Targeted Delivery of a Potent STING Agonist Payload via an Antibody–Drug Conjugate Drives Robust Antitumor Activity in Preclinical Models

Stimulator of IFN genes (STING) is an innate immune pathway that activates a type I IFN response upon detection of intracellular DNA from foreign pathogens as well as tumor cells. STING signaling is critical for antiviral immunity and can be co-opted to drive an antitumor immune response. However, STING activation requires careful and controlled agonism to drive immune activation in the tumor microenvironment (TME) while avoiding toxic systemic immune activation. Indeed, nontargeted small-molecule STING agonist therapeutics have shown limited antitumor activity in the clinic, likely due to their short half-life and poor retention within the TME. We hypothesized that targeted delivery of a potent STING agonist payload directly to the TME via an antibody-drug conjugate (ADC) may overcome some of these limitations. In this study, we report the development of a novel STING agonist ADC with a noncleavable linker-payload (ncSTING). Tumor-targeted ADCs employing this linker-payload (ncSTING ADC) elicited robust antitumor activity in a variety of preclinical murine tumor models. We found that Fcγ receptor binding affected antitumor activity as ADCs with a wild-type Fc drove more antitumor activity than ADCs with an Fcγ receptor-binding mutant Fc in a subset of tumor models. Moreover, tumor-targeted ncSTING ADCs elicited tumor regression with reduced systemic immune activation compared with the systemic administration of the released payload. Altogether, these data provide a therapeutic rationale for the targeted delivery of a potent STING agonist payload via an ADC.