Abstract 1894: Click Activated Protodrugs Against Cancer (CAPAC™): A modular platform for tumor directed oncology therapeutics
Authors: McFarland Jesse M. , Mahmoodi Amir , Zakharian Michael , Srinivasan Sangeetha , Yee Nathan A. , Oneto José M. Mejía 
Published: June 2022

Abstract
The CAPAC platform aims to help patients beat cancer by activating powerful cancer therapies at the tumor site(s). The core click chemistry technology is agnostic to therapeutic agent or indication. The modular nature of the platform allows targeting strategies based on tumor’s location, antigens, or both to be combined with therapeutics utilizing multiple mechanisms of action to deliver highly effective treatments tailored to each patient.
The lead clinical candidate SQ3370 consists of a tetrazine-modified sodium hyaluronate biopolymer (SQL70) that is injected at the tumor site and followed by multiple systemic doses of trans-cyclooctene (TCO)-modified protodrug based on doxorubicin (Dox). Efficient covalent reaction between tetrazine and TCO moieties activates the protodrug and releases active Dox. SQ3370 provides enhanced safety and efficacy in preclinical models compared to conventional Dox, and is being evaluated in a Phase I study in advanced solid tumors (NCT04106492).
The efficacy of SQ3370 is from biopolymer-induced activation of protodrug at the tumor site. Data will be presented from mice treated with biopolymer injected peritumorally versus distal-to-tumor, prior to protodrug dosing. Results show significant improvement in tumor growth inhibition and survival in peritumorally-activated SQ3370 compared to distally-activated SQ3370 or conventional Dox. Quantification of protodrug activation in a pharmacokinetic model in rats showed at least 10 to 20% of the protodrug dose is activated by the biopolymer, resulting in over 300 times higher exposure of Dox to tumor versus systemic (plasma) exposure.
New TCO-modified protodrugs have been synthesized and preclinical results for the candidate based on monomethyl auristatin E (MMAE) paired with SQL70 will be presented. TCO-MMAE was selected for in vivo evaluation because of its high cytotoxicity-attenuation (93-fold) in vitro. In naive mice, the maximum tolerated dose (MTD) of TCO-MMAE, given as 5 daily doses after an injection of SQL70 biopolymer, was established at 20-times higher than the MTD of conventional MMAE. The antitumor efficacy of TCO-MMAE will be evaluated in future studies.
In addition, preliminary results on the use of tetrazine-conjugated antibodies as a targeting agent capable of treating disperse disease when paired with an appropriate TCO-protodrug will be presented.
In conclusion, the CAPAC platform is a novel approach that enables targeting of injectable and non-injectable tumors. CAPAC expands the therapeutic potential of anticancer drugs by increasing exposure to tumors and minimizing systemic adverse effects. The CAPAC platform can also be combined with other therapies to modulate the immune response and modify the tumor microenvironment.
Citation Format: Jesse M. McFarland, Amir Mahmoodi, Michael Zakharian, Sangeetha Srinivasan, Nathan A. Yee, José M. Mejía Oneto. Click Activated Protodrugs Against Cancer (CAPAC™): A modular platform for tumor directed oncology therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1894.