Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Drug Insight: using monoclonal antibodies to treat multiple sclerosis

Nature Clinical Practice Neurology volume 1, pages 34–44 (2005)Cite this article

Abstract

Multiple sclerosis (MS) is an immunopathological, presumably autoimmune, disease of the CNS. Several immunomodulatory treatments, including various preparations of interferon-β, glatiramer acetate and mitoxantrone, have been approved for MS therapy. Because these agents are only partially effective, the search for better therapies continues. Therapeutic monoclonal antibodies (mAbs), a class of biotechnological agents, allow the precise targeting of molecules involved in pathological processes. Therapeutic mAbs have shown much promise in the treatment of many disorders, including inflammatory and putative autoimmune diseases such as MS. These agents have intrinsic limitations, however, such as induction of neutralizing 'anti-antibodies', systemic inflammatory reactions and severe adverse effects, some of which remain to be explained. Most notably, natalizumab (Tysabri®), a mAb against α4 integrin, was very effective in suppressing MS activity, but had to be withdrawn from the market because several treated patients developed progressive multifocal leukoencephalopathy. This article reviews the state of development of various therapeutic mAbs for MS treatment.

Key Points

  • The development of therapeutic strategies for multiple sclerosis (MS) has followed the evolution of pathogenetic concepts, and current models of immunopathogenesis offer numerous molecular targets for monoclonal antibody (mAb) therapy

  • The initial goal of mAb treatment was to deplete subsets of immune cells that were suspected to be pathogenically important, but evidence has accumulated to suggest that non-depleting mAbs can also have subtle immunoregulatory effects

  • Because T cells are considered to have a central role in MS, they are primary therapeutic targets. Other potential targets include various costimulatory molecules, adhesion molecules and cytokines

  • Despite promising results in animal models, clinical experience has shown that mAb treatment can have unexpected effects and adverse reactions when applied to patients. Some mAbs, however, have shown sufficient promise to justify cautious optimism that they might find a place in MS therapy

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Types of therapeutic monoclonal antibodies.
Figure 2: Possible targets of therapeutic mAbs in multiple sclerosis.

Similar content being viewed by others

References

  1. Compston A and Coles A (2002) Multiple sclerosis. Lancet 359: 1221–1231

    Article  Google Scholar 

  2. Noseworthy JH et al. (2000) Multiple sclerosis. N Engl J Med 343: 938–952

    Article  CAS  Google Scholar 

  3. Arnason BGW (1993) Interferon beta in multiple sclerosis. Neurology 43: 641–643

    Article  CAS  Google Scholar 

  4. Goodin DS et al. (2002) Disease modifying therapies in multiple sclerosis: Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology 58: 169–178

    Article  CAS  Google Scholar 

  5. Miller DH (2002) MRI monitoring of MS in clinical trials. Clin Neurol Neurosurg 104: 236–243

    Article  Google Scholar 

  6. Zamvil SS and Steinman L (2003) Diverse targets for intervention during inflammatory and neurodegenerative phases of multiple sclerosis. Neuron 38: 685–688

    Article  CAS  Google Scholar 

  7. Sospedra M and Martin R (2005) Immunology of multiple sclerosis. Annu Rev Immunol 23: 683–747

    Article  CAS  Google Scholar 

  8. Hafler DA et al. (2005) Multiple sclerosis. Immunol Rev 204: 208–231

    Article  CAS  Google Scholar 

  9. Hemmer B et al. (2002) New concepts in the immunopathogenesis of multiple sclerosis. Nat Rev Neurosci 3: 291–301

    Article  CAS  Google Scholar 

  10. Hohlfeld R and Wekerle H (2004) Autoimmune concepts of multiple sclerosis as a basis for selective immunotherapy: From pipe dreams to (therapeutic) pipelines. Proc Natl Acad Sci USA 101 (Suppl 2): S14599–S14606

    Article  Google Scholar 

  11. Hohlfeld R (1997) Biotechnological agents for the immunotherapy of multiple sclerosis. Principles, problems and perspectives. Brain 120: 865–916

    Article  Google Scholar 

  12. Waldmann H (1989) Manipulation of T-cell responses with monoclonal antibodies. Annu Rev Immunol 7: 407–444

    Article  CAS  Google Scholar 

  13. Hafler DA and Weiner HL (1988) Anti-CD4 and anti-CD2 monoclonal antibody infusions in subjects with multiple sclerosis. Immunosuppressive effects and human antimouse responses. Ann N Y Acad Sci 540: 557–559

    Article  CAS  Google Scholar 

  14. Hafler DA et al. (1986) Immunologic responses of progressive multiple sclerosis patients treated with an anti-T-cell monoclonal antibody, anti-T12. Neurology 36: 777–784

    Article  CAS  Google Scholar 

  15. Weiner HL (2004) Curing MS: How Science is Solving the Mysteries of Multiple Sclerosis. New York: Crown Publishers

    Google Scholar 

  16. Hafler DA and Weiner HL (1987) In vivo labeling of blood T cells: rapid traffic into cerebrospinal fluid in multiple sclerosis. Ann Neurol 22: 89–93

    Article  CAS  Google Scholar 

  17. Ransohoff RM et al. (2003) Three or more routes for leukocyte migration into the central nervous system. Nat Rev Immunol 3: 569–581

    Article  CAS  Google Scholar 

  18. Weinshenker BG et al. (1991) An open trial of OKT3 in patients with multiple sclerosis. Neurology 41: 1047–1052

    Article  CAS  Google Scholar 

  19. Swinnen LJ (1999) Overview of posttransplant B-cell lymphoproliferative disorders. Semin Oncol 26 (Suppl 14): S21–S25

    Google Scholar 

  20. Chatenoud L (2003) CD3-specific antibody-induced active tolerance: from bench to bedside. Nat Rev Immunol 3: 123–132

    Article  CAS  Google Scholar 

  21. Keymeulen et al. (2005) Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. New Engl J Med 352: 2598–2608

    Article  CAS  Google Scholar 

  22. Rumbach L et al. (1996) Biological assessment and MRI monitoring of the therapeutic efficacy of a monoclonal anti-T CD4 antibody in multiple sclerosis patients. Mult Scler 1: 207–212

    Article  CAS  Google Scholar 

  23. van Oosten BW et al. (1997) Treatment of multiple sclerosis with the monoclonal anti-CD4 antibody cM-T412: results of a randomized, double-blind, placebo-controlled, MR-monitored phase II trial. Neurology 49: 351–357

    Article  CAS  Google Scholar 

  24. Llewellyn-Smith N et al. (1997) Effects of anti-CD4 antibody treatment on lymphocyte subsets and stimulated tumor necrosis factor alpha production: a study of 29 multiple sclerosis patients entered into a clinical trial of cM-T412. Neurology 48: 810–816

    Article  CAS  Google Scholar 

  25. Rep MH et al. (1997) Treatment with depleting CD4 monoclonal antibody results in a preferential loss of circulating naive T cells but does not affect IFN-gamma secreting TH1 cells in humans. J Clin Invest 99: 2225–2231

    Article  CAS  Google Scholar 

  26. Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25+ CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6: 345–352

    Article  CAS  Google Scholar 

  27. Babbe H et al. (2000) Clonal expansion of CD8+ T cells dominate the T cell infiltrate in active multiple sclerosis lesions shown by micromanipulation and single cell polymerase chain reaction. J Exp Med 192: 393–404

    Article  CAS  Google Scholar 

  28. Skulina C et al. (2004) Multiple sclerosis: Brain-infiltrating CD8+ T cells persist as clonal expansions in the cerebrospinal fluid and blood. Proc Natl Acad Sci USA 101: 2428–2433

    Article  CAS  Google Scholar 

  29. van Oosten BW et al. (1996) Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2. Neurology 47: 1531–1534

    Article  CAS  Google Scholar 

  30. TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group (1999) Neurology 53: 457–465

  31. Sicotte NL and Voskuhl RR (2001) Onset of multiple sclerosis associated with anti-TNF therapy. Neurology 57: 1885–1888

    Article  CAS  Google Scholar 

  32. Mohan N et al. (2001) Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum 44: 2862–2869

    Article  CAS  Google Scholar 

  33. Keane J et al. (2001) Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 345: 1098–1104

    Article  CAS  Google Scholar 

  34. Rice GP et al. (2005) Anti-α4 integrin therapy for multiple sclerosis: mechanisms and rationale. Neurology 64: 1336–1342

    Article  CAS  Google Scholar 

  35. Steinman L (2005) Case history: Blocking adhesion molecules as therapy for multiple sclerosis: natalizumab. Nat Rev Drug Discov 4: 510–518

    Article  CAS  Google Scholar 

  36. Miller DH et al. (2003) A controlled trial of Natalizumab for relapsing multiple sclerosis. N Engl J Med 348: 15–23

    Article  CAS  Google Scholar 

  37. Kleinschmidt-DeMasters BK and Tyler KL (2005) Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 353: 369–374

    Article  CAS  Google Scholar 

  38. Langer-Gould A et al. (2005) Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 353: 375–381

    Article  CAS  Google Scholar 

  39. Van Assche G et al. (2005) Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med 353: 362–368

    Article  CAS  Google Scholar 

  40. Berger JR and Koralnik IJ (2005) Progressive multifocal leukoencephalopathy and natalizumab—unforeseen consequences. N Engl J Med 353: 414–416

    Article  CAS  Google Scholar 

  41. t'Hart BA et al. (2004) Modelling of multiple sclerosis: lessons learned in a non-human primate. Lancet Neurol 3: 588–597

    Article  Google Scholar 

  42. Wing MG et al. (1996) 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 98: 2819–2826

    Article  CAS  Google Scholar 

  43. Coles AJ et al. (1999) Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet 354: 1691–1695

    Article  CAS  Google Scholar 

  44. Coles AJ et al. (1999) Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann Neurol 46: 296–304

    Article  CAS  Google Scholar 

  45. Moreau T et al. (1994) Preliminary evidence from magnetic resonance imaging for reduction in disease activity after lymphocyte depletion in multiple sclerosis. Lancet 344: 298–301

    Article  CAS  Google Scholar 

  46. Bielekova B et al. (2004) Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon beta. Proc Natl Acad Sci USA 101: 8705–8708

    Article  CAS  Google Scholar 

  47. Rose JW et al. (2004) Treatment of multiple sclerosis with an anti-interleukin-2 receptor monoclonal antibody. Ann Neurol 56: 864–867

    Article  CAS  Google Scholar 

  48. Baecher-Allan C and Hafler DA (2004) Suppressor T cells in human diseases. J Exp Med 200: 273–276

    Article  CAS  Google Scholar 

  49. Viglietta V et al. (2004) Loss of functional suppression by CD4+ CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med 199: 971–979

    Article  CAS  Google Scholar 

  50. Rizvi SA and Bashir K (2004) Other therapy options and future strategies for treating patients with multiple sclerosis. Neurology 63 (Suppl 6): S47–S54

    Article  Google Scholar 

  51. Cree BA et al. (2005) An open label study of the effects of rituximab in neuromyelitis optica. Neurology 64: 1270–1272

    Article  CAS  Google Scholar 

  52. Monson NL et al. (2005) Effect of rituximab on the peripheral blood and cerebrospinal fluid B cells in patients with primary progressive multiple sclerosis. Arch Neurol 62: 258–264

    Article  Google Scholar 

  53. National Multiple Sclerosis Society USA [http://www.nationalmssociety.org/research.asp]

  54. Killestein J et al. (2002) Antibody-mediated suppression of Vbeta5.2/5.3(+) T cells in multiple sclerosis: results from an MRI-monitored phase II clinical trial. Ann Neurol 51: 467–474

    Article  CAS  Google Scholar 

  55. Köhler G and Milstein C (1975) Continuous cultures of fused cells secreting antibody components of isologous erythrocytes. Nature 256: 495–497

    Article  Google Scholar 

  56. Alkan SS (2004) Monoclonal antibodies: the story of a discovery that revolutionized science and medicine. Nat Rev Immunol 4: 153–156

    Article  CAS  Google Scholar 

  57. Brekke OH and Sandlie I (2003) Therapeutic antibodies for human diseases at the dawn of the twenty-first century. Nat Rev Drug Discov 2: 52–62

    Article  CAS  Google Scholar 

  58. Breedveld FC (2000) Therapeutic monoclonal antibodies. Lancet 355: 735–740

    Article  CAS  Google Scholar 

  59. Schnipper LE and Strom TB (2001) A magic bullet for cancer—how near and how far? N Engl J Med 345: 283–284

    Article  CAS  Google Scholar 

  60. Clark M (2000) Antibody humanization: a case of the 'Emperor's new clothes'? Immunol Today 21: 397–402

    Article  CAS  Google Scholar 

  61. Lublin F et al. (1999) A phase II trial of anti-CD11/CD18 monoclonal antibody in acute exacerbations of multiple sclerosis [abstract #290]. Neurology 52 (Suppl 2)

Download references

Acknowledgements

The authors thank Dr Emanuelle Waubant for sharing information on rituximab trials, and gratefully acknowledge the support of the Max-Planck Society, Deutsche Forschungsgemeinschaft (DFG, SFB 571), and Hermann and Lilly Schilling Foundation.

Author information

Authors and Affiliations

  1. Institute for Clinical Neuroimmunlogy, Klinikum Grosshadern, Ludwig Maximilians University of Munich,

    Reinhard Hohlfeld

  2. Clinical Section of the Department of Neuroimmunology at the Max Planck Institute of Neurobiology, Munich, Germany

    Reinhard Hohlfeld

  3. Professor and Director of the Department of Neuroimmunology at the Max Planck Institute of Neurobiology, Munich, Germany

    Hartmut Wekerle

Authors
  1. Reinhard Hohlfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hartmut Wekerle
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Reinhard Hohlfeld.

Ethics declarations

Competing interests

Reinhard Hohlfeld participated in clinical trials of Tysabri and received grant support and consultancy fees from Biogen Idec.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hohlfeld, R., Wekerle, H. Drug Insight: using monoclonal antibodies to treat multiple sclerosis. Nat Rev Neurol 1, 34–44 (2005). https://doi.org/10.1038/ncpneuro0016

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpneuro0016

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing