Abstract
BackgroundB cells play a central role in multiple sclerosis (MS) through production of injurious antibodies, secretion of pro-inflammatory cytokines, and antigen presentation. The therapeutic success of monoclonal antibodies (mAbs) targeting B cells in some but not all individuals suffering from MS highlights the need for a method to stratify patients and monitor response to treatments in real-time. Herein, we describe the development of the first CD19 positron emission tomography (PET) tracer, and its evaluation in a rodent model of MS, experimental autoimmune encephalomyelitis (EAE).MethodsFemale C57BL/6 J mice were induced with EAE through immunization with myelin oligodendrocyte glycoprotein (MOG1–125). PET imaging of naïve and EAE mice was performed 19 h after administration of [64Cu]CD19-mAb. Thereafter, radioactivity in organs of interest was determined by gamma counting, followed by ex vivo autoradiography of central nervous system (CNS) tissues. Anti-CD45R (B220) immunostaining of brain tissue from EAE and naïve mice was also conducted.ResultsRadiolabelling of DOTA-conjugated CD19-mAb with 64Cu was achieved with a radiochemical purity of 99% and molar activity of 2 GBq/μmol. Quantitation of CD19 PET images revealed significantly higher tracer binding in whole brain of EAE compared to naïve mice (2.02 ± 0.092 vs. 1.68 ± 0.06 percentage of injected dose per gram, % ID/g, p = 0.0173). PET findings were confirmed by ex vivo gamma counting of perfused brain tissue (0.22 ± 0.020 vs. 0.12 ± 0.003 % ID/g, p = 0.0010). Moreover, ex vivo autoradiography of brain sections corresponded with PET imaging results and the spatial distribution of B cells observed in B220 immunohistochemistry—providing further evidence that [64Cu]CD19-mAb enables visualization of B cell infiltration into the CNS of EAE mice.ConclusionCD19-PET imaging can be used to detect elevated levels of B cells in the CNS of EAE mice, and has the potential to impact the way we study, monitor, and treat clinical MS.
Highlights
B cells play a central role in multiple sclerosis (MS) through production of injurious antibodies, secretion of pro-inflammatory cytokines, and antigen presentation
Disease induction EAE was induced by subcutaneous injection of MOG1-125 in female C57BL/6 J mice to evaluate the utility of [64Cu]CD19-Monoclonal antibody (mAb) for in vivo detection of B cells in a murine model of MS
B cells were found in dense clusters similar to follicle-like structures observed in the meninges of MS patients, with a highly heterogeneous spatial distribution [16]
Summary
B cells play a central role in multiple sclerosis (MS) through production of injurious antibodies, secretion of pro-inflammatory cytokines, and antigen presentation. Newer B cell therapies have been developed that target CD19; a pan-B cell surface marker expressed across a broader range of B cell subsets than CD20 [5] One such example is inebilizumab [6], which demonstrated favorable safety and tolerability in a phase I MS trial and marked efficacy in neuromyelitis optica (NMO), another immune-mediated CNS disease affecting the spinal cord and optical nerve [7, 8]. These promising B cell-targeted therapies exist, there is currently no way to accurately select patients for these treatments or to quantify their effects on B cell load in the CNS and peripheral organs
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