Is CD20 therapy getting rid of the cause of MS?


2022 was the year of re-birth of a view that Epstein Barr Virus (EBV( is a cause of MS in the eyes of many scientists……so I expect to hear that MS therapies are being rebranded as anti-viral therapies. ProfG has been saying this for ages, so I hear it all the time….is this how CD19+ CAR-T therapy would work?

What’s the logic?

All effective therapies in MS target B cells to some extent. EBV infects and lives in B cells so it is obvious that if you remove B cells you remove EBV….so all B cell therapies are EBV therapies. Some more than others. We have heard how teriflunomide may be anti-viral…but I say it is either a weak anti-viral or the idea isn’t that good because of its efficacy. However ,the obvious ones are with the CD20 B cell therapies

Ocrelizumab depletes CD20 B cells…..EBV makes CD20+ memory B cells to live in….EBV is the cause of MS…….therefore ocrelizumab is depleting EBV and the cause of MS.

B cells generate plasma cells (CD20 negative) that are the cells that make antibodies and we know all too well from SARS-CoV2 vaccinations that CD20 depleting antibodies can inhibit the level of viral (SARS-CoV-2) responses.

We have also had anti-EBV antibodies (notably those against EBNA-1) cross-react with nerve proteins to cause/augment MS too. So as ocrelizumab inhibits active MS, does it affect antibodies to EBV?

Pham HPT, Saroukhani S, Lindsey JW. The concentrations of antibodies to Epstein-Barr virus decrease during ocrelizumab treatment. Mult Scler Relat Disord. 2023 Jan 2;70:104497. doi: 10.1016/j.msard.2023.104497.

Background: Epstein-Barr Virus (EBV) is strongly associated with multiple sclerosis (MS). After initial infection, EBV maintains a life-long latent infection in B lymphocytes. Depletion of B lymphocytes from the blood with the anti-CD20 antibody ocrelizumab (OCR) markedly reduces disease activity in MS. Our objective was to measure the effect of OCR treatment on the antibody response to EBV and human antigens that are cross-reactive with EBV.

Methods: Blood was collected from MS patients before and during OCR treatment. Antibodies to three EBV antigens (EBNA-1, BFRF3, and gp350) and three human proteins that are cross-reactive with EBV (septin-9, DLST, and HNRNPL) were quantified with Western blots. Antibodies to EBNA-1 and BFRF3 were also quantified with ELISA.

Results: Antibodies to the EBV proteins BFRF3 and EBNA-1 measured on Western blot were significantly decreased after 12 months on OCR. Subsequent testing with ELISA confirmed the decrease for both BFRF3 and EBNA-1. With Western blots, there was a trend to decreased antibody response to septin-9 and DLST, but not HNRNPL. Total IgG concentration did not change.

Conclusion: The antibody response to some EBV antigens decreases in OCR treated patients. The benefit of OCR for MS may be through removal of EBV antigenic stimulus.

So here, there is a drop in EBV-specific antibodies over 12 months at a time when total IgG has not dropped. However, the drop is only about 20% over the year and MRI lesions would drop over 90% in this time and MS would be inhibited, so I suspect that removing EBV atibodies are not the main treatment benefit from ocrelizumab. Ocrelizumab is not going to target the antibody producing cells directly but can stop them forming, so does this suggest that there is a turn over of EBV specific B cells. I suspect so as we will be encountering this virus frequently. In the paper is says “The change in the antibody response is noteworthy since antibody responses decay slowly, with the antibody response to EBV estimated to have a half life on the order of thousands of years in healthy humans (Amanna et al., 2007).” 

Although IgG levels do not drop in the first year of treatment with time IgG levels do drop (10-20% within about 5 years) and this is associated with the occurrence of serious infections (based on Swedish rituximab data) suggesting that infection specific antibodies drop with time.

We know that ocrelizumab drops IgM antibody levels by about 25% within a few months and this may increase to over 50% with time. So the question is, Is there anything special going on? Is there something magic about ocrelizumab and anti-EBV antibodies or is it a generalized phenomenon? Clearly responses to EBV proteins are not all affected equally, but it a shame that responses to other viruses were not compared. What happens with SARS-CoV-2 antibodies?

CoI: None

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  • > What happens with SARS-CoV-2 antibodies?

    I never got measurable cd20 and no antibodies despite three rounds of Comirnaty… My suspicion is that the people who got antibodies from the vaccine had minimal levels of cd20 cells?

  • so I suspect that removing EBV atibodies are not the main treatment benefit from ocrelizumab.

    There is evidence that the antibody-
    producing function of B-lineage cells is
    important in some multiple sclerosis lesions.7
    However, because of the rapidity of the clinical
    response to B-cell depletion (as early as 8 to 12
    weeks), even before the reduction of circulating
    immunoglobulin, it seems more likely that other
    functions of B cells, including antigen presentation
    to helper T cells and cytokine production, are
    more relevant

    Yep others do also

    DOI: 10.1056/NEJMra1401483l

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