ACTRIMS 2021 Guess what ocrelizumab depletes memory B cells and in doing so gets rid of EBV infected cells

A

This is a bit of a No-S-Sherlock moment. If you take anti-CD20 antibodies it depleted peripheral blood B cells out of sight. So in this study they look at the CD19 B cell subsets and conclude it depletes naive and memory B cells which express CD20. There is no suggestion that it may work because of this, but if there is no body because it has been blasted with a shot-gun you would not expect to find the head living. However, we can now say ocrelizumab depletes memory B cells from the blood, it is not officical as the manusfactures have confirmed what we showed last year, using their data from 2012.

S. Hauser, N. Strauli, A. Raievska, C. Harp, H. Koendgen, H. Kletzl, U. Bonati, X. Jia, A. Herman, L. Kappos, A. Bar-Or

Background: B cells play a pathogenic role in multiple sclerosis (MS), with certain B-cell subsets (memory, plasmablast/plasma cells) elevated in cerebrospinal fluid (CSF) vs blood. B cells, including those in central nervous system lymphoid aggregates, have been implicated in chronic inflammation potentially responsible for disease progression. Ocrelizumab (OCR) depletes CD19+ B cells in blood and CSF, reduces CSF immunoglobulin (Ig) G synthesis, and reduces disease activity and progression in patients with relapsing multiple sclerosis (RMS).
Objectives: To assess the impact of OCR treatment on blood B cells and B-cell subsets in patients with RMS from the OPERA I (NCT01247324) and OPERA II (NCT01412333) trials.
Methods: Total B-cell (CD19+) and B-cell subset (mature naive [CD19+/IgD+/CD27], memory B cell [CD19+/CD27+/CD38low], double-negative memory B cell [CD19+/IgD/CD27] and plasmablast/plasma cell [CD19+/CD27++/CD38++]) levels were measured via flow cytometry in whole blood samples in 1,645 patients with RMS at study baseline and before each OCR infusion (weeks 24, 48, 72, 96). Median cell count (cells/μL) was calculated across timepoints, and the proportion of patients with median B-cell count below the lower limit of quantification was assessed for each B-cell subtype across treatment arms and mean OCR exposure quartiles (measured as mean OCR concentration over treatment duration).
Results: Total B cells and all B-cell subsets were significantly depleted by OCR (p<0.005) and progressively depleted following repeated dosing. Patients in the upper quartiles of OCR exposure had a higher proportion of B-cell/B-cell-subset depletion when compared with patients in the lowest quartile (all p<0.005). CD19+/CD27++/CD38++ cells, mainly plasmablasts in blood, had the lowest relative reduction, and mature naive B cells had the greatest.
Conclusions: Ocrelizumab treatment induces a significant depletion of all B-cell subsets measured, with CD19+/CD27++/CD38++ cells reducing the least, likely representing plasmablasts with low/absent CD20 expression. Greater ocrelizumab exposure, as well as repeated dosing, was associated with greater reduction of all B-cell subsets

So bring on the DoDo (Double Dose) as it says you are under dosing or if you are being vaccinated for Covid-19 we can create a hypothesis for DrRuth in that the larger people will make a larger COVID-19 vaccine response because they will repopulate their B cells better. However it also says that the plasmablasts don’t get depleted very well and this is good because when you get vaccinated these and the plasma cells make antibodies, so once they are formed they will not be smashed by subsequent doses.

It also seems t be sales-time as we get a two-for-one poster.

Deplete your B cells and you get rid of memory B cells, but guess what you also get rid of EBV because it creates and lives in memory B cells

P064 / P064 – Ocrelizumab treatment decreases the cellular immune response to autologous Epstein-Barr virus infected cells. J. W. Lindsey, H. P. Pham

Background: Epstein-Barr virus (EBV) is strongly associated with multiple sclerosis (MS), but the mechanism by which EBV might cause MS is unclear. After initial infection, EBV maintains a life-long latent infection in B lymphocytes. Depletion of circulating B lymphocytes with the anti-CD20 monoclonal antibody ocrelizumab (OCR) is an extremely effective treatment for MS. We hypothesize that MS results from molecular mimicry between EBV and brain antigens, and that the disease process is driven by repeated activation of the cross-reactive immune response by the persistent, EBV-infected cells. We also hypothesize that OCR reduces disease activity by depleting EBV-infected cells, thus removing the driving stimulus for the autoimmune reaction. If this is the case, then the anti-EBV immune response should decrease with OCR treatment.
Objectives: Our objective was to measure the anti-EBV immune response over time in OCR treated patients.
Methods: We collected blood from 30 MS patients before starting OCR and after 6 and 12 months of treatment, isolated peripheral blood mononuclear cells (PBMC), and stored the PBMC frozen in liquid nitrogen. When all blood samples for a patient were collected, we thawed the cells and stimulated them with EBV, varicella zoster virus (VZV), autologous EBV-infected lymphoblastoid cell lines (LCL), and the mitogen PMA. Tritiated thymidine was added on day 4, and the assay was harvested and counted on day 5. The proliferation was expressed as the counts per minute (cpm) with each antigen. To control for the anticipated variation in proliferative capacity between blood samples collected at different times, we analyzed the data as ratios between responses expected to change (EBV and LCL) and responses expected to remain stable (VZV, PMA).
Results: The ratio of cpm with LCL to cpm with PMA decreased over time, with the ratio at 12 months being decreased by a mean of 32% compared to baseline. The response to LCL was decreased at 12 months in 22 of 30 subjects (p=0.005, binomial distribution). The ratio of cpm with EBV to VZV did not change significantly, with a mean decrease of 7%, and 14 of 27 subjects with a decrease. The mean cpm with LCL was decreased at 12 months while the cpm with PMA was higher. Neither of these trends were statistically significant, but the result with PMA suggests that the frozen cells lost proliferative capacity over time.
Conclusions: The proliferative response to autologous LCL decreases after OCR treatment. This suggests that the mechanism of action of OCR may be via the removal of the EBV infected cells. Treatments specifically targeting EBV infected cells could be more effective with less concerns for immunosuppression.

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