Abstract 7214: A click chemistry-based HER2 targeting agent activates a decoupled MMAE payload making it highly differentiated in efficacy and safety than ADCs

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 of 1) an activator that targets 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 reunites 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 activity window of antibody drug conjugates (ADCs). Here we compare a HER2-targeting activator + a monomethyl auristatin E (MMAE) payload with an ADC that binds the same target and carries the same payload, as well as other targeting formats. The activator SQT01 is composed of a HER2-binding Fab conjugated with tetrazines (Tz). The protodrug SQP22 is formed by coupling trans-cyclooctene (TCO, with a releasable linker) to MMAE, a cytotoxic spindle poison. An efficient covalent reaction between tetrazine and TCO moieties releases active MMAE at the tumor. Mice bearing human NCI-N87 HER2+ tumor were treated with 1) SQT01, 2) a non-binding isotype Fab-Tz, or 3) saline. After 18 h, all mice received either vehicle (10% HPCD), SQP22 protodrug, a non-releasable MMAE TCO-protodrug analog of SQP22, or a di-peptide-containing TCO-protodrug analog. We also tested CAPAC’s approach with SQT06 (a full-length IgG trastuzumab-Tz conjugate) that was followed by an SQP22 dose after 4 days. The dosing of SQP22 with the Fab-Tz and IgG-Tz is timed to allow for systemic clearance of the targeting activator. Fabs have a shorter half-life than IgG, so we dosed SQP22 at 18 h after SQT01 instead of the 4-day timepoint with SQT06. To allow comparisons with ADCs, additional groups received a single dose of commercially available disitamab vedotin (DV) or a HER2-Fab-vedotin. SQT01+SQP22 induced a strong tumor growth inhibition comparable to SQT06+SQP22, but significantly better than DV, and SQT01+non-releasable protodrug analog. Dosing with SQT01 with a protease cleavable dipeptide-TCO protodrug analog or a molar equivalent dose of HER2-Fab-vedotin were highly toxic and intolerable. Based on preclinical observations, SQT01+SQP22 was safe and tolerated, and there was no observed body weight loss. These data demonstrate that the CAPAC platform, which separates the targeting agent from the payload, provides a clear benefit in terms of safety and efficacy compared with small or large format proteins with the classic fixed construct of ADCs (e. g. a fixed drug to antibody ratio). Citation Format: Sangeetha Srinivasan, Stefanie Wagner, George Coricor, Jesse M. McFarland, Tri-Hung Nguyen, José M. Mejía Oneto. A click chemistry-based HER2 targeting agent activates a decoupled MMAE payload making it highly differentiated in efficacy and safety than ADCs 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 (6Suppl): Abstract nr 7214.