Lei Yaxin, Zheng Minglei, Chen Peng, Seng Ng Chen, Peng Loh Teck, Liu Huitao
Henan Linker Technology Key Laboratory, College of Advanced Interdisciplinary Science and Technology, Henan University of Technology, NO. 100 Lianhua Street, Zhengzhou, 450001, China.
College of Food Science and Engineering, Henan University of Technology, NO. 100 Lianhua Street, Zhengzhou, 450001, China.
ChemMedChem. 2025 Aug 2;20(15):e202500262. doi: 10.1002/cmdc.202500262. Epub 2025 Jun 24.
Inspired by the "magic bullet" concept proposed over a century ago, antibody-drug conjugates (ADCs) are developed to enhance cancer therapy by linking monoclonal antibodies to a cytotoxic payload, aiming to overcome the limitations of conventional chemotherapy. To date, 17 ADCs have received regulatory approval for treating both hematologic and solid tumors. Despite their clinical success, developing ADCs with optimal therapeutic potential remains challenging. While selecting the appropriate antibody and cytotoxin is crucial, the linker plays a pivotal role in determining plasma stability and efficient payload release at the tumor site. Over the past decade, advances in linker technology have significantly improved the pharmacokinetics, efficacy, and toxicity profiles of ADCs. This review provides an overview of clinically validated linkers and recent innovations in linker design, focusing on drug release triggers, bioconjugation strategies, the impact of spacers on hydrophilicity, traceless drug release, and linker architecture, as well as a discussion of the bystander effect, offering insights for the rational design of next-generation ADCs.
受一个多世纪前提出的“神奇子弹”概念启发，抗体药物偶联物（ADCs）通过将单克隆抗体与细胞毒性载荷连接起来得以开发，旨在增强癌症治疗效果，克服传统化疗的局限性。迄今为止，已有17种ADC药物获得监管批准，用于治疗血液系统肿瘤和实体瘤。尽管它们在临床上取得了成功，但开发具有最佳治疗潜力的ADC药物仍然具有挑战性。虽然选择合适的抗体和细胞毒素至关重要，但连接子在决定血浆稳定性和在肿瘤部位有效释放载荷方面起着关键作用。在过去十年中，连接子技术的进步显著改善了ADC药物的药代动力学、疗效和毒性特征。本文综述了经过临床验证的连接子以及连接子设计的最新创新，重点关注药物释放触发因素、生物偶联策略、间隔基对亲水性的影响、无痕药物释放和连接子结构，同时讨论旁观者效应，为下一代ADC药物的合理设计提供见解。
