Monoclonal antibody therapy in multiple sclerosis: Critical appraisal and new perspectives

Expert Review of Neurotherapeutics

Volumn 15, Issue 3, 2015, Pages 251-268

  D'amico, Emanuele ^a   Caserta, Cinzia ^b   Patti, Francesco ^b  

^a Rehabilitationskrankenhaus Ulm gGmbH   (Germany)

^b UNIVERSITY OF CATANIA   (Italy)

Author keywords

immunogenicity; induction therapy; mAbs; multiple sclerosis; Phase III studies; safety

Indexed keywords

ALEMTUZUMAB; CHEMOKINE; DACLIZUMAB; LEUCINE RICH REPEAT AND IMMUNOGLOBULIN DOMAIN CONTAINING NOGO RECEPTOR INTERACTING PROTEIN 1 ANTIBODY; MEDI 551; MONOCLONAL ANTIBODY; MOR 103; NATALIZUMAB; OCRELIZUMAB; OFATUMUMAB; RITUXIMAB; TABALUMAB; TOCILIZUMAB; UNCLASSIFIED DRUG; USTEKINUMAB; IMMUNOSUPPRESSIVE AGENT;

ARTICLE; B LYMPHOCYTE; CHILL; DRUG SAFETY; FEVER; HEADACHE; HUMAN; IMMUNOGENICITY; MULTIPLE SCLEROSIS; MUSCLE SPASM; MYELOOPTIC NEUROPATHY; NAUSEA; NEUROMYELITIS OPTICA SPECTRUM DISORDER; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); RANDOMIZED CONTROLLED TRIAL (TOPIC); RESPIRATORY TRACT INFECTION; URINARY TRACT INFECTION; IMMUNOTHERAPY; PROCEDURES;

ANTIBODIES, MONOCLONAL; HUMANS; IMMUNOSUPPRESSIVE AGENTS; IMMUNOTHERAPY; MULTIPLE SCLEROSIS;

EID: 84923338772     PISSN: 14737175     EISSN: 17448360     Source Type: Journal    
DOI: 10.1586/14737175.2015.1008458     Document Type: Article

References (130)

1. Derwenskus J, Lublin FD. Future treatment approaches to multiple sclerosis. Handb Clin Neurol 2014;122:563-77
2. Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 1975;256: 495-7
3. Strebhardt K, Ullrich A. Paul Ehrlich's magic bullet concept: 100 years of progress. Nature Rev Cancer 2008;8:473-80
4. Ferran C, Dy M, Sheehan K, et al. Cascade modulation by anti-tumor necrosis factor monoclonal antibody of interferon-gamma, interleukin 3 and interleukin 6 release after triggering of the CD3/T cell receptor activation pathway. Eur J Immunol 1991;21:2349-53
5. Hansel TT, Kropshofer H, Singer T, et al. The safety and side effects of monoclonal antibodies. Nat Rev Drug Discov 2010; 9(4):325-38
6. Nissim A, Chernajovsky Y. Historical development of monoclonal antibody therapeutics. Handb Exp Pharmacol 2008 (181):3-18
7. Pendley C, Schantz A, Wagner C. Immunogenicity of therapeutic monoclonal antibodies. Curr Opin Mol Ther 2003;5(2): 172-9
8. Parish C.R, Liew FY. Immune response to chemically modified flagellin. 3. Enhanced cell-mediated immunity during high and low zone antibody tolerance to flagellin. J Exp Med 1972;135:298-311
9. Swann PG, Tolnay M, Muthukkumar S, et al. Considerations for the development of therapeutic monoclonal antibodies. Curr Opin Immunol 2008;20(4):493-9
10. Lutterotti A, Martin R. Getting specific: monoclonal antibodies in multiple sclerosis. Lancet Neurol 2008;7:538-47
11. Fontoura P. Monoclonal antibody therapy in multiple sclerosis: paradigm shifts and emerging challenges. MAbs 2010;2(6): 670-81
12. Carrithers MD. Update on Disease-Modifying Treatments for Multiple Sclerosis. Clin Ther 2014;36(12):1938-45
13. Kawamoto E, Nakahashi S, Okamoto T, et al. Anti-integrin therapy for multiple sclerosis. Autoimmune Diseases 2012;357101, pp. 6
14. Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon b-1a for multiple sclerosis. N Engl J Med 2005;353:369-74
15. Langer-Gould A, Atlas SW, Green AJ, et al. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005;353:375-81
16. 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;353:362-8
17. 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
18. Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006;354(9):911-23
19. Planas R, Martin R, Sospedra M. Long-term safety and efficacy of natalizumab in relapsing-remitting multiple sclerosis: impact on quality of life. Patient Relat Outcome Meas 2014;5:25-33
20. Stephenson JJ, Kern DM, Agarwal SS, et al. Impact of natalizumab on patient-reported outcomes in multiple sclerosis: a longitudinal study. Health Qual Life Outcomes 2012;10:155
21. O'Connor P, Goodman A, Kappos L, et al. Long-term safety and effectiveness of natalizumab redosing and treatment in the STRATA MS Study. Neurology 2014; 83(1):78-86
22. Butzkueven H, Kappos L, Pellegrini F, et al. Efficacy and safety of natalizumab in multiple sclerosis: interim observational programme results. J Neurol Neurosurg Psychiatry 2014;85(11):1190-7
23. Clifford DB. Progressive multifocal leukoencephalopathy therapy. J Neurovirol 2014. [Epub ahead of print]
24. Schwab N, Schneider-Hohendorf T, Posevitz V, et al. L-Selectin is a possible biomarker for individual PML risk in natalizumab-treated MS patients. Neurology 2013;81(10):865-71
25. Knier B, Hemmer B, Korn T. Novel monoclonal antibodies for therapy of multiple sclerosis. Expert Opin Biol Ther 2014;14(4):503-13
26. Administration USFaD. Available from: www.fda.gov 10903 New Hampshire Avenue. Silver Spring, MD 20993. Ph. 1-888-INFO-FDA (1-888-463-6332) 2013 [February 2014]
27. Tan K, Roda R, Ostrow L, et al. PML-IRIS in patients with HIV infection: clinical manifestations and treatment with steroids. Neurology 2009;72(17):1458-64
28. Giacomini PS, Rozenberg A, Metz I, Araujo D. Maraviroc and JC virus-associated immune reconstitution inflammatory syndrome. N Engl J Med 2014;370(5):486-8
29. Pucci E, Giuliani G, Solari A, et al. Natalizumab for relapsing remitting multiple sclerosis. Cochrane Database Syst Rev 2011;10:CD007621
30. Borisow N, Friedemann P, Dörr J. Optimal management of multiple sclerosis during pregnancy: current perspectives. Degenerative Neurological & Neuromuscular Disease 2014;4:111-21
31. Vennegoor A, Rispens T, Strijbis EM, et al. Clinical relevance of serum natalizumab concentration and anti-natalizumab antibodies in multiple sclerosis. Mult Scler 2013;19(5):593-600
32. Havla J, Kleiter I, Kümpfel T. Bridging, switching or drug holidays - how to treat a patient who stops natalizumab? Ther Clin Risk Manag 2013;9:361-9
33. Lugaresi A, di Ioia M, Travaglini D, et al. Risk-benefit considerations in the treatment of relapsing-remitting multiple sclerosis. Neuropsychiatr Dis Treat 2013;9:893-914
34. Fox RJ, Cree BA, De Sèze J, et al. MS disease activity in RESTORE: a randomized 24-week natalizumab treatment interruption study. Neurology 2014;82(17):1491-8
35. Alinari L, Lapalombella R, Andritsos L, et al. Alemtuzumab (Campath-1H) in the treatment of chronic lymphocytic leukemia. Oncogene 2007;26:3644-53
36. Coles AJ. Alemtuzumab therapy for multiple sclerosis. Neurotherapeutics 2013; 10(1):29-33
37. Haudebourg T, Poirier N, Vanhove B. Depleting T-cell subpopulations in organ transplantation. Transpl Int 2009;22(5): 509-18
38. Robak T. Alemtuzumab for B-cell chronic lymphocytic leukemia. Expert Rev Anticancer Ther 2008;8(7):1033-51
39. 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): 225-37
40. Moreau T, Thorpe J, Miller D, et al. Preliminary evidence from magnetic resonance imaging for reduction in disease activity after lymphocyte depletion in multiple sclerosis. Lancet 1994;344(8918): 298-301
41. 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
42. 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
43. Paolillo A, Coles AJ, Molyneux PD, et al. Quantitative MRI in patients with secondary progressive MS treated with monoclonal antibody Campath 1H. Neurology 1999;53(4):751-7
44. CAMMS223 Trial Investigators; Coles AJ, Compston DA, et al. Alemtuzumab vs interferon beta-1a in early multiple sclerosis. N Engl J Med 2008;359(17):1786-801
45. Coles AJ, Fox E, Vladic A, et al. Alemtuzumab versus interferon beta-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes. Lancet Neurol 2011; 10(4):338-48
46. Jones JL, Anderson JM, Phuah CL, et al. Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity. Brain 2010;133(Pt 8): 2232-47
47. Cox AL, Thompson SA, Jones JL, et al. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur J Immunol 2005; 35(11):3332-42
48. Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 2012;380(9856):1819-28
49. Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 2012;380(9856): 1829-39
50. Tuohy O, Costelloe L, Hill-Cawthorne G, et al. Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy. J Neurol Neurosurg Psychiatry 2014;86(2): 208-15
51. Phase IIIB-IV long-term follow-up study for patients who participated in CAMMS03409 (TOPAZ). Available from: https:// clinicaltrials.gov/ct2/show/NCT02255656
52. Somerfield J, Hill-Cawthorne GA, Lin A, et al. A novel strategy to reduce the immunogenicity of biological therapies. J Immunol 2010;185(1):763-8
53. Klotz L, Meuth SG, Wiendl H. Immune mechanisms of new therapeutic strategies in multiple sclerosis-A focus on alemtuzumab. Clin Immunol 2012;142(1):25-30
54. Garnock-Jones KP. Alemtuzumab: a review of its use in patients with relapsing multiple sclerosis. Drugs 2014;74(4):489-504
55. Disanto G, Morahan JM, Barnett MH, et al. The evidence for a role of B cells in multiple sclerosis. Neurology 2012;78(11): 823-32
56. Mann MK, Ray A, Basu S, et al. Pathogenic and regulatory roles for B cells in experimental autoimmune encephalomyelitis. Autoimmunity 2012; 45(5):388-99
57. Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 2008;358(7):676-88
58. Castillo-Trivino T, Braithwaite D, Bacchetti P, Waubant E. Rituximab in relapsing and progressive forms of multiple sclerosis: a systematic review. PLoS One 2013;8(7):e66308
59. Medina F, Segundo C, Campos-Caro A, et al. The heterogeneity shown by human plasma cells from tonsil, blood, and bone marrow reveals graded stages of increasing maturity, but local profiles of adhesion molecule expression. Blood 2002;99(6): 2154-61
60. Hammer O. CD19 as an attractive target for antibody-based therapy. MAbs 2012; 4(5):571-7
61. Dotan E, Aggarwal C, Smith MR. Impact of rituximab (Rituxan) on the treatment of B-cell non-Hodgkin's lymphoma. P T 2010;35(3):148-57
62. Dale RC, Brilot F, Duffy LV, et al. Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease. Neurology 2014;83(2):142-50
63. Bar-Or A, Calabresi PA, Arnold D, et al. Rituximab in relapsing-remitting multiple sclerosis: a 72-week, open-label, phase I trial. Ann Neurol 2008;63(3):395-400
64. Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 2008;358(7):676-88
65. Hawker K, O'Connor P, Freedman MS, et al. Rituximab in patients with primary progressive multiple sclerosis: results of a randomized double-blind placebo-controlled multicenter trial. Ann Neurol 2009;66(4): 460-71
66. Rommer PS, Patejdl R, Winkelmann A, et al. Rituximab for secondary progressive multiple sclerosis: a case series. CNS Drugs 2011;25(7):607-13
67. Comparison of rituximab induction therapy followed by glatiramer acetate therapy to glatiramer acetate monotherapy for MS (GATEWAY II). Available from: https:// clinicaltrials.gov/ct2/show/NCT01569451
68. Double blind combination of rituximab by intravenous and intrathecal injection versus placebo in patients with low-inflammatory secondary progressive multiple sclerosis (RIVITaLISe). Available from: https:// clinicaltrials.gov/ct2/show/NCT01212094
69. A phase 1 trial of intrathecal rituximab for progressive multiple sclerosis patients. Available from: https://clinicaltrials.gov/ct2/ show/NCT02253264
70. Kim SH, Huh SY, Lee SJ, et al. A 5-year follow-up of rituximab treatment in patients with neuromyelitis optica spectrum disorder. JAMA Neurol 2013;70(9):1110-17
71. Sorensen PS, Lisby S, Grove R, et al. Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: a phase 2 study. Neurology 2014;82(7): 573-81
72. Iorio R, Damato V, Alboini PE, Evoli A. Efficacy and safety of rituximab for myasthenia gravis: a systematic review and meta-analysis. J Neurol 2014. [Epub ahead of print]
73. Beres SJ, Graves J, Waubant E. Rituximab use in pediatric central demyelinating disease. Pediatr Neurol 2014;51(1):114-18
74. Fajt ML, Petrov AA. Desensitization protocol for rituximab-induced serum sickness. Curr Drug Saf 2014;9(3):240-2
75. Kausar F, Mustafa K, Sweis G, et al. Ocrelizumab: a step forward in the evolution of B-cell therapy. Expert Opin Biol Ther 2009;9:889-95
76. Kappos L, Li D, Calabresi PA, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet 2011;378:1779-87
77. A study of ocrelizumab in comparison with interferon beta-1a (rebif) in patients with relapsing multiple sclerosis. Available from: https://clinicaltrials.gov/ct2/show/NCT01247324
78. A Study of ocrelizumab in patients with primary progressive multiple sclerosis. Available from: https://clinicaltrials.gov/ct2/ show/NCT01194570
79. Reid K. UPDATE 4-Roche, Biogen suspends arthritis drug after deaths. 8 March 2010. Available from: www. reuters.com/article/2010/03/08/rocheidUSLDE62705720100308 [Last accessed on 20 October 2014]
80. Zhang B. Ofatumumab. MAbs 2009;1: 326-31
81. Of atumumab subcutaneous administration in subjects with relapsing-remitting multiple sclerosis (MIRROR). Available from: https://clinicaltrials.gov/ct2/show/NCT01457924
82. Taylor PC, Quattrocchi E, Mallett S, et al. Ofatumumab, a fully human anti-CD20 monoclonal antibody, in biological-naive, rheumatoid arthritis patients with an inadequate response to methotrexate: a randomised, double-blind, placebo-controlled clinical trial. Ann Rheum Dis 2011;70(12):2119-12
83. Østergaard M, Baslund B, Rigby W, et al. Of atumumab, a human anti-CD20 monoclonal antibody, for treatment of rheumatoid arthritis with an inadequate response to one or more disease-modifying antirheumatic drugs: results of a randomized, double-blind, placebo-controlled, phase I/II study. Arthritis Rheum 2010;62(8):2227-38
84. Ward E, Mittereder N, Kuta E, et al. A glycoengineered anti-CD19 antibody with potent antibody-dependent cellular cytotoxicity activity in vitro and lymphoma growth inhibition in vivo. Br J Haematol 2011;155(4):426-37
85. Safety and tolerability study of medi-551, a b-cell depleting agent, to treat relapsing forms of multiple sclerosis. Available from: https://clinicaltrials.gov/ct2/show/NCT01585766
86. Suresh T, Lee LX, Joshi J, Barta SK. New antibody approaches to lymphoma therapy. J Hematol Oncol 2014;7(1):58. [Epub ahead of print]
87. Manetta J, Bina H, Ryan P, et al. Generation and characterization of tabalumab, a human monoclonal antibody that neutralizes both soluble and membrane-bound B-cell activating factor. J Inflamm Res 2014;7:121-31
88. Saito Y, Miyagawa Y, Onda K, et al. B-cell-activating factor inhibits CD20-mediated and B-cell receptormediated apoptosis in human B cells. Immunology 2008;125(4):570-90
89. A Study of patients with relapsing remitting multiple sclerosis. Available from: https:// clinicaltrials.gov/ct2/show/NCT00882999
90. Pfender N, Martin R. Daclizumab (anti-CD25) in multiple sclerosis. Exp Neurol 2014;262PA:44-51
91. Bielekova B. Daclizumab therapy for multiple sclerosis. Neurotherapeutics 2013; 10(1):55-67
92. 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 USA 2004; 101(23):8705-8
93. Rose JW, Watt HE, White AT, Carlson NG. Treatment of multiple sclerosis with an anti-interleukin-2 receptor monoclonal antibody. Ann Neurol 2004;56: 864-7
94. Rose JW, Burns JB, Bjorklund J, et al. II trial in relapsing and remitting multiple sclerosis. Neurology 2007;69:785-9
95. Wynn D, Kaufman M, Montalban X, et al. Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta. Lancet Neurol 2010;9(4): 381-90
96. Gold R, Giovannoni G, Selmaj K, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet 2013; 381(9884):2167-75
97. Havrdova E, Giovannoni G, Stefoski D, et al. Disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with daclizumab high-yield process in the SELECT study. Mult Scler 2014; 20(4):464-70
98. Giovannoni G, Gold R, Selmaj K, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECTION): a multicentre, randomised, double-blind extension trial. Lancet Neurol 2014;13(5):472-81
99. Arnold DL, Kappos L, Havrdova E, et al. Brain MRI results of decide: a randomized, double-blind trial of DAC HYP vs. IFNb-1a in RRMS patients
100. Selmaj K, Kappos L, Arnold DL, et al. Safety and tolerability of daclizumab HYP treatment in relapsing-remitting multiple sclerosis: results of the decide study
101. Safety and efficacy extension study of daclizumab high yield process (DAC HYP) (biib019) in participants who have completed study 205ms202 (nct00870740) to treat relapsing remitting multiple sclerosis (SELECTED). Available from: https:// clinicaltrials.gov/ct2/show/NCT01051349
102. Patel DD, Lee DM, Kolbinger F, Antoni C. Effect of IL-17A blockade with secukinumab in autoimmune diseases. Ann Rheum Dis 2013;72(Suppl 2):ii116-23
103. Shabgah AG, Fattahi E, Shahneh FZ. Interleukin-17 in human inflammatory diseases. Postepy Dermatol Alergol 2014; 31(4):256-61
104. van den Berg WB, McInnes IB. Th17 cells and IL-17 a-focus on immunopathogenesis and immunotherapeutics. Semin Arthritis Rheum 2013;43(2):158-70
105. Luchtman DW, Ellwardt E, Larochelle C, Zipp F. IL-17 and related cytokines involved in the pathology and immunotherapy of multiple sclerosis: current and future developments. Cytokine Growth Factor Rev 2014;25(4):403-13
106. Fernandez O, Alvarez-Cermeno JC, Arroyo-Gonzalez R, et al. Review of the novelties presented at the 27th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (II). Rev Neurol 2012;54(12):
107. Fernandez O, Alvarez-Cermeno JC, Arroyo-Gonzalez R, et al. Review of the novelties presented at the 27th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (I). Rev Neurol 2012;54(11): 677-9
108. McInnes IB, Sieper J, Braun J, et al. Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II proof-of-concept trial. Ann Rheum Dis 2014;73(2):349-56
109. Genovese MC, Durez P, Richards HB, et al. Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study. Ann Rheum Dis 2013;72(6):863-9
110. Efficacy and Safety of AIN457 (Secukinumab) in Patients With Relapsing Multiple Sclerosis. Available from: https:// clinicaltrials.gov/ct2/show/NCT01874340
111. Zhang X, Morcos PN, Saito T, Terao K. Clinical pharmacology of tocilizumab for the treatment of systemic juvenile idiopathic arthritis. Expert Rev Clin Pharmacol 2013; 6(2):123-37
112. Navarro-Millan I, Singh JA, Curtis JR. Systematic review of tocilizumab for rheumatoid arthritis: a new biologic agent targeting the interleukin-6 receptor. Clin Ther 2012;34(4):788-802.e3
113. Maimone D, Guazzi GC, Annunziata P. IL-6 detection in multiple sclerosis brain. J Neurol Sci 1997;146(1):59-65
114. Malmestrom C, Andersson BA, Haghighi S, Lycke J. IL-6 and CCL2 levels in CSF are associated with the clinical course of MS: implications for their possible immunopathogenic roles. J Neuroimmunol 2006;175(1-2):176-82
115. Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006;441(7090): 235-8
116. Yamamura T, Miyake S. B-cell-directed therapy: which B cells should be targeted and how? Immunotherapy 2012;4(5):455-7
117. Sato H, Kobayashi D, Abe A, et al. Tocilizumab treatment safety in rheumatoid arthritis in a patient with multiple sclerosis: a case report. BMC Res Notes 2014;7:641
118. Behrens F, Tak PP, Ostergaard M, et al. MOR103, a human monoclonal antibody to granulocyte-macrophage colonystimulating factor, in the treatment of patients with moderate rheumatoid arthritis: results of a phase Ib/IIa randomised, double-blind, placebo-controlled, dose-escalation trial. Ann Rheum Dis 2014. [Epub ahead of print]
119. Disis ML, Bernhard H, Shiota FM, et al. Granulocyte-macrophage colony-stimulating factor: an effective adjuvant for protein and peptide-based vaccines. Blood 1996;88(1): 202-10
120. Phase Ib Study to Evaluate MOR103 in Multiple Sclerosis. Available from: https:// clinicaltrials.gov/ct2/show/NCT01517282
121. Pepinsky RB, Shao Z, Ji B, et al. Exposure levels of anti-LINGO-1 Li81 antibody in the central nervous system and dose-efficacy relationships in rat spinal cord remyelination models after systemic administration. J Pharmacol Exp Ther 2011;339(2):519-29
122. Tran JQ, Rana J, Barkhof F, et al. Randomized phase I trials of the safety/ tolerability of anti-LINGO-1 monoclonal antibody BIIB033. Neurol Neuroimmunol Neuroinflamm 2014;1(2):e18
123. Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of BIIB033 in Participants With Relapsing Forms of Multiple Sclerosis When Used Concurrently With Avonex (SYNERGY). Available from: https://clinicaltrials.gov/ct2/ show/NCT01864148
124. 215ON201 BIIB033 In Acute Optic Neuritis (AON) (RENEW). Available from: https://clinicaltrials.gov/ct2/show/ NCT01721161
125. Curtin F, Lang AB, Perron H, et al. GNbAC1, a humanized monoclonal antibody against the envelope protein of multiple sclerosis-associated endogenous retrovirus: a first-in-humans randomized clinical study. Clin Ther 2012;34(12): 2268-78
126. Derfuss T, Curtin F, Lang A, et al. GNbAC1, a Humanized Monoclonal Antibody Against The Multiple Sclerosis Associated Retrovirus Envelope Protein, Is Well Tolerated In Patients With Multiple Sclerosis. (P2.217) Neurology 2014; 82(10 Suppl):P2.217
127. Benson JM, Peritt D, Scallon BJ, et al. Discovery and mechanism of ustekinumab: a human monoclonal antibody targeting interleukin-12 and interleukin-23 for treatment of immune-mediated disorders. MAbs 2011;3(6):535-45
128. Annunziato F, Cosmi L, Liotta F, et al. Human Th1 dichotomy: origin, phenotype and biologic activities. Immunology 2014. [Epub ahead of print]
129. Ryan C, Thrash B, Warren RB, Menter A. The use of ustekinumab in autoimmune disease. Expert Opin Biol Ther 2010;10(4): 587-604
130. Segal BM, Constantinescu CS, Raychaudhuri A, et al. Repeated subcutaneous injections of IL12/ 23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol 2008; 7(9):796-804