ImmunoGen, Inc, 830 Winter Street, Waltham, MA 02451, USA.
Br J Clin Pharmacol. 2013 Aug;76(2):248-62. doi: 10.1111/bcp.12044.
Despite considerable effort, application of monoclonal antibody technology has had only modest success in improving treatment outcomes in patients with solid tumours. Enhancing the cancer cell-killing activity of antibodies through conjugation to highly potent cytotoxic 'payloads' to create antibody-drug conjuates (ADCs) offers a strategy for developing anti-cancer drugs of great promise. Early ADCs exhibited side-effect profiles similar to those of 'classical' chemotherapeutic agents and their performance in clinical trials in cancer patients was generally poor. However, the recent clinical development of ADCs that have highly potent tubulin-acting agents as their payloads have profoundly changed the outlook for ADC technology. Twenty-five such ADCs are in clinical development and one, brentuximab vedotin, was approved by the FDA in August, 2011, for the treatment of patients with Hodgkin's lymphoma and patients with anaplastic large cell lymphoma, based on a high rate of durable responses in single arm phase II clinical trials. More recently, a second ADC, trastuzumab emtansine, has shown excellent anti-tumour activity with the presentation of results of a 991-patient randomized phase III trial in patients with HER2-positive metastatic breast cancer. Treatment with this ADC (single agent) resulted in a significantly improved progression-free survival of 9.6 months compared with 6.4 months for lapatinib plus capecitabine in the comparator arm and significantly prolonged overall survival. Besides demonstrating excellent efficacy, these ADCs were remarkably well tolerated. Thus these, and other ADCs in development, promise to achieve the long sought goal of ADC technology, that is, of having compounds with high anti-tumour activity at doses where adverse effects are generally mild.
尽管付出了相当大的努力，但单克隆抗体技术在改善实体瘤患者的治疗效果方面仅取得了适度的成功。通过将高度有效的细胞毒性“有效载荷”与抗体缀合来增强抗体的癌细胞杀伤活性，从而创建抗体药物偶联物（ADC），为开发具有巨大潜力的抗癌药物提供了一种策略。早期的 ADC 表现出与“经典”化学治疗剂相似的副作用特征，并且它们在癌症患者中的临床试验表现通常较差。然而，最近具有高活性微管作用剂作为有效载荷的 ADC 的临床开发极大地改变了 ADC 技术的前景。目前有 25 种此类 ADC 正在临床开发中，一种 ADC，即 brentuximab vedotin，于 2011 年 8 月获得 FDA 批准，用于治疗霍奇金淋巴瘤和间变性大细胞淋巴瘤患者，这是基于单臂 II 期临床试验中高比例的持久缓解率。最近，第二种 ADC，trastuzumab emtansine，在 HER2 阳性转移性乳腺癌患者的 991 例随机 III 期试验中呈现出出色的抗肿瘤活性，结果令人瞩目。与比较组中 lapatinib 加卡培他滨相比，该 ADC（单药）治疗可使无进展生存期显著改善（9.6 个月），总生存期显著延长。这些 ADC 不仅显示出优异的疗效，而且耐受性也非常好。因此，这些以及其他正在开发中的 ADC 有望实现人们长期以来一直追求的 ADC 技术目标，即具有高抗肿瘤活性的化合物，在这些剂量下不良反应通常较轻。
