title: Predictive immunogenicity of Refacto AF.
abstract: 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 AF, a third-generation recombinant B domain-deleted FVIII was marketed. The aim of this study was to compare the immunogenicity of Refacto AF to that of two recombinant full-length FVIII products: Helixate and Advate. 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 AF was less endocytosed than full-length recombinant products. At lower concentrations, however, Refacto AF was endocytosed by DCs and activated T cells as well as Helixate and Advate. The levels of inhibitory anti-FVIII IgG induced by Refacto AF in FVIII-deficient mice were lower or equal to that induced by Helixate and Advate respectively. The predicted immunogenicity of Refacto AF is identical to or lower than that of the two recombinant full-length FVIII products available on the French market.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche en Santé (UMR S), Centre de Recherche des Cordeliers, Paris, France; Université Pierre et Marie Curie-Paris 6, UMR, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes, UMR S, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Delignat
authors.forename: Y
authors.initials: Y
authors.lastname: Repessé
authors.forename: L
authors.initials: L
authors.lastname: Gilardin
authors.forename: J D
authors.initials: JD
authors.lastname: Dimitrov
authors.forename: Y C
authors.initials: YC
authors.lastname: Lone
authors.forename: S V
authors.initials: SV
authors.lastname: Kaveri
authors.forename: S
authors.initials: S
authors.lastname: Lacroix-Desmazes
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004705:Endocytosis; D005169:Factor VIII / Q000009:adverse effects* / Q000276:immunology* / Q000378:metabolism / Q000627:therapeutic use; D006467:Hemophilia A / Q000188:drug therapy / Q000276:immunology; D006801:Humans; D006825:Hybridomas / Q000276:immunology; D037181:Lectins, C-Type / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D051379:Mice; D011956:Receptors, Cell Surface / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; C427184:recombinant factor VIII SQ; D005169:Factor VIII
keywords: factor VIII; haemophilia A; immunogenicity; inhibitors; prediction; refacto® AF