Introduction

The rationally designed pyrrolobenzodiazepine (PBD) dimers emerged around ten years ago as a new class of drug component for antibody-drug conjugates (ADC). They produce highly cytotoxic DNA cross-links, exploiting a completely different cellular target to the auristatin and maytansinoid tubulin inhibitor classes and a different mode of DNA damage to other DNA interacting warheads such as calicheamicin.

Areas covered

The properties which make the PBD dimers suitable warheads for ADCs, and the development of the two main payload structures talirine and tesirine, are discussed. The clinical experience with the twenty PBD dimer-containing ADCs to enter the clinic is reviewed, with a focus on vadastuximab talirine and rovalpituzumab tesirine, both of which were discontinued following pivotal studies, and loncastuximab tesirine and camidanlumab tesirine which are progressing towards approval.

Expert opinion

Reviewing the clinical efficacy and safety data from almost forty clinical trials of PBD dimer-containing ADCs highlights the complexities and challenges of ADC early clinical development. It enables some conclusions to be made about reasons for failure and suggests strategies to optimise the future clinical development of this promising class of ADCs in a rapidly expanding field.

中文翻译：

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递送吡咯并苯并二氮杂（PBD）二聚体的抗体-药物偶联物（ADC）

介绍

合理设计的吡咯并苯并二氮杂（PBD）二聚体作为抗体-药物偶联物（ADC）的一类新型药物成分出现于大约十年前。它们产生高度细胞毒性的DNA交联键，对auristatin和美登木素生物碱微管蛋白抑制剂类别使用完全不同的细胞靶标，并对其他与DNA相互作用的战斗部（例如加利车霉素）破坏DNA的方式不同。

覆盖区域

讨论了使PBD二聚体适合用作ADC战斗部的特性，以及两种主要有效负载结构talirine和tesirine的开发。回顾了二十个含PBD二聚体的ADC进入临床的临床经验，重点是瓦达他昔单抗他利林和rovalpituzumab tesirine，它们在关键性研究后均已停用，而loncastuximab tesirine和camidanlumab tesirine正在逐步获得批准。

专家意见

回顾近40项含PBD二聚体的ADC的临床试验的临床疗效和安全性数据，突显了ADC早期临床开发的复杂性和挑战。它使人们能够对失败的原因做出一些结论，并提出在快速发展的领域中优化这一有前途的ADC类的未来临床开发的策略。