title: Bispecific antibody to ErbB2 overcomes trastuzumab resistance through comprehensive blockade of ErbB2 heterodimerization.
abstract: The anti-ErbB2 antibody trastuzumab has shown significant clinical benefits in metastatic breast cancer. However, resistance to trastuzumab is common. Heterodimerization between ErbB2 and other ErbBs may redundantly trigger cell proliferation signals and confer trastuzumab resistance. Here, we developed a bispecific anti-ErbB2 antibody using trastuzumab and pertuzumab, another ErbB2-specific humanized antibody that binds to a distinct epitope from trastuzumab. This bispecific antibody, denoted as TPL, retained the full binding activities of both parental antibodies and exhibited pharmacokinetic properties similar to those of a conventional immunoglobulin G molecule. Unexpectedly, TPL showed superior ErbB2 heterodimerization-blocking activity over the combination of both parental monoclonal antibodies, possibly through steric hindrance and/or inducing ErbB2 conformational change. Further data indicated that TPL potently abrogated ErbB2 signaling in trastuzumab-resistant breast cancer cell lines. In addition, we showed that TPL was far more effective than trastuzumab plus pertuzumab in inhibiting the growth of trastuzumab-resistant breast cancer cell lines, both in vitro and in vivo. Importantly, TPL treatment eradicated established trastuzumab-resistant tumors in tumor-bearing nude mice. Our results suggest that trastuzumab-resistant breast tumors remain dependent on ErbB2 signaling and that comprehensive blockade of ErbB2 heterodimerization may be an effective therapeutic avenue. The unique potential of TPL to overcome trastuzumab resistance warrants its consideration as a promising treatment in the clinic.
authors.affiliation: Authors' Affiliations: International Joint Cancer Institute, the Second Military Medical University; National Engineering Research Center for Antibody Medicine; State Key Laboratory of Antibody Medicine and Targeted Therapy; School of Medicine, Shanghai Jiao Tong University, Shanghai; and PLA General Hospital Cancer Center, PLA Postgraduate Medical School, Beijing, People's Republic of China.
authors.forename: Bohua
authors.initials: B
authors.lastname: Li
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Meng
authors.forename: Lei
authors.initials: L
authors.lastname: Zheng
authors.forename: Xunmin
authors.initials: X
authors.lastname: Zhang
authors.forename: Qing
authors.initials: Q
authors.lastname: Tong
authors.forename: Wenlong
authors.initials: W
authors.lastname: Tan
authors.forename: Shi
authors.initials: S
authors.lastname: Hu
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Yang
authors.initials: Y
authors.lastname: Chen
authors.forename: Jinjing
authors.initials: J
authors.lastname: Song
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.forename: Dapeng
authors.initials: D
authors.lastname: Zhang
authors.forename: Sheng
authors.initials: S
authors.lastname: Hou
authors.forename: Weizhu
authors.initials: W
authors.lastname: Qian
authors.forename: Yajun
authors.initials: Y
authors.lastname: Guo
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D055503:Protein Multimerization / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
chemical_list: D018033:Antibodies, Bispecific; D061067:Antibodies, Monoclonal, Humanized; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C485206:pertuzumab