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N‐glycans of complex glycosylated biopharmaceuticals and their impact on protein clearance

Fabian Higel,Theresa Sandl,C. Kao,Nicole Pechinger,F. Sörgel,W. Friess,F. Wolschin,Andreas Seidl

Published 2019 in European journal of pharmaceutics and biopharmaceutics

ABSTRACT

ABSTRACT N‐glycosylation is a common post‐translational modification of biopharmaceutical products. Certain types of N‐glycans have been shown to influence important properties of monoclonal antibody products including pharmacokinetics and effector functions. Complex biopharmaceuticals e.g. Fc fusion proteins may contain several N‐ and O‐glycosylation sites. Domain specific characterization of two Fc fusion proteins showed an Fc N‐glycosylation pattern comparable to IgG molecules. The receptor N‐glycosylation was found to contain some larger and more complex N‐glycans compared to the Fc part. Analyses of samples from non‐clinical studies of the two studied fusion proteins indicate that their N‐glycans impact pharmacokinetic properties. Interestingly, besides the type of N‐glycan this influence on the pharmacokinetics depends also on the glycosylation site and thus the accessibility on the protein. The same type of N‐glycan can influence the clearance of fusion proteins when located at the receptor part, but not if located at the Fc part. In this study, it is shown that N‐glycans with terminal galactose or N‐acetylglucosamine residues have a negative impact on serum half‐life when located at the receptor part. Terminal sialylation of galactose residues prevents this faster clearance even when only one sialic acid is present. O‐acetylation, a modification of sialic acids does not impact pharmacokinetics. Thus, type and accessibility of N‐glycan moieties of fusion proteins both play an important role in pharmacokinetics. Finally, detailed site specific analysis is critical in the development of biopharmaceuticals.

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