Abstract LB245: ONM-501, a dual-activating polyvalent STING agonist, enhances tumor retention and demonstrates favorable preclinical safety profile

Abstract

Abstract Background: The Stimulator of Interferon Genes (STING) plays a crucial role in the innate immune response. Several previous STING agonist development compounds have shown limited therapeutic efficacy in oncology clinical trials. ONM-501 is a novel STING agonist: the endogenous STING agonist 2’,3’-cyclic GMP-AMP (cGAMP) is encapsulated within PC7A micelles. PC7A induces polyvalent STING condensation and prolongs immune activation. cGAMP-PC7A nanoparticles offer a dual ‘burst’ and ‘sustained’ STING activation. The anti-tumor efficacy and pharmacodynamic analysis of ONM-501 in multiple tumor models have been demonstrated previously. Here we report the pharmacokinetic (PK) and biodistribution (BD) analysis of ONM-501 in mice and safety evaluation in mice, rats and primates. Methods: PC7A polymers conjugated with LiCOR 800CW were mixed with unlabeled PC7A in 1:9 ratio and cGAMP was encapsulated into micelles to generate an “always-on” fluorescently labelled ONM-501-CW800. Naïve or tumor-bearing mice were injected subcutaneously (SC) or intratumorally (IT) with ONM-501-CW800, respectively, and plasma and multiple organ samples were collected; the whole tissue specimens were first imaged ex vivo using LiCOR Pearl Imaging system, and then homogenized and the fluorescence quantified against standard curves prepared by spiking ONM-501-CW800 into a homogenate of the relevant matrix. PK parameters were calculated using non-compartmental methods. Safety and tolerability were evaluated by single- and multiple-dose SC injections in naïve animals up to the highest feasible doses. Results: The BD pattern of ONM-501-CW800 was similar after IT and SC injections. The highest concentrations were observed at the injection sites and draining lymph nodes at all timepoints for both routes of administration. The concentrations in the injection site were much higher in tumors following IT than in dermal tissue following SC injection. After a 50 µg dose, systemic exposure to ONM-501-CW800 was ~1.8- and 2.4-fold lower after IT than SC injection based on Cmax and AUC(inf), respectively. The plasma t½ after IT injection, 17.4 hours, was ~1.3-fold longer than after SC injection, 12.9 hours. The Cmax and AUC (inf) in tumors were ~144- and 120-fold higher than in plasma after IT injection, with a t½ of 25.2 hours in tumors. In single-dose toxicology studies, ONM-501 was well tolerated in mice, rats and monkeys without severe or irreversible systemic toxicities up to the maximum feasible SC doses at 74, 45 and 30 mg/kg, respectively. In the 4-week repeat-dose GLP toxicology studies, the highest non-severely toxic SC dose (HNSTD) was 30 and 7.5 mg/kg in rats and monkeys, respectively. Conclusions: Systemic exposure to ONM-501 was lower after IT than SC administration, which is consistent with increased ONM-501 retention in tumors. Combined with preclinical toxicology studies, ONM-501 showed a favorable pharmacokinetic, tolerability and safety profile that support its continued development in cancer patients. Citation Format: Zirong Chen, Gang Huang, Katy Torres, Fiona Stavros, Alessandra Ahmed, Jason Miller, Tian Zhao, Jinming Gao, Ruolan Han. ONM-501, a dual-activating polyvalent STING agonist, enhances tumor retention and demonstrates favorable preclinical safety profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB245.