Skip to main content

Advertisement

SpringerLink
Log in

Biotherapeutics for the treatment of multiple sclerosis: hopes and hazards

  • Neurology and Preclinical Neurological Studies - Review Article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

Multiple sclerosis (MS), the most common cause of neurological disability in young adults, represents the prototypic inflammatory autoimmune disorder of the central nervous system. Increased understanding of the immunopathological processes underlying this disease, advances in biotechnology, development of powerful magnetic resonance imaging technologies together with improvements in clinical trial design have translated into a variety of new and innovative therapeutic avenues. In this review, we will highlight recent therapeutic developments in MS and critically discuss new challenges associated with these new treatment options.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Aktas O, Küry P, Kieseier B, Hartung HP (2010) Fingolimod is a potential novel therapy for multiple sclerosis. Nat Rev Neurol 6:373–382

    Article  PubMed  CAS  Google Scholar 

  • Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, Lee S, Plavina T, Scanlon JV, Sandrock A, Bozic C (2012) Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 366(20):1870–1880. doi:10.1056/NEJMoa1107829

    Article  PubMed  CAS  Google Scholar 

  • CAMMS Investigators, Coles AJ, Compston DA, Selmaj KW, Lake SL, Moran S, Margolin DH, Norris K, Tandon PK (2008) Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med 359(17):1786–1801. doi:10.1056/NEJMoa0802670

    Article  PubMed  Google Scholar 

  • Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Fisher E, Brinar VV, Giovannoni G, Stojanovic M, Ertik BI, Lake SL, Margolin DH, Panzara MA, Compston DA, CARE-MS I investigators (2012) Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 380(9856):1819–1828. doi:10.1016/S0140-6736(12)61769-3

    Article  PubMed  CAS  Google Scholar 

  • Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Miller T, Fisher E, Sandbrink R, Lake SL, Margolin DH, Oyuela P, Panzara MA, Compston DA, CARE-MS I investigators (2012) Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 380(9856):1829–1839. doi:10.1016/S0140-6736(12)61768-1

    Article  PubMed  CAS  Google Scholar 

  • DeAngelis LM (2009) Natalizumab: a double-edged sword? Ann Neurol 66(3):262–263. doi:10.1002/ana.21813

    Article  PubMed  Google Scholar 

  • Engelhardt B, Ransohoff RM (2012) Capture, crawl, cross: the T cell code to breach the blood-brain barriers. Trends Immunol 33(12):579–589. doi:10.1016/j.it.2012.07.004

    Article  PubMed  CAS  Google Scholar 

  • Hartung HP (2009) New cases of progressive multifocal leukoencephalopathy after treatment with natalizumab. Lancet Neurol 8(1):28–31. doi:10.1016/S1474-4422(08)70281-3

    Article  PubMed  Google Scholar 

  • Hartung HP, Polman C, Bertolotto A, Deisenhammer F, Giovannoni G, Havrdova E, Hemmer B, Hillert J, Kappos L, Kieseier B, Killestein J, Malcus C, Comabella M, Pachner A, Schellekens H, Sellebjerg F, Selmaj K, Sorensen PS (2007) Neutralising antibodies to interferon beta in multiple sclerosis: expert panel report. J Neurol 254(7):827–837. doi:10.1007/s00415-006-0486-3

    Article  PubMed  CAS  Google Scholar 

  • Hartung HP, Montalban X, Sorensen PS, Vermersch P, Olsson T (2011) Principles of a new treatment algorithm in multiple sclerosis. Expt Rev Neurother 11(3):351–362. doi:10.1586/ern.11.15

    Article  Google Scholar 

  • Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, Bar-Or A, Panzara M, Sarkar N, Agarwal S, Langer-Gould A, Smith CH, Group HT (2008) B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 358(7):676–688. doi:10.1056/NEJMoa0706383

    Article  PubMed  CAS  Google Scholar 

  • Havrdova E, Galetta S, Hutchinson M, Stefoski D, Bates D, Polman CH, O’Connor PW, Giovannoni G, Phillips JT, Lublin FD, Pace A, Kim R, Hyde R (2009) Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study. Lancet Neurol 8(3):254–260. doi:10.1016/S1474-4422(09)70021-3

    Article  PubMed  Google Scholar 

  • Hemmer B, Frohman E, Hartung H-P, Stüve O (2006) Central nervous system infections: a potential complication of systemic immunotherapy. Curr Opin Neurol 19:271–276

    Article  PubMed  CAS  Google Scholar 

  • International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium 2, Sawcer S, Hellenthal G, Pirinen M, Spencer CC, Patsopoulos NA, Moutsianas L, Dilthey A, Su Z, Freeman C, Hunt SE, Edkins S, Gray E, Booth DR, Potter SC, Goris A, Band G, Oturai AB, Strange A, Saarela J, Bellenguez C, Fontaine B, Gillman M, Hemmer B, Gwilliam R, Zipp F, Jayakumar A, Martin R, Leslie S, Hawkins S, Giannoulatou E, D’Alfonso S, Blackburn H, Martinelli Boneschi F, Liddle J, Harbo HF, Perez ML, Spurkland A, Waller MJ, Mycko MP, Ricketts M, Comabella M, Hammond N, Kockum I, McCann OT, Ban M, Whittaker P, Kemppinen A, Weston P, Hawkins C, Widaa S, Zajicek J, Dronov S, Robertson N, Bumpstead SJ, Barcellos LF, Ravindrarajah R, Abraham R, Alfredsson L, Ardlie K, Aubin C, Baker A, Baker K, Baranzini SE, Bergamaschi L, Bergamaschi R, Bernstein A, Berthele A, Boggild M, Bradfield JP, Brassat D, Broadley SA, Buck D, Butzkueven H, Capra R, Carroll WM, Cavalla P, Celius EG, Cepok S, Chiavacci R, Clerget-Darpoux F, Clysters K, Comi G, Cossburn M, Cournu-Rebeix I, Cox MB, Cozen W, Cree BA, Cross AH, Cusi D, Daly MJ, Davis E, de Bakker PI, Debouverie M, D’Hooghe MB, Dixon K, Dobosi R, Dubois B, Ellinghaus D, Elovaara I, Esposito F, Fontenille C, Foote S, Franke A, Galimberti D, Ghezzi A, Glessner J, Gomez R, Gout O, Graham C, Grant SF, Guerini FR, Hakonarson H, Hall P, Hamsten A, Hartung HP, Heard RN, Heath S, Hobart J, Hoshi M, Infante-Duarte C, Ingram G, Ingram W, Islam T, Jagodic M, Kabesch M, Kermode AG, Kilpatrick TJ, Kim C, Klopp N, Koivisto K, Larsson M, Lathrop M, Lechner-Scott JS, Leone MA, Leppa V, Liljedahl U, Bomfim IL, Lincoln RR, Link J, Liu J, Lorentzen AR, Lupoli S, Macciardi F, Mack T, Marriott M, Martinelli V, Mason D, McCauley JL, Mentch F, Mero IL, Mihalova T, Montalban X, Mottershead J, Myhr KM, Naldi P, Ollier W, Page A, Palotie A, Pelletier J, Piccio L, Pickersgill T, Piehl F, Pobywajlo S, Quach HL, Ramsay PP, Reunanen M, Reynolds R, Rioux JD, Rodegher M, Roesner S, Rubio JP, Ruckert IM, Salvetti M, Salvi E, Santaniello A, Schaefer CA, Schreiber S, Schulze C, Scott RJ, Sellebjerg F, Selmaj KW, Sexton D, Shen L, Simms-Acuna B, Skidmore S, Sleiman PM, Smestad C, Sorensen PS, Sondergaard HB, Stankovich J, Strange RC, Sulonen AM, Sundqvist E, Syvanen AC, Taddeo F, Taylor B, Blackwell JM, Tienari P, Bramon E, Tourbah A, Brown MA, Tronczynska E, Casas JP, Tubridy N, Corvin A, Vickery J, Jankowski J, Villoslada P, Markus HS, Wang K, Mathew CG, Wason J, Palmer CN, Wichmann HE, Plomin R, Willoughby E, Rautanen A, Winkelmann J, Wittig M, Trembath RC, Yaouanq J, Viswanathan AC, Zhang H, Wood NW, Zuvich R, Deloukas P, Langford C, Duncanson A, Oksenberg JR, Pericak-Vance MA, Haines JL, Olsson T, Hillert J, Ivinson AJ, De Jager PL, Peltonen L, Stewart GJ, Hafler DA, Hauser SL, McVean G, Donnelly P, Compston A (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476(7359):214–219. doi:10.1038/nature10251

    Article  PubMed  CAS  Google Scholar 

  • Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM, Fischer JS, Goodkin DE, Granger CV, Simon JH, Alam JJ, Bartoszak DM, Bourdette DN, Braiman J, Brownscheidle CM, Coats ME, Cohan SL, Dougherty DS, Kinkel RP, Mass MK, Munschauer FE 3rd, Priore RL, Pullicino PM, Scherokman BJ, Whitham RH et al (1996) Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol 39(3):285–294. doi:10.1002/ana.410390304

    Article  PubMed  CAS  Google Scholar 

  • Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, Myers LW, Panitch HS, Rose JW, Schiffer RB (1995) Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 45(7):1268–1276

    Article  PubMed  CAS  Google Scholar 

  • Jones JL, Anderson JM, Phuah CL, Fox EJ, Selmaj K, Margolin D, Lake SL, Palmer J, Thompson SJ, Wilkins A, Webber DJ, Compston DA, Coles AJ (2010) Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity. Brain 133(Pt 8):2232–2247. doi:10.1093/brain/awq176

    Article  PubMed  Google Scholar 

  • Kappos L, Li D, Calabresi PA, O’Connor P, Bar-Or A, Barkhof F, Yin M, Leppert D, Glanzman R, Tinbergen J, Hauser SL (2011) Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet 378(9805):1779–1787. doi:10.1016/S0140-6736(11)61649-8

    Article  PubMed  CAS  Google Scholar 

  • Kieseier BC, Wiendl H, Hartung HP, Leussink VI, Stuve O (2011) Risks and benefits of multiple sclerosis therapies: need for continual assessment? Curr Opin Neurol 24(3):238–243. doi:10.1097/WCO.0b013e32834696dd

    Article  PubMed  Google Scholar 

  • Kleinschmidt-DeMasters BK, Miravalle A, Schowinsky J, Corboy J, Vollmer T (2012) Update on PML and PML-IRIS occurring in multiple sclerosis patients treated with natalizumab. J Neuropathol Exp Neurol 71(7):604–617. doi:10.1097/NEN.0b013e31825caf2c

    Article  PubMed  CAS  Google Scholar 

  • Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D (2005) Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 353(4):375–381. doi:10.1056/NEJMoa051847

    Article  PubMed  CAS  Google Scholar 

  • Linker RA, Kieseier BC (2008) Innovative monoclonal antibody therapies in multiple sclerosis. Therap Adv Neurol Disorders 1(1):43–52. doi:10.1177/1756285608093945

    Article  Google Scholar 

  • Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, Sandrock AW, AFFIRM Investigators (2006) A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 354(9):899–910. doi:10.1056/NEJMoa044397

    Article  PubMed  CAS  Google Scholar 

  • PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group (1998) Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet 352(9139):1498–1504

    Google Scholar 

  • Riminton DS, Hartung HP, Reddel SW (2011) Managing the risks of immunosuppression. Curr Opin Neurol 24:217–223

    Article  PubMed  Google Scholar 

  • Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, Lublin FD, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA, Sandrock AW, SENTINEL Investigators (2006) Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 354(9):911–923. doi:10.1056/NEJMoa044396

    Article  PubMed  CAS  Google Scholar 

  • Schmedt N, Andersohn F, Garbe E (2012) Signals of progressive multifocal leukoencephalopathy for immunosuppressants: a disproportionality analysis of spontaneous reports within the US Adverse Event Reporting System (AERS). Pharmacoepidemiol Drug Safety 21(11):1216–1220. doi:10.1002/pds.3320

    Article  CAS  Google Scholar 

  • Sundqvist E, Warnke C, Khademi M (2011) Genetic influence on anti-JC-virus antibody seropositivity in MS patients and controls. Multi Scler 17(Suppl 10):S358

    Google Scholar 

  • The IFNB Multiple Sclerosis Study Group, The University of British Columbia MS/MRI Analysis Group (1995) Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. Neurology 45(7):1277–1285

    Article  Google Scholar 

  • Van Assche G, Van Ranst M, Sciot R, Dubois B, Vermeire S, Noman M, Verbeeck J, Geboes K, Robberecht W, Rutgeerts P (2005) Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med 353(4):362–368. doi:10.1056/NEJMoa051586

    Article  PubMed  Google Scholar 

  • Warnke C, Meyer zu Horste G, Hartung HP, Stuve O, Kieseier BC (2009) Review of teriflunomide and its potential in the treatment of multiple sclerosis. Neuropsychiatr Dis Treatm 5:333–340

    CAS  Google Scholar 

  • Warnke C, Menge T, Hartung HP, Racke MK, Cravens PD, Bennett JL, Frohman EM, Greenberg BM, Zamvil SS, Gold R, Hemmer B, Kieseier BC, Stuve O (2010) Natalizumab and progressive multifocal leukoencephalopathy: what are the causal factors and can it be avoided? Arch Neurol 67(8):923–930. doi:10.1001/archneurol.2010.161

    Article  PubMed  Google Scholar 

  • Warnke C, Adams O, Gold R, Hartung HP, Hohlfeld R, Wiendl H, Kieseier BC (2011a) Progressive multifocal leukoencephalopathy under natalizumab. Initial possibilities for risk stratification? Der Nervenarzt 82(4):475–480. doi:10.1007/s00115-010-3091-8

    Article  PubMed  CAS  Google Scholar 

  • Warnke C, Adams O, Hartung HP, Gold R, Hemmer B, Hohlfeld R, Stangel M, Zipp F, Wiendl H, Kieseier BC (2011b) Risk stratification of progressive multifocal leukoencephalopathy under natalizumab: recommendations for JC virus serology. Der Nervenarzt 82(10):1314–1319. doi:10.1007/s00115-011-3319-2

    Article  PubMed  CAS  Google Scholar 

  • Warnke C, Stuve O, Hartung HP, Fogdell-Hahn A, Kieseier BC (2011c) Critical appraisal of the role of fingolimod in the treatment of multiple sclerosis. Neuropsychiatr Dis Treatm 7:519–527. doi:10.2147/NDT.S10481

    CAS  Google Scholar 

  • Warnke C, Hermanrud C, Lundkvist M, Fogdell-Hahn A (2012) Anti-drug antibodies. Drugs Ther Stud 2(1):e11

    Google Scholar 

  • Warnke C, Pawlita M, Dehmel T, Posevitz-Fejfar A, Hartung HP, Wiendl H, Kieseier BC, Adams O (2013a) An assay to quantify species-specific anti-JC virus antibody levels in MS patients. Multi Scler [Epub ahead of print]

  • Warnke C, Ramanujam R, Plavina T, Bergström T, Goelz S, Subramanyam M, Kockum I, Rahbar A, Kieseier BC, Holmén C, Olsson T, Hillert J, Fogdell-Hahn A (2013b) Changes to anti-JCV antibody levels in a Swedish national MS cohort. J Neurol Neurosurg Psychiatry [Epub ahead of print]

  • Wiendl H, Kieseier B (2013) Multiple sclerosis: reprogramming the immune repertoire with alemtuzumab in MS. Nat Rev Neurol 9(3):125–126. doi:10.1038/nrneurol.2013.2

    Article  PubMed  CAS  Google Scholar 

  • Yednock TA, Cannon C, Fritz LC, Sanchez-Madrid F, Steinman L, Karin N (1992) Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature 356(6364):63–66. doi:10.1038/356063a0

    Article  PubMed  CAS  Google Scholar 

  • Yousry TA, Major EO, Ryschkewitsch C, Fahle G, Fischer S, Hou J, Curfman B, Miszkiel K, Mueller-Lenke N, Sanchez E, Barkhof F, Radue EW, Jager HR, Clifford DB (2006) Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 354(9):924–933. doi:10.1056/NEJMoa054693

    Article  PubMed  CAS  Google Scholar 

  • Yousry TA, Pelletier D, Cadavid D, Gass A, Richert ND, Radue EW, Filippi M (2012) Magnetic resonance imaging pattern in natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol 72(5):779–787. doi:10.1002/ana.23676

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Work from the authors was supported by grants from the German Ministry for Education and Research (BMBF, “German Competence Network Multiple Sclerosis” (KKNMS), Natalizumab-Pharmakovigilanzstudie, 01GI1002). Furthermore we have received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. [115303], resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. Dr Warnke was supported by an ECTRIMS (European Committee for treatment and research in MS) fellowship stipend.

Author information

Authors and Affiliations

  1. Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Moorenstrasse 5, 40225, Duesseldorf, Germany

    Clemens Warnke, Bernd C. Kieseier & Hans-Peter Hartung

Authors
  1. Clemens Warnke
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bernd C. Kieseier
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hans-Peter Hartung
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hans-Peter Hartung.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Warnke, C., Kieseier, B.C. & Hartung, HP. Biotherapeutics for the treatment of multiple sclerosis: hopes and hazards. J Neural Transm 120 (Suppl 1), 55–60 (2013). https://doi.org/10.1007/s00702-013-1055-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-013-1055-4

Keywords

Search

Navigation