Targeting nectin-4 by antibody-drug conjugates for the treatment of urothelial carcinoma.
Targeting nectin-4 by antibody-drug conjugates for the treatment of urothelial carcinoma.
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DOI：
10.1080/14712598.2021.1929168
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发表时间：
2021-07
影响因子：
4.6
通讯作者：
Rosenberg JE
中科院分区：
文献类型：
--
作者：
Wong JL;Rosenberg JE
Nectin-4是一种在尿路上皮癌和其他几种恶性肿瘤中过表达的肿瘤相关抗原。它已成为新型肿瘤导向疗法的引人注目的靶标，特别是作为抗体-药物缀合物（ADC）的组分，这是一类不断增长的抗癌治疗剂。nectin-4导向疗法的开发由enfortumab vedotin（EV）领导，enfortumab vedotin是一种ADC，由对nectin-4具有特异性的全人单克隆抗体通过可切割接头与微管抑制剂MMAE缀合组成。EV于2019年被批准为治疗尿路上皮癌的一流药物。本文讨论了与ADC设计相关的一般原则以及我们目前对正常生理学和恶性肿瘤中的nectin-4的理解，然后回顾了EV的发展以及靶向nectin-4的其他药物缀合物策略。EV为nectin-4导向疗法的临床实用性提供了概念验证，并为ADC作为一类重要的抗癌剂提供了进一步的支持。nectin-4靶向方法的未来发展将受益于对健康和疾病中nectin-4生物学的更深入理解，以及对治疗活性和抗性机制的详细探索。
Nectin-4 is a tumor-associated antigen overexpressed in urothelial carcinoma and several other malignancies. It has emerged as a compelling target for novel tumor-directed therapies, particularly as a component of antibody-drug conjugates (ADCs), a growing class of anti-cancer therapeutic agents. Development of nectin-4-directed therapies has been led by enfortumab vedotin (EV), an ADC comprised of a fully human monoclonal antibody specific for nectin-4 conjugated via a cleavable linker to the microtubule inhibitor MMAE. EV was approved in 2019 as a first-in-class agent for the treatment of urothelial carcinoma. This article discusses general principles relevant to ADC design and our current understanding of nectin-4 in normal physiology and malignancy, followed by a review of the development of EV as well as additional drug conjugate strategies targeting nectin-4. EV offers proof-of-concept for the clinical utility of nectin-4-directed therapies and provides further support for ADCs as an important class of anti-cancer agents. Future development of nectin-4-targeted approaches will benefit from a deeper understanding of nectin-4 biology in both health and disease, as well as a detailed exploration of the mechanisms underlying therapeutic activity and resistance.
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