Cladribine and Childhood Immunity

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Some Scientists appear to get trained not to speculate but do the experiment and show the data. This makes for nice science where you dot the i’s and cross the t’s. However, it is drain on resource and time, especially if you have to do the work yourself. However, it also makes sure no-one steals you ideas. However ideas are “ten a penny” and if you are having the idea someone else is having it too. As we say in the lab “snooze and you lose”. You can’t do all the work yourself. But it is rewarding when others get the information that support your ideas. A bit of non-reflected glory

When COVID-19 came along we speculated on what would happen, we were not far off but didn’t get everything right. But, you can’t fail if you don’t try ,

When ProfG and Merck dropped the ball in 2010 and cladribine was withdrawn from the market, it allowed ProfK to pick up the pieces to develop a treatment option for people with MS. No-one/few were interested in cladribine until the ball was picked-up again in 2017.

We had to think how cladribine was working. In 2010 the story was that it was a T and B cell depleter, I am sure in some peoples minds it still is. But because of our speculation in 2016/2017 that memory B cells may be an important part of the biology of MS therapeutics, it suggested we should focus on the B cell compartment to ask some simple questions.

Sure enough as predicted and we found that memory B cells demonstrated marked and long-term depletion using subcutaneous cladribine.

Ceronie B, Jacobs BM, Baker D, Dubuisson N, Mao Z, Ammoscato F, Lock H, Longhurst HJ, Giovannoni G, Schmierer K. Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells. J Neurol. 2018; 265:1199-1209

It is simple biology

Would the same happen with cladribine tablets?…There is no reason why not. Inject cladribine and you get about twice the amount in the blood compared to that ingested. Sure enough that is what was found, by others. You can’t do everything and by the time oral cladribine was NICEd and approved in the UK the work had already been done elsewhere.

Moser T, Schwenker K, Seiberl M, Feige J, Akgün K, Haschke-Becher E, Ziemssen T, Sellner J. Long-term peripheral immune cell profiling reveals further targets of oral cladribine in MS. Ann Clin Transl Neurol. 2020; 7:2199-2212.

Adapted from Moser et al. 2020

Nice work and this showed a nice anlaysis over time. It showed us what we thought would happen based on CD20-depleting antibodies and our own cladribine work. Importantly it told me what was likely to happen following COVID-19 vaccination. I could speculate that it would faciltate a vaccine antibody response as these are generated by immature/naive B cells and they repopulated quickly after cladribine treatment they would give a response.

This what we and other have subsequently shown

Tallantyre EC, Vickaryous N, Anderson V, Asardag AN, Baker D, Bestwick J, Bramhall K, Chance R, Evangelou N, George K, Giovannoni G, Godkin A, Grant L, Harding KE, Hibbert A, Ingram G, Jones M, Kang AS, Loveless S, Moat SJ, Robertson NP, Schmierer K, Scurr MJ, Shah SN, Simmons J, Upcott M, Willis M, Jolles S, Dobson R. COVID-19 Vaccine Response in People with Multiple Sclerosis. Ann Neurol. 2021 Oct 22. doi: 10.1002/ana.26251

What about the vaccine response after it has formed?

In humans immunity once formed is relatively life-long

So what about antibodies and plasma cells. We really want cladribine to enter the CNS and scrub the brain clean of oligoclonal bands (antibodies) and inflammation.

However, what did the biology say?

Once I discovered gene expression data bases it said that cladribine may not be as active at getting rid of plasma cells as it does for naive and memory B cells . Maybe the dose would be big enough to get rid of the plasma cells maybe it wouldn’t

Would I be sad..maybe because it may not scrub the brain clean immediately, it may in the longer term, but importantly it would mean that you would not loose you childhood immunity to childhood infections. So we put our head on the block and speculated this.

Baker D, Pryce G, Herrod SS, Schmierer K. Potential mechanisms of action related to the efficacy and safety of cladribine. Mult Scler Relat Disord. 2019;30:176-186. doi: 10.1016/j.msard.2019.02.018.

What does cladribine do to childhood immunity

When cladribine got dropped those experiments were not done and so when cladribine was brought back in 2017, we didn’t have the answers. When COVID-19 and vaccines came along we knew nothing about vaccinations.

The importance of this has taken a new meaning in the COVID-19 era.

If the agents get rid of plasma cells your COVID-19 vaccinations disappear too. But most MS treatments deplete your memory B cells. Does this get rid of your childhood immunity responses. The answer for drugs we know about is no. The plasma cells are long-lived.

Why did we suggest cladribine may not get rid plasma cells

Because when you look in the cells that make antibodies they do not express alot of the target for cladribine. For that matter they don’t contain alot of the target for ocrelizumab, ofatumumab, alemtuzumab and fingolimod, siponimod, ozanimod and ponesimod. This would suggest once you get an antibody response you will keep. This is known for alemtuzumab and ocrelizumab/rituximab and this may be the explaining biology.

http://www.genomicscape.com (rituximab is used off-label. Ublixtuzimab is not yet approved)

This view is supported by the new data.

Moser T, O’Sullivan C, Puttinger C, Feige J, Pilz G, Haschke-Becher E, Cadamuro J, Oberkofler H, Hitzl W, Harrer A, Kraus J, Trinka E, Wipfler P. Pre-Existing Humoral Immunological Memory Is Retained in Patients with Multiple Sclerosis Receiving Cladribine Therapy. Biomedicines. 2021 Oct 31;9(11):1584.

Cladribine (CLAD) is a lymphodepleting agent approved for active relapsing multiple sclerosis (MS). The impact of CLAD on the adaptive humoral immune system has not sufficiently been studied. This study aimed to assess the influence of CLAD treatment on specific-antibody titres to common pathogens. We included 18 MS patients treated with CLAD. Serum IgG antibody levels to measles, mumps, rubella, hepatitis B and varicella zoster virus (VZV), as well as diphtheria and tetanus toxins, were measured prior to the initiation of treatment and at 12 and 24 months after first CLAD administration. Moreover, specimens were longitudinally analyzed regarding absolute blood concentrations of IgG and main lymphocyte subsets. No reduction in antibody levels against measles, mumps, rubella, VZV, hepatitis B, diphtheria toxin and tetanus toxin associated with CLAD treatment was observed. Loss of seroprotection occurred in <1%. We found no significant impact of CLAD on absolute serum IgG levels. Absolute lymphocyte counts were significantly reduced at the end of each treatment year (p < 0.00001 and p < 0.000001). This study suggests that CLAD does not interfere with the pre-existing humoral immunologic memory in terms of pathogen-specific antibody titres.

You and I have a plausible reason to explain these observation. In this case I hope “Can’t work because of COVID and you lose” is not the answer here”

In this study it shows us what we know already and that is that IgG (antibody) levels do not reduce over a year of treatment. This is true of ocrelizumab in the first year, but give it a few years and IgG levels drop. I suspect with cladribine this will not be a problem as you are not depleting B cells for ever. But it would be good to ask the same question in a few years time. maybe ProfK will have the answer.

Also whilst we are at it, Dr Moser is on a roll and has some other ideas of how cladribine works

Moser T, Hoepner L, Schwenker K, Seiberl M, Feige J, Akgün K, Haschke-Becher E, Ziemssen T, Sellner J. Cladribine Alters Immune Cell Surface Molecules for Adhesion and Costimulation: Further Insights to the Mode of Action in Multiple Sclerosis. Cells. 2021;10:3116.

Cladribine (CLAD) is a deoxyadenosine analogue prodrug which is given in multiple sclerosis (MS) as two short oral treatment courses 12 months apart. Reconstitution of adaptive immune function following selective immune cell depletion is the presumed mode of action. In this exploratory study………Immune reconstitution by oral CLAD was associated with modification of the pro-migratory and pro-inflammatory surface patterns of cell adhesion molecules and costimulatiory molecules involved in cell activation in immune cell subsets. This observation pertains primarily to B cells, which are key cells underlying MS pathogenesis.

COI: Multiple

Dislcaimer: There is no advice here

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17 comments

  • Thanks so much for all your hard work on Clad. This blog made me turn down Rituximab which is sort of a blanket decision DMT in my Nordic MS clinic, and opt for an IRT/clad 11 months ago. Never looked back since. Look forward to your continued work on Sizomus and scrubbing the CNS clean!

  • “So what about antibodies and plasma cells. We really want cladribine to enter the CNS and scrub the brain clean of oligoclonal bands (antibodies) and inflammation.”

    The Sizomus trial is exactly about this. But, if the CNS is scrubbed clean of Plasma cells, what prevents them from just coming straight back?

    Also, aren’t the Plasma cells just doing their job? If ebv is in the CNS causing damage, then aren’t the Plasma cells producing antibodies against ebv ie to encourage T cells to enter the CNS and kill the ebv infection the cells?

    If we could answer the question as to why B cells / plasma cells are in the CNS, we would be a lot closer to understanding what MS is.

    • What prevents them comming straight back….MS treatments

      Aren’t plasma cells just doing their job…I doubt it they should be there. Antibodies to EBV most studies would not support the view that oligoclonal bands are against EBV
      same reason plasma cells are in the joints in arthritis, in the kidney in SLE

      • Not the same disease pathophysiology

        Type I IFNs, which include IFN-β, elevate expression of B cell activation factor (BAFF), increase B cell activity and drive the production of autoantibody in systemic lupus erythematosus (SLE) and neuromyelitis optica (NMO), promoting inflammation(1–3). Inone sense, these are “type 1 IFN diseases” where B cell autoantibody production is clearly
        pathogenic. In RRMS IFN-β also increases serum levels of BAFF and B cell activity(4, 5),
        yet in a seeming paradox IFN-β reduces inflammation and decreases relapses(6).

        Apples for apples?

        Schubert et al.

    • So would agreed with you

      we could not find an association
      between increased plasma cell numbers and a natalizumab
      treatment failure. Treatment concepts in MS and
      NMOSD with atacicept (TACI-Ig),
      which reduces circulating
      B cells and plasma cells by the neutralization of
      BAFF and APRIL, were stopped due to disease exacerbations
      (44, 45), raising the question as to which role
      plasma cells play in disease activity. Growing evidence
      indicates regulatory properties for plasma cells during
      neuroinflammation. Machado-Santos
      et al observed IL-10-
      producing
      plasma cells in MS lesions (46). Moreover,
      Rojas et al demonstrated in an animal model of MS that
      gut-derived
      IgA-producing
      plasma cell precursors may
      migrate into the CNS and ameliorate clinical severity inan IL-10-
      dependent
      manner (47). We could also find a
      fraction of IL-10-
      positive
      plasma cells in a small number
      of analyzed patients

      • re: atacicept
        This decreased plasma cells and mature b cells, but increased memory B cells. If there was a positive disease-modifying effect from reducing plasma cells, it would probably be overwritten by the negative effect from increasing memory B cells. Disease activity in these studies is also usually measured by lesions/relapses, which are all memory B cells. I don’t think this invalidates SIZOMUS at all.

  • But arnt B cells trained in the bone marrow and the memory from that just churns out more B cells.

    Are these cells auto reactive? Or if someone (maybe EBV) turning them auto reactive with in the blood stream.

  • Thank you for all the recent insights MD1. Your posts seem to generate a good debate in the comments section.

    For me, I like to think that since Clad is a small molecule DMT and can penetrate the BBB, CNS, and bone marrow, most of the infected B cells should be wiped out. What prevents them from coming back or being reactivated? I do not know! But more DMTs scare me as I tend to get the 1% AE.

    I love reading Luis comments, they are just way too scientific sometimes, at least for an economist like me. I think I agree with his position?!?

    During my Clad treatment period (2yrs) I am taking a daily anti-viral prophylactic. Mainly because I could not get the shingles vaccine but also hoping that when my “new” B cells are repopulated in the presence of a heavy anti-viral, this could prevent the cells from being reinfected. Similar to the HIV drugs for MS theory. Not sure it is going to work, but can’t hurt and helps prevent shingles.

    Data indicates daily anti-vitals are safe when taken at prescribed levels (e.g. higher than normal but not excessive). Going to have a LP at the end of two years and I am very interested in the results. Particularly since I was previously on OCR and TERI before CLAD. Last LP was when I was diagnosed with MS.

    • Prof K used to give anti viral with cladribine in the early days but does not now……

      OK LP after 2 years is that for neurofilament or oligoclonal bands

      • Wonder why Prof. K stopped using them, or if they had any impact on his cohort….

        And yes, LP for both and anything else the university docs want to test with my spinal fluid. Hopefully this will be my last LP, as the procedure is very unpleasant. But so is a fast disease progression (without multiple relapses) and three DMTs in the same amount of years since diagnosis.

        • They developed nice shiny coats….but seriously there were some unwanted effects and importantly people were not getting the infections.

  • Theoretically, anti-CD-20 agents would be a better B-cell IRT since it takes longer for B-cells to return?

    If we only look at B-cells, are there attributes of IRTs other than CNS penetration that differentiate therapies (if we don’t care about routes of administrate)? Are the returned B-cells different in Clad vs antiCD20’s? Are B-cells returned from Alemtuzumab more autoreactive?

    • It takes a long time for the B cells to recover because the antibody hangs around a long time, if the double dose occurs then it will be even longer.

      it has been argued T and B cell targetting makes a difference I am not so sure need head to head data.
      As the returned B cells the same for clad and anti-CD20 good question..I dont know alough Im sure there is an ocrleizumab study. B cells returning after alemtuzumab I would say are more autoreactive as they cause autoimmunity

  • In case you didn’t realize, the word “prosess” on your site is spelled incorrectly. I had similar issues on my website which hurt my credibility until someone pointed it out and I discovered some of the services like SpellHelper.com or SpellingCheck.com which help with these type of issues.

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