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: 10609402
• 负责人: Michelle Louise James
• 金额: $ 37.11万
• 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/10609402
• 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; 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; Human; Image; Immune; ImmunoPET; 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; Neurologic Dysfunctions; Non-Invasive Detection; Organ; Pathogenicity; Pathology; Patient Selection; 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; Variant; Visualization; biomarker driven; central nervous system demyelinating disorder; clinical translation; clinically relevant; comparison control; cost; disability; experimental study; imaging agent; immune cell infiltrate; immunoreactivity; improved; in vivo; insight; mouse model; multiple sclerosis patient; multiple sclerosis treatment; nervous system disorder; novel; patient stratification; 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）是影响的最常见的脱髓鞘中枢神经系统（CNS）疾病 年轻人，通常导致不可逆的神经功能障碍。 B淋巴细胞起着复杂而关键的作用 在MS病理学中的作用，是临床试验中几种治疗剂的靶标。而单克隆抗体 靶向B细胞表面标记CD20（即利妥昔单抗，ocrelizumab）大大减少了年化 复发率和延迟障碍进展，并非所有患者都反应，这可能是由于异体性质 多发性硬化症。当前，尚无批准的技术来非侵入性地可视化中枢神经系统中的B细胞以选择MS 抗B细胞疗法和监测治疗反应的患者。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，针对CD19和/或CD20标记的宠物示踪剂可以揭示有关该的动态信息 广泛的B细胞的病理生理学，最终实现了对B细胞负荷的治疗作用的定量 实时在中枢神经系统和外围器官中。迄今为止，只有一个CD20+ B细胞的宠物示踪剂已经发生 在MS中进行初步评估，并且尚未开发用于成像CD19的宠物示踪剂 B细胞的范围更广（包括疑似的致病抗体分泌浆质和循环 浆细胞）。在这里，我们建议基于临床认可的CD19和 CD20单克隆抗体疗法。这样的宠物示踪剂可能会经历相对较快的临床翻译和 立即对患者分层，剂量和实时治疗监测产生影响。我们的假设是 CD19和CD20靶向宠物示踪剂将使各种B细胞的非侵入性，灵敏和特定检测 在MS的背景下，中枢神经系统和外围的子集。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，该成像在体内检测和量化B细胞中的体内检测和定量 MS的鼠模型中的中枢神经系统和周围组织，称为实验性自身免疫性脑脊髓炎 （eae）。在此提案中，除了开发第一个报告的人类外，我们还将基于我们已发表的数据 CD19-PET示踪剂。我们将通过以下特定目标来实现我们的目标：1）开发免疫-PET示踪剂 为了成像不同的B细胞吸收，2）评估细胞中CD19和CD20成像剂的生物学作用 3）评估CD19/CD20 PET示踪剂用于检测CNS中B细胞的特异性和灵敏度 MS小鼠模型的周围除了预测治疗反应的能力外。完成这些 实验将提供有关哪种B细胞宠物示踪剂似乎最有前途的宝贵信息 临床翻译同时还阐明了大脑中MS中B细胞的体内病理生理学和 超过。该提案解决了巨大的未满足临床需求，我们独特的方法具有很高的潜力 影响我们学习，监控和治疗MS的方式。

项目成果

Imaging CD19+ B Cells in an Experimental Autoimmune Encephalomyelitis Mouse Model using Positron Emission Tomography.

使用正电子发射断层扫描对实验性自身免疫性脑脊髓炎小鼠模型中的 CD19 B 细胞进行成像。

• DOI: 10.3791/64133
• 发表时间: 2023
• 期刊: Journal of visualized experiments : JoVE
• 作者: Reyes,SamanthaT;Azevedo,ECarmen;Cropper,HaleyC;Nagy,Sydney;Deal,EmilyM;Chaney,AislingM;James,MichelleL
• 通讯作者: James,MichelleL