Development of a First-in-Class Click Chemistry-Based Cancer Therapeutic, from Preclinical Evaluation to a...

Area of Science:

• Oncology
• Bioorthogonal Chemistry
• Drug Delivery Systems

Background:

• Precise drug activation at tumor sites without systemic toxicity remains a significant challenge in cancer therapy.
• Click Activated Protodrugs Against Cancer (CAPAC) is a pretargeting strategy utilizing bioorthogonal click chemistry for targeted drug activation.
• This approach offers broad applicability to various targeted therapeutics.

Purpose of the Study:

• To describe the preclinical development and clinical translation of SQ3370, a CAPAC-based cancer therapeutic.
• To evaluate the safety, efficacy, and immune-modulating effects of SQ3370 in preclinical models and a first-in-human trial.

Main Methods:

• SQ3370, a first-in-class CAPAC therapeutic, employs a clickable pretargeting agent and a chemically attenuated doxorubicin (Dox) payload.
• Preclinical studies in mouse tumor models and a first-in-human dose-escalation trial (NCT04106492) in patients with advanced solid tumors were conducted.
• Safety, toxicology, pharmacokinetics, and immune responses were assessed across species and in patients.

Main Results:

• SQ3370 effectively inhibited tumor progression in mouse models via safe and selective Dox release at tumor sites.
• The therapy demonstrated a favorable safety profile in dogs and humans, with no dose-limiting toxicities observed at escalated doses.
• SQ3370 modulated doxorubicin pharmacokinetics and induced T-cell-dependent immune responses, including CD8+ T-cell activation.

Conclusions:

• SQ3370 represents the first clinical demonstration of in vivo click chemistry for targeted chemotherapy delivery.
• The therapy not only delivered chemotherapy but also elicited beneficial immune responses, potentially aiding in treating metastatic disease.
• Consistent safety and efficacy across species underscore the translatability of CAPAC technology, positioning click chemistry as a promising modality for targeted cancer therapeutics.