Multiple sclerosis (MS) is a complex disease that causes a great deal of disability, especially in the young adult population. There have been several immunomodulatory agents that have been approved by the Food and Drug Administration for MS, including glatiramer acetate, interferon-β1a and -β1b, mitoxantrone, and corticosteroids. The effectiveness of these therapies has not been optimal, and drugs, such as monoclonal antibodies, that more selectively target the pathogenetic process of MS have been sought. These agents have their own intrinsic limitations such as systemic inflammatory reactions, induction of neutralizing antiantibodies, and even life-threatening infectious processes. The agent that has been in the forefront of the discussion is natalizumab, a monoclonal antibody (mAb) against α4 integrin, which shows much promise in suppressing MS activity. However, 3 individuals treated with natalizumab developed a life-threatening infection, progressive multifocal leukoencephalopathy. This article reviews the role of mAbs in the treatment of MS, particularly their advantages over other drugs and their limitations, which have to be overcome for these agents to be at the forefront in the treatment of MS.
Goodin DS, Frohman EM, Garmany GP Jr, et al. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology.2002;58(2):169-178.
8.
Sotgiu S., Pugliatti M., Sotgiu A., Sanna A., Rosati G.Does the “hygiene hypothesis” provide an explanation for the high prevalence of multiple sclerosis in Sardinia?Autoimmunity . 2003;36(5):257-260.
9.
Alter M., Halpern L., Kurland LT, Bornstein B., Leibowitz U., Silberstein J.Multiple sclerosis in Israel. Prevalence among immigrants and native inhabitants. Arch Neurol.1962;7: 253-263.
10.
Dean G., Kurtzke JFOn the risk of multiple sclerosis according to age at immigration to South Africa. Br Med J.1971;3(5777): 725-729.
11.
Ropper AH, Adams RD, Victor M., Brown RH, Victor M.Adams and Victor's Principles of Neurology. 8th ed. New York, NY: McGraw-Hill; 2005.
12.
McAlpine D., Compston A.Distribution of multiple sclerosis. In: Compston A, Confavreux C, Lassmann H, et al, eds. McAlpine's Multiple Sclerosis. 4th ed. Philadelphia, Pa: Churchill Livingstone/Elsevier; 2005.
13.
Anderson DW , Ellenberg JH, Leventhal CM, Reingold SC, Rodriguez M., Silberberg DHRevised estimate of the prevalence of multiple sclerosis in the United States. Ann Neurol.
14.
Orlewska E. , Mierzejewski P., Zaborski J., et al. A prospective study of the financial costs of multiple sclerosis at different stages of the disease. Eur J Neurol.2005;12(1):31-39.
15.
Kasper DL, Harrison TRHarrison's Principles of Internal Medicine. 16th ed. New York, NY: McGraw-Hill ; 2005.
16.
Confavreux C., Vukusic S., Adeleine P.Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain.2003;126(pt 4):770-782.
17.
Confavreux C., Vukusic S.Natural history of multiple sclerosis: a unifying concept. Brain. 2006;129(pt 3):606-616.
18.
Birk K., Rudick R.Pregnancy and multiple sclerosis. Arch Neurol.1986;43(7):719-726.
19.
Atkins EJ, Biousse V., Newman NJThe natural history of optic neuritis. Rev Neurol Dis. 2006;3(2):45-56.
20.
Beck RW, Trobe JD, Moke PS, et al. High- and low-risk profiles for the development of multiple sclerosis within 10 years after optic neuritis: experience of the optic neuritis treatment trial. Arch Ophthalmol.2003;121(7):944-949.
21.
Pozzilli C. , Marinelli F., Romano S., Bagnato F.Corticosteroids treatment. J Neurol Sci.2004;223(1):47-51.
22.
Zivadinov R. , Rudick RA, De Masi R., et al. Effects of IV methylprednisolone on brain atrophy in relapsing-remitting MS. Neurology.2001;57(7):1239-1247.
23.
Gijbels K., Engelborghs S., De Deyn PPExperimental autoimmune encephalomyelitis: an animal model for multiple sclerosis . Neurosci Res Commun.2000;26(3):193-206.
24.
Bolton C., Flower RJThe effects of the anti-glucocorticoid RU 38486 on steroid-mediated suppression of experimental allergic encephalomyelitis (EAE) in the Lewis rat. Life Sci.1989;45 (1):97-104.
25.
Bolton C., O'Neill JK, Allen SJ, Baker D.Regulation of chronic relapsing experimental allergic encephalomyelitis by endogenous and exogenous glucocorticoids. Int Arch Allergy Immunol.1997;114(1):74-80.
26.
Barnes D., Hughes RA, Morris RW, et al. Randomised trial of oral and intravenous methylprednisolone in acute relapses of multiple sclerosis. Lancet. 1997;349(9056):902-906.
27.
Beck RW, Cleary PA, Anderson MM Jr, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Engl J Med.1992;326(9):581-588.
28.
Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. European Study Group on interferon beta-1b in secondary progressive MS. Lancet. 1998;352(9139):1491-1497.
29.
Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet. 1998;352(9139):1498-1504.
30.
Panitch H., Goodin DS, Francis G., et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS: the EVIDENCE Trial. Neurology. 2002;59(10):1496-1506.
31.
Teitelbaum D., Arnon R., Sela M.Copolymer 1: from basic research to clinical application. Cell Mol Life Sci.1997;53 (1):24-28.
32.
Bornstein MB , Miller A., Slagle S., et al. A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis. N Engl J Med.1987;317(7):408-414.
33.
Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and improves disability in relapsingremitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology.1995;45(7): 1268-1276.
34.
Rudick RA, Cohen JA, Weinstock-Guttman B., Kinkel RP, Ransohoff RMManagement of multiple sclerosis. N Engl J Med.1997;337(22):1604-1611.
35.
Jeffery DR, Herndon R.Review of mitoxantrone in the treatment of multiple sclerosis. Neurology. 2004;63(12 suppl 6): S19-S24.
36.
Edan G., Miller D., Clanet M., et al. Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomised multicentre study of active disease using MRI and clinical criteria. J Neurol Neurosurg Psychiatry. 1997;62(2):112-118.
37.
Millefiorini E., Gasperini C., Pozzilli C., et al. Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 24-month clinical and MRI outcome. J Neurol.1997;244(3):153-159.
38.
Hartung HP, Gonsette R., Konig N., et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet. 2002;360(9350): 2018-2025.
39.
Fox EJManagement of worsening multiple sclerosis with mitoxantrone: a review. Clin Ther.2006;28(4):461-474.
40.
Alkan SSMonoclonal antibodies: the story of a discovery that revolutionized science and medicine. Nat Rev Immunol. 2004;4(2):153-156.
41.
Brekke OH, Sandlie I.Therapeutic antibodies for human diseases at the dawn of the twenty-first century. Nat Rev Drug Discov. 2003;2(1):52-62.
Life-threatening brain infection in patients with systemic lupus erythematosus after Rituxan (rituximab) treatment [press release]. Washington, DC: US Food and Drug Administration; December 18, 2006.
44.
Clark M.Antibody humanization: a case of the “Emperor's new clothes”?Immunol Today. 2000;21(8):397-402.
45.
Rice GP, Hartung HP, Calabresi PAAnti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale . Neurology. 2005;64(8):1336-1342.
46.
Steinman L.Blocking adhesion molecules as therapy for multiple sclerosis: natalizumab. Nat Rev Drug Discov. 2005;4(6): 510-518.
47.
Madri JA, Graesser D., Haas T.The roles of adhesion molecules and proteinases in lymphocyte transendothelial migration. Biochem Cell Biol.1996;74(6):749-757.
48.
Damle NK, Aruffo A.Vascular cell adhesion molecule 1 induces T-cell antigen receptor-dependent activation of CD4+T lymphocytes. Proc Natl Acad Sci U S A . 1991;88(15): 6403-6407.
49.
Burkly LC, Jakubowski A., Newman BM, Rosa MD, Chi-Rosso G., Lobb RRSignaling by vascular cell adhesion molecule-1 (VCAM-1) through VLA-4 promotes CD3-dependent T cell proliferation. Eur J Immunol.1991;21(11):2871-2875.
Barry ST, Ludbrook SB, Murrison E., Horgan CMAnalysis of the alpha4beta1 integrin-osteopontin interaction. Exp Cell Res.2000;258(2):342-351.
52.
Stuve O., Marra CM, Jerome KR, et al. Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann Neurol.2006;59(5):743-747.
53.
Tubridy N., Behan PO, Capildeo R., et al. The effect of anti-alpha4 integrin antibody on brain lesion activity in MS. The UK Antegren Study Group. Neurology. 1999;53(3):466-472.
54.
Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis . N Engl J Med.2003;348(1):15-23.
55.
Chaudhuri A. , Behan PONatalizumab for relapsing multiple sclerosis . N Engl J Med.2003;348(16):1598-1599.
56.
Polman CH, O'Connor PW, Havrdova E., et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med.2006;354(9):899-910.
57.
Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis . N Engl J Med.2006;354(9):911-923.
58.
Van Assche G , Van Ranst M, Sciot R., et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med.2005;353(4):362-368.
59.
Kleinschmidt-DeMasters BK, Tyler KLProgressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med.2005;353(4):369-374.
60.
Langer-Gould A., Atlas SW, Green AJ, Bollen AW, Pelletier D.Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med.2005;353(4):375-381.
61.
Koralnik IJOverview of the cellular immunity against JC virus in progressive multifocal leukoencephalopathy. J Neurovirol . 2002;8(suppl 2):59-65.
62.
Koralnik IJ , Du Pasquier RA, Letvin NLJC virus-specific cytotoxic T lymphocytes in individuals with progressive multifocal leukoencephalopathy. J Virol.2001;75(7):3483-3487.
63.
Greenlee JEProgressive multifocal leucoencephalopathy in the era of natalizumab: a review and discussion of the implications. Int MS J. 2006;13(3):100-107.
64.
Ault GS, Stoner GLBrain and kidney of progressive multifocal leukoencephalopathy patients contain identical rearrangements of the JC virus promoter/enhancer. J Med Virol.1994;44 (3):298-304.
65.
von Andrian UH, Engelhardt B.Alpha4 integrins as therapeutic targets in autoimmune disease. N Engl J Med.2003;348(1): 68-72.
Niino M., Bodner C., Simard ML, et al. Natalizumab effects on immune cell responses in multiple sclerosis . Ann Neurol.2006; 59(5):748-754.
68.
Berger JR, Houff S.Progressive multifocal leukoencephalopathy: lessons from AIDS and natalizumab . Neurol Res. 2006; 28(3):299-305.
69.
Major E.JC virus in the CSF and plasma of natalizumab treated patients. Paper presented at: the 21st Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 28—October 1, 2005; Thessaloniki, Greece.
70.
Natalizumab (Tysabri®) information. US Food and Drug Administration Web site. Available at: http://www.fda.gov/cder/drug/infopage/natalizumab/. Accessed 2006.
71.
Waldmann H.Manipulation of T-cell responses with monoclonal antibodies. Annu Rev Immunol. 1989;7:407-444.
72.
Hafler DA, Weiner HLAnti-CD4 and anti-CD2 monoclonal antibody infusions in subjects with multiple sclerosis. Immunosuppressive effects and human antimouse responses. Ann N Y Acad Sci.1988;540:557-559.
73.
Hafler DA, Fallis RJ, Dawson DM, Schlossman SF, Reinherz EL, Weiner HLImmunologic responses of progressive multiple sclerosis patients treated with an anti-T-cell monoclonal antibody, anti-T12. Neurology. 1986;36(6):777-784.
74.
Hafler DA, Weiner HLIn vivo labeling of blood T cells: rapid traffic into cerebrospinal fluid in multiple sclerosis. Ann Neurol.1987;22(1):89-93.
75.
Ransohoff RM, Kivisakk P., Kidd G.Three or more routes for leukocyte migration into the central nervous system . Nat Rev Immunol. 2003;3(7):569-581.
76.
Weinshenker BG , Bass B., Karlik S., Ebers GC, Rice GPAn open trial of OKT3 in patients with multiple sclerosis. Neurology. 1991;41(7):1047-1052.
77.
Cree B.Emerging monoclonal antibody therapies for multiple sclerosis. Neurologist. 2006;12(4):171-178.
78.
Riechmann L., Clark M., Waldmann H., Winter G.Reshaping human antibodies for therapy. Nature. 1988;332(6162):323-327.
79.
van Oosten BW , Lai M., Hodgkinson S., et al. Treatment of multiple sclerosis with the monoclonal anti-CD4 antibody cM-T412: results of a randomized, double-blind, placebo- controlled, MRmonitored phase II trial. Neurology . 1997;49(2): 351-357.
80.
Sicotte NL, Voskuhl RROnset of multiple sclerosis associated with anti-TNF therapy. Neurology. 2001;57(10):1885-1888.
81.
Mohan N., Edwards ET, Cupps TR, et al. Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum.2001;44(12):2862-2869.
82.
van Oosten BW , Barkhof F., Truyen L., et al. Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2. Neurology. 1996;47(6):1531-1534.
83.
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. Neurology. 1999;53(3):457-465.
84.
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.
85.
Perkins JG, Flynn JM, Howard RS, Byrd JCFrequency and type of serious infections in fludarabine-refractory B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma: implications for clinical trials in this patient population. Cancer. 2002;94(7):2033-2039.
86.
Coles AJ, Wing MG, Molyneux P., et al. Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann Neurol.1999;46(3):296-304.
87.
Coles A., Deans J., Compston A.Campath-1H treatment of multiple sclerosis: lessons from the bedside for the bench. Clin Neurol Neurosurg.2004;106(3):270-274.
88.
Coles AJ, Wing M., Smith S., et al. Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet. 1999 ;354(9191):1691-1695.
89.
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.
90.
Multiple sclerosis fully enrolled phase 2: genzyme oncology clinical trials . Genzyme Web site. Available at: http://www.genzymeoncology.com/onc/clinical/clinical_trial_onc.asp .Accessed 2005.
91.
National Institutes of Health.A phase II study comparing low-and high-dose CAMPATH and high-dose Rebif in patients with early, active relapsing-remitting multiple sclerosis. Clinical Trial.gov Web site. Available at: http://www.clinicaltrials.gov/ct/show/NCT00050778?order=1.
92.
Genzyme. Data suggest strong treatment effect for patients using Campath: serious adverse events in trial require comprehensive risk management plan . Available at: http://www.genzyme.com/corp/media/GENZ%20PR-091605.asp .
93.
Maloney DG, Grillo-Lopez AJ, White CA, et al. IDEC-C2B8 (rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood. 1997;90(6):2188-2195.
94.
National Institutes of Health.This is a phase II/III, randomized, double-blind, parallel group, placebo controlled, multicenter study to evaluate the safety and efficacy of rituximab in adults with primary progressive multiple sclerosis (PPMS). ClinicalTrial.govWebsite. Available at: http://www.clinicaltrials.gov/ct/show/NCT00087529?order=1.
95.
National Institutes of Health.This is a phase II, randomized, double-blind, parallel group, placebo-controlled, multicenter study to evaluate the safety and efficacy of rituximab in adults with relapsing-remitting multiple sclerosis (RRMS). ClinicalTrial.govWebsite. Available at: http://www.clinical-trials.gov/ct/show/NCT00097188?order=1.
96.
Cree BA, Lamb S., Morgan K., Chen A., Waubant E., Genain C.An open label study of the effects of rituximab in neuromyelitis optica. Neurology. 2005;64(7):1270-1272.
97.
Monson NL, Cravens PD, Frohman EM, Hawker K., Racke MKEffect of rituximab on the peripheral blood and cerebrospinal fluid B cells in patients with primary progressive multiple sclerosis. Arch Neurol.2005;62(2):258-264.
98.
Bielekova B. , Richert N., Howard T., et al. Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon beta. Proc Natl Acad Sci U S A. 2004;101(23):8705-8708.
99.
Rose JW, Watt HE, White AT, Carlson NGTreatment of multiple sclerosis with an anti-interleukin-2 receptor monoclonal antibody. Ann Neurol.2004;56(6):864-867.
100.
Killestein J., Olsson T., Wallstrom E., et al. Antibody-mediated suppression of Vbeta5.2/5.3(+) T cells in multiple sclerosis: results from an MRI-monitored phase II clinical trial. Ann Neurol.2002;51(4):467-474.
101.
Beck P.Rituxan (rituxamab) linked to two deaths in Lupus patients. Medpage. Available at: http://www.medpagetoday.com/ProductAlert/Prescriptions/tb/4729 .
102.
National Multiple Sclerosis Society USA. Research Accessed December 19, 2006. Available at: http://www.nationalmssociety.org/research.asp.
