ABSTRACT

Introduction: We discuss chemical conjugation strategies for antibody-drug conjugates (ADCs) from an industrial perspective and compare three promising chemical conjugation technologies to produce site-specific ADCs.

Areas covered: Currently, nine ADCs are commercially approved and all are produced by chemical conjugation technology. However, seven of these ADCs contain a relatively broad drug distribution, potentially limiting their therapeutic indices. In 2019, the first site-specific ADC was launched on the market by Daiichi-Sankyo. This achievement, and an analysis of clinical trials over the last decade, indicates that current industrial interest in the ADC field is shifting toward site-specific conjugation technologies. From an industrial point of view, we aim to provide guidance regarding established conjugation methodologies that have already been applied to scale-up stages. With an emphasis on highly productive, scalable, and synthetic process robustness, conjugation methodologies for ADC production is discussed herein.

Expert opinion: All three chemical conjugation technologies described in this review have various advantages and disadvantages, therefore drug developers can utilize these depending on their biological and/or protein targets. The future landscape of the ADC field is also discussed.

摘要

简介：我们从工业角度讨论抗体-药物偶联物 (ADC) 的化学偶联策略，并比较三种有前景的化学偶联技术以生产位点特异性 ADC。

涵盖的领域：目前，9 个 ADC 已获得商业批准，均采用化学偶联技术生产。然而，其中 7 个 ADC 包含相对广泛的药物分布，可能会限制其治疗指数。2019 年，第一三共在市场上推出了第一个特定于站点的 ADC。这一成就以及对过去十年临床试验的分析表明，当前对 ADC 领域的工业兴趣正在转向位点特异性偶联技术。从工业的角度来看，我们的目标是为已应用于放大阶段的已建立的共轭方法提供指导。重点是高产、可扩展和合成工艺的稳健性，本文讨论了用于 ADC 生产的共轭方法。

专家意见：本综述中描述的所有三种化学偶联技术都有各种优点和缺点，因此药物开发人员可以根据其生物和/或蛋白质靶标来利用这些技术。还讨论了 ADC 领域的未来前景。