Chari Ravi V J
ImmunoGen, Inc., 128 Sidney Street, Cambridge, Massachusetts 02139, USA.
Acc Chem Res. 2008 Jan;41(1):98-107. doi: 10.1021/ar700108g. Epub 2007 Aug 18.
The therapeutic activity of most anticancer drugs in clinical use is limited by their general toxicity to proliferating cells, including some normal cells. Although, chemists continue to develop novel cytotoxic agents with unique mechanisms of action, many of these compounds still lack tumor selectivity and have not been therapeutically useful. Monoclonal antibodies that bind to specific markers on the surface of tumor cells offer an alternative therapy that is tumor specific and thus less toxic. Although highly selective, very few monoclonal antibodies are therapeutically useful since they only display modest cell killing activity. The linkage of monoclonal antibodies to highly cytotoxic drugs can be viewed as a means of (a) conferring higher tumor selectivity to cytotoxic drugs that are too toxic to be used on their own or (b) conferring cell killing power to monoclonal antibodies that are tumor-specific but not sufficiently cytotoxic. This Account provides a brief history of the development of antibody-drug conjugates and shows how the lessons learned from the first generation of conjugates has guided the development of more effective antitumor agents. The three components of antibody-drug conjugates, that is, the monoclonal anitbody, the cytotoxic drug, and the linker connecting the drug to the antibody, have been methodically studied and optimized. The antimitotic drug maytansine was chosen for use in the targeted delivery approach because of its high in vitro potency. Analogues of maytansine bearing a disulfide substituent that allowed linkage to monoclonal antibodies via disulfide bonds were prepared. These analogues retain the high potency of the parent drug. The stability of the disulfide link in antibody-maytansinoid conjugates was varied by introduction of methyl substituents on the carbon atoms geminal to the disulfide link. The optimized disulfide linker was stable in circulation in vivo. The circulation half-life of the cytotoxic drug was increased from just a few hours for the unconjugated drug to several days for the conjugate. Upon binding of the conjugate to the tumor cell, internalization and lysosomal processing released the potent cytotoxic agent inside the cell. These conjugates displayed high target-specific cytotoxicity in vitro. The antitumor activity of these targeted agents was superior to that of the antibodies alone or the standard anticancer drugs in human tumor xenograft models. Several conjugates from this new class of tumor-targeted anticancer agents are currrently undergoing clinical evaluation. The progress made in the targeted delivery approach and initial clinical results opens the door to the future development of highly potent drugs that were too toxic on their own to be therapeutically useful.
大多数临床使用的抗癌药物的治疗活性受到其对增殖细胞（包括一些正常细胞）的一般毒性的限制。尽管化学家们不断开发具有独特作用机制的新型细胞毒性药物，但这些化合物中的许多仍然缺乏肿瘤选择性，并且在治疗上没有用处。与肿瘤细胞表面特定标志物结合的单克隆抗体提供了一种肿瘤特异性的替代疗法，因此毒性较小。尽管具有高度选择性，但很少有单克隆抗体在治疗上有用，因为它们仅表现出适度的细胞杀伤活性。将单克隆抗体与高细胞毒性药物连接可以被视为一种手段：（a）赋予对自身毒性太大而无法单独使用的细胞毒性药物更高的肿瘤选择性；（b）赋予具有肿瘤特异性但细胞毒性不足的单克隆抗体细胞杀伤能力。本综述简要介绍了抗体 - 药物偶联物的发展历程，并展示了从第一代偶联物中学到的经验教训如何指导更有效的抗肿瘤药物的开发。抗体 - 药物偶联物的三个组成部分，即单克隆抗体、细胞毒性药物以及将药物连接到抗体的连接子，已经得到了系统的研究和优化。抗有丝分裂药物美登素因其在体外的高效力而被选用于靶向递送方法。制备了带有二硫取代基的美登素类似物，该取代基允许通过二硫键与单克隆抗体连接。这些类似物保留了母体药物的高效力。通过在与二硫键相连的碳原子上引入甲基取代基，改变了抗体 - 美登素类偶联物中二硫键连接的稳定性。优化后的二硫键连接子在体内循环中是稳定的。细胞毒性药物的循环半衰期从游离药物的仅几小时增加到偶联物的几天。当偶联物与肿瘤细胞结合后，内化和溶酶体加工会在细胞内释放出强效细胞毒性剂。这些偶联物在体外显示出高靶向特异性细胞毒性。在人肿瘤异种移植模型中，这些靶向药物的抗肿瘤活性优于单独的抗体或标准抗癌药物。这类新型肿瘤靶向抗癌药物中的几种偶联物目前正在进行临床评估。靶向递送方法取得的进展和初步临床结果为那些自身毒性太大而无法用于治疗的高效药物的未来发展打开了大门。
