Ding Mengyuan, Chen Ming, Cheng Zhiyang, Jin Jiyu, Lu Wei, Zhu Shulei
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062 PR China.
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062 PR China.
Bioorg Med Chem. 2025 Apr 1;120:118084. doi: 10.1016/j.bmc.2025.118084. Epub 2025 Jan 29.
Antibody-drug conjugates (ADCs) with camptothecin derivatives as payloads have been a hot topic of interest and research since the launch of DS-8201a. As an important component of ADCs, the adequate stability of the linker during circulation and its rapid release at the target site are crucial for the efficient efficacy of ADCs. Although traditional quaternary ammonium ADCs based on dipeptide linkers were highly stable and could be released by specific enzymes, their poor in vitro anti-tumor activity had limited their further exploration. We applied a methylsulfonylethylamine-modified MAC self-elimination system to a valine-alanine linker and constructed a quaternary ammonium ADC (HER2-11) that combines both stability and cleavability. The optimization of the linker effectively improved the in vitro cellular activity of conventional quaternary ammonium ADCs, but the complex intracellular cleavage mechanism of HER2-11 resulted in a weaker anti-tumor activity compared to HER2-GGFG-DXd, which provides great reference value for the continued research of this type of linker in the future.
自DS-8201a推出以来，以喜树碱衍生物为有效载荷的抗体药物偶联物（ADC）一直是备受关注和研究的热门话题。作为ADC的重要组成部分，连接子在循环过程中的充分稳定性及其在靶位点的快速释放对于ADC的高效疗效至关重要。尽管基于二肽连接子的传统季铵盐ADC具有高度稳定性且可被特定酶释放，但其体外抗肿瘤活性较差限制了其进一步探索。我们将甲磺酰乙胺修饰的MAC自消除系统应用于缬氨酸-丙氨酸连接子，并构建了一种兼具稳定性和可裂解性的季铵盐ADC（HER2-11）。连接子的优化有效提高了传统季铵盐ADC的体外细胞活性，但HER2-11复杂的细胞内裂解机制导致其抗肿瘤活性比HER2-GGFG-DXd弱，这为今后该类型连接子的持续研究提供了重要参考价值。
