Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut.
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut
Pharmacol Rev. 2022 Jul;74(3):680-711. doi: 10.1124/pharmrev.121.000499.
Drug conjugates, including antibody-drug conjugates, are a step toward realizing Paul Ehrlich's idea from over 100 years ago of a "magic bullet" for cancer treatment. Through balancing selective targeting molecules with highly potent payloads, drug conjugates can target specific tumor microenvironments and kill tumor cells. A drug conjugate consists of three parts: a targeting agent, a linker, and a payload. In some conjugates, monoclonal antibodies act as the targeting agent, but new strategies for targeting include antibody derivatives, peptides, and even small molecules. Linkers are responsible for connecting the payload to the targeting agent. Payloads impact vital cellular processes to kill tumor cells. At present, there are 12 antibody-drug conjugates on the market for different types of cancers. Research on drug conjugates is increasing year by year to solve problems encountered in conjugate design, such as tumor heterogeneity, poor circulation, low drug loading, low tumor uptake, and heterogenous expression of target antigens. This review highlights some important preclinical research on drug conjugates in recent years. We focus on three significant areas: improvement of antibody-drug conjugates, identification of new conjugate targets, and development of new types of drug conjugates, including nanotechnology. We close by highlighting the critical barriers to clinical translation and the open questions going forward. SIGNIFICANCE STATEMENT: The development of anticancer drug conjugates is now focused in three broad areas: improvements to existing antibody drug conjugates, identification of new targets, and development of new conjugate forms. This article focuses on the exciting preclinical studies in these three areas and advances in the technology that improves preclinical development.
药物偶联物，包括抗体药物偶联物，是朝着实现保罗·埃尔利希（Paul Ehrlich） 100 多年前提出的治疗癌症“魔弹”的想法迈出的一步。通过平衡具有高潜力有效载荷的选择性靶向分子，药物偶联物可以靶向特定的肿瘤微环境并杀死肿瘤细胞。药物偶联物由三个部分组成：靶向剂、连接子和有效载荷。在一些偶联物中，单克隆抗体充当靶向剂，但新的靶向策略包括抗体衍生物、肽，甚至小分子。连接子负责将有效载荷连接到靶向剂上。有效载荷影响杀死肿瘤细胞的重要细胞过程。目前，市场上有 12 种用于不同类型癌症的抗体药物偶联物。药物偶联物的研究逐年增加，以解决偶联物设计中遇到的问题，如肿瘤异质性、循环不良、载药量低、肿瘤摄取率低和靶抗原表达异质性。这篇综述强调了近年来药物偶联物的一些重要临床前研究。我们重点关注三个重要领域：抗体药物偶联物的改进、新偶联物靶点的鉴定以及新型药物偶联物的开发，包括纳米技术。最后，我们强调了临床转化的关键障碍和未来的悬而未决的问题。
抗癌药物偶联物的开发现在集中在三个广泛的领域：现有抗体药物偶联物的改进、新靶点的鉴定以及新偶联物形式的开发。本文重点介绍了这三个领域令人兴奋的临床前研究以及提高临床前开发的技术进步。
