Repairing with alemtuzumab

R

If you are taking alemtuzumab you may be familiar with the idea that alemtuzumab promotes remyelination.

Here we have a new paper saying that by measuring electrical activity of nerves from the eye to the brain they can see remyelination after alemtuzumab treatment.

Masuda H, Mori M, Kuwabara S. Remyelination and neuroprotective effects of alemtuzumab therapy in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2021 Oct:jnnp-2021-326821.

I would say this is nothing new, indeed ProfC/ProfJ from Cambridge has infered the same effect based on the observation that people treated early in their MS appeared to recover function.

Jones JL, Anderson JM, Phuah CL, Fox EJ, Selmaj K, Margolin D, Lake SL, Palmer J, Thompson SJ, Wilkins A, Webber DJ, Compston DA, Coles AJ. Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity. Brain. 2010 Aug;133(Pt 8):2232-47

This is great but to burst a bubble, I have to ask how does this work?

There are two major problems well three or maybe four….

  1. Alemtuzumab penetrates the CNS very poorly, so how does it cause remylination if if doesn’t enter the CNS?..OK you may argue abit gets in like the anti-Lingo which is 99.9% excluded from the CNS. However even is some gets int the CNS the next big problem is……..
  2. Oligodendrocytes don’t express CD52. So how does it directly stimulate repair if CD52 is not present on myelinating cells?
data from http://www.brainseq.org and http://www.biogps.org

3. Protective autoimmunty, which means myelin reactive autoimmunity promotes repair because they produce nerve survival factors, is a concept created by the immunological mafia to create a controversial-view based on some arguably, dogey EAE and spinal injury data in and around 2010 that could explain the clinical observation. This was put into the main stream immunological world view, as the concept was not questioned. However, if autommunity was all good, why would all treatments that stop immune cells entering the CNS, be a good thing? To be clear I have no problem with the concept of protective autoimmunity, as I see part of inflammation is destroying the infection and repairing the damage, so it is not surprising that you can find T cells that do useful things. But you have to ask about the balance.

4. You can make your own idea up here….etc.

I will have a go at a simplistic argument

My idea is that the recovery after alemtuzumab was shown in people with relapsing disease treated early following disease onset, when repair capacity, such as oligodendrocyte precursors, still being present around MS lesions. Alemtuzumab stops cells entering the brain and therefore oligodendrocyte precursor repair the damage and there is no direct effect. You dont need the repair agent to enter the CNS. Any agent that stops inflammation will allow repair there is nothing special about alemtuzumab. We just need a similar trial study treating at onset when there are compensatory mechanisms.

COI None relevant

General Disclaimer: Please note that the opinions expressed here are those of the author and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.

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MouseDoctor

17 comments

  • MD,

    Been part of this blog’s fan club since inception and am reasonably familiar with your thoughts on various DMTs.

    Inflammation on the side, what do you think about the fact that alemtuzumab – unlike natalizumab and ocrelizumab – is the only agent normalising BVL loss for some?

    Therefore, why would you want to be treated with anything else if the younger you was diagnosed with MS?

    Tony

    • Alemtuzumab is a good drug but would be better if you could be de-risk the issues.

      Where is the data that you start treating ocrelizumab or natalizumab at diadgnosis, until this is shown then comparing the BV effects is not a fair comparison because after a few years the compensatory capacity has been diminished. If you look at cladribine 9 year on brain volume loss 0.5% do it at onset and it is normalised 0.1-0.2%. Sweden needs to do this data with rituximab…once they do an I am wrong I will shut up.

    • “Therefore, why would you want to be treated with anything else if the younger you was diagnosed with MS?…Tony”

      A better question is why would a doctor prescribe a medication that doesn’t normalize brain loss..?

      Prefer total ignorance/apathy….as the alternative is psychosis.

      • A better question is why would a doctor prescribe a medication that doesn’t normalize brain loss..? Yes:-(

    • Graf J, Leussink VI, Soncin G, Lepka K, Meinl I, Kümpfel T, Meuth SG, Hartung HP, Havla J, Aktas O, Albrecht P. Relapse-independent multiple sclerosis progression under natalizumab. Brain Commun. 2021 Oct 9;3(4):fcab229.

  • How about what they hypothesize in the 2010 paper of Jones et al. that you reference:
    “Here we show that after alemtuzumab, and only when specifically stimulated with myelin basic protein, peripheral blood mononuclear cell cultures produced increased concentrations of brain-derived neurotrophic factor, platelet-derived growth factor and ciliary neurotrophic factor.”

    • Yes that is the basis of why there could be repair, but why would these cells traffic into the CNS when the CNS drivers are being shut down

    • Perhaps, rather like was seen with Copaxone way back when, whenever a new flavour of the week mechanism appeared, alemtuzumab miraculously seemed to influence that too. Same phenomenon was reported for a positive influence on T regulatory cells (elegantly shot down by MD1 way back) etc etc etc.
      All dubious IMHO and moreover, not necessary to explain alemtuzumabs undoubted efficacy.

      • Are all DMTs that are good at preventing active inflammation equally good at inducing confirmed disability improvement?

        Natalizumab is good at preventing new lesions in the CNS, but is it equally likely to get CDI after natalizumab than alemtuzumab or HSCT?

      • So I gathered from MD1 and 2 the known mechanism of Alemtuzumab undoubted efficacy is the alem population were treated early?

  • If ocrelizumab was used as an IRT for the first two years, say doubled dose, it would have the same longer term efficacy as Alemtuzumab in your opinion MD or if you have to make a guess? From what I read from you, Memory B-cells is the only immune cell in the blood responsible for MS relapse/progression, which can be treated by antibodies.

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