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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

The Function of the Human Interferon-β1a Glycan Determined in Vivo

Medical Biotechnology Center, University of Southern Denmark, Odense C, Denmark (L.D.-O., M.M., B.F.); and Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark (M.T.-A., P.H.)

Recombinant human interferon-β (rhIFN-β) is the leading therapeutic intervention shown to change the cause of relapsing-remitting multiple sclerosis, and both a nonglycosylated and a significantly more active glycosylated variant of rhIFN-β are used in treatment. This study investigates the function of the rhIFN-β1a glycan moiety and its individual carbohydrate residues, using the myxovirus resistance (Mx) mRNA as a biomarker in Mx-congenic mice. We showed that the Mx mRNA level in blood leukocytes peaked 3 h after s.c. administration of rhIFN-β1a. In addition, a clear dose-response relationship was confirmed, and the Mx response was shown to be receptor-mediated. Using specific glycosidases, different glycosylation analogs of rhIFN-β1a were obtained, and their activities were determined. The glycosylated rhIFN-β1a showed significantly higher activity than its deglycosylated counterpart, due to a protein stabilization/solubilization effect of the glycan. It is interesting to note that the terminating sialic acids were essential for these effects. Conclusively, the structure/bioactivity relationship of rhIFN-β1a was determined in vivo, and it provided a novel insight into the role of the rhIFN-β1a glycan and its carbohydrate residues. The possibilities of improving the pharmacological properties of rhIFN-β1a using glycoengineering are discussed.

Address correspondence to: Lasse Dissing-Olesen, Medical Biotechnology Center, University of Southern Denmark, Winsløwparken 25, 2, DK-5000 Odense C, Denmark. E-mail: ldolesen{at}health.sdu.dk