Fc gamma receptors: glycobiology and therapeutic prospects

Abstract

Therapeutic antibodies hold great promise for the treatment of cancer and autoimmune diseases, and developments in antibody–drug conjugates and bispecific antibodies continue to enhance treatment options for patients. Immunoglobulin (Ig) G antibodies are proteins with complex modifications, which have a significant impact on their function. The most important of these modifications is glycosylation, the addition of conserved glycans to the antibody Fc region, which is critical for its interaction with the immune system and induction of effector activities such as antibody-dependent cell cytotoxicity, complement activation and phagocytosis. Communication of IgG antibodies with the immune system is controlled and mediated by Fc gamma receptors (FcγRs), membrane-bound proteins, which relay the information sensed and gathered by antibodies to the immune system. These receptors are also glycoproteins and provide a link between the innate and adaptive immune systems. Recent information suggests that this receptor glycan modification is also important for the interaction with antibodies and downstream immune response. In this study, the current knowledge on FcγR glycosylation is discussed, and some insight into its role and influence on the interaction properties with IgG, particularly in the context of biotherapeutics, is provided. For the purpose of this study, other Fc receptors such as FcαR, FcεR or FcRn are not discussed extensively, as IgG-based antibodies are currently the only therapeutic antibody-based products on the market. In addition, FcγRs as therapeutics and therapeutic targets are discussed, and insight into and comment on the therapeutic aspects of receptor glycosylation are provided.

Epigenetic modulation of AREL1 and increased HLA expression in brains of multiple system atrophy patients

“…The identification of altered epigenetic modules further support the involvement of innate and adaptive immune compartments in MSA. The most prominent modules that seems to be affected in MSA, are related to the lymphocyte homing receptor (ITGA4) [55], the antibody-binding receptor FCER1G [56], and the cytokine TNF [57], which has been previously investigated in MSA patients. To characterize whether the observed differences in gene methylation are functionally relevant, we investigated gene expression of HLA molecules.…”

A Targeted Vaccine against COVID-19: S1-Fc Vaccine Targeting the Antigen-Presenting Cell Compartment Elicits Protection against SARS-CoV-2 Infection

“…The S1-Fc fusion protein serves as the antigen to achieve immunization. The human immunoglobulin Fc moiety is thought to engage with FcR + expressing cells such as dendritic cells, macrophages and B cells, thus, targeting the antigen-presenting cell compartment 20 . The S1 domain of the SARS-CoV-2 spike protein serves as the immunogenic antigen to mount antiviral humoral and adaptive immune responses.…”

Site-specific glycosylation mapping of Fc gamma receptor IIIb from neutrophils of health donors

“…However, to produce and investigate antennary fucosylation, which was observed at high levels for FcγRIIIb, the HEK293 system constitutes a better vehicle. Nevertheless, glycoengineering provides us with the possibilities to create specific FcγRIIIb structures in order to study the functional properties of different processing levels 50,51 . As shown in a mutagenesis study of the recombinant FcγRIIIa and its mouse orthologue FcγRIV, N-glycans at N162 were a critical element for antibody binding 25,52 .…”