR and CD226; and/or

(n) inhibits or blocks the interaction between PVRL2 and TIGIT, the interaction between PVRL3 and TIGIT, and/or the interaction between PVRL4 and TIGIT.

1 1. A pharmaceutical composition comprising the polypeptide of any one of claims 1 to 10.

AMENDED SHEET (ARTICLE 19)

85

12. A cell comprising or producing the polypeptide of any one of claims 1 to 10.

13. A polynucleotide comprising a polynucleotide that encodes the polypeptide of any one of claims 1 to 10.

A vector comprising the polynucleotide of clai

15. Use of the polypeptide of any one of claims 1 to 10, for the preparation of a medicament for activating or increasing an immune response in a subject.

16. Use of the polypeptide of any one of claims 1 to 10, for the preparation of a medicament for treating cancer in a subject.

17. The use of claim 16, wherein the cancer is selected from the group consisting of colorectal cancer, ovarian cancer, pancreatic cancer, lung cancer, liver cancer, breast cancer, kidney cancer, prostate cancer, gastrointestinal cancer, melanoma, cervical cancer, bladder cancer, glioblastoma, and head and neck cancer.

18. Use of a soluble receptor comprising a PVR variant for the preparation of a medicament for increasing an immune response in a subject, wherein the soluble receptor:

(i) inhibits the interaction between TIGIT and PVR;

(ii) inhibits the interaction between CD96 and PVR;

(iii) inhibits the interaction between TIGIT and PVR and inhibits the interaction between CD96 and PVR; or

(iv) inhibits the interaction between TIGIT and PVR, inhibits the interaction between CD96 and PVR, and does not inhibit the interaction between CD226 and PVR.

19. Use of a soluble receptor comprising a PVR variant for the preparation of a medicament for inhibiting tumor growth in a subject, wherein the soluble receptor:

(i) inhibits the interaction between TIGIT and PVR;

AMENDED SHEET (ARTICLE 19)

86 (ii) inhibits the interaction between CD96 and PVR;

(iii) inhibits the interaction between TIGIT and PVR and inhibits the interaction between CD96 and PVR; or

(iv) inhibits the interaction between TIGIT and PVR, inhibits the interaction between CD96 and PVR, and does not inhibit the interaction between CD226 and PVR.

The use of any one of claims 15 to 19, wherein the medicament is used in combination least one additional therapeutic agent.

21. The use of claim 20, wherein the additional therapeutic agent is an. immune response stimulating agent.

22. The use of claim 20 or claim 21, wherein the additional therapeutic agent is a chemotherapeutic agent.

23. The use of claim 20 or claim 21, wherein the additional therapeutic agent is an antibody.

24. A method of increasing the activity of T-cells, NIC cells, monocytes/macrophages, B- cells, and/or cytolytic T-cells (CTL) comprising contacting the cells with an effective amount of the polypeptide of any one of claims 1 to 10.

25. A method of inhibiting tumor growth comprising contacting the tumor or tumor cell with an effective amount of the polypeptide of any one of claims 1 to 10.

AMENDED SHEET (ARTICLE 19)

87