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.