+

WO1997011966A1 - Polypeptides et leur utilisation dans le traitement et la prophylaxie d'une maladie auto-immune - Google Patents

Polypeptides et leur utilisation dans le traitement et la prophylaxie d'une maladie auto-immune Download PDF

Info

Publication number
WO1997011966A1
WO1997011966A1 PCT/GB1996/002382 GB9602382W WO9711966A1 WO 1997011966 A1 WO1997011966 A1 WO 1997011966A1 GB 9602382 W GB9602382 W GB 9602382W WO 9711966 A1 WO9711966 A1 WO 9711966A1
Authority
WO
WIPO (PCT)
Prior art keywords
ala
val
gly
seq
leu
Prior art date
Application number
PCT/GB1996/002382
Other languages
English (en)
Inventor
James Stephen Thompson
Christopher John Elson
Original Assignee
Peptide Therapeutic Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Peptide Therapeutic Limited filed Critical Peptide Therapeutic Limited
Priority to AU70912/96A priority Critical patent/AU7091296A/en
Publication of WO1997011966A1 publication Critical patent/WO1997011966A1/fr

Links

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)
    • 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 polypeptides and fragments thereof, 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
  • the disease is the third most common of the elderly and causes a tremendous burden of pain and suffering. It has been known for some time that an association exists between HLA-DR4 and RA suggesting a T-cell involvement [Stasney, New Eng. J. Med. (1978) 298:869 and Watanabe et al, J. exp. Med. (1989) 169:2263] and a genetic contribution to the disease.
  • recent twin studies [Silman ⁇ t al, Brit. J. Rheumatol.
  • 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.
  • Chat 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 present. Since environmental factors are clearly important in RA, microbial agents and hence hsp's were implicated.
  • Hsps are grouped in gene families according co their molecular weight and sequence homology within individual groups.
  • hsp60 (60KD) gene family includes members hsp65 (mycobacterial) and hsp5 ⁇ (mammalian) .
  • mice become sensitised to hsp by exDOsure 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 preim unisatiOn 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 cr 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 hsp 64 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 Mycobacterium 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 up to 21 amino acid residues which comprises or consists of the sequence
  • VGLTLENADLSL (SEQ ID 107) or a homologue or functional equivalent or mimetic thereof.
  • the above described polypeptide sequence corresponds to amino acids 302-314 of microbial (mycobacterial) hsp65.
  • the invention also provides che use of such a polypeptide in the prophylaxis or treacment of auto-immune disease such as RA. 8
  • 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.
  • type II collagen another potential joint antigen
  • RA trans-mucosal memorane mode of administration
  • Full sequence information in respect of human hsp58 is known for example from Jindal et al . Mol . Cell Biol . 1989 , 9 : 2279 -2283 . It is therefore proposed that human hsp58 or fragments thereof are useful in the prophylaxis or treatment of RA.
  • the present invention provides the use of human hsp58 or a fragment thereof containing or consisting of the amino acid sequence
  • VLNRLKVGLQV (SEQ ID 108 ) or a homologue or functional equivalent or mimetic thereof in the prophylaxis or treatment of auto- immune disease such as RA; and provides novel polypeptide fragments of up to 21 amino acid residues , per se .
  • This region is a non-conserved region and is mammalian specific . This means that the region will not cross - react with the bacterial form of the protein and administered transmucosally, would induce T-cell tolerance to it and thus prevent arthritis .
  • the present invention further provides a polypeptide of up to 21 amino acid residues comprising or consisting of the sequence
  • polypeptides include fragments of human hsp58 protein, in particular those including the amino acid residues corresponding to 271-257 of hsp65 or homologues thereof; i.e. the amino acid sequence
  • a particularly preferred polypeptide will consist only of the amino acids VLNRLKVGLQV.
  • hsp58 containing amino acid residues corresponding to 302-314 of hsp65 is also important for this application. This region is also a non- conserved region and is mammalian specific.
  • the present invention further provides the use of human hsp58 fragment containing or consisting of the amino acid sequence
  • LTLNLEDVQPHD (SEQ ID 110) or a homologue or functional equivalent or mimetic thereof in the prophylaxis or treatment of auto-immune disease such as RA; and provides novel polypeptide fragments of up to 21 amino acid residues, per se.
  • the invention further provides a polypeptide of up to 21 amino acid residues comprising or consisting of the sequence
  • LTLNLEDVQPHD (SEQ ID 110 ) or a homologue or functional equivalent or mimetic thereof .
  • a parcicularly preferred polypeptide will consist only of the amino acids
  • polypeptides of the invention have been found to have a prophylactic or therapeutic effect when applied immunogenically in the treatment of RA .
  • the invention further provides a vaccine for the prophylactic or therapeutic treatment of RA which vaccine comprises a polypeptide as described above .
  • the polypeptide is suitably administered in a trans -mucosal membrane manner for example , orally or nasally .
  • the polypeptide may be formulated as 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.
  • a pharmaceutical composition in combination with a pharmaceutically acceptable carrier or excipient.
  • Suitable carriers include solid or liquid carriers.
  • formulations including solid carriers include tablets or suspensions for oral administration or suppositories.
  • Suitable liquid carriers include oils or water.
  • the compositions may be adapted for nasal administration by inhalers, atomizers or sprays as are available in the art.
  • polypeptide or a pharmaceutical composition including the polypeptide, parenterally, for example sub ⁇ cutaneously, intramuscularly, intravenously or intra peritoneally.
  • 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 human hsp58 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 'homologue' refers to peptides having an amino acid sequence which is are at least 60%, preferably 70 and most preferably at least 80V homologous tc 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 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. (SEQ IDs Nos. 1-106)
  • Figure 2 shows a comparison of the proliferative response of T cells from each of 6 arthritic mice (top panel) , 6 protected mice (middle panel) and 6 normal mice (n-6) to the eleven pools of overlapping peptides defined in Figure 1;
  • Figure 3 shows the results of studies to determine the protection against PIA of mice pre-immunised with microbial hsp65 polypeptides
  • Figure 4 shows the entire amino acid sequence of human hsp58 (top line) in corresponding relationship to the entire sequence of microbial hsp65 (lower line) ; (SEQ IDs Nos. 107-109)
  • Figure 5 shows the sequences and % homology of 5 peptides in the region hsp65 m 251-312 and the corresponding sequences of hsp58; (SEQ IDs Nos. 110-117) 15
  • Figure 7 shows the prophylactic effect of pre-immunisation with polypeptides of the invention at 10 days prior to pristane injection (D---10) .
  • 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) Fl hybrids to CBA mice and selecting those mice with Igb allotype in their serum.
  • Completed peptides were extracted from the resin using trifluoroacetic acid and suitable scavengers, and isolated by solvent evaporation and precipitation with methanol 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.
  • the nonadherent cells were then gently aspirated followed by washing with medium. These cells were then used as the T cell enriched fractions. A purity of .85V 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) .
  • the cultures consisted of 1.25 x 10 s purified splenic T-cells plus 1.25 x 10 s APC per ml, in a volume of 2ml in a 24 well plate (Flow) in the presence or absence of the various antigens 92.5-10 ⁇ g/ml). Alternatively, some cultures were set up in a volume of 200 ⁇ l in round bottom 96 well plates (Flow) . All cultures were incubated at 37°C in a humidified atmosphere of 5V C02 and 95V air.
  • mice against PIA Protection of mice against PIA by immunisation with microbial Hsp65 fragments
  • mice were immunised intraperitoneally 10 days before pristane challenge as follows :
  • each polypeptide was administered as an emulsion in IFA.
  • the polypeptide fragment used in the pre-immunisation of group 3 was manufactured by Cambridge Research Biochemicals of Northwich, Cheshire UK.
  • VGLTLENADLSL is effective in producing a beneficial effect.
  • amino acids 261-271 of microbial hsp 6 5 can be useful in prophylaxis or treatment of auto-immune d isease.
  • Figure 4 shows the two complete sequences in corresponding alignment, with hspS ⁇ above hsp ⁇ S. Note that the numbering of hsp65 amino acids is used herein. References herein to amino acid sequence numbers for human fragments (from hsp58) are the numbers of the corresponding hsp60 sequence region. Thus, for example, reference herein to human hsp58 region h 261-271 corresponds to microbial m 261-271 but is, in fact, amino acid 287-297 of the upper sequence of Figure 4. Likewise, h 302-314 corresponds to m 302-314 but is, in fac t amino acids 330-341 of the upper sequence of Figure 4 .
  • Figure 5 tabulates the V homology of 5 sequences of the complete region covered by hsp65 m 251-312.
  • mice against PIA Protection of mice against PIA by oral immunisation with human hsp58 fragment.
  • the eleven amino acid polypeptide of sequence VLNRLKVGLQV (h 261-271) :SEQ ID 108) was prepared for use in the Example by Cambridge Research Biochemicals, Gadbrook Par, Nothwich,
  • mice Male CBA/Igb mice aged between 4 and 8 weeks are suitably used. Arthritis can be induced by two intraperitoneal injections of 0.5ml of pristane 50 days apart as described above. Mice which are to be subjected to an immunisation regime are given oral doses of polypeptide dissolved in saline, administered orally with 23
  • Each animal should receive a single dose on 5 consecutive days (up to and including the day of challenge with pristane) of 50 micrograms of polypeptide.
  • mice can be examined visually for the incidence of arthritis in the tarsal (ankle) joints at various time points. This may be assessed for example using a micrometer and comparing enlarged joints with normal joints. In this way, the protective effect of the polypeptide can be demonstrated.
  • the experiment is terminated 200 days after pristane injection.
  • stifle (knee) joints may be dissected out, fixed in neutral-buffered formalin and decalicified. If longitudinal sections are prepared and stained with haematoxylin and eosin, arthritis may be further assessed, for example by a veterinary pathologist.
  • the assessment is carried out blind and joint changes graded according to the following system:
  • Synovial hyperplasia with pannus formation and mild inflammation (polymorphonuclear leucocytes-PMN) or non-inflammatory mild articular cartilage degeneration.
  • a proliferative T-cell assay may be carried out as described in Experiment 1 above which will further confirm the effectiveness of this polypeptide.
  • Example 1 Protection of mice against PIA by nasal immunisation with human hso65 fragment.
  • Example 1 may be repeated except that instead of oral administration, the polypeptide is given nasally.
  • the animal is first anaesthetized and then laid on its back.
  • a 50 microlitre drop of solution containing 50micrograms of the polypeptide described in Example 1 are then placed on the nostrils. As soon as the animal becomes conscious, the drop is rapidly inhaled. This procedure is repeated five times on five consecutive days in the same way as the oral dosing described in Example 1.
  • Monitoring of the animals may be carried out in the same way as described above, whereupon a protective effect is shown.
  • Figure 6 shows the therapeutic effect of administration of polypeptides according to the invention 60 days after first administration of pristane. 50 milligrams of peptide was administered ip as an emulsion IFA to each mouse at day 60. This was after two pristane injections, 50 days apart, one at day 0 and one at day 50. This timing is judged to be just prior to the development/onset phase of PIA. The percentage arthritis was assessed by visual scoring with the assessment being made at the 210th day (D-210) . As can be seen from the figure, each of the peptides according to the invention pro d uces a reduc t ion in percentage arthritis in comparison to the control (IPP only) .
  • Figure 7 shows the prophylactic effect of pre-immunisation with peptides according to the invention 10 days prior to the first pristane injection. From these results it appears that h 261-271 may actually increase the incidence of PIA whereas h 302-314 may have little or no effect reduction of arthritis. However, m 302-314 clearly appears to give a significant reduction or nearly 4 fold in the percentage arthritis.
  • polypeptides of the invention may be useful prophylaxis, some may be useful in treatment, and some may have both prophylactic and therapeutic activity although not all polypeptides of the invention are expected to show both activities.
  • MOLECULE TYPE peptide (xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 12 :
  • MOLECULE TYPE peptide (xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 54 :
  • MOLECULE TYPE peptide
  • SEQUENCE DESCRIPTION SEQ ID NO: 59:
  • MOLECULE TYPE peptide (xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 62 :
  • MOLECULE TYPE peptide
  • SEQUENCE DESCRIPTION SEQ ID NO: 96:

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Immunology (AREA)
  • Rehabilitation Therapy (AREA)
  • Rheumatology (AREA)
  • Toxicology (AREA)
  • Zoology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des polypeptides et des fragments de ceux-ci, l'utilisation de ces polypeptides et fragments dans la prévention, le diagnostic et le traitement d'une maladie auto-immune telle que la polyarthrite rhumatoïde, ainsi que des procédés de préparation de ces fragments. Des exemples de tels polypeptides comprennent des fragments de la protéine de choc thermique hsp58 humaine. Cette invention concerne également un polypeptide possédant jusqu'à 21 restes d'acides aminés, lesquels comprennent les séquences suivantes ou sont composés de celles-ci: (a) VGLTLENADLSL (SEQ ID 107), (2) VLNRLKVGLQV (SEQ ID 108), (3) LTLNLEDVQPHD (SEQ ID 110), ou un homologue ou un équivalent fonctionnel ou un imitateur de ce polypeptide. L'invention concerne encore un vaccin destiné au traitement prophylactique ou thérapeutique de la polyarthrite rhumatoïde et comprenant un polypeptide tel celui décrit ci-dessus.
PCT/GB1996/002382 1995-09-27 1996-09-26 Polypeptides et leur utilisation dans le traitement et la prophylaxie d'une maladie auto-immune WO1997011966A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU70912/96A AU7091296A (en) 1995-09-27 1996-09-26 Polypeptides and their use in treatment and prophylaxis of auto-immune disease

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9519737.2A GB9519737D0 (en) 1995-09-27 1995-09-27 Polypeptides and their use in treatment and prophylaxis of auto-immune
GB9519737.2 1995-09-27

Publications (1)

Publication Number Publication Date
WO1997011966A1 true WO1997011966A1 (fr) 1997-04-03

Family

ID=10781379

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1996/002382 WO1997011966A1 (fr) 1995-09-27 1996-09-26 Polypeptides et leur utilisation dans le traitement et la prophylaxie d'une maladie auto-immune

Country Status (3)

Country Link
AU (1) AU7091296A (fr)
GB (1) GB9519737D0 (fr)
WO (1) WO1997011966A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0947524A1 (fr) * 1998-03-30 1999-10-06 Upither B.V. Nouveaux peptides destinés au traitement de maladies auto-immunes
WO2001016174A3 (fr) * 1999-08-30 2002-01-17 Rolf Kiessling Induction d'une reponse de lymphocytes t cytotoxiques par des determinants antigeniques restreints par hla de categorie 1a de proteines de choc thermique mycobacteriennes 65
WO2002012286A3 (fr) * 2000-08-09 2003-07-31 Univ California San Diego Proteines et peptides du stress et methodes d'utilisation
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
WO2006032216A3 (fr) * 2004-09-24 2007-05-18 Ct Ingenieria Genetica Biotech Peptides et derives du type apl de la hsp60 et compositions pharmaceutiques
US7576177B2 (en) 2002-01-31 2009-08-18 Andromeda Biotech Ltd. Hsp peptides and analogs for modulation of immune responses via antigen presenting cells
US7608683B2 (en) 2000-08-09 2009-10-27 The Regents Of The University Of California Stress proteins and peptides and methods of use thereof
US8691772B2 (en) 2005-01-04 2014-04-08 Yeda Research And Development Co. Ltd. HSP60, HSP60 peptides and T cell vaccines for immunomodulation
US10703784B2 (en) * 2011-09-30 2020-07-07 La Jolla Institute For Allergy And Immunology Antigens and epitopes derived from Mycobacterium tuberculosis

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112724238B (zh) * 2021-01-21 2022-05-31 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

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989012455A1 (fr) * 1988-06-15 1989-12-28 Whitehead Institute For Biomedical Research Proteines de stress et leurs utilisations
WO1994029459A1 (fr) * 1993-06-04 1994-12-22 Whitehead Institute For Biomedical Research Proteines du stress et leurs utilisations
WO1995025744A1 (fr) * 1994-03-21 1995-09-28 Rijksuniversiteit Utrecht Fragments peptidiques de proteines de stress microbiennes, et composition pharmaceutique a base de ceux-ci destinee au traitement et a la prevention des maladies inflammatoires
WO1996018646A2 (fr) * 1994-12-16 1996-06-20 Regents Of The University Of Minnesota Peptides de proteines de choc thermique et procedes de modulation d'une maladie auto-immune du systeme nerveux central

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989012455A1 (fr) * 1988-06-15 1989-12-28 Whitehead Institute For Biomedical Research Proteines de stress et leurs utilisations
WO1994029459A1 (fr) * 1993-06-04 1994-12-22 Whitehead Institute For Biomedical Research Proteines du stress et leurs utilisations
WO1995025744A1 (fr) * 1994-03-21 1995-09-28 Rijksuniversiteit Utrecht Fragments peptidiques de proteines de stress microbiennes, et composition pharmaceutique a base de ceux-ci destinee au traitement et a la prevention des maladies inflammatoires
WO1996018646A2 (fr) * 1994-12-16 1996-06-20 Regents Of The University Of Minnesota Peptides de proteines de choc thermique et procedes de modulation d'une maladie auto-immune du systeme nerveux central

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6673770B1 (en) * 1998-03-30 2004-01-06 Upither B.V. Peptides for the treatment, prophylaxis, diagnosis and monitoring of autoimmune diseases
WO1999050282A3 (fr) * 1998-03-30 2001-03-29 Upither B V Nouveaux peptides pour le traitement, la prophylaxie, le diagnostic et la surveillance des maladies auto-immunes
EP0947524A1 (fr) * 1998-03-30 1999-10-06 Upither B.V. Nouveaux peptides destinés au traitement de maladies auto-immunes
WO2001016174A3 (fr) * 1999-08-30 2002-01-17 Rolf Kiessling Induction d'une reponse de lymphocytes t cytotoxiques par des determinants antigeniques restreints par hla de categorie 1a de proteines de choc thermique mycobacteriennes 65
AU2001285427B2 (en) * 2000-08-09 2007-03-22 The Regents Of The University Of California, San Diego Stress proteins and peptides and methods of use thereof
JP2004518430A (ja) * 2000-08-09 2004-06-24 ザ レジェンツ オブ ザ ユニバーシティー オブ カリフォルニア サン ディエゴ ストレスタンパク質およびペプチドならびにその使用方法
US6989146B2 (en) 2000-08-09 2006-01-24 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
WO2002012286A3 (fr) * 2000-08-09 2003-07-31 Univ California San Diego Proteines et peptides du stress et methodes d'utilisation
US7608683B2 (en) 2000-08-09 2009-10-27 The Regents Of The University Of California Stress proteins and peptides and methods of use thereof
US7576177B2 (en) 2002-01-31 2009-08-18 Andromeda Biotech Ltd. Hsp peptides and analogs for modulation of immune responses via antigen presenting cells
EP2157101A1 (fr) 2002-01-31 2010-02-24 Andromeda Bio Tech Ltd. Peptides HSP et analogues pour la modulation de réponses immunes via des cellules présentant l'antigène
JP2008514553A (ja) * 2004-09-24 2008-05-08 セントロ デ インジエニエリア ジエネテイカ イ バイオテクノロジア Ｈｓｐ６０のペプチド及びａｐｌ型誘導体並びに医薬組成物
WO2006032216A3 (fr) * 2004-09-24 2007-05-18 Ct Ingenieria Genetica Biotech Peptides et derives du type apl de la hsp60 et compositions pharmaceutiques
KR101054332B1 (ko) 2004-09-24 2011-08-04 센트로 데 인제니에리아 제네티카 와이 바이오테크놀로지아 Ｈｓｐ60의 펩티드 및 이들의 유도형 ａｐｌ 및 약학적조성물
EP2371847A1 (fr) 2004-09-24 2011-10-05 Centro De Ingenieria Genetica Y Biotecnologia Peptides et leur APL de type dérivé du HSP60 et compositions pharmaceutiques
CN101935345B (zh) * 2004-09-24 2013-12-11 遗传工程与生物技术中心 Hsp60的肽和apl型衍生物及药物组合物
US8691772B2 (en) 2005-01-04 2014-04-08 Yeda Research And Development Co. Ltd. HSP60, HSP60 peptides and T cell vaccines for immunomodulation
US10703784B2 (en) * 2011-09-30 2020-07-07 La Jolla Institute For Allergy And Immunology Antigens and epitopes derived from Mycobacterium tuberculosis

Also Published As

Publication number Publication date
AU7091296A (en) 1997-04-17
GB9519737D0 (en) 1995-11-29

Similar Documents

Publication Publication Date Title
Saoudi et al. TH2 activated cells prevent experimental autoimmune uveoretinitis, a TH1‐dependent autoimmune disease
KR100433750B1 (ko) 마이코박테리움튜베르큘로시스항원을포함하는폴리펩타이드및이를포함하는약제학적조성물
US7084247B2 (en) Identification of self and non-self antigens implicated in autoimmune diseases
KR101776157B1 (ko) 생물학적 물질 및 이의 용도
AU2002341266A1 (en) Use of HMGB1 for the activation of dendritic cells
EP1432441A2 (fr) Utilisation de hmgb1 pour l'activation de cellules dendritiques
JP2008195718A (ja) Ｔ細胞エピトープペプチド
AU4278296A (en) Compositions and treatment for multiple sclerosis
EP0804475A1 (fr) Polypeptides et leur utilisation dans le traitement et la prophylaxie de maladies auto-immunes
WO1997011966A1 (fr) Polypeptides et leur utilisation dans le traitement et la prophylaxie d'une maladie auto-immune
EP1119253A1 (fr) NOUVELLES MOLECULES SPECIFIQUES DE Th2 ET LEURS UTILISATIONS
CN108929383B (zh) 重组Slit2D2(C386S)-HSA融合蛋白及其在预防和/或治疗肺部炎症中的应用
AU746372B2 (en) Novel preventives/remedies for immunopathy
EP0785947B1 (fr) Peptides dotes d'une activite anti-inflammatoire
WO2001010893A2 (fr) Antagonistes de l'interleukine-16
WO1992011289A1 (fr) Formation d'antigene
Anderson et al. Molecular mapping of interactions between a Mycobacterium leprae-specific T cell epitope, the restricting HLA-DR2 molecule, and two specific T cell receptors.
WO1999013895A1 (fr) Nouvelles compositions de polypeptides inhibitrices de l'activite du canal potassium et leurs utilisations
US5639869A (en) Mycoplasma arthritidis T-cell mitogen
US5976543A (en) 12-kDa protein derived from M. Tuberculosis useful for treatment of autoimmune diseases
US6254861B1 (en) Hematopoietic growth factor derived from T lymphocytes
JP4176820B2 (ja) スギ花粉アレルゲンＣｒｙｊＩＩエピトープ
Sitaraman Myasthenia gravis: Role of cytokines in disease and design of therapy
WO2003000718A2 (fr) Nouveau peptide et son utilisation
JP2006045230A (ja) Ｔ細胞エピトープペプチド

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE HU IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TR TT UA UG US UZ VN AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载