Abstract A052: Enhancing potency through synergy: QP101, a novel HER2 targeting dual payload ADC shows potent preclinical activities

Abstract Recent advancements of antibody-drug conjugates (ADCs) with topoisomerase I (TOP1) inhibitors payload have been remarkable in the treatment of various cancers. However, their expansion into broader clinical applications remains constrained by safety concerns related to the overall payload contents and emergence of resistance against the TOP1 inhibitor payload itself. To overcome these limitations, we developed a novel dual-payload ADC (QP101) designed to co-deliver two cytotoxic agents, TOP1 inhibitor and cyclin-dependent kinase 7 (CDK7) inhibitor, showing distinct synergy mechanisms of action. This strategy aims to maximize anti-tumor activity by addressing ADC refractory conditions through synergy between two payloads, while simultaneously minimizing the TOP1 inhibitor contents by targeting multiple tumor vulnerabilities. QP101 induces robust tumor regression in vivo across diverse preclinical tumor models. QP101 also demonstrates good tolerability in the preliminary toxicology study in non-human primates. These findings support further development of QP101 as a next-generation HER2 targeting ADC with improved efficacy and safety balance. Citation Format: Yeong-In Yang, Hwankyu Kang, Jaehee Jang, Wongyun Ahn, Jungeun Lee, YongSoo Kim, Donghoon Yu, Jeongjun Kim, Seung-Joo Lee, Jaeseung Kim, Kiyean Nam. Enhancing potency through synergy: QP101, a novel HER2 targeting dual payload ADC shows potent preclinical activities [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A052.