Abstract 1688: Empowering development of next generation ADCs & XDCs through advanced WuXiDARx conjugation technologies

Abstract Background: Antibody drug conjugates (ADCs) and various types of bioconjugates (XDCs) have garnered increasing attention over the past decade. These novel payloads and payload combinations require advanced conjugation technologies to fully achieve their therapeutic potential. Conventionally, interchain cysteine coupling serves as the most clinically validated conjugation technologies. However, such methods have two major flaws: (1) heterogeneity from stochastic coupling (except for DAR8); and (2) instability during circulation due to maleimide retro-Michael addition. Solutions: To address these needs, WuXi XDC has built a platform through internal development and external collaboration. This platform includes two parts: (1) WuXiDARx™ conjugation technology WuXiDARx™ conjugates at interchain cystines which are the most clinical validated site, as 13 out of 18 commercial ADCs are developed through cysteine conjugation. This technology features: • Flexible DAR choices (WuXiDAR1TM, WuXiDAR2TM, WuXiDAR4TM, WuXiDAR6TM) • Improved homogeneity: ≥ 85% for DAR1 and DAR2; or ≥ 65% for DAR4 and DAR6 • Enhanced efficacy and safety profiles • Compatibility with IgG1 mAb • Compatibility with novel ADCs (e.g., dual-payload ADCs, bispecific ADCs) and XDCs (e.g., AOCs, APCs) • Simple and robust conjugation process • Validated technology: 7 ADCs in clinical trials, 10 CMC projects, up to > 2 kg batch size (2) Thiol reactive connector technologies Conventional interchain cysteine conjugation uses maleimide connector to react with the thiol groups from the antibody. However, the reverse reaction (retro-Michael addition) may result in premature release of the payload-linkers in circulation. To solve this problem, X-LinC connector is developed to replace the maleimide connector, which has shown good plasma stability and is fully compatible with WuXiDARxTM. A different way to create homogeneous DAR4 ADCs is by using thiol-rebridging connectors. CysLink technology incorporates a stable thiol-rebridging connector into the platform. Unlike traditional connectors, the CysLink version produces ADCs with fewer thiol mismatches and half-antibody ratios, and it works with WuXiDARxTM to offer additional DAR options (e.g., DAR1). Conclusion: The combination of WuXiDARxTM, X-LinC, and CysLink offers an integrated solution to utilize the most clinically validated conjugation sites, which is helping accelerate ADCs/XDCs pipeline development from clients. Citation Format: Qirui Fan, Hu Chen, Jingjie Huang, Lin Zhang, Zekun Wang, Ding Wei, Guoguang Wei, Yanjie Zhao, Laisen Wang, Cindy Cheng, Marie Zhu, . Empowering development of next generation ADCs & XDCs through advanced WuXiDARx conjugation technologies [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 1688.