LOW ANTIGENICITY FACTOR VIII

低抗原性因子 VIII

• 批准号: 6073667
• 负责人: GARRETT E BERGMAN
• 金额: $ 9.86万
• 依托单位: OCTAGEN CORPORATION
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6073667
• 关键词: antigens; biotherapeutic agent; coagulation factor VIII; hemophilia As; human subject; laboratory mouse; neutralizing antibody; protein engineering; recombinant proteins

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".

我们的目标是获得低抗原性重组 fVIII 产品的注册，用于治疗具有人 fVIII 中和抗体的患者。此类抑制剂患者包括在用替代人fVIII治疗时产生同种抗体的甲型血友病患者，以及产生针对内源性fVIII的自身抗体的“获得性血友病”患者。自 1986 年以来，美国已成功使用血浆来源的猪 fVIII (HYATE:C) 治疗抑制剂患者。HYATE:C 对此类患者有效，因为针对人 fVIII 的抗体通常不会与猪 fVIII 发生交叉反应。全长猪fVIII的克隆使得低抗原性重组猪fVIII和值得临床开发的重组人/猪fVIII构建体的开发成为可能。在本次资助的第一阶段，申请人将获得 HYATE:C、重组猪 fVIII 和人/猪杂交 fVIII 的体外抗原性数据。该数据将用作选择先导重组低抗原性 Nm 蛋白的基础，然后在血友病小鼠模型中测试其体内功效。数据收集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性新药 (IND) 申请。拟议的商业应用：大约 26% 的 A 型血友病患者产生抗体。 很大一部分人无法用人 fVIII 成功治疗。 重组、低抗原性 fVIII 产品将在 fVIII 抑制剂患者市场上具有良好的竞争力，并成为“获得性血友病”的一线疗法。