WO2015044761A1 - Dérivé d'acide diaminodécanedioïque utile en tant qu'inhibiteur de l'activité de il -15 et de il -2 - Google Patents

Dérivé d'acide diaminodécanedioïque utile en tant qu'inhibiteur de l'activité de il -15 et de il -2 Download PDF

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WO2015044761A1
WO2015044761A1 PCT/IB2014/001939 IB2014001939W WO2015044761A1 WO 2015044761 A1 WO2015044761 A1 WO 2015044761A1 IB 2014001939 W IB2014001939 W IB 2014001939W WO 2015044761 A1 WO2015044761 A1 WO 2015044761A1
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diaminodecanedioic
acid derivative
acid
cells
treatment
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PCT/IB2014/001939
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Katarzyna KOZIAK
Barbara ŻYŹYŃSKA-GRANICA
Sławomir FILIPEK
Szymon NIEWIECZERZAŁ
Bartosz TRZASKOWSKI
Oliwia Zegrocka-Stendel
Małgorzata DUTKIEWICZ
Piotr KRZECZYŃSKI
Elżbieta KACZMAREK
Magdalena Winiarska
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Warszawski Uniwersytet Medyczny
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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

Definitions

  • Diaminodecanedioic acid derivative as the inhibitor of IL-15 and IL-2 activity.
  • the present invention relates to the diaminodecanedioic acid derivative for the use in the treatment of the diseases related to interleukin 15 and interleukin 2 overproduction, such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, sarcoidosis, T-cell leukemias or transplant rejection.
  • diseases related to interleukin 15 and interleukin 2 overproduction such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, sarcoidosis, T-cell leukemias or transplant rejection.
  • Interleukin 15 is the cytokine exerting pleiotropic activity towards immune system cells as well as other cell types. IL-15 exhibits broad spectrum bioactivity, therefore it is placed at the top of the pro-inflammatory cytokines cascade. The impairment of the mechanisms regulating the .expression of the IL-15 results in the overproduction of this cytokine and contributes directly to the development of such pathologies as inflammatory processes, autoimmune diseases, infections and neoplastic changes. IL-15 is considered a crucial cytokine in the etiology of rheumatoid arthritis (Mclnnes I.B. et al. , Nat. Med. 2, 175-82 (1996; Mclnnes I.B.
  • mice model of the disease Villadsen L.S. et al. , J. Clin. Invest. 1 12, 1571 -80 (2003)
  • reduction of carrageenan-induced inflammation in mice Wei X et al., J. Immunol. 167, 277-82 (2001 )
  • mice prolonged survival of heart allotransplants
  • RA Rheumatoid arthritis
  • connective tissue which affects on average about 1 % of the world's population.
  • Recent estimates have shown higher prevalence in women than in men (3: 1 ).
  • the highest prevalence of RA has been reported in the 30-60 age range. According to the estimates, about 30% of people afflicted with RA suffer from severe symptoms and within several years end up with a disability.
  • the average life span of people suffering from RA is about 10 years shorter, according to the statistical data. It is thought that the onset of RA results from the complex combination of many factors, such as genetic predisposition, impaired innate and acquired immune response and environmental components. Pharmacological treatment of RA, currently available on the medical market, does not remove the cause of the disease.
  • Non-steroidal anti-inflammatory drugs are medications, which as well as having pain-relieving (analgesic) effects, have the effect of reducing the inflammation, when used over a period of time. They suppress the symptoms of the disease, but do not stop the progress of the illness.
  • DMARDs disease-modifying antirheumatic drugs
  • the other synthetic DMARDs are leflunomide, sulfasalazine, hydroxychloroquine, D-penicillamine, gold salts, azathioprine, cyclosporine and cyclophosphamide.
  • TNF tumor necrosis factor
  • infliximab chimeric anti-TNF monoclonal antibody
  • etanercept fusion protein, consisting of the extracellular receptor domain p75 for TNF and the Fc fragment of the human antibody lgG1 );
  • fusion protein composed of the Fc region of the immunoglobulin lgG1 fused to the extracellular domain of CTLA-4.
  • rituximab chimeric monoclonal antibody against the protein CD20 primarily found on the surface of mature B cells acting by eliminating B cells.
  • Tocilizumab humanized monoclonal antibody against interleukin 6 receptor, has been approved for the European pharmaceutical market as the first IL-6 inhibitor.
  • phase II clinical trials carried out by Amgen company with AMG-714 previously HuMax-IL15
  • HuMax-IL15 human monoclonal antibody that targets IL-15
  • Peptides of modified sequences mimicking IL-15 have also been proposed as potential pharmaceuticals in the rheumatoid arthritis treatment. These peptides are supposed to bind to the receptor IL-15Ra subunit, which should result in the inhibition of T cells proliferation, diminished TNF-a induction as well as expression of IL-8 and IL-6. To date the efficacy of these new compounds has not been proved in clinical studies.
  • cytokines which participate in the pathogenesis of inflammatory diseases, induced by interleukin 15 overproduction.
  • interleukin 2 In the complex network of the immune mediators, interleukin 2 (IL-2) is regarded the pivotal cytokine controlling proliferation and differentiation of the immune cells.
  • IL-2 activates, among others, proliferation and differentiation of T lymphocytes, differentiation of T lymphocytes towards cytotoxic T lymphocytes, growth and differentiation of B lymphocytes, activation and proliferation of NK cell, and macrophages activation. Under physiological conditions IL-2 is not detected in a blood serum. Due to its contribution to the activation and stimulation of the effector function of the immune cells, this cytokine is considered one of the chief inflammatory mediators in the autoimmune diseases.
  • IL-2 is released predominantly by activated T helper lymphocytes (CD4+), it is also secreted by CD8+ T lymphocytes, dendritic cells and thymus-derived lymphocites (128).
  • the downstream effect of IL-2 occurs through its high-affinity binding to the receptor IL-2R, consisting of three subunits: IL-2Ra subunit, which is IL-2 specific and IL-2R3 and IL-2Ry subunits, which are shared with IL-15.
  • Serum soluble form of IL-2 receptor (slL-2Ra, Tac peptide) is released into circulation by the immune cells.
  • IL-2/IL-2R complex and/or their antagonists, for example, murine monoclonal antibodies (anti-TAC-M) directed toward the human slL-2Ra receptor, are used in the medical treatment. Due to their strong immunogenicity, humanized monoclonal antibodies (anti-TAC-H) recently have been engineered and introduced into clinical practice.
  • Anti-Tac diaclizumab, Zenapax
  • the monoclonal antibodies prevent IL-2 binding, among others, to T lymphocytes, thus hampering IL-2 mediated cell response involved in the process of allograft rejection. (WWW.drugbank.ca/drugs/BTD00007).
  • the known small chemical molecules of potential application in rheumatoid arthritis, which interfere with the interaction of the receptor IL-15Ra and its ligand (IL-15) are only phenylpyrazole anilide derivatives, disclosed by Ushio H. et al. in Letters in Drug Design Discovery, 5, 292-296 (2008),.
  • the molecule Y-320 belonging to the aforementioned group of compounds of proven high bioavailability and in vitro activity, inhibits IL-15-induced T cells activity.
  • the aim of the present invention was to select a molecule, which would effectively inhibit the biological activity of both IL-15 and IL-2 by selective binding to IL-15 specific IL-15Ra receptor and concomitant blocking IL-2Rp as well as IL-2Ry receptor subunits shared by these two cytokines.
  • the present invention provides 2,9-diaminodecanedioic acid as the inhibitor of IL-15Ra and shared by IL-15 and IL-2, IL-2R IL-2Ry receptor subunits, which can be used in the prevention and treatment of the diseases related to interleukin 15 and interleukin 2 overproduction.
  • Fig. 1 shows the effect of 2,9-diaminodecanedioic acid on proliferation of IL-15-stimulated PBMC.
  • Fig. 2 shows the effect of 2,9-diaminodecanedioic acid on proliferation of IL-2 -stimulated PBMC.
  • Fig. 3 shows the effect of 2,9-diaminodecanedioic acid on IL-15-induced TNF-a synthesis in PBMC.
  • Fig. 4 shows the effect of 2,9-diaminodecanedioic acid on IL-2-induced TNF-a synthesis in PBMC.
  • Fig. 5 shows the effect of 2,9-diaminodecanedioic acid on IL-15-induced IL-17 synthesis in PBMC.
  • Fig. 6 shows the effect of 2,9-diaminodecanedioic acid on IL-2-induced IL-17 synthesis in PBMC. Disclosure of the invention
  • 2,9-Diaminodecanedioic acid derivative for use according to the invention can be 2,9- diaminodecanedioic acid as the single optical isomer thereof or the mixture of optical isomers at any ratio, as for example racemic mixture.
  • the present invention encompasses the use of 2,9-diaminodecanedioic acid as the racemic or the non-racemic mixture, the single optical isomer as well as the pharmaceutically acceptable salts and aliphatic esters thereof, such as dimethyl or diethyl ester.
  • 2,9-Diaminodecanedioic acid also referred to as 2,9-diaminosebacic acid
  • 2,9-diaminosebacic acid is commonly known as the starting material in peptides and polyamides synthesis.
  • the single optical isomers of 2,9-diaminodecanedioic acid can be obtained according to any method known to those skilled in the art, such as chiral HPLC or enzymatic or using chiral auxilary resolution or they can by synthesized in a enantioselective manner from the chiral starting compounds.
  • 2,9-Diaminodecanedioic acid derivatives can be also prepared and used as the pharmaceutically acceptable salts with acids.
  • the term ..pharmaceutically acceptable salts refers to the salts formed with the pharmaceutically acceptable inorganic and organic acids.
  • the inorganic acids belong to the group comprising, for example, hydrochloric, hydrobromic, sulfuric and nitric acids.
  • the organic acids belong to the group comprising, for example, fumaric, maleic, phosphoric, glycolic, lactic, adipic, ascorbic, salicylic, succinic, tartaric, acetic, citric, formic, benzoic, malonic, p-toluenesulfonic, methanesulfonic, naphthalene-2-sulfonic, benzenesulfonic acids and the others.
  • the preferred salts of 2,9-diaminodecanedioic acid derivatives are the salts with hydrochloric acid.
  • 2,9-diaminodecanedioic acid derivative is ( ⁇ )-2,9-diaminodecanedioic acid hydrochloride.
  • the preferred aliphatic esters of 2,9-diaminodecanedioic acid for use according to the invention are the esters with C 1-3 alcohols, such as dimethyl or diethyl ester.
  • 2,9-diaminodecanedioic acid derivative can be used to hamper IL-15 and IL-2-induced excessive cells' responses, due to blocking IL-15 specific IL- 15Ra receptor and IL-2R and IL-2Ry receptor subunits, shared by these two cytokines.
  • 2,9-diaminodecanedioic acid derivative can be used in the prevention and treatment of the diseases from the group comprising rheumatoid arthritis, psoriasis, inflammatory bowel disease, sarcoidosis, T-cell leukemias and transplant rejection.
  • 2,9-diaminodecanedioic acid derivative can be used in the treatment of rheumatoid arthritis.
  • 2,9-diaminodecanedioic acid derivative can be administered to an individual in the need of such a treatment, in particular to a human, at therapeutically effective dose.
  • treatment refers to the suppression of a state, a disorder or a disease, which means inhibition, reduction or delay of the disease development, recurrence of the illness or at least one of its symptoms, or a recovery, meaning the regression of a state, a disorder or a disease or at least one of its symptoms.
  • the term 'therapeutically effective dose' refers to the amount of the compound sufficient to produce a therapeutic response when administered to an individual in order to cure a state, a disorder or a disease.
  • the 'therapeutically effective dose' will vary depending on the nature of the selected compound and the route of its administration, a kind of a disease and its status, age, body weight, physical condition, susceptibility to the treatment of the patient, and it can be recommended by a skilled physicians on the basis of their own experience and the results of clinical trials.
  • the daily therapeutic dose of 2,9-diaminodecanedioic acid derivative can be administered as a single dose or divided doses administered in certain intervals of time, for example as two, three, four or more daily doses.
  • 2,9-diaminodecanedioic acid derivative per se may be considered, in general it will be used as active ingredient of the pharmaceutical formulation, of the appropriate finished dosage form suited to the particular route of administration.
  • Another embodiment of the present invention relates to the use of 2,9- diaminodecanedioic acid derivative for manufacturing of the pharmaceutical formulation for the prevention or treatment of the diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, sarcoidosis, T-cell leukemias or transplant rejection.
  • the other embodiment of the present invention relates to the pharmaceutical formulation comprising 2,9-diaminodecanedioic acid derivative as the active ingredient and the pharmaceutically acceptable carriers and/or excipients for the prevention or treatment of the diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, sarcoidosis, T-cell leukemias or transplant rejection.
  • the pharmaceutical formulation - except for the active ingredient - may also contain traditional pharmaceutically acceptable carriers and/or excipients which are inert and do not interact with the active ingredient.
  • the pharmaceutical composition may be formulated in any pharmaceutical form suitable for the systemic administration, for example oral administration, such as tablets and capsules, starch capsules, coated tablets or enteric tablets; as powders or granules; as a solution, a suspension or an emulsion.
  • Tablets and capsules for oral administration may contain excipients routinely used in pharmaceutical practice, such as binders, diluents, disintegrants or lubricants.
  • the tablets may be coated by any method known in the art.
  • Liquid pharmaceutical compositions for oral administration may be manufactured as, for example, aqueous or oily suspensions, solutions, emulsions, syrups and elixirs or they may be produced as dry substances for the preparation of solutions or suspensions ex tempore with water or other suitable diluent.
  • Liquid pharmaceutical formulations may contain excipients routinely used in pharmaceutical practice, such as dispersing and emulsifying agents, non-aqueous carriers (they may comprise eatable oils) or preservatives. The selection and amount of the excipients depends on the pharmaceutical dosage form and the route of drug administration.
  • the pharmaceutical composition may be formulated into any suitable pharmaceutical form, by any method known in the art, using any pharmaceutically acceptable carriers, diluents, fillers and other excipients.
  • the pharmaceutical formulation for oral administration may be formulated, in particular, as capsules.
  • the active substance is combined with the carrier and the resulting composition is used to fill in gelatin shells.
  • the gelatin capsules can be manufactured as having soft or hard gelatin shells, depending on the composition of gel mass used in the production process.
  • Soft capsules' gel mass consists of plasticizers, such as glycerol, sorbitol; preservatives, such as benzoic acid, its salts and alkyl hydroxybezoates, colorants and flavors.
  • the capsules' filling may be used as oily solution, suspension or emulsion.
  • the suitable diluents embrace, for example castor oil, coconut oil, olive oil, palm oil, corn oil, arachis oil, synthetic and natural triglycerides of fatty acids, unsaturated medium-chain fatty acids, modified long-chain fatty acids, glycol esters, polyethylene glycols and others.
  • Suitable excipients comprise tensides, for example lecitin, mono- and diglycerides, fatty acids esters with polyoxoethylene sorbitane.
  • the pharmaceutical formulation suitable for parenteral administration may be used as a ready suspension, lyophilizate, suspension ex tempore or concentrate for intravenous infusions.
  • These formulations may be formulated as unit dosage forms in ampoules, initially filled syringes, low capacity infusions, or in multi-dosage containers consisting of preservatives and carriers, diluents, stabilizers and/or dispersing agents.
  • the carriers suitable for the intravenous administration of the pharmaceutical formulation comprise, for example, sterile aqueous solutions, such as the solution of physiological salt, the solutions of carbohydrates, for example, glucose, mannitol, dextrose, lactose and aqueous buffer solutions, for example, phosphate buffers.
  • the pharmaceutical composition may also contain other excipients routinely used to maintain isoosmoticity, antioxidants, preservatives and others.
  • the active ingredient may be used as the powder obtained due to isolation of a solid compound under septic conditions or by lyophilisation from the solvent, for the preparation of suspensions ex tempore in a suitable diluent, for example, sterile water deprived of pyrogenic substances.
  • 2-induced cells' response has been proved during in vitro studies.
  • the results have also demonstrated inhibition of cell proliferation as well as reduced synthesis of TNF-ct and IL-17, induced by the said cytokines.
  • 2,9-diaminodecanedioic acid derivative will have the potential to be used in the prevention and treatment of IL-15 overproduction related diseases and inflammations, such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, sarcoidosis, T-cell leukemias or transplant rejection.
  • PBMC peripheral blood mononuclear cells
  • PBMC peripheral blood mononuclear cells
  • 2,9-Diaminodecanedioic acid (R6) was initially selected at the screening stage, on the basis of the three dimensional structure of the model of [IL-15Ra y - IL-15] protein complex. 2,9-Diaminodecanedioic acid was used as salt with hydrochloric acid.
  • bromodeoxyuridine (BrdU) was added to the culture medium at the concentration recommended by the manufacturer. After the completion of the incubation cells were centrifuged (10 min., 160xg) and fixed. Further experimental steps were performed according to the manufacturer's protocol.
  • Fig. 1 and Fig. 2 The effects of 2,9-diaminodecanedioic acid at different concentrations on IL-15 and IL- 2-induced PBMC proliferation are presented in Fig. 1 and Fig. 2 respectively. The results are expressed as the percentage change of proliferating cells with regard to the control cells stimulated with IL-15 or IL-2.
  • PBMC peripheral blood mononuclear cells
  • Fig. 3 The effect of 2,9-diaminodecanedioic acid at different concentrations (20 ⁇ , 50 ⁇ , 100 ⁇ and 200 ⁇ ) on IL-15-induced TNF- ⁇ synthesis in PBMC is depicted in Fig. 3.
  • Fig. 4 The effect of 2,9-diaminodecanedioic acid at 100 ⁇ concentration on IL-2-induced TNF-a synthesis in PBMC is depicted in Fig. 4.
  • 2,9-Diaminodecanedioic acid significantly reduces IL-15 or IL-2-induced TNF-a synthesis in PBMC in comparison with the IL-15 and IL-2 stimulated control cells.
  • PBMC peripheral blood mononuclear cells
  • IL-15 5 ng/ml
  • IL-2 5 ng/ml
  • the culture medium was collected from each well to determine the IL-17 concentration, cells were harvested and lysed, and the concentration of total protein was measured in cell lysates.
  • the obtained values of IL-17 concentration were calculated for 1 mg of protein. The results are expressed as the percentage change of the concentration of IL-17 synthesized in PBMC with regard to the control cells stimulated with 11-15 or IL-2.
  • Fig. 5 The effect of 2,9-diaminodecanedioic acid at different concentrations (20 ⁇ , 50 ⁇ , 100 ⁇ and 200 ⁇ ) on the IL-15-induced IL-17 synthesis in PBMC is depicted in Fig. 5.
  • Fig. 6 The effect of 2,9-diaminodecanedioic acid at 100 ⁇ concentration on IL-2-induced IL-17 synthesis in PBMC is depicted in Fig. 6.
  • 2,9-Diaminodecanedioic acid significantly reduces IL-15-induced IL-17 synthesis in
  • PBMC in comparison with IL-15-stimulated control cells. Strong inhibitory effect of 2,9- diaminodecanedioic acid on IL-17 synthesis is also observed in cells stimulated with IL-2.
  • Increased cell proliferation is one of the characteristic responses to IL-15 or IL-2 stimulation.
  • IL- 5 or IL-2-induced increase of cell proliferation does not occur.
  • PBMC peripheral blood mononuclear cells isolated from blood of healthy donors was evaluated in the assay using a fluorescent CSFE dye (Molecular Dynamics, Great Britain) and in the bromodeoxyuridine incorporation test (BrdU) (BrdU Cell Proliferation Assay, Calbiochem, USA).
  • PBMC population consists of several cell types, among others, there are lymphocytes and monocytes. Due to expression of IL-15 and IL-2 receptors on the surface of the membrane, extensive proliferation of these cells occurs in response to interleukin 15 or interleukin 2 stimulation .
  • the inhibition of cell proliferation in the presence of the tested compound can be a visible sign of the cells' death caused by the cytotoxic or apoptotic activity of the analyzed compound.
  • the effect of 2,9-diaminodecanedioic acid on cells' viability was tested measuring the lactate dehydrogenase (LDH) concentration in the culture medium and cultured cells (CytoTox 96 Non-Radioactive Cytotoxicity Assay, Promega, USA).
  • LDH lactate dehydrogenase
  • CytoTox 96 Non-Radioactive Cytotoxicity Assay, Promega, USA LDH is a cytosolic enzyme which under physiological conditions is not released from cells. However, when a cell membrane damage or cell death occurs, LDH enzyme is released into the matrix. Increased LDH activity in the culture medium correlates with the increased number of dead cells resulting from the cytotoxic effect of the tested compound.
  • LDH activity measured in cell lysates is used for the assessment of a number of living cells.
  • the results of the following study has demonstrated biological activity of 2,9-diaminodecanedioic acid, which inhibits 11-15 or IL-2- induced PBMC proliferation and does not trigger the apoptotic pathway.
  • the experiments were repeated three time on PBMC form different donors.
  • PBMC Peripheral blood mononuclear cells
  • IL-15 or IL-2 stimulation not only by increased proliferation, but also by synthesizing many pro-inflammatory cytokines, among others, for example, TNF-a and IL-17.
  • the inhibition of IL-15 and IL-2 biological activity should result in the reduced cell proliferation and decreased syntheses of TNF-a and IL-17.
  • 2,9-Diaminodecanedioic acid at different concentrations was used to assess its effect on IL-15 and IL-2-iduced other cytokines syntheses.
  • the biological activity of 2,9- diaminodecanedioic acid was evaluated measuring the TNF-a and IL-17 concentrations in the culture media collected after the completion of the incubation, using the immunoenzymatic ELISA tests.

Abstract

La présente invention se rapporte à un dérivé d'acide 2,9-diaminodécanedioïque destiné à être utilisé en tant qu'inhibiteur des récepteurs IL -15 et IL -2 dans la prévention et le traitement des maladies liées à la surproduction de IL -15 et de IL -2.
PCT/IB2014/001939 2013-09-30 2014-09-29 Dérivé d'acide diaminodécanedioïque utile en tant qu'inhibiteur de l'activité de il -15 et de il -2 WO2015044761A1 (fr)

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