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

对大脑及其他部位的 B 细胞进行成像：开发免疫 PET 工具箱以增进对多发性硬化症的理解和治疗

• 批准号: 10397150
• 负责人: Michelle Louise James
• 金额: $ 37.1万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10397150
• 关键词: Address; Affect; Affinity; Aftercare; American; Antibodies; Area; B cell therapy; B-Lymphocyte Subsets; B-Lymphocytes; Biological; Brain; CD19 gene; CD20 Antigens; Cell Count; Cell surface; Cells; Cellular Assay; Cellular biology; Central Nervous System Diseases; Clinic; Clinical; Clinical Trials; Complex; Data; Detection; Development; Disease; Dose; Evaluation; Experimental Autoimmune Encephalomyelitis; FDA approved; Fc domain; Flow Cytometry; Functional disorder; Future; Goals; Gold; Human; Image; Immune; Immunoglobulin Fragments; In Vitro; Individual; Injections; Knowledge; Label; Light; MS4A1 gene; Mediating; Monitor; Monoclonal Antibodies; Monoclonal Antibody CD20; Morbidity - disease rate; Multiple Sclerosis; Mus; Mutate; Myelin; Nature; Nerve Degeneration; Neuraxis; Neurologic Dysfunctions; Organ; Pathogenicity; Pathology; Patients; Peripheral; Phenotype; Physiological; Plasma Cells; Plasmablast; Play; Positron-Emission Tomography; Prediction of Response to Therapy; Publishing; Radioimmunoconjugate; Relapse; Reporting; Role; Sensitivity and Specificity; Signal Transduction; Surface Antigens; Techniques; Therapeutic; Therapeutic Effect; Therapeutic Monoclonal Antibodies; Time; Tissues; Tracer; Translating; Tumor-infiltrating immune cells; Variant; base; biomarker-driven; central nervous system demyelinating disorder; clinical translation; clinically relevant; cost; disability; experimental study; imaging agent; immunoreactivity; improved; in vivo; insight; mouse model; multiple sclerosis patient; multiple sclerosis treatment; nervous system disorder; novel; patient stratification; radiotracer; response; rituximab; spatiotemporal; success; therapeutic target; treatment optimization; treatment response; young adult

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.

项目摘要 多发性硬化症（MS）是最常见的中枢神经系统（CNS）脱髓鞘疾病， 年轻人，往往导致不可逆的神经功能障碍。B淋巴细胞在免疫系统中起着复杂而关键的作用， 在MS病理学中的作用，并且是临床试验中几种治疗剂的靶点。虽然单克隆抗体 靶向B细胞表面标志物CD 20（即利妥昔单抗、Ocrelizumab）显著降低了 复发率和延迟残疾进展，但并非所有患者都有反应，可能是由于 女士目前，还没有批准的技术来非侵入性地可视化CNS中的B细胞以选择MS 患者进行抗B细胞治疗并监测治疗反应。正电子发射断层扫描（PET）成像 通过跟踪B细胞提供高度特异性的定量信息，具有填补这些空白的巨大潜力。 值得注意的是，靶向CD 19和/或CD 20标记物的PET示踪剂可以揭示关于细胞的动态信息。 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 在中枢神经系统和周围器官的真实的时间。迄今为止，仅对一种用于CD 20 + B细胞的PET示踪剂进行了研究。 在MS中进行了初步评估，并且没有开发PET示踪剂用于成像CD 19，表达在 更广泛的B细胞（包括可疑的分泌病原性抗体的浆母细胞和循环 浆细胞）。在这里，我们建议基于临床批准的CD 19开发新型免疫PET示踪剂， CD 20单克隆抗体治疗。这种PET示踪剂可以经历相对快速的临床转化， 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 靶向CD 19和CD 20的PET示踪剂将能够非侵入性、灵敏和特异地检测各种B细胞， 在MS的背景下，我们以前已经证明了B的可行性， 细胞特异性PET成像与[64 Cu]利妥昔单抗，这使得体内检测和定量的B细胞， MS小鼠模型（称为实验性自身免疫性脑脊髓炎）中的CNS和外周组织 （EAE）。在这项提案中，我们将建立在我们公布的数据，除了开发第一个报告的人类 CD 19-PET示踪剂。我们将通过以下具体目标来实现我们的目标：1）开发免疫PET示踪剂 用于成像不同的B细胞亚群，2）评估CD 19和CD 20成像剂在细胞中的生物效应， 评价CD 19/CD 20 PET示踪剂检测CNS中B细胞的特异性和灵敏度 和MS小鼠模型的外周，以及它们预测治疗反应的能力。完成这些 实验将提供关于哪种B细胞PET示踪剂最有希望用于 临床翻译，同时也阐明了MS中B细胞在脑中的体内病理生理学， 超越。该提案解决了一个重大的未满足的临床需求，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MS的方式。