Polysialylation of human coagulation factor VIII

Abstract A process for manufacturing of a polysialylated recombinant coagulation factor VIII (PSA-rFVIII) based on the full-length rFVIII product ADVATE (octocog alfa) has been developed by Baxter/Baxalta. For conjugation with rFVIII, a 20 kDa aminooxy-PSA reagent is prepared. This reagent is used for coupling to the carbohydrate moiety of rFVIII, predominantly to the N-glycans located in the B domain. The N-glycans can be mildly oxidized with NaIO4 to form aldehyde groups which are reacting with the aminooxy reagent in the presence of a nucleophilic catalyst to form stable oxime linkages. Then the product is purified by a sequence of chromatographic steps followed by an ultrafiltration and diafiltration procedure. The resulting PSA-rFVIII product, called by the company BAX 826, shows a significant prolongation of its pharmacological half-life when compared with ADVATE. Moreover, a clinical phase 1 study in patients with severe hemophilia A was performed, which demonstrated adequate safety and tolerability and a prolongation of relevant pharmacokinetic characteristics.