ImmunoGen, Inc. , 830 Winter Street, Waltham, Massachusetts 02451, United States.
J Med Chem. 2014 Aug 28;57(16):6949-64. doi: 10.1021/jm500766w. Epub 2014 Jul 10.
Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that combines the antitumor properties of the humanized anti-human epidermal growth factor receptor 2 (HER2) antibody, trastuzumab, with the maytansinoid, DM1, a potent microtubule-disrupting agent, joined by a stable linker. Upon binding to HER2, the conjugate is internalized via receptor-mediated endocytosis, and an active derivative of DM1 is subsequently released by proteolytic degradation of the antibody moiety within the lysosome. Initial clinical evaluation led to a phase III trial in advanced HER2-positive breast cancer patients who had relapsed after prior treatment with trastuzumab and a taxane, which showed that T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine. In 2013, T-DM1 received FDA approval for the treatment of patients with HER2-positive metastatic breast cancer who had previously received trastuzumab and a taxane, separately or in combination, the first ADC to receive full approval based on a randomized study.
曲妥珠单抗-美坦新偶联物（T-DM1）是一种抗体-药物偶联物，它将人源化抗人表皮生长因子受体 2（HER2）抗体曲妥珠单抗的抗肿瘤特性与美登素衍生物 DM1 相结合，DM1 是一种有效的微管破坏剂，通过稳定的连接子连接。与 HER2 结合后，该偶联物通过受体介导的内吞作用被内化，并且抗体部分在溶酶体中通过蛋白水解降解后，随后释放出 DM1 的活性衍生物。初步临床评估导致了一项 III 期临床试验，该试验入组了先前接受曲妥珠单抗和紫杉烷治疗后复发的晚期 HER2 阳性乳腺癌患者，结果表明 T-DM1 显著延长了无进展生存期和总生存期，且毒性低于拉帕替尼加卡培他滨。2013 年，T-DM1 获得 FDA 批准，用于治疗先前接受过曲妥珠单抗和紫杉烷（单独或联合使用）治疗的 HER2 阳性转移性乳腺癌患者，这是第一个基于随机研究获得完全批准的 ADC。
