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.

项目总结

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