Development of a First-in-Class Click Chemistry–Based Cancer Therapeutic, from Preclinical Evaluation to a First-in-Human Dose Escalation Clinical Trial
Abstract
Abstract Purpose: Achieving precise drug activation without associated toxicities is a significant challenge in developing cancer therapeutics. Click Activated Protodrugs Against Cancer is a pretargeting approach that uses bioorthogonal click chemistry in vivo to selectively capture and activate drugs at tumors and can be applied to a wide variety of targeted therapeutics. The first-in-class Click Activated Protodrugs Against Cancer–based cancer therapeutic SQ3370 uses a clickable pretargeting agent that reacts with a chemically attenuated clickable payload of doxorubicin (Dox) and releases the active cytotoxic drug in situ. Patients and Methods: We describe the preclinical development and translation of SQ3370 to a first-in-human dose-escalation clinical trial in adult patients with advanced solid tumors (NCT04106492). Results: SQ3370 inhibited tumor progression across several mouse tumor models through the safe and selective release of Dox in tumors at concentrations unachievable by conventional treatment. SQ3370 exhibited safety when administered at 8.9 times the veterinary Dox dose in dogs and 15 times the conventional Dox dose in patients, with no reported protocol-defined dose-limiting toxicities. In patients, SQ3370 modulated active Dox pharmacokinetics and enabled T-cell–dependent immune responses, including cytotoxic CD8+ T-cell expansion and activation in tumors and systemically. Conclusions: SQ3370, the first demonstration of click chemistry within the human body…
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