afucosylation

Afucosylation refers to the absence or substantial reduction of the core fucose sugar on the N-linked glycans that decorate the Fc region of immunoglobulin G (IgG) antibodies. The primary site is the N-linked glycan at asparagine 297 in the IgG Fc, and afucosylation does not affect antigen binding but alters effector functions.

The most notable effect of afucosylation is an enhanced interaction with Fc gamma receptors, particularly FcγRIIIa on natural killer cells. This increased binding augments antibody-dependent cellular cytotoxicity (ADCC), a key mechanism by which therapeutic antibodies can eliminate target cells. Afucosylation can also influence engagement with FcγRIIIb on neutrophils, contributing to broader changes in effector activity.

In biotechnology, afucosylation is intentionally engineered to boost therapeutic efficacy. Production approaches include knocking out the FUT8 gene, which encodes the enzyme responsible for adding core fucose, in mammalian cell lines such as CHO cells, or applying enzymatic methods to remove fucose after synthesis. Several approved or clinically advanced antibodies are produced in afucosylated formats; examples include obinutuzumab, an anti-CD20 antibody, and mogamulizumab, an anti-CCR4 antibody, both designed to exhibit enhanced ADCC.

Natural occurrence and clinical relevance are variable. IgG glycosylation patterns can shift with age, infection, or vaccination, and certain infections have been associated with higher levels of afucosylated IgG, which may influence disease severity or immune responses. From a manufacturing perspective, glycoform profiles, including afucosylation, contribute to batch-to-batch variability and require careful quality control to balance efficacy and safety.