title: 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: Section for Stem Cell Transplantation and Immunotherapy, Department of Internal Medicine II, University Hospital Schleswig-Holstein and Christian-Albrechts-University, Kiel, Germany.
authors: Katja
authors: K
authors: Klausz
authors: Sven
authors: S
authors: Berger
authors: Jeroen J
authors: JJ
authors: Lammerts van Bueren
authors: Stefanie
authors: S
authors: Derer
authors: Stefan
authors: S
authors: Lohse
authors: Michael
authors: M
authors: Dechant
authors: Jan G J
authors: JG
authors: van de Winkel
authors: Matthias
authors: M
authors: Peipp
authors: Paul W H I
authors: PW
authors: Parren
authors: Thomas
authors: T
authors: Valerius
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity; D016466:CHO Cells; D045744:Cell Line, Tumor; D003165:Complement System Proteins / Q000276:immunology*; D006224:Cricetinae; D003602:Cytotoxicity, Immunologic; D018604:Epitope Mapping; D066246:ErbB Receptors / Q000276:immunology* / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D009504:Neutrophils / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C410723:epidermal growth factor receptor VIII; D003165:Complement System Proteins; C546618:zalutumumab; D066246:ErbB Receptors