Systemic Administration Of Sting Agonist Antibody-Drug Conjugates Elicit Potent Anti-Tumor Immune Responses With Minimal Induction Of Circulating Cytokines

STING pathway agonism has emerged as a potential therapeutic mechanism to stimulate an innate anti-tumor immune response. While in principle systemic administration of a STING agonist would have many therapeutic benefits, including the delivery of STING to all tumor lesions, such an approach may be limited by toxicity. Antibody-drug conjugates (ADCs) constitute a proven therapeutic modality that is ideally suited to enable systemic administration without associated toxicity concerns via a targeted delivery strategy. Herein, we demonstrate that systemically administered STING agonist ADCs have greater anti-tumor activity as well as greatly improved tolerability compared to an intravenously (IV) administered, unconjugated (free) agonist. We generated novel STING agonist ADCs by leveraging our Immunosynthen platform, in which the chemical scaffold for bioconjugation is optimized for the STING agonist, resulting in an ADC that has desirable physicochemical and drug-like properties. We have studied the in vitro activity and mechanism of action of STING agonist ADCs in monoculture and co-culture systems. STING agonist ADCs were at least 100-fold more potent in inducing interferon and cytokines as well as tumor cell-killing relative to free agonist. STING agonist ADCs against several targets (antigens) have been evaluated for anti-tumor activity and pharmacodynamic and pharmacokinetic properties in multiple xenograft and syngeneic models. A single administration of STING agonist ADC resulted in target-dependent, durable, and complete regressions. Importantly, the STING agonist ADC led to an increase in tumor-localized inflammatory cytokines and significant immune cell infiltration, while levels of systemic cytokines remained low. In contrast, IV administered free agonist induced up to 100-fold higher levels of systemic cytokines with concomitant body weight loss but only modest tumor growth delay. In summary, Immunosynthen represents a novel STING agonist ADC platform. We have demonstrated target-dependent anti-tumor immune responses in vitro and in vivo for multiple targets, tumor models, and mouse strains. In each case the STING agonist ADC was more active and better tolerated than the IV administered free agonist. Citation Format: Raghida A. Bukhalid, Jeremy R. Duvall, Naniye Malli Cetinbas, Kalli C. Catcott, Kenneth Avocetien, Keith W. Bentley, Stephen Bradley, Tyler Carter, Chen-Ni Chin, Susan Clardy, Scott D. Collins, Timothy Eitas, Brian D. Jones, Eugene W. Kelleher, Rebecca Mosher, Mark Nazzaro, Marina Protopopova, Pamela Shaw, Kelly Slocum, Elena Ter-Ovanesyan, LiuLiang Qin, Joshua D. Thomas, Ling Xu, Liping Yang, Jeffrey Zurita, Dorin Toader, Marc Damelin, Timothy B. Lowinger. Systemic administration of STING agonist antibody-drug conjugates elicit potent anti-tumor immune responses with minimal induction of circulating cytokines [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 6706.