No abstract

Prostaglandin E2 (PGE2) binds to four G-protein-coupled EP receptors, of which both EP2 and EP4 are abundantly expressed by tumor-infiltrating immune cells including DCs, NK cells, Tregs, cytotoxic T cells and TAMs. Signaling via EP2 and EP4 is immunosuppressive, preventing the mounting of effective anti-tumor immune responses leading to tumor immune escape and tumor progression. Currently, several EP4 selective antagonists and an EP2/4 dual antagonist are being developed for anti-cancer immunotherapy. Using a combination of EP2 and EP4 selective antagonists in different tumor mouse models, we could demonstrate that dual EP2/EP4 blockade is more effectively activating anti-tumor immunity compared to targeting either receptor alone. The concurrent inhibition of EP2 and EP4 resulted in tumor regression and induction of immunological memory. Together with published data showing similar findings, our results suggest that simultaneous targeting of EP2 and EP4 could be a promising new therapeutic approach to overcome cancer immune evasion. Idorsia Pharmaceuticals has identified ACT-1002-4391 as a novel, potent antagonist of EP2 and EP4 receptors with an excellent duality profile. In vitro, ACT-1002-4391 is capable of modulating immune cell proliferation and/or function and is superior to EP2 or EP4 selective inhibition in that respect. In vivo, ACT-1002-4391 displays strong and dose-dependent single agent anti-tumor efficacy in a syngeneic mouse tumor model. Based on the excellent selectivity and duality profile, ACT-1002-4391 will be advanced into clinical development by Idorsia Pharmaceuticals. Citation Format: Sébastien Jeay, Stefan Diethelm, Agnes Knopf, Marie Goxe, Marie Daugan, Julie Erupathil, Julien Pothier, Davide Pozzi, Thierry Sifferlen, Lorenza Wyder, Isabelle Lyothier, Olivier Corminboeuf, Francois Lehembre, Imke Renz, Dominique Meyer. ACT-1002-4391 - A novel potent antagonist of the prostaglandin E2 receptors EP2 and EP4 with excellent duality [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1809.