Alemtuzumab is a humanized monoclonal antibody that is administered daily for 5 days, and then no further therapy is required for 12 months. It causes rapid and prolonged lymphocyte depletion; the consequent homeostatic reconstitution leads to a radically reformed lymphocyte pool with a relative increase in regulatory T cells and expansion of autoreactive T cells. Although previously licensed for the treatment of B-cell chronic lymphocytic leukemia, it is now been considered for licensing in the treatment of multiple sclerosis (MS). From a disappointing experience with alemtuzumab in progressive MS, Alastair Compston and I argued that immunotherapies should be given early in the course of the disease. In a unique program of drug development in MS, alemtuzumab has been compared in 1 phase 2 trial and 2 phase 3 trials with the active comparator interferon beta-1a. In all trials, alemtuzumab was more effective in suppressing relapses than interferon beta-1a. In one phase 2 and one phase 3 trial, alemtuzumab also reduced the risk of accumulating disability compared with interferon beta-1a. Indeed, alemtuzumab treatment led to an improvement in disability and a reduction in cerebral atrophy. The safety issues are infusion-associated reactions largely controlled by methylprednisolone, antihistamines, and antipyretics; mild-to-moderate infections (with 3 opportunistic infections from the open-label experience: 1 case each of spirochaetal gingivitis, pyogenic granuloma, and Listeria meningitis); and autoimmunity. Usually autoimmunity is directed against the thyroid gland, but causes (1 %) immune thrombocytopenia, and in a few cases antiglomerular basement membrane syndrome. Alemtuzumab is an effective therapy for early relapsing-remitting MS, offering disability improvement at least to 5 years after treatment. Its use requires careful monitoring so that potentially serious side effects can be treated early and effectively.
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Alasdair Coles has received honoraria and consulting fees, and his department has received research grants from Ilex Oncology and Genzyme, which are both involved in the commercial development of alemtuzumab. Coles and colleagues have submitted a patent for the prediction of autoimmunity after alemtuzumab. The clinical trials reported here have been funded by Ilex Oncology and Genzyme (a Sanofi company). The scientific work done in Cambridge has been supported by the Medical Research Council, the Wellcome Trust, the Moulton Foundation, the Grand Charity of The Freemasons and the Multiple Sclerosis Society of the UK. Alasdair Coles is supported by the Cambridge Biomedical Research Centre of the National Institute of Health Research. The clinical work was done in the Wellcome Clinical Research Facility. Full conflict of interest disclosures is available in the electronic supplementary material for this article.
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