Abstract 2056: Click chemistry enabled selective activation of highly cytotoxic MMAE payload at tumors using TROP2 targeting agent

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 reunite 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 index of antibody drug conjugates (ADCs). Here we present a TROP2-targeting activator with a monomethyl auristatin E (MMAE) payload. TROP2 expression has been observed in many cancers that express low-HER2. The clinical efficacy of anti-TROP2 ADCs is hindered by undesirable side effects, limiting their potential therapeutic window. We have developed the targeting activator SQT02, a TROP2 Fab binder conjugated with ~2.2 tetrazines per protein, and SQP22, an attenuated protodrug of MMAE coupled with trans-cyclooctene (TCO). The reaction between tetrazine and TCO moieties releases MMAE at the tumor site. Previously we have demonstrated that SQP22 is attenuated compared to free MMAE and in combination with a HER2 targeting activator led to significant tumor inhibition with no observable toxicity. The CAPAC platform’s modular nature allows seamless exchange of targeting agents or payloads, thus enabling different therapeutic combinations to be generated quickly and efficiently, like SQT02 in combination with SQP22. Dosing of SQT02 occurs prior to dosing with SQP22 to reduce non-specific activation while enabling higher payload activation at the tumor site to induce tumor cell death. In vitro, SQT02 bound NCI-N87 human gastric cancer cells with similar EC50 (~0.07 μg/mL) to an antibody that binds to TROP2. In vivo, treatment of SQT02 followed by SQP22 led to 60% tumor growth inhibition compared to Sacituzumab govitecan's 35% inhibition in the NCI-N87 xenograft model. No body weight loss was observed in the animals treated with SQT02 in combination with SQP22. We have demonstrated the use of click chemistry to deliver a highly potent cytotoxic agent to tumors, causing significant growth inhibition. The flexibility and adaptability of the CAPAC platform allowed us to quickly develop therapeutic combinations that can be deployed to accelerate the path to the clinic. Our findings provide evidence for developing SQT02 in combination with SQP22 for the treatment of TROP2 expressing cancers. Citation Format: George Coricor, Jesse M. McFarland, Sangeetha Srinivasan, Stefanie Wagner, Tri-Hung Nguyen, Jose M. Mejia Oneto. Click chemistry enabled selective activation of highly cytotoxic MMAE payload at tumors using TROP2 targeting agent [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 2056.