Department of Molecular Microbiology and Biotechnology, The George S. Wise Faculty of Life Sciences, Tel-Aviv University, Ramat Aviv, Israel.
Department of Molecular Microbiology and Biotechnology, The George S. Wise Faculty of Life Sciences, Tel-Aviv University, Ramat Aviv, Israel.
Drug Resist Updat. 2015 Jan;18:36-46. doi: 10.1016/j.drup.2014.11.001. Epub 2014 Nov 21.
Antibody-based therapy of various human malignancies has shown efficacy in the past 30 years and is now one of the most successful and leading strategies for targeted treatment of patients harboring hematological malignancies and solid tumors. Antibody-drug conjugates (ADCs) aim to take advantage of the affinity and specificity of monoclonal antibodies (mAbs) to selectively deliver potent cytotoxic drugs to antigen-expressing tumor cells. Key parameters for ADC include choosing the optimal components of the ADC (the antibody, the linker and the cytotoxic drug) and selecting the suitable cell-surface target antigen. Building on the success of recent FDA approval of brentuximab vedotin (Adcetris) and ado-trastuzumab emtansine (Kadcyla), ADCs are currently a class of drugs with a robust pipeline with clinical applications that are rapidly expanding. The more ADCs are being evaluated in preclinical models and clinical trials, the clearer are becoming the parameters and the challenges required for their therapeutic success. This rapidly growing knowledge and clinical experience are revealing novel modalities and mechanisms of resistance to ADCs, hence offering plausible solutions to such challenges. Here, we review the key parameters for designing a powerful ADC, focusing on how ADCs are addressing the challenge of multiple drug resistance (MDR) and its rational overcoming.
在过去的 30 年中，基于抗体的疗法已经在治疗各种人类恶性肿瘤方面显示出了疗效，并且现在已经成为治疗患有血液恶性肿瘤和实体瘤的患者的最成功和最领先的靶向治疗策略之一。抗体药物偶联物（ADC）旨在利用单克隆抗体（mAb）的亲和力和特异性，将有效细胞毒性药物选择性地递送至表达抗原的肿瘤细胞。ADC 的关键参数包括选择 ADC 的最佳组成部分（抗体、连接子和细胞毒性药物）和选择合适的细胞表面靶抗原。基于最近 FDA 批准的 Brentuximab Vedotin（Adcetris）和 ado-trastuzumab emtansine（Kadcyla）的成功，ADC 目前是一类具有强大临床应用管线的药物，应用正在迅速扩展。随着越来越多的 ADC 在临床前模型和临床试验中进行评估，对于其治疗成功所需的参数和挑战也越来越清晰。这种快速增长的知识和临床经验揭示了新型的耐药机制和对 ADC 的耐药性，从而为这些挑战提供了合理的解决方案。在这里，我们回顾了设计强大 ADC 的关键参数，重点介绍了 ADC 如何应对多重耐药性（MDR）的挑战及其合理克服。
