title: RETRACTED: Silencing EGFR/HER3 signaling with a novel anti-EGFR domain II/IV antibody.
abstract: Dysfunction of the epidermal growth factor receptor (EGFR) family, is the key process in tumorigenesis, and anti-EGFR therapeutic strategies such as cetuximab therapy now are used in the treatment of cancer. However, resistance to cetuximab is commonly reported. Comprehensive blockade of EGFR signaling using different antibodies might be critical to treat cancer effectively and limit drug resistance with potent novel mechanisms. Here, we launch a screen of a phage display library to isolate a novel anti-EGFR antibody, YAH627. YAH627 exhibits superior efficacy in inhibiting EGFR activation, particularly by blocking EGF/HRG-induced EGFR/HER3 heterodimerization and signaling, verifying it as an impressive candidate for clinical translation as a therapeutic antibody. Moreover, we use epitope analysis validates that the epitope of this antibody is within domains II and IV of EGFR and traps EGFR in a silent conformation. Moreover, combining YAH627 with cetuximab produces synergistic antitumor activity in vitro and in vivo. Taken together, our report establishes that YAH627 possesses a novel mechanism of action that, in combination with cetuximab, may achieve clinical efficacy in EGFR-driven cancers.
authors.affiliation: Translational Medicine Research InstituteInternational Joint Cancer InstituteThe Second Military Medical UniversityShanghai200433China; Cancer CenterPLA General HospitalPLA Postgraduate School of Medicine28 Fuxing RoadBeijing100853China; Asian-Pacific Biosignatures CenterTianjin Joint Academy of Biomedicine and TechnologyTianjin300457China. Electronic address: hus@aftertumor.com.
authors.forename: Shi
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of AnesthesiologyJinling HospitalSchool of MedicineNanjing UniversityNanjing210002China.
authors.forename: Haibin
authors.initials: H
authors.lastname: Dai
authors.affiliation: Translational Medicine Research InstituteInternational Joint Cancer InstituteThe Second Military Medical UniversityShanghai200433China; Asian-Pacific Biosignatures CenterTianjin Joint Academy of Biomedicine and TechnologyTianjin300457China.
authors.forename: Tiancheng
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Cancer CenterPLA General HospitalPLA Postgraduate School of Medicine28 Fuxing RoadBeijing100853China; Asian-Pacific Biosignatures CenterTianjin Joint Academy of Biomedicine and TechnologyTianjin300457China.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Fu
authors.affiliation: Asian-Pacific Biosignatures CenterTianjin Joint Academy of Biomedicine and TechnologyTianjin300457China.
authors.forename: Sandra D
authors.initials: SD
authors.lastname: Berezov
authors.affiliation: School of Life SciencesTianjin UniversityTianjin300072China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: Molecular Drug Discovery CenterXi'an Jinwa Pharmaceutical Co., LtdXi'anShaanxi710000China.
authors.forename: Daniel
authors.initials: D
authors.lastname: Jorissen
authors.affiliation: Molecular Drug Discovery CenterXi'an Jinwa Pharmaceutical Co., LtdXi'anShaanxi710000China.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Takeda
authors.affiliation: Translational Medicine Research InstituteInternational Joint Cancer InstituteThe Second Military Medical UniversityShanghai200433China; Asian-Pacific Biosignatures CenterTianjin Joint Academy of Biomedicine and TechnologyTianjin300457China; Molecular Drug Discovery CenterXi'an Jinwa Pharmaceutical Co., LtdXi'anShaanxi710000China. Electronic address: augus.bethune@aftertumor.com.
authors.forename: Augus N
authors.initials: AN
authors.lastname: Bethune
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D010766:Phosphorylation; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; C512478:EGFR protein, human; C581292:ERBB3 protein, human; D066246:ErbB Receptors; D020893:Receptor, ErbB-3
keywords: Cancer; Cetuximab resistance; EGFR; Epitope; Transmembrane signal transduction