Abstract 4934: CAPAC: a modular platform that can improve the safety and efficacy of existing cancer therapies

Abstract

Abstract Click chemistry is a Nobel Prize winning technology that has been widely used in research across the life sciences. Shasqi’s Click Activated Protodrugs Against Cancer (CAPACTM) platform is pioneering the therapeutic application of click chemistry reactions in humans. The 1st gen CAPAC technology enables activation of potent anti-cancer agents at the tumor site while reducing systemic exposure and is comprised of a tetrazine-modified biopolymer (tumor targeting agent) injected intratumorally and a systemically administered trans-cyclooctene-modified payload, named a protodrug. Our lead clinical candidate SQ3370 (SQL70 biopolymer + SQP33, doxorubicin protodrug), is being evaluated in a Phase 2a study in solid tumors (NCT04106492). CAPAC platform is highly modular and can be applied to multiple cancer drugs especially those with narrow therapeutic index(s) due to toxicity. Because the tumor targeting agent (i.e., biopolymer) is separate from the protodrug, it enables the flexibility of interchanging different protodrugs with different mechanism of actions such as tubulin inhibitors (e.g., paclitaxel), topoisomerase inhibitors (e.g., exatecan), immune activators (e.g., TLR agonists), and others. This benefit can be translated in the clinic with tailored combinations for individual patients. Here we will present data on protodrugs of paclitaxel, exatecan, and TLR7/8a agonist. These therapeutics have shown considerable safety concerns either alone or in combination with other therapies in the clinic and may benefit from the precise activation at the tumor site that can be achieved by the CAPAC platform. In vitro cytotoxicity assays showed ≥20 fold-attenuation of both paclitaxel and exatecan protodrugs in various cancer lines. In a proliferation assay using mouse splenocytes we observed ≥100-fold attenuation of a TLR7/8a protodrug. These results suggest that the protodrugs may exhibit higher therapeutic indeces with enhanced safety profile. We tested the anti-tumor efficacy of paclitaxel protodrug in combination with SQL70 biopolymer in NCI-N87 gastric cancer xenograft tumor model. The doses of paclitaxel protodrug were 4x or 10x molar equivalent to the MTD of conventional paclitaxel. We observed significant reduction of tumor growth compared to vehicle (p<0.0001) and minimal body weight loss suggesting enhanced safety profile. In vivo studies to determine the safety and efficacy of these protodrugs are ongoing and will be presented. The data presented illustrates how the CAPAC platform is modular and expands the therapeutic window of different cancer therapies to achieve greater effect. This modularity enables the rapid access of therapeutic combinations. Moreover, as the click chemistry activation is independent of biological characteristics of tumors, CAPAC payloads are highly translatable across species and accelerate the path to the clinic. Citation Format: George Coricor, Jesse M. McFarland, Masa Aleckovic, Sangeetha Srinivasan, John Lee, Leslie Priddy, Matthew Tso, Tri-Hung Nguyen, Jose M. Mejia Oneto. CAPAC: a modular platform that can improve the safety and efficacy of existing cancer therapies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4934.