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• • A—HUMAN NECESSITIES
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  • A61P25/00—Drugs for disorders of the nervous system
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• • 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
• • 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
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
  • A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• inhibitors of alanyl aminopeptidases Use of inhibitors of alanyl aminopeptidases and pharmaceutical compositions comprising them
• the present invention relates to the use of one or more inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity for inducing the production of TGF- ⁇ 1 and expression of TGF- ⁇ 1 in and / or on Treg cells and the use for the prevention and / or treatment of autoimmune diseases, allergies, arteriosclerosis and for the suppression of graft rejection.
• the invention further relates to uses in which peptide fragments of pathogenic autoantigens or synthetic analogs and / or specific antigenic components of pathogenic microorganisms are additionally used.
• the joint application of inhibitors against the above-mentioned enzymes with disease-specific antigens enhances the targeted action of the inhibitors against pathogenic T-cell clones and is suitable for the specific therapy of immunologically related diseases.
• Fig. 5 The inhibition of autoreactive T cells via soluble (a) or membrane-bound TGF-ßl (b) is shown schematically in Fig. 5.
• the membrane-bound TGF-ßl on Treg has a direct inhibitory effect on autoreactive T cells by binding to their TGF-ßl receptor (cell-cell contact), which can be seen in Fig. 5 (b) above.
• This cell contact can be achieved through the simultaneous binding of both Treg and autoreactive T cells to an antigen-presenting cell (APC, in particular dendritic cells).
• APC antigen-presenting cell
• previous binding of the Treg to the APC can change it (lack of costimulatory signals) so that a subsequently binding autoreactive T cell is not activated (anergy).
• the Treg and autoreactive T cell are characterized by the same antigen specificity.
• Treg natural regulatory T cells
• Treg cells arise in the thymus [Kawahata K. et al., J. Immunol. 168: 4399-4405, 2002] and account for 5-10% of the T cells in peripheral blood. They have an inhibitory effect on CD4 + T cells of the same antigen specificity via direct cell contact. This inhibitory effect is shown by a strong expression of TGF-ßl in the Treg reached.
• the TGF-ßl is presented on the surface of the Treg and binds to the TGF-ßl receptor on autoreactive T cells, which represents a completely new mechanism of action of this strong immunosuppressive cytokine [Nakamura et al., J Exp Med 194: 629- 644, 2001].
• Treg cells inhibit autoimmunity more efficiently than the immune response to "foreign" antigens [Romagnoli P et al., J hnmunol 168: 1644-1648, 2002]. Therefore, restrictions or losses in the functioning of Treg cells are of particular pathogenetic importance in the development of autoimmune disorders.
• a direct relationship between the number / function of Treg cells and the manifestation of autoimmune diseases is for type I diabetes [Boudaly S et al., Eur Cytokine Netw 13: 29-37, 2002; Gregori S et al., Diabetes 51: 1367-1374, 2002], autoimmune encephalomyelitis (animal model of multiple sclerosis) [Furtado GC et al., Hnmunol Rev 182: 122-134, 2001; Muhallab S et al., Scand J Hnmunol 55: 264-273, 2002; Hamilton NH et al., Scand J hnmunol 55: 171-177, 2002], for the "autoimmune ovarian disease" (AOD) [Tung KS et al., Hnmunol Rev 182: 135- 148, 2001], and for the disease Crohn [Neurath MF et al., J Exp Med 195: 1129-1143, 2002].
• Treg cells are also responsible for suppressing intestinal or pulmonary inflammation [Singh B et al., Hnmunol Rev 182: 190-200, 2001; Hori S et al., Eur J Hnmunol 32: 1282-1291, 2002].
• the role of Treg cells in suppressing rejection episodes after allogeneic (foreign) organ transplantation is also clearly demonstrated [Kingsley CI et al., J hnmunol 168: 1080-1086, 2002; Taylor PA et al., Blood 99: 3493-3499, 2002; Chiffoleau E et al., Jnnmunol 168: 5058-5069, 2002].
• each Treg cell clone is directed against a specific antibody and inhibits autoreactive T cells of the same antigen specificity under normal physiological conditions, in the case of Autoimmune diseases lose this Treg function and auto-reactive T cell clones, such as those used in type I diabetes against proteins of the pancreatic beta cell, lead to the outbreak of the autoimmune disease.
• this antigen specificity can also be used therapeutically, by increasing or increasing the number / function of these cells through targeted "antigen-specific" activation in vivo or ex vivo of Treg cells (or of denritic cells activating these cells) getting produced.
• TGF-ßl for the regulation of immunological hyperreactivity
• two recent publications show that the overproduction of TGF-ßl in CD4 + cells caused by genetic manipulation can suppress the disease process.
• Th2 cells are crucially involved in the pathogenesis, the function of pathogenic Th2 cell clones can accordingly be effectively inhibited by transgenic overproduction of TGF- ⁇ 1 [Hansen G et al., J Clin ivest 105: 61-70 , 2000; Thorbecke GJ et al., Cytokine Growth Factor Rev 11: 89-96, 2000].
• the present invention has for its object to provide an efficient method for the induction of production and expression of TGF-ßl in and / or on Treg cells, which is also for the prevention and / or treatment of autoimmune diseases, allergies, arteriosclerosis and the suppression of Graft rejection on humans or animals is suitable. Another object is to provide corresponding pharmaceutical preparations with which these objects can be achieved.
• inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity induce the production of TGF-ßl and expression of TGF-ßl in and / or on Treg cells and thus for the prevention and treatment of Autoimmune diseases, allergies and arteriosclerosis are suitable and can serve to suppress transplant rejections.
• the invention therefore relates to the use of one or more inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity for inducing the production of TGF- ⁇ 1 and expression of TGF- ⁇ 1 in and / or on Treg cells.
• inhibitors of alanyl aminopeptidases and all inhibitors of enzymes of the same substrate specificity come into consideration as inhibitors.
• ⁇ -ketoamides particularly preferred among these are ⁇ -ketoamides, ⁇ -aminophosphinic acids, N-phenylhomophthalimides, ⁇ -aminophosphonates and phebestin, 3-amino-2-oxo-4-phenylbutanoic acid amides being particularly preferred as ⁇ -ketoamides, D-Phe- as ⁇ -aminophosphinic acids ⁇ [PO (OH) -CH 2 ] -Phe-Phe, as N-phenylhomophthalimide PAQ-22, as ⁇ -aminophosphonates RB3014 and / or phebestin, and very particularly preferably PAQ-22, RB3014 and / or phebestin.
• cytosolic alanyl aminopeptidase As an enzyme with the same substrate specificity as the alanyl aminopeptidases, cytosolic alanyl aminopeptidase may be mentioned here by way of example.
• PAQ-22 is specific for the cytosolic alanyl aminopeptidase.
• As a preferred inhibitor of the cytosolic alanyl Aminopeptidase is therefore used PAQ-22, or a mixture of several inhibitors comprising PAQ-22.
• the inhibition of the enzymatic activity of the membrane-bound alanyl aminopeptidase increases the gene expression of TGF-ßl in Treg cells and the expression of the immunosuppressive cytokm TGF-ßl ("transforming growth factor ßl") in / on regulatory cells.
• TGF-ßl selectively strengthens or restitutes the function of Treg cells and is due to the above-mentioned relationships between the expression of TGF-ßl on the Treg cells and the inhibitory effect on autoreactive T-lymphocytes are suitable to overcome the functional deficits of Treg cells existing in autoimmune diseases and inflammatory diseases, in allergies and in rejection episodes after organ transplantation and thus to allow the prevention of these diseases and / or to improve the course or the severity of these diseases and / or cure these diseases. All of these diseases and the rejection episodes after organ transplantation are due to the lack of a sufficiently effective natural immunosuppressive principle, i.e. H. insufficiently functioning immunoregulatory cells, including deficient production of TGF-ßl.
• the induction of TGF- ⁇ 1 according to the invention is not restricted to individual antigen-specific T cell clones.
• the invention therefore also relates to the use of one or more inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity for the prevention and / or treatment of autoimmune disorders.
• the use according to the invention is preferred for the prevention and / or treatment of rheumatoid arthritis, lupus erythematosus, multiple sclerosis, IDDM, Crohn's disease, ulcerative colitis, psoriasis, neurodermatitis, glomerulonephritis, interstitial nephritis, vasculitis, autoimmune ScMeldhdäfflemischendiseases chronic anemia, autoimmune diseases with an inflammatory genesis such as arteriosclerosis.
• an inhibitor or several inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity are also used for the prevention and / or treatment of type I allergies according to Gell and Coombs or allergies of the type ⁇ , HI or IV.
• the use for the prevention and / or treatment of bronchial asthma or hay fever as type I allergy according to Gell and Coombs and / or contact allergies as type ⁇ , DI or IV allergies is preferred.
• the invention further relates to the use of one or more inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity for suppressing graft rejection, preferably in kidney or bone marrow transplants.
• inhibitors of alanyl aminopeptidases and all inhibitors of enzymes of the same substrate specificity come into consideration as inhibitors.
• Preferred are actinonin, leuhistin, phebestin, amastatin, bestatin, probestin, arphamenin, MR 387, ⁇ -aminothiols, ⁇ -aminophosphinic acids and their esters and salts, ⁇ -aminophosphonates, ⁇ -aminoboronic acids, ⁇ -aminoaldehydes, hydroxamates of ⁇ -amino acids, N-phenylphthalimide, N-phenylhomophthalimide, ⁇ -ketoamides, thalidomide and their derivatives are used.
• ⁇ -ketoamides, ⁇ -aminophosphinic acids, N-phenylhomophthalimides, ⁇ -aminophosphonates and phebestin are particularly preferred, 3-amino-2-oxo-4-phenylbutanoic acid amides being particularly preferred as ⁇ -ketoamides, D-Phe- as ⁇ -aminophosphinic acids ⁇ [PO (OH) -CH 2 ] -Phe-Phe, as N-phenylhomophthalimide PAQ-22, as ⁇ -aminophosphonates RB3014 and / or phebestin, and very particularly preferably PAQ-22, RB3014 and / or phebestin
• cytosolic alanyl aminopeptidase As an enzyme with the same substrate specificity as the alanyl aminopeptidases, cytosolic alanyl aminopeptidase may be mentioned here by way of example.
• PAQ-22 is specific for the cytosolic alanyl aminopeptidase.
• As a preferred inhibitor of the cytosolic alanyl Aminopeptidase is therefore used PAQ-22, or a mixture of several inhibitors comprising PAQ-22.
• the invention therefore also relates to the use of inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity for the induction of production of TGF- ⁇ 1 and expression of TGF- ⁇ 1 in and / or on Treg cells and for the prevention and / or treatment of Autoimmune diseases, allergies, hay fever, arteriosclerosis and to suppress transplant rejection, in which peptide fragments of pathogenic autoantigens or synthetic analogues and / or specific antigenic components of pathogenic microorganisms are additionally used.
• peptide fragments of pathogenic autoantigens or synthetic analogs and / or specific antigenic components of pathogenic microorganisms are additionally used.
• Preferred peptide fragments of pathogenic autoantigens in multiple sclerosis are MBP (myelin basic protein), MOG (myelin oligodendrocyte glycoprotein), MAG (myelin associated glycoprotein) and PLP (proteolipid protein), preferred specific antigenic components of pathogenic microorganisms are coat proteins or membrane glycolipid complexes.
• the invention therefore also relates to the use of one or more inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity for the manufacture of a medicament or a pharmaceutical preparation for inducing the production of TGF-ßl and expression of TGF-ßl in and / or on Treg cells.
• inhibitors of alanyl aminopeptidases and all inhibitors of enzymes of the same substrate specificity come into consideration as inhibitors. Actinonine, leuhistine, phebestine, amastatin, bestatin, probestin, arphamenine, MR 387, ⁇ -aminothiols, ⁇ -aminophosphinic acids and their esters and salts, ⁇ -aminophosphonates, ⁇ -aminoboronic acids, ⁇ -aminoaldehydes, hydroxamates of ⁇ -amino acids are preferred. N-phenylphthalimide, N-phenylhomophthalimide, ⁇ -ketoamides, thalidomide and their derivatives are used.
• ⁇ -ketoamides particularly preferred among these are ⁇ -ketoamides, ⁇ -aminophosphinic acids, N-phenylhomophthalimides, ⁇ -aminophosphonates and phebestin, 3-amino-2-oxo-4-phenylbutanoic acid amides being particularly preferred as ⁇ -ketoamides, D-Phe- as ⁇ -aminophosphinic acids ⁇ [PO (OH) -CH 2 ] -Phe-Phe, as N-phenylhomophthalimide PAQ-22, as ⁇ -aminophosphonates RB3014 and / or phebestin, and very particularly preferably PAQ-22, RB3014 and / or phebestin.
• cytosolic alanyl aminopeptidase As an enzyme with the same substrate specificity as the alanyl aminopeptidases, cytosolic alanyl aminopeptidase may be mentioned here by way of example.
• PAQ-22 is specific for the cytosolic alanyl aminopeptidase. PAQ-22 is therefore used as the preferred inhibitor of cytosolic alanyl aminopeptidase, or a mixture of several inhibitors comprising PAQ-22 is used.
• the invention also relates to the use of an inhibitor or several inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity for the production of a medicament or a pharmaceutical preparation for the prevention and / or treatment of autoimmune disorders, of type I allergies according to Gell and Coombs, such as hay fever, ⁇ , HI or IV type allergies and the use in the manufacture of a medicament or a pharmaceutical preparation for suppressing transplant rejection.
• Preferred diseases and types of transplantation are listed in subclaims 26, 27, 29 and 31.
• Preferred inhibitors of alanyl aminopeptidases and enzymes of the same substrate specificity are mentioned in claims 32 to 35.
• peptide fragments of pathogenic autoantigens in multiple sclerosis or synthetic analogues and / or specific antigenic components of pathogenic microorganisms may additionally be used, MBP (myelin basic protein), MOG (myelin oligodendrocyte glycoprotein), MAG (myelin associated glycoprotein) and / or PLP (proteolipid protein) and / or as specific antigenic components are more pathogenic as preferred peptide fragments of pathogenic autoantigens
• MBP myelin basic protein
• MOG myelin oligodendrocyte glycoprotein
• MAG myelin associated glycoprotein
• PLP proteolipid protein
• the present invention relates to a pharmaceutical preparation comprising an inhibitor or more inhibitors of alanyl aminopeptidases and / or enzymes of the same substrate specificity and one or more pharmacologically acceptable carriers, additives and / or auxiliaries.
• the invention also relates to a pharmaceutical preparation containing an inhibitor or several inhibitors of alanyl aminopeptidases and / or enzymes of the same substrate specificity and peptide fragments of pathogenic autoantigens or synthetic analogs and / or specific antigenic components of pathogenic microorganisms, and one or more pharmacologically acceptable carriers, additives - And / or auxiliary substances.
• the invention shows that for the treatment of inflammatory diseases and autoimmune diseases as well as allogeneic rejection reactions and allergies, for the development of which the proliferation and activation of pathogenic T cell clones play a central role, the application of inhibitors of the abovementioned enzymes or appropriate preparations and dosage forms are suitable.
• the simultaneous application of disease-specific antigens further increases this therapeutic effect and narrows the effect on the pathogenetically relevant process.
• the application of aminopeptidase inhibitors to induce TGF- ⁇ 1 expression in / on Treg cells and thus to increase the immunosuppressive function of this pathogenetically important inhibitory T cell population provides a novel method for the diseases mentioned and a supplementary one in the central one is a form of therapy that intervenes.
• inhibitors of alanyl aminopeptidases and / or of enzymes of the same substrate specificity can be used in pharmaceutically acceptable formulation complexes as inhibitors, substrates, pseudo-substrates, inhibitory peptides and peptide derivatives and as antibodies of this enzyme.
• Preferred inhibitors are Bestaun, Phebestin, Probestin, Actinonin, Leuhistin, RB3014, PAQ-22 and their derivatives, Phebestin, RB3014 and / or PAQ-22 are particularly preferred.
• the administration can take place in all suitable forms, for example as a topical application in the form of creams, ointments, pastes, gels, solutions, sprays, liposomes, shaking mixtures, hydrocolloid dressings or other dermatological bases / vehicles including instillative application or as a systemic application oral, transdermal, intravenous, subcutaneous, intracutaneous, inhalative, intramuscular use in suitable formulations or in suitable galenics or in connection with or incorporation into microparticles to overcome the blood-brain barrier.
• the application of "disease-specific" antigens petid fragments, lipopolysaccharides, etc.
• in appropriate dosage forms can increase the success of the therapy.
• TGF- / 31 human regulatory T lymphocytes (CD4 + CD25 + ) after incubation with the inhibitor phebestin.
• the T cells were incubated with phebestin for 24 hours without addition (control), with addition of PHA and PMA and with simultaneous addition of PHA / PMA.
• PHA phythema agglutinin
• PMA phorbol myristate acetate
• the surface expression of TGF-ßl was then measured using flow cytometry using the commercially available polyclonal anon-TGF-ßl antibody (chicken anti-human; R&D Systems). The results are shown in Figure 1.
• T cells were incubated for 24 hours without addition (control), with addition of PHA and PMA or with simultaneous addition of PHA PMA with phebestin.
• PHA phytoaddition factor
• PMA phorbol myristate acetate
• the content of TGF / 31 mRNA was then determined by means of quantitative RT-PCR using the i-cycler. The results are shown in Figure 2.
• T cells were incubated with PAQ-22 for 24 hours without addition (control), with addition of PHA and PMA or with simultaneous addition of PHA / PMA.
• PHA phytoaddition factor
• PMA phorbol myristate acetate
• T cells were incubated with RB3014 for 72 hours without addition (control), with addition of PHA and PMA or with simultaneous addition of PHA / PMA.
• PHA phytoaddition factor
• PMA phorbol myristate acetate
• the content of TGF- ⁇ 1 mRNA was then determined by means of quantitative RT-PCR using the i-cycler. The results are shown in Figure 4.

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