Unveiling the molecular and immunological drivers of antibody-drug conjugates in cancer treatment.

IF 66.8 1区 医学 Q1 ONCOLOGY
Alfred Zippelius,Sara M Tolaney,Paolo Tarantino,Joseph P Balthasar,Greg M Thurber
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引用次数: 0

Abstract

After decades of investment, antibody-drug conjugates (ADCs) are finally demonstrating their potential, marked by a growing number of clinical approvals, applications in earlier lines of treatment and integration into drug combinations, including immunotherapies. This progress has spurred investment in developing new ADCs and expanding the use of approved ADCs in clinical practice. The design of ADCs is complex, involving multiple molecular components that interact with both tumour and host tissue microenvironments. In this Review, we explore the molecular and immunological factors influencing ADC efficacy and toxicity. We describe how the molecular components of ADCs determine their systemic, tissue and cellular distribution, which ultimately dictates therapeutic efficacy. These interactions also determine the toxicity profile and set limitations on maximum dosing. Finally, we discuss the impact of ADC treatment on immune cells, emphasizing the distinct but interconnected roles of immunogenic cell death, activation of immune cells such as dendritic cells and antibody-Fc interactions. These mechanisms are crucial for increasing efficacy beyond the direct cytotoxic effects of the payload. By providing insights into the intricate interactions of ADCs, this Review aims to inform the rational design of combination therapies and guide the development of the next generation of clinically effective ADCs.
揭示癌症治疗中抗体-药物偶联物的分子和免疫学驱动因素。
经过几十年的投资,抗体-药物偶联物(adc)终于显示出其潜力,其标志是越来越多的临床批准,在早期治疗线中的应用以及与药物组合(包括免疫疗法)的整合。这一进展刺激了对开发新的adc的投资,并扩大了已批准adc在临床实践中的使用。adc的设计是复杂的,涉及与肿瘤和宿主组织微环境相互作用的多个分子成分。本文综述了影响ADC疗效和毒性的分子和免疫因素。我们描述了adc的分子成分如何决定它们的系统、组织和细胞分布,最终决定了治疗效果。这些相互作用也决定了毒性特征,并设定了最大剂量限制。最后,我们讨论了ADC治疗对免疫细胞的影响,强调了免疫原性细胞死亡、免疫细胞(如树突状细胞)的激活和抗体- fc相互作用的独特但相互关联的作用。这些机制对于提高有效性至关重要,超出了有效载荷的直接细胞毒性作用。通过深入了解adc之间复杂的相互作用,本综述旨在为联合治疗的合理设计提供信息,并指导下一代临床有效adc的开发。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Nature Reviews Cancer
Nature Reviews Cancer 医学-肿瘤学
CiteScore
111.90
自引率
0.40%
发文量
97
审稿时长
6-12 weeks
期刊介绍: Nature Reviews Cancer, a part of the Nature Reviews portfolio of journals, aims to be the premier source of reviews and commentaries for the scientific communities it serves. The correct abbreviation for abstracting and indexing purposes is Nat. Rev. Cancer. The international standard serial numbers (ISSN) for Nature Reviews Cancer are 1474-175X (print) and 1474-1768 (online). Unlike other journals, Nature Reviews Cancer does not have an external editorial board. Instead, all editorial decisions are made by a team of full-time professional editors who are PhD-level scientists. The journal publishes Research Highlights, Comments, Reviews, and Perspectives relevant to cancer researchers, ensuring that the articles reach the widest possible audience due to their broad scope.
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