Unlocking the Potential of E7766: A Pan-Genotypic STING Agonist for Cancer Immunotherapy

The study introduces E7766, a newly identified STING agonist with a unique structure, which is being explored for its potential as an immunotherapy treatment for solid tumors via intratumoral injection and for non-muscle invasive bladder cancer (NMIBC) that does not respond to Bacillus Calmette-Guerin (BCG) through intravesical administration.

E7766 was crafted to enhance binding affinity to various STING protein isoforms. It underwent comprehensive evaluation across multiple studies, including biochemical, molecular, cellular, in vivo, ex vivo, and analyses using primary human tumor and cellular samples to assess its potency, mechanisms, and biomarker translation. Innovative preclinical models were created to simulate NMIBC and metastatic deep lesion scenarios, and co-crystallization studies with genetic variant proteins were conducted.

Results indicate that E7766, classified as a Macrocycle-Bridged STING Agonist, exhibits high specificity and potent activity in both human and mouse STING systems. It showed consistent potency across seven human STING genotypes with an IC50 range of 0.15-0.79 μM, outperforming a standard cyclic dinucleotide STING agonist that displayed lower potency and greater variability. The co-crystal structures revealed the structural rationale behind E7766's superior binding to STING proteins. In a preclinical mouse model of NMIBC, E7766 administered intravesically showed dose-dependent and curative effects without serious side effects, inducing significant levels of IFNβ, CXCL10, and other STING pathway mediators within the bladder. Furthermore, a single intratumoral injection of E7766 into mice with dual CT26 tumors in the liver and subcutaneously resulted in a cure rate of 90%, with no recurrence for over 8 months. Remarkably, the cured animals developed a robust immune memory response to the tumor cells, even in the absence of CD8+ T cells or NK cells.

In conclusion, E7766 is a novel and potent STING agonist that acts across all genotypes, showing promising curative effects in murine models of BCG-resistant NMIBC and metastatic deep lesions. Discussions for clinical trials of E7766 are ongoing.