Abstract 6739: Antibody-drug conjugates with novel payloads are enabled by an ultra-high DAR platform

Abstract Antibody-drug conjugates (ADCs) have emerged as a powerful modality to increase the therapeutic index of potent chemotherapy drugs by selectively increasing drug delivery to tumor cells while minimizing exposure to non-tumor tissue. Recent advances have improved efficacy by increasing the drug-antibody ratio (DAR) and optimizing linkers to reduce payload release in plasma and increase release within tumor tissue. Despite this significant progress and the clinical success of recent ADCs, particularly in breast cancer, challenges persist, including managing toxicity and diversifying payload classes to broaden the clinical applications of ADCs. This study demonstrates the engineering and biological potency of ADCs comprised of 50-200 single or mixed kinase inhibitors, enabling the utilization of previously unusable payloads. Small molecules are linked to a specialized polymer scaffold using cathepsin-cleavable linkers and internalized by tumor cells in an antibody target-dependent manner, where they inhibit signaling pathways essential for survival. These HER2-targeted biomolecules combined with payloads inhibiting PI3K/mTOR (apitolisib) or MEK (cobimetinib) demonstrate the use of ADCs as precision medicine to selectively target cancer cells via antibody and payload. For example, many HER2-positive tumors also carry oncogenic mutations in the PI3K pathway rendering those tumors exquisitely sensitive to these ADCs, especially when HER2 expression is low. As shown in Table 1, PI3K pathway mutations can increase the sensitivity to ADCs with apitolisib as a payload, in some cases surpassing the potency of the exatecan derivative DXd in trastuzumab-DXd (DAR8). We will also present data supporting the in vivo safety and efficacy of these ADCs which may provide a novel solution to expand the therapeutic landscape, particularly for HER2-positive cancers. Citation Format: Emmalyn Lecky, Adam Voelker, Isabella Ranieri, Andrew Kassick, Cassandra Crihfield, Christopher Fried, Destiny Carpenter, David Wilson, Robert Fryberger, Jingyi Li, Amanda Mincey, Matthew Cummings, Alex Toker, Krzysztof Matyjaszewski, Antonina Simakova, Laura E. Benjamin. Antibody-drug conjugates with novel payloads are enabled by an ultra-high DAR platform [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 6739.