Sassoon Ingrid, Blanc Véronique
Sanofi Oncology, Vitry-sur-Seine, France.
Methods Mol Biol. 2013;1045:1-27. doi: 10.1007/978-1-62703-541-5_1.
Biological therapies play an increasing role in cancer treatment, although the number of naked antibodies showing clinical efficacy as single agent remains limited. One way to enhance therapeutic potential of antibodies is to conjugate them to small molecule drugs. This combination is expected to bring together the benefits of highly potent drugs on the one hand and selective binders of specific tumor antigens on the other hand. However, designing an ADC is more complex than a simple meccano game, requiring thoughtful combination of antibody, linker, and drugs in the context of a target and a defined cancer indication. Lessons learned from the first-generation antibody-drug conjugate (ADC) and improvement of the technology guided the design of improved compounds which are now in clinical trials. Brentuximab vedotin (Adcetris(®)), an anti-CD30 antibody conjugated to a potent microtubule inhibitor for the treatment of Hodgkin's lymphoma and anaplastic large cell lymphomas, is the only marketed ADC today. A total of 27 ADC are currently undergoing clinical trials in both hematological malignancies and solid tumor indications. Among them, T-DM1 (trastuzumab emtansine), an ADC comprised of trastuzumab conjugated to DM1, via a non-cleavable linker, is showing very promising results in phase III for the treatment of HER2-positive refractory/relapsed metastatic breast cancer. Other compounds, such as CMC-544, SAR3419, CDX-011, PSMA-ADC, BT-062, and IMGN901 currently in clinical trials, targeting varied antigens and bearing different linker and drugs, contribute to the learning curve of ADC, as do the discontinued ADC. Current challenges include improvement of the therapeutic index, linked to a careful selection of the targets, a better understanding of ADC mechanism of action, the management and understanding of ADC off-target toxicities, as well as the selection of appropriate clinical settings (patient selection, dosing regimen) where these molecules can bring highest clinical benefit.
生物疗法在癌症治疗中发挥着越来越重要的作用，尽管作为单一药物显示出临床疗效的裸抗体数量仍然有限。增强抗体治疗潜力的一种方法是将它们与小分子药物偶联。这种组合有望一方面带来高效药物的益处，另一方面带来特定肿瘤抗原的选择性结合剂的益处。然而，设计一个抗体药物偶联物（ADC）比简单的组装玩具游戏要复杂得多，需要在目标和特定癌症适应症的背景下，对抗体、连接子和药物进行深思熟虑的组合。从第一代抗体药物偶联物（ADC）中吸取的经验教训以及技术的改进指导了现在正在进行临床试验的改良化合物的设计。维布妥昔单抗（安适利（®）），一种与强效微管抑制剂偶联的抗CD30抗体，用于治疗霍奇金淋巴瘤和间变性大细胞淋巴瘤，是目前唯一上市的ADC。目前共有27种ADC正在血液系统恶性肿瘤和实体瘤适应症的临床试验中。其中，T-DM1（曲妥珠单抗-emtansine），一种由曲妥珠单抗通过不可裂解连接子与DM1偶联而成的ADC，在治疗HER2阳性难治性/复发性转移性乳腺癌的III期试验中显示出非常有前景的结果。其他目前正在临床试验中的化合物，如CMC-544、SAR3419、CDX-011、PSMA-ADC、BT-062和IMGN901，靶向不同抗原并带有不同的连接子和药物，与已停用的ADC一样，有助于ADC的经验积累。当前的挑战包括提高治疗指数，这与仔细选择靶点、更好地理解ADC的作用机制、管理和理解ADC的脱靶毒性以及选择合适的临床环境（患者选择、给药方案）有关，在这些临床环境中这些分子可以带来最大的临床益处。
