Abstract 4423: Advancing ADC therapeutics with next-generation site-specific glycan conjugation and dual-payload flexibility

Abstract The unique technology by enabling site-specific glycan-based conjugation via a proprietary dual-function enzyme offers an innovative approach for developing antibody-drug conjugates (ADCs). This advanced technology facilitates the production of homogeneous ADCs at a specific drug-to-antibody ratio (DAR) from DAR2 to DAR16, while maintaining the integrity and function of the native antibody. A key feature of the technology is its proprietary linker, specifically designed to enhance payload stability and enable selective release within the tumor, thereby potentially broadening the therapeutic index.Expanding upon its core capabilities, the new technologies serve as a dual-payload platform, enabling the development of site-specific ADCs carrying two distinct payloads. This technology allows for flexible DAR construction, including both equal and asymmetric payload ratios, providing versatility to tailor ADCs for optimized therapeutic outcomes. Moreover, the ability to specify distinct conjugation sites further enhances its flexibility for diverse payload combinations, including cytotoxic agents, immunomodulators, anti-tumor inhibitors, and degraders. The platform also accommodates both mono- and multi-specific antibodies, broadening its applicability across therapeutic modalities.Here we used microtubule inhibitor and Topoisomerase I inhibitor to demonstrate the site-specific dual-payload platform. In preclinical studies, the site-specific dual-payload ADCs exhibited superior cytotoxicity and promising antitumor activity in various tumor models, compared to approved and benchmark single payload ADCs, underscoring their potential for enhanced antitumor efficacy. Importantly, these ADCs maintained structural integrity andavoided antibody aggregation. These features provide a strong foundation for the future clinical development of biomolecules derived from this site-specific dual-payload technology.Through the integration of glycan engineering, dual-function enzymatic control, proprietary linker chemistry, and flexible payload conjugation, the site-specific dual-payload technology suite provides a robust and adaptable solution to overcome key limitations in current ADC design. Continued innovation and clinical translation of the site-specific dual-payload platform may unlock new therapeutic possibilities to overcome drug resistance and is applicable across oncology and beyond. Citation Format: Wei-Chien Tang, Yu-Hung Chen, Chih-Kang Chang, Ting-Wei Liu, Hung-Yi Lin, Wei-Jhen Huang, Chi-Huan Lu, Ren-Yu Hsu, Nan-Hsuan Wang, Ya-Chi Chen, Teng-Yi Huang. Advancing ADC therapeutics with next-generation site-specific glycan conjugation and dual-payload flexibility 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 4423.