抗体药物偶联物连接体的化学设计与合成。

IF 2.9 4区 医学 Q3 CHEMISTRY, MEDICINAL
Mark Frigerio, Andrew F Kyle
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引用次数: 24

摘要

抗体药物偶联物(Antibody Drug Conjugates, adc)利用单克隆抗体的靶向能力,将有效的细胞毒性载荷传递到预定的靶点。该连接体包括适合于附着在抗体上的偶联功能、通常包含亲水性元件的间隔单元和释放强效细胞毒性战斗部的触发器。了解ADC设计的相互冲突的需求,既要保证系统循环的稳定性,又要保证ADC达到预期目标后有效的有效载荷释放,这对于有效的连接器开发至关重要。ADC连接器的设计已经采用了多种不同的方法,随着对复杂设计复杂性的理解的增加,越来越多的优雅解决方案不断被报道。本文综述了ADC连接体的合成方法,以及连接体设计对抗体偶联、ADC药代动力学和有效载荷释放的影响。讨论了商业adc以及目前处于临床、临床前和早期开发阶段的adc中使用的链接器方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The Chemical Design and Synthesis of Linkers Used in Antibody Drug Conjugates.
Antibody Drug Conjugates (ADCs) use targeting ability of monoclonal antibodies to deliver potent cytototoxic payloads to their intended target. The linker encompasses a conjugating functionality suitable for attachment to the antibody, a spacer unit that typically incorporates a hydrophilic element and a trigger which releases the potent cytototoxic warhead. Understanding the conflicting requirements of ADC design, providing stability in systemic circulation but efficient payload release once the ADC reaches its intended target, is crucial to effective linker development. ADC linker design has been approached in a variety of different ways, with increasingly elegant solutions continuing to be reported as understanding of the intricate design complexities increases. This review focuses on the synthetic approaches used in ADC linkers, and the impact of linker design on antibody conjugation, ADC pharmacokinetics and payload release. Linker approaches utilized in commercial ADCs as well as ADCs currently in clinical, pre-clinical and early stage development are discussed.
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来源期刊
CiteScore
6.40
自引率
2.90%
发文量
186
审稿时长
3-8 weeks
期刊介绍: Current Topics in Medicinal Chemistry is a forum for the review of areas of keen and topical interest to medicinal chemists and others in the allied disciplines. Each issue is solely devoted to a specific topic, containing six to nine reviews, which provide the reader a comprehensive survey of that area. A Guest Editor who is an expert in the topic under review, will assemble each issue. The scope of Current Topics in Medicinal Chemistry will cover all areas of medicinal chemistry, including current developments in rational drug design, synthetic chemistry, bioorganic chemistry, high-throughput screening, combinatorial chemistry, compound diversity measurements, drug absorption, drug distribution, metabolism, new and emerging drug targets, natural products, pharmacogenomics, and structure-activity relationships. Medicinal chemistry is a rapidly maturing discipline. The study of how structure and function are related is absolutely essential to understanding the molecular basis of life. Current Topics in Medicinal Chemistry aims to contribute to the growth of scientific knowledge and insight, and facilitate the discovery and development of new therapeutic agents to treat debilitating human disorders. The journal is essential for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important advances.
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