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Enhanced EGFR inhibition and distinct epitope recognition by EGFR antagonistic mAbs C225 and 425
Journal article   Open access   Peer reviewed

Enhanced EGFR inhibition and distinct epitope recognition by EGFR antagonistic mAbs C225 and 425

Vishal Kamat, Joshua M Donaldson, Csaba Kari, Marlene R D Quadros, Peter I Lelkes, Irwin Chaiken, Simon Cocklin, John C Williams, Elisabeth Papazoglou and Ulrich Rodeck
Cancer biology & therapy, v 7(5), pp 726-733
May 2008
DOI: https://doi.org/10.4161/cbt.7.5.6097
PMID: 18424917
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.4161/cbt.7.5.6097View
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Abstract

Epitope Mapping NIH 3T3 Cells ErbB Receptors - antagonists & inhibitors Antibodies, Monoclonal - pharmacology Humans Molecular Conformation Tyrphostins - pharmacology Dose-Response Relationship, Drug Antibodies, Monoclonal, Humanized Animals Cell Line, Tumor Epitopes - chemistry Mice Cetuximab Antibodies, Monoclonal - chemistry Drug Screening Assays, Antitumor
Monoclonal antibodies (mAbs) that inhibit activation of the epidermal growth factor receptor (EGFR) have shown therapeutic potential in select malignancies including breast cancer. Here, we describe that combined use of two such mAbs, C225 (Cetuximab) and 425 (EMD55900), reduced growth and survival of EGFR overexpressing MDA-MB-468 breast cancer cells more effectively than either antibody alone. Similarly, the C225/425 antibody combination more effectively inhibited AKT and MAPK phosphorylation in MDA-MB-468 cells. Surface plasmon resonance, size exclusion chromatography and analytical ultracentrifugation demonstrated that mAbs C225 and 425 simultaneously bind to distinct antigenic epitopes on domain III of the soluble wild-type EGFR. Furthermore, neither mAb competed with the other for binding to cells expressing either wild-type EGFR or a mutant EGFR (EGFRvIII) associated with neoplasia. Mutagenesis experiments revealed that residues S460/G461 in EGFR domain III are essential components of the 425 epitope and clearly distinguish it from the EGF/ TGFalpha binding site and the C225 interaction interface. Collectively, these results support the conclusion that therapeutic EGFR blockade in cancer patients by combined use of mAbs C225 and 425 could provide advantages over the use of the two antibodies as single agents.

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Collaboration types
Domestic collaboration
Web of Science research areas
Oncology
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