Complement‐mediated tumor‐specific cell lysis by antibody combinations targeting epidermal growth factor receptor (EGFR) and its variant III (EGFRvIII)

Monoclonal antibodies (mAb) against variant III of epidermal growth factor receptor (EGFRvIII) hold promise for improving tumor selectivity of EGFR‐targeted therapy. Here, we compared Fc‐mediated effector functions of three mAb against EGFRvIII (MR1‐1, ch806, 13.1.2) with those of zalutumumab, a hig...

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Published in:Cancer science 2011-10, Vol.102 (10), p.1761-1768
Main Authors: Klausz, Katja, Berger, Sven, Lammerts van Bueren, Jeroen J., Derer, Stefanie, Lohse, Stefan, Dechant, Michael, van de Winkel, Jan G. J., Peipp, Matthias, Parren, Paul W. H. I., Valerius, Thomas
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal - immunology
Antibodies, Monoclonal - metabolism
Antibody-Dependent Cell Cytotoxicity
Biological and medical sciences
Cell Line, Tumor
CHO Cells
Complement System Proteins - immunology
Cricetinae
Cytotoxicity, Immunologic
Epitope Mapping
HEK293 Cells
Humans
Medical sciences
Neutrophils - immunology
Receptor, Epidermal Growth Factor - immunology
Receptor, Epidermal Growth Factor - metabolism
Tumors
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Summary:Monoclonal antibodies (mAb) against variant III of epidermal growth factor receptor (EGFRvIII) hold promise for improving tumor selectivity of EGFR‐targeted therapy. Here, we compared Fc‐mediated effector functions of three mAb against EGFRvIII (MR1‐1, ch806, 13.1.2) with those of zalutumumab, a high affinity EGFR mAb in advanced clinical trials. MR1‐1 and ch806 demonstrated preferential and 13.1.2 exclusive binding to EGFRvIII, in contrast to zalutumumab, which bound both wild‐type and EGFRvIII. All four human IgG1κ mAb mediated antibody‐dependent cellular cytotoxicity (ADCC) of EGFRvIII‐expressing cells with mononuclear cells and isolated monocytes, while only zalutumumab in addition triggered ADCC by polymorphonuclear cells. Interestingly, combinations of zalutumumab and EGFRvIII mAb specifically mediated complement‐dependent cytotoxicity (CDC) of EGFRvIII‐transfected but not wild‐type cells. Moreover, EGFRvIII‐specific CDC was significantly enhanced when zalutumumab was combined with a Fc‐engineered variant of MR1‐1 (K326A/E333A). These observations confirm the immunotherapeutic potential of antibody combinations against EGFR, and demonstrate that tumor selectivity can be improved by combining therapeutic EGFR mAb with an antibody against EGFRvIII. (Cancer Sci 2011; 102: 1761–1768)
ISSN:1347-9032
1349-7006
DOI:10.1111/j.1349-7006.2011.02019.x