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Treatment of autoimmune conditions with Copolymer 1 and related copolymers

a technology of autoimmune conditions and copolymer, which is applied in the field of treating autoimmune conditions with copolymer 1 and related copolymers, can solve the problems of limiting the effectiveness of drugs, limiting the long-term treatment of autoimmune diseases, and difficult production of therapeutic compositions containing natural folded proteins, etc., to achieve the effects of preventing autoimmune diseases, blocking immune cell recognition and attack, and stimulating the growth and function of copolymer 1-specific t cells

Inactive Publication Date: 2010-11-25
PRESIDENT & FELLOWS OF HARVARD COLLEGE & YEDA RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0032]Surprisingly, Copolymer 1 and the Terpolymers of the present invention can be used to treat a variety of autoimmune diseases in a heterogeneous patient population. These Terpolymers can inhibit some of the physiological responses of T cells that attack self-antigens as these diseases progress. Moreover, Copolymer 1 and the Terpolymers of the present invention bind with high affinity to antigen presenting cells from different genetic backgrounds and to several class II MHC molecules to block immune cell recognition and attack. In addition, the Terpolymers can stimulate the growth and functioning of Copolymer 1-specific T cells to further treat and prevent various autoimmune diseases.

Problems solved by technology

However, these agents can be toxic when used for more than short periods of time or cause undesirable side effects.
However, therapeutic compositions containing natural folded proteins are often difficult to produce, formulate, store, and deliver.
Moreover, the innate heterogeneity of the immune system can limit the effectiveness of drugs and complicate long-term treatment of autoimmune diseases.

Method used

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  • Treatment of autoimmune conditions with Copolymer 1 and related copolymers
  • Treatment of autoimmune conditions with Copolymer 1 and related copolymers
  • Treatment of autoimmune conditions with Copolymer 1 and related copolymers

Examples

Experimental program
Comparison scheme
Effect test

example i

Preparation of Polypeptides

Preparation of Protected Polypeptides

[0100]Protected polypeptides are prepared as described by Teitelbaum et al., using the N-carboxyanhydride (NCA) blocked amino acids tyrosine, alanine, glutamic acid and trifluoroacetyllysine dissolved in dioxane. 1 EUR. J. IMMUN. 242 (1971). The carboxylate group on glutamic acid is blocked with a benzyl (BZ) group.

[0101]The polymerization process is initiated by the addition of 0.01-0.02% diethylamine. The reaction mixture is stirred at room temperature for 20 hours and then poured into water. The protected polypeptide product is filtered, washed with water and dried. The removal of the γ-benzyl blocking groups from the glutamate residue is carried out by treating the protected polypeptide 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 protected polypeptide.

Preparing Polypeptides with Mo...

example 2

Low Molecular Weight Polypeptides

In Vivo Tests

[0123]Three batches of copolymer-1 having an average molecular weight of 7.3 and 8.4 KDa (less than 2.5% copolymer-1 species over 40 KDa) and 22 KDa (more than 5% copolymer-1 species over 40 KDa) were subjected to the toxicity test described below. Five mice were used in each experimental group.

Method

[0124]Copolymer-1 is dissolved in distilled water to yield a solution of 2 mg / ml of the active ingredient. Each mouse is injected with 0.5 ml 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 is designated “non-toxic”. If, however, one or more of the mice had died or had shown adverse signs, then the batch is designated “toxic”.

Results

[0125]Three of five mice died after 48 hou...

example 3

Suppression of EAE by the Polypeptides

[0131]Injection of Copolymer 1 in incomplete Freund's adjuvant before disease induction can suppress experimental allergic encephalomyelitis (EAE). This suppression appears to be mediated by Copolymer 1-specific suppressor T cells of the TH2 type which cross react with myelin basic protein. Lando et al., 123 J. IMMUNOL. 2156 (1979); Aharoni et al., 17 EUR. J. IMMUNOL. 23 (1993); Aharoni et al., 94 PROC. NATL. ACAD. SCI. USA 10821 (1997). Other researchers have observed that the therapeutic effect of Copolymer 1 in multiple sclerosis patients is also associated with the induction of TH2 cells. Lahat et al., 244 J. Neurol. 129 (1997). In this example, EAE is suppressed to by different polypeptides of the present invention.

Methods

Copolymer 1

[0132]Copolymer 1 batches # 02095 and 55495, with average molecular weights of 6000 Da and 5800 Da, respectively, were obtained from Teva Pharmaceutical Industries (Petach Tikva, Israel).

Terpolymers

[0133]Four te...

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PUM

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Abstract

The present invention is directed to polypeptides containing at least three amino acids randomly joined in a linear array; wherein at least one of the three amino acids is an aromatic amino acid, at least one of the three amino acids is a charged amino acid and at least one amino acid is an aliphatic amino acid. In a preferred embodiment the polypeptide contains three or four of the following amino acids: tyrosine, alanine, glutamic acid or lysine. According to the present invention, the present polypeptides bind to antigen presenting cells, purified human lymphocyte antigens (HLA) and / or Copolymer 1-specific T cells. Moreover, according to the present invention, these polypeptides can be formulated into pharmaceutical compositions for treating autoimmune disease. The present invention further contemplates methods of treating an autoimmune disease in a mammal by administering a pharmaceutically effective amount of any one of the present polypeptides to the mammal.

Description

RELATED APPLICATIONS[0001]The present application is a divisional of U.S. Ser. No. 09 / 768,872, filed Jan. 23, 2001 which is a continuation of PCT / US99 / 16747, filed Jul. 23, 1999, which claims the benefit of provisional applications 60 / 093,859 filed Jul. 23, 1998, 60 / 101,825, filed Sep. 25, 1998, 60 / 102,960, filed Oct. 2, 1998, 60 / 106,350, filed Oct. 30, 1998, and 60 / 108,184, filed Nov. 12, 1998, all of which are incorporated by reference herein.GOVERNMENT FUNDING[0002]This invention was made in part with government support under grant CA47554 awarded by the National Institutes of Health. The government has certain rights in the invention.INTRODUCTION[0003]The present invention provides compositions and methods for treating autoimmune diseases using therapeutically effective amounts of a polypeptide related to Copolymer 1. Copolymer 1 is a heterogeneous mixture of synthetic random linear copolymers of tyrosine, alanine, glutamic acid and lysine and, in appropriate therapeutic amounts...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/02A61P37/00A61P19/02A61P25/28A61P29/00
CPCA61K38/16G01N33/6842A61K31/785C08G73/02Y10S514/886Y10S514/885Y10S514/866Y10S514/903Y10S424/81A61P19/02A61P25/28A61P29/00A61P37/00
Inventor AHARONI, RINATEITELBAUM, DVORAARNON, RUTHSELA, MICHAELFRIDKIS-HARELI, MASHASTROMINGER, JACK L.
Owner PRESIDENT & FELLOWS OF HARVARD COLLEGE & YEDA RES
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