title: A bispecific anti-ErbB2 antibody potently induces ErbB2 internalization and suppresses ErbB2-overexpressing tumor growth.
abstract: The anti-ErbB2 humanized antibody trastuzumab was approved for ErbB2-positive metastatic gastric and gastro-esophageal junction cancer in 2010. Despite the effectiveness of trastuzumab, its efficacy remains variable and often modest. Thus, there is an urgent need to improve ErbB2-targeting therapy. Down-regulation of surface receptors induced by monoclonal antibody (mAb) contributes to its antitumor efficacy. Previous studies have demonstrated that if two anti-ErbB2 mAbs did not compete with each other for binding to ErbB2, the combination of them can enhance ErbB2 internalization. In the present study, we investigated ErbB2 internalization-inducing ability of non-competitive anti-ErbB2 mAb combinations and surprisingly found that most of the mAb combinations tested did not down-regulate ErbB2. Only 4 of 18 non-competitive mAb pairs efficiently induced ErbB2 internalization. Interestingly, although the non-competitive anti-ErbB2 mAbs trastuzumab and pertuzumab, either alone or in combination, were ineffective at inducing ErbB2 internalization, TPL, a bispecific antibody engineered from trastuzumab and pertuzumab, potently down-regulated the ErbB2 molecule. Importantly, TPL exhibited a far greater antitumor effect on ErbB2-overexpressing gastric cancer cell line than trastuzumab plus pertuzumab, suggesting that it may be a promising agent for the treatment of gastric cancer.
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, Shanghai, 200433, People's Republic of China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, Shanghai, 200433, People's Republic of China.
authors.forename: Lingfei
authors.initials: L
authors.lastname: Wang
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, Shanghai, 200433, People's Republic of China.
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Chong
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, Shanghai, 200433, People's Republic of China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Yu
authors.affiliation: School of Medicine, Nankai University, Tianjin, 300071, People's Republic of China.
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Meng
authors.affiliation: Department of Vascular Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Dong
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, Shanghai, 200433, People's Republic of China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, Shanghai, 200433, People's Republic of China.
authors.forename: Huajing
authors.initials: H
authors.lastname: Wang
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, Shanghai, 200433, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, Shanghai, 200433, People's Republic of China.
authors.forename: Tian
authors.initials: T
authors.lastname: Xia
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, Shanghai, 200433, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, Shanghai, 200433, People's Republic of China. Electronic address: bohuali1020@163.com.
authors.forename: Bohua
authors.initials: B
authors.lastname: Li
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D013347:Subcellular Fractions / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents
keywords: Bispecific antibody; Down-regulation; ErbB2; Gastric cancer; Monoclonal antibody