How does alemtuzumab work

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

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