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Efficacy of fucose analogues and their acetylated forms on IgG glycosylation

The glycosylation status of an antibody affects its therapeutic efficacy. Studies have shown that reduced fucosylation of the IgG core leads to increased cytotoxic activity by the antibody, particularly those that are used for the treatment of cancer. This is mediated by enhancing the binding of IgG to FcγrIIIα of NK cells and thereby stimulating antibody-dependent cell-mediated cytotoxicity. 

The transfer of fucose from guanosine diphosphate fucose (GDP-fucose) onto the core glycan structure is mediated by fucosyltransferases (FUTs). The addition of fluorinated fucose analogues results in reduced protein fucosylation, by inhibiting FUTs. The fluorinated fucose analogues are converted into donor substrates (GDP-2F-Fuc and GDP-6F-Fuc) that compete with the FUT substrate GDP-Fuc. As a result of negative feedback, increased fluorinated fucoses inhibit the synthesis of GDP-Fuc. 

Thus, the development of fucose analogues has become of therapeutic interest as a tool to reduce core fucosylation of antibodies. Furthermore, peracetylated fucose analogues were developed, which become deacetylated in the cytoplasm by esterases. This study compared the efficacy of peracetylated sugars with the unprotected forms, based on previous observations that showed high cell permeability of peracetylated sugars due to increased hydrophobicity. 

In this study, two fucose analogues, 5-alkynylfucose (from Carbosynth) and 2-deoxy-2-fluorofucose, were compared with their acetylated forms to test their effects on core IgG fucosylation of antibodies. Previous studies demonstrated strong inhibitory effect of 5-alkynylfucose (>80%) on FUT8. Assessment of IgG core fucosylation following the addition of unprotected and peracetylated 5-alkynylfucose analogues revealed reduced fucosylation of the IgG core, greater than the reduction by the 2F-Fuc analogues. However, this was accompanied by high incorporation of the alkynylated fucose analogue into the core glycan structure that may have implications on the safety and efficacy of the antibody. For both fucose analogues, the acetylated forms caused slightly greater reduction in core fucosylations. 

The high efficiency of 5-alkynylfucose in reducing core fucosylation may be attributed to its known inhibitory effect on GDP-4-keto-6-deoxymannose 3,5-epimerase-4-reductase (FX). FX is an enzyme that is required for the synthesis of GDP-Fuc. Furthermore, the high incorporation of 5-alkynylfucose into the core glycan structure results in accumulation of GDP-5-alkynylfucose, leading to reduced concentration of FUT substrates via negative feedback and thus reduced core fusosylation.

For further details, please refer to the original paper: Zimmermann et al, 2019.

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