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bioRxiv · 10.1101/2023.03.28.534654

SQ3370, the first clinical click chemistry-activated cancer therapeutic, shows safety in humans and translatability across species

Srinivasan, S.·Yee, N. A.·Zakharian, M.·Aleckovic, M.·Mahmoodi, A.·Nguyen, T.-H.·Mejia Oneto, J. M.
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Abstract

BackgroundSQ3370 is the first demonstration of the Click Activated Protodrugs Against Cancer (CAPAC) platform that uses click chemistry to activate drugs directly at tumor sites, maximizing therapeutic exposure. SQ3370 consists of a tumor-localizing biopolymer (SQL70) and a chemically-attenuated doxorubicin (Dox) protodrug SQP33; the protodrug is activated upon clicking with the biopolymer at tumor sites. Here, we present data from preclinical studies and a Phase 1 dose-escalation clinical trial in adult patients with advanced solid tumors (NCT04106492) demonstrating SQ3370s activation at tumor sites, safety, systemic pharmacokinetics (PK), and immunological activity. MethodsTreatment cycles consisting of an intratumoral or subcutaneous injection of SQL70 biopolymer followed by 5 daily intravenous doses of SQP33 protodrug were evaluated in tumor-bearing mice, healthy dogs, and adult patients with solid tumors. ResultsSQL70 effectively activated SQP33 at tumor sites, resulting in high Dox concentrations that were well tolerated and unachievable by conventional treatment. SQ3370 was safely administered at 8.9x the veterinary Dox dose in dogs and 12x the conventional Dox dose in patients, with no dose-limiting toxicity reported to date. SQ3370s safety, toxicology, and PK profiles were highly translatable across species. SQ3370 increased cytotoxic CD3+ and CD8+ T-cells in patient tumors indicating T-cell-dependent immune activation in the tumor microenvironment. ConclusionsSQ3370, the initial demonstration of click chemistry in humans, enhances the safety of Dox at unprecedented doses and has the potential to increase therapeutic index. Consistent safety, toxicology, PK, and immune activation results observed with SQ3370 across species highlight the translatability of the click chemistry approach in drug development. Trial registrationNCT04106492; 7 September 2019

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Srinivasan, S., Yee, N. A., Zakharian, M., Aleckovic, M., Mahmoodi, A., Nguyen, T.-H., Mejia Oneto, J. M.. 2023-03-29. SQ3370, the first clinical click chemistry-activated cancer therapeutic, shows safety in humans and translatability across species. https://doi.org/10.1101/2023.03.28.534654

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