抗体药物联合物（ADC）是一种新的药物类别，现在迅速发展为高度有效的实体瘤治疗方法。ADC通过将传统化疗药物与高选择性的靶向单克隆抗体结合，实现了一种新的方式。抗HER2治疗通过选择性地靶向表达人表皮生长因子受体2（HER2）的癌细胞，其中曲妥珠单抗是第一个取得成功结果的HER2靶向单克隆抗体，成为抗HER2治疗的支柱。曲妥珠单抗联合物（T-DCs）利用曲妥珠单抗作为选择性抗体将细胞毒性药物引导进入癌细胞内。曲妥珠单抗乳酸酰化物（T-DM1）和曲妥珠单抗-德霉素（T-Dxd）是经批准的两种T-DCs。T-Dxd和其他五种T-DCs是“第二代ADCs”，首先在HER2阳性乳腺癌中进行测试，然后在HER2低表达的乳腺癌和其他展现出杰出和创新药代动力学和药效学特性的癌症中展现了很有前途的结果。目前产生的证据正在确立它们作为一种完全新的药物类别，对实体癌症治疗具有有效性，但也提示医师要注意非传统的毒性概况。T-DCs在HER2阳性乳腺癌中的角色已经得到了广泛的评估。而在本综述中，我们首次在文献中概述了曲妥珠单抗联合物（T-DCs）已批准和/或临床研究开发的情况，特别关注了它们在HER2低表达的乳腺癌和其他与乳腺癌不同的实体瘤中的疗效和安全性概况。我们从分析T-DCs生物学特征入手，阐述了其药代动力学和安全性概况的差异，然后介绍了这些新兴T-DCs在HER2低表达的乳腺癌和其他HER2过表达和/或突变实体瘤中的活性和疗效的主要证据，最后，我们概述了这些化合物应如何分配的复杂且仍在发展中的情境。我们还重点评估了与其他药物如免疫疗法、化疗和靶向疗法联合使用以增强T-DCs活性并最终克服未来的耐药机制的可能性联合策略。版权所有 ©2023作者。由Elsevier Ltd.出版。保留所有权利。

A novel class of drugs, antibody-drug conjugates (ADCs), are now rapidly emerging as highly effective treatments for solid tumours. ADCs conjugate conventional chemotherapeutics with highly selective targeted monoclonal antibodies. Anti-HER2 therapies selectively target cancer cells expressing human epidermal growth factor receptor 2 (HER2), among them trastuzumab has been the first HER2-targeting monoclonal antibody to achieve successful results that made it the backbone of anti-HER2 therapies. Trastuzumab drug conjugates (T-DCs), use trastuzumab as a selective antibody to lead cytotoxic drugs inside cancer cells. Trastuzumab-emtansine (T-DM1) and trastuzumab-deruxtecan (T-Dxd) are the two approved T-DCs. T-Dxd along with other five T-DCs represents "second generation ADCs" that has been firstly tested in HER2 positive breast cancer (BC) and then in HER2-low BC and other cancers showing promising results thanks to extraordinary and innovative pharmacokinetic and pharmacodynamic characteristics. The evidence generated so far are establishing them as a completely new class of agents effective in solid cancer treatments but also warrants physicians against unconventional toxicity profiles. The role of T-DCs in HER2-positive BC has been largely reviewed, while in this review, we provided for the first time in literature an overview of trastuzumab drug conjugates (T-DCs) approved and/or in clinical development with a specific focus on their efficacy and safety profile in HER2-low BC and other solid tumours different from BC. We started by analysing T-DCs biological characteristics that underly the differences in T-DCs pharmacodynamics and safety profile, then presented the main evidence on the activity and efficacy of these emerging T-DCs in HER2-low BC and other HER2 overexpressing and/or mutated solid tumours and lastly, we provided an overview of the complex and still evolving scenario in which these compounds should be allocated. A specific focus on possible combination strategies with other drugs such as immunotherapy, chemotherapy and target therapy, to increase T-DCs activity and eventually overcome future upcoming resistance mechanisms, are here also critically reviewed.Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.