Immunotherapy with binding agents
Binding agents that modulate the immune response are disclosed. The binding agents may include soluble receptors, polypeptides, and/or antibodies. Also disclosed are methods of using the binding agents for the treatment of diseases such as cancer.
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 (SEQ ID NO:1), wherein the substitutions comprise substitutions in one or more amino acids corresponding to amino acids 65, 67, 72, 74, 81, 82, 84, and 85 of wild-type PVR (SEQ ID NO:1), and wherein the PVR variant specifically binds the extracellular domain of human TIGIT and does not bind 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 , wherein the one or more amino acid substitutions comprise substitutions in one or more amino acids:
(a) corresponding to amino acid 72 of wild-type PVR (SEQ ID NO:1);
(b) corresponding to amino acid 82 of wild-type PVR (SEQ ID NO:1); or
(c) corresponding to amino acid 72 and amino acid 82 of wild-type PVR (SEQ ID NO:1).
4. The polypeptide of claim 1 , wherein the PVR variant comprises an amino acid sequence selected from the group consisting of SEQ NO:18, SEQ ID NO:19, SEQ ID NO:20, and SEQ ID NO:21.
5. The polypeptide of claim 1 , which is a soluble receptor.
6. The polypeptide of claim 1 , 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.
8. The polypeptide of claim 1 , 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 claim 1 , 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;
(l) 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.
11. A pharmaceutical composition comprising the polypeptide of claim 1 .
12. The polypeptide of claim 1 , wherein the PVR variant comprises SEQ ID NO:18.
13. The polypeptide of claim 1 , wherein the PVR variant comprises SEQ ID NO:19.
14. The polypeptide of claim 1 , wherein the PVR variant comprises SEQ ID NO:20.
15. The polypeptide of claim 1 , wherein the PVR variant comprises SEQ ID NO:21.