Sunday, 10 November 2013

Alemtuzumab produces regulatory cells

Zhang X, Tao Y, Chopra M, Ahn M, Marcus KL, Choudhary N, Zhu H, Markovic-Plese S. Differential Reconstitution of T Cell Subsets following Immunodepleting Treatment with Alemtuzumab (Anti-CD52 Monoclonal Antibody) in Patients with Relapsing-Remitting Multiple Sclerosis. J Immunol. 2013 Nov [Epub ahead of print]

Alemtuzumab (anti-CD52 mAb) provides long-lasting disease activity suppression in relapsing-remitting multiple sclerosis (RRMS). The objective of this study was to characterize the immunological reconstitution of T cell subsets and its contribution to the prolonged RRMS suppression following alemtuzumab-induced lymphocyte depletion. The study was performed on blood samples from RRMS patients enrolled in the CARE-MS II clinical trial, which was recently completed and led to the submission of alemtuzumab for U.S. Food and Drug Administration approval as a treatment for RRMS. Alemtuzumab-treated patients exhibited a nearly complete depletion of circulating CD4+ lymphocytes at day 7. During the immunological reconstitution, CD4+CD25+CD127 low regulatory T cells preferentially expanded within the CD4+ lymphocytes, reaching their peak expansion at month 1. The increase in the percentage of TGF-β1-, IL-10-, and IL-4-producing CD4+ cells reached a maximum at month 3, whereas a significant decrease in the percentages of Th1 and Th17 cells was detected at months 12 and 24 in comparison with the baseline. A gradual increase in serum IL-7 and IL-4 and a decrease in IL-17A, IL-17F, IL-21, IL-22, and IFN-γ levels were detected following treatment. In vitro studies have demonstrated that IL-7 induced an expansion of CD4+CD25+CD127low regulatory T cells and a decrease in the percentages of Th17 and Th1 cells. In conclusion, our results indicate that differential reconstitution of T cell subsets and selectively delayed CD4+ T cell repopulation following alemtuzumab-induced lymphopenia may contribute to its long-lasting suppression of disease activity.

Well we have to wait until next week until the FDA pass judgement but looks like they may sit on the fence and wait to see what crops up in European studies post-marketing before dipping their toe in the water. There is massive T cell depletion following alemtuzumab and this lasts for years. Rather than been being kept at low cell numbers so that disease does not return, this study suggests there maybe the generation of regulatory cells formed that can keep disease forming cells in check. This may help explain why Alemtuzumab is an induction therapy that does not need to be repeatedly given. The question has to be what do these regulatory cells do in terms of B cell autoimmunities, is it the yin and yang of immunology inhibits Th1/Th17 whilst increasing Th2 activity which may lead to antibody formation. 

Given the posturing of the FDA about risks following Alemtuzumab, the adage that we can deal with autoimmune thyroiditis that arises that some blasé clinicians needs to be taken more seriously and dealt with more effectively! 

ProfG has been saying this for some time maybe Pharma will listen?

CoI: Team G have received research funding from Sanofi Genzyme

2 comments:

  1. I think that this drug wont be used very much because of recent development in USA and price tag in EU + risk like secondary autoimmune diseases and in recent FDA report also cancer.

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    1. What recent development in the USA? Please clarify such a sweeping statement. I think it would be very sad if such a useful drug was put on hold by the FDA. Comparing the risks of secondary autoimmune disease with alemtuzumab to PML with tysabri, I know which risks I'd rather run. Also the possibility of no relapses, no disease progression and no other medication/dosing regime for years (apart from monthly checks)- it's a no brainer.

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