Abstract 1793: Pre-targeting with in vivo click chemistry enables preferential drug exposure in tumors versus normal tissues

作者：Travis L. Biechele, Maša Alečković, Stefanie Wagner, George Coricor, Sangeetha Srinivasan, Tri‐Hung Nguyen, Jesse M. McFarland, Nathan A. Yee, Michael Zakharian, José Manuel Mejía Oneto · 发表于：Cancer Research · 年份：2025 · DOI：10.1158/1538-7445.am2025-1793 · 被引用次数：1 · 研究领域：Cancer Research and Treatments、Click Chemistry and Applications、Nanoplatforms for cancer theranostics

Abstract Off-target toxicity has long been a dose-limiting factor for antibody-drug conjugates (ADCs) and targeted radiopharmaceutical therapies (TRT). This fundamental limitation primarily arises due to the catabolic elimination process of both therapeutic modalities which exposes healthy tissues to cytotoxic agents. Pre-targeting offers a transformative solution to overcome these challenges as it separates the tumor-targeting and payload-delivery steps, thereby minimizing systemic exposure and maximizing on-target effects. Leveraging this concept, we present Click Activated Protodrugs Against Cancer (CAPAC®) technology as the ideal pre-targeting reunion platform. CAPAC uses in vivo click chemistry to selectively capture drug payloads at tumors with minimal systemic exposure, thus extending the therapeutic window of targeted therapies. CAPAC employs a two-component system: 1) a clickable binder infusion targeting a tumor antigen, and 2) a subsequent infusion of a clickable payload (“protodrug”). These two components “click” at tumors, enabling delivery of high therapeutic payload to the target while sparing normal tissues. We have generated proof-of-concept data on CAPAC using clickable binders against HER2, TROP2, and CEACAM5, which we paired with different clickable payloads, including a trans-cyclooctene (TCO)-modified biotin probe and a protodrug of monomethyl auristatin E (MMAE). We evaluated the anti-tumor efficacy, pharmacokinetics (PK), and biodistribution across CDX...