Unique carbohydrate–carbohydrate interactions are required for high affinity binding between FcγRIII and antibodies lacking core fucose

TLDR

Antibody‑mediated cellular cytotoxicity depends on antigen–antibody complexes binding Fcγ receptors, and afucosylated IgGs exhibit markedly higher affinity for FcγRIIIa, prompting development of glycoengineered therapeutics to harness this effect. The study aims to determine crystal structures of FcγRIIIa bound to afucosylated or fucosylated Fc to elucidate how core fucosylation regulates ADCC. High‑resolution crystal structures of the FcγRIIIa–Fc complexes were obtained, revealing the molecular basis of core fucose‑mediated affinity modulation. The structures show that afucosylated Fc engages FcγRIIIa through unique carbohydrate–carbohydrate contacts that are absent or weakened in the fucosylated complex, accounting for the higher affinity and enhanced ADCC.

Abstract

Antibody-mediated cellular cytotoxicity (ADCC), a key immune effector mechanism, relies on the binding of antigen-antibody complexes to Fcγ receptors expressed on immune cells. Antibodies lacking core fucosylation show a large increase in affinity for FcγRIIIa leading to an improved receptor-mediated effector function. Although afucosylated IgGs exist naturally, a next generation of recombinant therapeutic, glycoenginereed antibodies is currently being developed to exploit this finding. In this study, the crystal structures of a glycosylated Fcγ receptor complexed with either afucosylated or fucosylated Fc were determined allowing a detailed, molecular understanding of the regulatory role of Fc-oligosaccharide core fucosylation in improving ADCC. The structures reveal a unique type of interface consisting of carbohydrate-carbohydrate interactions between glycans of the receptor and the afucosylated Fc. In contrast, in the complex structure with fucosylated Fc, these contacts are weakened or nonexistent, explaining the decreased affinity for the receptor. These findings allow us to understand the higher efficacy of therapeutic antibodies lacking the core fucose and also suggest a unique mechanism by which the immune system can regulate antibody-mediated effector functions.