Abstract 3173: XYD-295 and XYD-338: Novel hydrophilic site specific linker platform enables next generation dual payload ADCs with enhanced efficacy and safety

Abstract Background: The therapeutic potential of Antibody-Drug Conjugates (ADCs) is often limited by linker technology. Conventional hydrophobic linkers usually lead to ADC aggregation, rapid plasma clearance, and undesired cleavage in blood and normal tissues. We have developed a novel linker platform to overcome these challenges, enabling the construction of more stable, homogenous, and efficacious ADCs, including dual-payload formats. Methods: Our ADC platform was designed to have: 1) High stability to minimize undesired payload release; 2) High hydrophilicity to improve solubility, and reduce the formation of aggregates; and 3) Efficient enzymatic cleavage and release of potent payload within the tumor. This linker was site-specifically conjugated to antibodies targeting diverse antigens (including DLL3, PD-L1, ADAM9, B7H3, EGFR, and cMET) and equipped with potent payloads such as microtubule inhibitor and a topoisomerase I inhibitor, individually or in dual-payload formats. Results: ADCs generated with this novel linker demonstrated superior stability in plasma and significantly slower clearance rates compared with ADCs with conventional linkers. These improved pharmacokinetic profiles were translated into stronger anti-tumor efficacy in multiple animal models. XYD-295 with TOP1 inhibitor payload, XYD-338 with microtubule inhibitor payload and the dual-payload format, all showed enhanced and synergistic tumor killing in vitro and in vivo. Furthermore, this designed linker supported a higher drug load with reduced aggregation, and improved safety profile in preclinical studies, suggesting a higher therapeutic index. Several ADCs based on XYD-295, XYD-338 and the dual-payload format were expected entry into clinical study in 2026. Conclusion: XYD-295 and XYD-338 facilitates the construction of more stable, homogenous, and efficacious ADCs, including dual-payload formats Citation Format: Weng Hang HO, Pengfei Rong, Mengrui Zhao, Jun Li, Xidong Zhang, Hui Ding, Fangxing Ouyang, Jun Wang, Jiangcheng Xu, Yang Liu, Jiawang Liu, Kyoungwoo Lee. XYD-295 and XYD-338: Novel hydrophilic site specific linker platform enables next generation dual payload ADCs with enhanced efficacy and safety 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 3173.