Abstract 9P
Background
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. The lead candidate, SQ3370, is being evaluated in a phase I study in patients with advanced solid tumors (NCT04106492). We describe the safety, pharmacokinetics (PK), and therapeutic benefits of SQ3370, the lead candidate of the CAPAC Platform, in vivo.
Methods
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 systemically as 5 daily doses. SQP33 has attenuated toxicity and is converted to active Dox by SQL70 at the tumor site through an efficient covalent reaction between tetrazine and TCO moieties.
Results
In canines, the highest non-severely toxic dose of SQ3370 was found to be 8.95 times higher when compared to the conventional dose of Dox. There were minimal and reversible systemic adverse events, with no evidence of cardiotoxicity. The PK analysis in dogs showed that SQL70 efficiently captures SQP33 from circulation and releases active Dox throughout the treatment period. In the absence of SQL70, SQP33 was found to be stable and did not spontaneously activate. In mice, at least 50% of the SQL70 remains at the injection site for 2-4 weeks, and plasma levels of SQP33 and Dox are similar across SQL70 injection locations. SQ3370 elicited dose-dependent anti-tumor responses in three syngeneic dual tumor models.
Conclusions
SQ3370 enables higher concentrations of the active drug at the tumor site and minimizes systemic adverse effects associated with conventional chemotherapy. The CAPAC Platform represents a new therapeutic modality to treat solid tumors by using a drug with known efficacy, such as Dox, and expanding its pharmacological capabilities.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Shasqi.
Funding
Shasqi.
Disclosure
S. Srinivasan, N.A. Yee, A. Mahmoodi, M. Zakharian, M.W. Saville: Financial Interests, Personal, Full or part-time Employment: Shasqi; Financial Interests, Personal, Stocks/Shares: Shasqi. J.M. Mejía Oneto: Financial Interests, Personal, Member of the Board of Directors: Shasqi; Financial Interests, Personal, Stocks/Shares: Shasqi.