Abstract 1996: Intravenous administration of the small molecule STING agonist CRD5500 elicits potent anti-tumor immune responses in cold tumors

Abstract

Abstract Background: Innate immune signaling mediated through STING (Stimulator of Interferon Genes) generates a Type I interferon (Type 1 IFN) signal that increases T cell infiltration into cold or non-inflamed tumors leading to significant regression1. CRD5500 is a small molecule STING agonist that has demonstrated excellent systemic tolerability in primate GLP toxicology studies and is scheduled for IND filing with the US FDA in the first half of 2022. The compound binds to STING at a unique location that is outside the dimeric cleft that is the natural ligand binding site2. While this first-in class agent cross-reacts with cynomolgus monkey STING and activates all five major variants of human STING with similar potency, it does not cross-react with rodent STING. Here we demonstrate the potent anti-tumor activity of CRD5500 administered intravenously in a range of immunologically cold murine tumors implanted in human STING knock-in mice. Methods: The functional potency of STING across species was evaluated in STING over-expressing HEK293T cells and PBMCs. Human STING KI mice (Genoway) were used to monitor anti-tumor effects of CRD5500 dosed IV or IT against the following tumors: B16F10 (melanoma), PANO2 (pancreatic), C1498 (acute myeloid leukemia) and LL2 (lung). Intravenous pharmacokinetic and pharmacodynamic evaluation was carried out in cynomolgus monkeys. Results: CRD5500’s activated the different variants of human STING with EC50 values that ranged from 10-70 nM in an pIRF3 reporter assay. Treatment of hSTING transfected cells, human tumor cell lines or hPBMC with CRD5500 led to dose dependent activation of STING. Further, CRD5500 treatment of human DCs and PBMCs led to the induction of inflammatory cytokines such as IFNβ and TNFα. Intravenous administration of CRD5500 in human STING knock-in mice caused tumor regression in several cold tumor models such as B16F10, PANO2, LL2, C1498. Further, CRD5500 demonstrated the abscopal effect in B16F10 tumors when administered via intratumoral route. The compound was well tolerated at high doses in the primate GLP study when administered intravenously and caused dose and exposure dependent increases in CXCL10. Conclusion: The ability of CRD5500 to generate impressive anti-tumor immune responses in cold tumors as a single agent coupled with its excellent IV safety profile in non-human primates make it well suited for FIH investigations planned for mid-2022 under a US FDA IND.