EP0804475A1 - Polypeptides et leur utilisation dans le traitement et la prophylaxie de maladies auto-immunes - Google Patents

Polypeptides et leur utilisation dans le traitement et la prophylaxie de maladies auto-immunes

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Publication number
EP0804475A1
EP0804475A1 EP95932816A EP95932816A EP0804475A1 EP 0804475 A1 EP0804475 A1 EP 0804475A1 EP 95932816 A EP95932816 A EP 95932816A EP 95932816 A EP95932816 A EP 95932816A EP 0804475 A1 EP0804475 A1 EP 0804475A1
Authority
EP
European Patent Office
Prior art keywords
seq
ala
val
leu
gly
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP95932816A
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German (de)
English (en)
Inventor
Stephen James Thompson
Christopher John Elson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi Pasteur Holding Ltd
Original Assignee
Peptide Therapeutics Ltd
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Filing date
Publication date
Application filed by Peptide Therapeutics Ltd filed Critical Peptide Therapeutics Ltd
Publication of EP0804475A1 publication Critical patent/EP0804475A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/35—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Mycobacteriaceae (F)
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies

Definitions

  • the present invention relates to polypeptide fragments, to their use in the prevention, diagnosis and treatment of auto-immune disease such as rheumatoid arthritis, and to methods of preparing these fragments.
  • Autoimmune diseases are thought to arise as a result of similarities between a foreign molecule or antigen and a molecular structure of the organism itself. Chronic forms of arthritis are thought to involve autoimmunity to constituents of the joints in particular of the connective tissues of the body.
  • RA Rheumatoid arthritis
  • pristane-induced arthritis This model is based upon the finding that a proportion of mice injected intraperitoneally with the paraffin oil pristane (2, 6, 10, 14-tetramethylpentadecane) develop a chronic T-cell dependent inflammatory arthritis between 60 and 200 days later depending on the strain of mice [Potter M, J. Immunol. (1981) 127:1591, Bedwell et al, J. Immunol. (1987) 25:393, Wooley et al. Arthritis. Rheum. (1987 ) 32:1022, Wooley et al, Arthritis. Rheum.
  • heat shock proteins are immunodominant antigens in a number of infectious diseases, such as tuberculosis and leishmania. These infectious diseases can have similar abnormalities as observed in RA such as raised agalactosyl-IgG levels, the organs involved and range of autoantibodies presen . Since environmental factors are clearly important in RA, microbial agents and hence hsp's were implicated.
  • Hsps are grouped in gene families according to their molecular weight and sequence homology within individual groups.
  • hsp60 (60KD) gene family includes members hsp65 (mycobacterial) and hsp58 (mammalian) .
  • mice proliferate more vigorously in vitro in response to hsp65 than T-cells from age matched normal or non-arthritic mice. Furthermore, if the mice are immunised with hsp65 in incomplete Freud's adjuvant (IFA) prior to pristane challenge, the disease will not develop [Thompson et al , Eur. J. Immunol. (1990) 20:2479 and Thompson et al, Autoimmunity, (1991) 11:89] . This protective effect is specific to hsp65 and is not induced by the E.coli equivalent GroEl or other unrelated antigens [Thompson et al, Eur. J.
  • mice become sensitised to hsp by exposure to microbial flora in the environment and that this process is necessary for the induction of arthritis by pristane injection. If so, it would be predicted that there is a relationship between sensitisation to hsp65 and susceptibility to PIA. Experiments carried out by the applicants suggest that this hypothesis is correct.
  • hsp 58 has been detected in the joints of patients with RA [Karlsson-Parra et al, Scand. J. Immunol. (1990) 31:283] and T-cells from mice with PIA react with joint extracts [Thompson et al, Eur. J. Immunol. (1990) 20:2479] it seems reasonable to postulate that hsp58 could be a target antigen in the joints of mice developing PIA.
  • mice with PIA and animals protected from the development of arthritis by hps65 preimmunisation exhibit elevated immune responses to the 65kD mycobacterial heat shock protein. It would be expected that only mice with PIA should develop autoimmune responses to the 60kD family of hsps whereas the response of mice pre-immunised with hsp65 should be restricted to microbial specific determinants . In other words, the response elicted by immunisation with hps65 in IFA differs from that induced by sensitisation with environmental/bowel microorganisms.
  • T cell-mediated response to mycobacterial antigens has been implicated in the pathogenesis of inflammatory arthritis both in experimental animal models and in man. In adjuvant arthritis in rats, it has been established that the disease can be initiated by T cell clones specific for the 65-kDa mycobacterial heat-shock protein.
  • Rats may also be protected to subsequent adjuvant arthritis induction by pre-immunisation with either a 65 KDa specific T cell line or with the hsp itself (Van Eden et al. , Nature, 1988, 331:171 and Holoshitz et al. , Science 1983, 219:56) .
  • EP-A-322990 describes polypeptides having amino acid sequence 172-192 of a bacterial hsp65 and their use as immunogens for inducing resistance to auto-immune disease.
  • WO 92/04049 discloses that a peptide comprising the amino acid sequence corresponding to positions 180 - 186 of the Mvcobacterium tuberculosis protein hsp65 is effective in the prevention and treatment of immune-related disease such as autoimmune arthritis .
  • the present invention provides a polypeptide of 9 or more amino acid residues which comprises the sequence
  • VVNKIRG (SEQ ID 107 ) or a homologue or functional equivalent or mimetic thereof .
  • the polypeptide may preferably consist of up to a total of 21 amino acid residues , more preferably it may consist of 9 to 11 residues .
  • the 7-mer sequence defined above ' (or its homologous or functional equivalents or mimetics) may be referred to hereafter as "the motif" of the present invention. This motif corresponds to the sequence 261-267 of microbial (mycobacterial) hsp65.
  • the invention also provides a polypeptide of up to 21 amino acid residues which comprises or consists of the sequence
  • polypeptide sequence corresponds to amino acids 261- 271 of microbial hsp65 .
  • the full sequence of microbial hsp65 is shown for example in EP-A- 262 710 .
  • this reference describes a microbial hsp65 from Mvcobacterium bovis .
  • there is substantial sequence homology between microbial hsp65s (generally in excess of 60% and up to 98% ) and so the corresponding region of any microbial hsp65 can be identified and falls within the scope of the present invention.
  • E x a mp le s of the polypeptides of the invention also include fra g ment s of microbial hsp65 protein including the motif , such as amino acid residues 251-267 (SEQ ID 51) .
  • polypeptides of the invention have been found to have a protective effect against auto- immune disease and in particular against the onset of RA when used in a preimmunisation procedure .
  • these polypeptides presented in this way would be expected to induce T H 2 cells , they would also be of use in the treatment of RA .
  • the invention further provides a vaccine for the prophylactic or therapeutic immunisation of a patient against auto- immune disease such as RA, which vaccine comprises a polypeptide as described above .
  • the polypeptide is suitably administered parenterally for example sub-cutaneously , intramuscularly, intravenously or intraperitoneally .
  • the polypeptide may also be administered in a trans -mucosal membrane manner , for example orally or nasally or in the form of a suppository .
  • polypeptides of the invention are suitably administered in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier or excipient .
  • Such compositions form a further aspect of the invention .
  • Suitable carriers include liquid carriers such as oils or water .
  • Suitable carriers also include solid carriers which may, for example , provide formulations including tablets or suspensions for oral administration or suppositories .
  • Th e composi t ions or formulations including the polypeptide of the inven t ion as active ingredient may be adapted for nasal a d minis t ra t ion by inhalers, atomizers or sprays as are available
  • polypeptides of the invention can be produced using various techniques which would be apparent to the skilled person. For example, they may be obtained by fragmentation of microbial hsp65 using conventional techniques after which the desired fragments obtained by purification, again using techniques which are known in the art. However peptides obtained by this method are less likely to have the precisely the desired length.
  • polypeptides may be obtained using recombinant DNA technology.
  • the nucleotide sequence encoding the desired polypeptide can be incorporated into a suitable host using a vector system which causes expression of the polypeptide.
  • polypeptides sequences may be generated entirely synthetically using standard chemical methods or peptide synthesizers available in the art.
  • the expression 'homolog-ue' refers to peptides having an amino acid sequence which is are at least 60%, preferably 70% and most preferably at least 80% homologous to the described polypeptide.
  • the expression 'functional equivalent' ' or 'mimetic' relates to any chemical, which may be a peptide or other organic chemical which produces similar effects in vivo to the compounds of the present invention. In particular, such compounds will produce a protective immunogenic response against RA which is better than that obtained using whole hsp65 when applied in pristane-induced arthritis model using tests as described in the examples hereinafter.
  • Figure 1 is the peptide library comprising eleven pools of overlapping peptides corresponding to the entire sequence of microbial hsp65 which are used in the examples;
  • Figure 3 shows the results of an experiment to investigate the stimulation of T-cell responses in-vitro from hsp65 pre-immunised mice using a peptide derived from microbial hsp65;
  • Figure ⁇ + shows the results of studies to determine the protection against PIA of mice pre-immunised with certain polypeptides .
  • Figure 7 shows the effect of adding increasing amounts of "Cold” viral Haemagglutinin upon binding of 20 ⁇ g of biotinylated polypeptide (hsp 261-271: SEQ ID 108) to class II receptors on human EBV-transformed B-cell lines;
  • Figure 8 shows dose-dependant binding of biotinylated polypeptide (hsp 261-271: SEQ ID 108) to class II receptors on human EBV-transformed B-cell lines;
  • Figure 9 shows the cytokine profile of T cells stimulated with peptide fragment hsp 261-271 of the invention or whole hsp65.
  • Example 1 Proliferation of T cells in-vitro from PIA mice, hsp65 protected mice and normal age-matched mice.
  • CBA/Igb mice Male CBA/Igb mice aged between 4 and 8 weeks were used unless otherwise specified. CBA/Igb mice were obtained by back-crossing (101 strain x CBA) FI hybrids to CBA mice and selecting those mice with Igb allotype in their serum.
  • mice Artiir t s induction by pris tane .
  • One group of six mice were immunised intraperitoneally with 50 micrograms of mycobacterial hsp65 administered as an emulsion in incomplete Freuds adjuvant (IFA) .
  • This group formed the protected group of mice.
  • After ten days, this group and a further group of S mice received two intraperitoneal injections of 0.5ml of pristane 50 days apart (Aldrich Chemical Co., Milwaukee, WI.) in order to induce arthritis.
  • a final group of 'normal' mice were maintained as controls.
  • Synthetic peptides used as antigens in immunisation studies were synthesised using a simultaneous multiple-peptide solid phase synthetic method [Houghton R.A. Proc. Natl. Acad. Sci. USA. (1985) 82:5131] using a polyamide resin [Arshady et al, J. Chem. Soc. Perkin Trans. (1981) 1.529] and FMOC chemistry.
  • the complete library is shown in Figure 1.
  • Completed peptides were extracted from the resin using trifluoroacetic acid and suitable scavengers, arid isolated by solvent evaporation and precipitation with ethanol and diethylether. Purity was checked by amino acid analysis and by HPLC. Irrelevant control antigens BSA and human IgG were also used along with the mitogen ConA.
  • T-cells and APC for cul ture .
  • spleens of individual mice were aseptically removed and single cell suspensions made in a Petri dish containing RPMI-1640 medium supplemented with 20mM HEPES (pH 7.2, Flow Labs) .
  • Erythrocytes were removed by treating the spleen cells with 0.83% (w/v) NH4C1 solution buffered with Tris (pH 7.2) .
  • cells were suspended in RPMI-1640 HEPES at 1.25 x 10 7 cells/ml.
  • Responder T cells were enriched according to the panning method of Engleman et al [Engle an et al. J. Immunol.
  • T cell enriched fractions were then used as the T cell enriched fractions. A purity of .85% was achieved as assessed by anti-Thy 1.2 staining using flow cytometry (FACScan, Becton Dickinson Ltd. , Oxford, GB) . Normal mouse spleen cells were used as antigen presenting cells. In these experiments the APC were irradiated 1000 rads from a caesium source (Gravatom Industries, Gosport, GB) .
  • HEPES and 0.5% fresh normal mouse serum were obtained from 1.25 x 10 ⁇ purified splenic T-cells plus 1.25 x 10* .APC per ml, in a volume of 2ml in a 24 well plate
  • the cells were then harvested onto glass fibre filter mats (Whatman Ltd., Maidstone, GB) using a multiple sample harvester (Skatron AS, Lier, Norway) and the 3 H-Thymidine incorporated into newly synthesized DNA measured using conventional liquid scintillation procedures with a LKB rackbeta counter (LKB-Wallac Ltd., Pharmacia, Uppsala, Sweden) .
  • a ' "group of hsp65 preim unised or PIA protected animals were prepared in accordance with the procedures described in Example 1. Following essentially the same procedure, spleen cells from the mice were cultured and then challenged with antigen
  • mice against PIA Protection of mice against PIA by immunisation with microbial Hsp65 fragments
  • mice Male CBA/Igb mice aged between 4 and 8 weeks as described in Example 1 were used unless otherwise specified.
  • mice were immunised intraperitoneally 10 days before pristane challenge as follows:
  • mice pre-immunisation polypeptide
  • each polypeptide was administered as an emulsion in IFA.
  • the polypeptide fragments used in the pre-immunisation of group 3 was manufactured by Cambridge Research Biochemicals of Northwich, Cheshire, UK.
  • Arthritis induction by pris tane Arthritis was then induced as described in Example 1 by two intraperitoneal injections of 0.5ml of pristane 50 days apart. The animals were examined for the incidence of arthritis in the ankle joints at various time points. The final incidence was assessed 200 days post pristane injection. The arthritis was assessed by measuring the ankle joints with a micrometer. In CBA/Ig° mice the swollen joints ranged in size from 3.0-4.0mm compared with normal joints which had a range from 2.5-2.8mm. However, this difference could easily be distinguished, and in most experiments the joints were assessed visually, arthritis being scored at present or absent [Thompson et al, Eur. J. Immunol. (1990) 20:2479 and Barker et al, Autoimmunity. (1992) 14:73] .
  • Figure 5 shows the results of an experiment to assess the therapeutic efficacy of a peptide according to the invention in treatment of PIA.
  • 50 microgrammes of peptide was administered ip as an emulsion in IFA to each mouse at day 60. This treatment followed two pristane injections, 50 days apart, one at day 0 and one at day 50. Day 60 is judged to be the stage just prior to the development/onset phase of PIA. Strikingly, the polypeptide hsp 261-271 appears to have completely prevented the onset of PIA symptoms in all mice. The percentage arthritis was assessed both by visual scoring and histological scoring.
  • Figure 6 shows the results of an experiment to assess the prophylactic efficacy of a peptide according to the invention in prevention of PIA.
  • peptide was administered 10 days prior to the first pristane injection (day -10) .
  • two pristane injections were given 50 days apart, one at day 0 and one at day 50.
  • the results show that pre-immunisation with, peptide according to the invention significantly reduces the percentage of arthritis. 21
  • Figure 7 there is shown the effect of adding increasing amounts of "Cold” viral Haemagglutinin upon the binding of 20 microgrammes of biotinylated peptide fragment hsp 261-271 to class II on human EBV- ransformed B-cell lines.
  • Figure 7 shows the effects of increasing dose of non-biotinylated (“Cold”) viral Haemagglutinin (which binds indiscriminately to class II receptors) upon the percentage binding by a fixed concentration of biotinylated hsp 261-271.
  • FIG 8 shows the dose-dependent binding of biotinylated hsp 261-271 to either the SW or SF cell lines.
  • the SW B-cell line has a greater affinity for the peptide, with peak binding (about 60%) occurring at 50 microgrammes peptide. At higher doses of peptide the percentage binding decreases.
  • the SF B-cell line binds little or no peptide at concentrations up to 50 microgrammes, after which the percentage binding increases with concentration of peptide utilised.
  • the data from Figures 7 and 8 appears to show that, at low concentrations, viral Haemagglutinin actually potentiates the binding of the biotinylated peptide to both cell lines (e.g.
  • Figure 9 shows results from an experiment to determine the cytokine profile of T-cells from mice in response to various stimulation protocols .
  • the first two sets of data in figure 3 represent cytokine profiles of T-cells pre-immunised with native hsp65 prior to pristane injection and restimulated either with peptide hsp 261-271 (hsp (PEP)) or with native hsp (hsp (hsp)) whilst in co-culture with APCs .
  • the data presented in sets 3 and 4 represents a protocol comprising pristane injection followed by stimulation with peptide 261-267 (IPP(pep)) or pristane injection followed by stimulation with native hsp (IPP(hsp)) whilst in co-culture with APCs.
  • hsp produces an approximately 3 fold increase in IL4 compared to hsp (hsp)
  • IPP(pep) produces an approximately 2 fold increase in IL4 compared to IPP(hsp) .
  • measurement of the amount of cytokine released was by ELISA.
  • T H 1 cells are induced which leads to pristane induced arthritis due to determinant spreading
  • T H 2 cells are induced which leads to protection due to repertoire limitation. This gives rise to the possibility of devising methods for the D rophylaxis or treatment of arthritis and other auto-immune disease .
  • Glu Lys lie Gly Ala Glu Leu Val Lys Glu Val Ala Lys Lys Thr Asp 1 5 10 15
  • MOLECULE TYPE peptide (xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 33 :
  • MOLECULE TYPE peptide
  • SEQUENCE DESCRIPTION SEQ ID NO: 48:
  • MOLECULE TYPE peptide (xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 53 :

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Abstract

L'invention concerne des fragments de polypeptides d'un nombre de restes d'acides aminés égal ou supérieur à 9, qui comprennent la séquence VVNKIRG (SEQ ID NO.107), leur utilisation dans la prévention, le diagnostic et le traitement de maladies auto-immunes, telles que la polyarthrite rhumatoïde, ainsi que des procédés de préparation de ces fragments.
EP95932816A 1994-09-27 1995-09-27 Polypeptides et leur utilisation dans le traitement et la prophylaxie de maladies auto-immunes Withdrawn EP0804475A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9419553 1994-09-27
GB9419553A GB9419553D0 (en) 1994-09-27 1994-09-27 Polypeptides and their use in the treatment of auto-immune disease
PCT/GB1995/002295 WO1996010039A1 (fr) 1994-09-27 1995-09-27 Polypeptides et leur utilisation dans le traitement et la prophylaxie de maladies auto-immunes

Publications (1)

Publication Number Publication Date
EP0804475A1 true EP0804475A1 (fr) 1997-11-05

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EP95932816A Withdrawn EP0804475A1 (fr) 1994-09-27 1995-09-27 Polypeptides et leur utilisation dans le traitement et la prophylaxie de maladies auto-immunes

Country Status (6)

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EP (1) EP0804475A1 (fr)
JP (1) JPH10509136A (fr)
AU (1) AU3571095A (fr)
CA (1) CA2200338A1 (fr)
GB (1) GB9419553D0 (fr)
WO (1) WO1996010039A1 (fr)

Cited By (1)

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CN112724238A (zh) * 2021-01-21 2021-04-30 浙江辉肽生命健康科技有限公司 具有氨基酸结构fregttpkpk的生物活性肽及其制备方法和应用

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AU3225097A (en) * 1996-06-03 1998-01-05 Auragen, Inc. Immunotherapy for autoimmune disease
IT1290828B1 (it) 1997-03-25 1998-12-11 Zetesis Spa Uso di proteine estraibili da organi animali per la preparazione di medicamenti per il trattamento di condizioni patologiche
US7488476B2 (en) 1998-11-05 2009-02-10 Hadasit Medical Research Services & Development Ltd. B-cell epitope peptides of HSP 65, DNA encoding said peptides, antibodies directed against said peptides and the different uses thereof in the treatment of inflammatory and autoimmune diseases
US8158125B2 (en) 1998-11-05 2012-04-17 Hadasit Medical Research Services & Development Ltd. B-cell epitope peptides of HSP 65, novel amino acid sequences, DNA encoding the amino acid sequences of said peptides, antibodies directed against said peptides and different uses thereof in the treatment of inflammatory and autoimmune diseases
EP1127064B1 (fr) * 1998-11-05 2006-01-11 Hadasit Medical Research Services & Development Co. Ltd. Nouvelles sequences d'acides amines, adn codant pour celles-ci, anticorps diriges contre ces sequences, et utilisations differentes associees
US7608683B2 (en) 2000-08-09 2009-10-27 The Regents Of The University Of California Stress proteins and peptides and methods of use thereof
EP1652856A1 (fr) * 2000-08-09 2006-05-03 The Regents of The University of California San Diego Peptides dérivés de protéines de stress et méthodes d'utilisation
US6989146B2 (en) * 2000-08-09 2006-01-24 The Regents Of The University Of California Stress proteins and peptides and methods of use thereof
AU2002227406A1 (en) * 2000-12-13 2002-06-24 Argonex Pharmaceuticals Mhc class i associated peptides for prevention and treatment of tuberculosis
WO2003063759A2 (fr) 2002-01-31 2003-08-07 Peptor Ltd. Peptides de hsp et analogues pour la modulation des reponses immunitaires par l'intermediaire des cellules presentant l'antigene
CU23504A1 (es) 2004-09-24 2010-04-13 Ct Ingenieria Genetica Biotech Péptidos y derivados tipo apl de la hsp60 y composiciones farmacéuticas
US8691772B2 (en) 2005-01-04 2014-04-08 Yeda Research And Development Co. Ltd. HSP60, HSP60 peptides and T cell vaccines for immunomodulation

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US5114844A (en) * 1989-03-14 1992-05-19 Yeda Research And Development Co., Ltd. Diagnosis and treatment of insulin dependent diabetes mellitus
WO1992004049A1 (fr) * 1990-09-06 1992-03-19 Rijksuniversiteit Te Utrecht Inhibiteurs de la reponse de lymphocytes et de maladies immunitaires
AU699007B2 (en) * 1994-03-21 1998-11-19 Rijksuniversiteit Utrecht Peptide fragments of microbial stress proteins and pharmaceutical composition made thereof for the treatment and prevention of inflammatory diseases

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112724238A (zh) * 2021-01-21 2021-04-30 浙江辉肽生命健康科技有限公司 具有氨基酸结构fregttpkpk的生物活性肽及其制备方法和应用

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JPH10509136A (ja) 1998-09-08
GB9419553D0 (en) 1994-11-16
AU3571095A (en) 1996-04-19
CA2200338A1 (fr) 1996-04-04
WO1996010039A1 (fr) 1996-04-04

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