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.

中文翻译：

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抗体靶向药物和耐药性-挑战和解决方案。

在过去的30年中，以抗体为基础的各种人类恶性肿瘤疗法已显示出疗效，现在已成为针对具有血液恶性肿瘤和实体瘤的患者进行靶向治疗的最成功，最领先的策略之一。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的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的最佳成分（抗体，接头和细胞毒性药物）以及选择合适的细胞表面靶抗原。在最近FDA批准了brentuximab vedotin（Adcetris）和ado-trastuzumab emtansine（Kadcyla）的成功基础上，ADC目前是一类药物，具有强大的产品线，其临床应用正在迅速扩展。在临床前模型和临床试验中对ADC的评估越多，就越清晰地成为其治疗成功所需的参数和挑战。这种迅速增长的知识和临床经验揭示了新型的抗ADC的方式和机制，因此为此类挑战提供了可行的解决方案。在这里，我们回顾了设计功能强大的ADC的关键参数，重点关注ADC如何应对多重耐药性（MDR）及其合理克服的挑战。因此，为应对此类挑战提供了可行的解决方案。在这里，我们回顾了设计功能强大的ADC的关键参数，重点关注ADC如何应对多重耐药性（MDR）及其合理克服的挑战。因此，为应对此类挑战提供了可行的解决方案。在这里，我们回顾了设计功能强大的ADC的关键参数，重点关注ADC如何应对多重耐药性（MDR）及其合理克服的挑战。