title: Preclinical efficacy of Sym004, novel anti-EGFR antibody mixture, in esophageal squamous cell carcinoma cell lines.
abstract: Epidermal growth factor receptor (EGFR) is a well-validated oncological target molecule for monoclonal antibody therapies and Sym004 is a novel anti-EGFR antibody mixture comprising two recombinant chimeric IgG1 antibodies against non-overlapping epitopes of EGFR. Because EGFR is highly expressed in the majority of esophageal squamous cell carcinomas (ESCCs), we investigated the efficacy of Sym004 in human ESCC cell lines. Forty eight ESCC cell lines were treated with three kinds of anti-EGFR antibodies (Sym004, cetuximab, and panitumumab). Genetic background was investigated by next generation sequencing. The internalization of anti-EGFR antibodies into ESCC cells and inhibition of the EGFR signaling cascade by anti-EGFR antibodies were investigated in vitro. Furthermore, growth inhibition by anti-EGFR antibody treatment was investigated in vitro and in vivo. Sym004 treatments were more effective at inducing EGFR internalization and degradation than the two other anti-EGFR antibodies. Sym004 was more sensitive significantly to cell lines with EGFR gene amplification than those without amplification (P = 0.002). Growth inhibition of Sym004 was greater than in that of cetuximab or panitumumab in vitro and in vivo. These studies showed that Sym004 exhibited antitumor activity in some ESCC cell lines in preclinical settings and warrant a clinical evaluation in patients with ESCC. EGFR amplification is a potential biomarker of response to Sym004.
authors.affiliation: Division of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.|Advanced Clinical Research of Cancer, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Fukuoka
authors.affiliation: Division of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kojima
authors.affiliation: Division of Developmental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Yoshikatsu
authors.initials: Y
authors.lastname: Koga
authors.affiliation: Division of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Yamauchi
authors.affiliation: Department of Translational Oncology, Fundamental Innovative Oncology Core Center, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Department of Translational Oncology, Fundamental Innovative Oncology Core Center, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Komatsuzaki
authors.affiliation: Department of Translational Oncology, Fundamental Innovative Oncology Core Center, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sasaki
authors.affiliation: Division of Developmental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yasunaga
authors.affiliation: Division of Developmental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsumura
authors.affiliation: Division of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Doi
authors.affiliation: Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.|Advanced Clinical Research of Cancer, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsu
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D000068818:Cetuximab / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005784:Gene Amplification; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D000077544:Panitumumab; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000077544:Panitumumab; C569270:futuximab; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab
keywords: Sym004; epidermal growth factor receptor; esophageal squamous cell carcinoma