Increasing Fc?RIIa affinity of an Fc?RIII-optimized anti-EGFR antibody restores neutrophil-mediated cytotoxicity.

ABSTRACT: 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 Fc?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 Fc?RIIIb isoform, which is described to be ineffective in triggering ADCC. Here, non-fucosylated or protein-engineered anti-EGFR antibodies with optimized Fc?RIIIa affinities demonstrated the expected benefit in NK cell-mediated ADCC, but did not mediate ADCC by PMN, which could be restored by Fc?RIIIb blockade. Furthermore, eosinophils and PMN from paroxysmal nocturnal hemoglobinuria patients that expressed no or low levels of Fc?RIIIb mediated effective ADCC with Fc?RIII-optimized anti-EGFR antibody. Additional experiments with double Fc?RIIa/Fc?RIII-optimized constructs demonstrated enhanced PMN-mediated ADCC compared with single Fc?RIII-optimized antibody. In conclusion, our data demonstrate that Fc?RIIIb engagement impairs PMN-mediated ADCC activity of Fc?RIII-optimized anti-EGFR antibodies, while further optimization of Fc?RIIa binding significantly restores PMN recruitment.

SUBMITTER: Derer S 

PROVIDER: S-EPMC3984330 | biostudies-literature | 2014 Mar-Apr

REPOSITORIES: biostudies-literature