Evaluation of the Antigenicity of Black Restricted FVIII Haplotypes and Haplotype

因子VIII的黑色限制性单倍型的抗原性评价 摘要 大约30%的先天性血友病A（HA）患者产生中和活性的同种抗体 因子VIII蛋白的替代。这些患者被称为抑制剂患者，通常接受治疗。 用所谓的旁路剂如重组（r）FVIIa和FEIBA。代理商的数量更多 价格昂贵，并且在完全控制出血方面通常不如FVIII有效。老年HA抑制剂患者 与可以用FVIII管理的患者相比，这些患者的活动性经常降低。虽然罕见， 获得性HA是由患者自身内源性FVIII自身抗体的突然产生引起的， 危及生命的情况。获得性HA用免疫应答调节剂治疗，通常与 绕过代理。一种与抑制剂患者的现存抗体具有低反应性的FVIII治疗剂 并且不引起不良的免疫应答，这将是对现有疗法的显著进步。我们 我们已经鉴定了几种人类FVIII单倍型，我们认为这些单倍型可能代表某些人的低抗原性FVIII。 抑制剂患者更重要的是，我们相信使用这样的单倍型作为起始模板， 代表了制备通用低抗原性FVIII构建体的富有成效的方法， 大多数抑制剂患者。非洲黑人血统的HA患者发生FVIII抑制物的频率是 白色HA患者。FVIII基因（F8）的重测序研究揭示了四种常见的非同义词- 单核苷酸多态性（ns-SNPs），连同两个罕见的ns-SNPs，编码八种不同的基因， 野生型FVIII蛋白称为单倍型（H）1，H2，...，H8。非洲黑人后裔表示， 所有FVIII单倍型，但H6除外，迄今为止，H6仅在亚洲人中鉴定。H3和H4 FVIII仅发生在 在黑人人口中。定义H3和H4单倍型的ns-SNP位于免疫显性内， FVIII的表位。这是有趣的，因为它表明这些变化可能赋予与FVIII不同的反应性 抑制剂的在与莫尔豪斯医学院的詹姆斯·利拉德博士的合作下，我们计划测试 天然存在的Black限制性H3和H4 FVIII蛋白单倍型和杂合H3/H4的抗原性 FVIII在本1期项目中。

Evaluation of the Antigenicity of Black-Restricted Haplotypes of Factor VIII ABSTRACT About 30% of congenital Hemophilia A (HA) patients develop alloantibodies that neutralize the activity of replacement Factor (F) VIII proteins. Such patients, who are termed inhibitor patients, are typically treated with so called bypassing agents such as recombinant (r) FVIIa and FEIBA. Bypassing agents are more expensive and in general less effective than FVIII in fully controlling bleeding. Older HA inhibitor patients frequently have reduced mobility in comparison to patients who can be managed with FVIII. Although rare, acquired HA, caused by the sudden development of autoantibodies to the patient's own endogenous FVIII, is a life threatening condition. Acquired HA is treated with immune-response modulators, often in combination with bypassing agents. A FVIII therapeutic that possessed low reactivity with an inhibitor patient's extant antibodies and did not elicit an adverse immune response would be a significant advance over current therapies. We have identified several human FVIII haplotypes that we believe could represent low antigenic FVIII for some inhibitors patients. More importantly, we believe that using such haplotypes as starting templates may represent a fruitful approach to prepare a universal low antigenicity FVIII construct that would offer efficacy for most inhibitor patients. HA patients of Black African ancestry develop FVIII inhibitors twice as frequently as White HA patients. Resequencing studies of the FVIII gene (F8) have revealed four common nonsynonymous- single-nucleotide polymorphisms (ns-SNPs) that, together with two infrequent ns-SNPs, encode eight distinct wild-type FVIII proteins referred to as haplotype (H)1, H2, ..., H8. Individuals of Black African descent express all FVIII haplotypes except H6, which, to date, has only been identified in Asians. H3 and H4 FVIII occur only in the Black population. The ns-SNPs that define the H3 and H4 haplotypes reside within immunodominant epitopes of FVIII. This is intriguing as it suggests that these variations may impart differing reactivity with FVIII inhibitors. In collaboration with Dr. James Lillard, of the Morehouse School of Medicine, we plan to test the antigenicity of the naturally occurring Black restricted H3 and H4 FVIII protein haplotypes and a hybrid H3/H4 FVIII in this Phase 1 project.