EP1427755A2 - Utilisation de peptides comportant des modifications de type post-traductionnel dans le cadre du traitement de pathologies auto-immunes - Google Patents
Utilisation de peptides comportant des modifications de type post-traductionnel dans le cadre du traitement de pathologies auto-immunesInfo
- Publication number
- EP1427755A2 EP1427755A2 EP02798771A EP02798771A EP1427755A2 EP 1427755 A2 EP1427755 A2 EP 1427755A2 EP 02798771 A EP02798771 A EP 02798771A EP 02798771 A EP02798771 A EP 02798771A EP 1427755 A2 EP1427755 A2 EP 1427755A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- lysine
- sequence seq
- serine
- acetylated
- phosphorylated
- 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.)
- Ceased
Links
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Classifications
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
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- A—HUMAN NECESSITIES
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- 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]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the subject of the present invention is new peptides transformed so as to include post-translational type modifications, such as phosphorylation or acetylation of one or more amino acids.
- the invention also relates to their production methods, and to their uses in pharmaceutical compositions in the context of
- the identification of the sequences of the 70K protein recognized by the self-reactive T cells began in 1998.
- the inventors first synthesized 20 overlapping peptides covering the sequence of the 70K protein and studied the recognition of these peptides by the antibodies of MRL / lpr lupus mice as well as the self-reactive CD4 + T cells of these mice.
- these 20 peptides they identified the peptide corresponding to the sequence 131-151 (RIHMVYSKRSGKPRGYAFIEY) of the protein 70K recognized very early by the antibodies of these mice (Monneaux et al, 2000).
- This peptide is capable of stimulating in vitro the proliferation and the secretion of IL-2 of CD4 + T cells purified from the lymph nodes.
- this sequence also represents a major epitope of the 70K protein in another lupus mouse model, the NZB / W mouse (FIG.
- the peptide 131-151 is moreover capable of binding to various class II molecules of the major histocompatibility complex (both murine and human; FIG. 2).
- This universal character constitutes an advantage for the use of this sequence in the development of therapeutic strategies in the context of human systemic lupus erythematosus.
- the inventors then wished to determine the exact nature of the sequence of the 70K protein capable of activating the self-reactive T cells.
- the inventors synthesized several peptides corresponding to the phosphorylated and acetylated forms on the serine and lysine residues of peptide 131-151, and studied the capacity of these peptides to be recognized by the T lymphocytes and the antibodies of lupus mice.
- the present invention follows from the demonstration by the Inventors that these phosphorylated and acetylated peptides are recognized in an equal or even superior manner to the parent peptide which is not phosphorylated and not acetylated by CD4 + T cells and the antibodies of lupus mice, and that DNA administration of these phosphorylated and acetylated peptides decreases the production of high levels of antibodies directed against DNA, delays the onset of glomerulonephritis and prolongs the survival of animals, while the parent peptide does not, on the other hand, induce any statistically significant effect .
- the object of the present invention is to provide new peptides which can be used for the preparation of medicaments in the context of the treatment of autoimmune diseases, and more particularly lupus, having the advantage of being significantly more effective than the peptides used up to now.
- the modified peptides of the invention are specific for deleterious cells and target only these cells, unlike immunosuppressants, cytokines, or other molecules currently used which act globally on the immune system.
- the subject of the invention is the use of peptides comprising epitopes of mammalian self proteins recognized by antibodies produced by the immune system of mammals suffering from autoimmune pathologies, and, where appropriate, by T cells. auxiliaries of said mammals, said epitopes being such that at least one of their amino acids comprises a modification of the post-translational type, for the preparation of a medicament intended for the prevention or treatment of said autoimmune pathologies.
- post-translational type modification is meant in what precedes and what follows, any type of modification of the amino acids of a given protein capable of occurring in vivo in the cells of the organism, such as the phosphorylation processes. , acetylation, or other.
- a more particular subject of the invention is the aforementioned use of peptides as defined above, comprising epitopes of which at least one of their amino acids is modified so that it is in a phosphorylated form, or acetylated.
- the invention relates more particularly to the aforementioned use of peptides comprising epitopes derived from proteins of human or animal origin defined above, said proteins being chosen from nucleoproteins, proteins from the nucleosome, from the spliceosome, from the ribonucleoprotein particle Ro , or ribosome for example.
- the invention also relates to the use of peptides as defined above, for the preparation of a medicament intended for prevention or treatment:
- non-specific systemic organ diseases such as systemic lupus erythematosus (LED), rheumatoid arthritis, mixed connectivity, Sjôgren syndrome, or chronic juvenile arthritis .
- autoimmune organ pathologies such as multiple sclerosis, insulin-dependent diabetes, Crohn's disease, or oily diseases.
- a more particular subject of the invention is the use of peptides as defined above, for the preparation of a medicament intended for the prevention or treatment of
- the invention relates more particularly to the aforementioned use of peptides comprising epitopes derived from the human or murine protein U1-70K of the spliceosome (described in particular in Klein Gunnewiek et al, 1997).
- a more particular subject of the invention is also the above-mentioned use of peptides comprising the sequence delimited by amino acids 131 and 151 of the human or murine protein U1-70K, and corresponding to the following sequence SEQ ID NO: 1: RIHMVYSKRSGKPRGYAFIEY in which at least one of the amino acids comprises a modification of the post-translational type, in particular in which at least one of the amino acids is phosphorylated, or acetylated.
- the invention relates more particularly to the aforementioned use of peptides comprising the sequence SEQ ID NO: 1 in which at least one of the serine residues in position 7 or 10 is phosphorylated, and / or at least one of the lysine residues in position 8 or 12 is acetylated. :
- a more particular subject of the invention is the aforementioned use of peptides comprising the sequence SEQ ID NO: 1 in which:
- the invention more particularly still relates to the aforementioned use of peptides chosen from the following:
- a more particular subject of the invention is also the above-mentioned use of peptides chosen from the following:
- sequence SEQ ID NO: 1 in which the serine in position 7 is phosphorylated the sequence SEQ ID NO: 1 in which the serine in position 10 is phosphorylated
- the invention also relates to any pharmaceutical composition characterized in that it comprises at least one peptide chosen from those defined above, in combination with a pharmaceutically acceptable vehicle.
- the invention more particularly relates to any pharmaceutical composition as defined above, characterized in that it comprises at least one peptide chosen from those comprising the sequence SEQ ID NO: 1 in which at least one of the amino acids involves a modification of the post-translational type, in particular by phosphorylation, or acetylation.
- the invention relates more particularly to any pharmaceutical composition as defined above, characterized in that it comprises at least one peptide chosen from those comprising the sequence SEQ ID NO: 1 in which at least one of the serine residues in position 7 or 10 is phosphorylated, and / or at least one of the lysine residues in position 8 or
- a more particular subject of the invention is any pharmaceutical composition as defined above, characterized in that it comprises at least one peptide chosen from those comprising the sequence SEQ ID NO: 1 in which:
- the serine in position 7 is phosphorylated, and / or the serine in position 10 is phosphorylated,
- the invention more particularly still relates to any pharmaceutical composition as defined above, characterized in that it comprises at least one peptide chosen from the following:
- the invention more particularly relates to any pharmaceutical composition as defined above, characterized in that it comprises at least one peptide chosen from the following: - the sequence SEQ ID NO: 1 in which the serine in position 7 is phosphorylated,
- the abovementioned pharmaceutical compositions of the invention are characterized in that they are in a form which can be administered by the systemic route (namely by the intravenous, intramuscular, intraperitoneal, subcutaneous route), or non-invasive (for example intranasal route) , oral, or epicutaneous).
- the abovementioned pharmaceutical compositions of the invention are characterized in that the daily doses of peptides in humans are from approximately 100 ng to approximately 5 mg.
- the invention also relates to the peptides comprising the sequence delimited by amino acids 131 and 151 of the human U1-70K protein, or murine, and corresponding to the following sequence SEQ ID NO: 1: RIHMVYSKRSGKPRGYAFIEY in which one at least of the amino acid is phosphorylated, or acetylated.
- a more particular subject of the invention is the above-mentioned peptides, comprising the sequence SEQ ID NO: 1 in which at least one of the serine residues in position 7 or 10 is phosphorylated, and / or one at least of the lysine residues in position 8 or 12 is acetylated.
- the invention relates more particularly to the above-mentioned peptides, comprising the sequence SEQ ID NO: 1 in which:
- the invention relates more particularly still to the following peptides: the sequence SEQ ID NO: 1 in which the serine in position 7 is phosphorylated,
- sequence SEQ ID NO: 1 in which the lysine in position 8 is acetylated the sequence SEQ ID NO: 1 in which the lysine in position 12 is acetylated
- the phosphorylated peptides PI 37 (corresponding to the sequence SEQ ID NO: 1 in which the serine in position 7 is phosphorylated), and P140 (corresponding to the sequence SEQ ID NO: 1 in which the serine in position 10 is phosphorylated), and the acetylated peptides Acl38 (corresponding to the sequence SEQ ID NO: 1 in which the lysine in position 8 is acetylated), Acl42 (corresponding to the sequence SEQ ID NO: 1 in which the lysine in position 12 is acetylated), and Acl38 + 142 (corresponding to the sequence SEQ ID NO: 1 in which the lysine at position 8 and that at position 12 are acetylated), as well as the scrambled peptide Se: YVSRYFGSAIRHEPKMKIYRG, and the scrambled peptide ScP corresponding to Se in which the serine in position 8 is phosphorylated, (used as negative controls in the tests which follow) corresponding respectively to the
- the protein 70K being strongly phosphorylated in vivo (Woppmann et al, 1993), and although the number of phosphorylated sites and their identity are not known, the inventors have synthesized several peptides corresponding to the phosphorylated and acetylated forms respectively on the serine and lysine residues of peptide 131-151, and studied the capacity of these peptides to be recognized by T lymphocytes and antibodies from lupus mice. The inventors demonstrate in the context of the present invention that the phosphorylated peptide in position 140 is recognized in an equal or even superior manner to the non-phosphorylated peptide by CD4 + T cells and the antibodies of lupus mice (FIG. 13).
- the two peptides (phosphorylated at position 140 and not phosphorylated) were used for a study of restoration of self-tolerance. These two peptides were injected intravenously and intranasally into pre-auto mice, and the course of the disease in these mice was monitored.
- the 3 acetylated peptides are at least as well or even better recognized than the parent peptide by the CD4 + T cells of normal mice immunized against the unmodified peptide: the proliferation rates are higher, the IL2 secretion rates are equivalent and the interferon ⁇ production rates are higher,
- the 3 acetylated peptides are at least as well or even better recognized than the parent peptide by the CD4 + T cells of autoimmune mice: the proliferation rates are higher,
- the 3 acetylated peptides are recognized by the antibodies of mice directed against the parent peptide.
- the inventors have demonstrated that the peptides 131-151 and PI 40 are capable of binding various human MHC class II molecules (HLA-DR1, -DR4 and -DRU) (Figure 19).
- CD4 + T lymphocytes (A) from MRL / lpr lupus mice; the graph on the left represents the proliferation of CD4 + T cells expressed in stimulation indices as defined above in the presence of the peptide 131-151, phosphorylated peptides PI 37 and PI 40 and two scrambled peptides phosphorylated or not (Se and ScP); the positivity limit corresponds to 2.0; the graph on the right represents the secretion of IL-2 (mU / ml) in the presence of peptide 131-151, peptides P137 and P140 and peptides Se and ScP.
- A CD4 + T lymphocytes
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- Animal Behavior & Ethology (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
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- Toxicology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Gastroenterology & Hepatology (AREA)
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- Obesity (AREA)
- Dermatology (AREA)
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Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP10183969A EP2338908A1 (fr) | 2001-09-18 | 2002-09-18 | Peptides comportant des modifications de type post-translationnel et leur utilisation dans le cadre du traitement de pathologies auto-immunes |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0112041 | 2001-09-18 | ||
| FR0112041A FR2829768B1 (fr) | 2001-09-18 | 2001-09-18 | Utilisation de peptides comportant des modifications de type post-traductionnel dans le cadre du traitement de pathologies auto-immunes |
| PCT/FR2002/003186 WO2003025014A2 (fr) | 2001-09-18 | 2002-09-18 | Utilisation de peptides comportant des modifications de type post-traductionnel dans le cadre du traitement de pathologies auto-immunes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1427755A2 true EP1427755A2 (fr) | 2004-06-16 |
Family
ID=8867384
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP02798771A Ceased EP1427755A2 (fr) | 2001-09-18 | 2002-09-18 | Utilisation de peptides comportant des modifications de type post-traductionnel dans le cadre du traitement de pathologies auto-immunes |
| EP10183969A Withdrawn EP2338908A1 (fr) | 2001-09-18 | 2002-09-18 | Peptides comportant des modifications de type post-translationnel et leur utilisation dans le cadre du traitement de pathologies auto-immunes |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP10183969A Withdrawn EP2338908A1 (fr) | 2001-09-18 | 2002-09-18 | Peptides comportant des modifications de type post-translationnel et leur utilisation dans le cadre du traitement de pathologies auto-immunes |
Country Status (7)
| Country | Link |
|---|---|
| US (3) | US7872098B1 (https=) |
| EP (2) | EP1427755A2 (https=) |
| JP (1) | JP4160505B2 (https=) |
| AU (1) | AU2002362383B2 (https=) |
| CA (1) | CA2460704A1 (https=) |
| FR (1) | FR2829768B1 (https=) |
| WO (1) | WO2003025014A2 (https=) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE60234843D1 (de) * | 2001-09-06 | 2010-02-04 | Centre Nat Rech Scient | Modifizierte peptide und deren verwendung zur behandlung von autoimmunkrankheiten |
| FR2931360B1 (fr) * | 2008-05-20 | 2012-05-18 | Centre Nat Rech Scient | Nanoparticules contenant un peptide, vecteurs les contenant et utilisations pharmaceutiques desdits nanoparticules et vecteurs |
| ES2618402T3 (es) * | 2011-12-13 | 2017-06-21 | Centre National De La Recherche Scientifique | Péptidos modificados y su uso para tratar enfermedades autoinmunitarias |
| US10213482B2 (en) | 2014-12-12 | 2019-02-26 | Immupharma France Sa | Methods of treating chronic inflammatory diseases |
| WO2021198135A1 (en) * | 2020-03-29 | 2021-10-07 | Immupharma France Sa | Method of treating viral infections |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE60234843D1 (de) * | 2001-09-06 | 2010-02-04 | Centre Nat Rech Scient | Modifizierte peptide und deren verwendung zur behandlung von autoimmunkrankheiten |
-
2001
- 2001-09-18 FR FR0112041A patent/FR2829768B1/fr not_active Expired - Lifetime
-
2002
- 2002-09-18 US US10/489,967 patent/US7872098B1/en active Active
- 2002-09-18 CA CA002460704A patent/CA2460704A1/fr not_active Abandoned
- 2002-09-18 EP EP02798771A patent/EP1427755A2/fr not_active Ceased
- 2002-09-18 AU AU2002362383A patent/AU2002362383B2/en not_active Expired
- 2002-09-18 EP EP10183969A patent/EP2338908A1/fr not_active Withdrawn
- 2002-09-18 JP JP2003528859A patent/JP4160505B2/ja not_active Expired - Lifetime
- 2002-09-18 WO PCT/FR2002/003186 patent/WO2003025014A2/fr not_active Ceased
-
2010
- 2010-10-27 US US12/913,232 patent/US8475800B2/en not_active Expired - Lifetime
-
2013
- 2013-06-11 US US13/914,997 patent/US20140004136A1/en not_active Abandoned
Non-Patent Citations (1)
| Title |
|---|
| See references of WO03025014A2 * |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2829768B1 (fr) | 2003-12-12 |
| FR2829768A1 (fr) | 2003-03-21 |
| US20140004136A1 (en) | 2014-01-02 |
| JP2005510469A (ja) | 2005-04-21 |
| EP2338908A1 (fr) | 2011-06-29 |
| US7872098B1 (en) | 2011-01-18 |
| WO2003025014A2 (fr) | 2003-03-27 |
| US20120149652A1 (en) | 2012-06-14 |
| WO2003025014A3 (fr) | 2004-02-19 |
| US8475800B2 (en) | 2013-07-02 |
| JP4160505B2 (ja) | 2008-10-01 |
| CA2460704A1 (fr) | 2003-03-27 |
| AU2002362383B2 (en) | 2008-10-09 |
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Inventor name: GUILLET, JEAN-GERARD Inventor name: GUICHARD, GILLES Inventor name: BRIAND, JEAN-PAUL Inventor name: MONNEAUX, FANNY, SYLVIE, MICHELE Inventor name: MULLER, SYLVIANE |
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