An anti-ErbB2 fully human antibody circumvents trastuzumab resistance.
An anti-ErbB2 fully human antibody circumvents trastuzumab resistance.
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抗 ErbB2 全人源抗体可规避曲妥珠单抗耐药性
DOI：
10.18632/oncotarget.11562
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发表时间：
2016-10-11
期刊：
影响因子：
--
通讯作者：
Li B
中科院分区：
文献类型：
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作者：
Lu Q;Wang L;Zhang Y;Yu X;Wang C;Wang H;Yang Y;Chong X;Xia T;Meng Y;Wang Y;Lu C;Zhou L;Li B
曲妥珠单抗是一种抗HER 2/ErbB 2人源化抗体，在ErbB 2阳性乳腺癌治疗中显示出巨大的临床益处。尽管其有效性，曲妥珠单抗的反应率是有限的，耐药是常见的。本研究从噬菌体抗体库中筛选出一株新的抗ErbB 2抗体，命名为H2-18。先前的研究已经证明曲妥珠单抗识别结构域IV的质膜区域，而另一种人源化ErbB 2特异性抗体帕妥珠单抗结合结构域II中心附近的ErbB 2。我们的晶体学分析表明，H2-18识别的表位在ErbB 2分子的结构域I内。H2-18在曲妥珠单抗敏感和耐药乳腺癌细胞系中均有效诱导程序性细胞死亡（PCD），而曲妥珠单抗和帕妥珠单抗单独或联合使用时仅表现出非常弱的PCD诱导活性。更重要的是，H2-18在体外和体内抑制曲妥珠单抗耐药乳腺癌细胞的生长比曲妥珠单抗加帕妥珠单抗更有效。总之，H2-18显示出克服曲妥珠单抗耐药性的独特能力，这表明它具有很大的潜力被转化为临床。
Trastuzumab, an anti-HER2/ErbB2 humanized antibody, has shown great clinical benefits in ErbB2-positive breast cancer treatment. Despite of its effectiveness, response rate to trastuzumab is limited and resistance is common. Here, we developed a new anti-ErbB2 antibody, denoted as H2-18, which was isolated from a phage display human antibody library. Previous studies have demonstrated that trastuzumab recognizes the juxtamembrane region of domain IV, and pertuzumab, another humanized ErbB2-specific antibody, binds to ErbB2 near the center of domain II. Our crystallographic analysis showed that the epitope recognized by H2-18 is within domain I of the ErbB2 molecule. H2-18 potently induced programmed cell death (PCD) in both trastuzumab-sensitive and -resistant breast cancer cell lines, while trastuzumab and pertuzumab, either used alone or in combination, only exhibits very weak PCD-inducing activity. More importantly, H2-18 could inhibit the growth of trastuzumab-resistant breast cancer cells far more effectively than trastuzumab plus pertuzumab, both in vitro and in vivo. In conclusion, H2-18 shows a unique ability to overcome trastuzumab resistance, suggesting that it has the great potential to be translated to the clinic.