title: An anti-ErbB2 fully human antibody circumvents trastuzumab resistance.
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.
authors: International Joint Cancer Institute, The Second Military Medical University, Shanghai, People's Republic of China.
authors: Qiong
authors: Q
authors: Lu
authors: International Joint Cancer Institute, The Second Military Medical University, Shanghai, People's Republic of China.
authors: Lingfei
authors: L
authors: Wang
authors: International Joint Cancer Institute, The Second Military Medical University, Shanghai, People's Republic of China.
authors: Yajun
authors: Y
authors: Zhang
authors: International Joint Cancer Institute, The Second Military Medical University, Shanghai, People's Republic of China.
authors: Xiaojie
authors: X
authors: Yu
authors: International Joint Cancer Institute, The Second Military Medical University, Shanghai, People's Republic of China.
authors: Chao
authors: C
authors: Wang
authors: International Joint Cancer Institute, The Second Military Medical University, Shanghai, People's Republic of China.
authors: Huajing
authors: H
authors: Wang
authors: International Joint Cancer Institute, The Second Military Medical University, Shanghai, People's Republic of China.
authors: Yang
authors: Y
authors: Yang
authors: International Joint Cancer Institute, The Second Military Medical University, Shanghai, People's Republic of China.
authors: Xiaodan
authors: X
authors: Chong
authors: International Joint Cancer Institute, The Second Military Medical University, Shanghai, People's Republic of China.
authors: Tian
authors: T
authors: Xia
authors: School of Medicine, Nankai University, Tianjin, People's Republic of China.
authors: Yanchun
authors: Y
authors: Meng
authors: Central Laboratory, Navy General Hospital, Beijing People's Republic of China.
authors: Yuxiao
authors: Y
authors: Wang
authors: Department of Gastroenterology, The Affiliated Hospital of Nantong University, Nantong, Jiangsu, People's Republic of China.
authors: Cuihua
authors: C
authors: Lu
authors: Central Laboratory, Navy General Hospital, Beijing People's Republic of China.
authors: Lijun
authors: L
authors: Zhou
authors: International Joint Cancer Institute, The Second Military Medical University, Shanghai, People's Republic of China.
authors: Bohua
authors: B
authors: Li
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: ErbB2; breast cancer; programmed cell death; trastuzumab resistance; domain I-specific antibody