Abstract 1731: Hydrophilicity-enhanced linker technology enables site-specific degrader-antibody conjugates with improved stability and enhanced activity

Abstract Proteolysis-targeting chimeras (PROTACs) have emerged as a novel modality for targeted protein degradation, enabling catalytic removal of disease-related proteins rather than transient inhibition. Despite their mechanistic advantages, most PROTACs suffer from poor drug-like properties—high molecular weight, highly hydrophobic, and with limited permeability—leading to suboptimal pharmacokinetics and formulation challenges. To overcome these limitations, the concept of degrader-antibody conjugates (DACs) has recently gained attention, leveraging antibody-mediated delivery to transport degraders selectively into target cells. DACs can reduce systemic exposure and overcome permeability barriers, thereby expanding the therapeutic utility of degraders. However, bioconjugation of PROTAC payloads remains hindered by issues such as antibody aggregation, inefficient conjugation, and constraints in achieving optimal drug-to-antibody ratios (DAR). Here, we selected a representative BET degrader as the proof-of-concept payload to evaluate the feasibility of DAC construction. Leveraging glycan site-specific technology, we achieved DAC construction with tunable DARs and robust conjugate stability. To address the intrinsic physicochemical challenges of PROTACs, proprietary linker technology was incorporated to enhance hydrophilicity and mitigate aggregation. Proprietary linker also provides high serum stability and enables precise release in the tumor site, potentially broadening the therapeutic index. This BET DAC is anticipated to be applicable to both solid and hematologic malignancies. In vitro studies showed that glycan site-specific DACs preserved antibody binding, maintained high stability, and facilitated efficient intracellular delivery of active degraders. Functional analyses confirmed target protein degradation with time- and dose-dependent kinetics, accompanied by strong cytotoxicity in antigen-positive models. These results establish clear proof of concept for our linker-enabled DAC platform. Through the integration of site-specific glycan conjugation and proprietary linker chemistry, this DAC platform offers a versatile and scalable solution to overcome hydrophobic degrader limitations, paving the way for next generation of targeted degradation therapeutics. Citation Format: Yu-Hung Chen, Wei-Chien Tang, Chi-Dian Lu, Hung-Yi Lin, Wei-Jhen Huang, Nan-Hsuan Wang, Ya-Chi Chen, Teng-Yi Huang. Hydrophilicity-enhanced linker technology enables site-specific degrader-antibody conjugates with improved stability and enhanced 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 1731.