N-linked glycosylation modulates the immunogenicity of recombinant human factor VIII in hemophilia A mice

Haematologica
Jesse D LaiS W Pipe

Abstract

Immune responses to factor VIII remain the greatest complication in the treatment of severe hemophilia A. Recent epidemiological evidence has highlighted that recombinant factor VIII produced in baby hamster kidney cells is more immunogenic than factor VIII produced in Chinese hamster ovary cells. Glycosylation differences have been hypothesized to influence the immunogenicity of these synthetic concentrates. In two hemophilia A mouse models, baby hamster kidney cell-derived factor VIII elicited a stronger immune response compared to Chinese hamster ovary cell-derived factor VIII. Furthermore, factor VIII produced in baby hamster kidney cells exhibited accelerated clearance from circulation independent of von Willebrand factor. Lectin and mass spectrometry analysis of total N-linked glycans revealed differences in high-mannose glycans, sialylation, and the occupancy of glycan sites. Factor VIII desialylation did not influence binding to murine splenocytes or dendritic cells, nor surface co-stimulatory molecule expression. We did, however, observe increased levels of immunoglobulin M specific to baby hamster kidney-derived factor VIII in naïve hemophilia A mice. De-N-glycosylation enhanced immunoglobulin M binding, suggesting th...Continue Reading

Citations

Feb 12, 2019·Journal of Thrombosis and Haemostasis : JTH·Laura L SwystunDavid Lillicrap
Jul 23, 2019·Haemophilia : the Official Journal of the World Federation of Hemophilia·Shannon L MeeksUNKNOWN Members of Working Group 3, the NHLBI State of the Science Workshop on factor VIII inhibitors: Generating a national bluepri
Apr 21, 2020·Journal of Thrombosis and Haemostasis : JTH·Cheng MaLei Li
Feb 18, 2020·British Journal of Haematology·Matthew CormierDavid Lillicrap
Jan 31, 2020·Frontiers in Immunology·Sebastien Lacroix-DesmazesKathleen P Pratt
Feb 9, 2021·Frontiers in Immunology·Flora PeyvandiIsabella Garagiola
Feb 3, 2021·Journal of Thrombosis and Haemostasis : JTH·Haarin ChunAndrey G Sarafanov
Dec 5, 2021·Journal of Thrombosis and Haemostasis : JTH·Jasmine ItoGlaivy Batsuli

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Methods Mentioned

BETA
glycosylation
enzyme-linked immunosorbent assay
ELISA
Chip
flow cytometry

Software Mentioned

Mascot
Agilent Masshunter Quantitative Analysis
GlycoMod

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