Someone said you have you seen this?…AAN2019

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A presentation at AAN2019, seemingly attempts to discredit the view that we suggested that neutralizing antibodies can be important for some people with MS who are taking alemtuzumab. So you asked have I seen it?

Antidrug Antibodies Have Minimal Impact on the Pharmacodynamic Profile and Clinical Efficacy of Alemtuzumab in RRMS Patients From the CARE-MS Studies Tjalf Ziemssen , Antonio Bertolotto , Samuel F Hunter , Jan Lycke , Alan Jacobs , Luke Chung , Qifeng Yu , Isabel Firmino , Christopher LaGanke

However it is been presented in support to the approval of people being allowed to use dose 3 or more in treatment failers. But of course I haven’t seen it….I’m not at the meeting but I guess it is similar to the poster presented at ECTRIMS 2018 by only Jacobs A, Chung L , Yu Q , Firmino I which did not seem to have the extra academics. I will get to see it as we have Spies (Neuros) at the meeting and the code means we can get it whilst the link is active.

The poster at ETRIMS 2018 reports on anti-drug antibodies and says they make no effect. Sure I buy and know this at the population level. This was presented much earlier by the Cambridge group.

However the ADA are made up of binding antibodies and neutralizing antibodies. Binding antibody levels are about 90% more common than neutralizing antibodies. So we need to askwhat happens when you only look at neutralizing antibodies. In the CARE-MS trials 75% of people had binding ADA but only about 30% had the neutralizing antibodies that could stop the drug working. Those with low levels (Titres) of neutralizing antibody levels still deplete, we know and accept this. So is it surprising that ADA do not impact on the clinical course. Not really

What happens to the individuals?. This is the information that I have asked about over and over again. Some people will not respond the question is how many?

The neutralizing antibodies were invisible from Google searches as they were called “inhibitory antibodies” in the regulatory documents, rather than neutralizing antibodies. I stumbled across them because the document containing the inhibitory antibodies in MS on page XXX had neutralizing antibodies in relation to a monkey experiment on page YY.

That set off my conpiracy theory.

I suspect that the dosing schedule of alemtuzumab was actually generted to limit the effect of ADA, Cambridge even did studies to get rid of them, you wouldn’t do that if they were not an issue. But they were never mentioned during the commercial development. The irony is that alemtuzumab was the worlds first antibody designed to get rid of ADA, when its biology makes it probably the worse antibody for generating ADA, because I think it blocks tolerance and so all the immune system sees when it is being infused is alemtuzumab and over 60% of people make ADA in the first month when there are essentially no lymphocytes at least in the circulation.

This makes you ask is being hidden?

In the past, in the haste to show that you can go onto fingolimod if alemtuzumab fails they pinged out a a poster at the European Neurolgy meeeting in 2015, but forgot to look at the actual response and perhaps the reason why the person was switched to fingolimod, as they were perhaps too focused on fingolimod. They (Selmaj et al.2015) showed that 2 out of 6 people did not deplete on the third cycle of alemtuzumab. One imagines this may contribute to the idea to switch to fingolimod.

Of course we know that most people respond to alemtuzumab, we don’t need to see the poster we can read the work from Cambridge. The question is how many don’t?

If you dig you find dirt, mole hills contain dirt , this subtifuge allows one to make a mountain, well at least three papers, of it.

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MouseDoctor

6 comments

  • I am one of those patients who on the third round did not deplete at all. In fact, it increased my lymphocyte count by the 30 day post infusions mark, and continued to proliferate lymphocyte count very rapidly to a level that my body even pre-Lemtrada had never seen. I questioned my clinic and my Neuro intensely, and apparently this made it to the national level of health as it had to be reported as an adverse reaction. The aftermath of the experience threw me into a massive relapse that has taken months and months out of my life trying to recover from. It was denied to me that I had any ADA that would have been the cause of such an experience. I would be happy to share more about this experience to anyone in your team who needs clinical data.

    • Please do get in contact, our contact emails are on the blog.

      I am very sorry to hear your experience. This is exactly the reason I am being a pain in the manufacturer’s bum as it is not the population that sufferes it is the individual. I believe this aspect could and should have been de-risked by testing. They have the data and my questions, but evasion is key.

      However, if your neuro has not been told that ADA exist then it is hard to think about. If you have frozen blood samples from that time they can be tested. I know it is no concellation to you, but people on the drug need to be be aware to be vigulent.

      We too had one person who was not doing well on alemtuzumab which made us ask the question about ADA and we were likewise fobbed off. The sad thing is that these can be measured and it could help inform about the value of the third, forth dose and demonstrates that you have to check your lymphocyte depletion after each cycle and if you are not depleting you need to think about switch

  • An anti CD20 complication

    Immunological phenotyping identifies a subgroup of MS patients experiencing a pro-inflammatory immune cell activation upon therapeutic B cell removal
    http://indexsmart.mirasmart.com/AAN2019/PDFfiles/AAN2019-001530.pdf

    Objective: To study how anti-CD20 treatment of multiple sclerosis (MS) patients affects activation and cytokine production of myeloid antigen-presenting cells (APC) and T cells and whether a pre-existing regulatory B cell phenotype correlates with the extent of immune cell activation upon therapeutic B cell removal.
    Results: We identified a triangle of B, T and myeloid cells, in which B cell-derived interleukin-6 enhanced myeloid APC and T cell activation. Conversely, B cell-produced interleukin-10 regulated the APC-T cell axis in an anti-inflammatory manner. Reflecting these interactions, we identified distinct subgroups of MS patients with a pro- versus anti-inflammatory differentiation of monocytes and T cells after therapeutic removal of B cells.
    Conclusions: The B cell-generated cytokine milieu is capable of shaping the activity of other immune cells. While in most MS patients, anti-CD20 treatment resulted in a desirable immunological outcome, others displayed an accentuated immune cell activation. We hypothesize that the latter situation reflects the loss of pre-existing B cell regulation, which we are currently evaluating. In context with clinical data, these investigations aim to generate immunological biomarkers to identify individual patients in whom B cells should not be unselectively eradicated

    • This is interesting, thanks i will
      incorporate this into my next paper as it speaks to the need to be selective. A neurologist has suggested this possibility in the past. The precursor immature B cells are sometimes called transitional cells they may also be called regulatory B cells, they are depleted but usually come back first but IL-10 is a regulator. So i can see there could be issues

      • Read also this

        Treatment with IFN-β induces BAFF expression in myeloid cells, which in turn promote the expansion of transitional B cells. These transitional B cells have a regulatory function in autoimmune diseases and are capable of producing large amounts of IL-10 to suppress antigen mediated T-cell activity in healthy individuals. Remarkably, in SLE transitional B cells induce effector T-cell responses and are likely pro-inflammatory(10). Taken together, these data suggest that in RRMS patients IFN-β increases BAFF expression, and unlike in SLE and NMO, skews the B cell population toward a regulatory phenotype.

        Anti-CD20 therapy, such as rituximab, is remarkably effective in RRMS. This may seem to contradict our model. Yet, rituximab therapy has been shown to elevate BAFF levels in patients and regulatory transitional B cells are preferentially expanded after anti-CD20
        therapy(28), similar to what we found in IFN-β treated RRMS suggesting a possibly convergent mechanism. We hypothesize that a subset of RRMS patients who fail IFN-β therapy have pathogenic B cell responses or inadequate activation of regulatory B cell activity

        doi:10.4049/jimmunol.1402029

        Looks like antibodies are anti-inflamatory too

        However, more recent studies indicate that antibodies can also exert significant anti-inflammatory effects, which limit or even inhibit autoimmune pathogenesis. The pro- and anti-inflammatory effects of antibodies depend on their isotype (76) and on their Fc N-linked glycosylation patterns (77, 78). While IgGs with low levels of galactosylation promote inflammation, sialylated IgGs have a strong anti-inflammatory capacity (79, 80). Highly glycosylated IgG antibodies have been shown to inhibit autoimmune inflammation in mouse models (76, 81, 82). Changes in autoantibody glycosylation have been observed during the course of human autoimmune diseases, possibly providing an interesting novel diagnostic tool, but also suggesting that the antibody glycosylation pattern can alter the clinical course of autoimmune disorders (83

        In relapsing-remitting MS, the frequencies of IL-10+ CD19+ B cells were significantly reduced in patients experiencing a relapse compared with that in patients in remission (217), indicating that the clinical outcome of the disease also depends on the availability of IL-10-producing B cells.

        Moreover, a “good responder” to RTX in myasthenia gravis showed a rapid repopulation of CD19+ IL-10+ B cells after from 8 to 9 months compared with a “non-responder,” where repopulation was delayed (219). This shows that the kinetics of the IL-10+ B cell repopulation is related to the responsiveness to RTX. Similarly, Colliou et al. (221) have shown that RTX-treated PV patients in complete remission had fourfold higher numbers of IL-10+ CD19+ B cells compared with patients in incomplete remission. In SLE patients responding well to RTX treatment, IL-10+ CD24hi CD38hi B cells were found to repopulate and exhibited a restored suppressive function compared to non-responders (222

        Targeting B Cells and Plasma Cells in Autoimmune Diseases

        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924791/

        It seems that plasma cells are not all equal

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