Low Immunogenicity Factor VIII

描述(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类的、低免疫原性的重组因子VIII(“fVIIl”)形式，这种情况是由于先天性凝血血浆蛋白fVIll缺乏或不足引起的。血友病A最初是用替代人FVIII治疗的，这种FVIII可以是基因工程的，也可以是从混合血浆中衍生出来的。然而，大约25%的这类血友病患者会产生针对人类fV11的显著抑制抗体，这严重地使这种疾病的治疗复杂化。该项目的总体目标是在某些临床前研究中进一步评估两个假定的低免疫原性FVIII结构，以及评估其他密切相关的分子。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fV11构建物的随机试验； 2.在血友病A小鼠中确定当前两个候选者之一(以下简称“A2C2ep3”)的免疫原性； 3.比较A2C2ep3和缺失FVIII的野生型重组人b结构域(以下简称HSQ)的清除率； 4.比较A2C2ep3和HSQ对血友病A小鼠的止血效果； 5.比较A2C2ep3和HSQ与磷脂的结合情况； 6.比较A2C2ep3和HSQ与人von Willebrand因子(VWF)的结合情况； 7.优化A2C2ep3和第二个较早确定的候选基因在命名为BHK-M的新生仓鼠肾脏来源细胞系中的表达。

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.