Neurotherapeutics

, Volume 10, Issue 1, pp 29–33 | Cite as

Alemtuzumab Therapy for Multiple Sclerosis

Review

Abstract

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.

Keywords

Multiple sclerosis Alemtuzumab Antibody Disability Autoimmunity 

Notes

Acknowledgments

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.

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Supplementary material

13311_2012_159_MOESM1_ESM.pdf (511 kb)
ESM 1(PDF 510 kb)

References

  1. 1.
    Riechmann L, et al. Reshaping human antibodies for therapy. Nature 1988;332:323-327.PubMedCrossRefGoogle Scholar
  2. 2.
    Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 1975;256:495-497.PubMedCrossRefGoogle Scholar
  3. 3.
    Waldmann H, Hale G. CAMPATH: from concept to clinic. Phil Trans Roy Soc Lond B Biol Sci 2005;360:1707-1711.CrossRefGoogle Scholar
  4. 4.
    Lockwood CM, et al. Remission induction in Behcet's disease following lymphocyte depletion by the anti-CD52 antibody CAMPATH 1-H. Rheumatology (Oxford) 2003;42:1539-1544.CrossRefGoogle Scholar
  5. 5.
    Dick AD, et al. Campath-1H therapy in refractory ocular inflammatory disease. Br J Ophthalmol 2000;84:107-109.PubMedCrossRefGoogle Scholar
  6. 6.
    Isaacs JD, et al. Monoclonal antibody therapy of chronic intraocular inflammation using Campath-1H. Br J Ophthalmol 1995;79:1054-1055.PubMedCrossRefGoogle Scholar
  7. 7.
    Isaacs JD, et al. Monoclonal antibody therapy of diffuse cutaneous scleroderma with CAMPATH-1H. J Rheumatol 1996;23:1103-1106.PubMedGoogle Scholar
  8. 8.
    Isaacs JD, et al. CAMPATH-1H in rheumatoid arthritis — an intravenous dose-ranging study. Br J Rheumatol 1996;35:231-240.PubMedCrossRefGoogle Scholar
  9. 9.
    Newman DK, et al. Prevention of immune-mediated corneal graft destruction with the anti-lymphocyte monoclonal antibody. CAMPATH-1H. Eye (Lond) 1995;9(pt 5):564-569.CrossRefGoogle Scholar
  10. 10.
    Hale G. The CD52 antigen and development of the CAMPATH antibodies. Cytotherapy 2001;3:137-143.PubMedCrossRefGoogle Scholar
  11. 11.
    Xia MQ, et al. Structure of the CAMPATH-1 antigen, a glycosylphosphatidylinositol-anchored glycoprotein which is an exceptionally good target for complement lysis. Biochem J 1993;293(pt 3):633-640.PubMedGoogle Scholar
  12. 12.
    Xia MQ, et al. Characterization of the CAMPATH-1 (CDw52) antigen: biochemical analysis and cDNA cloning reveal an unusually small peptide backbone. Eur J Immunol 1991;21:1677-1684.PubMedCrossRefGoogle Scholar
  13. 13.
    Hu Y, et al. Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model. Immunology 2009;260-270.Google Scholar
  14. 14.
    Wing MG, et al. Mechanism of first-dose cytokine-release syndrome by CAMPATH 1-H: involvement of CD16 (FcgammaRIII) and CD11a/CD18 (LFA-1) on NK cells. J Clin Invest 1996;98:2819-2826.PubMedCrossRefGoogle Scholar
  15. 15.
    Moreau T, et al. Transient increase in symptoms associated with cytokine release in patients with multiple sclerosis. Brain 1996;119(pt 1):225-237.PubMedCrossRefGoogle Scholar
  16. 16.
    Hill-Cawthorne GA, et al. Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis. J Neurol Neurosurg Psychiatry 2012;83:298-304.PubMedCrossRefGoogle Scholar
  17. 17.
    Cox AL, et al. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur J Immunol 2005;35:3332-3342.PubMedCrossRefGoogle Scholar
  18. 18.
    Thompson SA, et al. B-cell reconstitution and BAFF after alemtuzumab (Campath-1H) Treatment of Multiple Sclerosis. J Clin Immunol 2009;99-105.Google Scholar
  19. 19.
    Kurtzke JF. Rating neurologic impairment in multiple-sclerosis — an Expanded Disability Status Scale (EDSS). Neurology 1983;33:1444-1452.PubMedCrossRefGoogle Scholar
  20. 20.
    Coles AJ, et al. Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann Neurol 1999;46:296-304.PubMedCrossRefGoogle Scholar
  21. 21.
    Coles AJ, et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol 2006;253:98-108.PubMedCrossRefGoogle Scholar
  22. 22.
    Coles AJ, et al. Alemtuzumab more effective than interferon beta-1a at 5-year follow-up of CAMMS223 Clinical Trial. Neurology 2012;1069-78.Google Scholar
  23. 23.
    Berker D, et al. Prevalence of incidental thyroid cancer and its ultrasonographic features in subcentimeter thyroid nodules of patients with hyperthyroidism. Endocrine 2011;39:13-20.PubMedCrossRefGoogle Scholar
  24. 24.
    Somerfield J, et al. A novel strategy to reduce the immunogenicity of biological therapies. J Immunol 2010;185:763-768.PubMedCrossRefGoogle Scholar
  25. 25.
    Clatworthy MR, Wallin EF, Jayne DR. Anti-glomerular basement membrane disease after alemtuzumab. N Engl J Med 2008;359:768-769.PubMedCrossRefGoogle Scholar
  26. 26.
    Hsiao LT, et al. Relapse of Graves' disease after successful allogeneic bone marrow transplantation. Bone Marrow Transplant 2001;28:1151-1153.PubMedCrossRefGoogle Scholar
  27. 27.
    Gilquin J, et al. Delayed occurrence of Graves' disease after immune restoration with HAART. Lancet 1998;352:1907-1908.PubMedCrossRefGoogle Scholar
  28. 28.
    Jones JL, et al. IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). J Clin Invest 2009;119:2052-2061.PubMedGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2012

Authors and Affiliations

  1. 1.Department of Clinical NeurosciencesUniversity of Cambridge, Addenbrooke’s HospitalCambridgeUK

Personalised recommendations