Glatiramer acetate is a mixture of synthetic peptides that are cross-reactive with
MBP. The antigen-based therapy induces a shift to an anti-inflammatory Th2 bias and
is used in the treatment of relapsing-remitting multiple sclerosis. Like other
peptide antigens, GA induces an antibody response in all patients. In contrast to
biologically active agents, such as the recombinant interferon beta drugs, GA is a
peptide antigen that lacks intrinsic biological activity. In vitro and
in vivo data have shown that GA-reactive antibodies are not neutralizing.
Antibodies do not alter the principal immunological effects of GA, including binding
to MHC Class II molecules, activation and proliferation of GA-reactive T cells, and
the release of anti-inflammatory Th2 cytokines. Higher antibody titres do not appear
to be associated with a deterioration in clinical endpoints, such as relapse rate,
EDSS progression or the occurrence of side effects in MS patients treated with GA.
The presence of GA-reactive antibodies may promote remyelination and enhance the
immunological and clinical effects of GA, indicating that they may be part of GA's
mechanism of action. Multiple Sclerosis 2007; 13:
S28—S35. http://msj.sagepub.com
Martin R., McFarland HF, McFarlin DEImmunological aspects of demyelinating diseases. Annu Rev Immunol1992; 10: 153—87.
2.
Ben-Nun A., Mendel I., Bakimer R., Fridkis-Hareli M., Teitelbaum D. et al. The autoimmune reactivity to myelin oligodendrocyte glycoprotein (MOG) in
multiple sclerosis is potentially pathogenic: effect of copolymer 1 on
MOG-induced disease. J Neurol1996; 243(Suppl 1): S14—22.
3.
Tejada-Simon MV, Zang YC, Yang D., Hong J., Li S. et al. Aberrant T cell responses to myelin antigens during clinical exacerbation
in patients with multiple sclerosis . Int Immunol2000; 12: 1641—50.
4.
Hellings N., Baree M., Verhoeven C., D'hooghe MB, Medaer R. et al. T-cell reactivity to multiple myelin antigens in multiple sclerosis
patients and healthy controls. J Neurosci Res2001; 63: 290—302.
5.
Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J. et al. 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. Neurol1995; 45: 1268—76.
6.
Jacobs LD, Cookfair DL, Rudick RA, Herndon RM, Richert JR et al. Intramuscular interferon beta-1a for disease progression in relapsing
multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol1996; 39: 285—94.
7.
The IFNB Multiple Sclerosis Study Group.Interferon beta-1b is effective in relapsing-remitting multiple sclerosis.
I. Clinical results of a multicenter, randomized, double-blind,
placebo-controlled trial. Neurol1993; 43: 655—61.
8.
PRISMS (Prevention of Relapses and Disability by Interferon beta-1a
Subcutaneously in Multiple Sclerosis) Study Group.Randomised double-blind placebo-controlled study of interferon beta-1a in
relapsing/remitting multiple sclerosis. Lancet1998; 352: 1498—504.
9.
Noronha A., Toscas A., Jensen MAInterferon beta decreases T cell activation and interferon gamma production
in multiple sclerosis. J Neuroimmunol1993 ; 46: 145—53.
10.
Coclet-Ninin J., Dayer JM, Burger D.Interferon-beta not only inhibits interleukin-1beta and tumor necrosis
factor-alpha but stimulates interleukin-1 receptor antagonist production in
human peripheral blood mononuclear cells. Eur Cytokine Netw1997; 8: 345—49.
11.
Wang X., Chen M., Wandinger KP, Williams G., Dhib-Jalbut S.IFN-beta-1b inhibits IL-12 production in peripheral blood mononuclear cells
in an IL-10-dependent mechanism: relevance to IFN-beta-1b therapeutic
effects in multiple sclerosis. J Immunol2000; 165: 548—57.
12.
Chabot S., Williams G., Yong VWMicroglial production of TNF-alpha is induced by activated T lymphocytes.
Involvement of VLA-4 and inhibition by interferon beta-1b. J Clin Invest1997; 100: 604—12.
13.
Calabresi PA , Pelfrey CM, Tranquill LR, Maloni H., McFarland HFVLA-4 expression on peripheral blood lymphocytes is downregulated after
treatment of multiple sclerosis with interferon beta . Neurology1997; 49: 1111—16.
14.
Stuve O., Dooley NP, Uhm JH, Antel JP, Francis GS et al. Interferon beta-1b decreases the migration of T lymphocytes in vitro:
effects on matrix metalloproteinase-9. Ann Neurol1996; 40: 853—63.
15.
Hartung HP, Munschauer F. 3rd, Schellekens H.Significance of neutralizing antibodies to interferon beta during treatment
of multiple sclerosis: expert opinions based on the Proceedings of an
International Consensus Conference. Eur J Neurol2005; 12: 588—601.
16.
Antonelli G. , Currenti M., Turriziani O., Dianzani F.Neutralizing antibodies to interferon-alpha: relative frequency in patients
treated with different interferon preparations . J Infect Dis1991; 163: 882—85.
17.
Lok AS, Lai CL, Leung EKInterferon antibodies may negate the antiviral effects of recombinant
alpha-interferon treatment in patients with chronic hepatitis B virus infection. Hepatology1990; 12: 1266—70.
18.
Prummer O.Interferon-alpha antibodies in patients with renal cell carcinoma treated
with recombinant interferon-alpha-2A in an adjuvant multicenter trial. The
Delta-P Study Group. Cancer1993; 71: 1828—34.
19.
Dummer R., Muller W., Nestle F. et al. Formation of neutralizing antibodies against natural interferon-beta, but
not against recombinant interferon-gamma during adjuvant therapy for
high-risk malignant melanoma patients. Cancer1991; 67: 2300—304.
20.
Fierlbeck G. , Schreiner T., Schaber B. et al. Neutralizing interferon beta antibodies in melanoma patients treated with
recombinant and natural interferon beta . Cancer Immunol Immunother1994; 39: 263—68.
21.
Herndon RM, Rudick RA, Munschauer FE 3rd, et al. Eight-year immunogenicity and safety of interferon beta-1a-Avonex treatment
in patients with multiple sclerosis. Mult Scler2005; 11: 409—19.
22.
Francis GS, Rice GP, Alsop JC et al. Interferon beta-1a in MS: results following development of neutralizing
antibodies in PRISMS. Neurology2005; 65: 48—55.
23.
The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group.Neutralizing antibodies during treatment of multiple sclerosis with
interferon beta-1b: experience during the first three years . Neurology1996; 47: 889—94.
24.
Li DK, Zhao GJ, Paty DW et al. Randomized controlled trial of interferon-beta-1a in secondary progressive
MS: MRI results. Neurology2001 ; 56: 1505—13.
25.
Polman C., Kappos L., White R. et al. Neutralizing antibodies during treatment of secondary progressive MS with
interferon beta-1b. Neurology2003 ; 60: 37—43.
26.
Bitsch A., Dressel A., Meier K. et al. Autoantibody synthesis in primary progressive multiple sclerosis patients
treated with interferon beta-1b. J Neurol2004; 251: 1498—501.
27.
Giovannoni G. , Goodman A.Neutralizing anti-IFNß antibodies: How much more evidence do we
need to use them in practice?Neurology2005; 65: 6—8.
28.
Francis GS, Rice GP, Alsop JC, PRISMS Study Group.Interferon beta-1a in MS: results following development of neutralizing
antibodies in PRISMS. Neurology2005; 65: 48—55.
29.
Kappos L., Clanet M., Sandberg-Wollheim M. et al. Neutralizing antibodies and efficacy of interferon beta-1a: a 4-year
controlled study. Neurology2005; 65: 40—47.
30.
Sorensen PS , Koch-Henriksen N., Ross C. et al. Appearance and disappearance of neutralizing antibodies during
interferon-beta therapy. Neurology2005; 65: 33—39.
31.
Bertolotto A., Malucchi S., Milano E. et al. Interferon beta neutralizing antibodies in multiple sclerosis: neutralizing
activity and cross-reactivity with three different preparations. Immunopharmacology2000; 48: 95—100.
32.
Perini P., Facchinetti A., Bulian P. et al. Interferon-beta (INF-beta) antibodies in interferon-beta1a- and
interferon-beta1b-treated multiple sclerosis patients. Prevalence, kinetics,
cross-reactivity, and factors enhancing interferon-beta immunogenicity in vivo. Eur Cytokine Netw2001; 12: 56—61.
33.
Kivisakk P. , Alm GV, Fredrikson S., Link H.Neutralizing and binding anti-interferon-beta (IFN-beta) antibodies. A
comparison between IFN-beta-1a and IFN-beta-1b treatment in multiple sclerosis. Eur J Neurol2000; 7: 27—34.
34.
Khan OA, Dhib-Jalbut SSNeutralizing antibodies to interferon beta-1a and interferon beta-1b in MS
patients are cross-reactive. Neurology1998 ; 51: 1698—702.
35.
Tomassini V. , Paolillo A., Russo P. et al. Predictors of long-term clinical response to interferon beta therapy in
relapsing multiple sclerosis. J Neurol2005; Sep 14, Epub ahead of print. Accessed 15, September 2005.
36.
Teitelbaum D., Aharoni R., Sela M., Arnon R.Cross-reactions and specificities of monoclonal antibodies against myelin
basic protein and against the synthetic copolymer 1. Proc Natl Acad Sci USA1991; 88: 9528—32.
37.
Aharoni R., Teitelbaum D., Sela M., Arnon R.Copolymer 1 induces T cells of the T helper type 2 that crossreact with
myelin basic protein and suppress experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA1997; 94: 10821—26.
38.
Miller A., Shapiro S., Gershtein R. et al. Treatment of multiple sclerosis with copolymer-1 (Copaxone): implicating
mechanisms of Th1 and Th2/Th3 immune-deviation. J Neuroimmunol1998; 92: 113—21.
39.
Neuhaus O., Farina C., Yassouridis A. et al. Multiple sclerosis: comparison of copolymer-1-reactive T-cell lines from
treated and untreated subjects reveals cytokine shift from T helper 1 to T
helper 2 cells. Proc Natl Acad Sci USA2000; 97: 7452—57.
40.
Weber MS, Starck M., Wagenpfeil S. et al. Multiple sclerosis: glatiramer acetate inhibits monocyte reactivity in
vitro and in vivo. Brain2004; 127: 1370—78.
41.
Kim HJ, Ifergan I., Antel JP et al. Type 2 monocyte and microglia differentiation mediated by glatiramer
acetate therapy in patients with multiple sclerosis. J Immunol2004; 172: 7144—53.
42.
Dhib-Jalbut S., Chen M., Said A. et al. Glatiramer acetate-reactive peripheral blood mononuclear cells respond to
multiple myelin antigens with a Th2-biased phenotype. J Neuroimmunol2003; 140: 163—71.
43.
Arnon R., Sela M.Immunomodulation by the copolymer glatiramer acetate. J Mol Recognit2003; 16: 412—21. 44. Chen M., Valenzuela RM, Dhib-Jalbut S.Glatiramer acetate-reactive T cells produce brain-derived neurotrophic factor . J Neurol Sci2003; 215: 37—44.
44.
Ziemssen T. , Kumpfel T., Schneider H. et al. Secretion of brain-derived neurotrophic factor by glatiramer
acetate-reactive T-helper cell lines: Implications for multiple sclerosis therapy. J Neurol Sci2005 ; 233: 109—12.
45.
Aharoni R., Kayhan B., Eilam R. et al. Glatiramer acetate-specific T cells in the brain express T helper 2/3
cytokines and brain-derived neurotrophic factor in situ. Proc Natl Acad Sci USA2003; 100: 14157—62.
46.
Hong J., Li N., Zhang X., Zheng B., Zhang JZInduction of CD4+CD25+ regulatory T cells by copolymer-I through activation
of transcription factor Foxp3. Proc Natl Acad Sci USA2005; 102: 6449—54.
47.
Putheti P., Soderstrom M., Link H., Huang YMEffect of glatiramer acetate (Copaxone) on CD4+CD25high T regulatory cells
and their IL-10 production in multiple sclerosis. J Neuroimmunol2003; 144: 125—31.
48.
Karandikar NJ, Crawford MP, Yan X. et al. Glatiramer acetate (Copaxone) therapy induces CD8(+) T cell responses in
patients with multiple sclerosis. J Clin Invest2002; 109: 641—49.
49.
Kim HJ, Ifergan I., Antel JP et al. Type 2 monocyte and microglia differentiation mediated by glatiramer
acetate therapy in patients with multiple sclerosis. J Immunol2004; 172: 7144—53.
50.
Chabot S., Yong FP, Le DM et al. Cytokine production in T lymphocyte-microglia interaction is attenuated by
glatiramer acetate: a mechanism for therapeutic efficacy in multiple sclerosis. Mult Scler2002; 8: 299—306.
51.
Aharoni R., Teitelbaum D., Sela M., Arnon R.Bystander suppression of experimental autoimmune encephalomyelitis by T
cell lines and clones of the Th2 type induced by copolymer 1. J Neuroimmunol1998; 91: 135—46.
52.
Aharoni R., Arnon R., Eilam R.Neurogenesis and neuroprotection induced by peripheral immunomodulatory
treatment of experimental autoimmune encephalomyelitis. J Neurosci2005; 25: 8217—28.
53.
Maier K., Kuhnert AV, Taheir N., Sättler MB et al. Effects of glatiramer acetate and interferon-beta on neurodegeneration in a
model of multiple sclerosis: a comparative study. Am J Pathol2006; 169: 1353—64.
54.
Brenner T., Arnon R., Sela M. et al. Humoral and cellular immune responses to Copolymer 1 in multiple sclerosis
patients treated with Copaxone. J Neuroimmunol2001; 115: 152—60.
55.
Farina C., Vargas V., Heydari N. et al. Treatment with glatiramer acetate induces specific IgG4 antibodies in
multiple sclerosis patients. J Neuroimmunol2002; 123: 188—92.
56.
Lanzavecchia A.Receptor-mediated antigen uptake and its effect on antigen presentation to
class II-restricted T lymphocytes. Ann Rev Immunol1990; 8: 773—93.
57.
Schalke BC, Klinkert WE, Wekerle H., Dwyer DSEnhanced activation of a T cell line specific for acetylcholine receptor
(AChR) by using anti-AChR monoclonal antibodies plus receptors. J Immunol1985; 134: 3643—48.
58.
Aharoni R., Teitelbaum D., Arnon R., Sela M.Copolymer 1 inhibits manifestations of graft rejection. Transplantation2001; 72: 598—605.
59.
Webb C., Teitelbaum D., Arnon R., Sela M.In vivo and in vitro immunological cross-reactions between basic
encephalitogen and synthetic basic polypeptides capable of suppressing
experimental allergic encephalomyelitis. Eur J Immunol1973; 3: 279—86.
60.
Teitelbaum D. , Aharoni R., Arnon R., Sela M.Specific inhibition of the T-cell response to myelin basic protein by the
synthetic copolymer Cop-1. Proc Natl Acad Sci USA1988; 85: 9724—28.
61.
Teitelbaum D. , Milo R., Arnon R., Sela M.Synthetic copolymer 1 inhibits human T-cell lines specific for myelin basic protein. Proc Natl Acad Sci USA1992; 89: 137—41.
62.
Teitelbaum D., Brenner T., Abramsky O. et al. Antibodies to glatiramer acetate do not interfere with its biological
functions and therapeutic efficacy. Mult Scler2003; 9: 592—99.
63.
Basile E., Gibbs E., Aziz T., Oger J.During 3 years treatment of primary progressive multiple sclerosis with
glatiramer acetate, specific antibodies switch from IgG1 to IgG4. J Neuroimmunol2006; 177: 161—66.
64.
Ishizaka A. , Sakiyama Y., Nakanishi M. et al. The inductive effect of interleukin-4 on IgG4 and IgE synthesis in human
peripheral blood lymphocytes. Clin Exp Immunol1990; 79: 392—96.
65.
Lanzavecchia, A.Receptor-mediated antigen uptake and its effect on antigen presentation to
Class II-restricted T lymphocytes. Ann Rev Immunol1990; 8: 773—93.
66.
Schalke Bcg , Flinkert Wef, Wekerle H., Dusyer DSEnhanced activation of a T cell line specific for acetylcholine receptor
(AChR) by using anti-AChR monoclonal antibodies plus receptors. J Immunol1985; 34: 3643—48.
67.
Bornstein MB , Miller A., Slagle S., Weitzmann M. et al. A pilot trial of Copolymer 1 in exacerbating— remitting multiple sclerosis. N Engl J Med1987; 317: 408—14.
68.
Meiner Z., Kott E., Schechter D. et al. Copolymer 1 in relapsing-remitting multiple sclerosis: a
multi-centre trial. In Abramsky O, Ovadia H eds. Frontiers in multiple sclerosis: clinical research and
therapy. Martin Dunitz, 1997: 213—21.
69.
Johnson KP, Brooks BR, Cohen JA et al. Extended use of glatiramer acetate (Copaxone) is well tolerated and
maintains its clinical effect on multiple sclerosis relapse rate and degree
of disability. Neurology1998; 50: 701—708.
70.
Johnson KP, Brooks BR, Ford CC et al. Sustained clinical benefits of glatiramer acetate in relapsing multiple
sclerosis patients observed for 6 years. Copolymer 1 Multiple Sclerosis
Study Group. Mult Scler2000; 6: 255—66.
71.
Johnson KP, Ford CC, Lisak RP, Wolinsky JSNeurologic consequence of delaying glatiramer acetate therapy for multiple
sclerosis: 8-year data. Acta Neurol Scand2005; 111: 42—47.
72.
Sindic CJ, Seeldrayers P., Vande Gaer L. et al. Long-term follow up of glatiramer acetate compassionate use in Belgium. Acta Neurol Belg2005; 105: 81—85.
73.
Zhang JY, Luo XG, Xian CJ et al. Endogenous BDNF is required for myelination and regeneration of injured
sciatic nerve in rodents. Eur J Neurosci2000; 12: 4171—80.
74.
Li L., Xu Q., Wu Y. et al. Combined therapy of methylprednisolone and brain-derived neurotrophic
factor promotes axonal regeneration and functional recovery after spinal
cord injury in rats. Chin Med J (Engl)2003 ; 116: 414—18.
75.
Sarchielli P., Greco L., Stipa A. et al. Brain-derived neurotrophic factor in patients with multiple sclerosis. J Neuroimmunol2002; 132: 180—88.
76.
Ure DR, Rodriguez M.Polyreactive antibodies to glatiramer acetate promote myelin repair in
murine model of demyelinating diseases. FASEB2002 ; 16: 1260—62.
77.
Rodriguez M. , Miller DJ, Lennon VAImmunoglobulins reactive with myelin basic protein promote CNS remyelination. Neurology1996; 46: 538—45.
78.
Salama HH, Hong J., Zang Ycq et al. Blocking effects of serum reactive antibodies induced by glatiramer acetate
treatment in multiple sclerosis. Brain2003; 126: 2638—47.
