Increasing FcaγRIIa affinity of an FcaγRIII-optimized anti-EGFR antibody restores neutrophil-mediated cytotoxicity

Stefanie Derer, Pia Glorius, Martin Schlaeth, Stefan Lohse, Katja Klausz, Umesh Muchhal, John R. Desjarlais, Andreas Humpe, Thomas Valerius, Matthias Peipp*

*Corresponding author for this work
27 Citations (Scopus)


Antibody-dependent cell-mediated cytotoxicity (ADCC) has been suggested as an essential mechanism for the in vivo activity of cetuximab, an epidermal growth factor receptor (EGFR)-targeting therapeutic antibody. Thus, enhancing the affinity of human IgG1 antibodies to natural killer (NK) cell-expressed Fcγ RIIIa by glyco- or protein-engineering of their Fc portion has been demonstrated to improve NK cell-mediated ADCC and to represent a promising strategy to improve antibody therapy. However, human polymorphonuclear (PMN) effector cells express the highly homologous FcγRIIIb isoform, which is described to be ineffective in triggering ADCC. Here, non-fucosylated or protein-engineered anti-EGFR antibodies with optimized FcγRIIIa affinities demonstrated the expected benefit in NK cell-mediated ADCC, but did not mediate ADCC by PMN, which could be restored by FcaγRIIIb blockade. Furthermore, eosinophils and PMN from paroxysmal nocturnal hemoglobinuria patients that expressed no or low levels of FcγRIIIb mediated effective ADCC with FcγRIII-optimized anti-EGFR antibody. Additional experiments with double FcγRIIa/FcγRIII-optimized constructs demonstrated enhanced PMN-mediated ADCC compared with single FcγRIII-optimized antibody. In conclusion, our data demonstrate that FcγRIIIb engagement impairs PMN-mediated ADCC activity of FcγRIII-optimized anti-EGFR antibodies, while further optimization of FcγRIIa binding significantly restores PMN recruitment.

Original languageEnglish
Issue number2
Pages (from-to)409-421
Number of pages13
Publication statusPublished - 2014

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)


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