Characterization of broadly neutralizing antibodies against JC virus

贝丝以色列女执事医疗中心的传染病医生陈萨布丽娜·谭博士试图 确立自己作为一个独立的物理学家，科学家进行神经病毒学的转化研究， 免疫学。K02奖将为她提供必要的保护时间和支持，以完成 在研究针对JC病毒（进行性多灶性肺炎的病原体）的抗体应答中， 白质脑病（PML）：1）表征抗JCV的中和抗体：2）确定是否 补体参与JCV免疫应答/中和;和3）广泛鉴定和克隆 中和抗体作为PML（由JCV引起的疾病）的潜在疗法。为了实现这些， 博士Tan召集了一批优秀的顾问和合作者。迈克尔·科兰博士和约恩博士 陈博士的实验室就在病毒学和疫苗研究中心（CVVR）， 将提供有关抗体中和试验的建议和指导。Dr. Schmitz，Flow主任 细胞计数核心设施，也将指导B细胞分选和分离。安妮·尼科尔森-韦勒博士， 传染病科的一位医生正在为谭博士的补体研究提供建议。基思·雷曼博士，高级 马萨诸塞州大学MassBiologics的主任将为克隆和构建 重组广泛中和单克隆抗体。 PML仍然是一种常见的致死性中枢神经系统（CNS）机会性感染性疾病 HIV感染者和接受免疫调节药物（如那他珠单抗或 富马酸二甲酯由于在大多数PML患者中检测到预先存在的抗JCV抗体，因此它们在PML中的作用可能是不确定的。 中枢神经系统感染的控制受到质疑。然而，最近的研究表明， JCV VP1衣壳蛋白的改变可改变糖基化并可能改变抗体结合。因此，在本发明中， 需要更好地研究JCV的抗体控制。我们的总体目标是更好地了解和利用 抗体免疫应答用于预防和治疗PML。核心假设是JCV特异性 中和抗体控制血液和脑中的JCV增殖。我们认为， CNS中抗JCV的抗体介导的应答以及抗JCV的广泛中和抗体的分离 JCV有可能转化为一类新的治疗方法。我们将通过追踪两个 具体目标：目标1。目的：研究JCV中和抗体的功能和作用机制， 患者目标2.鉴定抗JCV的广泛中和抗体。 这些拟议的研究将进一步发展谭博士作为抗体领域独立医生科学家的职业生涯， 介导的对CNS中病毒的应答，生成申请所需的初步数据， 在第3年获得R01，并为PML创造一种新的治疗方法。

Dr. Chen Sabrina Tan, an Infectious Diseases physician at Beth Israel Deaconess Medical Center, seeks to establish herself as an independent physician-scientist conducting translational research in Neuro Virology and Immunology. A K02 award will provide the protected time and support necessary for her to accomplish the following goals in studying antibody responses against JC virus, the etiologic agent of Progressive Multifocal Leukoencephalopathy (PML): 1) characterize neutralizing antibodies against JCV: 2) determine if complement participates in JCV immune response/neutralization; and 3) identify and clone broadly neutralizing antibodies as potential therapies for PML, the disease caused by JCV. To accomplish these, Dr. Tan has assembled a group of excellent advisors and collaborators. Drs. Michael Seaman and Joern Schmitz, long-term members of Center for Virology and Vaccine Research (CVVR), where Dr. Tan’s lab is located, will provide advice and guidance on antibody neutralization assays. Dr. Schmitz, Director of the Flow Cytometry Core Facilities, will also guide B cell sorting and isolation. Dr. Anne Nicholson-Weller, a member of the Division of Infectious Diseases, is advising Dr. Tan on complement studies. Dr. Keith Reimann, Senior Director at MassBiologics, University of Massachusetts, will advise on cloning and construction of the recombinant broadly neutralizing monoclonal antibodies. PML remains an often fatal opportunistic infectious disease of the central nervous system (CNS) in patients with HIV and those with multiple sclerosis treated with immune-modulatory medications such as natalizumab or dimethyl-fumarate. Since pre-existing anti-JCV antibodies are detected in most PML patients, their role in controlling CNS infection has been questioned. However, recent work has revealed that single amino acid alterations in the JCV VP1 capsid protein could change glycosylation and possibly alter antibody binding. Thus, antibody control of JCV needs to be better studied. Our overall goal is to better understand and harness the antibody immune response for prevention and treatment of PML. The central hypothesis is that JCV-specific neutralizing antibodies control JCV proliferation in the blood and brain. We posit that characterization of antibody-mediated responses against JCV in the CNS and isolation of broadly neutralizing antibodies against JCV has the potential to translate into a new class of therapeutics. We will test this hypothesis by pursuing two specific aims: Aim 1. To characterize the function and mechanism of JCV-neutralizing antibodies in patients. Aim 2. Identify broadly neutralizing antibodies against JCV. The proposed studies will further develop Dr. Tan’s career as an independent physician-scientist in antibody- mediated responses against viruses in the CNS, generate the necessary preliminary data to apply for and obtain an R01 by year 3, and create a novel therapy for PML.