Ado-trastuzumab Emtansine (T-DM1): An Antibody-Drug Conjugate (ADC) for HER2-Positive Breast Cancer
Ado-trastuzumab Emtansine (T-DM1): An Antibody-Drug Conjugate (ADC) for HER2-Positive Breast Cancer
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DOI：
10.1021/jm500766w
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发表时间：
2014-08-28
影响因子：
7.3
通讯作者：
Chari, Ravi V. J.
中科院分区：
文献类型：
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作者：
Lambert, John M.;Chari, Ravi V. J.
曲妥珠单抗-美坦新偶联物（T-DM 1）是一种抗体药物偶联物，它结合了人源化抗人表皮生长因子受体2（HER 2）抗体曲妥珠单抗的抗肿瘤特性和美登木素生物碱DM 1（一种强效微管破坏剂），并通过稳定的接头连接。在与HER 2结合后，缀合物通过受体介导的内吞作用内化，随后通过溶酶体内抗体部分的蛋白水解降解释放DM 1的活性衍生物。最初的临床评价导致在既往接受曲妥珠单抗和紫杉烷治疗后复发的晚期HER 2阳性乳腺癌患者中进行III期试验，结果显示T-DM 1显著延长了无进展生存期和总生存期，毒性低于拉帕替尼加卡培他滨。2013年，T-DM 1获得FDA批准用于治疗既往单独或联合接受曲妥珠单抗和紫杉烷的HER 2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。
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 HI 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.