ABSTRACT

Introduction

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.

Areas covered

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.

Expert opinion

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.

中文翻译：

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抗体-药物偶联物靶向 nectin-4 治疗尿路上皮癌

摘要

介绍

Nectin-4 是一种在尿路上皮癌和其他几种恶性肿瘤中过度表达的肿瘤相关抗原。它已成为新型肿瘤定向疗法的一个引人注目的靶标，特别是作为抗体-药物偶联物 (ADC) 的一个组成部分，这是一种不断增长的抗癌治疗药物。nectin-4 导向疗法的开发由 enfortumab vedotin (EV) 领导，EV 是一种 ADC，由一种对 nectin-4 特异的全人源单克隆抗体组成，通过可切割的接头与微管抑制剂 MMAE 偶联。EV 于 2019 年被批准为治疗尿路上皮癌的一流药物。

涵盖的领域

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 nectin-4 的理解，然后回顾了 EV 的发展以及针对 nectin-4 的其他药物偶联策略。

专家意见

EV 为 nectin-4 导向疗法的临床应用提供了概念验证，并为 ADC 作为一类重要的抗癌药物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 生物学的更深入了解，以及对治疗活性和耐药性机制的详细探索。