Jnj-'6196: A Next Generation Sting Agonist With Potent Preclinical Activity By The Iv Route

The Stimulator of Interferon Genes (STING) protein is a key mediator of innate immunity that plays a central role in the immune response to invading pathogens (bacterial, viral) and transformed cells. A next generation human STING agonist, JNJ-‘6196 was developed that cures mice of their tumors in preclinical models when administered by the IV route. JNJ-‘6196 was rationally selected to have a weaker binding affinity and fast off rate but functionally is a strong cytokine inducer and an efficient activator of human dendritic cells. JNJ-‘6196 exhibits a unique cytokine induction profile in human PBMCs compared to other cyclic dinucleotides (CDNs) that are not curative by the IV route in mice with higher levels of pro-inflammatory cytokines that mediate antitumor activity and lower levels of those that promote suppressive M2 macrophages. In preclinical models of cancer in mice, JNJ-‘6196 eliminates bilateral tumors when administered IV, and demonstrates activity over a wide therapeutic range. Cured mice are immune to further re-challenge due to the expansion and persistence of tumor specific CD8+ T-cells following JNJ-‘6196 administration. Moreover, JNJ-‘6196 increased the effectiveness of checkpoint inhibitors, turning a PD-1 resistant model into a responsive model. Although it is a very potent inducer of antitumor cytokines in mouse and cyno, it is tolerated at similar dose levels as other CDNs that are not systemically active. The functional properties that confer systemic activity were investigated by comparing gene signatures of JNJ-‘6196 to another CDN that was not curative when administered by the IV route. Differences in the intensity of cytokine gene induction were likely responsible for systemic activity rather than genes that were selectively induced by this IV-active compound. The pharmacologic mode of action of JNJ-‘6196 was investigated and found to be Cmax driven based on efficacy and cytokine readouts. JNJ-‘6196 creates an immune inflamed microenvironment in tumors and could expand the population of patients that respond to immunotherapy. The ability to administer JNJ-96196 systemically and the potential to synergize with other immunotherapeutics could create unique combination modalities and differentiate this compound from other STING agonists. Citation Format: Szeman Ruby Chan, Gilles Bignan, Emily Pierson, Sally Mahady, Hayley Ta, Wim Schepens, Jan Willem Thuring, Heng Keang Lim, Monicah Otieno, Thomas Wilde, Monica Singer, Nancy Bogdan, Shefali Patel, Leo Luistro, Liam Campion, Melissa Smith, Diana Wiley, Kathryn Packman, Michael Allegrezza, Caitlin Morgan, Jocelyn Sendecki, Glenn Van Aller, Daniel Krosky, Peter Connolly, James Edwards, Kim Staquet, Stuart L. Emanuel. JNJ-‘6196: A next generation STING agonist with potent preclinical activity by the IV route [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5567A.