Glatiramer Acetate (Copaxone)
Int J Clin Pract 2001 Jul-Aug;55(6):394-8
Queen Elizabeth Hospital, Queen Elizabeth NeuroScience Centre, Edgbaston, Birmingham B15 2TH, UK
PMID# 11501229; UI# 21393237
Glatiramer Acetate (Copaxone) is a novel preparation of synthetic Peptides composed of four Amino Acids.
Laboratory studies have shown that it prevents, or modifies, Experimental Allergic EncephaloMyelitis, the animal model for Multiple Sclerosis (MS), in several mammalian species.
Its mode of action has not been fully elucidated but it is known to induce Suppressor T-Cells, known to be deficient in MS.
And competitively inhibits the effect of CNS Myelin Antigens, thought to be important in the PathoGenesis of MS, through MHC blockade.
Controlled clinical trials have shown it to improve the natural history of MS by reducing both the relapse rate and the resultant Disability.
GA shows similar efficacy to Interferon-beta (IFN-ß) but with fewer systemic side-effects and appears to be better tolerated by patients.
It has thus justified its place in the new era of disease-modifying treatments for MS.
While the evidence suggests GA should be considered as first-line therapy in selected patients, its differing mechanism of action also gives patients and doctors the option of an alternative agent.
When the efficacy of IFN-ß is waning or side-effects predominate.
Glatiramer Acetate (Copaxone®) Induces Degenerate, Th2-polarized Immune Responses In Multiple Sclerosis
Duda PW, Schmied MC, Cook SL, Krieger JI, Hafler DA
J Clin Invest 2000 Apr;105(7):967-76
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Laboratory of Molecular Immunology, Boston, Massachusetts 02115, USA
PMID# 10749576; UI# 20213446
We examined the effect of Glatiramer Acetate, a random copolymer of Alanine, Lysine, Glutamic Acid, and Tyrosine, on Antigen-specific T-Cell responses in patients with Multiple Sclerosis (MS).
Glatiramer Acetate (Copaxone) functioned as a universal Antigen, inducing proliferation, independent of any prior exposure to the polymer, in T-Cell lines prepared from MS or healthy subjects.
However, for most patients, daily injections of Glatiramer Acetate abolished this T-Cell response and promoted the secretion of IL-5 and IL-13, which are characteristic of Th2 Cells.
The surviving Glatiramer Acetate-reactive T-Cells exhibited a greater degree of degeneracy as measured by cross-reactive responses to combinatorial Peptide libraries.
Thus, it appears that, in some individuals, in vivo administration of Glatiramer Acetate induces highly cross-reactive T-Cells that secrete Th2 Cytokines.
To our knowledge, Glatiramer Acetate is the first agent that suppresses human AutoImmune Disease and alters Immune Function by engaging the T-Cell Receptor.
This compound may be useful in a variety of AutoImmune Disorders in which Immune deviation to a Th2 type of response is desirable.
Binding Motifs of Copolymer-1 To
Multiple Sclerosis & Rheumatoid Arthritis
Associated HLA-DR Molecules
Fridkis-Hareli M, Neveu JM, Robinson RA, Lane WS, Gauthier L, Wucherpfennig KW, Sela M, Strominger JL
J Immunol 1999 Apr 15;162(8):4697-4704
Harvard University, Dept of Molecular and Cellular Biology, and Microchemistry Facility, Cambridge, MA 02138; Harvard Medical School, Dana Farber Cancer Institute, Boston, MA 02115; and The Weizmann Institute of Science, Dept of Immunology, Rehovot, Israel
Copolymer-1 (Cop-1, poly (Y, E, A, K)) is a random synthetic Amino Acid. Copolymer-1 effective in the treatment of Relapsing forms of Multiple Sclerosis (MS).
Cop-1 binds promiscuously, with high affinity and in a Peptide -specific manner to purified MS-associated HLA-DR2 (DRB1*1501) and Rheumatoid Arthritis-associated HLA-DR1 (DRB1*0101) or HLA-DR4 (DRB1*0401) molecules.
In the present work at least 95% of added Cop-1 could be bound to recombinant "empty" HLA-DR1 and -DR4, and 80% could be bound to HLA-DR2 proteins.
Amino Acid composition, HPLC profiles, and sequencing patterns of Cop-1 eluted by acid extraction from HLA-DR molecules were similar to those of the unseparated Cop-1.
Protruding N-terminal ends of Cop-1 bound to HLA-DR1, -DR2, or -DR4 molecules were then treated with Aminopeptidase I, followed by Elution, HPLC, and pool sequencing.
In contrast to untreated or unbound Cop-1, this material exhibited distinct motifs at some positions.
With increases in levels of E at the first and second cycles, of K at the second and third cycles, and of Y (presumably at P1 of the bound Peptide) at the third to fifth cycles, regardless of the HLA-DR molecule employed.
No preference was seen at the following cycles that were mainly A.
These first pooled HLA-DR binding epitopes provide clues to the components of Cop-1 that are biologically active in suppressing MS and possibly Rheumatoid Arthritis.
Copolymer 1 Acts Against The ImmunoDominant Epitope 82-100 Of Myelin Basic Protein By T-Cell Receptor Antagonism In Addition To Major Histocompatibility Complex Blocking
Aharoni R, Teitelbaum D, Arnon R, Sela M
Proc Natl Acad Sci USA 1999 Jan 19;96(2):634-639
The Weizmann Institute of Science, Dept of Immunology, Rehovot 76100, Israel
The synthetic random Amino Acid Copolymer Copolymer 1 (Cop-1, Copaxone, Glatiramer Acetate) suppresses Experimental AutoImmune EncephaloMyelitis, slows the progression of disability, and reduces relapse rate in Multiple Sclerosis (MS).
Cop-1 binds to various Class II Major Histocompatibility Complex (MHC) molecules and inhibits the T-Cell responses to several Myelin Antigens.
In this study we attempted to find out whether, in addition to MHC blocking, Cop-1, which is Immunologically cross-reactive with Myelin Basic Protein (MBP), inhibits the response to this AutoAntigen by T-Cell Receptor (TCR) antagonism.
Two experimental systems, "prepulse assay" and "split APC assay," were used to discriminate between competition for MHC molecules and TCR antagonism.
The results in both systems using T-Cell lines/clones from mouse and human origin indicated that Cop-1 is a TCR antagonist of the 82-100 Epitope of MBP.
In contrast to the broad specificity of the MHC blocking induced by Cop-1, its TCR antagonistic activity was restricted to the 82-100 determinant of MBP.
And could not be demonstrated for ProteoLipid Protein Peptide or even for other MBP Epitopes.
Yet, it was shown for all the MBP 82-100-specific T-Cell lines/clones tested that were derived from mice as well as from an MS patient.
The ability of Cop-1 to act as altered Peptide and induce TCR antagonistic effect on the MBP p82-100 ImmunoDominant determinant response elucidates further the mechanism of Cop-1 therapeutic activity in Experimental AutoImmune EncephaloMyelitis and MS.
Effect of Copolymer-1
On Serial Gadolinium-Enhanced MRI
In Relapsing/Remitting Multiple Sclerosis
Mancardi GL, Sardanelli F, Parodi RC, Melani E, Capello E, Inglese M, Ferrari A, Sormani MP, Ottonello C, Levrero F, Uccelli A, Bruzzi P
Neurology 1998 Apr;50(4):1127-1133
Univ of Genoa, Dept of Neurological Sciences, Genoa, Italy
PMID# 9566406; UI# 98226057
We examined the effect of Copolymer-1 (Cop-1) on Magnetic Resonance (MR) imaging changes in 10 patients with Relapsing/Remitting Multiple Sclerosis (RRMS).
Monthly Gadolinium (Gd)-enhanced MR imaging was performed for 9 to 27 months in the pretreatment period followed by 10 to 14 additional months during Cop-1 treatment.
MR images were evaluated by two radiologists (F.S. and R.C.P.) masked to the scan date.
We found a 57% decrease in the frequency of new Gd-enhancing Lesions and in the mean area/month of new Gd-enhancing Lesions in the Cop-1 treatment period.
Compared with the pretreatment period (0.92 versus 2.20 lesions per month and 22 mm2 versus 43 mm2 area/month; p = 0.1, Wilcoxon signed rank test).
Percentage change in Lesion load area on T2-weighted images showed a decrease in the accumulation of Lesion area during treatment, which was significant for the patient group with a longer pretreatment period (p = 0.05, Friedman test).
These results demonstrate a reduction in the number of new Gd-enhancing Lesions and in the Lesion load during Cop-1 treatment compared with the preceding period without therapy.
And are suggestive of an effect of Cop-1 on MR abnormalities observed in Multiple Sclerosis.