Fine epitope mapping of B cell response in patients with hemophilia A: Pilot

A 型血友病患者 B 细胞反应的精细表位作图：试点

• 批准号: 8462767
• 负责人: Shannon L. Meeks
• 金额: $ 11.7万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-22 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8462767
• 关键词: Address; Antibodies; B-Lymphocyte Epitopes; B-Lymphocytes; Biological; Biological Assay; Bypass; C2 Domain; Characteristics; Clinical Trials; Coagulation Process; Complication; Data; Development; Dose; Epitope Mapping; Epitopes; Event; Factor VIII; Factor VIIa; Generations; Genotype; Goals; Hemophilia A; Hemorrhage; Hemostatic Agents; Immune Tolerance; Immune response; In Vitro; Infusion procedures; Kinetics; Knowledge; Life; Maps; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mus; Patients; Pilot Projects; Plasma; Prospective Studies; Sample Size; Sampling; Specificity; Staging; Statistical Data Interpretation; System; Testing; Thrombin; Time; Treatment Cost; antibody inhibitor; base; design; improved; in vivo; inhibitor/antagonist; novel; patient population; prospective; recombinant antihemophilic factor VIII; response; trial comparing

DESCRIPTION (provided by applicant): Thirty percent of patients with severe hemophilia treated with factor fVIII (fVIII) develop anti-fVIII antibodies (inhibitors). This is the most significant complication in the management of patients with hemophilia A leading to increases in morbidity as well as cost of treatment. These antibodies that develop can inhibit the biological activity of fVIII. There are 5 domains of fVIII that have known functional significance with antibodies most often being directed against the A2 and C2 domains of fVIII. However, we have recently shown that epitopes within the C2 doman of fVIII have unique characteristics. The specific epitope (classical vs. nonclassical) within the C2 domain was more important than inhibitor titer in response to fVIII in acquired hemophilia plasma and a murine monoclonal antibody (MAb) system with very high titer nonclassical inhibitors responding to fVIII. The central hypothesis of this pilot project is to describe the spectrum of B-cell epitopes that are represented in hemophilia A inhibitor patient plasmas to provide data for statistical analysis to design a prospective clinical trial comparing epitope spectrum and response to treatment with fVIII and to results of immune tolerance therapy. We propose to map the patient polyclonal plasma to specific B-cell epitopes using a panel of murine anit-fVIII monoclonal antibodies to all domains of fVIII except the B domain. We will compare the epitope spectrum to genotype as well response to treatment with fVIII in multiple in vitro coagulation assays. In a subset of patients we will have two samples from different points in time and we will compare the change of epitope spectrum and response to fVIII at the different time points.

描述（由申请方提供）：30%接受因子VIII（fVIII）治疗的重度血友病患者产生抗fVIII抗体（抑制剂）。这是血友病A患者管理中最显著的并发症，导致发病率和治疗费用增加。产生的这些抗体可以抑制FVIII的生物活性。存在5个具有已知功能意义的fVIII结构域，其中抗体最常针对fVIII的A2和C2结构域。然而，我们最近表明，在FVIII的C2结构域内的表位具有独特的特征。在获得性血友病血浆和鼠单克隆抗体（MAb）系统中，C2结构域内的特异性表位（经典与非经典）比对fVIII应答的抑制剂滴度更重要，该系统具有对fVIII应答的极高滴度非经典抑制剂。中央 该试点项目的假设是描述血友病A抑制剂患者血浆中代表的B细胞表位谱，以提供用于统计分析的数据，从而设计比较表位谱和对fVIII治疗的应答以及免疫耐受治疗结果的前瞻性临床试验。我们建议使用一组鼠抗FVIII单克隆抗体将患者多克隆血浆映射到特定的B细胞表位，该抗体针对除B结构域之外的FVIII的所有结构域。我们将在多种体外凝血试验中比较表位谱与基因型以及对FVIII治疗的反应。在一个患者亚组中，我们将有来自不同时间点的两个样本，我们将比较表位谱的变化和在不同时间点对FVIII的应答。