How do core fucose and other Fc glycans change what an antibody does?

Why

Each IgG heavy chain carries an N-linked glycan at position 297 in the Fc. It is not decoration. Reviews of IgG structural modification report that removing the glycan at N297 abolishes binding to all Fc gamma receptors and to C1q, except for weak residual binding to the high-affinity Fc gamma receptor I.

The glycan's composition matters as well. Core fucose sits at the base of the structure, and antibodies made without it bind Fc gamma receptor IIIa far more strongly, with reported increases of up to about 20-fold, and up to about 40-fold when afucosylation is combined with high galactose content. Natural killer cells carry this receptor, so afucosylation translates into stronger killing of target cells.

Obinutuzumab, an anti-CD20 antibody, is glycoengineered with reduced fucose content. There is a second reason this matters. The receptor has two common variants, V158 and F158, and the V158 form binds IgG with roughly tenfold higher affinity.

Afucosylation can lessen the disadvantage of the weaker genotype, and cell-based assays using donor cells of one genotype can mislead.