Wednesday, 22 November 2017

Imaging B cells

B cells are becoming increasingly seen as an important subset of cells and they have been implicated as drivers of progressive MS. 

There will be an increasing number of B cell therapies arriving and so being able to assess whether they get rid of B cells in the brain is an important step. 

This study reports on the production of an imaging tool.  They use rituximab to image B cells in EAE. They show an increased disease. I was excited

Then I thought about it and now I have some doubts. 


The degree of infiltration in mouse EAE compared to MS is massive and the antibody is given during marked blood brain barrier dysfunction when antibody will get into mouse brain. 

However, the amount of antibody reaching the brain is going to be very very low in humans. Will it be enough?

We will need a chemical that gets in the brain. 

Also there is always a question of resolution and whether PET (positron emission tomography) can detect anything other than large aggregates.

However it's a start.

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Imaging B Cells in a Mouse Model of Multiple Sclerosis Using 64Cu-Rituximab PET.

James ML, Hoehne A, Mayer AT, Lechtenberg K, Moreno M, Gowrishankar G, Ilovich O, Natarajan A, Johnson EM, Nguyen J, Quach L, Han M, Buckwalter M, Chandra S, Gambhir SS.

J Nucl Med. 2017 Nov;58(11):1845-1851. doi: 10.2967/jnumed.117.189597. Epub 2017 Jul 7.

B lymphocytes are a key pathologic feature of multiple sclerosis (MS) and are becoming an important therapeutic target for this condition. Currently, there is no approved technique to noninvasively visualize B cells in the central nervous system (CNS) to monitor MS disease progression and response to therapies. Here, we evaluated 64Cu-rituximab, a radiolabeled antibody specifically targeting the human B cell marker CD20, for its ability to image B cells in a mouse model of MS using PET.

Methods: To model CNS infiltration by B cells, experimental autoimmune encephalomyelitis (EAE) was induced in transgenic mice that express human CD20 on B cells. EAE mice were given subcutaneous injections of myelin oligodendrocyte glycoprotein fragment1-125 emulsified in complete Freund adjuvant. Control mice received complete Freund adjuvant alone. PET imaging of EAE and control mice was performed 1, 4, and 19 h after 64Cu-rituximab administration. Mice were perfused and sacrificed after the final PET scan, and radioactivity in dissected tissues was measured with a γ-counter. CNS tissues from these mice were immunostained to quantify B cells or were further analyzed via digital autoradiography.

Results: Lumbar spinal cord PET signal was significantly higher in EAE mice than in controls at all evaluated time points (e.g., 1 h after injection: 5.44 ± 0.37 vs. 3.33 ± 0.20 percentage injected dose [%ID]/g, P < 0.05). 64Cu-rituximab PET signal in brain regions ranged between 1.74 ± 0.11 and 2.93 ± 0.15 %ID/g for EAE mice, compared with 1.25 ± 0.08 and 2.24 ± 0.11 %ID/g for controls (P < 0.05 for all regions except striatum and thalamus at 1 h after injection). Similarly, ex vivo biodistribution results revealed notably higher 64Cu-rituximab uptake in the brain and spinal cord of huCD20tg EAE, and B220 immunostaining verified that increased 64Cu-rituximab uptake in CNS tissues corresponded with elevated B cells.

Conclusion: B cells can be detected in the CNS of EAE mice using 64Cu-rituximab PET. Results from these studies warrant further investigation of 64Cu-rituximab in EAE models and consideration of use in MS patients to evaluate its potential for detecting and monitoring B cells in the progression and treatment of this disease. These results represent an initial step toward generating a platform to evaluate B cell-targeted therapeutics en route to the clinic

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