WO1994002509A1 - Peptides de blocage des hla-dr3 et leur application au traitement des maladies auto-immunes associees aux hla-dr3 - Google Patents

Peptides de blocage des hla-dr3 et leur application au traitement des maladies auto-immunes associees aux hla-dr3 Download PDF

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Publication number
WO1994002509A1
WO1994002509A1 PCT/NL1993/000151 NL9300151W WO9402509A1 WO 1994002509 A1 WO1994002509 A1 WO 1994002509A1 NL 9300151 W NL9300151 W NL 9300151W WO 9402509 A1 WO9402509 A1 WO 9402509A1
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Prior art keywords
peptide
hla
amino acid
peptides
cell
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PCT/NL1993/000151
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English (en)
Inventor
Annemieke Geluk
Thomas Henricus Maria Ottenhoff
Rene Rudolf Pieter De Vries
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Rijksuniversiteit Leiden
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Application filed by Rijksuniversiteit Leiden filed Critical Rijksuniversiteit Leiden
Priority to AU47628/93A priority Critical patent/AU4762893A/en
Publication of WO1994002509A1 publication Critical patent/WO1994002509A1/fr

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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
    • C07K14/195—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • HLA-DR3 blocking peptides and their use in the treatment of HLA- DR3 associated autoimmune diseases
  • the invention is concerned with the selection of peptides that can be used in a medical treatment of autoimmune diseases, in particular autoimmune diseases which are associated with human leukocyte antigens (HLA) of type HLA-DR3, such as type I diabetes, Grave's disease, Sj ⁇ gren's syndrome and myasthenia gravis.
  • HLA human leukocyte antigens
  • the human immune system can cause disease not only by producing too many antibodies, as in the case of allergies, but also by the production of T cells against healthy cells of the own body. Such T cells reactive with "self-molecules can cause autoimmune diseases.
  • HLA human leukocyte antigens
  • HLA antigens/molecules are encoded by 6 extremely polymorphic closely linked genes on chromosome 6. There are 3 genes (A,B,C) coding for so-called class I molecules, which are present on the surface of all nucleated cells and can bind and present e.g. virus derived antigenic peptides to CD8 + (cytotoxic) T lymphocytes, which then can kill e.g. virus infected cells. Three other genes (DR, DQ, DP) code for so-called class II molecules, HLA-DR being the most important .
  • HLA-DR molecules are tissue antigens that are normally present on professional antigen cells, such as B cells and macrophages and that can bind and present peptides from proteins or microbes taken up by those cells to CD4 + helper T cells, which in turn can activate other lymphocytes.
  • Each helper T cell can only recognize antigen (peptide) presented by one of the two different HLA-DR molecules present in most individuals.
  • the terminology also used to describe this phenomenon is that each T cell response is restricted by a particular HLA-DR molecule or antigen.
  • helper T cell which is a class II restricted CD4 positive T cell, plays a central role in orchestrating the immune response. It produces cytokines or lymphokines which regulate at least all the other antigen-activated components of the immune system.
  • a possible strategy would be to prevent the HLA molecule from binding and presenting an auto-antigen that induces an autoimmune disease. Particularly if certain HLA alleles are exclusively or preferentially presenting such an auto-antigen, this can be done in at least two ways; one is the use of antibodies against the HLA molecule or more specifically against a particular combination of peptide and HLA, and the second is the development of peptides or other compounds that prevent the disease inducing epitope from binding to the disease related HLA molecule.
  • T cell receptors are preferentially used to recognize a particular peptide-HLA combination, we could use antibodies or even better active strategies like vaccination with attenuated disease inducing T cells or T cell receptor peptides.
  • Another strategy which at first glance seems to be less specific, uses an antibody directed against the CD4 molecule used by the helper T cell to recognize the HLA class II molecule.
  • a HLA class II blocking peptide should not be immunogenic (i.e. not activate T cells) and preferably bind selectively to a certain DR type (allele) .
  • DR3-restricted helper T cell responses are blocked in an allele (DR3) specific way with the use of peptides derived by single amino acid substitutions from a DR3- restricted immunodominant peptide epitope of the 65kD heat shock protein of Mycobacteria hsp65 p4-15.
  • the present invention provides a peptide comprising the amino acid sequence
  • a n _ ⁇ is any amino acid
  • a n is I, L or V;
  • a n+ ⁇ is A, H or Q;
  • a n+2 is Y, S, R or P;
  • a n+ 3 is D, E or Q;
  • a n+4 is E or D
  • a n+ 5 is any amino acid; with the proviso that said sequence differs by one amino acid substitution from the sequence T I A Y D E E.
  • Amino acids are identified herein by the one-letter code, i.e. T refers to threonine (Thr), I to isoleucine (lie), A to alanine (Ala), Y to tyrosine (Tyr) , D to aspartic acid (Asp) , E to glutamic acid (Glu) , etc.
  • a n _ ⁇ is T
  • a n + 5 is
  • a n is I, and/or A n+ 3 is D. More preferably the invention relates to a peptide wherein
  • a n _x is T; A n is I;
  • a n+ 1 is A, H or Q;
  • a n+2 is Y, S, R or P;
  • a n+3 is D
  • Specific examples of preferred embodiments of the invention are peptides comprising an amino acid sequence selected from the group consisting of T I A Y D D E (SEQ ID N0:1)
  • the length of peptides according to the invention may vary between broad limits, but will vary practically from about 7 to about 30 amino acids.
  • the peptide has a length of from about 8 to about 20 amino acids.
  • the amino group of the amino-terminal amino acid may be modified, e.g. acylated.
  • the carboxy group of the carboxy-terminal amino acid may be modified, e.g. amidated.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a HLA DR3 blocking effective amount of a peptide according to the invention as defined above and a pharmaceutically acceptable carrier or diluent.
  • the invention also provides a method of treating a HLA DR3 related autoimmune disease, comprising administering a HLA DR3 blocking effective amount of a peptide according to the invention as defined above to a person or mammal suffering from said HLA DR3 related autoimmune disease.
  • Figure 1 Binding to HLA-DR17 BLCL of biotinylated, single substituted analogs of hsp65 p4-15. The position of substitution and the amino acid residue that is substituted (single letter code) are indicated on the x-axis. The percentage of binding relative to the native peptide p4-15 was calculated by dividing the mean fluorescence, corrected for background fluorescence, of each peptide by the mean fluorescence of p4-15 and is indicated on the y-axis. The results represent the mean of three independent experiments.
  • FIG. 2A Inhibition of hsp65 p4-15 stimulated activation of DR3-restricted T cell clones by selected single amino acid substituted analogs of p4-15.
  • the amount of competitor peptide added is indicated in fold-excess on the x-axis . Proliferation is expressed in cpm on the y-axis. SI for competitor peptides without p4-15 were ⁇ l . Results were reproducible in several independent experiments.
  • Figure 2B Inhibition of 30/31kD dependent activation of DR3- restricted T cell clones by selected single amino acid substituted analogs of ⁇ 4-15 (see legend Fig.2A) .
  • FIG. 2C Lack of inhibition of hsp65 p418-427 specific DR2- restricted T cell clone R2F10 and of hsp65 p412-425 specific DR1- restricted T cell clone N3A9 by selected substituted peptides (see legend Fig.2A) .
  • Antigen recognition by CD4 + T cells involves the formation of a trimolecular complex between the TCR, MHC class II molecule and processed antigen (1-3) .
  • Processed antigen consists of peptidic antigen fragments that can be represented by linear synthetic peptides (4, 5) .
  • linear synthetic peptides (4, 5) .
  • individual amino acid residues in an immunogenic peptide can be defined either as TCR (epitope) or MHC (agretope) contact residues or spacer residues.
  • HLA-DR17 The peptide is not recognized in the context of any other HLA-DR molecule (9) , most probably because it binds specifically to HLA-DR17(3) molecules (10) only.
  • HLA-DR17, p3-13 and several TCRs We have now further examined the interactions between HLA-DR17, p3-13 and several TCRs by using the single amino acid substitution strategy to determine agretope and epitope residues in p3-13.
  • p3-13 analogs that bound to HLA-DR17 but had lost the capacity to stimulate p3-13 reactive T cell clones and tested their capacity to inhibit the proliferation of p3-13 reactive clones and other HLA-DR17 restricted T cells to respectively p3-13 and other antigens presented by HLA-DR17.
  • DR3 specific competitor peptides may be of interest given the association of HLA-DR3 with a considerable number of autoimmune diseases (15) .
  • the sequence of another known T cell epitope, tetanus toxoid pl273-1284 (25) , which is DR52a-restricted, contained the same amino acid residues equally spaced from each other by two amino acids .
  • the DR17 specific peptide binding pocket is preserved in DR52a molecules as the residues of the hypervariable region of DRB3 molecules in DR52a, that are supposed to form the peptide binding groove (10) , are identical to those of DRB1 molecules of DR17.
  • analysis of two newly defined DR3-restricted epitopes, from the hsp70, hspl8 and the 30/31kD protein of M are two newly defined.
  • This motif is composed of a large, hydrophobic residue (I, L, V) at position n, followed by a negatively charged (D, E) or polar (Q) residue at position n+3.
  • a negative charge at position n+3 is critical for peptide-DR17 binding is consistent with our finding that the peptide binding groove of DR17 molecules contains a positively charged pocket, specific for HLA-DR17 molecules (10) .
  • residue n (I, L, V) should be flanked by one or more amino acids on its N-terminal side (data not shown) and probably cannot be situated next to the positively charged N-terminus of the peptide.
  • MHC class II molecule contains a single peptide binding site, as indicated by X-ray crystallography (39) and peptide competition studies (40) it might be feasible to design peptides that bind to MHC molecules but do not activate disease- causing T cells . Such peptides would then act as antagonists for recognition of self-antigens .
  • the competitor peptides are also able to inhibit the activation of two other hsp65 non-reactive, DR3-restricted T cell clones (Fig.2B) .
  • the possibility to inhibit the response of these 30/3lkD reactive clones with single amino acid substituted analogs of hsp65 p4-15 shows that the inhibition does not, thus far, depend on either the stimulator peptides or the stimulated T cell.
  • these competitor peptides do not inhibit the response of a DRl-restricted or a DR2-restricted T cell clone (Fig.2C), inhibition is allele specific.
  • inhibitory peptides may induce tolerance of auto-reactive helper T cells, suggests that not only passive but also active immunomodulation might be achieved by MHC-binding peptides. In that case short-term courses of limited duration might also be effective. In both cases such immunomodulatory peptides would have to be administered in such a way that effective concentrations can be obtained in the antigen presenting cells presenting the disease inducing auto-antigen.
  • a set of 240 single amino acid substituted analogs of hsp65 p4-15 (each residue substituted by all 20 amino acids including the natively occurring amino acid) was synthesized using the Pepscan (16) method. All other peptides were made on an ABIMED 422 synthesiser (ABIMED, Langenfeld, Germany) using the simultaneous multiple peptide synthesis method (17) . N- and C-terminal truncated peptides of hsp65 p2-13 were also synthesized in their N-terminal biotinylated form.
  • HAR Al, B8, Cw7, DR17(3), DR52a, Dw3, DQw2, DPw4
  • AVL Al, B8, Cw7, DR17(3), DR52a, Dw3, DQw2, DPw4
  • CAA Al, B8, Cw7, DR17(3), DR52a, Dw3, DQw2, DPw4
  • RSH RSH (DR18(3), DR52a, Dw3)
  • OOS DR1, Dwl
  • IWB DR15(2), Dw2)
  • BSM DR4, DR53, Dw4)
  • ATH DR11(5), DR52b, Dw5), ABO (DR14(6), DR52b, Dw9)
  • EKR DR7, DR53, Dw7)
  • MADURA MADURA
  • EBV-B lymphoblastoid cell lines (BLCL, 3xl0 5 /sample) were incubated with the biotinylated peptide (50 ⁇ M) at 37°C for 20 h.
  • biotinylated peptide 50 ⁇ M
  • cells were labelled in each experiment with a biotinylated monoclonal antibody specific for HLA-DR (5 ⁇ l; Becton Dickinson, CA) at 4°C for one hour.
  • Peptide or anti-DR preincubation were followed by labelling with FITC-avidin D (lO ⁇ g/ml; lOO ⁇ l; Vector Labs, CA) at 4°C for 30 mi .
  • Proliferation was assayed by mixing 10 4 T cells, irradiated DR-matched allogeneic PBMC (5 x 10 4 /well) and Ag (final concentration 5 ⁇ g/ml, 05 ⁇ g/ml and 0.05 ⁇ g/ml) . After 66 h of cultur 1 ⁇ Ci [ H]thymidine was added to each well and 18 h later cells were collected on glass fiber filter strips and the radioactivity incorporated into the DNA was determined by liquid scintillation counting. Both biotinylated and unbiotinylated were tested for T cell proliferation using the DR3-restricted clones CAApl5 1-1, Rpl5 1-1, R1F9 and DAApl5 1-1.
  • the stimulator peptide for the 65kD reactive clones p4-15 (final concentration lng/ml) was used and for the 30/31kD reactive clones the DR3-restricted epitope (final concentration 0.2 ⁇ g/ml) of the 30/31kD protein (Thole et al. in preparation) .
  • Toxicity of competitor peptides was checked by mixing either T cells (10 4 /well) and 10% IL2 (Lymphocult-T, Biotest, Frankfurt/M., FRG) or PBMC (5 x 10 4 /well) and 0.5% PHA (Wellcome Diagnostics, Dartford, UK) with competitor peptide (final concentration lO ⁇ g/ml) .
  • Results single amino acid substitution analogs that completely lacked T cell stimulatory potency for all four T cell clones but still bound to DR17 were tested for their ability to inhibit the response of the p3-13 reactive T cell clones CAApl5 1-1 and Rpl5 1-1 to p4-15.
  • This peptide represents the sequence of a DR2-restricted epitope on this protein and does not bind to DR17 (data not shown) .
  • coincubation of p418-427 and p4-15 did not reduce the proliferation of the DR3-restricted clones (Fig.2A) .
  • Competitor analogs for defined T cell antigens peptides incorporating a putative binding motive and polyproline or polyglycine spacers.
  • (+) indicates a critical role for the amino acid in contacting either the TCR or the DR17 molecule; ( ⁇ ) indicates that the residue can be substituted by other amino acids but partly loses its ability to activate T cells; (-) indicates that the amino acid does not contribute to either TCR or MHC binding; (?) indicates probably no critical role for TCR contacting, but because of a positive involvement in MHC binding this could not be definitely interpreted.

Abstract

Peptide comportant la séquence d'acides aminés An-1 An An+1 An+2 An+3 An+4 An+5, dans laquelle An-1 représente n'importe quel acide aminé; An représente I, L ou V; An+1 représente A, H, ou Q; An+2 représente Y, S, R ou P; An+3 représente D, E ou Q; An+4 représente E ou D; An+5 représente n'importe quel acide aminé; à condition que ladite séquence diffère de la séquence T I A Y D E E par une substitution d'acide aminé. On a également prévu l'application du peptide à activité de blocage des HLA-DR3 au traitement des maladies auto-immunes associées aux HLA-DR3.
PCT/NL1993/000151 1992-07-15 1993-07-14 Peptides de blocage des hla-dr3 et leur application au traitement des maladies auto-immunes associees aux hla-dr3 WO1994002509A1 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
FR2736831A1 (fr) * 1995-07-19 1997-01-24 Centre Nat Rech Scient Sequences nucleotidiques et peptidiques pour le traitement de la myasthenie
WO1997026538A1 (fr) * 1996-01-19 1997-07-24 Virginia Mason Research Center Strategie de determinant antigenique de peptide specifique d'un allele aux fins de la mise au point de vaccin
US5874405A (en) * 1994-12-16 1999-02-23 Birnbaum; Gary Heat shock protein peptides that share sequences with cyclic nucleotide phosphodiesterase and methods for modulating autoimmune central nervous system disease
US6232522B1 (en) 1990-01-31 2001-05-15 Oklahoma Medical Research Foundation Non-human animal model for systemic lupus erythematosis
US7192715B2 (en) 1993-11-30 2007-03-20 Oklahoma Medical Research Foundation Diagnostics and therapy of epstein-barr virus in autoimmune disorders
US7273613B1 (en) 1997-01-13 2007-09-25 The Board of Regents, The University of Oklahoma Diagnostics and therapy of Epstein-Barr virus in autoimmune disorders
US7276341B2 (en) 1990-01-31 2007-10-02 Oklahoma Medical Research Foundation Methods and reagents for diagnosis of autoantibodies
US7576177B2 (en) 2002-01-31 2009-08-18 Andromeda Biotech Ltd. Hsp peptides and analogs for modulation of immune responses via antigen presenting cells
US8691772B2 (en) 2005-01-04 2014-04-08 Yeda Research And Development Co. Ltd. HSP60, HSP60 peptides and T cell vaccines for immunomodulation

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0262710A1 (fr) * 1986-09-09 1988-04-06 De Staat Der Nederlanden Vertegenwoordigd Door De Minister Van Welzijn, Volksgezondheid En Cultuur Utilisation d'un peptide pour la préparation de compositions pour le soulagement, le traitement ou le diagnostique de maladies autoimmunes, notamment des affections arthritiques, et de composés dérivés dudit peptide, des microorganismes synthétisant ledit peptide ou de composés dérivés dudit peptide, ainsi que des compositions pharmaceutiques et diagnostiques et des kits de tests

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0262710A1 (fr) * 1986-09-09 1988-04-06 De Staat Der Nederlanden Vertegenwoordigd Door De Minister Van Welzijn, Volksgezondheid En Cultuur Utilisation d'un peptide pour la préparation de compositions pour le soulagement, le traitement ou le diagnostique de maladies autoimmunes, notamment des affections arthritiques, et de composés dérivés dudit peptide, des microorganismes synthétisant ledit peptide ou de composés dérivés dudit peptide, ainsi que des compositions pharmaceutiques et diagnostiques et des kits de tests

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
A. GELUK ET AL.: "Binding of a major T cell epitope of mycobacteria to a specific pocket within HLA-DRw17(DR3) molecules", EUROPEAN JOURNAL OF IMMUNOLOGY, vol. 22, no. 1, January 1992 (1992-01-01), WEINHEIM, pages 107 - 113 *
A. KONIECZNY: "Nucleotide sequence of lupin leghemoglobin I cDNA", NUCLEIC ACIDS RESEARCH, vol. 15, no. 16, 25 August 1987 (1987-08-25), ARLINGTON, VIRGINIA US, pages 6742 *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6232522B1 (en) 1990-01-31 2001-05-15 Oklahoma Medical Research Foundation Non-human animal model for systemic lupus erythematosis
US7276341B2 (en) 1990-01-31 2007-10-02 Oklahoma Medical Research Foundation Methods and reagents for diagnosis of autoantibodies
US7192715B2 (en) 1993-11-30 2007-03-20 Oklahoma Medical Research Foundation Diagnostics and therapy of epstein-barr virus in autoimmune disorders
WO1996018646A3 (fr) * 1994-12-16 1996-09-06 Univ Minnesota Peptides de proteines de choc thermique et procedes de modulation d'une maladie auto-immune du systeme nerveux central
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
US5874405A (en) * 1994-12-16 1999-02-23 Birnbaum; Gary Heat shock protein peptides that share sequences with cyclic nucleotide phosphodiesterase and methods for modulating autoimmune central nervous system disease
US5958416A (en) * 1994-12-16 1999-09-28 Regents Of The University Of Minnesota Heat shock protein peptides and methods for modulating autoimmune central nervous system disease
WO1997004093A1 (fr) * 1995-07-19 1997-02-06 Centre National De La Recherche Scientifique Sequences nucleotidiques et peptidiques pour le traitement de la myasthenie
FR2736831A1 (fr) * 1995-07-19 1997-01-24 Centre Nat Rech Scient Sequences nucleotidiques et peptidiques pour le traitement de la myasthenie
WO1997026538A1 (fr) * 1996-01-19 1997-07-24 Virginia Mason Research Center Strategie de determinant antigenique de peptide specifique d'un allele aux fins de la mise au point de vaccin
US7273613B1 (en) 1997-01-13 2007-09-25 The Board of Regents, The University of Oklahoma Diagnostics and therapy of Epstein-Barr virus in autoimmune disorders
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
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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