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Specific glycosyltransferase inhibitors for the control of antibody glycoforms


Antibody glycosylation is a post-translational modification that occurs on the Fc region and has a critical role in antibody effector function. Glycoengineering allows to produce antibodies with specific glycoforms which alter their binding properties and therapeutic efficacy. 

The IgG antibodies contain a conserved glycosylation site on the asparagine N297, which is part of the Fc region on the heavy chain (Figure 1). The core glycan is a bi-antennary oligosaccharide consisting of N-acetylglucosamine and mannose residues. Immunoglobulins in the human serum contain variable levels of other sugars such as fucose, galactose, and sialic acid, which influences their biological function. However, on average the IgG N-glycans consists of high fucose levels (95%), intermediate levels of galactose (45%), and low levels of sialic acid (10%).

 Citations - Antibody glycosylation control

Figure 1. Antibody glycosylation. A) The image shows IgG antibody anatomy including the site for N-glycan attachment on the asparagine 297 on the heavy chain. B) Use of specific glycosyltransferase inhibitors allows to control the antibody glycoform production. The treatment with 2FF leads to the production of afucosylated glycans, 2FG instead prevents galactose incorporation on the oligosaccharide.


In recent studies, Carbosynth compounds 2-deoxy-2-fluoro-L-fucose (2FF) and 2-deoxy-2-fluoro-D-galactose (2FG) were used as decoy substrates to create hypo-fucosylated and hypo-galactosylated antibodies (Treffers et al. 2019; Dekkers et al. 2017; Dekkers et al. 2016). The compounds 2FF and 2FG were added to the HEK cell culture expressing IgG1 antibodies and reduced the fucosylaton of the N297 glycan down to 15% as well as galactosylation to 9% (Dekkers et al. 2016).

All three studies cited below showed that the alteration in glycoform profile on IgG1 antibodies resulted in different affinity to Fcγ receptors.

The use of glycosyltransferase inhibitors is a versatile tool for the control of glyco-profile on antibodies since these allow fine-tuning to achieve the desired inhibition level. The use of glycosyltransferase inhibitors is a convenient approach for antibody glycoengineering since the alternative of generating genetic knockdowns or stable cell transfections of glycosyltransferases is technically more challenging and expensive.


For more details, read the original papers published in Frontiers in Immunology and Scientific Reports: Treffers et al., 2019; Dekkers et al., 2017; Dekkers et al., 2016.


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