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

Abstract

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.

• Authors: Katja Klausz, Sven Berger, Jeroen J Lammerts van Bueren, Stefanie Derer, Stefan Lohse, Michael Dechant, Jan G J van de Winkel, Matthias Peipp, Paul W H I Parren, Thomas Valerius
• Journal: Cancer science (Cancer Sci) Vol. 102 Issue 10 Pg. 1761-8 (Oct 2011) ISSN: 1349-7006 [Electronic] England
• PMID: 21718386 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 Japanese Cancer Association.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• epidermal growth factor receptor VIII
• Complement System Proteins
• zalutumumab
• ErbB Receptors

Topics

• Animals
• Antibodies, Monoclonal (immunology, metabolism)
• Antibodies, Monoclonal, Humanized
• Antibody-Dependent Cell Cytotoxicity
• CHO Cells
• Cell Line, Tumor
• Complement System Proteins (immunology)
• Cricetinae
• Cytotoxicity, Immunologic
• Epitope Mapping
• ErbB Receptors (immunology, metabolism)
• HEK293 Cells
• Humans
• Neutrophils (immunology)