Chimeric cytokine receptors bearing a PD-1 ectodomain
Provided herein are PD-1 chimeric cytokine receptors. When present on chimeric antigen receptor (CAR)-bearing immune cells, such receptors allow for increased immune cell activation, proliferation, persistence, and/or potency, when engaged with PD-1 ligands or activation with an anti-PD-1 antibody. Also provided are methods of making and using the chimeric cytokine receptors described herein.
1. A PD-1 chimeric cytokine receptor comprising:
a. a PD-1 ectodomain or an antigen binding domain of an anti-PD-L1 or an anti-PD-L2 antibody;
b. a transmembrane domain;
c. a Janus Kinase (JAK)-binding domain; and
d. a recruiting domain comprising a STAT-recruiting domain from IL2Rb,
wherein the transmembrane domain and JAK-binding domain comprise SEQ ID NO: 40, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, or SEQ ID NO: 27.
2. The chimeric cytokine receptor of claim 1 , wherein the PD-1 chimeric cytokine receptor is dimerized, and each monomer comprises:
a. the PD-1 ectodomain;
b. the transmembrane domain;
c. the Janus Kinase (JAK)-binding domain; and
d. the recruiting domain.
3. The chimeric cytokine receptor of claim 1 , wherein the PD-1 ectodomain comprises a wild type PD-1 ectodomain sequence.
4. The chimeric cytokine receptor of claim 1 , wherein the PD-1 ectodomain comprises one or more mutations to the wild type PD-1 ectodomain sequence.
5. The chimeric cytokine receptor of claim 4 , wherein the PD-1 ectodomain comprising one or more mutations has a higher binding affinity for its ligand than a wild type PD-1 ectodomain.
6. The chimeric cytokine receptor of claim 1 , wherein the PD-1 ectodomain comprises an amino acid sequence selected from SEQ ID NOs: 2-5, 132-133, and 168-169.
7. The chimeric cytokine receptor of claim 1 , wherein the antigen binding domain is a scFv.
8. The chimeric cytokine receptor of claim 1 , wherein the chimeric cytokine receptor is activated when the PD-1 ectodomain is bound to PD-L1 or PD-L2.
9. The chimeric cytokine receptor of claim 1 , wherein the chimeric cytokine receptor is activated when the PD-1 ectodomain is bound to an anti-PD-1 antibody.
10. The chimeric cytokine receptor of claim 9 , wherein the anti-PD-1 antibody is nivolumab or pembrolizumab.
11. The chimeric cytokine receptor of claim 1 , wherein the JAK-binding domain is a JAK2-binding domain.
12. The chimeric cytokine receptor of claim 1 , wherein the STAT-recruiting domain from IL2Rb comprises SEQ ID NO: 77.
13. The chimeric cytokine receptor of claim 1 , wherein the receptor is constitutively active and can be further induced.
14. The chimeric cytokine receptor of claim 1 , wherein the STAT-recruiting domain from IL2Rb comprises SEQ ID NO: 76.
15. The chimeric cytokine receptor of claim 2 , wherein the PD-1 ectodomain comprises a wild type PD-1 ectodomain sequence.
16. The chimeric cytokine receptor of claim 1 , wherein the transmembrane domain and JAK-binding domain comprise SEQ ID NO: 40.
17. The chimeric cytokine receptor of claim 16 , wherein the STAT-recruiting domain from IL2Rb comprises SEQ ID NO: 77.
18. The chimeric cytokine receptor of claim 16 , wherein the STAT-recruiting domain from IL2Rb comprises SEQ ID NO: 76.
19. The chimeric cytokine receptor of claim 1 , wherein the transmembrane domain and JAK-binding domain comprise SEQ ID NO: 23.
20. The chimeric cytokine receptor of claim 19 , wherein the STAT-recruiting domain from IL2Rb comprises SEQ ID NO: 77.
21. The chimeric cytokine receptor of claim 19 , wherein the STAT-recruiting domain from IL2Rb comprises SEQ ID NO: 76.
22. The chimeric cytokine receptor of claim 1 , wherein the transmembrane domain and JAK-binding domain comprise SEQ ID NO: 24.
23. The chimeric cytokine receptor of claim 22 , wherein the STAT-recruiting domain from IL2Rb comprises SEQ ID NO: 77.
24. The chimeric cytokine receptor of claim 22 , wherein the STAT-recruiting domain from IL2Rb comprises SEQ ID NO: 76.
25. The PD-1 chimeric cytokine receptor of claim 1 , wherein the transmembrane domain and JAK-binding domain comprise SEQ ID NO: 25.
26. The chimeric cytokine receptor of claim 25 , wherein the STAT-recruiting domain from IL2Rb comprises SEQ ID NO: 77.
27. The chimeric cytokine receptor of claim 25 , wherein the STAT-recruiting domain from IL2Rb comprises SEQ ID NO: 76.
28. The chimeric cytokine receptor of claim 1 , wherein the transmembrane domain and JAK-binding domain comprise SEQ ID NO: 26.
29. The chimeric cytokine receptor of claim 28 , wherein the STAT-recruiting domain from IL2Rb comprises SEQ ID NO: 77.
30. The chimeric cytokine receptor of claim 28 , wherein the STAT-recruiting domain from IL2Rb comprises SEQ ID NO: 76.
31. The PD-1 chimeric cytokine receptor of claim 1 , wherein the transmembrane domain and JAK-binding domain comprise SEQ ID NO: 27.
32. The chimeric cytokine receptor of claim 31 , wherein the STAT-recruiting domain from IL2Rb comprises SEQ ID NO: 77.
33. The chimeric cytokine receptor of claim 31 , wherein the STAT-recruiting domain from IL2Rb comprises SEQ ID NO: 76.