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.
So double-dosing works because of more complete depletion rather than more OCR going into CNS? Gotta work on my body weight to maximize protection then :)..
I think the second idea is the driver…I believe efficacy in relapse is not related to size but it is for progression, this could predict that the memory Bs get it. But thanks for this because it is something we can test.
Isn’t the second study relevant and shouldn’t “healthy” RMS specimens like me be getting OCR to zap EBV cells.?How much needs to be done consequent on this study before such a scenario is a possible/probabl/certain?
Will rituximab do the same thing?
So I’m more protected as a thin person?
And cure EBV, cure MS. Hmm who’s suggested that before?
You know me I just re-cycle ideas until people think they are their own:-)
So OCR could be an effective treatment for chronic active EBV?
“Treatments specifically targeting EBV infected cells could be more effective with less concerns for immunosuppression.”
Yes yes yes. And yes again. Please hurry.
With the btk inhibitors pharma all jumped in at once. Do you expect the same thing to happen in terms of targeting ebv will pharma once again all jump in at once ?
I think Merck got in there first and gave them all a sniff it was a good idea. With regards to EBV what will Moderna do…licence of MS franchise
Interesting thank you for sharing your thoughts 🙂
Could this suggest anything about a different disease etiology for the minority who fail on an anti-CD20 while fully suppressed?
maybe I am willing to entertain this but there are ocreliuma failures due to genetics related to ocrelizumab
if one fails on rituximab, would ofatumumab or ocrelizumab make a difference?
I add a question on this topic: those who fail on Anti-CD20 fail to deplete or have relapses despite depletion?
There are clearly people who relapse despite depletion, not sure on how many people fail to deplete
It would be very interesting to look into the population of those who relapse.
If they fail to deplete we know what is going on.
If they deplete and they relapse shortly after the treatment maybe the drug did not kick in on time. If they relapse despite depletion and sustained depletion maybe we are in front of a different disease or genetics that does involve the CD20… weren’t those people investigated more in depth? 🙁
A bit unrelated but it has to do with Anti-CD20 and EBV. I came across this:
that points to this:
They say that there is a way to sensitize EBV to ganciclovir in people taking rtx adding dexamethasone. Do you think it could be useful to try to clear EBV? Thank you
Show the evidence otherwise it si just an idea….
if they try the same procedure with Ublituximab I’m sure they would find a stronger ebv removal
Not sure why ubituximab is engineered to be like ocrelizumab