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Research Paper
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
volume 7 | issue 5
May 2008Pages: 726 - 733
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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/ TGF-α 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.
Authors
Vishal Kamat
School of Biomedical Engineering, Science & Health Systems, Drexel University, Philadelphia, PA
Joshua M. Donaldson
Department of Biochemistry and Molecular Biology Thomas Jefferson University, Philadelphia, PA
Csaba Kari
Department of Dermatology & Cutaneous Biology Thomas Jefferson University, Philadelphia, PA
Marlene R.D. Quadros
Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, PA
Peter I. Lelkes
School of Biomedical Engineering, Science & Health Systems, Drexel University, Philadelphia, PA;
Irwin Chaiken
Department of Biochemistry, Drexel University, Philadelphia, PA
Simon Cocklin
Department of Biochemistry, Drexel University, Philadelphia, PA
John C. Williams
Department of Biochemistry and Molecular Biology Thomas Jefferson University, Philadelphia, PA
Elisabeth Papazoglou
School of Biomedical Engineering, Science & Health Systems, Drexel University, Philadelphia, PA
Ulrich Rodeck
Department of Dermatology & Cutaneous Biology Thomas Jefferson University, Philadelphia, PA