The CAPAC™ platform aims to help patients beat cancer by activating cancer therapies at the tumor site(s) while minimizing systemic exposure. The core click chemistry technology is agnostic to the therapeutic agent and can be applied to a broad range of cancer drugs that are otherwise limited by toxicity. The modular nature of the platform allows targeting strategies based on a 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 clinical candidate SQ3370 consists of two components: first, a tetrazine-modified biopolymer (SQL70) is injected intratumorally, acting as a targeting agent; second, a trans-cyclooctene (TCO)-modified protodrug of doxorubicin (Dox) is administered intravenously. Efficient reaction between tetrazine and TCO moieties activates the protodrug and releases Dox. SQ3370 minimizes plasma concentrations of Dox thereby enhancing safety and efficacy in preclinical models compared to conventional Dox and is being evaluated in a Phase I study in advanced solid tumors (NCT04106492).

New TCO-modified protodrugs have been synthesized and preclinical results for protodrugs based on monomethyl auristatin E (MMAE) will be presented. TCO-MMAE was selected for in vivo evaluation because of its high cytotoxicity-attenuation (up to 700-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 with tetrazine-conjugated targeting agents in two different models was demonstrated. In the absence of an activating agent, no tumor growth inhibition or acute toxicity was observed.

The efficiency of TCO-MMAE capture in vivo by click reaction and release of the cytotoxin at the tumor have been investigated and preliminary results will be presented.

In conclusion, the CAPAC™ platform is a novel approach that utilizes click chemistry in vivo to expand the therapeutic potential of anticancer drugs by increasing exposure to tumors and minimizing systemic adverse effects.

Nathan Yee

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