Abstract 1347: The CAPAC Platform maximizes therapeutic benefit and reduces systemic cytotoxic exposure in small and large animals
Authors: Sangeetha Srinivasan, Nathan A. Yee, Amir Mahmoodi, Michael Zakharian, M. Wayne Saville, Jose M. Mejia Oneto
Journal: Cancer Research (2021)

Abstract The Click Activated Protodrugs Against Cancer (CAPACTM) platform aims to beat cancer without poisoning the body by activating powerful cancer therapies at the tumor site(s). CAPAC's mechanism of activation is based on click chemistry and is therefore agnostic to tumor characteristics, biomarker expression or other biological factors that vary across patients. This allows the CAPAC platform to be readily applicable to diverse tumor types. We describe the safety, pharmacokinetic and therapeutic benefits of SQ3370, the lead candidate of the CAPAC Platform, in small and large animals. SQ3370 consists of 2 components, SQL70 biopolymer and SQP33 protodrug. First, SQL70, a tetrazine-modified sodium hyaluronate biopolymer, is injected at the tumor site. Then, SQP33, a trans-cyclooctene (TCO)-modified protodrug of Doxorubicin (Dox) is given by IV infusion as 5 daily doses. The SQP33 protodrug has attenuated toxicity and is converted to active Dox by the SQL70 biopolymer at the tumor site through a highly efficient covalent reaction between tetrazine and TCO moieties. In mice, when administered in subcutaneous, intramuscular or intraperitoneal regions, around 50% of SQL70 was detectable after 2 weeks at the injection site. Biodistribution results suggested clearance of SQL70 by hepatic and renal routes. The MTD of SQ3370 in mice was nearly 20-times that of conventional Dox. Anti-tumor efficacy was evident even at 0.37x the MTD of SQ3370 suggesting that increasing the SQ3370 dosage to its MTD can maximize therapeutic benefit. Safety evaluation in 72 dogs that received either SQL70 biopolymer alone, SQP33 protodrug alone or both together (SQ3370) showed that all agents were well tolerated. The Highest Non-Severely Toxic Dose (HNSTD) of SQ3370 was 8.95 mg/kg/cycle in Dox Eq, at which dose there were minimal systemic adverse events and no evidence of cardiotoxicity. (The standard veterinary clinical dose for Dox in dogs is 1 mg/kg/cycle). The PK profiles in dogs demonstrated that SQL70 biopolymer efficiently captures the protodrug from circulation and releases active Dox. In conclusion, the CAPAC Platform represents a new therapeutic modality to treat solid tumors by using a drug with known efficacy, such as doxorubicin, and expanding its pharmacological capabilities. The CAPAC Platform enables higher concentrations of the active drug at the tumor site and minimizes systemic adverse effects associated with conventional chemotherapy. SQ3370 is currently being evaluated in a Phase I study in patients with advanced solid tumors (https://clinicaltrials.gov/ct2/show/NCT04106492). Citation Format: Sangeetha Srinivasan, Nathan A. Yee, Amir Mahmoodi, Michael Zakharian, M. Wayne Saville, Jose M. Mejia Oneto. The CAPAC Platform maximizes therapeutic benefit and reduces systemic cytotoxic exposure in small and large animals [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1347.