ABSTRACT

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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为癌症治疗提供吡咯并苯二氮卓 (PBD) 二聚体的抗体-药物偶联物 (ADC)

摘要

介绍

大约十年前，设计合理的吡咯并苯二氮卓 (PBD) 二聚体作为抗体-药物偶联物 (ADC) 的一类新药物成分出现。它们产生高度细胞毒性的 DNA 交联，利用与 auristatin 和美登素类微管蛋白抑制剂类完全不同的细胞靶标以及对其他 DNA 相互作用弹头（如加利车霉素）的不同 DNA 损伤模式。

涵盖的领域

讨论了使 PBD 二聚体适合 ADC 弹头的特性，以及两种主要有效载荷结构 talirine 和 tesirine 的开发。回顾了 20 种含有 PBD 二聚体的 ADC 进入临床的临床经验，重点关注在关键研究后停产的 vadastuximab talirine 和 rova​​lpituzumab tesirine，以及正在获得批准的 loncastuximab tesirine 和 camidanlumab tesirine。

专家意见

回顾近 40 项含 PBD 二聚体 ADC 的临床试验的临床疗效和安全性数据，突出了 ADC 早期临床开发的复杂性和挑战。它使我们能够就失败的原因得出一些结论，并建议在快速扩展的领域中优化这一有前途的 ADC 类别的未来临床开发的策略。