WO1995031990A1 - Copolymer-1 improvements in compositions of copolymers - Google Patents

Copolymer-1 improvements in compositions of copolymers Download PDF

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Publication number
WO1995031990A1
WO1995031990A1 PCT/US1995/006551 US9506551W WO9531990A1 WO 1995031990 A1 WO1995031990 A1 WO 1995031990A1 US 9506551 W US9506551 W US 9506551W WO 9531990 A1 WO9531990 A1 WO 9531990A1
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WO
WIPO (PCT)
Prior art keywords
copolymer
molecular weight
fraction
kilodaltons
species
Prior art date
Application number
PCT/US1995/006551
Other languages
French (fr)
Inventor
Eliezer Konfino
Michael Sela
Dvora Teitelbaum
Ruth Arnon
Original Assignee
Yeda Research And Development Co., Ltd.
Lemmon Company
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Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=26939072&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO1995031990(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to SK1493-96A priority Critical patent/SK283699B6/en
Priority to AU26021/95A priority patent/AU2602195A/en
Priority to EE9600170A priority patent/EE03423B1/en
Priority to AT95920632T priority patent/ATE212857T1/en
Priority to TJ96000421A priority patent/TJ392B/en
Priority to HU9603243A priority patent/HU223473B1/en
Priority to JP7530519A priority patent/JPH10500955A/en
Priority to SI9530577T priority patent/SI0762888T1/en
Priority to MD97-0024A priority patent/MD1443G2/en
Priority to DE2002199030 priority patent/DE10299030I1/en
Priority to EP95920632A priority patent/EP0762888B1/en
Priority to BR9507758A priority patent/BR9507758A/en
Priority to CA002191088A priority patent/CA2191088C/en
Priority to CNB200410064296XA priority patent/CN1310673C/en
Priority to NZ287335A priority patent/NZ287335A/en
Priority to BRPI9507758-8A priority patent/BRPI9507758B1/en
Priority to KR1019960706612A priority patent/KR100403750B1/en
Priority to PL95317331A priority patent/PL181026B1/en
Priority to UA96114382A priority patent/UA62908C2/en
Priority to DK95920632T priority patent/DK0762888T3/en
Priority to DE69525340T priority patent/DE69525340T2/en
Application filed by Yeda Research And Development Co., Ltd., Lemmon Company filed Critical Yeda Research And Development Co., Ltd.
Publication of WO1995031990A1 publication Critical patent/WO1995031990A1/en
Priority to FI964600A priority patent/FI120236B/en
Priority to NO19964976A priority patent/NO324528B1/en
Priority to HK98108818A priority patent/HK1008657A1/en
Priority to NL300096C priority patent/NL300096I2/en
Priority to LU90987C priority patent/LU90987I2/en

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • 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
    • A61P25/28—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
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4713—Autoimmune diseases, e.g. Insulin-dependent diabetes mellitus, multiple sclerosis, rheumathoid arthritis, systemic lupus erythematosus; Autoantigens
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
    • C08G69/08—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids
    • C08G69/10—Alpha-amino-carboxylic acids

Definitions

  • Copolymer-l is a synthetic polypeptide analog of myelin basic protein (MBP) , which is a natural component of the myelin sheath. It has been suggested as a potential therapeutic agent for multiple sclerosis (Eur. J. Immunol. [1971] 1:242; and J. Neurol. Sci. [1977] 31:433) . All references cited herein are hereby incorporated by reference in their entirety. Interest in copolymer-l as an immunotherapy for multiple sclerosis stems from observations first made in the 1950's that myelin components such as MBP prevent or arrest experimental autoimmune encephalomyelitis (EAE) . EAE is a disease resembling multiple sclerosis that can be induced in susceptible animals.
  • MBP myelin basic protein
  • Copolymer-l was developed by Drs. Sela, Arnon, and their co-workers at the Weizmann Institute (Rehovot, Israel) . It was shown to suppress EAE (Eur. J. Immunol. [1971] 1:242; U.S. Patent No. 3,849,550) . More recently, copolymer-l was shown to be beneficial for patients with the exacerbating-remitting form of multiple sclerosis (N. Engl. J. Med. [1987] 317:408) . Patients treated with daily injections of copolymer-l had fewer exacerbations and smaller increases in their disability status than the control patients.
  • Copolymer-l is a mixture of polypeptides composed of alanine, glutamic acid, lysine, and tyrosine in a molar ratio of approximately 6:2:5:1, respectively. It is synthesized by chemically polymerizing the four amino acids forming products with average molecular weights of 23,000 daltons (U.S. Patent No. 3,849,550).
  • the present invention relates to a composition of copolymer-l substantially free of species of copolymer-l having a molecular weight of over 40 kilodaltons (KDa) .
  • the invention further relates to a copolymer-l having over 75% of its molar fraction within the molecular weight range from about 2 KDa to about 20 KDa.
  • the invention relates to a copolymer-l having an average molecular weight of about 4 to about 8.6 KDa.
  • the invention relates to a pharmaceutical composition and a method for the treatment of multiple sclerosis, using the above-discussed copolymer-l.
  • Figure 1 displays the molecular weight distribution of three batches of copolymer-l, showing the proportion of species with molecular weight above 0KDa.
  • Figure 2 shows similar data relating to the molar fraction.
  • the present invention relates to a composition of copolymer-l substantially free of species of copolymer-l having a molecular weight of over 40 kilodaltons (KDa) .
  • the composition contains less than 5% of species of copolymer-l having a molecular weight of 40 KDa or more. More preferably, the composition contains less than 2.5% of species of copolymer-l having a molecular weight of 40 KDa, or more.
  • the invention further relates to a copolymer-l having over 75% of its molar fraction within the molecular weight range from about 2 KDa to about 20 KDa.
  • the invention relates to a copolymer-l having an average molecular weight of about 4 to about 8.6 KDa.
  • the invention relates to a copolymer-l having an average molecular weight of about 4 to about 8 KDa and a copolymer-l having an average molecular weight of about 6.25 to about 8.4 KDa.
  • Copolymer-l may be prepared by methods known in the art, for example, the process disclosed in U.S. Patent 3,849,550, wherein the N-carboxyanhydrides of tyrosine, alanine, y-benzyl glutamate and E-N-trifluoro-acetyllysine are polymerised at ambient temperature in anhydrous dioxane with diethylamine as initiator.
  • the deblocking of the y- carboxyl group of the glutamic acid is effected by hydrogen bromide in glacial acetic acid and is followed by the removal of tr-i trifluoroacetyl groups from the lysine residues by 1M piperidine.
  • the terms "ambient temperature” and "room temperature” should be understood to mean a temperature ranging from about 20 to about 26 °C.
  • the copolymer-l with the required molecular weight profile can be obtained either by methods known per se. Such methods include chromatography of copolymer-l containing high molecular weight species and collecting the fractions without the undesired species or by partial acid or enzymatic hydrolysis to remove the high molecular weight species with subsequent purification by dialysis or ultrafiltration. A further method to obtain copolymer-l with the desired molecular weight profile is by preparing the desired species while the amino acids are still protected and then obtain the correct species directly upon removing the protection.
  • the compositions of the present invention may be formulated by conventional methods known in the art. Preferably, the composition is lyophilized and formed into an aqueous solution suitable for sub-cutaneous injection. Alternatively, copolymer-l may be formulated in any of the forms known in the art for preparing oral, nasal, buccal, or rectal formulations of peptide drugs.
  • copolymer-l is administered daily to patients suffering from multiple sclerosis at a dosage of 20mg.
  • a column for gel filtration, FRACTOGEL TSK HW55 (600 x 26mm) was prepared in a Superformance 26 Merck cartridge according to the manufacturer's instructions.
  • the column was equilibrated with water and acetone solution was injected for total volume determination.
  • the column was equilibrated with ' 0.2M ammonium acetate buffer pH 5.0.
  • 30 ml copolymer-l samples (20mg/ml, in 0.2M ammonium acetate pH 5.0) were loaded on the column and fractions were collected every 10 minutes.
  • a fraction having an average molecular weight of 7-8 KDa was isolated between 120-130 minutes (Batch A) .
  • UV absorbance at 275 nm was determined in a UVIKON 810 spectrophotometer. Samples were diluted to obtain a UV absorbance lower than 1 Absorption Unit. The molecular distribution of the 2 batches was determined on a calibrated gel filtration column (Superose 12) .
  • Copolymer-l batch A was found to have an average molecular weight of 7-8 KDa. 2.5% of this batch had a molecular weight above 32 KDa, but no copolymer-l species present in this batch had a molecular weight of over 40 KDa.
  • Copolymer-l was dissolved in distilled water to yield a solution of 2mg/ml of the active ingredient. Each mouse was injected with 0.5ml of the test solution into the lateral tail vein. Mice were observed for mortality and relevant clinical signs over a 48 hour period. Observations were recorded 10 minutes, 24 hours and 48 hours post-injection. If, at the end of 48 hours, all the animals were alive and no adverse signs had been observed, then the batch was designated "non-toxic”. If, however, one or more of the mice had died or had shown adverse signs, then the batch was designated "toxic".
  • Histamine (or serotonin) release from basophile is an in vitro model for immediate hypersensitivity.
  • the Rat Basophilic Leukemia cell line (RBL-2H 3 ) was developed and characterized as a highly sensitive, uniform, easy to maintain in culture and reproducible system (E.L. Basumian, C. Isersky, M.G. Petrino and R.P. Siraganian. Eur. J. Immunol. 11, 317 (1981)).
  • the physiological stimulus for histamine release involves binding of the antigen to membrane-bound IgE molecules, resulting in the latter's cross-linking and the consequent triggering of an intricate biochemical cascade.
  • Rat Basophilic Leukemia cells (RBL-2H 3 ) are loaded with [ 3 H] -serotonin, followed by incubation with 100 ⁇ g of the copolymer-l to be tested. Batches of copolymer-l which induce non-specific degranulation, release [ 3 H] -serotonin into the medium. The radioactivity in the medium is counted by a scintillation counter and the total radiolabeled serotonin incorporated into the cells is determined in the pelleted cells. Percent degranulation is calculated as the percentage of serotonin released out of the total incorporated.
  • Trifluoroacetyl-Copolymer-l Protected copolymer-l is prepared as described by Teitelbaum et al. Eur. J. Immun. Vol. 1 p. 242 (1971) from the N-carboxyanhydrides of tyrosine (18g) , alanine (50g) , y-benzyl glutamate (35g) and trifluoroacetyllysine (83g) dissolved in 3.5 liters of dioxane.
  • Trifluoroacetyl-Copolymer-l Protected copolymer-l is prepared as described by Teitelbaum et al. Eur. J. Immun. Vol. 1 p. 242 (1971) from the N-carboxyanhydrides of tyrosine (18g) , alanine (50g) , ⁇ -benzyl glutamate (35g) and trifluoroacetyllysine (83g) dissolved in 3.5 liters of dioxane.
  • the polymerization process is initiated by the addition of 0.01 - 0.02% diethylamine.
  • the reaction mixture is stirred at room temperature for 24 hours and then poured into 10 liters water.
  • the product (protected copolymer- 1) is filtered, washed with water and dried.
  • Protected copolymer-l is treated with 33% HBr in acetic acid which removes the omega benzyl protecting group from the 5-carboxylate of the glutamate residue and cleaves the polymer to smaller polypeptides.
  • the time needed for obtaining copolymer-l of molecular weight 7,000 ⁇ 2,000 Da depends on the reaction temperature and the size of protected copolymer-l. At temperatures of between 20- 28°C a test reaction is performed on every batch at different time periods for example, from 10-50 hours. The results concerning the molecular weights of these small scale reactions are calculated and a curve of molecular weight against time is drawn. The time needed for obtaining molecular weight 7,000 ⁇ 2,000 Da is calculated from the curve and performed ⁇ larger scale reaction.

Abstract

The present invention relates to an improved composition of copolymer-1 comprising copolymer-1 substantially free of species having a molecular weight of over 40 kilodaltons.

Description

COPOLYMER-1 IMPROVEMENTS IN COMPOSITIONS OF COPOLYMERS
This application is a continuation-in-part of U.S.S.N. 08/344,248, filed November 23, 1994, which is a continuation of U.S.S.N. 08/248,037, filed May 24, 1994.
Background of the Invention
Copolymer-l is a synthetic polypeptide analog of myelin basic protein (MBP) , which is a natural component of the myelin sheath. It has been suggested as a potential therapeutic agent for multiple sclerosis (Eur. J. Immunol. [1971] 1:242; and J. Neurol. Sci. [1977] 31:433) . All references cited herein are hereby incorporated by reference in their entirety. Interest in copolymer-l as an immunotherapy for multiple sclerosis stems from observations first made in the 1950's that myelin components such as MBP prevent or arrest experimental autoimmune encephalomyelitis (EAE) . EAE is a disease resembling multiple sclerosis that can be induced in susceptible animals.
Copolymer-l was developed by Drs. Sela, Arnon, and their co-workers at the Weizmann Institute (Rehovot, Israel) . It was shown to suppress EAE (Eur. J. Immunol. [1971] 1:242; U.S. Patent No. 3,849,550) . More recently, copolymer-l was shown to be beneficial for patients with the exacerbating-remitting form of multiple sclerosis (N. Engl. J. Med. [1987] 317:408) . Patients treated with daily injections of copolymer-l had fewer exacerbations and smaller increases in their disability status than the control patients.
Copolymer-l is a mixture of polypeptides composed of alanine, glutamic acid, lysine, and tyrosine in a molar ratio of approximately 6:2:5:1, respectively. It is synthesized by chemically polymerizing the four amino acids forming products with average molecular weights of 23,000 daltons (U.S. Patent No. 3,849,550).
It is an object of the present invention to provide an improved composition of copolymer-l.
Summary of the Invention The present invention relates to a composition of copolymer-l substantially free of species of copolymer-l having a molecular weight of over 40 kilodaltons (KDa) .
The invention further relates to a copolymer-l having over 75% of its molar fraction within the molecular weight range from about 2 KDa to about 20 KDa.
In addition, the invention relates to a copolymer-l having an average molecular weight of about 4 to about 8.6 KDa.
Moreover, the invention relates to a pharmaceutical composition and a method for the treatment of multiple sclerosis, using the above-discussed copolymer-l.
Brief Description of the Drawings
Figure 1 displays the molecular weight distribution of three batches of copolymer-l, showing the proportion of species with molecular weight above 0KDa. Figure 2 shows similar data relating to the molar fraction.
Detailed Description of the Invention The present invention relates to a composition of copolymer-l substantially free of species of copolymer-l having a molecular weight of over 40 kilodaltons (KDa) . Preferably, the composition contains less than 5% of species of copolymer-l having a molecular weight of 40 KDa or more. More preferably, the composition contains less than 2.5% of species of copolymer-l having a molecular weight of 40 KDa, or more.
The invention further relates to a copolymer-l having over 75% of its molar fraction within the molecular weight range from about 2 KDa to about 20 KDa.
In addition, the invention relates to a copolymer-l having an average molecular weight of about 4 to about 8.6 KDa. In particular, the invention relates to a copolymer-l having an average molecular weight of about 4 to about 8 KDa and a copolymer-l having an average molecular weight of about 6.25 to about 8.4 KDa.
Copolymer-l, according to the present invention, may be prepared by methods known in the art, for example, the process disclosed in U.S. Patent 3,849,550, wherein the N-carboxyanhydrides of tyrosine, alanine, y-benzyl glutamate and E-N-trifluoro-acetyllysine are polymerised at ambient temperature in anhydrous dioxane with diethylamine as initiator. The deblocking of the y- carboxyl group of the glutamic acid is effected by hydrogen bromide in glacial acetic acid and is followed by the removal of tr-i trifluoroacetyl groups from the lysine residues by 1M piperidine. For the purposes of the application, the terms "ambient temperature" and "room temperature" should be understood to mean a temperature ranging from about 20 to about 26 °C.
The copolymer-l with the required molecular weight profile can be obtained either by methods known per se. Such methods include chromatography of copolymer-l containing high molecular weight species and collecting the fractions without the undesired species or by partial acid or enzymatic hydrolysis to remove the high molecular weight species with subsequent purification by dialysis or ultrafiltration. A further method to obtain copolymer-l with the desired molecular weight profile is by preparing the desired species while the amino acids are still protected and then obtain the correct species directly upon removing the protection. The compositions of the present invention may be formulated by conventional methods known in the art. Preferably, the composition is lyophilized and formed into an aqueous solution suitable for sub-cutaneous injection. Alternatively, copolymer-l may be formulated in any of the forms known in the art for preparing oral, nasal, buccal, or rectal formulations of peptide drugs.
Typically, copolymer-l is administered daily to patients suffering from multiple sclerosis at a dosage of 20mg.
The invention will be exemplified but not necessarily limited by the following Examples.
EXAMPLE 1
Chromato raphic method of preparation of low-toxicity copolymer-l Two batches of copolymer-l were prepared according to the methods known in the art, for example, U.S. Patent No. 3,849,550.
One batch was then subjected to chromatographic separation, as described below.
A column for gel filtration, FRACTOGEL TSK HW55 (600 x 26mm) was prepared in a Superformance 26 Merck cartridge according to the manufacturer's instructions. The column was equilibrated with water and acetone solution was injected for total volume determination. The column was equilibrated with' 0.2M ammonium acetate buffer pH 5.0. 30 ml copolymer-l samples (20mg/ml, in 0.2M ammonium acetate pH 5.0) were loaded on the column and fractions were collected every 10 minutes. A fraction having an average molecular weight of 7-8 KDa was isolated between 120-130 minutes (Batch A) .
Molecular Weight Analysis
UV absorbance at 275 nm was determined in a UVIKON 810 spectrophotometer. Samples were diluted to obtain a UV absorbance lower than 1 Absorption Unit. The molecular distribution of the 2 batches was determined on a calibrated gel filtration column (Superose 12) .
Copolymer-l batch A was found to have an average molecular weight of 7-8 KDa. 2.5% of this batch had a molecular weight above 32 KDa, but no copolymer-l species present in this batch had a molecular weight of over 40 KDa.
The other batch of copolymer-l which was not subjected to chromatography, had an average molecular weight of 12 KDa. 2.5% of the batch had a molecular weight above 42KDa and 5% of the total copolymer-l species in this batch had a molecular weight of over 40 KDa.
EXAMPLE 2
Toxicity Analysis A: In Vivo
Three batches of copolymer-l having an average molecular weight of 7.3 and 8.4 KDa (less than 2.5% copolymer-l species over 40KDa) and 22KDa (more than 5% copolymer-l species over 40KDa) were subjected to the toxicity test described below. In each case 5 mice were used in each experimental group.
Method
Copolymer-l was dissolved in distilled water to yield a solution of 2mg/ml of the active ingredient. Each mouse was injected with 0.5ml of the test solution into the lateral tail vein. Mice were observed for mortality and relevant clinical signs over a 48 hour period. Observations were recorded 10 minutes, 24 hours and 48 hours post-injection. If, at the end of 48 hours, all the animals were alive and no adverse signs had been observed, then the batch was designated "non-toxic". If, however, one or more of the mice had died or had shown adverse signs, then the batch was designated "toxic".
The batches with the average molecular weight of 7.3 and 8.4 KDa were both designated "non-toxic", whereas in the batch with the average molecular weight of 22KDa, 3 out of 5 mice had died at the end of 48 hours, and it was consequently designated "toxic".
B: In Vitro
RBL - Decrranulation test
I. Introduction
Histamine (or serotonin) release from basophile is an in vitro model for immediate hypersensitivity. The Rat Basophilic Leukemia cell line (RBL-2H3) was developed and characterized as a highly sensitive, uniform, easy to maintain in culture and reproducible system (E.L. Basumian, C. Isersky, M.G. Petrino and R.P. Siraganian. Eur. J. Immunol. 11, 317 (1981)). The physiological stimulus for histamine release involves binding of the antigen to membrane-bound IgE molecules, resulting in the latter's cross-linking and the consequent triggering of an intricate biochemical cascade. Beside these physiological, immunoglobulin-mediated triggers, degranulation can be induced by different non-IgE- mediated stimuli. Among these are various peptides and synthetic polymers, e.g. polylysine (R.P. Siraganian. Trends in Pharmacological Sciences, October 432 (1983)). The RBL degranulation test is, therefore, used in order to screen out those batches of copolymer-l which evoke substantial degranulation and thus might elicit undesirable local and/or systemic side effects. II. Principle of the test method
Rat Basophilic Leukemia cells (RBL-2H3) , are loaded with [3H] -serotonin, followed by incubation with 100 μg of the copolymer-l to be tested. Batches of copolymer-l which induce non-specific degranulation, release [3H] -serotonin into the medium. The radioactivity in the medium is counted by a scintillation counter and the total radiolabeled serotonin incorporated into the cells is determined in the pelleted cells. Percent degranulation is calculated as the percentage of serotonin released out of the total incorporated.
III. Results
Four batches of copolymer-l, with average molecular weight between 6,250-14,500 were analyzed for both % of the species with molecular weight over 40KDa and for degranulation of RBL's. Results are summarized in the following table.
Average % of species with % Serotonin M.W. (Daltons) M.W. over 40KDa Release
6,250 < 2.5 12.4
7,300 < 2.5 21.0
13,000 > 5 66.9
14,500 > 5 67.8
As can be seen, when the % of high molecular weight species is low (< 2.5), the % release of serotonin, indicative of toxicity, is low, and vice versa.
EXAMPLE 3
Preparation of Trifluoroacetyl-Copolymer-l Protected copolymer-l is prepared as described by Teitelbaum et al. Eur. J. Immun. Vol. 1 p. 242 (1971) from the N-carboxyanhydrides of tyrosine (18g) , alanine (50g) , y-benzyl glutamate (35g) and trifluoroacetyllysine (83g) dissolved in 3.5 liters of dioxane.
The polymerization process is initiated by the addition of 0.01 - 0.02% diethylamine. The reaction mixture is stirred at room temperature for 24 hours and then poured into 10 liters water. The product (protected copolymer- 1) is filtered, washed with water and dried. The removal of the gamma-benzyl blocking groups from the glutamate residue is carried out by treating the protected copolymer-l with 33% hydrobromic acid in glacial acetic acid at room temperature for 6-12 hours with stirring. The product is poured into excess water, filtered, washed and dried, yielding the trifluoroacetyl-copolymer-l.
EXAMPLE 4
Preparation of Trifluoroacetyl-Copolymer-l Protected copolymer-l is prepared as described by Teitelbaum et al. Eur. J. Immun. Vol. 1 p. 242 (1971) from the N-carboxyanhydrides of tyrosine (18g) , alanine (50g) , τ-benzyl glutamate (35g) and trifluoroacetyllysine (83g) dissolved in 3.5 liters of dioxane.
The polymerization process is initiated by the addition of 0.01 - 0.02% diethylamine. The reaction mixture is stirred at room temperature for 24 hours and then poured into 10 liters water. The product (protected copolymer- 1) is filtered, washed with water and dried.
Protected copolymer-l is treated with 33% HBr in acetic acid which removes the omega benzyl protecting group from the 5-carboxylate of the glutamate residue and cleaves the polymer to smaller polypeptides. The time needed for obtaining copolymer-l of molecular weight 7,000±2,000 Da depends on the reaction temperature and the size of protected copolymer-l. At temperatures of between 20- 28°C a test reaction is performed on every batch at different time periods for example, from 10-50 hours. The results concerning the molecular weights of these small scale reactions are calculated and a curve of molecular weight against time is drawn. The time needed for obtaining molecular weight 7,000±2,000 Da is calculated from the curve and performed ι larger scale reaction. On average, working at 26°C trie time period is 17 hours. The product is poured into excess water, filtered, washed and dried, yielding the trifluoroacetyl- copolymer-l. Preparation of low-toxicity copolymer-l
20g of trifluoroacetyl-copolymer-l are dispersed in 1 liter of water to which lOOg piperidine are added. The mixture is stirred for 24 hours at room temperature and filtered. The solution of crude copolymer-l is distributed into dialysis bags and dialyzed at 10°-20°C against water until a pH = 8 is attained. It is then dialyzed against about 0.3% acetic acid and again water until a pH = 5.5-6.0 is obtained. This solution is then concentrated and lyophilized to dryness.

Claims

1. A copolymer-l fraction substantially free of species of copolymer-l having a molecular weight of over 40 kilodaltons.
2. A copolymer-l fraction, wherein said fraction contains less than 5% of species of copolymer-l having a molecular weight of over 40 kilodaltons.
3. The copolymer-l fraction according to claim 2, wherein the fraction contains less than 2.5% of species of copolymer-l having a molecular weight of over 40 kilodaltons.
4. The copolymer-l fraction according to claim 2, wherein over 75% of said fraction is within a molecular weight range from about 2 kilodaltons to about 20 kilodaltons.
5. A copolymer-l fraction, wherein said copolymer-l has an average molecular weight of about 4 to about 8 kilodaltons.
6. A copolymer-l fraction, wherein said copolymer-l has an average molecular weight of about 6.25 to about 8.4 kilodaltons.
7. A composition for the treatment of multiple sclerosis, comprising a pharmaceutically effective amount of a copolymer-l fraction, wherein said fraction contains less than 5% of species of copolymer-l having a molecular weight of over 40 kilodaltons, and a pharmaceutically acceptable carrier.
8. The composition according to claim 7, wherein the copolymer-l fraction contains less than 2.5% of species of copolymer-l having a molecular weight of over 40 kilodaltons.
9. The composition according to claim 7, wherein over 75% of said copolymer-l in said fraction is within a molecular weight range of about 2 kilodaltons to about 20 kilodaltons.
10. A composition for the treatment of multiple sclerosis, comprising a pharmaceutically effective amount of a copolymer-l fraction, wherein said copolymer-l in said fraction has an average molecular weight of about 4 to about 8 kilodaltons, and a pharmaceutically acceptable carrier.
11. A composition for the treatment of multiple sclerosis, comprising a pharmaceutically effective amount of a copolymer-l fraction, wherein said copolymer-l in said fraction has an average molecular weight of about 6.25 to about 8.4 kilodaltons, and a pharmaceutically acceptable carrier.
PCT/US1995/006551 1994-05-24 1995-05-23 Copolymer-1 improvements in compositions of copolymers WO1995031990A1 (en)

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CA002191088A CA2191088C (en) 1994-05-24 1995-05-23 Copolymer-1 improvements in compositions of copolymers
DK95920632T DK0762888T3 (en) 1994-05-24 1995-05-23 Copolymer-1 improvements in copolymer preparations
EE9600170A EE03423B1 (en) 1994-05-24 1995-05-23 Copolymer-1, a process for its preparation and compositions comprising it
AT95920632T ATE212857T1 (en) 1994-05-24 1995-05-23 IMPROVEMENTS IN COMPOSITIONS OF COPOLYMERS CONTAINING COPOLYMER-1
TJ96000421A TJ392B (en) 1994-05-24 1995-05-23 Fraction of copolymer-1 and method prodaction of it, composition for the treatment of multiple sclerosis, farmaceutical composition, method for the t reatment of multiple sclerosis.
HU9603243A HU223473B1 (en) 1994-05-24 1995-05-23 Copolymer-1 fraction having low toxicity for treating multiple sclerosis, process for producing it and pharmaceutical compositions comprising same
JP7530519A JPH10500955A (en) 1994-05-24 1995-05-23 Copolymer 1
SI9530577T SI0762888T1 (en) 1994-05-24 1995-05-23 Copolymer-1 improvements in compositions of copolymers
MD97-0024A MD1443G2 (en) 1994-05-24 1995-05-23 Copolymer-1 fraction, process for preparation thereof and compositions on base thereof for cerebrospinal sclerosis treatment
DE2002199030 DE10299030I1 (en) 1994-05-24 1995-05-23 Improvements in compositions of copolymers containing copolymer-1
EP95920632A EP0762888B1 (en) 1994-05-24 1995-05-23 Copolymer-1 improvements in compositions of copolymers
BR9507758A BR9507758A (en) 1994-05-24 1995-05-23 Copolymer-1 fraction and composition for the treatment of multiple sclerosis
CNB200410064296XA CN1310673C (en) 1994-05-24 1995-05-23 Composition of multiple scattered mixture contg.polypeptide and its pharm compsn.
SK1493-96A SK283699B6 (en) 1994-05-24 1995-05-23 Fraction of copolymer-1, composition comprising this fraction, process for its preparation and use for production of medicament for treatment of disseminated sclerosis
UA96114382A UA62908C2 (en) 1994-05-24 1995-05-23 Fractions of copolymer-1, methods for preparation thereof, compositions and a method for treatment of disseminated sclerosis
BRPI9507758-8A BRPI9507758B1 (en) 1994-05-24 1995-05-23 copolymer fraction-1; composition for the treatment of multiple sclerosis; pharmaceutical composition
KR1019960706612A KR100403750B1 (en) 1994-05-24 1995-05-23 Copolymer-1 improvements in compositions of copolymers
PL95317331A PL181026B1 (en) 1994-05-24 1995-05-23 Copolymer-1 of an improvement in composition of copolymers
NZ287335A NZ287335A (en) 1994-05-24 1995-05-23 Copolymer-1 composition substantially free of species of copolymer -1 with a mw of from 4 kda to 8 kda, in particular 6.25 kda to 8.4 kda
AU26021/95A AU2602195A (en) 1994-05-24 1995-05-23 Copolymer-1 improvements in compositions of copolymers
DE69525340T DE69525340T2 (en) 1994-05-24 1995-05-23 IMPROVEMENTS IN COMPOSITIONS CONTAINING COPOLYMERS KOPOLYMER-1
FI964600A FI120236B (en) 1994-05-24 1996-11-15 Copolymer-1 Improvements in Copolymer Mixtures
NO19964976A NO324528B1 (en) 1994-05-24 1996-11-22 Copolymer-1 fraction, process for its preparation, use, composition and scavenger for preparing a composition for the treatment of multiple sclerosis and copolymer-1 preparation
HK98108818A HK1008657A1 (en) 1994-05-24 1998-07-02 Copolymer-1 improvements in compositions of copolymers
NL300096C NL300096I2 (en) 1994-05-24 2002-07-29 Improvements of copolymer-1 in compositions of copolymers.
LU90987C LU90987I2 (en) 1994-05-24 2002-08-05 Copaxone and its pharmaceutically acceptable derivatives

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Cited By (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996032119A1 (en) * 1995-04-14 1996-10-17 Yeda Research And Development Co. Ltd. Pharmaceutical compositions comprising synthetic peptide copolymer for prevention of gvhd
EP0975351A1 (en) * 1997-01-10 2000-02-02 Yeda Research And Development Co. Ltd. Treatment of multiple sclerosis through ingestion or inhalation of copolymer-1
US6036957A (en) * 1990-03-30 2000-03-14 Autoimmune, Inc. Suppression of T-cell proliferation using peptide fragments of myelin basic protein
US6054430A (en) * 1994-05-24 2000-04-25 Yeda Research And Development Co., Ltd. Copolymer-1 improvements in compositions of copolymers
US6514938B1 (en) 1998-09-25 2003-02-04 Yeda Research And Development Co. Ltd. At The Weizmann Institute Of Science Copolymer 1 related polypeptides for use as molecular weight markers and for therapeutic use
EP1292279A1 (en) * 2000-06-05 2003-03-19 Teva Pharmaceutical Industries Ltd. The use of glatiramer acetate (copolymer 1) in the treatment of central nervous system disorders
US6800287B2 (en) 1998-09-25 2004-10-05 Yeda Research And Development Co., Ltd. Copolymer 1 related polypeptides for use as molecular weight markers and for therapeutic use
US6800285B2 (en) 2000-06-20 2004-10-05 Moses Rodriguez Treatment of central nervous system diseases by antibodies against glatiramer acetate
WO2006004749A2 (en) 2004-06-25 2006-01-12 Id Biomedical Corporation Of Quebec Compositions and methods for treating neurological disorders
US7022663B2 (en) 2000-02-18 2006-04-04 Yeda Research And Development Co., Ltd. Oral, nasal and pulmonary dosage formulations of copolymer 1
US7026285B2 (en) 1999-04-02 2006-04-11 The Bingham And Women's Hospital, Inc. Immunomodulating polymers
US7033582B2 (en) 2000-06-05 2006-04-25 Teva Pharmaceutical Industries, Ltd. Use of glatiramer acetate (copolymer 1) in the treatment of central nervous system disorders
WO2006050122A1 (en) * 2004-10-29 2006-05-11 Sandoz Ag Processes for preparing glatiramer
US7090982B2 (en) 1991-10-22 2006-08-15 The Governors Of The University Of Alberta Methods of predicting therapeutic efficacy of treatment of a multiple sclerosis patient
EP1799703A2 (en) 2004-09-09 2007-06-27 Teva Pharmaceutical Industries Ltd Process for preparation of mixtures of polypeptides using purified hydrobromic acid
US7279172B2 (en) 1998-07-23 2007-10-09 Yeda Research And Development Co., Ltd. Treatment of autoimmune conditions with copolymer 1 and related copolymers
WO2008006026A1 (en) * 2006-07-05 2008-01-10 Momenta Pharmaceuticals, Inc. Improved process for the preparation of copolymer-1
US7368429B2 (en) 1991-10-22 2008-05-06 The Governors Of The University Of Alberta Peptide specificity of anti-myelin basic protein and the administration of myelin basic protein peptides to multiple sclerosis patients
US7425332B2 (en) 1998-07-23 2008-09-16 Yeda Research And Development Co., Ltd. Treatment of autoimmune conditions with Copolymer 1 and related Copolymers
US7429374B2 (en) 2001-12-04 2008-09-30 Teva Pharmaceutical Industries, Ltd. Process for the measurement of the potency of glatiramer acetate
US7566767B2 (en) 1998-07-23 2009-07-28 President And Fellows Of Harvard College Synthetic peptides and methods of use for autoimmune disease therapies
WO2010140157A1 (en) * 2009-06-04 2010-12-09 Council Of Scientific & Industrial Research Aprocess for the preparation of copolymer - 1 (cop-i), composed of l-alanine, l-lysine, l-glutamic acid and l-tyrosine-drug for the treatment of multiple sclerosis
US7884187B2 (en) 2008-04-16 2011-02-08 Momenta Pharmaceuticals, Inc. Analysis of amino acid copolymer compositions
US8008276B2 (en) 2000-12-05 2011-08-30 The Brigham And Women's Hospital, Inc. Use of zwitterionic polysaccharides for the specific modulation of immune processes
US8058235B1 (en) 2009-04-03 2011-11-15 Momenta Pharmaceuticals, Inc. Water-mediated control of depolymerization step of glatiramer acetate synthesis
US8206726B2 (en) 2006-02-06 2012-06-26 The Brigham And Women's Hospital, Inc. Zwitterionic polysaccharides for promotion of immune system maturation and health
US8324348B1 (en) 2011-07-11 2012-12-04 Momenta Pharmaceuticals, Inc. Evaluation of copolymer diethylamide
EP2239269B1 (en) * 1998-09-25 2013-01-16 Yeda Research And Development Co., Ltd. Use of peptides derived from copolymer-1 as molecular weight markers
US8377885B2 (en) 2010-01-04 2013-02-19 Mapi Pharma Ltd. Depot systems comprising glatiramer or pharmacologically acceptable salt thereof
EP2642290A1 (en) 2012-03-19 2013-09-25 Synthon BV Glatiramer acetate human monocytic cell line-based potency assay
WO2013139728A1 (en) 2012-03-19 2013-09-26 Synthon Bv Glatiramer acetate human monocyte cell-based potency assay
US8753833B2 (en) 2007-06-21 2014-06-17 Momenta Pharmaceuticals, Inc. Copolymer assay
US8796226B2 (en) 2010-01-04 2014-08-05 Mapi Pharma Ltd. Depot systems comprising glatiramer or a pharmacologically acceptable salt thereof
WO2014128079A1 (en) 2013-02-19 2014-08-28 Synthon B.V. Glatiramer acetate multidose formulation
WO2014060942A3 (en) * 2012-10-20 2014-10-23 Mahesh Kandula Compositions and methods of for the treatment of multiple sclerosis and neurodegenerative diseases
WO2014173463A1 (en) 2013-04-26 2014-10-30 Synthon Bv Glatiramer acetate human monocytic cell line-based potency assay
US9095547B2 (en) 2011-07-11 2015-08-04 Momenta Pharmaceuticals, Inc. Structure assessment of heterogeneous polypeptide mixture
US9155776B2 (en) 2009-08-20 2015-10-13 Yeda Research & Development Co., Ltd. Low frequency glatiramer acetate therapy
US9200114B2 (en) 2011-04-21 2015-12-01 Mapi Pharma Ltd. Random pentapolymer for treatment of autoimmune diseases
US9265790B2 (en) 2003-03-31 2016-02-23 The Brigham And Women's Hospital, Inc. Zwitterionic immunomodulators for the treatment of asthma and allergy
US9499868B2 (en) 2011-10-10 2016-11-22 Teva Pharmaceutical Industries, Ltd. Determination of single nucleotide polymorphisms useful to predict response for glatiramer acetate
US9539281B2 (en) 2011-07-12 2017-01-10 The Brigham And Women's Hospital, Inc. Lipid-containing PSA compositions, methods of isolation and methods of use thereof
US9617596B2 (en) 2012-10-10 2017-04-11 Teva Pharmaceutical Industries, Ltd. Biomarkers predictive for clinical response for glatiramer acetate
US9625473B2 (en) 2010-10-11 2017-04-18 Teva Pharmaceutical Industries Ltd. Cytokine biomarkers as predictive biomarkers of clinical response for glatiramer acetate
EP3170836A1 (en) * 2015-11-23 2017-05-24 Chemi SPA Rp-hplc analysis of complex polypeptide mixtures
US9702007B2 (en) 2013-10-21 2017-07-11 Teva Pharmaceuticals Industries, Ltd. Genetic markers predictive of response to glatiramer acetate
US10772918B2 (en) 2013-05-10 2020-09-15 California Institute Of Technology Probiotic prevention and treatment of colon cancer
US10857177B2 (en) 2015-08-19 2020-12-08 President And Fellows Of Harvard College Lipidated PSA compositions and methods
US11103566B2 (en) 2010-05-20 2021-08-31 California Institute Of Technology Antigen specific Tregs and related compositions, methods and systems
US11167003B2 (en) 2017-03-26 2021-11-09 Mapi Pharma Ltd. Methods for suppressing or alleviating primary or secondary progressive multiple sclerosis (PPMS or SPMS) using sustained release glatiramer depot systems
US11331335B2 (en) 2015-06-10 2022-05-17 California Institute Of Technology Sepsis treatment and related compositions methods and systems
US11419887B2 (en) 2010-04-07 2022-08-23 California Institute Of Technology Vehicle for delivering a compound to a mucous membrane and related compositions, methods and systems
USRE49251E1 (en) 2010-01-04 2022-10-18 Mapi Pharma Ltd. Depot systems comprising glatiramer or pharmacologically acceptable salt thereof
US11491181B2 (en) 2016-07-15 2022-11-08 President And Fellows Of Harvard College Glycolipid compositions and methods of use
US11622973B2 (en) 2007-11-09 2023-04-11 California Institute Of Technology Immunomodulating compounds and related compositions and methods

Families Citing this family (74)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002503658A (en) * 1998-02-13 2002-02-05 オートイミューン インク Treatment of multiple sclerosis using COP-1 and Th-2 promoting cytokines
AU6281599A (en) * 1998-10-02 2000-04-26 Yeda Research And Development Co. Ltd. Alternate day administration of copolymer 1 for treating autoimmune diseases
AU780188B2 (en) * 2000-01-20 2005-03-03 Yeda Research And Development Co. Ltd. The use of copolymer 1 and related peptides and polypeptides and T cells treated therewith for neuroprotective therapy
ATE329608T1 (en) * 2000-02-18 2006-07-15 Yeda Res & Dev FORMULATIONS OF COPOLYMER 1 (GLATIRAMER ACETATE) FOR ORAL, NASAL AND PULMONARY ADMINISTRATION
AU783031B2 (en) * 2000-06-07 2005-09-15 Yeda Research And Development Co. Ltd. The use of copolymer 1 and related peptides and polypeptides and T cells treated therewith for treating diseases caused or exacerbated by glutamate toxicity
AU6887101A (en) * 2000-06-20 2002-01-02 Caprion Pharmaceuticals, Inc. Copolymers and methods of treating prion-related diseases
IL137460A0 (en) * 2000-07-24 2001-07-24 Yeda Res & Dev Identifying antigen clusters for monitoring a global state of an immune system
US20040037828A1 (en) 2002-07-09 2004-02-26 Bar-Ilan University Methods and pharmaceutical compositions for healing wounds
GB2369896A (en) 2000-12-06 2002-06-12 Marconi Comm Ltd Tunable optical filter actuator
KR100442122B1 (en) * 2001-07-31 2004-07-30 한국전기연구원 Brushless generator with permanent magnet
CA2469092C (en) * 2001-12-06 2013-02-19 Yeda Research And Development Co. Ltd Copolymer 1 vaccine and methods for treatment of amyotrophic lateral sclerosis (als)
AU2002360696A1 (en) * 2001-12-21 2003-07-30 Ilex Oncology, Inc. Combination comprising anti-cd52 antibodies and other therapeutic agents for treatment for multiple sclerosis
ES2386435T3 (en) 2003-01-07 2012-08-21 Yeda Research And Development Co., Ltd. Vaccine in the form of eye drops containing copolymer 1 for therapeutic immunization
AU2004206120B2 (en) * 2003-01-21 2009-09-24 Yeda Research And Development Co. Ltd. COP 1 for treatment of inflammatory bowel diseases
CA2518079A1 (en) * 2003-03-04 2004-10-28 Teva Pharmaceutical Industries, Ltd. Combination therapy with glatiramer acetate and alphacalcidol for the treatment of multiple sclerosis
AU2004285553B2 (en) * 2003-10-31 2009-12-10 Teva Pharmaceutical Industries, Ltd. Nanoparticles for drug delivery
CA2546077C (en) 2003-11-12 2016-07-05 Yeda Research And Development Co. Ltd. Vaccine and method for treatment of neurodegenerative diseases
JP4808631B2 (en) 2003-12-09 2011-11-02 イエダ リサーチ アンド デベロップメント カンパニー リミテッド Method and vaccine comprising Copolymer 1 for the treatment of psychiatric disorders
JP2008500276A (en) * 2004-02-02 2008-01-10 ミクスチャー サイエンセズ、 インク． Peptide mixture having immunomodulating activity
WO2005085323A2 (en) * 2004-03-01 2005-09-15 Peptimmune, Inc. Methods and compositions for treatment of autoimmune diseases
US20070244056A1 (en) * 2004-03-03 2007-10-18 Liat Hayardeny Combination Therapy With Glatiramer Acetate and Riluzole
US20050260770A1 (en) * 2004-04-01 2005-11-24 Cohen Irun R Antigen array and diagnostic uses thereof
US20060194725A1 (en) * 2004-05-07 2006-08-31 James Rasmussen Methods of treating disease with random copolymers
US7655221B2 (en) * 2004-05-07 2010-02-02 Peptimmune, Inc. Methods of treating disease with random copolymers
KR20070036062A (en) 2004-05-07 2007-04-02 펩팀문, 인코포레이티드 Methods of treating disease with random copolymers
PL1797109T3 (en) * 2004-09-09 2016-11-30 Mixtures of polypeptides, compositions containing and processes for preparing same, and uses thereof
US8324641B2 (en) * 2007-06-29 2012-12-04 Ledengin, Inc. Matrix material including an embedded dispersion of beads for a light-emitting device
WO2006057003A2 (en) * 2004-11-29 2006-06-01 Yeda Research And Development Co. Ltd. Induction of neurogenesis and stem cell therapy in combination with copolymer 1
CN101111252A (en) * 2005-02-02 2008-01-23 泰华制药工业有限公司 Process for producing polypeptide mixtures using hydrogenolysis
US20100167983A1 (en) * 2007-10-22 2010-07-01 Teva Pharmaceutical Industries, Ltd. Combination therapy with glatiramer acetate and rasagiline for the treatment of multiple sclerosis
US20080261894A1 (en) * 2005-02-17 2008-10-23 Rivka Kreitman Combination Therapy with Glatiramer Acetate and Rasagiline for the Treatment of Multiple Sclerosis
EP1891233A4 (en) * 2005-04-25 2010-03-24 Yeda Res & Dev Markers associated with the therapeutic efficacy of glatiramer acetate
WO2007081975A2 (en) * 2006-01-11 2007-07-19 Teva Pharmaceutical Industries, Ltd. Method of treating multiple sclerosis
CA2649296A1 (en) 2006-04-13 2007-10-25 Peptimmune, Inc. Methods for designing and synthesizing directed sequence polymer compositions via the directed expansion of epitope permeability
ES2565035T3 (en) 2006-04-28 2016-03-30 Momenta Pharmaceuticals, Inc. Methods to evaluate peptide mixtures
KR100831796B1 (en) * 2006-05-29 2008-05-28 엘지전자 주식회사 An image display device for having time shift function and method for playing of the same
ES2605154T3 (en) 2006-06-28 2017-03-13 Yeda Research And Development Company Limited Copolymer 1 for the treatment of age-related macular degeneration
US20090029766A1 (en) * 2007-07-26 2009-01-29 Lutnick Howard W Amusement gaming access and authorization point
US8993722B2 (en) * 2007-07-31 2015-03-31 Natco Pharma Limited Process for the preparation glatiramer acetate (copolymer-1)
EP2207566A1 (en) 2007-10-16 2010-07-21 Peptimmune, Inc. Methods for designing and preparing vaccines comprising directed sequence polymer compositions via the directed expansion of epitopes
BRPI0819001A2 (en) * 2007-11-28 2014-10-07 Teva Pharma "METHOD FOR DELAYING CLINICALLY DEFENTIVE MULTIPLE SCIENCE ACCESS IN A PATIENT RISK OF CLINICALLY DEVELOPING MULTIPLE DECLINING PROCEDURE IN THE CURRENT DEVELOPMENT OF THE PROGRESS OF MONITOR RISK DEVELOPING CLINICALLY DEFINING MULTIPLE SCLEROSIS, A METHOD TO REDUCE DEFINITIVE MULTIPLE SCLEROSIS SYMPTOMS IN A PATIENT SUGGESTIVE MULTIPLE SCLEROSIS, METHOD TO DELAY THE PROGRESS FOR CLINICALLY DEFINING MULTIPLE SCLEROSIS IN A PATIENT WHO HAS A FIRST CLINICAL EVENT SUGGESTED BY THE MUSCLES
PL2307448T3 (en) * 2008-08-07 2015-10-30 Sigma Aldrich Co Llc Preparation of low molecular weight polylysine and polyornithine in high yield
AU2009279636A1 (en) * 2008-08-07 2010-02-11 Scinopharm Taiwan, Ltd. Synthesis of glatiramer acetate
AR074881A1 (en) 2008-12-24 2011-02-16 Synthon Bv A PROCESS TO PURIFY A MIXTURE OF POLYMERS
PT2275086E (en) * 2009-07-15 2012-05-18 Teva Pharma Reduced volume formulation of glatiramer acetate and methods of administration
US8920373B2 (en) 2009-07-15 2014-12-30 Teva Pharmaceutical Industries, Ltd. Reduced volume formulation of glatiramer acetate and methods of administration
US8691790B2 (en) * 2009-07-27 2014-04-08 James Layne Boucher Therapy of neurological inflammatory diseases with (5'-deoxy-5'-adenosyl) cobamamide, recombinant human growth hormone, interleukins IL-1, IL-6, IL-11, epidermal growth factor, and physiotherapy
WO2011086470A1 (en) 2010-01-13 2011-07-21 Ramot At Tel-Aviv University Ltd Treatment of multiple sclerosis
US8759302B2 (en) * 2010-03-16 2014-06-24 Teva Pharmaceutical Industries, Ltd. Methods of treating a subject afflicted with an autoimmune disease using predictive biomarkers of clinical response to glatiramer acetate therapy in multiple sclerosis
EP2563804A4 (en) * 2010-04-27 2014-09-17 Reddys Lab Ltd Dr Preparation of polypeptides and salts thereof
JP2013535474A (en) 2010-07-29 2013-09-12 ドクター レディズ ラボラトリーズ リミテッド Molecular weight marker for glatiramer acetate
ES2654291T3 (en) 2011-02-14 2018-02-13 Usv Private Limited Copolymer-1, preparation process and its methods of analysis
US20140348861A1 (en) 2011-05-05 2014-11-27 National Institute Of Immunology Synthetic peptides and random copolymers for the treatment of autoimmune disorders
US8575198B1 (en) 2011-09-07 2013-11-05 Momenta Pharmaceuticals, Inc. In-process control for the manufacture of glatiramer acetate
US20140045740A1 (en) * 2012-08-13 2014-02-13 Momenta Pharmaceuticals, Inc. Analysis of glatiramer acetate
PL2774640T3 (en) 2013-03-08 2015-04-30 Teva Pharma Re-useable injector device for syringe
PL2774639T3 (en) 2013-03-08 2015-07-31 Teva Pharma Re-useable injector device for syringe
AU2014244550B2 (en) 2013-03-14 2018-11-01 Mylan Inc. Glatiramer acetate response biomarker mRNA potency assay
CN103265624B (en) * 2013-05-27 2015-04-22 成都圣诺生物制药有限公司 Method for preparing copaxone
CN104371012A (en) * 2013-08-12 2015-02-25 深圳翰宇药业股份有限公司 Synthesis method of glatiramer acetate
TWI717314B (en) 2013-10-24 2021-02-01 美商麥蘭股份有限公司 Human t cell line assay for evaluating immunologic identity of glatiramer acetate preparations
EP3090064B1 (en) 2013-12-31 2019-11-13 Yeda Research and Development Co. Ltd. Diagnosis of systemic lupus erythematosus using oligonucleotides antigens
KR20230097209A (en) 2014-03-12 2023-06-30 예다 리서치 앤드 디벨럽먼트 캄파니 리미티드 Reducing systemic regulatory t cell levels or activity for treatment of disease and injury of the cns
CN104844697B (en) 2014-09-26 2018-10-23 深圳翰宇药业股份有限公司 The preparation method of acetic acid copaxone
US9155775B1 (en) 2015-01-28 2015-10-13 Teva Pharmaceutical Industries, Ltd. Process for manufacturing glatiramer acetate product
CN107533058A (en) 2015-03-01 2018-01-02 免疫阵列有限公司 Use albumen, peptide and oligonucleotides diagnostic antigen systemic loupus erythematosus
ES2744179T3 (en) 2015-09-24 2020-02-24 Chemi Spa Analysis of the molecular weight distribution of complex polypeptide mixtures
CN107522774B (en) * 2016-06-22 2021-07-02 深圳翰宇药业股份有限公司 Real-time control method for piperidine residual quantity in glatiramer acetate preparation process
WO2018002930A1 (en) 2016-06-30 2018-01-04 Stem Cell Medicine Ltd. Treatment of inflammatory bowel disease with long acting glatiramer and adipose-derived stem cells
US11471421B2 (en) 2016-08-28 2022-10-18 Mapi Pharma Ltd. Process for preparing microparticles containing glatiramer acetate
DK3506921T3 (en) 2016-08-31 2023-07-31 Mapi Pharma Ltd DEPOT SYSTEMS INCLUDING GLATIRAMER ACETATE
CN110573170A (en) 2017-05-15 2019-12-13 干细胞医药有限公司 Treatment of multiple sclerosis using adipose derived stem cells
US11413311B2 (en) 2017-05-15 2022-08-16 Mapi Pharma Ltd. Treatment of multiple sclerosis with long acting glatiramer and adipose-derived stem cells
WO2019175869A1 (en) 2018-03-12 2019-09-19 Yeda Research And Development Co. Ltd Treatment of a heart disease

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3849550A (en) * 1971-04-21 1974-11-19 Yeda Res & Dev Therapeutic copolymer
EP0383620A2 (en) * 1989-02-17 1990-08-22 Repligen Corporation Process for making genes encoding random polymers of amino acids

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4444760A (en) * 1983-06-17 1984-04-24 Merck & Co., Inc. Purification and characterization of a protein fibroblast growth factor
JPS6053535A (en) 1983-09-02 1985-03-27 Nitto Boseki Co Ltd Production of regular polyaminoacid resin
SU1182051A1 (en) 1984-04-28 1985-09-30 Таджикский государственный университет им.В.И.Ленина Polytripeptides possessing oenantic selectivity in reactions of hydrolysis of carbobenzoxy-d-1 alanine n-nitrophenyl esters
IE59233B1 (en) 1985-06-18 1994-01-26 Univ Emory Use of biologically active copolymers for the manufacture of a medicament for stimulating the growth of an animal
DD257174A3 (en) 1985-12-20 1988-06-08 Ve Forschungszentrum Biotechno PROCESS FOR PREPARING THE PEPTIDES Z ALA ALA LON P NITRANILIDE OR Z ASP ASP PHE OME WITH METALOPROTEASE
SU1469826A1 (en) 1986-05-30 1995-11-20 Институт Высокомолекулярных Соединений Ан Ссср Copolymer of l-lysine and l-glutamic acid containing side groups and showing prolonged hypotensive activity and compensatory effect at hemorrhagic shock, and a method of its preparing
US4828706A (en) * 1988-03-07 1989-05-09 Spectrum Medical Industries Process for performing a dialysis operation
US4908404A (en) * 1988-08-22 1990-03-13 Biopolymers, Inc. Synthetic amino acid-and/or peptide-containing graft copolymers
DE8900366U1 (en) * 1989-01-13 1989-08-03 Indag Gesellschaft Fuer Industriebedarf Mbh, 6904 Eppelheim, De
SU1690368A1 (en) 1989-07-20 1995-08-20 Институт Высокомолекулярных Соединений Ан Ссср Statistic copolymers as low toxic compounds having prolonged hypotensive action and method for their production
DE3930733A1 (en) 1989-09-14 1991-03-28 Roehm Gmbh METHOD FOR PRODUCING A COMPLEX MEDICINAL PRODUCT
JP2653255B2 (en) * 1990-02-13 1997-09-17 武田薬品工業株式会社 Long-term sustained release microcapsules
AU3130793A (en) * 1991-11-12 1993-06-15 E.I. Du Pont De Nemours And Company Collagen-like polypeptides
US5800808A (en) * 1994-05-24 1998-09-01 Veda Research And Development Co., Ltd. Copolymer-1 improvements in compositions of copolymers
US6214791B1 (en) * 1997-01-10 2001-04-10 Yeda Research And Development Co. Ltd. Treatment of multiple sclerosis through ingestion or inhalation of copolymer-1
JP2001524011A (en) 1997-05-06 2001-11-27 クワンタ・ビジョン Tissue analyzer
AU780188B2 (en) * 2000-01-20 2005-03-03 Yeda Research And Development Co. Ltd. The use of copolymer 1 and related peptides and polypeptides and T cells treated therewith for neuroprotective therapy
US6936539B2 (en) * 2003-09-24 2005-08-30 Micron Technology, Inc. Antireflective coating for use during the manufacture of a semiconductor device

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3849550A (en) * 1971-04-21 1974-11-19 Yeda Res & Dev Therapeutic copolymer
EP0383620A2 (en) * 1989-02-17 1990-08-22 Repligen Corporation Process for making genes encoding random polymers of amino acids

Cited By (93)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6036957A (en) * 1990-03-30 2000-03-14 Autoimmune, Inc. Suppression of T-cell proliferation using peptide fragments of myelin basic protein
US7368429B2 (en) 1991-10-22 2008-05-06 The Governors Of The University Of Alberta Peptide specificity of anti-myelin basic protein and the administration of myelin basic protein peptides to multiple sclerosis patients
US7090982B2 (en) 1991-10-22 2006-08-15 The Governors Of The University Of Alberta Methods of predicting therapeutic efficacy of treatment of a multiple sclerosis patient
US6054430A (en) * 1994-05-24 2000-04-25 Yeda Research And Development Co., Ltd. Copolymer-1 improvements in compositions of copolymers
WO1996032119A1 (en) * 1995-04-14 1996-10-17 Yeda Research And Development Co. Ltd. Pharmaceutical compositions comprising synthetic peptide copolymer for prevention of gvhd
US5858964A (en) * 1995-04-14 1999-01-12 Yeda Research And Development Co. Ltd. Pharmaceutical compositions comprising synthetic peptide copolymer for prevention of GVHD
EP0975351A1 (en) * 1997-01-10 2000-02-02 Yeda Research And Development Co. Ltd. Treatment of multiple sclerosis through ingestion or inhalation of copolymer-1
EP0975351A4 (en) * 1997-01-10 2002-05-15 Yeda Res & Dev Treatment of multiple sclerosis through ingestion or inhalation of copolymer-1
CZ297983B6 (en) * 1997-01-10 2007-05-16 Yeda Research And Development Co., Ltd Enteric coated capsules of pharmaceutical composition administered by ingestion and intended for the treatment of multiple sclerosis
US7566767B2 (en) 1998-07-23 2009-07-28 President And Fellows Of Harvard College Synthetic peptides and methods of use for autoimmune disease therapies
US7425332B2 (en) 1998-07-23 2008-09-16 Yeda Research And Development Co., Ltd. Treatment of autoimmune conditions with Copolymer 1 and related Copolymers
US7279172B2 (en) 1998-07-23 2007-10-09 Yeda Research And Development Co., Ltd. Treatment of autoimmune conditions with copolymer 1 and related copolymers
US6514938B1 (en) 1998-09-25 2003-02-04 Yeda Research And Development Co. Ltd. At The Weizmann Institute Of Science Copolymer 1 related polypeptides for use as molecular weight markers and for therapeutic use
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
US7615359B2 (en) 1998-09-25 2009-11-10 Yeda Research And Development Co., Ltd. Copolymer 1 related polypeptides for use as molecular weight markers and for therapeutic use
US6800287B2 (en) 1998-09-25 2004-10-05 Yeda Research And Development Co., Ltd. Copolymer 1 related polypeptides for use as molecular weight markers and for therapeutic use
US7074580B2 (en) 1998-09-25 2006-07-11 Yeda Research And Development Co., Ltd. Copolymer 1 related polypeptides for use as molecular weight markers and for therapeutic use
EP2239269B1 (en) * 1998-09-25 2013-01-16 Yeda Research And Development Co., Ltd. Use of peptides derived from copolymer-1 as molecular weight markers
US8399211B2 (en) 1998-09-25 2013-03-19 Yeda Research And Development Co., Ltd. Copolymer 1 related polypeptides for use as molecular weight markers and for therapeutic use
US7026285B2 (en) 1999-04-02 2006-04-11 The Bingham And Women's Hospital, Inc. Immunomodulating polymers
US7083777B1 (en) 1999-04-02 2006-08-01 The Brigham And Women's Hospital, Inc. Immunomodulating polymers
US7022663B2 (en) 2000-02-18 2006-04-04 Yeda Research And Development Co., Ltd. Oral, nasal and pulmonary dosage formulations of copolymer 1
EP1292279A4 (en) * 2000-06-05 2005-01-12 Teva Pharma The use of glatiramer acetate (copolymer 1) in the treatment of central nervous system disorders
US7033582B2 (en) 2000-06-05 2006-04-25 Teva Pharmaceutical Industries, Ltd. Use of glatiramer acetate (copolymer 1) in the treatment of central nervous system disorders
EP1292279A1 (en) * 2000-06-05 2003-03-19 Teva Pharmaceutical Industries Ltd. The use of glatiramer acetate (copolymer 1) in the treatment of central nervous system disorders
US6800285B2 (en) 2000-06-20 2004-10-05 Moses Rodriguez Treatment of central nervous system diseases by antibodies against glatiramer acetate
US8008276B2 (en) 2000-12-05 2011-08-30 The Brigham And Women's Hospital, Inc. Use of zwitterionic polysaccharides for the specific modulation of immune processes
US8389228B2 (en) 2001-12-04 2013-03-05 Teva Pharmaceutical Industries, Ltd. Process for the measurement of the potency of glatiramer acetate
US7923215B2 (en) 2001-12-04 2011-04-12 Teva Pharmaceutical Industries, Ltd. Process for the measurement of the potency of glatiramer acetate
US7429374B2 (en) 2001-12-04 2008-09-30 Teva Pharmaceutical Industries, Ltd. Process for the measurement of the potency of glatiramer acetate
US9265790B2 (en) 2003-03-31 2016-02-23 The Brigham And Women's Hospital, Inc. Zwitterionic immunomodulators for the treatment of asthma and allergy
WO2006004749A2 (en) 2004-06-25 2006-01-12 Id Biomedical Corporation Of Quebec Compositions and methods for treating neurological disorders
EP2332569A2 (en) 2004-06-25 2011-06-15 ID Biomedical Corporation of Quebec Compositions and methods for treating neurological disorders
EP2332570A1 (en) 2004-06-25 2011-06-15 ID Biomedical Corporation of Quebec Compositions and methods for treating neurological disorders
EP2177528A1 (en) * 2004-09-09 2010-04-21 Teva Pharmaceutical Industries Ltd. Process for the preparation of mixtures of trifluoroacetyl glatiramer acetate using purified hydrobromic acid
EP1799703A2 (en) 2004-09-09 2007-06-27 Teva Pharmaceutical Industries Ltd Process for preparation of mixtures of polypeptides using purified hydrobromic acid
EP2361924A1 (en) * 2004-09-09 2011-08-31 Teva Pharmaceutical Industries Ltd. Process for the preparation of mixtures of trifluoroacetyl glatiramer acetate using purified hydrobromic acid
EP1799703A4 (en) * 2004-09-09 2008-09-03 Teva Pharma Process for preparation of mixtures of polypeptides using purified hydrobromic acid
AU2005282249B2 (en) * 2004-09-09 2012-08-02 Teva Pharmaceutical Industries, Ltd. Process for preparation of mixtures of polypeptides using purified hydrobromic acid
US8729229B2 (en) 2004-10-29 2014-05-20 Sandoz Ag Processes for preparing a polypeptide
US8536305B2 (en) 2004-10-29 2013-09-17 Sandoz Ag Processes for preparing a polypeptide
WO2006050122A1 (en) * 2004-10-29 2006-05-11 Sandoz Ag Processes for preparing glatiramer
US8206726B2 (en) 2006-02-06 2012-06-26 The Brigham And Women's Hospital, Inc. Zwitterionic polysaccharides for promotion of immune system maturation and health
WO2008006026A1 (en) * 2006-07-05 2008-01-10 Momenta Pharmaceuticals, Inc. Improved process for the preparation of copolymer-1
EP2143728A1 (en) * 2006-07-05 2010-01-13 Momenta Pharmaceuticals, Inc. Improved process for the preparation of copolymer-1
US8753833B2 (en) 2007-06-21 2014-06-17 Momenta Pharmaceuticals, Inc. Copolymer assay
US11622973B2 (en) 2007-11-09 2023-04-11 California Institute Of Technology Immunomodulating compounds and related compositions and methods
US9395374B2 (en) 2008-04-16 2016-07-19 Momenta Pharmaceuticals, Inc. Analysis of amino acid copolymer compositions
US9410964B2 (en) 2008-04-16 2016-08-09 Momenta Pharmaceuticals, Inc. Analysis of amino acid copolymer compositions
US8329391B2 (en) 2008-04-16 2012-12-11 Momenta Pharmaceuticals, Inc. Analysis of amino acid copolymer compositions
US8592142B2 (en) 2008-04-16 2013-11-26 Momenta Pharmaceuticals, Inc. Analysis of amino acid copolymer compositions
US7884187B2 (en) 2008-04-16 2011-02-08 Momenta Pharmaceuticals, Inc. Analysis of amino acid copolymer compositions
US10160992B2 (en) 2008-04-16 2018-12-25 Momenta Pharmaceuticals, Inc. Analysis of amino acid copolymer compositions
US9085796B2 (en) 2008-04-16 2015-07-21 Momenta Pharmaceuticals, Inc. Analysis of amino acid copolymer compositions
EP2277050B2 (en) † 2008-04-16 2022-09-28 Momenta Pharmaceuticals, Inc. Analysis of amino acid copolymer compositions
US8058235B1 (en) 2009-04-03 2011-11-15 Momenta Pharmaceuticals, Inc. Water-mediated control of depolymerization step of glatiramer acetate synthesis
US8859489B2 (en) 2009-04-03 2014-10-14 Momenta Pharmaceuticals, Inc. Water-mediated control of depolymerization step of glatiramer acetate synthesis
WO2010140157A1 (en) * 2009-06-04 2010-12-09 Council Of Scientific & Industrial Research Aprocess for the preparation of copolymer - 1 (cop-i), composed of l-alanine, l-lysine, l-glutamic acid and l-tyrosine-drug for the treatment of multiple sclerosis
US9150609B2 (en) 2009-06-04 2015-10-06 Council Of Scientific & Industrial Research Process for the preparation of copolymer-1 using a polymer supported dialkylamine initiator
US9402874B2 (en) 2009-08-20 2016-08-02 Yeda Research & Development Co., Ltd. Low frequency glatiramer acetate therapy
US9155776B2 (en) 2009-08-20 2015-10-13 Yeda Research & Development Co., Ltd. Low frequency glatiramer acetate therapy
USRE49251E1 (en) 2010-01-04 2022-10-18 Mapi Pharma Ltd. Depot systems comprising glatiramer or pharmacologically acceptable salt thereof
US8796226B2 (en) 2010-01-04 2014-08-05 Mapi Pharma Ltd. Depot systems comprising glatiramer or a pharmacologically acceptable salt thereof
US8377885B2 (en) 2010-01-04 2013-02-19 Mapi Pharma Ltd. Depot systems comprising glatiramer or pharmacologically acceptable salt thereof
US11419887B2 (en) 2010-04-07 2022-08-23 California Institute Of Technology Vehicle for delivering a compound to a mucous membrane and related compositions, methods and systems
US11103566B2 (en) 2010-05-20 2021-08-31 California Institute Of Technology Antigen specific Tregs and related compositions, methods and systems
US9625473B2 (en) 2010-10-11 2017-04-18 Teva Pharmaceutical Industries Ltd. Cytokine biomarkers as predictive biomarkers of clinical response for glatiramer acetate
US9200114B2 (en) 2011-04-21 2015-12-01 Mapi Pharma Ltd. Random pentapolymer for treatment of autoimmune diseases
US8759484B2 (en) 2011-07-11 2014-06-24 Momenta Pharmaceuticals, Inc. Evaluation of copolymer diethylamide
US9714898B2 (en) 2011-07-11 2017-07-25 Momenta Pharmaceuticals, Inc. Structure assessment of heterogeneous polypeptide mixture
US9095547B2 (en) 2011-07-11 2015-08-04 Momenta Pharmaceuticals, Inc. Structure assessment of heterogeneous polypeptide mixture
US8324348B1 (en) 2011-07-11 2012-12-04 Momenta Pharmaceuticals, Inc. Evaluation of copolymer diethylamide
US8765911B2 (en) 2011-07-11 2014-07-01 Momenta Pharmaceuticals, Inc. Evaluation of copolymer diethylamide
US9539281B2 (en) 2011-07-12 2017-01-10 The Brigham And Women's Hospital, Inc. Lipid-containing PSA compositions, methods of isolation and methods of use thereof
US9499868B2 (en) 2011-10-10 2016-11-22 Teva Pharmaceutical Industries, Ltd. Determination of single nucleotide polymorphisms useful to predict response for glatiramer acetate
EP2642290A1 (en) 2012-03-19 2013-09-25 Synthon BV Glatiramer acetate human monocytic cell line-based potency assay
WO2013139728A1 (en) 2012-03-19 2013-09-26 Synthon Bv Glatiramer acetate human monocyte cell-based potency assay
US9617596B2 (en) 2012-10-10 2017-04-11 Teva Pharmaceutical Industries, Ltd. Biomarkers predictive for clinical response for glatiramer acetate
WO2014060942A3 (en) * 2012-10-20 2014-10-23 Mahesh Kandula Compositions and methods of for the treatment of multiple sclerosis and neurodegenerative diseases
WO2014128079A1 (en) 2013-02-19 2014-08-28 Synthon B.V. Glatiramer acetate multidose formulation
US9702866B2 (en) 2013-04-26 2017-07-11 Synthon B.V. Glatiramer acetate human monocytic cell line-based potency assay
EP3118626A1 (en) 2013-04-26 2017-01-18 Synhton B.V. Glatiramer acetate human monocytic cell line-based potency assay
WO2014173463A1 (en) 2013-04-26 2014-10-30 Synthon Bv Glatiramer acetate human monocytic cell line-based potency assay
EP3118625A1 (en) 2013-04-26 2017-01-18 Synhton B.V. Glatiramer acetate human monocytic cell line-based potency assay
WO2014174070A1 (en) 2013-04-26 2014-10-30 Synthon B.V. Glatiramer acetate human monocytic cell line-based potency assay
US10772918B2 (en) 2013-05-10 2020-09-15 California Institute Of Technology Probiotic prevention and treatment of colon cancer
US9702007B2 (en) 2013-10-21 2017-07-11 Teva Pharmaceuticals Industries, Ltd. Genetic markers predictive of response to glatiramer acetate
US11331335B2 (en) 2015-06-10 2022-05-17 California Institute Of Technology Sepsis treatment and related compositions methods and systems
US10857177B2 (en) 2015-08-19 2020-12-08 President And Fellows Of Harvard College Lipidated PSA compositions and methods
US10539568B2 (en) 2015-11-23 2020-01-21 Chemi, S.P.A. RP-HPLC analysis of complex polypeptide mixtures
EP3170836A1 (en) * 2015-11-23 2017-05-24 Chemi SPA Rp-hplc analysis of complex polypeptide mixtures
US11491181B2 (en) 2016-07-15 2022-11-08 President And Fellows Of Harvard College Glycolipid compositions and methods of use
US11167003B2 (en) 2017-03-26 2021-11-09 Mapi Pharma Ltd. Methods for suppressing or alleviating primary or secondary progressive multiple sclerosis (PPMS or SPMS) using sustained release glatiramer depot systems

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