Imaging B cells in the brain and beyond: developing an immuno-PET toolbox to improve understanding and treatment of multiple sclerosis

项目摘要 多发性硬化症(MS)是最常见的脱髓鞘中枢神经系统(CNS)疾病 年轻人，常常导致不可逆转的神经功能障碍。B淋巴细胞扮演着复杂而关键的角色 在多发性硬化症病理中的作用，并在临床试验中是几种疗法的靶点。而单抗 靶向B细胞表面标记CD20(即Rituximab，Ocrelizumab)显著减少年化 复发率和延迟残疾进展，并不是所有患者都有反应，可能是由于 目前，还没有批准的技术来无创地可视化中枢神经系统中的B细胞以选择多发性硬化症 患者接受抗B细胞治疗并监测治疗反应。正电子发射断层扫描(PET)成像 有巨大的潜力通过跟踪B细胞提供高度特异的定量信息来填补这些空白。 值得注意的是，针对CD19和/或CD20标记的PET示踪剂可以揭示 广泛的B细胞的病理生理学，最终能够量化对B细胞负荷的治疗效果 在中枢神经系统和外周器官中进行实时检测。到目前为止，只有一种用于CD20 B细胞的PET示踪剂 在MS中的初步评估，还没有开发出用于成像CD19的PET示踪剂，CD19表达在 范围更广的B细胞(包括疑似致病抗体分泌的浆母细胞和循环 浆细胞)。在这里，我们建议开发基于临床批准的CD19和CD19的新型免疫-PET示踪剂 CD20单抗治疗。这种PET示踪剂可以进行相对较快的临床翻译和 对患者分层、给药和实时治疗监测产生直接影响。我们的假设是 以CD19和CD20为靶点的PET示踪剂将使各种B细胞的非侵入性、敏感性和特异性检测成为可能 在中枢神经系统和外周的子集，在女士的背景下，我们以前已经证明了B的可行性 用[64Cu]利妥昔单抗进行细胞特异性PET成像，使体内B细胞的检测和定量成为可能 实验性自身免疫性脑脊髓炎MS小鼠模型的中枢神经系统和外周组织 (EAE)。在这项提案中，除了开发第一例报告的人类外，我们还将建立在我们已发表的数据的基础上 CD19-PET示踪剂。我们将通过以下具体目标实现我们的目标：1)开发免疫-PET示踪剂 为了对不同的B细胞亚群进行成像，2)评估CD19和CD20显像剂在细胞和 3)评价CD19/CD20 PET示踪剂检测中枢B细胞的特异性和敏感性 以及多发性硬化症小鼠模型的外围，以及它们预测治疗反应的能力。完成这些任务 实验将提供关于哪些B细胞PET示踪剂最有希望的宝贵信息 临床翻译，同时也揭示了大脑和大脑中多发性硬化症B细胞的体内病理生理学 更远一点。这项建议解决了一个重要的未得到满足的临床需求，我们独特的方法具有很高的潜力 影响我们研究、监测和治疗多发性硬化症的方式。

Project Summary Multiple sclerosis (MS) is the most common demyelinating central nervous system (CNS) disease affecting young adults, often resulting in irreversible neurological dysfunction. B lymphocytes play a complex and critical role in MS pathology and are the target of several therapeutics in clinical trials. While monoclonal antibodies targeting the B cell surface marker CD20 (i.e. Rituximab, Ocrelizumab) dramatically reduce the annualized relapse rate and delay disability progression, not all patients respond, likely due to the heterogenous nature of MS. Currently, there is no approved technique to noninvasively visualize B cells in the CNS in order to select MS patients for anti-B cell therapies and monitor treatment responses. Positron emission tomography (PET) imaging has enormous potential to fill these gaps by providing highly specific, quantitative information by tracking B cells. Notably, PET tracers targeting CD19 and/or CD20 markers could reveal dynamic information on the pathophysiology of a wide range of B cells, ultimately enabling quantification of therapeutic effects on B cell load in the CNS and peripheral organs in real time. To date, only one PET tracer for CD20+ B cells has undergone preliminary evaluation in MS, and no PET tracers have been developed for imaging CD19, expressed on a broader range of B cells (including suspected pathogenic antibody-secreting plasmablasts and circulating plasma cells). Here, we propose to develop novel immuno-PET tracers based on clinically approved CD19 and CD20 monoclonal antibody therapeutics. Such PET tracers could undergo relatively rapid clinical translation and have immediate impact on patient stratification, dosing, and real-time therapy monitoring. Our hypothesis is that CD19 and CD20-targeted PET tracers will enable non-invasive, sensitive, and specific detection of various B cell subsets in the CNS and periphery, in the context of MS. We have previously demonstrated the feasibility of B cell specific PET imaging with [64Cu]Rituximab, which enabled in vivo detection and quantification of B cells in CNS and peripheral tissues in a murine model of MS, known as experimental autoimmune encephalomyelitis (EAE). In this proposal, we will build on our published data in addition to developing the first reported human CD19-PET tracer. We will achieve our goals through the following specific aims: 1) Develop immuno-PET tracers for imaging different B cell-subsets, 2) Assess biological effects of CD19 and CD20 imaging agents in cells and mice, and 3) Evaluate the specificity and sensitivity of CD19/CD20 PET tracers for detecting B cells in the CNS and periphery of MS mouse models in addition to their ability to predict treatment response. Completing these experiments will provide invaluable information regarding which B cell PET tracers appear most promising for clinical translation while also shedding light on the in vivo pathophysiology of B cells in MS in the brain and beyond. This proposal addresses a significant unmet clinical need and our unique approach has high potential to impact the way we study, monitor, and treat MS.