Abstract 1765: YL413: A novel dual-payload anti-HER2 antibody-drug conjugate demonstrating potent preclinical activity

Abstract Antibody Drug Conjugates (ADC) have achieved great success as anti-cancer therapies, with 21 ADC drugs approved in the global market. Despite the initial response to ADC treatment, drug resistance and tumor relapse inevitably happen, driven by high heterogeneity in advanced tumors. Overcoming these resistance mechanisms is a critical challenge to next-generation ADC development for cancer therapy. To address these challenges, we developed YL413, a novel anti-HER2 ADC with two payloads of different MOAs: a topoisomerase 1 inhibitor and a microtubulin inhibitor. This dual-payload strategy is designed to mitigate resistance associated with single-agent therapies. YL413 was engineered with an appropriate drug-to-antibody ratio (topoisomerase I inhibitor to microtubule inhibitor) to optimize the therapeutic window. Trastuzumab, topoisomerase I inhibitors, and microtubule inhibitors were expected to demonstrate anti-tumor activity in clinical trials. In vitro, YL413 demonstrated comparable binding and internalization in the HER2+ cell line to Trastuzumab. YL413 demonstrated better cytotoxicity than Mon-payload ADCs against tumor cells in vitro. In Vivo, the dual-payload ADC exhibited superior efficacy in CDX models and the Ehertu-resistance models. In summary, we developed HER2 dual-payload ADCs to address Topo1 inhibitor-induced tumor resistance. The dual-payload HER2 ADC exhibited strong anti-tumor activity in vitro and in vivo, indicating potential to overcome Enhertu® resistance. YL413 retains Topo1 inhibitor efficacy, supplemented by a microtubule inhibitor, with possible use in earlier treatment lines. Citation Format: Hanwen Deng, Tao Wang, Wei Lian, Tingting Mao, Qing Zong, Chun Deng, Bingsong Xie, Tongtong Xue, Jiaqiang Cai. YL413: A novel dual-payload anti-HER2 antibody-drug conjugate demonstrating potent preclinical activity abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1765.