Low Immunogenicity Factor VIII

低免疫原性因子 VIII

• 批准号: 6831993
• 负责人: GARRETT E BERGMAN
• 金额: $ 10万
• 依托单位: OCTAGEN CORPORATION
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-16 至 2005-02-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6831993
• 关键词: blood coagulation; blood disorder chemotherapy; chemical binding; clearance rate; coagulation factor VIII; drug design /synthesis /production; enzyme linked immunosorbent assay; hemophilia As; hemostatics; immunogenetics; laboratory mouse; monoclonal antibody; pharmacokinetics; phospholipids; von Willebrand factor

DESCRIPTION (provided by applicant): Octagen's long-term goal is to develop an essentially human, low immunogenicity form of recombinant factor VIII ("fVIIl") for patients with hemophilia A, a condition caused by a congenital absence or insufficiency of the clotting plasma protein fVIll. Hemophilia A is treated initially with replacement human fVIII, which can be either genetically engineered or derived from pooled plasma. However, approximately 25 percent of such hemophiliacs develop significant inhibitor antibodies to human fVlll, which seriously complicates management of the disorder. The overall aims of this project are to further assess in certain pre-clinical studies two putative low immunogenicity fVIII constructs earlier identified through a collaboration between Octagen and Emory University researcher John S. Lollar, as well as to evaluate additional closely related molecules. In particular, the specific aims of the project are to: 1. conduct a randomized trial of candidate low immunogenicity fVlll constructs in hemophilia A mice; 2. determine the dose-dependent immunogenicity of one of the two current candidates in hemophilia A mice (hereafter that candidate is referred to as "A2C2epi3"); 3. compare the clearance of A2C2epi3 and a "wild-type" recombinant human b domain deleted fVIII (hereafter referred to as "HSQ"); 4. compare the hemostatic efficacy of A2C2epi3 and HSQ in hemophilia A mice; 5. compare the binding of A2C2epi3 and HSQ to phospholipid; 6. compare the binding of A2C2epi3 and HSQ to human von Willebrand factor (vWf); and 7. optimize the expression of A2C2epi3 and a second earlier identified candidate in a baby hamster kidney-derived cell line designated BHK-M.

描述（由申请人提供）：Octagen的长期目标是为血友病A患者开发一种基本上是人的、低免疫原性形式的重组因子VIII（“fVII”），血友病A是由凝血血浆蛋白fVII的先天性缺乏或不足引起的病症。血友病A最初用替代人fVIII治疗，其可以是基因工程的或来源于合并的血浆。然而，大约25%的此类血友病患者产生针对人fVIII的显著的抑制剂抗体，这使该病症的管理严重复杂化。本项目的总体目标是在某些临床前研究中进一步评估早期通过Octagen和Emory大学研究员John S. Lollar，以及评价其他密切相关的分子。具体而言，该项目的具体目标是：1.在血友病A小鼠中进行候选低免疫原性fVIII构建体的随机试验; 2.在血友病A小鼠中测定两种当前候选物之一的剂量依赖性免疫原性（此后该候选物被称为“A2 C2 epi 3”）; 3.比较A2 C2 epi 3和“野生型”重组人B结构域缺失的fVIII（下文称为“HSQ”）的清除率; 4.比较A2 C2 epi 3和HSQ在血友病A小鼠中的止血功效; 5.比较A2 C2 epi 3和HSQ与磷脂的结合; 6.比较A2 C2 epi 3和HSQ与人血管性血友病因子（vWf）的结合;和 7.优化A2 C2 epi 3和第二个早期鉴定的候选物在命名为BHK-M的幼仓鼠肾衍生细胞系中的表达。