title: A monoclonal antibody targeting ErbB2 domain III inhibits ErbB2 signaling and suppresses the growth of ErbB2-overexpressing breast tumors.
abstract: The anti-ErbB2 antibodies trastuzumab and pertuzumab in combination have recently been approved for the treatment of patients with ErbB2-positive metastatic breast cancer. Pertuzumab, which binds to ErbB2 near the center of domain II, and trastuzumab, which binds to the juxtamembrane region of ErbB2 domain IV, directly interfere with domain II- and domain IV-mediated heterodimerization contacts, respectively. In this study, we report a novel anti-ErbB2 antibody, 3E10, which binds to an epitope in domain III that appears to be located opposite to the dimerization interfaces in domain II and domain IV of ErbB2. Our data show that the 3E10 antibody inhibits ErbB2 heterodimerization via a mechanism that strikingly differs from trastuzumab and pertuzumab. It could be speculated that the 3E10 antibody may affect ErbB2 heterodimerization by causing major conformational changes of ErbB2. Furthermore, 3E10 provides synergistic inhibition of ErbB2 heterodimerization and signaling in combination with either trastuzumab or pertuzumab. The combination of these three anti-ErbB2 antibodies that have complementary mechanisms of action appears to be an extremely potent ErbB2 heterodimerization blocker. Compared with trastuzumab plus pertuzumab, the combination of trastuzumab, pertuzumab and 3E10 provides a more potent blockade of ErbB2 signaling. Consistent with this, trastuzumab plus pertuzumab plus 3E10 results in greater in vitro and in vivo antitumor activity in ErbB2-overexpressing breast tumor models, suggesting its potential use for treating ErbB2-overexpressing breast cancer.
authors.affiliation: School of Medicine, Nankai University, Tianjin, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Meng
authors.affiliation: International Joint Cancer Institute, the Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: L
authors.initials: L
authors.lastname: Zheng
authors.affiliation: International Joint Cancer Institute, the Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.affiliation: International Joint Cancer Institute, the Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Vascular Surgery, Changhai Hospital, Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: J
authors.initials: J
authors.lastname: Dong
authors.affiliation: International Joint Cancer Institute, the Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.affiliation: International Joint Cancer Institute, the Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: International Joint Cancer Institute, the Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: X
authors.initials: X
authors.lastname: Yu
authors.affiliation: International Joint Cancer Institute, the Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: International Joint Cancer Institute, the Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: T
authors.initials: T
authors.lastname: Xia
authors.affiliation: International Joint Cancer Institute, the Second Military Medical University, Shanghai, People's Republic of China.|State Key Laboratory of Antibody Medicine and Targeted Therapy, Shanghai, People's Republic of China.
authors.forename: D
authors.initials: D
authors.lastname: Zhang
authors.affiliation: School of Medicine, Nankai University, Tianjin, People's Republic of China.|State Key Laboratory of Antibody Medicine and Targeted Therapy, Shanghai, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Guo
authors.affiliation: International Joint Cancer Institute, the Second Military Medical University, Shanghai, People's Republic of China.|State Key Laboratory of Antibody Medicine and Targeted Therapy, Shanghai, People's Republic of China.
authors.forename: B
authors.initials: B
authors.lastname: Li