The Resurgence of Antibody Drug Conjugates in Cancer Therapeutics: Novel Targets and Payloads.
The Resurgence of Antibody Drug Conjugates in Cancer Therapeutics: Novel Targets and Payloads.
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DOI：
10.1200/edbk_281107
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发表时间：
2020-03-01
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影响因子：
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通讯作者：
Patnaik, Amita
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文献类型：
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作者：
Boni, Valentina;Sharma, Manish R;Patnaik, Amita
抗体药物偶联物（Antibody drug conjugates, adc）是一类新兴的治疗药物，由细胞毒性药物与抗体共价连接组成，该抗体直接针对肿瘤细胞和/或微环境表达的特定细胞表面靶点。adc利用抗体的特异性，使其作为载体将细胞毒性载荷传递到肿瘤中。对于这类复杂工程疗法来说，四个参数被认为是至关重要的：靶点选择、抗体、细胞毒性有效载荷以及偶联和连接体技术。事实证明，这类药物的开发比预期的要复杂。目前已经出现了一些挑战，包括缺乏真正的肿瘤抗原特异性，由于连接体不稳定，细胞毒性载荷早期释放到血液中，以及有效载荷的效力较低，导致毒性更大或与未结合的细胞毒性相比缺乏改善的功效。2013年，曲妥珠单抗emtansine被批准用于her2阳性乳腺癌，这证明了adc在实体肿瘤中的治疗应用。最近批准了两种新型adc：用于her2阳性乳腺癌的曲妥珠单抗德鲁德替康和用于局部晚期或转移性尿路上皮癌的强制维多汀。曲妥珠单抗deruxtecan的特点是具有独特的生化结构和一种新的细胞毒性有效负荷，deruxtecan是一种高效的拓扑异构酶I抑制剂。Enfortumab vedotin直接作用于nectin-4，是成功和战略性目标选择的一个例子。这篇综述的重点是选择合适的靶点和新型有效载荷的概念，讨论了adc在临床前和临床开发中的具体例子，并提供了与这类独特治疗方法相关的未来方向。
Antibody drug conjugates (ADCs) are an emerging class of therapeutics that consist of a cytotoxic agent linked covalently to an antibody, which is directed toward a specific cell surface target expressed by tumor cells and/or the microenvironment. ADCs leverage the specificity of the antibody such that it functions as a carrier to deliver the cytotoxic payload into the tumor. Four parameters are considered critical for this class of complex engineered therapeutics: target selection, antibody, cytotoxic payload, as well as conjugation and linker technology. The development of this class of drugs has proven more complex than expected. Several challenges have arisen, including a lack of true tumor antigen specificity, early release of the cytotoxic payload into the bloodstream due to linker instability, and low potency of the payload, resulting in either greater toxicity or lack of improved efficacy compared with unconjugated cytotoxics. The approval of trastuzumab emtansine in 2013 for HER2-positive breast cancer served as a proof of concept that ADCs have therapeutic application in solid tumors. Two novel ADCs have recently been approved: trastuzumab deruxtecan for HER2-positive breast cancer and enfortumab vedotin for locally advanced or metastatic urothelial cancer. Trastuzumab deruxtecan is distinguished by a unique biochemical structure with a novel cytotoxic payload, deruxtecan-a highly potent, topoisomerase I inhibitor. Enfortumab vedotin is directed toward nectin-4 and represents an example of successful and strategic target selection. This review focuses on the concepts underlying the choice of suitable targets and novel payloads, discusses specific examples of ADCs in preclinical and clinical development, and provides future directions related to this unique class of therapeutics.