Predictive immunogenicity of Refacto AF.

The administration of therapeutic factor VIII (FVIII) to treat or prevent haemorrhages in haemophilia A patients results, in up to 30% of the cases, in the development of inhibitory anti-FVIII antibodies. Much debate has taken place on the relevance of the nature of the FVIII product as a risk factor for inhibitor development. Thus, the plasma-derived vs. recombinant origin, the second vs. third generation of the product, or the presence of the B domain have been controversially evoked. A few years ago, Refacto (R) AF, a third-generation recombinant B domain-deleted FVIII was marketed. The aim of this study was to compare the immunogenicity of Refacto (R) AF to that of two recombinant full-length FVIII products: Helixate (R) and Advate (R). For the three recombinant FVIII products, we compared the binding to the mannose-sensitive endocytic receptor CD206, the dose-dependent endocytosis by immature monocyte-derived dendritic cells (DCs), the activation by FVIII-loaded DCs of a FVIII-specific HLA-DRB1*0101-restricted mouse T-cell hybridoma and the induction of inhibitory anti-FVIII IgG in FVIII-deficient mice. At elevated FVIII concentrations, Refacto (R) AF was less endocytosed than full-length recombinant products. At lower concentrations, however, Refacto (R) AF was endocytosed by DCs and activated T cells as well as Helixate (R) and Advate (R). The levels of inhibitory anti-FVIII IgG induced by Refacto (R) AF in FVIII-deficient mice were lower or equal to that induced by Helixate (R) and Advate (R) respectively. The predicted immunogenicity of Refacto (R) AF is identical to or lower than that of the two recombinant full-length FVIII products available on the French market.