期刊
CELLS
卷 12, 期 17, 页码 -出版社
MDPI
DOI: 10.3390/cells12172130
关键词
immunoglobulin Fc; sialylation; therapeutics; Fc & gamma;RIIb
类别
Fc glycosylation is crucial for antibody activity, and Fc sialylation is important for anti-inflammatory effects of IgGs. However, in vitro models using monomeric forms of antibodies have limited ability to determine the structure-activity relationship of Fc glycosylation. To overcome this, we utilized Fc-containing molecules displayed in monovalent and multivalent forms, and found that sialic acid mediates the phosphorylation of Fc?RIIb when IgG-Fc is displayed in a multivalent manner. This study provides new insights into the impact of Fc sialylation on immune cell signaling and characterization of anti-inflammatory activity of Fc-containing therapeutics.
Immunoglobulin (IgG) Fc glycosylation has been shown to be important for the biological activity of antibodies. Fc sialylation is important for the anti-inflammatory activity of IgGs. However, evaluating the structure-activity relationship (SAR) of antibody Fc glycosylation has been hindered using simplified in vitro models in which antibodies are often displayed in monomeric forms. Presenting antibodies in monomeric forms may not accurately replicate the natural environment of the antibodies when binding their antigen in vivo. To address these limitations, we used different Fc-containing molecules, displaying their Fc domains in monovalent and multivalent fashion. Given the inhibitory role of Fc gamma receptor IIb (Fc?RIIb) in autoimmune and inflammatory diseases, we focused on evaluating the impact of Fc sialylation on the activation of Fc?RIIb. We report for the first time that in human cellular systems, sialic acid mediates the induction of Fc?RIIb phosphorylation by IgG-Fc when the IgG-Fc is displayed in a multivalent fashion. This effect was observed with different types of therapeutic agents such as sialylated anti-TNFa antibodies, sialylated IVIg and sialylated recombinant multivalent Fc products. These studies represent the first report of the specific effects of Fc sialylation on Fc?RIIb signaling on human immune cells and may help in the characterization of the anti-inflammatory activity of Fc-containing therapeutic candidates.
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