Abstract 1569: Dual action tumor immune agonist (DATIA) ADCs activating STING pathway and subsequently inducing cytotoxicity of tumor cells exhibits potent and lasting in vivo tumor growth inhibition in multiple preclinical tumor antigen positive can

Abstract Introduction: TSN222, currently in Phase 1 clinical development for solid tumors, is a novel dual action tumor immune agonist (DATIA) via intratumoral administration. Its half-lives inside cells and in plasma were designed to be long enough for it to activate tumor STING pathways, and short enough to limit systemic inflammation. Its active metabolite is a DNA synthesis inhibitor, which subsequently induces apoptosis of the tumor cells and provides neoantigens for the emerging adaptive immune responses. The sequential dual actions of type I interferon production through STING pathway activation and latent cytotoxicity connects the innate and adaptive immune systems. Method: Antibody drug conjugates (ADCs) employing TSN222 as a payload were characterized for their activities in STING pathway activation and tumor killing by modulating the tumor microenvironment and adaptive immunity against the tumors, through selective tumor targeting by antibody and more convenient administration of i.v. injection. Results: TSN222 in cell-based assays has shown STING pathway stimulating activity that leads to type I interferon secretion and subsequent cytotoxicity to the cells. TSN222 is well tolerated in preclinical toxicology studies by s.c. administration and Phase 1 clinical trial by i.t. administration. One case of partial response (PR) has been observed during dose escalation at 800μg dosage level. Antibodies against Her2, Trop2 and Claudin18.2, respectively conjugated with TSN222 as a payload, have shown potent tumor growth inhibition (TGI) in antigen specific cancer cell lines and animal models. For example, a single i.v. dose of anti Her2 DATIA ADC at 0.6 mpk in SK-OV-3 her2+ CDX model afforded 109% TGI after 22 days, while the payload TSN222 at 1 mpk i.t. QWx3 gave a TGI of 21%. In EMT6-huHer2+ breast cancer model, a single i.v. dose of the ADC at 3 mpk induced complete remission (CR) at day 20. Upon rechallenging of the CR mice at day 33 with EMT6-huHer2+ and CT26 colorectal tumor cells, TGIs were 64% and -23 % relative to that in naïve mice, respectively, indicating tumor specific immunity was induced in the EMT6-huHer2+ mice. Conclusion: We have developed a tumor targeting immune stimulating ADC platform with novel mechanism of action that differentiates from other immune stimulating ADC approaches. The dual action of STING pathway activation and subsequent induction of apoptotic signals in tumor cells by the moderately toxic metabolite renders timely presentation of antigens to bridge the innate and adaptive immune system. With the preclinical proof-of-concept studies and ongoing clinical trial data of the payload to inform on safety and tolerability, the DATIA ADC platform is positioned to serve as a distinctly different approach for better safety and efficacy. Citation Format: Yanliang Zhang, Chunlan Dong, Guangming Chen, Qianxiang Zhou, Tony Zhang. Dual action tumor immune agonist (DATIA) ADCs activating STING pathway and subsequently inducing cytotoxicity of tumor cells exhibits potent and lasting in vivo tumor growth inhibition in multiple preclinical tumor antigen positive cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1569.