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Thomann, Marco; Reckermann, Katharina; Reusch, Dietmar; Prasser, Jessica; Tejada, Max L.
Molecular immunology, 20/May , Letnik: 73Journal Article
•Exploratory statistical analysis of data from 54 manufactured batches of an IgG1 therapeutic antibody (mAb1) suggests that ADCC activity is not only modulated by afucose but also by galactose.•We enzymatically modulate the galactose levels of four different batches of mAb1 and confirm that the presence of terminal galactose enhances ADCC activity.•The ADCC enhancing effect of galactose is observed in 4 additional monoclonal antibodies derived using standard CHO-based manufacturing processes.•In contrast, the ADCC activity of IgG1 monoclonal antibody glycoengineered to contain a high degree of afucosylation remains unchanged by the addition of galactose, suggesting that while the levels of galactose have some influence on ADCC activity, the impact of afucose is still predominant. The therapeutic activity of monoclonal antibodies can involve immune cell mediated effector functions including antibody-dependent cellular cytotoxicity (ADCC), an activity that is modulated by the structure of Fc-glycans, and in particular the lack of core fucose. The heterogeneity of these glycostructures and the inherent variability of traditional PBMC-based in vitro ADCC assays, have made it challenging to quantitatively assess the impact of other glycostructures on ADCC activity. We applied a quantitative NK cell based assay to generate a database consisting of Fc-glycostructure and ADCC data from 54 manufacturing batches of a CHO-derived monoclonal antibody. Explorative analysis of the data indicated that, apart from afucosylation, galactosylation levels could influence ADCC activity. We confirmed this hypothesis by demonstrating enhanced ADCC upon enzymatic hypergalactosylation of four different monoclonal antibodies derived using standard CHO manufacturing processes. Furthermore we quantitatively compare the effects of galactosylation and afucosylation in the context of glycan heterogeneity and demonstrate that while galactose can influence ADCC activity, afucosylation remains the primary driver of this activity.
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