EP1292279A1 - Verwendung von glatiramer acetat (copolymer 1) zur behandlung von störungen des zentralen nervensystems - Google Patents

Verwendung von glatiramer acetat (copolymer 1) zur behandlung von störungen des zentralen nervensystems

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Publication number
EP1292279A1
EP1292279A1 EP01941973A EP01941973A EP1292279A1 EP 1292279 A1 EP1292279 A1 EP 1292279A1 EP 01941973 A EP01941973 A EP 01941973A EP 01941973 A EP01941973 A EP 01941973A EP 1292279 A1 EP1292279 A1 EP 1292279A1
Authority
EP
European Patent Office
Prior art keywords
copolymer
disease
glatiramer acetate
cytokine
dose
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01941973A
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English (en)
French (fr)
Other versions
EP1292279A4 (de
Inventor
V. Wee Yong
Sophie Chabot
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Teva Pharmaceutical Industries Ltd
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Teva Pharmaceutical Industries Ltd
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Publication date
Application filed by Teva Pharmaceutical Industries Ltd filed Critical Teva Pharmaceutical Industries Ltd
Publication of EP1292279A1 publication Critical patent/EP1292279A1/de
Publication of EP1292279A4 publication Critical patent/EP1292279A4/de
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention provides methods of treating a mammalian subject having, or genetically predisposed to, an inflammatory, non-autoimmune central nervous system (CNS) disease, or alleviating the symptoms of such a disease.
  • CNS central nervous system
  • the nervous system of vertebrates is divided into the central nervous system, comprised of the brain and spinal cord, and the peripheral nervous system, consisting of the outlying nerves (22) .
  • the axons of most nerve cells are covered with a myelin sheath, a stack of specialized plasma membranes. Glial cells that wrap around the axons produce the myelin sheath. In the CNS, these glial cells are called oligodendrocytes .
  • Each region of myelin formed by an individual oligodendrocyte is separated from the next region by an unmyelinated area called the node of Ranvier (22) .
  • the myelin sheath acts as an electric insulator of the axon and all electric activity in axons is confined to the nodes of Ranvier.
  • multiple sclerosis This condition is a demyelinating disease.
  • Multiple sclerosis is a chronic, frequently progressive, inflammatory CNS disease characterized pathologically by primary demyelination and axonal injury.
  • conduction of action potentials by the demyelinated neurons is slowed (22) .
  • An autoimmune hypothesis is supported by the experimental autoimmune (allergic) encephalomyelitis (EAE) model, where the injection of certain myelin components into genetically susceptible animals leads to T lymphocyte-mediated CNS demyelination (58) .
  • EAE experimental autoimmune (allergic) encephalomyelitis
  • T lymphocytes Some researchers view activated T lymphocytes as a trigger of multiple sclerosis. They postulate that once T lymphocytes traverse the blood brain barrier (BBB) into the CNS parenchyma, they are reactivated following antigen presentation by microglia (53) .
  • BBB blood brain barrier
  • the entry of leukocytes into tissues is a multi-step process that includes adhesion onto endothelial cells and transmigration across the endothelial barrier.
  • MMPs matrix metalloproteinases
  • MMPs The inappropriate expression of MMPs is speculated to be involved in the pathogenesis of malignant gliomas, stroke and Alzheimer's disease. Furthermore, several lines of evidence suggest a role for MMPs in the disease process in multiple sclerosis (37, 91) .
  • immunohistochemically identified MMPs specifically MMP-3,- 7,-9 and -12
  • MMP-3,- 7,-9 and -12 on microglia, astrocytes and infiltrating leukocytes
  • a prominent method of microglia activation is believed to be a non-antigen-specific interaction between these cells and T lymphocytes, which generates cytokines within the CNS milieu (19, 20, 67) .
  • T lymphocytes and human microglia interact to generate significant amounts of TNF- ⁇ and IL-10 (14, 15) .
  • the effect of T lymphocytes on microglia is equipotent to that of lipopolysaccharide, a very effective microglia stimulator.
  • T cells infiltrated the CNS and aggregated around microglia, and that this was correspondent with an increase in IL-l ⁇ and TNF- ⁇ (61) .
  • a graft-versus-host disease (GVHD) model activated microglial cell clusters were invariably intimately associated with T cell infiltrates (68) .
  • TNF- ⁇ can influence lymphocyte trafficking across endothelium by up regulating the expression of various adhesion molecules involved in this process (76) , and is implicated in the process of demyelination. Indeed, TNF- ⁇ directly induces in vitro the apoptotic death of the myelin-producing cells in the brain, the oligodendrocytes (26, 45, 71), and intravitreal injection of TNF- ⁇ causes demyelination of mouse optic nerve axons (12) . In addition, TNF- ⁇ is pro-inflammatory.
  • TNF- ⁇ The level of TNF- ⁇ is found to be elevated in the serum, cerebrospinal fluid, and brain lesions of multiple sclerosis patients, and is correlated with the disease activity (13, 35, 62, 72). TNF- ⁇ is also implicated in the pathogenicity of EAE - the administration of antibodies to TNF- ⁇ or soluble TNF- ⁇ receptors prevents the transfer of EAE and abrogates autoimmune demyelination (63, 69, 70).
  • IL-12 is another pro-inflammatory cytokine which has a key role in switching uncommitted T lymphocytes to the pro- inflammatory Thl subset which secretes IFN- ⁇ and TNF- ⁇ / ⁇ (91) .
  • IL-l ⁇ also promotes an inflammatory response and has been associated with multiple sclerosis (66) .
  • the Th2 subset produces IL-4, IL-10 and IL-13, regulates humoral immunity and decreases local inflammation. Both IL-4 and IL-10 can inhibit the differentiation of naive precursors into Thl cells (91) . IL-4 promotes the activation of B lymphocytes and macrophages and also stimulates class switching of antibodies (22) .
  • IL-13 is a Th2 cytokine with important immunomodulating activities.
  • the best known IL-13 mediated function is its ability to drive the differentiation of naive CD4+ T cells towards a Th2 phenotype (75) .
  • the anti-inflammatory functions of IL-13 include the suppressive effect on the production of pro-inflammatory cytokines by activated monocytes or by alveolar macrophages (81) , the induction of 15-lipoxygenase (51) and the inhibition of prostaglandin E2 (PGE2) formation (27) .
  • Functions of IL-13 in the CNS and on glial cell functions are not well defined (87) .
  • IL-10 is an anti-inflammatory cytokine produced by a variety of cells, including monocytes/macrophages, T lymphocytes, and mast cells.
  • potential sources of IL-10 include microglia (86) and astrocytes (49) .
  • IL-10 has important anti-inflammatory properties.
  • IL-10 inhibits the production of proinflammatory cytokines by many cell types, including those of the mononuclear phagocytic lineage; indeed, IL-10 was shown to inhibit the production of TNF- ⁇ and IL-12 produced by monocytes, macrophages, and microglia (3, 9, 10, 24, 38).
  • IL-10 plays a role in causing T lymphocytes to undergo anergy (inactivation or unresponsiveness) (2) .
  • IL-10 anti-inflammatory functions of IL-10 include its inhibitory effect on the process of antigen presentation.
  • Treatment of macrophages/microglia with IL-10 down-regulated the expression of molecules essential for presentation of antigens, such as MHC class II (24) and the costimulatory molecules B7-1 and B7-2 (36) .
  • MHC class II 2
  • B7-1 and B7-2 3
  • IL-10 as an anti-inflammatory molecule is supported by the phenotype of IL-10-deficient mice; these mice develop chronic colitis, which appears to be mediated by the proinflammatory Thl cells (8, 23, 39).
  • cytokines are inducible, meaning that they are produced in response to certain stimuli.
  • IL-6 which activates B-lymphocytes (22), is constitutive.
  • the subject invention provides a method of treating a mammalian subject having an inflammatory, non-autoimmune central nervous system (CNS) disease, or alleviating the symptoms of such a disease, comprising administering glatiramer acetate (Copolymer 1) to the subject in an amount and for a duration of time effective to treat the inflammatory, non-autoimmune CNS disease.
  • CNS central nervous system
  • the subject invention also includes a method of treating a mammalian subject at risk of developing an inflammatory, non-autoimmune CNS disease comprising administering glatiramer acetate (Copolymer 1) to the subject in an amount and for a duration of time effective to minimize the severity of the inflammatory, non-autoimmune CNS disease that may occur in the subject or prevent its occurrence.
  • glatiramer acetate Copolymer 1
  • a method of inhibiting the activity of a matrix metalloproteinase comprising contacting the matrix metalloproteinase with glatiramer acetate (Copolymer 1) .
  • the subject invention contains a method of suppressing the production of a cytokine by activated T lymphocytes comprising contacting the activated T lymphocytes with glatiramer acetate (Copolymer 1) in an amount necessary to suppress cytokine production.
  • glatiramer acetate Copolymer 1
  • the subject invention also provides the use of glatiramer acetate (Copolymer 1) in the preparation of a pharmaceutical composition for the- treatment of an inflammatory, non-autoimmune central nervous system (CNS) disease, or alleviation of the symptoms of such a disease, wherein said pharmaceutical composition is administered to the subject in an amount and for a duration of time effective to treat the inflammatory, non-autoimmune CNS disease in a mammalian subject.
  • glatiramer acetate Copolymer 1
  • the subject invention further concerns the use of glatiramer acetate (Copolymer 1) in the preparation of a pharmaceutical composition for treating a mammalian subject at risk of developing an inflammatory, non-autoimmune CNS disease, wherein said pharmaceutical composition is administered to the subject in an amount and for a duration of time effective to minimize the severity of the inflammatory, non-autoimmune CNS disease that may occur in the subject or prevent its occurrence.
  • glatiramer acetate Copolymer 1
  • the subject invention includes the use of glatiramer acetate (Copolymer 1) in the preparation of a pharmaceutical composition for inhibiting the activity of a matrix metalloproteinase.
  • glatiramer acetate Copolymer 1
  • the subject invention also provides the use of glatiramer acetate (Copolymer 1) in the preparation of a pharmaceutical composition for suppressing the production of a cytokine by activated T lymphocytes.
  • glatiramer acetate Copolymer 1
  • Figure 1 shows the lack of effect of Copolymer 1 (glatiramer acetate (GA) ) on MMP-9 production by T lymphocytes.
  • AIM-V conditioned media were collected from anti-CD3 activated T lyphocytes either in the absence of any drug treatment (control) or in the presence of 25 ⁇ g/ml Copolymer 1 or 1000 IU/ml recombinant interferon ⁇ -lb.
  • Interferon ⁇ IFN- ⁇
  • IFN- ⁇ Interferon ⁇
  • Figure 2 demonstrates that Copolymer 1 is an inhibitor of the enzymatic activity of MMP-9.
  • IFN ⁇ -lb is not a direct MMP activity inhibitor, although it decreases the production of MMP-9 as demonstrated in Figure 1.
  • Positive controls, TIMP-1 and phenanthroline (phe) are shown to inhibit MMP activity in this assay.
  • Figure 2-A shows MMP-9 (the strongest band) from Baby Hamster Kidney (BHK) cells while Figure 2-B represents MMP-9 produced by T lymphocytes.
  • Figure 3 reveals that Copolymer 1 does not inhibit T lymphocyte migration across a fibronectin chamber.
  • Figure 3 -A demonstrates that 25 ⁇ g/ml Copolymer 1 treatment of T lymphocytes, for 1,2 or 3 days, did not affect the subsequent migration of cells across a fibronectin barrier compared to controls.
  • 3 days treatment of cells with IFN ⁇ -lb (1000 IU/ml) decreased migration by 20 - 50% as reported previously (77) .
  • Figure 3-B 3-day pretreatment of T lymphocytes with various concentrations of Copolymer 1 similarly did not affect transmigration. Values are mean + SEM of 3 analyzes each, and have been expressed as % of controls of the respective dose-response experiments .
  • FIG. 4 shows that Copolymer 1 pretreatment of activated T lymphocytes suppresses IL-10 and TNF- ⁇ production that is generated in T lymphocyte - U937 interactions.
  • Activated T lymphocytes in isolation produce undetectable IL-10 or TNF- ⁇ ;
  • PMA/lFN ⁇ -pretreated U937 cells have detectable IL-10 but negligible TNF- ⁇ levels.
  • Cytokines are significantly elevated in co-cultures and this is reduced dose-dependently by Copolymer 1 pretreatment of T lymphocytes. Values are mean + SEM of triplicate analyzes.
  • FIG. 5 reports that Copolymer 1 treatment of activated T lymphocytes also lead to the suppression of IL-4, IL-12 and IL-13 in T lymphocyte - U937 interactions.
  • Both T lymphocytes and PMA/lFN ⁇ -pretreated U937 cells do not secrete detectable amounts of IL-4, IL-12 or IL-13 into their conditioned medium.
  • levels of these cytokines are increased, although the levels are low in comparison to those for IL-10 or TNF- ⁇ (Fig. 4) ; amount of IL-4, IL-12 and IL-13 in T lymphocyte - U937 interactions are, respectively, 13, 12 and 62 pg/ml .
  • Figure 6 demonstrates that cytokine production in co- culture of T lymphocytes with fetal human microglia is reduced by Copolymer 1. Values are mean + SEM of 3 or 4 analyzes and are expressed as % of the mean of control T lymphocyte - microglia co-cultures (i.e. 0 ⁇ g/ml Copolymer 1) . The amount of TNF- ⁇ in control T lymphocyte - microglia co-culture was 1068 + 68 pg/ml while that for IL- 10 was 139 + 4 pg/ml.
  • Figure 7 reflects the effects of Copolymer 1 on cytokine production in adult human microglia and T lymphocyte co- cultures.
  • T lymphocytes nor microglia express IL-l ⁇ , IL-10 or TNF- ⁇ .
  • the levels of cytokines induced after 24h were 1012 + 86 pg/ml for TNF- ⁇ , 18 ⁇ 2 pg/ml for IL-l ⁇ and 46 + 2 pg/ml for IL-10.
  • IL-6 is constitutively expressed in microglia (1010 + 215 pg/ml) , but not in T lymphocytes.
  • Copolymer 1 pretreatment of T lymphocytes reduced the level of inducible cytokines in co-culture with microglia and also the level of expression of IL-6. Values are mean + SEM of triplicate cultures.
  • Figure 8 shows the morphology of microglia in T lymphocyte - microglia co-cultures.
  • Figure 8-A shows that adult human microglia are mostly bipolar in morphology in culture.
  • Figure 8-B demonstrates that T lymphocytes are present as single cells or clumps.
  • Figure 8-C reports that when T lymphocytes are co-cultured with microglia in the absence of Copolymer 1, bipolar microglia become rounded/ameboid in morphology (some microglia are shown by arrows) .
  • Figure 8-D reflects, this morphological transformation is prevented by Copolymer 1 pretreatment of T lymphocytes (some bipolar microglia are indicated by arrows) . All figures portray the same magnification, 400X.
  • Figure 9 reports that Copolymer 1 does not affect CXCR3 and CXCR4 expression on T lymphocytes .
  • All T lymphocytes were activated at time 0 with anti-CD3 antibody and Copolymer 1 (25 ug/ml) was added to some cultures at 3 hours. Cells were removed and stained at 1 ( Figures 9-A and 9-B) , 2 ( Figures 9C and 9-D) and 3 days ( Figures 9-E and 9-F) .
  • An isotype control antibody was used to stain control or Copolymer 1-treated T lymphocytes and the fluorescence of these did not differ. Thus, only the isotype staining for control T lymphocytes is displayed.
  • Figure 10 demonstrates that Copolymer 1 does not affect CXCR3 and CXCR4 expression on U937 cells.
  • Cells were treated with Copolymer 1 (25 ug/ml) or left untreated at time 0. Cells were removed and stained at 1 ( Figures 10-A and 10 -B) or 3 days ( Figures 10-C and 10-D) .
  • An isotype control antibody was used to stain control and Copolymer 1-treated cells and the fluorsecence of these did not differ. Thus, only the isotype staining for control U937 cells is displayed.
  • non-autoimmune disease refers to a condition characterized by a lack of significant immune-mediated damage to the diseased subject.
  • an inflammatory disease is characterized as a condition in which there is increased blood flow to the affected areas, resulting in swelling and heightened temperature, which may produce pain.
  • an inflammatory, non-autoimmune disease includes any disease which impacts the central nervous system, but does not include an autoimmune component and is associated with an inflammatory response in the subject afflicted with the disease.
  • Inflammatory, non-autoimmune diseases include, inter alia, Alzheimer's disease, Parkinson's disease, HIV encephalopathy, brain tumor, glaucoma, neuropathy, dementia, central nervous system infection, central nervous system bacterial infection, meningitis, stroke, and head trauma.
  • the subject invention encompasses a method of treating a mammalian subject having an inflammatory, non-autoimmune central nervous system (CNS) disease, or alleviating the symptoms of such a disease, comprising administering glatiramer acetate (GA or Copolymer 1) to the subject in an amount and for a duration of time effective to treat the inflammatory, non-autoimmune CNS disease.
  • glatiramer acetate G or Copolymer 1
  • the mammalian subject is human.
  • the disease is Alzheimer's Disease.
  • the disease is Parkinson's Disease .
  • the disease is HIV encephalopathy.
  • the disease is a brain tumor.
  • the disease is glaucoma.
  • the disease is neuropathy or dementia. In another embodiment, the disease is a CNS infection.
  • the CNS infection is a bacterial infection.
  • the bacterial infection is meningitis .
  • the disease results from stroke.
  • the disease results from head trauma .
  • the subject invention encompasses embodiments wherein the route of administration is oral, intravenous, intramuscular, subcutaneous, intraperitoneal, transdermal , nasal or rectal.
  • the preferred routes of administration are oral and subcutaneous injection.
  • the dose of glatiramer acetate (Copolymer 1) administered ranges from about .1 mg to about 1000 mg.
  • the dose of glatiramer acetate (Copolymer 1) administered ranges from about 1 mg to about 100 mg.
  • the dose of glatiramer acetate (Copolymer 1) administered ranges from about 5 mg to about 50 mg.
  • the dose of glatiramer acetate (Copolymer 1) administered ranges from about 10 mg to about 30 mg.
  • the dose of glatiramer acetate (Copolymer 1) administered is about 20 mg.
  • the dose of glatiramer acetate (Copolymer 1) administered ranges from about 0.05 mg/kg of body weight to about 50 mg/kg of body weight.
  • the dose of glatiramer acetate (Copolymer 1) administered ranges from about .1 mg/kg of body weight to about 10 mg/kg of body weight.
  • the dose of glatiramer acetate (Copolymer 1) administered ranges from about 0.1 mg/kg of body weight to about 1.0 mg/kg of body weight .
  • the dose of glatiramer acetate (Copolymer 1) administered is about 0.3 mg/kg of body weight .
  • the dose of glatiramer acetate (Copolymer 1) is administered at a frequency of about once every 30 days to about once every day. In a preferred embodiment, the dose of glatiramer acetate (Copolymer 1) is administered at a frequency of about once every 7 days to about once every day. In a more preferred embodiment, the dose of glatiramer acetate (Copolymer 1) is administered at a frequency of about once every day.
  • the glatiramer acetate (Copolymer 1) is administered as part of a therapeutic regimen during which a cytokine antagonist is also administered to the subject .
  • the subject invention also concerns a method of treating a mammalian subject at risk of developing an inflammatory, non-autoimmune CNS disease comprising administering glatiramer acetate (Copolymer 1) to the subject in an amount and for a duration of time effective to minimize the severity of the inflammatory, non-autoimmune CNS disease that may occur in the subject or prevent its occurrence.
  • glatiramer acetate Copolymer 1
  • the subject is human and the risk is associated with a genetic predisposition to a chronic medical condition.
  • the disease is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, glaucoma, dementia, neuropathy, stroke, and brain tumor .
  • the route of administration is oral, intravenous, intramuscular, subcutaneous, intraperitoneal, transdermal, nasal or rectal.
  • the subject invention additionally includes a method of inhibiting the activity of a matrix metalloproteinase comprising contacting the matrix metalloproteinase with glatiramer acetate (Copolymer 1) .
  • the matrix metalloproteinase is MMP-9. In another embodiment, the matrix metalloproteinase is in a subject.
  • the subject is human.
  • the subject invention further provides a method of suppressing the production of a cytokine by activated T lymphocytes comprising contacting the activated T lymphocytes with glatiramer acetate (Copolymer 1) in an amount necessary to suppress the production of the cytokine .
  • glatiramer acetate Copolymer 1
  • the cytokine is IL-1.
  • the cytokine is IL-4.
  • the cytokine is IL-6.
  • the cytokine is IL-10.
  • the cytokine is IL-12.
  • the cytokine is IL-13.
  • the cytokine is TNF-a.
  • the cytokine is in a subject.
  • the subject is human.
  • the subject invention also contains the use of glatiramer acetate (Copolymer 1) in the preparation of a pharmaceutical composition for the treatment of an inflammatory, non-autoimmune central nervous system (CNS) disease, or alleviation of the symptoms of such a disease, wherein said pharmaceutical composition is administered to the subject in an amount and for a duration of time effective to treat the inflammatory, non-autoimmune CNS disease in a mammalian subject.
  • glatiramer acetate Copolymer 1
  • the mammalian subject is human.
  • the disease is Alzheimer's Disease.
  • the disease is Parkinson's Disease.
  • the disease is HIV encephalopathy.
  • the disease is a brain tumor .
  • the disease is glaucoma.
  • the disease is neuropathy or dementia.
  • the disease is a CNS infection.
  • the CNS infection is a bacterial infection.
  • the bacterial infection is meningitis.
  • the disease results from stroke .
  • the disease results from head trauma.
  • the subject invention encompasses embodiments of the use wherein the route of administration is oral, intravenous, intramuscular, subcutaneous, intraperitoneal, transdermal, nasal or rectal .
  • the preferred routes of administration are oral and subcutaneous injection.
  • the dose of glatiramer acetate (Copolymer 1) administered ranges from about .1 mg to about 1000 mg.
  • the dose of glatiramer acetate (Copolymer 1) administered ranges from about 1 mg to about 100 mg.
  • the dose of glatiramer acetate (Copolymer 1) administered ranges from about 5 mg to about 50 mg.
  • the dose of glatiramer acetate (Copolymer 1) administered ranges from about 10 mg to about 30 mg.
  • the dose of glatiramer acetate (Copolymer 1) administered is about 20 mg.
  • the dose of glatiramer acetate (Copolymer 1) administered ranges from about 0.05 mg/kg of body weight to about 50 mg/kg of body weight.
  • the dose of glatiramer acetate (Copolymer 1) administered ranges from about .1 mg/kg of body weight to about 10 mg/kg of body weight.
  • the dose of glatiramer acetate (Copolymer 1) administered ranges from about 0.1 mg/kg of body weight to about 1.0 mg/kg of body weight .
  • the dose of glatiramer acetate (Copolymer 1) administered is about 0.3 mg/kg of body weight .
  • the dose of glatiramer acetate (Copolymer 1) is administered at a frequency of about once every 30 days to about once every day. In a preferred embodiment of the use, the dose of glatiramer acetate (Copolymer 1) is administered at a frequency of about once every 7 days to about once every day. In a more preferred embodiment of the use, the dose of glatiramer acetate (Copolymer 1) is administered at a frequency of about once every day.
  • the glatiramer acetate (Copolymer 1) is administered as part of a therapeutic regimen during which a cytokine antagonist is also administered to the subject.
  • the subject invention also concerns the use of glatiramer acetate (Copolymer 1) in the preparation of a pharmaceutical composition for treating a mammalian subject at risk of developing an inflammatory, non-autoimmune CNS disease, wherein said pharmaceutical composition is administered to the subject in an amount and for a duration of time effective to minimize the severity of the inflammatory, non-autoimmune CNS disease that may occur in the subject or prevent its occurrence.
  • glatiramer acetate Copolymer 1
  • the subject is human and the risk is associated with a genetic predisposition to a chronic medical condition.
  • the disease is selected from the group consisting of Alzheimer's Disease, Parkinson's Disease, glaucoma, dementia, neuropathy, stroke, and brain tumor.
  • the route of administration is oral, intravenous, intramuscular, subcutaneous, intraperitoneal , transdermal , nasal or rectal .
  • the subject invention additionally includes the use of glatiramer acetate (Copolymer 1) in the preparation of a pharmaceutical composition for inhibiting the activity of a matrix metalloproteinase.
  • the matrix metalloproteinase is MMP-9.
  • the matrix metalloproteinase is in a subject.
  • the subject is human.
  • the subject invention further provides the use of glatiramer acetate (Copolymer 1) in the preparation of a pharamcutical composition for suppressing the production of a cytokine by activated T lymphocytes.
  • glatiramer acetate Copolymer 1
  • the cytokine is IL-1.
  • the cytokine is IL-4.
  • the cytokine is IL-6.
  • the cytokine is IL- 10.
  • the cytokine is IL-12.
  • the cytokine is IL-13. In a further embodiment of the use, the cytokine is TNF-a.
  • the cytokine is in a subject.
  • the subject is human.
  • COPAXONE ® is the brand name for glatiramer acetate (formerly known as copolymer-1) .
  • Glatiramer acetate the active ingredient of COPAXONE ® , consists of the acetate salts of synthetic polypeptides, containing four naturally occurring amino acids: L-glutamic acid, L-alanine, L- tyrosine, and L-lysine with an average molar fraction of 0.141, 0.427, 0.095, and 0.338, respectively.
  • the average molecular weight of glatiramer acetate is 4,700 - 11,000 daltons.
  • glatiramer acetate is designated L- glutamic acid polymer with L-alanine, L-lysine and L- tyrosine, acetate (salt). Its structural formula is:
  • Copolymer 1 can be formulated into pharmaceutical compositions containing a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes any and all solvents, adjuvants, suspending agents, emulsifying agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, sweeteners, flavor enhancers and the like.
  • the pharmaceutically acceptable carriers may be prepared from a wide range of materials including, but not limited to, flavoring agents, sweetening agents and miscellaneous materials such as buffers and absorbents that may be needed in order to prepare a particular oral therapeutic composition.
  • the use of such media and agents with pharmaceutically active substances is well known in the art . Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated.
  • Copolymer 1 can be formulated into any form known in the art using procedures available to one of skill in the art. Copolymer 1 may be mixed with other food forms and consumed in solid, semi-solid, suspension or emulsion form. In one embodiment, the composition is formulated into a capsule or tablet using techniques available to one of skill in the art. However, the present compositions may also be formulated in another convenient form, such as an injectable solution or suspension, a spray solution or suspension, a lotion, a gum, a lozenge, a food or snack item. Food, snack, gum or lozenge items can include any ingestible ingredient, including sweeteners, flavorings, oils, starches, proteins, fruits or fruit extracts, vegetables or vegetable extracts, grains, animal fats or proteins.
  • compositions can be formulated into cereals, snack items such as chips, bars, gum drops, chewable candies or slowly dissolving lozenges.
  • Copolymer 1 can also be administered as dry powder or metered dose of solution by inhalation, or nose-drops and nasal sprays, using appropriate formulations and metered dosing units.
  • the present invention includes polypeptides and peptides which contain amino acids that are structurally related to tyrosine, glutamic acid, alanine or lysine and possess the ability to stimulate polyclonal antibody production upon introduction. Such substitutions retain substantially equivalent biological activity in their ability to suppress or alleviate the symptoms of the CNS disease.
  • substitutions are structurally-related amino acid substitutions, including those amino acids which have about the same charge, hydrophobicity and size as tyrosine, glutamic acid, alanine or lysine.
  • lysine is structurally-related to arginine and histidine
  • glutamic acid is structurally-related to aspartic acid
  • tyrosine is structurally-related to serine, threonine, phenylalanine and tryptophan
  • alanine is structurally-related to valine, leucine and isoleucine.
  • Copolymer 1 can be composed of 1-or d- amino acids. As is known by one of skill in the art, 1-amino acids occur in most natural proteins. However, d- amino acids are commerically available and can be substituted for some or all of the amino acids used to make Copolymer 1. The present invention contemplates Copolymer 1 consisting essentially of 1-amino acids, as well as Copolymer 1 consisting essentially of d-amino acids. Experimental Details
  • PBMC Isolation Heparinized blood was collected from normal volunteers, and subjected to Ficoll-Hypaque (Pharmacia Biotech, Mississauga, Ontario) centrifugation to obtain peripheral blood mononuclear cells (PBMNCs) as described previously (15) . After two washes, cells were suspended at a density of 1-2 million/ml in horizontal T-25 flasks (Nunc, Becton
  • AIM-V (GIBCO/BRL) , to which 1 ng/ml of an anti-CD3 antibody
  • T lymphocytes (OKT3, compliments of Jack Antel, Montreal, Canada) was added. Three hours after the anti-CD3 addition, the T-25 flasks were stood upright from their horizontal position in order to kill monocytes that had adhered. Floating cells, which were mostly lymphocytes, were left for a period of 72 hours at 37°C. Flow cytometry analysis of the MNC population at this 72 hour period indicated that CD3+ cells constituted about 90% of the total cell population, with approximately 60% CD4+ and 30% CD8+ ratio. B lymphocytes (CD19+) and NK cells (CD56+) consisted of 5-6% of the total MNC population, and no monocytes (CD14+) were detected. Henceforth, given that the majority of cells in the MNC population are T lymphocytes, these will be referred to as T lymphocytes .
  • Copolymer 1 (1-50 ⁇ g/ml) diluted in phosphate-buffered saline, was added to cultures 3 hours after the initiation of CD3 ligation, at the time that the T-25 flasks were altered from the horizontal to upright positions. Cells were left for 69h at 37°C, then collected, counted and resuspended in fresh AIM-V at density of 500,000 cells per ml. Following a second treatment with Copolymer 1, cells were left at 37°C for an additional 3h. Thereafter, 500il (250,000 cells) of the suspension was taken for migration assays described below.
  • the conditioned medium of cells was used, since MMPs are secreted enzymes. Essentially, for floating T lymphocytes contained within the T-25 flasks, 1 ml of conditioned medium was siphoned off and microfuged for 1 min to remove cells. Supernatant was collected, mixed in a 3.1 ratio (v/v) with 4x gel-loading SDS buffer, and used in zymographic assays. Similarly, for monocytes in wells of 96-well plates, conditioned medium was collected, microfuged, and mixed with 4x gel-loading SDS buffer.
  • Zymography is essentially SDS-PAGE except that gelatin is also added to the gel (77, 82) . After proteins were resolved based on molecular weight in SDS-PAGE, the gel was washed in a Triton X-100 buffer in order to remove SDS which thus allows protein renaturation. In a calcium- containing "reaction buffer" (77) , gelatinases (MMP-2 and -9) degraded gelatin in their immediate vicinity (other members of MMPs would also be detected if present in high amounts) .
  • Copolymer 1 was an inhibitor of the activity of MMPs, independent from its effect on levels of MMP protein, supernatants from BHK cells, a standard source of MMPs in many laboratories, or supernatants from T lymphocytes were resolved by electrophoresis in SDS-PAGE containing gelatin. During the development of the gelatinolytic activity, Copolymer 1 was added to the Triton-100 wash, and the "reaction buffer", described above. An inhibitor of MMP activity prevents gelatin degradation by gelatinases and the resultant size of the band of gelatinases would be smaller as compared to that obtained in the absence of inhibitors .
  • This chamber consists of two compartments separated by a polycarbonate membrane filter
  • Fibronectin was employed to simulate the basal lamina.
  • the bottom compartment of the migration chamber contained 10% FCS-supplemented AIM-V; the higher concentration of FCS in the bottom chamber served as a directional gradient (77) . After 5h at 37°C, the content of the lower chamber was collected, and the number of migrated T lymphocytes was counted with the Coulter Counter Zl .
  • Microglial Cells Fetal human microglia were isolated from brains obtained at legal and therapeutic abortions using a protocol described by Lee et al . (41). Specimens ranged in gestational age from 14 to 20 weeks. 2.5 X IO 4 microglia of over 95% purity were plated per well of a 96 well plate. Microglia culture medium was minimum essential medium supplemented with 5% FCS, 0.1% dextrose. For co-cultures, lOO ⁇ l containing 50,000 T lymphocytes in AIM-V (as described above) was added to individual wells of a 96-well plate already containing 25,000 microglia (or U937 monocytoid cells - see below) in microglia culture medium. Twenty four hours after, conditioned medium was collected for cytokine quantifications by ELISA.
  • Microglia were isolated from the resected brain tissue of patients undergoing surgical resection to treat intractable epilepsy. Microglia of over 95% purity was obtained using a previously detailed protocol (90) . Cells were used for interactions with T lymphocytes in a manner identical to that described for their fetal counter parts.
  • a human promonocytoid cell line U937 was also employed. Members of this cell line become microglia-like, as assessed by morphology and expression of cell surface molecules, when treated sequentially with 50 ng/ml of a protein kinase C activator, phorbol-12-myristate-13-acetate (PMA) (time 0-48) and 100 U/ml interferon- ⁇ (IFN ⁇ ) (from 48-72h) .
  • PMA protein kinase C activator
  • IFN ⁇ interferon- ⁇
  • T lymphocytes were used 1-3 days after the IFN ⁇ treatment. As with microglia, 50,000 T lymphocytes in AIM-V was added to individual wells of a 96-well plate already containing
  • Cytokine protein levels in the conditioned medium of microglia-T lymphocyte co-cultures were measured using enzyme-linked i munoabsorbent assay (ELISA) kits bought from BioSource International (Montreal, Canada) .
  • ELISA enzyme-linked i munoabsorbent assay
  • Chemokine and chemokine receptor expression are currently recognized to be important mechanisms that regulate the influx of leukocytes into the CNS. Notable is the up- regulation of the chemokine IP-10 and its receptor CXCR3 in the lesions of multiple sclerosis patients (74) . Flow cytometry was employed to determine whether Copolymer 1 affected the expression of the CXCR3 receptor. Activated T lymphocytes or U937 cells were treated with 25 ⁇ g/ml of Copolymer 1 for 1-3 days.
  • Fig. 1 Treatment of anti-CD3 activated T lymphocytes with Copolymer 1 (25 ⁇ g/ml, for 1,2 or 3d) did not affect their production of MMP-9 as compared to controls (Fig. 1) and neither did a higher concentration of Copolymer 1 (50 ⁇ g/ml) . Monocyte production of MMP-9 was also unaffected by Copolymer 1. In contrast, and in agreement with a previous report (77) , T lymphocytes treated with IFN ⁇ -lb produced less MMP-9 when compared to control T lymphocytes (Fig. 1) .
  • Figure 2 demonstrates that Copolymer 1 exhibited MMP inhibitory activity, since the size of the gelatinase band (MMP-9) was dose-dependently reduced by Copolymer 1 as compared to controls.
  • IFN ⁇ -lb which inhibits the production of MMP-9 (Fig. 1) , is not a direct inhibitor of MMP enzyme activity.
  • IL-13 was significantly reduced by Copolymer 1 in co- cultures of T lymphocytes with PMA/lFN ⁇ -treated U937, and this decrease was also observed for the pro-inflammatory cytokine, IL-12 (Fig. 5) .
  • Copolymer 1 pretreatment (72 h) of anti-CD3 ligated T lymphocytes results in the suppression of all inducible cytokines that were examined in the T lymphocyte-U937 interactions.
  • Copolymer 1 in reducing cytokine production in T lymphocyte - U937 co-cultures is not a result of a decrease in the proliferation of T lymphocytes, since Copolymer 1 does not decrease the number or size of T lymphocyte aggregates that form following anti-CD3 treatment, indicating that it does not affect the proliferation of T lymphocytes in any significant manner.
  • T lymphocytes led to the upregulation of IL-10 and TNF- ⁇ from previously undetectable levels, and this was also the case for IL-l ⁇ .
  • IL-6 was constitutively expressed at high levels by microglia (Fig. 7) .
  • the pretreatment of T lymphocytes with Copolymer 1 resulted in a dose-dependent inhibition of the inducible cytokines (IL-l ⁇ , IL-10 and TNF- ⁇ ) .
  • Copolymer 1 decreased the expression of the constitutive cytokine, IL-6 (Fig. 7) .
  • T lymphocytes have to be activated with anti-CD3 antibody since co-cultures of unactivated T lymphocytes (even in the presence of 50 U/ml IL-2) with microglia did not result in increased production of TNF- ⁇ . Moreover, it is necessary for T lymphocytes to be pretreated with Copolymer 1 since its reducing effect on cytokine production does not occur if it is added at the time of co-culture.
  • Figure 8 demonstrates that when adult microglia encounter activated T lymphocytes in vitro, the morphology of microglia transforms from a ramified/bipolar morphology to an ameoboid rounded form (14) .
  • T lymphocytes were pretreated with Copolymer 1
  • the morphological transformation of microglia in T lymphocyte - microglia co- culture was attenuated. This was also the case for fetal human microglia or PMA/IFN ⁇ -treated U937 cells in co- culture with activated T lymphocytes.
  • the lack of a morphological transformation of microglia is another indication that Copolymer 1-pretreatment of T lymphocytes resulted in their decreased ability to interact with microglia.
  • Copolymer 1 or glatiramer acetate (GA)
  • G glatiramer acetate
  • This drug is effective in treating multiple sclerosis.
  • the mechanism of action of Copolymer 1 in multiple sclerosis is based on its capacity to suppress an immune response, which specifically affects clinical manifestations of the disease.
  • the subject invention demonstrates that Copolymer 1 has additional biological activities, such as CNS anti-inflammation and remyelination.
  • Copolymer 1 The capability of Copolymer 1 to bind to MHC class II molecules of various genetic backgrounds, resulting in the inhibition of T-cell responses, led to the hypothesis that it may act as a general immunosuppressor .
  • Copolymer 1 administration of Copolymer 1 using different protocols (higher doses and/or more frequent administration) was shown to interfere with alloreactivity in vivo, prevent experimental GVHD and have a beneficial effect on skin and thyroid engrafment in mice models.
  • These effects of Copolymer 1 are most probably mediated by its ability to compete with antigens for their presentation by MHC molecules on antigen presenting cells, which has been shown to be dose-dependent .
  • Another proof for this postulate is the fact that D- Copolymer 1 - is very active in the mouse GVHD model. In fact - it is 10 times more active than L-Copolymer 1.
  • Copolymer 1 In view of the avid binding of Copolymer 1 to class II molecules on antigen presenting cells, studies were designed to examine whether it can interfere with T-cell mediated immune responses. Copolymer 1 reportedly inhibited in vitro T-cell responses to MBP in a dose- dependent manner (5, 11, 58, 60, 78, 80) . Due to the cross-reactivity between Copolymer 1 and MBP, this effect can be attributed not only to competition for the binding to MHC class II molecules, but also to mechanisms related to T-cell recognition (1, 73) . However, the inhibitory capacity of Copolymer 1 was shown to extend also to non cross-reactive T-cell responses (7, 60, 79, 83) . In this case, the inhibitory effect is most probably due to competition for binding to MHC class II molecules.
  • Copolymer 1 binds to murine and human antigen presenting cells irrespective of their MHC restriction (promiscuous binding) in a dose-dependent manner (29, 30) . Binding of Copolymer 1 to MHC class II molecules was demonstrated by its specific inhibition with anti-class II antibodies (30) . Evidence for the direct interaction of Copolymer 1 with various purified HLA-DR molecules has been recently reported (28) . Furthermore, Copolymer 1 was shown to compete and even displace antigens already bound to MHC class II molecules (30, 31, and 79) . Binding to MHC class II molecules is rapid and efficient (30) , and no processing seems to be required for this interaction (29) .
  • Copolymer 1 were significantly reduced in their capacity to transmigrate across a fibronectin barrier, when compared to cells from untreated multiple sclerosis patients (59) .
  • Fibronectin was used as a model of basal lamina. Since the transmigration of leukocytes across the fibronectin barrier is correlated with their expression of matrix metalloproteineses (42, 77, 88), it was of interest to assess the effect of Copolymer 1 on MMPs. The subject invention shows that Copolymer 1 inhibits MMP-9 enzyme activity, but does not decrease the production of MMP-9 by
  • T lymphocytes or monocytes T lymphocytes or monocytes. This inhibition does not alter lymphocyte transmigration.
  • Copolymer 1 is an inhibitor of MMP enzyme activity is relevant to MMP-mediated effects that are unrelated to leukocyte trafficking.
  • many cytokines e.g. TNF- ⁇ and TGF- ⁇
  • cytokine receptors e.g., TNFRs, IL-6R ⁇
  • adhesion molecules e.g., L-selectin, VCAM
  • MMPs have the capacity to convert promolecules (e.g.
  • pro-TNF- ⁇ to their active forms (e.g. TNF- ⁇ ), hence producing a proinflammatory environment within the CNS (91) .
  • the subject invention demonstrates the inhibition of MMP enzyme activity by Copolymer 1, which may decrease the conversion of procytokines to cytokines, resulting in a non-inflammatory milieu (Fig. 2) .
  • MMPs extracellular matrix
  • glatiramer acetate may prevent the disruption of the extracellular matrix, and prevent the detachment of cells from the extacellular matrix. A consequence is thus decreased neural cell death and thereby the progression of the disease is slowed.
  • MMPs are also implicated in cell- ECM interactions that govern processes as diverse as cellular differentiation, migration and inflammation.
  • MMP family members regulate angiogenesis, extension of neuronal growth cones and process formation by oligodendrocytes (54) .
  • MMPs may also suppress the production of anti-inflammatory cytokines, as suggested by the findings that the treatment of EAE animals with MMP inhibitors led to the increase of the anti-inflammatory cytokine, IL-4, within the CNS (43) ; the mechanism of this activity remains unexplained.
  • Immune deviation is a concept that has gained attention in recent years. This concept has its origin in the observation that uncommitted T lymphocytes can differentiate along either the Thl route, with the production of pro-inflammatory cytokines such as IFN- ⁇ , IL- 12 or TNF- ⁇ , or into the Th2 pathway with the production of Th2-like anti-inflammatory cytokines, including IL-4, IL-10, IL-13 or transforming growth factor- ⁇ s (TGF- ⁇ s); cells that produce TGF- ⁇ s have also been referred to as Th3 cells. Susceptibility to certain diseases has been attributed to a predominant Thl or Th2 response (46) .
  • Copolymer 1 does not have a preferential effect on Thl or Th2 type cytokines within the CNS, since all cytokines, including TNF- ⁇ , IL-4, IL-6, IL- 10, 11-12 and IL-13, are suppressed in the T lymphocyte - microglia interactions, creating a non-inflammatory milieu.
  • Copolymer 1 lessened the secretion of all cytokines tested (pro-inflammatory and anti-inflammatory) , treatment of patients with CNS conditions should result in lessened T lymphocyte-mediated inflammation. The decreased inflammation should lessen the severity of the disease. Neuronal and axonal integrity should also improve in inflammatory CNS disorders since inflammation is also associated with the destruction of neurons and axons. Furthermore, individuals at risk for developing CNS diseases could be treated with Copolymer 1 to prevent the onset of the disease or lessen its severity.
  • a cytokine that is capable of killing oligodendrocytes would also decrease the degree of oligodendrocyte loss and demyelination in the CNS of patients on Copolymer 1.
  • Copolymer 1 by inhibition of cytokine secretion, may decrease the generation of free radicals, which cause cellular damage and destruction. Therefore, Copolymer 1 would not only alleviate the symptoms associated with CNS inflammation, but also slow the progression of the CNS disease itself. Ref erences
  • Lymphocytes Involvement of VLA-4 and Inhibition by Interferon ⁇ -lb, (1997), J. Clin . Invest . , 100:604- 612.
  • Metalloproteinases-9 is Required for Oligodendroglial
  • Lymphotoxin Prevents Transfer of Experimental Allergic Encephalomyelitis, (1990), J. Exp . Med. ,
  • PLP Proteolipid Protein
  • Waubant E., D.E. Goodkin, L. Gee, P. Bacchetti, R. Sloan, T. Stewart, P.B. Anderson, G. Stabler, and K.

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US7425332B2 (en) 1998-07-23 2008-09-16 Yeda Research And Development Co., Ltd. Treatment of autoimmune conditions with Copolymer 1 and related Copolymers
US7163802B2 (en) 1998-09-25 2007-01-16 Yeda Research And Development Co., Ltd. Copolymer 1 related polypeptides for use as molecular weight markers and for therapeutic use
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HUP0302333A3 (en) 2005-07-28
JP2003535118A (ja) 2003-11-25
HUP0302333A2 (hu) 2003-11-28
PL363431A1 (en) 2004-11-15
EP1292279A4 (de) 2005-01-12
IL153236A0 (en) 2003-07-06

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