Delignat S, Repessé Y, Gilardin L, Dimitrov J D, Lone Y C, Kaveri S V, Lacroix-Desmazes S
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.
Haemophilia. 2014 Jul;20(4):486-92. doi: 10.1111/hae.12348. Epub 2013 Dec 30.
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.
给甲型血友病患者注射治疗性凝血因子VIII（FVIII）以治疗或预防出血，在高达30%的病例中会导致抑制性抗FVIII抗体的产生。关于FVIII产品的性质作为抑制剂产生的风险因素的相关性，已经进行了很多讨论。因此，血浆来源与重组来源、第二代与第三代产品，或B结构域的存在都曾引起争议。几年前，第三代重组B结构域缺失的FVIII产品Refacto AF上市。本研究的目的是比较Refacto AF与两种重组全长FVIII产品Helixate和Advate的免疫原性。对于这三种重组FVIII产品，我们比较了它们与甘露糖敏感的内吞受体CD206的结合、未成熟单核细胞衍生的树突状细胞（DC）的剂量依赖性内吞作用、FVIII负载的DC对FVIII特异性HLA-DRB1*0101限制性小鼠T细胞杂交瘤的激活作用，以及在FVIII缺陷小鼠中抑制性抗FVIII IgG的诱导情况。在FVIII浓度升高时，Refacto AF的内吞作用比全长重组产品少。然而，在较低浓度下，Refacto AF被DC内吞并激活T细胞的情况与Helixate和Advate相同。Refacto AF在FVIII缺陷小鼠中诱导的抑制性抗FVIII IgG水平分别低于或等于Helixate和Advate诱导的水平。Refacto AF的预测免疫原性与法国市场上现有的两种重组全长FVIII产品相同或更低。
