Structural basis for improved efficacy of therapeutic antibodies on defucosylation of their Fc glycans

Removal of the fucose residue from the N‐glycans of the Fc portion of immunoglobulin G (IgG) results in a dramatic enhancement of antibody‐dependent cellular cytotoxicity (ADCC) through improved affinity for Fcγ receptor IIIa (FcγRIIIa). Here, we present the 2.2‐Å structure of the complex formed between nonfucosylated IgG1‐Fc and a soluble form of FcγRIIIa (sFcγRIIIa) with two N‐glycosylation sites. The crystal structure shows that one of the two N‐glycans of sFcγRIIIa mediates the interaction with nonfucosylated Fc, thereby stabilizing the complex. However, fucosylation of the Fc N‐glycans inhibits this interaction, because of steric hindrance, and furthermore, negatively affects the dynamics of the receptor binding site. Our results offer a structural basis for improvement in ADCC of therapeutic antibodies by defucosylation.

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