Abstract 7213: Tumor targeted activation of an attenuated exatecan protodrug through Click Chemistry demonstrates efficacy in murine tumor studies

Abstract

Abstract Shasqi is advancing the Click Activated Protodrugs Against Cancer (CAPAC®) platform based on click chemistry, a Nobel Prize winning technology. The platform is modular and comprises 1) an activator that target specific antigens, and 2) inert cancer drugs, protodrugs, which are selectively activated at tumors via click chemistry. The CAPAC technology separates the tumor targeting function from the payload and re-unites them at the tumor creating the flexibility to optimize activity while limiting toxicity during preclinical and clinical development. The modularity of the platform enables the rapid development of new therapies as well as unlocking unique treatment benefits such as tunable combinations and payload cycling. We envision that CAPAC will expand the scope of potential targets, widen the therapeutic window, and enhance the safety of locally activated cancer therapeutics. Here, we demonstrate the efficacy and safety of our exatecan protodrug (SQP07) used with intratumorally injected activators. The activators, tetrazine-modified sodium hyaluronate biopolymer(s), are injected at the tumor site and followed by a systemic dose of SQP07, a trans-cyclooctene (TCO)-modified protodrug of exatecan (Exa). An efficient covalent reaction between tetrazine and TCO moieties releases active Exa at the tumor. In vitro cytotoxicity studies showed that SQP07 activated with tetrazine was effective against mouse and human tumor cell lines (MC38, CT26, EMT6 and NCI-N87); SQP07 without activator had potency attenuated by 60-133 fold. In vivo tumor distribution and activity of SQP07 with the intratumoral biopolymer activators was evaluated in an NCI-N87 gastric cancer xenograft model. Female C.B-17 SCID mice received a single intravenous dose of vehicle (10% HPCD), Exa (50 mg/kg) or biopolymer (40 or 100 μL intratumorally) followed by SQP07 or SQP07 alone (50 mg/kg Exa mol equivalent). 1 hour after biopolymer + SQP07 treatment, activated Exa was highly concentrated in the tumor and stroma. This led to tumor regression in animals up to 40 days, performing significantly better than the free drug cytotoxic, Exa alone. Similarly, median survival with biopolymer + SQP07 was higher (>81 days) compared to Exa (68.5 days). Toxicity, measured as body weight loss, was comparable (~5%) and transient between Exa and biopolymer + SQP07. SQP07 alone treatment without the biopolymer was not differentiated from the vehicle control. These data show that the CAPAC platform, which separates the targeting agent from the payload, is an effective way to administer cytotoxic therapies systemically. Additional work with other tumor models, different biopolymers and the SQP07 protodrug is ongoing. Citation Format: Sangeetha Srinivasan, Stefanie Wagner, George Coricor, Tri-Hung Nguyen, Jesse M. McFarland, José M. Mejía Oneto. Tumor targeted activation of an attenuated exatecan protodrug through Click Chemistry demonstrates efficacy in murine tumor studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7213.