RT Journal Article
SR Electronic
T1 SQ3370, the first clinical click chemistry-activated cancer therapeutic, shows safety in humans and translatability across species
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2023.03.28.534654
DO 10.1101/2023.03.28.534654
A1 Sangeetha Srinivasan
A1 Nathan A. Yee
A1 Michael Zakharian
A1 Maša Alečković
A1 Amir Mahmoodi
A1 Tri-Hung Nguyen
A1 José M. Mejía Oneto
YR 2023
UL http://biorxiv.org/content/early/2023/03/29/2023.03.28.534654.abstract
AB Background SQ3370 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 SQ3370’s activation at tumor sites, safety, systemic pharmacokinetics (PK), and immunological activity.Methods Treatment 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.Results SQL70 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. SQ3370’s 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.Conclusions SQ3370, 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 registration NCT04106492; 7 September 2019Competing Interest StatementSangeetha Srinivasan, Nathan A. Yee, Michael Zakharian, Maša Alečković, Tri-Hung Nguyen, José M. Mejía Oneto are paid employees and shareholders of Shasqi Inc. Amir Mahmoodi is a shareholder of Shasqi Inc. José M. Mejía is the Founder and CEO of Shasqi Inc.