Molecular Heterogeneity in FVIII Inhibitor Patients

FVIII 抑制剂患者的分子异质性

• 批准号: 8464234
• 负责人: John S. Lollar
• 金额: $ 36.17万
• 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: 2013-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464234
• 关键词: Affect; Antibodies; B-Lymphocytes; Biological; Biological Assay; Blood Plasma Volume; Bypass; C2 Domain; Coagulation Process; Complication; Cross-Sectional Studies; Data; Development; Dose; Enzyme-Linked Immunosorbent Assay; Epitope Mapping; Epitopes; Event; Fibrin; Generations; Genotype; Goals; Hemophilia A; Hemorrhage; Hemostatic Agents; Heterogeneity; Immune Tolerance; In Vitro; Individual; Infusion procedures; Injury; Institutional Review Boards; Kinetics; Knowledge; Lasers; Life; Maps; Measures; Microfluidics; Microspheres; Missense Mutation; Modeling; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Mus; Pathogenicity; Patients; Phenotype; Pilot Projects; Plasma; Protocols documentation; Recombinants; Recovery; Residual state; Risk; Role; Specificity; Staging; Structure; System; Tail; Testing; Thrombin; Treatment Cost; Variant; antibody inhibitor; base; clinical care; improved; in vitro Assay; in vitro testing; in vivo; inhibitor/antagonist; novel; research clinical testing; response

Thirty percent of patients with severe hemophilia treated with factor fVIII (fVlll) develop anti-fVIII antibodies (inhibitors). This is the most significant complication in the management of patients with hemophilia A leading to significant increases In morbidity as well as cost of treatment. Antibodies to fVIII can also develop in patients with previously normal coagulation leading to acquired hemophilia. These antibodies that develop can inhibit the biological activity of fVIII and necessitate the use of bypassing agents for the treatment of bleeding episodes. However, for unknown reasons, some patients display poor hemostatic response to bypass therapy. Thus, improved treatment options are needed, especially for severe or life-threatening bleeding events. Some biological determinants have been identified that increase the risk of inhibitor development. However, little is known about how hemophilia genotype relates to the ultimate epitope spectrum of the B-cell response or how the epitope spectrum affects the response to treatment and immune tolerance. We have recently shown that epitope specificity and inhibitor kinetics within the C2 domain are more important than inhibitor titer in response to fVlll in acquired hemophilia plasma and a murine monoclonal antibody (MAb) system. The central hypothesis of this project is that the inhibitor epitope spectrum of an individual patient can be used to predict the response to infusions of fVIII with or without bypassing agents. We propose to define further the epitopes on fVIII using a large panel of non-overlapping antl-fVIII MAbs in multiple in vitro assays (Aim 1). Given known discrepancies between the different in vitro assays and bleeding phenotype we will study the importance of different epitopes on murine in vivo bleeding phenotypes and fibrin clot structure (Aim 2). In Aim 3, we will adapt our novel ELISA-based epitope mapping protocol to a more robust microsphere-based assay and investigate in a cross-sectional study how polyclonal patient plasma epitope maps correlate with the response to fVIII and bypassing agents in vitro. Ultimately these results could provide a simple clinical test that may predict response to fVIII and bypassing agents in high titer acquired and congenital hemophilia patients.

用FVIII因子（FVLLL）治疗的严重血友病患者中有30％患有抗FVIII抗体 （抑制剂）。这是血友病患者的治疗中最重要的并发症 发病率和治疗成本显着增加。 FVIII的抗体也可以在 先前正常凝血的患者导致获得性血友病。这些发展的抗体 可以抑制FVIII的生物学活性，并需要使用绕过剂来处理 流血情节。但是，由于未知原因，一些患者对 旁路疗法。因此，需要改进的治疗选择，尤其是为了严重或威胁生命 出血事件。已经确定了一些生物决定因素，以增加抑制剂的风险 发展。但是，关于血友病基因型与最终表位的关系知之甚少 B细胞响应的光谱或表位光谱如何影响对治疗和免疫的反应 宽容。我们最近表明，C2结构域内的表位特异性和抑制剂动力学是 在获得的血浆血浆中对FVLLL响应的抑制剂滴度更重要 单克隆抗体（MAB）系统。该项目的中心假设是抑制剂表位 单个患者的频谱可用于预测有或没有的情况下对FVIII输注的反应 绕过代理。我们建议使用大型非重叠面板进一步定义FVIII的表位 在多个体外测定中进行的antl-FVIII mAb（AIM 1）。给定不同体外之间的已知差异 测定和出血表型我们将研究不同表位对鼠体内出血的重要性 表型和纤维蛋白凝块结构（AIM 2）。在AIM 3中，我们将调整我们的基于ELISA的新型表位映射 在横断面研究中进行更强大的基于微球的测定和调查的方案 多克隆患者血浆表位图与对FVIII的反应和体外绕过剂的反应相关。 最终，这些结果可能会提供一个简单的临床测试，可以预测对FVIII的反应并绕过 高滴水的药物获得了先天性血友病患者。