Abstract 342: First-in-class click chemistry-based pre-targeting of CEACAM5 tumor antigen selectively activates an MMAE payload at tumors

Abstract Targeted delivery technologies (ADC, TRT, etc.) are commonly dose-limited by off-target toxicities. Less than 1% of the dose is delivered to the tumor while the remainder follows the normal catabolic elimination route of the antigen-binder resulting in significant normal tissue exposure and toxicity. A pre-targeting approach such as Shasqi’s Click Activated Protodrugs Against Cancer (CAPAC®) technology, that separates the antigen-binder from the payload and reunites them only at the antigen is needed to overcome this limitation. CAPAC utilizes in-vivo click chemistry to selectively and rapidly reunite antigen-binders and payloads. Here we present preclinical data on a clickable CEACAM5 antigen-binder and a clickable monomethyl auristatin E (MMAE) payload or protodrug. We synthesized a clickable binder for CEACAM5 consisting of fragment antibodies covalently conjugated with the activating agent. The microtubule-disruptor, MMAE, was chemically attenuated with trans-cyclooctene to develop the protodrug, SQP22 (clickable payload). Both the clickable binder and protodrug were tested individually in vitro, with or without cells. They are currently being tested in vivo, individually or together, for efficacy and tolerability in naive tumor-free or tumor bearing CEACAM5-expressing cell-derived xenograft (CDX) rodent models. SQP22 showed a high level of attenuation (up to ∼700x) in cytotoxicity assays in vitro compared to the active payload and cleared rapidly in vivo, both important features of CAPAC protodrugs. Additionally, the drug metabolism and pharmacokinetic characterization showed a favorable drug profile for SQP22, supporting its further development as a clinical agent of the CAPAC platform. The CEACAM5-targeted Fab has a binding affinity (KD) of 0.046 nM and a strong binding potency of 0.78 nM (EC50) to a CEACAM5-expressing cell line. Efficacy data from gastric and pancreatic CDX models shows that the clickable binder with SQP22 significantly improves tumor growth inhibition over a clickable non-binding isotype control with SQP22 and other negative controls. Tolerability studies in rats at various dose levels are ongoing. We have developed a novel, first-in-class, CEACAM5 clickable binder that can selectively activate an MMAE payload using click chemistry-based pre-targeting. Our results show that the protodrug and the clickable binder have favorable characteristics. Moreover, efficacy data indicate a meaningful benefit in cancer CDX models over negative controls. These data support the continued development of CEACAM5 clickable binder in combination with MMAE clickable payload for the treatment of CEACAM5 expressing cancers. Citation Format: George Coricor, Masa Aleckovic, Sangeetha Srinivasan, Jesse McFarland, Stefanie Wagner, Nathan A. Yee, Tri-Hung Nguyen, Michael Zakharain, Travis Biechele, Jose M. Mejia Oneto. First-in-class click chemistry-based pre-targeting of CEACAM5 tumor antigen selectively activates an MMAE payload at tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 342.