Impact of Fc Glycosylation on Monoclonal Antibody Effector Functions and Degradation by Proteases

Abstract

IgGs are required to be N-glycosylated in the CH2 domain of the Fc to exhibit effector functions including antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC). This is because Fc glycosylation impacts antibody binding to Fc receptors and complement activating protein, C1q. Glycans found in the Fc are mainly complex biantennary structures with a high degree of heterogeneity containing different terminal sugars including sialic acid, galactose, N-acetylglucosamine and core fucose. Different terminal sugars may dramatically affect ADCC and CDC activities of antibodies. For example, absence of terminal sialic acid and/or core fucose results in significant increase in ADCC activity. Similarly, presence of bisecting N-acetylglucosamine residues also results in increased ADCC activity. Further, increase in terminal galactose content increases CDC activity but does not appear to affect ADCC activity. Additionally, Fc glycans may also affect antibody resistance to proteases. For example, glycosylated IgGs have been shown to be more resistant to papain digestions when compared to their aglycosylated or deglycosylated counterparts. In addition, presence or the absence of specific terminal sugars may also impact IgGs resistance to proteases. More recent data revealed that IgGs containing terminal N-acetylglucosamine residues are more resistant to papain digestions than the IgGs containing terminal sialic acid residues or terminal galactose residues. Hence, it appears that Fc glycans may play important roles in antibody stability and affect resistance to proteases in addition to impacting antibody effector functions.