Abstract 7481: The allosteric STING agonist CRD3874 is systemically tolerated demonstrates systemic tolerability

Abstract

Abstract Background: The activation of STING by CDN bind site targeting ligands leads to the generation of Type I interferons as well as pyroptosis and autophagy of the cell expressing STING due to STING’s ability to transport protons across the endoplasmic reticulum. CDN site targeting STING agonists tested in the clinic thus far have shown limited systemic tolerability as well as a tendency to kill the very immune cells that they are designed to activate. CRD3874 is an allosteric small-molecule human STING agonist with a unique binding mode that generates robust Type I interferon responses while simultaneously blocking STINGs proton transport activity that is associated with pyroptosis and autophagy. Methods: Allosteric binding was established using radioligand binding assays. Anti-cancer activity of CRD3874-SI by the IV route was evaluated in human STING KI C57/BL6 mice (genOway, France). Inflammasome and autophagy markers were studies in human and mouse cells. Results: In contrast with competitive STING agonists, CRD3874 potentiates the binding of radiolabeled cGAMP to STING. Treatment of immune cells with CRD3874 or other STING agonists, led to dose dependent increases in Type1 interferons and other pro-inflammatory cytokines. However, unlike other STING agonists, activation of STING by CRD3874 did not lead to induction of autophagy or Inflammasome markers in cells or mice. Intravenous administration of CRD3874-SI in human STING knock-in mice caused tumor regression and survival benefit in multiple murine tumor models. The compound was well tolerated at high doses in the primate GLP study when administered intravenously and caused dose and exposure dependent increases in cytokines. This profile of retaining the high efficacy of a STING agonist while demonstrating systemic safety is unique to CRD3874-SI. Conclusions: CRD3874 is a systemically administered STING agonist with promising single agent activity and an excellent IV safety profile in NHP. An investigator sponsored FIH Phase 1 trial with CRD3874-SI has been initiated at Memorial Sloan Kettering, NY, in sarcoma, MCC patients under the supervision of Dr. Ciara Kelly (NCT06021626). Citation Format: Monali Banerjee, Sandip Middya, Ritesh Shrivastava, Anindita Middya, Nagaswamy Mane, Nidhi Rawat, Thanilsana Soram, Debjani Chakraborty, Rajib Ghosh, Rubeena R. Mansuri, Dharmendra Yadav, Anuj Gautam, Anuj Singh, Kavita Puniya, David Pryde, Sourav Basu, Fabiane Sonego, Gaelle H. Martin, Kader Thiam, Arjun Surya. The allosteric STING agonist CRD3874 is systemically tolerated demonstrates systemic tolerability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7481.