Thomas Anish, Teicher Beverly A, Hassan Raffit
Thoracic and GI Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
Molecular Pharmacology Branch DCTD, National Cancer Institute, Bethesda, MD, USA.
Lancet Oncol. 2016 Jun;17(6):e254-e262. doi: 10.1016/S1470-2045(16)30030-4.
Antibody-drug conjugates are monoclonal antibodies conjugated to cytotoxic agents. They use antibodies that are specific to tumour cell-surface proteins and, thus, have tumour specificity and potency not achievable with traditional drugs. Design of effective antibody-drug conjugates for cancer therapy requires selection of an appropriate target, a monoclonal antibody against the target, potent cytotoxic effector molecules, and conjugation of the monoclonal antibody to cytotoxic agents. Substantial advances in all these aspects in the past decade have resulted in regulatory approval of ado-trastuzumab emtansine and brentuximab vedotin for clinical use. Several promising antibody-drug conjugates are now in late-phase clinical testing. Ongoing efforts are focused on identifying better targets, more effective cytotoxic payloads, and further improvements in antibody-drug linker technology. Improved understanding of the mechanistic basis of antibody-drug conjugate activity will enable design of rational combination therapies with other agents, including immunotherapy.
抗体药物偶联物是与细胞毒性药物偶联的单克隆抗体。它们利用对肿瘤细胞表面蛋白具有特异性的抗体，因此具有肿瘤特异性和传统药物无法达到的效力。设计用于癌症治疗的有效抗体药物偶联物需要选择合适的靶点、针对该靶点的单克隆抗体、强效细胞毒性效应分子，以及将单克隆抗体与细胞毒性药物偶联。在过去十年中，所有这些方面都取得了重大进展，导致ado曲妥珠单抗（ado-trastuzumab emtansine）和维布妥昔单抗（brentuximab vedotin）获得监管批准用于临床。目前有几种有前景的抗体药物偶联物正处于临床后期试验阶段。正在进行的工作集中在识别更好的靶点、更有效的细胞毒性载荷，以及进一步改进抗体药物连接技术。对抗体药物偶联物活性机制基础的更好理解将有助于设计与其他药物（包括免疫疗法）的合理联合疗法。
