Download PDF
Semin Neurol 2013; 33(01): 066-073
DOI: 10.1055/s-0033-1343797
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Alemtuzumab Treatment of Multiple Sclerosis

Alasdair J. Coles
1   Department of Clinical Neurosciences, Addenbrooke's Hospital, University of Cambridge, Cambridge, England, United Kingdom
› Author Affiliations
Further Information

Publication History

Publication Date:
25 May 2013 (online)

    Permissions and Reprints

Abstract

Alemtuzumab is a humanized monoclonal antibody directed against CD52. A single cycle of alemtuzumab, administered over 5 days, depletes lymphocytes. Reconstitution causes prolonged alterations in the lymphocyte repertoire, with relatively increased regulatory T-cell numbers and reduced naïve T cells. It is currently approved for the treatment of B-cell chronic lymphocytic leukemia and is being considered for licensing for multiple sclerosis (MS).

When first used, alemtuzumab successfully reduced relapses and new lesion formation based on magnetic resonance imaging in people with progressive MS, but this cohort continued to accumulate disability, associated with progressive cerebral atrophy, presumably due to axonal degeneration. From this experience, we advocated that immunotherapies should be given early in the course of the disease. Since then, one phase II and two phase III trials have shown that alemtuzumab reduces the relapse rate, compared with the active comparator interferon beta-1a (IFNβ-1a), in treatment-naïve and treatment-experienced MS up to 10 years from disease onset. Furthermore, in two of these trials, alemtuzumab reduced the risk of accumulating disability compared with IFNβ-1a; indeed alemtuzumab treatment led to an improvement in disability and reduction in cerebral atrophy. Safety issues are infusion-associated reactions, mainly controlled by methyl-prednisolone, antihistamines, and antipyretics; mild to moderate infections; and autoimmunity. After 5 years, 30 to 40% of alemtuzumab patients have developed autoimmunity, largely against the thyroid gland, but rarely (2%) against platelets in immune thrombocytopenia, and in a few cases, Goodpasture's renal syndrome.

Alemtuzumab is an effective therapy for early relapsing-remitting multiple sclerosis, 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
 

  • References

  • 1 Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 1975; 256 (5517) 495-497
    CrossrefPubMedSearch in Google Scholar
  • 2 Waldmann H, Hale G. CAMPATH: from concept to clinic. Philos Trans R Soc Lond B Biol Sci 2005; 360 (1461) 1707-1711
    PubMedSearch in Google Scholar
  • 3 Lockwood CM, Hale G, Waldman H, Jayne DR. Remission induction in Behçet's disease following lymphocyte depletion by the anti-CD52 antibody CAMPATH 1-H. Rheumatology (Oxford) 2003; 42 (12) 1539-1544
    CrossrefPubMedSearch in Google Scholar
  • 4 Dick AD, Meyer P, James T , et al. Campath-1H therapy in refractory ocular inflammatory disease. Br J Ophthalmol 2000; 84 (1) 107-109
    CrossrefPubMedSearch in Google Scholar
  • 5 Isaacs JD, Hale G, Waldmann H , et al. Monoclonal antibody therapy of chronic intraocular inflammation using Campath-1H. Br J Ophthalmol 1995; 79 (11) 1054-1055
    CrossrefPubMedSearch in Google Scholar
  • 6 Isaacs JD, Hazleman BL, Chakravarty K, Grant JW, Hale G, Waldmann H. Monoclonal antibody therapy of diffuse cutaneous scleroderma with CAMPATH-1H. J Rheumatol 1996; 23 (6) 1103-1106
    PubMedSearch in Google Scholar
  • 7 Isaacs JD, Manna VK, Rapson N , et al. CAMPATH-1H in rheumatoid arthritis—an intravenous dose-ranging study. Br J Rheumatol 1996; 35 (3) 231-240
    CrossrefPubMedSearch in Google Scholar
  • 8 Newman DK, Isaacs JD, Watson PG, Meyer PA, Hale G, Waldmann H. Prevention of immune-mediated corneal graft destruction with the anti-lymphocyte monoclonal antibody, CAMPATH-1H. Eye (Lond) 1995; 9 (Pt 5) 564-569
    CrossrefPubMedSearch in Google Scholar
  • 9 Cheetham GM, Hale G, Waldmann H, Bloomer AC. Crystal structures of a rat anti-CD52 (CAMPATH-1) therapeutic antibody Fab fragment and its humanized counterpart. J Mol Biol 1998; 284 (1) 85-99
    CrossrefPubMedSearch in Google Scholar
  • 10 Hale G. The CD52 antigen and development of the CAMPATH antibodies. Cytotherapy 2001; 3 (3) 137-143
    CrossrefPubMedSearch in Google Scholar
  • 11 Xia MQ, Hale G, Lifely MR , 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
    PubMedSearch in Google Scholar
  • 12 Xia MQ, Tone M, Packman L, Hale G, Waldmann H. Characterization of the CAMPATH-1 (CDw52) antigen: biochemical analysis and cDNA cloning reveal an unusually small peptide backbone. Eur J Immunol 1991; 21 (7) 1677-1684
    CrossrefPubMedSearch in Google Scholar
  • 13 Kirchhoff C, Krull N, Pera I, Ivell R. A major mRNA of the human epididymal principal cells, HE5, encodes the leucocyte differentiation CDw52 antigen peptide backbone. Mol Reprod Dev 1993; 34 (1) 8-15
    CrossrefPubMedSearch in Google Scholar
  • 14 Wing MG, Moreau T, Greenwood J , 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 (12) 2819-2826
    CrossrefPubMedSearch in Google Scholar
  • 15 Moreau T, Coles A, Wing M , et al. Transient increase in symptoms associated with cytokine release in patients with multiple sclerosis. Brain 1996; 119 (Pt 1) 225-237
    CrossrefPubMedSearch in Google Scholar
  • 16 Xia MQ, Hale G, Waldmann H. Efficient complement-mediated lysis of cells containing the CAMPATH-1 (CDw52) antigen. Mol Immunol 1993; 30 (12) 1089-1096
    CrossrefPubMedSearch in Google Scholar
  • 17 Hu Y, Turner MJ, Shields J , et al. Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model. Immunology 2009; 128 (2) 260-270
    CrossrefPubMedSearch in Google Scholar
  • 18 Waldmann H, Cobbold S. How do monoclonal antibodies induce tolerance? A role for infectious tolerance?. Annu Rev Immunol 1998; 16: 619-644
    CrossrefPubMedSearch in Google Scholar
  • 19 Hill-Cawthorne GA, Button T, Tuohy O , et al. Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis. J Neurol Neurosurg Psychiatry 2012; 83 (3) 298-304
    CrossrefPubMedSearch in Google Scholar
  • 20 Cox AL, Thompson SAJ, Jones JL , et al. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur J Immunol 2005; 35 (11) 3332-3342
    CrossrefPubMedSearch in Google Scholar
  • 21 Thompson SA, Jones JL, Cox AL, Compston DA, Coles AJ. B-cell reconstitution and BAFF after alemtuzumab (Campath-1H) treatment of multiple sclerosis. J Clin Immunol 2010; 30 (1) 99-105
    CrossrefPubMedSearch in Google Scholar
  • 22 Coles AJ, Fox E, Vladic A , et al. Alemtuzumab more effective than interferon β-1a at 5-year follow-up of CAMMS223 clinical trial. Neurology 2012; 78 (14) 1069-1078
    CrossrefPubMedSearch in Google Scholar
  • 23 Le Page E, Leray E, Taurin G , et al. Mitoxantrone as induction treatment in aggressive relapsing remitting multiple sclerosis: treatment response factors in a 5.  year follow-up observational study of 100 consecutive patients. J Neurol Neurosurg Psychiatry 2008; 79 (1) 52-56
    CrossrefPubMedSearch in Google Scholar
  • 24 Rebello P, Cwynarski K, Varughese M, Eades A, Apperley JF, Hale G. Pharmacokinetics of CAMPATH-1H in BMT patients. Cytotherapy 2001; 3 (4) 261-267
    CrossrefPubMedSearch in Google Scholar
  • 25 Rebello P, Hale G. Pharmacokinetics of CAMPATH-1H: assay development and validation. J Immunol Methods 2002; 260 (1-2) 285-302
    CrossrefPubMedSearch in Google Scholar
  • 26 Somerfield J, Hill-Cawthorne GA, Lin A , et al. A novel strategy to reduce the immunogenicity of biological therapies. J Immunol 2010; 185 (1) 763-768
    CrossrefPubMedSearch in Google Scholar
  • 27 Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983; 33 (11) 1444-1452
    CrossrefPubMedSearch in Google Scholar
  • 28 Coles AJ, Cox A, Le Page E , et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol 2006; 253 (1) 98-108
    CrossrefPubMedSearch in Google Scholar
  • 29 Cohen JA, Coles AJ, Arnold DL , et al; for the CARE-MS I investigators. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomized controlled phase 3 trial. Lancet 2012; 380 (9856) 1819-28
    CrossrefPubMedSearch in Google Scholar
  • 30 Coles AJ, Twyman CL, Arnold DL , et al; for the CARE-MS II investigators. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomized controlled phase 3 trial. Lancet 2012; 380 (9856) 1829-39
    CrossrefPubMedSearch in Google Scholar
  • 31 Rudick RA, Lee JC, Simon J, Ransohoff RM, Fisher E. Defining interferon beta response status in multiple sclerosis patients. Ann Neurol 2004; 56 (4) 548-555
    CrossrefPubMedSearch in Google Scholar
  • 32 Prosperini L, Gallo V, Petsas N, Borriello G, Pozzilli C. One-year MRI scan predicts clinical response to interferon beta in multiple sclerosis. Eur J Neurol 2009; 16 (11) 1202-1209
    CrossrefPubMedSearch in Google Scholar
  • 33 Rudick RA, Polman CH. Current approaches to the identification and management of breakthrough disease in patients with multiple sclerosis. Lancet Neurol 2009; 8 (6) 545-559
    CrossrefPubMedSearch in Google Scholar
  • 34 Ebers GC, Traboulsee A, Li D , et al; Investigators of the 16-year Long-Term Follow-Up Study. Analysis of clinical outcomes according to original treatment groups 16 years after the pivotal IFNB-1b trial. J Neurol Neurosurg Psychiatry 2010; 81 (8) 907-912
    CrossrefPubMedSearch in Google Scholar
  • 35 Shirani A, Zhao Y, Karim ME , et al. Association between use of interferon beta and progression of disability in patients with relapsing-remitting multiple sclerosis. JAMA 2012; 308 (3) 247-256
    CrossrefPubMedSearch in Google Scholar
  • 36 Coles AJ, Fox E, Vladic A , et al. Alemtuzumab versus interferon β-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes. Lancet Neurol 2011; 10 (4) 338-348
    CrossrefPubMedSearch in Google Scholar
  • 37 Kraimps JL, Bouin-Pineau MH, Mathonnet M , et al. Multicentre study of thyroid nodules in patients with Graves' disease. Br J Surg 2000; 87 (8) 1111-1113
    CrossrefPubMedSearch in Google Scholar
  • 38 Kim WB, Han S-M, Kim TY , et al. Ultrasonographic screening for detection of thyroid cancer in patients with Graves' disease. Clin Endocrinol (Oxf) 2004; 60 (6) 719-725
    CrossrefPubMedSearch in Google Scholar
  • 39 Berker D, Isik S, Ozuguz U , et al. Prevalence of incidental thyroid cancer and its ultrasonographic features in subcentimeter thyroid nodules of patients with hyperthyroidism. Endocrine 2011; 39 (1) 13-20
    CrossrefPubMedSearch in Google Scholar
  • 40 Hsiao LT, Liu JH, Yen CC , et al. Relapse of Graves' disease after successful allogeneic bone marrow transplantation. Bone Marrow Transplant 2001; 28 (12) 1151-1153
    CrossrefPubMedSearch in Google Scholar
  • 41 Gilquin J, Viard JP, Jubault V, Sert C, Kazatchkine MD. Delayed occurrence of Graves' disease after immune restoration with HAART. Highly active antiretroviral therapy. Lancet 1998; 352 (9144) 1907-1908
    CrossrefPubMedSearch in Google Scholar
  • 42 Broadley SA, Deans J, Sawcer SJ, Clayton D, Compston DAS. Autoimmune disease in first-degree relatives of patients with multiple sclerosis. A UK survey. Brain 2000; 123 (Pt 6) 1102-1111
    CrossrefPubMedSearch in Google Scholar
  • 43 Heinzlef O, Alamowitch S, Sazdovitch V , et al. Autoimmune diseases in families of French patients with multiple sclerosis. Acta Neurol Scand 2000; 101 (1) 36-40
    CrossrefPubMedSearch in Google Scholar
  • 44 Clatworthy MR, Wallin EF, Jayne DR. Anti-glomerular basement membrane disease after alemtuzumab. N Engl J Med 2008; 359 (7) 768-769
    CrossrefPubMedSearch in Google Scholar
  • 45 Jones JL, Phuah CL, Cox AL , 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 (7) 2052-2061
    PubMedSearch in Google Scholar