An anti-ErbB2 fully human antibody circumvents trastuzumab resistance

// Qiong Lu 1, * , Lingfei Wang 1, * , Yajun Zhang 1, * , Xiaojie Yu 1, * , Chao Wang 1 , Huajing Wang 1 , Yang Yang 1 , Xiaodan Chong 1 , Tian Xia 1 , Yanchun Meng 2 , Yuxiao Wang 4 , Cuihua Lu 3 , Lijun Zhou 4 , Bohua Li 1 1 International Joint Cancer Institute, The Second Military Medical University, Shanghai, People’s Republic of China 2 School of Medicine, Nankai University, Tianjin, People’s Republic of China 3 Department of Gastroenterology, The Affiliated Hospital of Nantong University, Nantong, Jiangsu, People’s Republic of China 4 Central Laboratory, Navy General Hospital, Beijing People’s Republic of China * These authors have contributed equally to this work Correspondence to: Bohua Li, email: bohuali1020@163.com Lijun Zhou, email: zhoulj63@163.com Cuihua Lu, email: lch670608@sina.com 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 ABSTRACT 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.