WO2016009253A1 - Une interleukine 15 recombinante est un agent thérapeutique pour le traitement de l'hyperactivité, la résistance (obstruction) et la fibrose des voies respiratoires dans l'asthme chronique - Google Patents

Une interleukine 15 recombinante est un agent thérapeutique pour le traitement de l'hyperactivité, la résistance (obstruction) et la fibrose des voies respiratoires dans l'asthme chronique Download PDF

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WO2016009253A1
WO2016009253A1 PCT/IB2014/063161 IB2014063161W WO2016009253A1 WO 2016009253 A1 WO2016009253 A1 WO 2016009253A1 IB 2014063161 W IB2014063161 W IB 2014063161W WO 2016009253 A1 WO2016009253 A1 WO 2016009253A1
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fibrosis
rll
airway
asthma
mice
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PCT/IB2014/063161
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Anil Mishra
Akanksha MISHRA
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Anil Mishra
Mishra Akanksha
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2086—IL-13 to IL-16
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • RECOMBINANT INTERLEUKIN-15 IS A THERAPEUTIC AGENT FOR THE TREATMENT OF AIRWAY HYPERACTIVITY, RESISTANCE (OBSTRUCTION) AND FIBROSIS IN CHRONIC ASTHMA
  • the invention disclosed herein generally related to the treatment and/or management of airway obstruction including resistance, hyperactivity and lung/esophageal fibrosis.
  • rlL-15 or IL-15 overexpressed by its agonist is a novel molecule for the treatment and management of pulmonary functional abnormalities like airway hyperreactivity, obstruction or fibrosis in chronic lung and esophageal inflammation.
  • Chronic asthma is normally associated with the esophageal inflammation, a disease termed as eosinophilic esophagitis (EoE) [Mishra et al. 2001, J. Clin. Invest. 2001, 103, 83-90].
  • IL-15 expression has been observed across a range of pulmonary inflammation, including chronic obstructive airways disease, sarcoidosis and pulmonary tuberculosis, compare to the healthy volunteers or in those with asthma (Muro, et al J Allergy Clin Immunol, 108, 2001, 970-975), Additionally, IL-15 is also found induced in the sputum of steroid-treated patients compared with that of untreated asthmatic patients ⁇ Komai- Koma, et al Clin Exp Allergy, 31, 2001, 1441-1448).
  • IL-15 transgenic expression suppressed development of ovalbumin-induced Tc1 responses in asthma (ishimitsu, et al J Immunol, 166, 200), 1991-2001).
  • IL-15 does not represent a therapeutic target in asthma.
  • IL-15 is shown as a pro-inflammatory factor in macrophage-dominant pulmonary conditions.
  • IL-15- mediated T cell and macrophage activation have also been reported; but it has been also shown that IL-15 protects TNFa-induced leukocyte apoptosis (Hiromatsu, et al J Infect Dis, 187 2003, 1442-1451).
  • IL-15 was shown to be an important trigger for IL-17-mediated pulmonary inflammation (Ziolkowska, J Immunol, 164, 2000, 2832-2838) and suggest a direct link between IL-15 and downstream leukocyte effector function and matrix damage.
  • Keratinocytes express both IL-15 and IL-15Ra, suggesting a role in autocrine regulation of keratinocytes in dermal inflammatory responses.
  • the dermal induction of IL-15 is associated with cutaneous malignancy
  • Asthma is a chronic, inflammatory pulmonary airway disease characterized by activation of inflammatory cells and mediators, variable obstruction, hyperresponsiveness and remodelling of the airway (Bousquet et al Am J. Res. Crit. Care Med 2000, 161:1720-1745; Postma and Kerstjens, Am J. Res. Crit. Care Med. 198, 158:S187-192; Skloot et al. 1985, 96:2393-2403).
  • In the United States nearly 25 million of the population, 8% adult and 9% children are suffering from asthma, a chronic inflammatory pulmonary disorder responsible for over 5000 deaths/year (http://www.aafa.org).
  • Antigen presenting cells interact with and activate T cell subsets (e.g. Th2) and initiate a series of immunological responses.
  • Th2 T cell subsets
  • a number of investigations provide evidence that asthma is a Th2-type malady that is induced in response to food and environmental antigens (Hogan et al. Nature immunology 2001, 2:353-360; Mishra et al. The Journal of clinical investigation 2001, 107:83-90; Rayapudi et al. Journal of leukocyte biology 2011, 88:337-346).
  • the airway inflammatory response in asthma is characterized by induced expression of multiple genes encoding cytokines, chemokines, and adhesion molecules, which are associated with recruitment of eosinophils and Th2 lymphocytes (Cohn, et al. Annual Review of Immunology 2004, 22:789-815).
  • chronic asthma is characterized by structural changes that are termed airway remodeling (Cohn, et al. Annual Review of Immunology 2004, 22:789-815; Davies et al. J. Allergy Clin. Immunol. 2003, 111:215-225).
  • Remodeling-associated changes in the airway include peribronchial fibrosis with increased deposition of collagen (types I, III, and V), smooth muscle hypertrophy/hyperplasia, and mucus secretion (Cohn, et al. Annual Review of Immunology 2004, 22:789-815; Davies et al. J. Allergy Clin. Immunol. 2003, 111:215-225). Repeated cycles of inflammation and repair in the airway in chronic asthma are considered to be the driving force for airway remodeling.
  • Fibrosis is important as it can occur early in the pathogenesis of asthma, and be associated with severity and resistance to therapy (Durrani et al. The Journal of allergy and clinical immunology 12011, 28:439-448). [0012] Fibrosis is not directly targeted or effectively treated by current asthma drugs including corticosteroids, characterization of airway fibrosis and how it is regulated will be essential for the development of novel therapies for asthma and other lung diseases (Becky Kelly, et al. American Journal of Respiratory and Critical Care Medicine 162:883-890).
  • Airway and parenchymal fibrosis can also be caused by other chronic inflammatory processes, infections, and exposure to a number of environmental agents like asbestos, silica, ionizing radiation and adverse side effects of certain medications (du Bois, Journal of the European Respiratory Society 2011, 20:132-133; Jeffery, American journal of respiratory and critical care medicine 2001; Naik, et al. American journal of physiology.2012, 164.S28-38; Phillips et al. Pulmonary pharmacology & therapeutics 2012, 25:281-285. Wells and Keiieher American journal of respiratory and critical care medicine 2013, 187:677-679; Zolak and de Andrade, Immunology and allergy clinics of North America 2012, 32:473-485).
  • Chronic asthma is a pulmonary disease characterized by inflammation and narrowing of the lung's small and medium airways, which eventuates in bronchial hyperactivity/obstruction and fibrosis (Kerstjens, Am J. Res. Crit. Care Med. 198, 158.S187-192; Skloot et al. 1985, 96:2393-2403).
  • Bronchial obstruction and fibrosis is developed not only in chronic asthma; but also subsequent to cigarette smoking, certain viral infections, exposure to number of environmental pollutants, as adverse effects of certain medicines, and autoimmune diseases, (du Bois, Journal of the European Respiratory Society 2011, 20:132-133; Jeffery, American Journal of Respiratory and Critical Care Medicine 2001; Naik, et al. American Journal of Physiology.2012, 164:S28-38; Phillips et al. Pulmonary Pharmacology &Ttherapeutics 2012, 25:281-285. Wells and Keiieher American Journal of Respiratory and Critical Care Medicine 2013, 187:677-679; Zolak and de Andrade, Immunology and Allergy Clinics of North America 2012, 32:473-485).
  • pulmonary asthma including fibrosis. Apart from bronchial obstruction, airway hyperactivity and remodeling in chronic asthma, other pulmonary functional abnormalities like idiopathic pulmonary fibrosis (IPF) affects between 132,000- 200,000 people (Johnson and Raghu. European Respiratory Journal 2005, 26:755-758; Raghu et al. American Journal of Respiratory and Critical Care Medicine 2006, 174:810-816).
  • IPF idiopathic pulmonary fibrosis
  • IL-15 is a yC cytokine and a member of the four a-helix bundle cytokine family. IL-15 is produced by a number of inflammatory cells including dendritic cells and epithelial cells (Under et al. The Journal of Investigative Dermatology 1998, 110:457-458; Morelli, et al. Blood 2001, 98:1512-1523). IL-15 is a requisite for the generation or maintenance of specific hematopoietic lineages.
  • IL-15 or IL-15 receptor (IL-15R)a defects are observed in naive and memory CD8 T cells, intestinal intraepithelial lymphocytes (IEL), and natural killer (NK) and NKT lineages (Kennedy and Park, Journal of Clinical Immunology 1996, 16:134-143; Lodolce, Immunity 1998, 9:669-676).
  • IL-15 can have various roles in development and homeostasis. IL-15 can act to increase survival, induce proliferation, and/or drive differentiation of hematopoietic cells.
  • the receptor for IL-15 is composed of an IL-15Ra chain, capable of binding IL-15 with high affinity in the absence of other receptor subunits, the IL-15/IL-2 receptor ⁇ chain, and the yC chain (Anderson, et al. Journal of Biological Chemistry 1995, 270:29862-29869; Giri, et al. Journal of Leukocyte Biology 1995, 57:763-766).
  • Soluble IL-15 can bind the IL-15R complex and induce signals in a manner similar to other cytokines and cytokine receptors (Giri, et al. Journal of leukocyte biology 1995, 57:763-766; Grabstein, et al. Science 1994, 264:965- 968).
  • IL-15 has been shown to increase cytokine production (Mori, et al. Journal of immunology 1996, 156:2400-2405), stimulate antibody production (Ruckert et al. Journal of Immunology 1998, 174:5507- 5515), and inhibit apoptosis of T cells, B cells and epithelial cells (Bulfone-Paus et al.
  • IL-15 has been implicated in the inflammatory responses of various infectious and autoimmune diseases including IBD, sarcoidosis, and chronic active hepatitis (Agostini et al. Journal of Immunology 1996, 157:910-918; Kakumu et al. Clin Exp Immunol 1997, 109:458- 463; Kirman and Nielsen, Am J Gastroenterol 1996, 91:1789-1794).
  • the lung and esophagus are the primary sites of entry for noxious environmental or food allergens that can trigger airway or esophagus remodeling, which contributes significantly to chronic asthma and eosinophil esophagitis (EoE).
  • the Important pathologic components associated to the tissue remodeling include fibrosis and abnormal innate and adaptive immune responses.
  • the asthma and EOE patients are associated with structural changes within the lung and esophagus including sub-epithelial fibrosis as well as chronic eosinophil's infiltration.
  • Recombinant IL-15 is a future therapeutic agent to treat the lung and esophageal fibrosis in asthma and eosinophilic esophagitis (EoE), not limited to only theses two diseases but may be applied to other tissue fibrosis. Most importantly, our data first time provide a therapeutic molecule (rlL-15) for the treatment of airway hyperreactivity and resistance in bronchial chronic asthma.
  • rlL-15 down regulates IL-13 and restricts goblet cell hyperplasia responsible for airway hyperreactivity and kills the fibroblasts that are responsible for collagen production, tissue remodeling and fibrosis. Fibroblast is the potent inducer of tissue fibrosis.
  • FIG. 1 rlL-15 treatment reduces fibrosis-associated proteins like a- SMA and collagen-1 and TGF- ⁇ in the lung following the induction of experimental asthma in mice.
  • the Western Blot immunobloting analysis of fibrosis associated proteins in the lung homogenates in response to aspergillus, saline and rlL-15 (15 microgram/2x/week) intratracheal ly treated aspergillus challenge mice is shown in the figure below.
  • the aspergillus challenge (group 1 ) induces all the three proteins level compare to saline (group 2), but rlL-15 treated and aspergllus challenged (group 3) mice show reduced expression compare to the aspergillus treated (group 1 ) alone.
  • GAPDH (housekeeping gene) expression shows that equal level of proteins is analyzed for a-SMA, TGF- ⁇ and collagen-1 protein levels in the lungs of each mouse. These data indicates that rlL-15 treatment protects fibrosis by down regulating fibrosis-inducing genes in the lung.
  • FIG. 1 rlL-15 pharmacological treatment protects mice from the induction of asthma and fibrosis associated Th2 (IL-5 and IL-13) and Th3 (TGF-beta) cytokines in Aspergillus-induced experimental asthma.
  • Th2 IL-5 and IL-13
  • TGF-beta Th3 cytokines
  • FIG. 3 rlL-15 pharmacological treatment protects mice from the lung accumulation of fibroblast in Aspergillus-induced experimental asthma.
  • the aspergillus challenged mice lung show high accumulation of fibroblast accumulation compare to saline challenged mice (B, original magnification 200x) and a reduced number of fibroblast accumulation in the lungs following rlL-15 treatment is shown (C).
  • Fibroblast are responsible for promoting fibrosis.
  • FIG. 4 Histopathological representation of reduced collagen (indicator of tissue fibrosis) accumulation in the lung and esophagus of rlL- 15 treatment in the aspergillus-induced mouse model of asthma and EoE.
  • the collagen accumulation in the lung and esophagus of mice following saline (1 A), aspergillus (1 B) challenged and Aspergillus challenged treated with recombinant rlL-15 treatment (15 microgram/2x/week) intratracheally is shown in the lung (1 C) (Original magnification 125x).
  • the collagen accumulation following saline (2D), Aspergillus (2E) and rlL-15 treated Aspergillus challenged (2F) mouse esophagus is shown.
  • Collagen accumulation is detected by trichrome staining, the saline treated mice show a base line collagen accumulation in the lung and esophagus that is significantly induced following Aspergillus treatment and reduced to baseline following rlL-15 treatment. Induced collagen accumulation is a characteristics feature of tissue remodeling and fibrosis.
  • FIG. 5 rlL-15 promotes concentration dependent fibroblast ( cells that promote fibrosis) apoptosis.
  • A. Flowcytometric analysis of apoptosis cells and dead cells treated with or without rlL-15 for 24h. Annexin-V positive cells are the apoptotic cells, live dead marker are the dead cells (a) control cells without rlL-15, treated with medium alone (b). Fibroblasts treated with 10 pg/ml of rlL-15 (c). Fibroblasts treated with 100 pg/ml of rlL-15 (d). Fibroblasts treated with 10 ng/ml and (e) 100ng/ml rlL-15.
  • FIG. 6 Pharmacological delivery of rlL-15 reduces goblet cell hyperplasia (cells responsible for mucus production and airway resistance) in the lungs of mice following the induction of Aspergillus-induced experimental asthma.
  • a representative light microscopic photomicrograph of lungs sections of saline, aspergillus and aspergillus challenged IL-15 treated (intratracheally, 15 microgram/2x/week) mice following Periodic Acid Schiff (PAS) staining show mucus producing cells (A to C) (Original magnification 200x). PAS positive cells are rarely observed in the saline treated mice (A).
  • rlL-15 improves airway hyperreactivity (PENH response) as measured by methyl choline response in aeroallergen-induced experimental asthma.
  • the allergen challenged mice treated with IL-15 show improved airway hyperreactivty (hyperactivity) (green line graph) compared to the mice challenged with Aspergillus allergen, (pink line graph).
  • airway hyperactivity measured by increase PENH response values after methacholine [MCH] challenge
  • MCH methacholine
  • rlL-15 15 microgram, intranasal, 2x/week
  • rlL-15 is a novel therapeutic molecule for the treatment of airway obstruction in experimental asthma.
  • the protective role of rlL-15 on lung function was assessed further by determined by examining the airway resistance and compliance in the experimental asthmatic mice.
  • FIG. 9 Recombinant (r) IL-15 pharmacological delivery show comparable eosinophilic lung and esophageal inflammation in Aspergillus challenge and 11-15 treated Aspergillus challenged mice following the induction of experimental EoE and asthma in mice. Pharmacological delivery of the rlL-15 (15 microgram/2xweek) in the lungs of Aspergillus fumigatus
  • TREATMENT compound (rlL-15) or agonist used as therapeutic agents BASED ON INVENTIONS as described above can be ADMIN ISTRATERED through oral or parenteral delivery routes (subcutaneous or Intravenous or intradermal, intratracheally) or via Inhaler.
  • Such therapeutics can be administered by any pharmaceutically acceptable carrier, including, for example, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like compatible with pharmaceutical administration.
  • the use of such media and agents for pharmaceutically active substance is known in the art.
  • Supplementary active compounds can also be incorporated into the compositions.
  • a pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Routes of administration include for example, but are not limited to intravenous, intramuscular and oral, and the like.
  • Solutions or suspensions used for appropriate routes of administration can include, for example, the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidant such as ascorbic acid or solution bisulfate; chelating agents such as ethylenediaminetetraaccetic acid; buffers such as acetates, citrates, or phosphates and agents for the adjustment of tonicity such as sodium chloride o dextrose, and the like.
  • a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents
  • antibacterial agents such as benzyl alcohol or methyl parabens
  • antioxidant such as ascorbic acid or solution bisulfate
  • chelating agents such as ethylene
  • the pH can be adjusted with acids or bases, such as for example, hydrochloric acid or sodium hydroxide, and the like.
  • the parenteral preparations can be enclosed in, for examples, disposable syringes, or multiple dose vials made of glass or plastic, and the like.
  • compositions suitable for injectable use include, for example, sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparations of sterile injectable solutions or dispersion, and the like.
  • suitable carriers include; for example, physiological saline, bacteriostatic water. Cremophor ELTM (BASF, Parsippany, NJ), Prolonged absorption of the injectable composition such as, for example aluminum monoestcarate and gelatin, and the like, phosphate buffered saline (PBS), and the like.
  • PBS phosphate buffered saline
  • the composition should be fluid to the extent that easy syringability exists.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the perfect method of preparation are vacuum drying and freeze-dying which yields a powder of a active ingredients plus any additional desired ingredients from a previously sterile-filtered solution thereof.
  • Oral composition generally includes an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tables, for example, oral administration, the agent can be contained in enteric forms to survive the stomach or further coated or mixed to be released in a particular region of the gastrointestinal tract. Similarly, inhaled compound included an inert diluent that agent can be contained in the respective organ or airway and survive for longer time. [00444] It is specifically advantageous to formulate oral or parenteral compositions in dosage unit form for case of administration and uniformity of dosage.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated, each unit containing a pre-determined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Those of skill in the art know such details.
  • Certain embodiments of the invention include using quantification data from a gene-expression (mRNA) analysis and/or form a tissue protein analysis, from a sample of blood, urine, saliva, lung or esophageal tissue or the like.
  • mRNA gene-expression
  • Embodiments of the invention include not only methods of conducting and interpreting such tests but also include reagents, kits, assay and the like, the conducting the analysis.
  • the combination with one or more others provide an enhanced clarity on the affect of the treatment molecule, rlL-15. Accordingly, the methods and materials of the invention are expressly contemplated to be used both alone and in combination with others.
  • IL-15 is induced in experimental and human asthma
  • rlL-15 down regulates pro-fibrotic cytokines like IL-13, TGFp in experimental asthma.
  • rlL-15 Pharmacological delivery of rlL-15 reduces allergen-induced goblet cell hyperplasia in mouse model of experiential asthma.
  • mice we next tested the hypothesis that allergen-induced airway hyperreactivity is protected in response to rlL-15 delivery in mice.
  • the mice we challenged with the aspergillus with or without rlL-15 treatment and saline were tested for PENH values in response to methacholine by whole body plethysmography. rlL-15 treatment significantly diminishes airway hyperreactivity in murine aspergillus experimental model of asthma.
  • rlL-15 is a novel therapeutic molecule for the treatment of airway obstruction in experimental asthma.
  • rlL-15 The protective role of rlL-15 on lung function was assessed further by determined by examining the airway resistance and compliance in the experimental asthmatic mice.
  • a baseline airway resistance using tracheal intubation was shown in saline treated and saline challenged mice; whereas, we show a significantly increased of the airway resistance at highest dose of methacholine (25mg/ml) concomitant with decreased compliance (Data is shown in Figure 8 A, B) in saline treated Aspergillus challenged mice.
  • Lung and esophageal fibrosis develops in human and experimental asthma and eosinophilic esophagitis.
  • Airway fibrosis is evident in human chronic asthma (Minshall, et al. American journal of respiratory cell and molecular biology 1997, 17(3): 326-333 and Roche et al. Lancet 1989, 1(8637): 520-524) and eosinophilic esophagitis (Mishra et al. 2008, Gastrentrology. 134, 204-214); therefore, we next established that similar airway fibrosis occurs in the murine model of allergen challenged asthma and we will employ for our studies.
  • the experimental model of asthma involves intranasal challenge to the mice with saline or aeroallergens (Aspergillus fumigatus extract).
  • rlL-15 The pharmacological delivery of rlL-15 to the lung during aspergillus challenge reduces fibrosis-associated proteins such as, a-SMA and collagen-1.
  • the protein expression was analyzed by performing a western blot analysis for both these proteins in the lung homogenates of aspergillus-challenged mice, aspergillus challenged treated with rlL-15 or saline challenged control mice.
  • the Western immune-blotting analysis showed enhanced levels of a-SMA and collagen-1 proteins following aspergillus challenged compare to saline challenge.
  • rlL-15 treatment blocked the increase in both of these proteins to the baseline levels observed in saline treated mice. Data is shown in Figure 1 D. This data demonstrates rlL-15's anti-fibrotic effect in an experimental asthma mouse model. EXAMPLE 9
  • rlL-15 treatment promotes fibroblast apoptosis/death.
  • the lung primary fibroblast was exposed in vitro to the various concentration of rlL-15 for 24 hours.
  • the fibroblast apoptosis/death was examined by flowcytometric analysis using AnnexinV and Live dead marker (eBioscience).
  • Fibroblasts treated with various concentration of rlL-15 indicated a concentration dependent fibroblast apoptosis/death. Data is shown in the figure 4.
  • the fibroblast apoptosis was also examined by caspase-3 cleavage in rlL-15 exposed primary lung fibroblasts.
  • Fibroblasts treated with rlL-15 in vitro demonstrated greater Caspase-3 cleavage compared to fibroblasts not treated with rlL-15.
  • DAPI mounting material is used to show the cell nucleus in blue and FITC stain for caspase-3 cleavage in green in the figures 4.
  • rlL-15 pharmacological delivery protects mice from fibroblast accumulation in the lung following the induction of experimental asthma.
  • the fibroblast accumulation in the lungs was detected by anti-FSP-1 (fibroblast specific protein-1 ) immunostaining in the tissue sections following aspergilus and rlL-15 treatment in mice.
  • the allergen challenged mice accumulated a number of anti-fibroblast (FSP-1 ) antibody stained cells compare to saline challenged mice that accumulation of fibroblast is reduced in the lungs following recombinant IL- 15 treatment. Data is shown in the figure 2E.

Abstract

Le procédé de l'invention et la composition de la présente invention concernent généralement le traitement et/ou la prise en charge de l'obstruction des voies aériennes comprenant la résistance, l'hyperactivité et la fibrose pulmonaire/œsophagienne. Nous affirmons que rIL-15 ou IL-15 surexprimé par son agoniste est une nouvelle molécule pour le traitement et la prise en charge d'anomalie fonctionnelle pulmonaire telle que l'hyperactivité, l'obstruction ou la fibrose des voies respiratoires dans une inflammation pulmonaire et œsophagienne chronique. L'asthme chronique est normalement associé à l'inflammation œsophagienne, une maladie appelée œsophagite à éosinophiles (EoE). En particulier, l'invention identifie la stratégie de traitement d'une hyperréactivité, résistance, obstruction et fibrose des voies respiratoires dans l'asthme expérimental comprenant la fibrose œsophagienne dans l'œsophagite à éosinophiles. Notre protéine rIL-15 identifiée et testée en préclinique ou son superagoniste seront prêts à être testés dans les essais cliniques sur des patients atteints d'asthme chronique et d'oesophagite à éosinophiles pour traiter une hyperactivité, une résistance et une fibrose des voies respiratoires chez des patients.
PCT/IB2014/063161 2014-07-16 2014-07-16 Une interleukine 15 recombinante est un agent thérapeutique pour le traitement de l'hyperactivité, la résistance (obstruction) et la fibrose des voies respiratoires dans l'asthme chronique WO2016009253A1 (fr)

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US20100240965A1 (en) * 2007-11-05 2010-09-23 The Regents Of The University Of Colorado, A Body Corporate Minimally-invasive measurement of esophageal inflammation
US20110245293A1 (en) * 2008-08-12 2011-10-06 Astrazeneca Ab Pharmaceutical product comprising a muscarinic receptor antagonist and a beta-2-adrenoceptor agonist

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030203909A1 (en) * 2000-08-09 2003-10-30 Hiroyuki Ushio Fused bicyclic amide compounds and medicinal use thereof
US20100240965A1 (en) * 2007-11-05 2010-09-23 The Regents Of The University Of Colorado, A Body Corporate Minimally-invasive measurement of esophageal inflammation
US20110245293A1 (en) * 2008-08-12 2011-10-06 Astrazeneca Ab Pharmaceutical product comprising a muscarinic receptor antagonist and a beta-2-adrenoceptor agonist

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115804821A (zh) * 2022-12-19 2023-03-17 新疆维吾尔药业有限责任公司 寒喘祖帕颗粒在制备治疗激素抵抗型哮喘药物中的应用

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