Antibody-drug conjugates: Current challenges and innovative solutions for precision cancer therapy.

IF 11.8 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Med Pub Date : 2025-09-30 DOI:10.1016/j.medj.2025.100849

Xingyu Zhou, Yanjie Han, Yuan Fang, Peiwen Ma, Jiawei Zhou, Yale Jiang, Shujun Xing, Qiyu Tang, Yiru Hou, Shuhang Wang, Ning Li

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Abstract

Antibody-drug conjugates (ADCs) have advanced cancer therapy by combining antibody specificity with cytotoxic potency. However, clinical experience has revealed challenges limiting their efficacy and safety. This review addresses key questions in ADC development and corresponding optimization strategies. It discusses the relationship between target antigen expression and clinical response and the role of antibodies beyond targeting. Enhancing ADC distribution via bispecific targeting and probody masking is summarized. Traditional assumptions in linker design, such as favoring maximum stability, are re-evaluated to improve clinical outcomes. Innovations in linker chemistry encompass tumor microenvironment-responsive release mechanisms and bioorthogonal reactions. Emerging payload strategies like immune-stimulating ADCs (ISACs) and degrader-antibody conjugates (DACs) expand therapeutic possibilities but introduce new safety challenges. Ultimately, merely increasing ADC structural complexity is insufficient. Understanding tumor delivery barriers and bridging preclinical-clinical gaps will be vital to fully realize the potential of ADCs in precision oncology.

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抗体-药物偶联物：精确癌症治疗的当前挑战和创新解决方案。

抗体-药物偶联物（adc）通过结合抗体特异性和细胞毒性，具有晚期癌症治疗的作用。然而，临床经验揭示了限制其有效性和安全性的挑战。本文综述了ADC开发中的关键问题和相应的优化策略。它讨论了靶抗原表达与临床反应之间的关系以及抗体在靶向之外的作用。总结了通过双特异性靶向和抗体掩蔽增强ADC分布的方法。重新评估连接器设计中的传统假设，例如支持最大稳定性，以改善临床结果。连接物化学的创新包括肿瘤微环境响应释放机制和生物正交反应。新兴的有效载荷策略，如免疫刺激adc （ISACs）和降解抗体偶联物（dac），扩大了治疗的可能性，但也带来了新的安全性挑战。最终，仅仅增加ADC的结构复杂性是不够的。了解肿瘤传递障碍和弥合临床前与临床之间的差距对于充分发挥adc在精准肿瘤学中的潜力至关重要。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Med MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

17.70

自引率

0.60%

发文量

102

期刊介绍： Med is a flagship medical journal published monthly by Cell Press, the global publisher of trusted and authoritative science journals including Cell, Cancer Cell, and Cell Reports Medicine. Our mission is to advance clinical research and practice by providing a communication forum for the publication of clinical trial results, innovative observations from longitudinal cohorts, and pioneering discoveries about disease mechanisms. The journal also encourages thought-leadership discussions among biomedical researchers, physicians, and other health scientists and stakeholders. Our goal is to improve health worldwide sustainably and ethically. Med publishes rigorously vetted original research and cutting-edge review and perspective articles on critical health issues globally and regionally. Our research section covers clinical case reports, first-in-human studies, large-scale clinical trials, population-based studies, as well as translational research work with the potential to change the course of medical research and improve clinical practice.