LOW ANTIGENICITY FACTOR VIII

我们的目标是获得一种低抗原性重组FVIII产品的注册，用于治疗抗人FVIII中和抗体的患者。这些抑制物患者包括那些血友病A患者，他们在接受替代人类FVIII治疗时产生同种异体抗体，以及“获得性血友病”患者，他们产生针对内源性FVIII的自身抗体。自1986年以来，美国已经成功地使用血浆来源的猪FVIII(HYATE：C)治疗了抑制剂患者。HYATE：C在这类患者中是有效的，因为抗人FVIII的抗体通常不与猪FVIII交叉反应。猪FVIII全长基因的克隆使构建具有临床应用价值的低抗原性重组猪FVIII和重组人/猪FVIII结构成为可能。在这项赠款的第一阶段，申请者将获得HYATE：C、重组猪FVIII和人/猪杂交FVIII的体外抗原性数据。这些数据将被用作选择先导重组低抗原性Nm蛋白的基础，然后将在血友病小鼠模型中进行体内疗效测试。收集数据的方式将使其能够用于支持向美国FDA提交候选治疗结构的研究新药(IND)。拟议的商业应用：大约26%的血友病A患者会产生抗体。很大一部分不能用人类FVIII成功治疗。一种重组的、低抗原性的FVIII产品将在FVIII抑制剂患者市场上很好地竞争，并成为治疗“获得性血友病”的一线药物。

Our goal is to obtain registration of a low antigenicity recombinant fVIII product for the treatment of patients with neutralizing antibodies against human fVIII. Such inhibitor patients include those with hemophilia A who develop alloantibodies when treated with replacement human fVIII, as well as patients with "acquired hemophilia" who develop autoantibodies against endogenous fVIII. Inhibitor patients have been successfully treated with plasma derived porcine fVIII (HYATE:C) in the US since 1986. HYATE:C is effective in such patients because antibodies against human fVIII frequently do not cross react with porcine fVIII. The cloning of full-length porcine fVIII has made possible the development of low antigenicity recombinant porcine fVIII and recombinant human/porcine fVIII constructs which merit clinical development. In Phase I of this grant applicant will obtain in vitro antigenicity data for HYATE:C, recombinant porcine fVIII and hybrid human/porcine fVIII. This data will be used as a basis for selecting a lead recombinant low antigenicity Nm protein that will then be tested for efficacy in vivo in a hemophilia mouse modeL Data will be collected in a manner so as enable its use in support of an Investigational New Drug (IND) filing for the candidate therapeutic construct with the United States FDA. PROPOSED COMMERCIAL APPLICATIONS: Approximately 26% of all hemophilia A patients develop antibodies. A significant portion cannot be successfully treated with human fVIII. A recombinant, low antigenicity fVIII product would compete well in the fVIII inhibitor patient market and be a first line therapy for "acquired hemophilia".