How does alemtuzumab work

H

We have made the case that many agents work because they target B cells, but the prevailing”immunologist” view is that augmentation of T regulatory cells is the key. This in part because following depletion there is a relative balance shift that causes more depletion of the CD4 T cells. Therefore there is a relative increase in the T reg to CD4 ratio. However if you look at the absolute number of cells then alemtuzumab causes an 80-90% depletion. So does this idea hold water?

I will leave it to you to decide on whether we should stick with immunological dogma and say it is all T regs or think outside the box. The memory B cell idea links into EBV biology, so how do T regs fit in with what we see in MS and as for alemtuzumab how does it explain the secodary autoimmunities that occur? Can you have it boths ways? Also remember dacilizumab worked in MS, but it depleted T regs.

Therapeutic Effect of Anti-CD52 Monoclonal Antibody in Multiple Sclerosis and Its Animal Models Is Mediated via T Regulatory Cells.

Kiapour N, Wu B, Wang Y, Seyedsadr M, Kapoor S, Zhang X, Elzoheiry M, Kasimoglu E, Wan Y, Markovic-Plese S.J Immunol. 2022 Jun 24:ji2100176. doi: 10.4049/jimmunol.2100176

The objective of this study is to determine the mechanism of action of anti-CD52 mAb treatment in patients with relapsing-remitting multiple sclerosis (RRMS). Experimental autoimmune encephalomyelitis (EAE), an animal model of the disease, was used to address the role of T regulatory cells (Tregs) in the anti-CD52 mAb-induced suppression of the disease.

In vitro studies on PBMCs from RRMS patients and matched healthy controls determined the effect of IL-7 on the expansion of CD4+CD25+CD127 Tregs and induction of their suppressive phenotype. This study using EAE animal models of MS has shown that mouse anti-CD52 mAb suppression of clinical disease was augmented by coadministration of IL-7 and partially reversed by anti-IL-7 mAb. In vitro human studies showed that IL-7 induced expansion of CD4+CD25+CD127 Tregs and increased their FOXP3, GITIR, CD46, CTLA-4, granzyme B, and perforin expression. Anti-CD52 mAb treatment of mice with relapsing-remitting EAE induced expansion of Foxp3+CD4+ Tregs and the suppression of IL-17A+CD4+ and IFN-γ+CD4+ cells in peripheral immune organs and CNS infiltrates. The effect was detected immediately after the treatment and maintained over long-term follow-up. Foxp3+CD4+ Treg-mediated suppression of IL-17A+CD4+ and IFN-γ+CD4+ cells in the spinal cord infiltrates was reversed after inducible Foxp3 depletion. Our results demonstrated that the therapeutic effect of U.S. Food and Drug Administration-approved anti-CD52 mAb is dependent on the presence of Tregs.

COI: multiple

Disclaimer These are the views of the author

About the author

MouseDoctor

18 comments

  • I’m still sticking to my own hypothesis.: These treatments work by depleting misbehaving, EBV infected, immune cells and then the bone marrow repopulates with new immune cells from uninfected stem cells. The more cells they deplete, like AHSCT, the more effective the treatment. Antivirals, which are used to prevent shingles in the post depletion phase probably reduced EBV reinfection. Relapses occur after treatment when EBV recovers. I have yet to see any objective evidence to invalidate this, although nobody seems to agree with me.

  • Who cares? The mechanisms of the DMTs are of little interest to the patient (I don’t know how my TV works, my interest is thatit turns on and works). Alemtuzumab was first used in MSers in the early 1990s, it’s crazy to think that researchers are trying to figure out how it works 30 years later.

    • Point taken, but if you can find out exactly how it works, rather than trotting out the dogma as in this paper, then there is the potential to design something that may work better in a more specific way avoiding the potential pitfalls with alemtuzumab.

      • Or alternatively stop developing partially effective depleting agents and work on the anti-EBV therapies with their “Lazarus” like effects. I would rather have a treatment that reverses the underlying disease process and gets me out of my wheelchair, rather than one which slows (but doesn’t prevent) my decline and renders me susceptible to opportunistic infections like CoVID-19 and UTIs. It’s a scandal that drug companies are still keeping us ill, but that’s what keeps them enormously profitable. I take heart from the knowledge that when somebody develops and markets an effective anti-EBV treatment, the dinosaurs will lose a fortune.

        • >It’s a scandal that drug companies are still keeping us ill
          Oh, come on. The drug companies are the only reason we have any treatments at all. Look at how useless government- and charity-funded clinical trials are. Look at how badly managed research in academia is. It’s drug company researchers that make all the breakthroughs. Instead of getting mad at big pharma we should be getting mad at organizations like the MS Society for squandering all of our treasure and credibility on obvious pseudoscience like CCSVI (remember that one?).

    • Well
      Do remember what was the technology off your tv set 30 years ago
      How about the internet (born January 1, 1983) 39 years ago

      How about smartphones (there were none)

      Toll like receptor was discover by Christiane Nüsslein-Volhard’s 1985

      So what i mean is that new tecnology allow you to study certain old problems with more detail
      New generation sequencing ,single cell sorting ,Multicolor Immunofluorescence Staining Protocol

      Are newer techiques that are avaiable just recently
      So makes sense to go back and study old problems and old drugs also

      • Luis,

        I don’t care!

        Researchers with too much time on their hands.

        We know EBV is the likely cause trigger so need an effective vaccine and antivirals.

        We know the real MS is smouldering away within the CNS so need drugs which get into the CNS .

        • Great
          So i am gonna tell this to my neuro doc and the 600

          Patients he treats no more ms drugs

          Maybe i will convince him to change its neuro status to become a virologist instead
          What do you think?

        • The BTKi drugs might just address this issue by targeting activated macrophages in the CNS. I agree the need for EBV targeted therapies should be expedited. But the funding shows lack of interest from the pharma side.

          • CCSVI Millions in Canada and Italy
            There are companies interested in EBV, e.g. Moderna.

          • cells exist for a reason, how r u comfortable with long-term complications if microglia/macrophages not doing their job in the CNS? Only time will tell.

          • Depleting immune cells causes PML. JCV is inert if your immune system is intact. We need alternative modes of attack, preferably targeting EVB rather than immune components that we evolved in humans because we need them.

    • But does it work really..?
      Go to FB user groups and you
      Find many fail..turn progressive
      And taken off treatment.

By MouseDoctor

Translate

Categories

Recent Posts

Recent Comments

Archives