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Essentials    Factor VIII inhibitors are the most serious complication in patients with hemophilia A.  Aggregates in biopharmaceutical products are an immunogenic risk factor.  Aggregates were identified in recombinant full‐length factor VIII products.  Aggregates in recombinant factor VIII products are identified by analytical ultracentrifugation.Summary   Background  The development of inhibitory anti‐factor  VIII  antibodies is the most serious complication in the management of patients with hemophilia A. Studies have suggested that recombinant full‐length  FVIII  is more immunogenic than plasma‐derived  FVIII , and that, among recombinant  FVIII  products, Kogenate is more immunogenic than Advate. Aggregates in biopharmaceutical products are considered a risk factor for the development of anti‐drug antibodies.    Objective  To evaluate recombinant full‐length  FVIII  products for the presence of aggregates.    Methods  Advate, Helixate and Kogenate were reconstituted to their therapeutic formulations, and subjected to sedimentation velocity ( SV ) analytical ultracentrifugation ( AUC ). Additionally, Advate and Kogenate were concentrated and subjected to buffer exchange by ultrafiltration to remove viscous cosolvents for the purpose of measuring  s  20,w  values and molecular weights.    Results  The major component of all three products was a population of ~7.5 S heterodimers with a weight‐average molecular weight of ~230 k D a. Helixate and Kogenate contained aggregates ranging from 12 S to at least 100 S, representing ≈ 20% of the protein mass. Aggregates greater than 12 S represented < 3% of the protein mass in Advate. An approximately 10.5 S aggregate, possibly representing a dimer of heterodimers, was identified in buffer‐exchanged Advate and Kogenate.  SV AUC  analysis of a plasma‐derived  FVIII  product was confounded by the presence of von Willebrand factor in molar excess over  FVIII .    Conclusions  Aggregate formation has been identified in recombinant full‐length  FVIII  products, and is more extensive in Helixate and Kogenate than in Advate.  SV AUC  is an important method for characterizing  FVIII  products.

journal of thrombosis and haemostasis

Identification of aggregates in therapeutic formulations of recombinant full‐length factor  VIII  products by sedimentation velocity analytical ultracentrifugation