An anti-ErbB2 fully human antibody circumvents trastuzumab resistance

作者：Lu, Qiong; Wang, Lingfei; Zhang, Yajun; Yu, Xiaojie; Wang, Chao; Wang, Huajing; Yang, Yang; Chong, Xiaodan; Xia, Tian; Meng, Yanchun; Wang, Yuxiao; Lu, Cuihua^*; Zhou, Lijun^*; Li, Bohua^*

来源：Oncotarget, 2016, 7(41): 67129-67141.

DOI：10.18632/oncotarget.11562

• ErbB2
• programmed cell death
• trastuzumab resistance
• domain I- specific antibody
• breast cancer

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.

• 出版日期2016-10-11
• 单位中国人民解放军第二军医大学; 南通大学; 南开大学; 中国人民解放军海军总医院