Abstract 5675: ThiOBI® platform, a novel hydrophilic linker for irreversible cysteine-selective biomolecular conjugation, demonstrated potent and durable antitumor activities in various animal models

Abstract The ThiOBI® platform represents a cutting-edge approach for the development of next-generation cysteine (Cys)-based drug conjugates including a wide range of cysteine-containing biomolecules, such as nanobodies, antibody fragments, and peptides. This platform leverages a novel hydrophilic stable linker that efficiently delivers the drug to the site of action to enhance therapeutic potential. In addition, an irreversible thiol conjugation enables Cys-selective biomolecular modification providing meticulous control of the drug conjugation process. Maleimide is a chemical group commonly used in the design of linkers for bio-conjugation, particularly in antibody-drug conjugates (ADCs), where it plays a key role in attaching a cytotoxic payload to the antibody through a linker. Seven FDA approved ADCs used Cys-maleimide chemistry. However, a major limitation of the traditional cysteine-maleimide conjugated ADCs is their instability due to retro-Michael deconjugation, which can lead to premature payload release in circulation. The ThiOBI® platform addresses this challenge by employing a stable hydrophilic linker to prevent such reaction ensuring drug delivery in a more controllable manner. This innovation profoundly improves stability and physicochemical properties of the conjugated biomolecules, minimizes off-target effects, and enhances the overall therapeutic index. In preclinical studies, ThiOBI®-based ADCs demonstrated potent and durable antitumor activities across a variety of animal models. Notably, the platform possesses substantial flexibility that is capable of incorporating a range of payloads and biomolecular formats, including antibody fragments, nanobodies, and peptides, all of which show enhanced therapeutic activity. This versatility allows for targeting a broader spectrum of cancers and diseases that are not easily addressed by conventional antibody-based ADCs. The promising preclinical results highlight the versatility and therapeutic promise of the ThiOBI® platform, positioning it as a powerful tool for the development of next-generation drug conjugates. The successful demonstration of potent and durable antitumor activities in animals provides a strong foundation for future clinical development of the biomolecules derived from ThiOBI®. Citation Format: Yu-Chao Huang, Ting-Wei Liu, Chi-Huan Lu, Ren-Yu Hsu, Nan-Hsuan Wang, Ya-Chi Chen, Ming-Tain Lai, Teng-Yi Huang. ThiOBI® platform, a novel hydrophilic linker for irreversible cysteine-selective biomolecular conjugation, demonstrated potent and durable antitumor activities in various animal models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5675.