An anti-ErbB2 fully human antibody circumvents trastuzumab resistance
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Qiong Lu1,*, Lingfei Wang1,*, Yajun Zhang1,*, Xiaojie Yu1,*, Chao Wang1, Huajing Wang1, Yang Yang1, Xiaodan Chong1, Tian Xia1, Yanchun Meng2, Yuxiao Wang4, Cuihua Lu3, Lijun Zhou4, Bohua Li1
1International Joint Cancer Institute, The Second Military Medical University, Shanghai, People’s Republic of China
2School of Medicine, Nankai University, Tianjin, People’s Republic of China
3Department of Gastroenterology, The Affiliated Hospital of Nantong University, Nantong, Jiangsu, People’s Republic of China
4Central Laboratory, Navy General Hospital, Beijing People’s Republic of China
*These authors have contributed equally to this work
Bohua Li, email: [email protected]
Lijun Zhou, email: [email protected]
Cuihua Lu, email: [email protected]
Keywords: ErbB2, programmed cell death, trastuzumab resistance, domain I- specific antibody, breast cancer
Received: May 09, 2016 Accepted: August 11, 2016 Published: August 24, 2016
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.
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