Abstract 3149: Development of a novel site-specific ADC glycan platform with potential for improved in vivo efficacy and stability of the ADC in animal studies

Abstract Antibody-drug conjugates (ADCs) represent a promising modality for delivering cytotoxic drugs to targeted tumor cells while avoiding off-tumor toxicities. Despite successes in the past 20 years, development of effective ADCs with broad therapeutic window remains challenging due to the complexity of conjugation technologies and the instability of the linkers. Most platforms currently in the market as well as under clinical development may face limitations ascribed to the heterogeneity of ADCs with various drug-to-antibody ratio (DAR). This likely resulted from random conjugation and poor overall biophysical characteristics caused by linker hydrophobicity. The limitations may impact the efficacy, safety, bioavailability, and the robustness of manufacturing process of these therapeutic agents. OBI developed a unique glycan ADC platform (GlycOBI) to enable a site-specific conjugation, which is in a 'Plug and Play' format and compatible with any antibodies, linkers, and payloads in various DAR. This is an efficient and scalable process to generate homogenous ADCs. This platform overcomes the limitations of traditional ADCs, resulting in the improvement of efficacy and stability. We developed a non-genetic, engineering-free approach to generate site-specific homogenous ADCs. This was achieved by utilizing OBI proprietary enzymatic technology (EndoSymeOBI), followed by the click chemistry to conjugate the hydrophilic linker-payload via the glycan site that naturally occurs on the antibody’s Fc region. The conjugation process avoids disrupting the antibody structure, ensuring the related ADC has similar biophysical characteristics compared to native antibody. Furthermore, OBI linker technology improves the conjugation efficiency of the payload, as well as reduces the aggregation propensity, and expands the half-life of the ADC products. Anti-TROP2 and anti-HER2 ADCs are developed based on OBI glycan ADC platform (GlycOBI) using a topoisomerase I inhibitor, exatecan, as the payload. Both ADCs demonstrated greater chemical stability in serum stability studies compared to competitor ADCs. Additionally, they showed broad activity against different cancer cell lines in vitro as well as in mouse xenograft models. The preclinical data presented here suggest that GlycOBI is an outstanding ADC platform to improve the performance of ADCs. Further investigations, including studies in the clinical settings, are warranted. Citation Format: Teng-Yi Huang, Yin-Cheng Hsieh, Ka-Shu Fung, Yu-Chao Huang, Chi-Sheng Shia, Ming-Feng Chiang, Nan-Hsuan Wang, Wan-Fen Li, Ming-Tain Lai. Development of a novel site-specific ADC glycan platform with potential for improved in vivo efficacy and stability of the ADC in animal studies abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 3149.