Abstract

Significance The N -glycan composition of the constant (Fc) domain of IgG can modulate antibody effector functions by affecting the ability of the Fc to bind various Fc receptors (FcγRs). Most therapeutic IgG antibodies carry heterogeneous N -glycans, which might not be optimal for their therapeutic purpose. To understand the contribution of each N -glycan component on antibody effector function, we generated homogeneous IgG1 glycoforms using a chemoenzymatic approach and performed side-by-side in vitro binding, antibody-dependent cell-mediated cytotoxicity (ADCC), and in vivo IgG-mediated cell depletion assays. Our results confirm the dominant positive effect of removing the core fucose on FcγRIIIA binding and ADCC. Our study further reveals that sialylation adversely impacts ADCC in the context of core fucosylation but not in its absence.