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Abstract Shasqi is advancing the Click Activated Protodrugs Against Cancer (CAPAC®) platform based on click chemistry, a Nobel Prize winning technology. The platform is modular and comprises 1) an activator that target specific antigens, and 2) inert cancer drugs, protodrugs, which are selectively activated at tumors via click chemistry. The CAPAC technology separates the tumor targeting function from the payload and reunites them at the tumor, creating the flexibility to optimize activity while limiting toxicity during preclinical and clinical development. The modularity of the platform enables the rapid development of new therapies as well as unlocking unique treatment benefits such as tunable combinations and payload cycling. We envision that CAPAC will expand the scope of potential targets and widen the therapeutic index of antibody drug conjugates (ADCs). Here we present proof of concept for a HER2-targeting activator with a monomethyl auristatin E (MMAE) payload. The activator SQT01 is composed of a HER2-binding Fab conjugated with tetrazines (Tz), a click chemistry component. The protodrug SQP22 is formed by coupling trans-cyclooctene (TCO), another click chemistry component, to MMAE, a cytotoxic spindle poison. SQT01 binding was confirmed via flow cytometry, while SQP22 was evaluated for stability and activation via the reaction of Tz and TCO moieties activating MMAE at the tumor site. In vivo activity was evaluated in a HER2+ gastric cancer (NCI-N87) xenograft model. SQP22 was stable in plasma and had minimal in vivo anti-tumor activity without the activator. When combined with SQT01 in tumor-bearing mice, SQP22 was rapidly activated and led to active MMAE at the tumor site within 15 minutes. In efficacy studies, this activation resulted in significant tumor growth inhibition compared to an isotype control or disitamab vedotin, an ADC that targets HER2 and carries an MMAE payload. Treatment with SQT01 and 3 daily doses of SQP22 resulted in 4/6 complete responses with no body weight loss. This response can be differentiated from the activity of the isotype control by modulating the dose levels of SQT01 or SQP22 and the time interval between the two. In a dose escalation study, increasing dose level combinations were evaluated. In another efficacy study the optimal timing between the administration of SQT01 and SQP22 was investigated. It was found that anti-tumor efficacy is maintained over a 4 to 24 hours dose gap, but non-specific activity is decreased by dosing SQP22 8 - 24 hours after SQT01, corresponding to increased safety. Additional toxicology studies are ongoing. This data indicates that the CAPAC platform, which separates the targeting agent from the payload, can be optimized for antigen specific efficacy and safety by modulating dose amounts and time intervals between both components. Citation Format: Stefanie Wagner, Maša Aleckovic, George Coricor, Sangeetha Srinivasan, Jesse McFarland, Tri-Hung Nguyen, Jose M. Mejía Oneto. Improving anti-tumor efficacy by modulating a separate HER2 activator and an MMAE payload and reuniting both through click chemistry abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 7216.
Wagner et al. (Fri,) studied this question.