Journal
MABS
Volume 7, Issue 5, Pages 863-870Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/19420862.2015.1053683
Keywords
cetuximab; sialylation; glycan modelling; core fucosylation; IgG; bisected glycans; Nicotiana benthamiana
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Funding
- Austrian Research Promotion Agency (Laura Bassi Center of Expertise Plant produced Bio-Pharmaceuticals) [822757]
- Austrian Science Fund [L575-B13, P22274]
- Austrian Science Fund (FWF) [L 575] Funding Source: researchfish
- Austrian Science Fund (FWF) [P22274, L575] Funding Source: Austrian Science Fund (FWF)
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We investigated N-glycan processing of immunoglobulin G1 using the monoclonal antibody cetuximab (CxMab), which has a glycosite in the Fab domain in addition to the conserved Fc glycosylation, as a reporter. Three GlcNAc (Gn) terminating bi-antennary glycoforms of CxMab differing in core fucosylation (alpha 1,3- and alpha 1,6-linkage) were generated in a plant-based expression platform. These GnGn, GnGnF(3), and GnGnF(6) CxMab variants were subjected in vivo to further processing toward sialylation and GlcNAc diversification (bisected and branching structures). Mass spectrometry-based glycan analyses revealed efficient processing of Fab glycans toward envisaged structures. By contrast, Fc glycan processing largely depend on the presence of core fucose. A particularly strong support of glycan processing in the presence of plant-specific core alpha 1,3-fucose was observed. Consistently, molecular modeling suggests changes in the interactions of the Fc carbohydrate chain depending on the presence of core fucose, possibly changing the accessibility. Here, we provide data that reveal molecular mechanisms of glycan processing of IgG antibodies, which may have implications for the generation of glycan-engineered therapeutic antibodies with improved efficacies.
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