Antibody–Drug Conjugates in Oncology: Principles, Clinical Development, and Future Directions

作者：Bisheng Cheng, Lanqi Gong, Z. Peter Wang, Peidan Peng, Kai Xu, Hai Huang, Peng Wu · 发表于：MedComm · 年份：2026 · DOI：10.1002/mco2.70699 · 被引用次数：4 · 研究领域：HER2/EGFR in Cancer Research、Advanced Breast Cancer Therapies、Monoclonal and Polyclonal Antibodies Research

Antibody-drug conjugates (ADCs) have emerged as a major therapeutic modality in oncology, enabling the targeted delivery of highly potent cytotoxic agents while expanding the therapeutic window in solid tumors. Recent clinical successes across breast, lung, and genitourinary cancers have highlighted that ADC efficacy is governed not only by target expression, but also by the integrated optimization of antibody engineering, linker chemistry, payload selection, and tumor-specific biology. In this review, we summarize the fundamental principles underpinning ADC design, including antibody format and Fc engineering, linker stability, payload classes, drug-to-antibody ratio optimization, and the bystander effect. We then discuss tumor antigen biology and target landscapes across solid tumors, with particular emphasis on how antigen density, heterogeneity, internalization kinetics, and intracellular trafficking shape clinical activity. Uro-oncological malignancies-especially urothelial carcinoma-are presented as a clinically advanced and instructive paradigm for ADC development. Experience from these tumors illustrates both the opportunities and limitations of ADC therapy, including mechanisms of response and resistance, biomarker-driven patient selection, rational combination strategies, and safety management in real-world practice. Finally, we provide a forward-looking perspective on next-generation ADC development, highlighting emerging conjugation technologies, bispecific and co...