Lewis Phillips Gail D, Li Guangmin, Dugger Debra L, Crocker Lisa M, Parsons Kathryn L, Mai Elaine, Blättler Walter A, Lambert John M, Chari Ravi V J, Lutz Robert J, Wong Wai Lee T, Jacobson Frederic S, Koeppen Hartmut, Schwall Ralph H, Kenkare-Mitra Sara R, Spencer Susan D, Sliwkowski Mark X
Genentech, Inc., South San Francisco, California 94080, USA.
Cancer Res. 2008 Nov 15;68(22):9280-90. doi: 10.1158/0008-5472.CAN-08-1776.
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, trastuzumab-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.
HER2是乳腺癌治疗中已得到验证的靶点。目前有两种药物被批准用于HER2阳性乳腺癌的治疗：1998年推出的曲妥珠单抗（赫赛汀）和2007年推出的拉帕替尼（泰立沙）。尽管有这些进展，但仍有一些患者在治疗过程中病情进展并最终死于该疾病。抗体靶向治疗的一种变体是利用抗体将细胞毒性药物特异性地递送至表达抗原的肿瘤。我们使用二硫键和硫醚接头，测定了曲妥珠单抗-美登素（微管解聚剂）缀合物的体外和体内疗效、药代动力学及毒性。评估了曲妥珠单抗-美登素缀合物对培养的正常细胞和肿瘤细胞的抗增殖作用。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，通过不可还原的硫醚接头（SMCC）与DM1连接的曲妥珠单抗，与未缀合的曲妥珠单抗或通过二硫键接头与其他美登素连接的曲妥珠单抗相比，显示出更高的活性。与其他缀合物相比，曲妥珠单抗-MCC-DM1的血清浓度保持升高，并且与游离DM1或通过可还原接头与DM1连接的曲妥珠单抗相比，大鼠的毒性可忽略不计。在所有HER2过表达的肿瘤细胞上均观察到强效活性，而未转化的细胞和HER2表达正常的肿瘤细胞系未受影响。此外，曲妥珠单抗-DM1对HER2过表达、曲妥珠单抗难治性肿瘤具有活性。总之，与未缀合的曲妥珠单抗相比，曲妥珠单抗-DM1显示出更高的活性，同时对HER2过表达的肿瘤细胞保持选择性。由于通过不可还原接头与DM1连接的曲妥珠单抗与所评估的可还原二硫键接头相比，疗效和药代动力学得到改善且毒性降低，因此选择曲妥珠单抗-MCC-DM1进行临床开发。
