Role of Fc Core Fucosylation in the Effector Function of IgG1 Antibodies

Abstract

The presence of fucose on IgG1 Asn-297 N-linked glycan is the modification of the human IgG1 Fc structure with the most significant impact on FcɣRIII affinity. It also significantly enhances the efficacy of antibody dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells in vitro, induced by IgG1 therapeutic monoclonal antibodies (mAbs). The effect of afucosylation on ADCC or antibody dependent phagocytosis (ADCP) mediated by macrophages or polymorphonuclear neutrophils (PMN) is less clear. Evidence for enhanced efficacy of afucosylated therapeutic mAbs in vivo has also been reported. This has led to the development of several therapeutic antibodies with low Fc core fucose to treat cancer and inflammatory diseases, seven of which have already been approved for clinical use. More recently, the regulation of IgG Fc core fucosylation has been shown to take place naturally during the B-cell immune response: A decrease in α-1,6 fucose has been observed in polyclonal, antigen-specific IgG1 antibodies which are generated during alloimmunization of pregnant women by fetal erythrocyte or platelet antigens and following infection by some enveloped viruses and parasites. Low IgG1 Fc core fucose on antigen-specific polyclonal IgG1 has been linked to disease severity in several cases, such as SARS-CoV 2 and Dengue virus infection and during alloimmunization, highlighting the in vivo significance of this phenomenon. This review aims to summarize the current knowledge about human IgG1 Fc core fucosylation and its regulation and function in vivo, in the context of both therapeutic antibodies and the natural immune response. The parallels in these two areas are informative about the mechanisms and in vivo effects of Fc core fucosylation, and may allow to further exploit the desired properties of this modification in different clinical contexts.

Beyond antibody fucosylation: α-(1,6)-fucosyltransferase (Fut8) as a potential new therapeutic target for cancer immunotherapy

“…Although more research is warranted on the supplementation of the exogenously transferred, or on the mitigation of the endogenously produced, afucosylated IgG in various disease settings, so far there are already seven afucosylated or low-fucosylated therapeutic hIgG1 approved by FDA/EMA [ 30 ], and > 20 are in clinical trials for cancer treatment [ 31 ]. For example, the anti-CD20 Obinutuzumab (or GA101) has only a < 30% reduction in fucosylation than Rituximab, but it has increased cell-mediated cytotoxicity and has been approved for treating patients with chronic lymphocytic leukemia or follicular lymphoma [ 31 , 32 ].…”

Uses and Challenges of Antiviral Polyclonal and Monoclonal Antibody Therapies

“…In addition to Fc engineering, there is a better understanding of specific Fc glycan structures and their association with different effector functions, e.g., afucosylated mAbs have better antibody dependent cellular cytotoxicity (ADCC) compared to highly fucosylated antibodies, and galactosylation is associated with complement dependent cytotoxicity (CDC) and can influence ADCC activity 77 . Therefore, cell lines have been engineered to produce mAbs with up to 100% afucosylation to enhance ADCC activity 74,78 . The understanding of the relationship between antibody glycan structures and Fc effector functions is ongoing and additional strategies may be developed to further engineer mAb glycan structures.…”

A Defucosylated Anti-EpCAM Monoclonal Antibody (EpMab-37-mG2a-f) Exerts Antitumor Activity in Xenograft Model

“…The composition of the N -linked glycans on IgG plays a critical role in effector functions [ 26 ]. In other antibody classes, the influence of glycans, particularly sialic acid, have been suggested [ 27 , 28 ].…”