title: A dual-targeting antibody against EGFR-VEGF for lung and head and neck cancer treatment.
abstract: An antibody simultaneously targeting epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), two major tumor growth-driving machineries, may provide a novel effective strategy for optimizing tumor targeting and maximizing potential clinical benefits. Human domain antibodies selected against VEGF and EGFR were formatted into a fully human dual-targeting IgG (DT-IgG) to directly target both antigens in a single molecule. We evaluated the efficacy of DT-IgG in comparison with bevacizumab and cetuximab alone and in combination in the lung cancer cell line A549 (low EGFR expression and KRAS mutant) and the head and neck squamous cell carcinoma (HNSCC) cell line Tu212 (high EGFR expression and KRAS wild type) in vitro and in vivo. DT-IgG suppressed Tu212 and A549 cell growth, inhibited EGFR activation and induced apoptosis as effectively as cetuximab, and neutralized VEGF as effectively as bevacizumab. DT-IgG induced EGFR-dependent VEGF internalization, constituting a novel antiangiogenesis mechanism. In xenograft models with lung and head and neck cancer cell lines, DT-IgG displayed efficacy equivalent to bevacizumab in diminishing tumor growth despite its short serum half-life (36 hr in rats) and both agents may constitute preferable alternatives to cetuximab in KRAS-mutant tumors. Immunofluorescence staining revealed that localization of DT-IgG was similar to that of cetuximab, largely associated with EGFR+tumor cells. Our proof of principle study suggests a DT-IgG against EGFR and VEGF as an alternative therapeutic strategy with potentially enhanced clinical benefit.
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Hongzheng
authors.initials: H
authors.lastname: Zhang
authors.forename: Sujin
authors.initials: S
authors.lastname: Yun
authors.forename: Thil D
authors.initials: TD
authors.lastname: Batuwangala
authors.forename: Michael
authors.initials: M
authors.lastname: Steward
authors.forename: Steve D
authors.initials: SD
authors.lastname: Holmes
authors.forename: Lin
authors.initials: L
authors.lastname: Pan
authors.forename: Mourad
authors.initials: M
authors.lastname: Tighiouart
authors.forename: Hyung Ju C
authors.initials: HJ
authors.lastname: Shin
authors.forename: Lydia
authors.initials: L
authors.lastname: Koenig
authors.forename: Wungki
authors.initials: W
authors.lastname: Park
authors.forename: Daniel
authors.initials: D
authors.lastname: Rycroft
authors.forename: Sreenivas
authors.initials: S
authors.lastname: Nannapaneni
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Wang
authors.forename: Zhuo Georgia
authors.initials: ZG
authors.lastname: Chen
authors.forename: Dong M
authors.initials: DM
authors.lastname: Shin
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000627:therapeutic use; D017209:Apoptosis; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000068818:Cetuximab; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000276:immunology*; D005434:Flow Cytometry; D006258:Head and Neck Neoplasms / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000473:pathology / Q000628:therapy*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D066246:ErbB Receptors; D000068818:Cetuximab