Targeting HER2-Positive Breast Cancer with Trastuzumab-DM1, an Antibody-Cytotoxic Drug Conjugate
Targeting HER2-Positive Breast Cancer with Trastuzumab-DM1, an Antibody-Cytotoxic Drug Conjugate
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DOI：
10.1158/0008-5472.can-08-1776
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发表时间：
2008-11-15
期刊：
影响因子：
11.2
通讯作者：
Sliwkowski, Mark X.
中科院分区：
文献类型：
--
作者：
Phillips, Gail D. Lewis;Li, Guangmin;Sliwkowski, Mark X.
HER 2是乳腺癌治疗中经过验证的靶点。目前有两种药物被批准用于HER 2阳性乳腺癌：曲妥珠单抗（赫赛汀），1998年推出，拉帕替尼（Tykerb），2007年。尽管取得了这些进展，但有些患者在治疗过程中仍会出现进展并死于疾病。抗体靶向治疗的一种变化是利用抗体将细胞毒性剂特异性递送至表达抗原的肿瘤。我们使用二硫化物和硫醚接头测定了曲妥珠单抗-美登木素生物碱（微管解聚剂）偶联物的体外和体内疗效、药代动力学和毒性。在培养的正常和肿瘤细胞上评价曲妥珠单抗-美登木素生物碱缀合物的抗增殖作用。在小鼠乳腺癌模型中测定了体内活性，并通过体重减轻评估了大鼠的毒性。令人惊讶的是，与未缀合的曲妥珠单抗或通过二硫化物接头与其他美登木素生物碱连接的曲妥珠单抗相比，通过不可还原的硫醚键（SMCC）与DM 1连接的曲妥珠单抗显示出上级活性。与其他偶联物相比，曲妥珠单抗-MCC-DM 1的血清浓度仍然升高，与游离DM 1或通过可还原接头与DM 1连接的曲妥珠单抗相比，大鼠中的毒性可忽略不计。在所有HER 2过表达肿瘤细胞上观察到有效活性，而具有正常HER 2表达的非转化细胞和肿瘤细胞系不受影响。此外，曲妥珠单抗-DM 1对HER 2过表达、曲妥珠单抗难治性肿瘤具有活性。总之，与非结合曲妥珠单抗相比，曲妥珠单抗-DM 1显示出更大的活性，同时保持对HER 2过表达肿瘤细胞的选择性。由于曲妥珠单抗通过不可还原接头与DM 1连接，与评价的可还原二硫化物接头相比，可改善疗效和药代动力学并降低毒性，因此选择曲妥珠单抗-MCC-DM 1进行临床开发。[Cancer Res 2008;68（22）：9280-90]
HER2 is a validated target in breast cancer therapy. Two drugs are currently approved for HER2-positive breast cancer: trastuzumab (Herceptin), introduced in 1998, and lapatinib (Tykerb), in 2007. Despite these advances, some patients progress through therapy and succumb to their disease. A variation on antibody-targeted therapy is utilization of antibodies to deliver cytotoxic agents specifically to antigen-expressing tumors. We determined in vitro and in vivo efficacy, pharmacokinetics, and toxicity of trastuzumab-maytansinoid (microtubule-depolymerizing agents) conjugates using disulfide and thioether linkers. Antiproliferative effects of trastuzumab-maytansinoid conjugates were evaluated on cultured normal and tumor cells. In vivo activity was determined in mouse breast cancer models, and toxicity was assessed in rats as measured by body weight loss. Surprisingly, trastuzumab linked to DM1 through a nonreducible thioether linkage (SMCC), displayed superior activity compared with unconjugated trastuzumab or trastuzumab linked to other maytansinoids through disulfide linkers. Serum concentrations of trastuzumab-MCC-DM1 remained elevated compared with other conjugates, and toxicity in rats was negligible compared with free DM1 or trastuzumab linked to DM1 through a reducible linker. Potent activity was observed on all HER2-overexpressing tumor cells, whereas nontransformed cells and tumor cell lines with normal HER2 expression were unaffected. In addition, trastuzuman-DM1 was active on HER2-overexpressing, trastuzumab-refractory tumors. In summary, trastuzumab-DM1 shows greater activity compared with nonconjugated trastuzumab while maintaining selectivity for HER2-overexpressing tumor cells. Because trastuzumab linked to DM1 through a nonreducible linker offers improved efficacy and pharmacokinetics and reduced toxicity over the reducible disulfide linkers evaluated, trastuzumab-MCC-DM1 was selected for clinical development. [Cancer Res 2008;68(22):9280-90]