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

描述（由申请人提供）：30%接受因子fVIII （fVIII）治疗的严重血友病患者产生抗fVIII抗体（抑制剂）。这是A型血友病患者管理中最重要的并发症，导致发病率和治疗费用增加。这些产生的抗体可以抑制fVIII的生物活性。已知fVIII的5个结构域具有重要的功能，抗体通常针对fVIII的A2和C2结构域。然而，我们最近发现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具有非常高滴度非经典抑制剂的小鼠单克隆抗体（MAb）系统中，对fVIII的反应中，C2结构域内的特异性表位（经典与非经典）比抑制剂滴度更重要。中央

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.