Abstract 7463: A linker platform for antibody drug conjugates (ADCs): expanding the therapeutic window

Abstract Although ADCs have demonstrated great clinical promise, their therapeutic window remains limited due to the complexity of this drug format. Factors contributing to this narrow safety window include the instability of the linkers, accelerated plasma clearance due to the hydrophobicity of the ADCs, and off-target toxicity caused by nonspecific uptake by non-antigen expression healthy cells, free payload pre-release in the circulation system, low tumor retention due to heterogeneity of tumor antigen level and ADC DAR value By preserving the essential functions of the antibody and the payload, an optimized linker can significantly enhance ADC therapeutic window by increasing hydrophilicity and stability while reducing non-specific endocytosis by non-tumor cells. We have designed a panel of novel linkers focused on improving hydrophilicity and stability of ADC, with a particular emphasis on reducing its off-target endocytosis. A key feature of our linkers is the inclusion of a negative charged side chain and hydrophilic chaperone, which not only minimizes non-specific uptake by non-tumor cells but also greatly enhances its hydrophilicity. The side chain linker with this special architecture allows efficient enzymatic cleavage to ensure rapid payload release intracellularly, and lead to superior bystander cell killing effect than the ADC with GGFG-Dxd linker system. One example exploiting the proprietary linker is Trastuzumab-BL-001-exatecan with a drug-to-antibody ratio (DAR) of 8, demonstrated hydrophilicity comparable to Trastuzumab-GGFG-Dxd (biosimilar) in HIC analysis, with no aggregation detected by analytical SEC. This ADC exhibited excellent stability, maintaining high solubility, and cytotoxicity under stressed conditions. It also resisted deconjugation in the presence of high concentration of N -acetylcysteine and showed exceptional stability in human and mouse plasma. Pharmacokinetic studies in rats indicated favorable pharmacokinetic properties, while efficacy testing in the NCI-N87 tumor model revealed comparable performance to Trastuzumab-GGFG-Dxd. Additionally, BLB-101 ADC, featuring the same linker, was well tolerated in non-human primates following repeated administration. In conclusion, our novel linker designs offer significant advantages, with features that could expand the therapeutic window of current ADCs by improving their stability, reducing off-target effects, increasing bystander activity, and maintaining efficacy. We are also expanding the utility of this class of linkers to enable ubiquitous design of dual-payload-ADC Degrader-Antibody-Conjugates. Citation Format: David Yi, Wen Zhang, John Liu, Suk Lee, Alice Chen. A linker platform for antibody drug conjugates (ADCs): expanding the therapeutic window [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 7463.