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WO2022005321A1 - Tocilizumab inhalé pour traiter des maladies respiratoires liées à l'interleukine-6 - Google Patents

Tocilizumab inhalé pour traiter des maladies respiratoires liées à l'interleukine-6 Download PDF

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Publication number
WO2022005321A1
WO2022005321A1 PCT/RU2020/000316 RU2020000316W WO2022005321A1 WO 2022005321 A1 WO2022005321 A1 WO 2022005321A1 RU 2020000316 W RU2020000316 W RU 2020000316W WO 2022005321 A1 WO2022005321 A1 WO 2022005321A1
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tocilizumab
pulmonary
interleukin
mammal
disease
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PCT/RU2020/000316
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Inventor
Veronika Igorevna SKVORTSOVA
Vladislav Nikolaevich KARKISCHENKO
Igor Anatolievich Pomytkin
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Federal State Budgetary Institution Scientific Center Of Biomedical Technologies Of Federal Medical And Biological Agency
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Federal State Budgetary Institution Scientific Center Of Biomedical Technologies Of Federal Medical And Biological Agency
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • 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
    • A61P11/06—Antiasthmatics
    • 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
    • A61P11/08—Bronchodilators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A61K2039/541—Mucosal route
    • A61K2039/544—Mucosal route to the airways

Definitions

  • the present invention is in the field of healthcare. More specifically, the invention relates to the use of inhaled tocilizumab in the treatment of interleukin-6 related respiratory diseases.
  • lnterleukin-6 is a small size cytokine (21 KDa) produced by cells from the innate immune system and non-immune cells such as pulmonary epithelial cells.
  • IL-6 is essential for regulation of acute phase immune process, but overproduction of IL-6 contributes to the pathogenesis of a variety of respiratory diseases.
  • Overexpression of IL-6 in pulmonary epithelial cells was observed in patients with asthma and other respiratory diseases.
  • Rincon M Irvin CG. Role of IL-6 in asthma and other inflammatory pulmonary diseases. Int J Biol Sci. 2012;8(9):1281-90. Increased levels of IL-6 were found in asthmatic patients. Yokoyama A et al.
  • IL-6 is a strong discriminator for severe disease in COVID-19. Henry BM et al. Clin Chem Lab Med. 2020, 58(7):1021 -1028. Elevated IL-6 levels in patients with COVID-19 are predictor of most severe course of the disease and the need for intensive care. Gubernatorova EO et al. Cytokine Growth Factor Rev. 2020, 53:13-24. IL-6 was elevated in influenza A/H1N1 virus pneumonia. Davey RT Jr et al. PLoS One. 2013;8(2):e57121. Elevated IL-6 levels in patients with community-acquired pneumonia are predictor for the severity of the disease. Ramirez P et al.
  • Tocilizumab is a recombinant humanized anti-human interleukin 6 receptor monoclonal antibody of the immunoglobulin lgG1 subclass with a molecular weight of approximately 148 kDa.
  • Tocilizumab binds to both membrane (mlL-6R) and soluble (slL-6R) interleukin-6 receptors (IL- 6R), thereby antagonizing action of IL-6 in patients with rheumatoid arthritis, systemic juvenile idiopathic arthritis, Castleman's disease, giant cell arteritis, and cytokine release syndrome.
  • tocilizumab is used in form of subcutaneous injections and intravenous infusions.
  • Pulmonary drug delivery represents a drug administration method that provides direct and fast topical treatments for respiratory diseases. Compared to intravenous or subcutaneous injections, it provides a painless and safer alternative. None is known about efficacy of inhaled tocilizumab in the treatment of IL-6 related respiratory diseases in comparison with conventional injection routes of tocilizumab administration.
  • inhaled tocilizumab is more effective in antagonizing IL-6 activity in a case of respiratory diseases compared to tocilizumab administered in the same dose by injections.
  • the present invention provides tocilizumab for use in the treatment of an interleukin-6 related respiratory disease in a mammal, in need thereof, by pulmonary administration.
  • a first aspect of the invention relates to tocilizumab for use in the treatment of an interleukin-6 related respiratory disease in a mammal by pulmonary administration in an amount of 0.1 to 100.0 mg per kg body weight of the mammal.
  • the invention relates to an aqueous pharmaceutical composition
  • an aqueous pharmaceutical composition comprising tocilizumab and a pharmaceutically acceptable excipient for use in the treatment of an interleukin-6 related respiratory disease in a mammal by pulmonary administration of said composition in a dose containing 0.1 to 100.0 mg tocilizumab per kg body weight of the mammal.
  • the invention relates to a method of treating an interleukin-6 related respiratory disease, which comprises a step of pulmonary administration of tocilizumab to a mammal in need thereof in an amount of 0.1 to 100.0 mg per kg body weight of the mammal.
  • the interleukin-6 related respiratory disease is selected from the group consisting of asthma, pneumonia, pulmonary edema, chronic obstructive pulmonary disease, and acute respiratory distress syndrome.
  • tocilizumab or formulations or composition thereof are administered pulmonary in form of aerosol having particle size from 0.5 to 10.0 microns, more preferably from 1 to 5 microns.
  • inhaled tocilizumab of the present invention have an advantage over conventional tocilizumab injections in that inhaled tocilizumab is more effective in the treatment of interleukin-6 related respiratory diseases.
  • this invention provides particularly advantageous composition and methods for achieving the therapeutic effect in a mammal suffering from an interleukin-6 related respiratory disease.
  • FIG.1 shows hematoxylin-eosin stained histological preparations of healthy lung tissue (0 h) and lung preparations obtained from animals after 24, 72, and 120 h of administering lipopolysaccharide (LPS), as described in example 2 of the invention.
  • LPS lipopolysaccharide
  • FIG.2 shows the Kaplan-Meier survival curves for mice with acute lung injury treated with inhaled tocilizumab in comparison with tocilizumab injection at the same dose, as described in example 2 of the invention.
  • the present invention provides tocilizumab for use in the treatment of an interleukin-6 related respiratory disease in a mammal by pulmonary administration in an amount of 0.1 to 100.0 mg per kg body weight of the mammal.
  • tocilizumab refers to a recombinant humanized anti-human interleukin-6 receptor (IL-6R) monoclonal antibody of the immunoglobulin lgG1 subclass that antagonizes interleukin-6 action in a mammalian body upon binding to both membrane (mlL-6R) and soluble (slL-6R) interleukin-6 receptors.
  • IL-6R humanized anti-human interleukin-6 receptor
  • interleukin-6 refers to native interleukin-6 from any species, including mouse, rat, bovine, and human, preferably human.
  • interleukin-6 related respiratory disease refers to a respiratory disease associated with interleukin-6 overproduction.
  • respiratory disease refers to a disease affecting the respiratory system including asthma, chronic bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), pneumonia, COVID- 19 related pneumonia, acute respiratory distress-syndrome (ARDS), COVID-19 related ARDS, a virus related ARDS, a virus related pneumonia, pulmonary edema, and pulmonary fibrosis.
  • the interleukin-6 related respiratory disease is selected from the group consisting of asthma, pneumonia, pulmonary edema, chronic obstructive pulmonary disease, and acute respiratory distress syndrome.
  • pulmonary administration refers to administration of tocilizumab or a formulation thereof through the lungs by inhalation.
  • inhalation refers to inhaling the vapor or dispersion of solid or liquid particles with added medication. In specific examples, inhaling can occur through a nebulizer or other aerosol- delivery device.
  • inhalation used with respect to formulations and compositions of the invention is synonymous with “pulmonary administration.”
  • treatment means to reverse, alleviate, or inhibit the progress of a disease to which this term is applied, or one or more symptoms of this disease.
  • treatment refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the disorder as well as those prone to having the disorder or diagnosed with the disorder or those in which the disorder is to be prevented.
  • mammal refers to any animal classified as a mammal, e.g. mouse, rat, bovine, and human.
  • the preferred mammal herein is a human.
  • tocilizumab is administered by inhalation in effective amounts.
  • effective amount refers to an amount of an active pharmaceutical ingredient (API) or formulations or compositions thereof that is sufficient to cause a reduction, reverse, alleviation, or inhibition of progress of a disease.
  • tocilizumab is pulmonary administered in an amount of 0.1 to 100.0 mg per kg body weight of a mammal.
  • tocilizumab or formulations or compositions thereof will be administered pulmonary in form of aerosol.
  • Numerous methods and devices are well-known from the art that can be employed to generate said aerosols in therapeutically useful size ranges and concentrations. Specifically, these are nebulizers, metered-dose inhalers (MDIs), and dry powder inhalers (DPIs).
  • MDIs metered-dose inhalers
  • DPIs dry powder inhalers
  • Nebulizers such as jet nebulizers or ultrasonic nebulizers are used for the delivery of aqueous pharmaceuticals.
  • MDIs suspends or dissolves drug powders into liquid propellants and when a metered quantity of the propellant is released from the storage canister, the propellant evaporates and expands quickly to disperse the powdered drug or liquid droplet drug.
  • propellants include, but are not limited to, chlorofluorocarbon, a hydrochlorofluorocarbon, or a hydrocarbon.
  • DPIs delivers a precisely measured dose medicine into the lungs in dry powder form. It is designed to generate a drug powder aerosol onto or via the inspiratory air flow.
  • any methods and devices, including nebulizers, MDIs, and DPIs may be used for pulmonary delivery of tocilizumab or pharmaceutical compositions thereof to a patient in need thereof.
  • tocilizumab refers to suspension of liquid or solid particles in a gaseous medium.
  • tocilizumab or compositions thereof can be administed pulmonary as aerosol in form of liquid formulations and dry powders.
  • tocilizumab is pulmonary administered in form of aerosol with particle size of 0.5 to 10.0 microns, preferably of 0.6 to 5.0 microns.
  • tocilizumab will typically be administered as a liquid or dry formulation in association with one or more pharmaceutically acceptable excipients.
  • the present invention provides an aqueous pharmaceutical composition
  • aqueous pharmaceutical composition comprising tocilizumab and a pharmaceutically acceptable excipient for use in the treatment of an interleukin-6 related respiratory disease in a mammal by pulmonary administration of the composition in a dose containing 0.1 to 100.0 mg tocilizumab per kg body weight of the mammal.
  • excipient describes any ingredient other than tocilizumab.
  • excipients include, but are not limited to, pharmaceutical water such as purified water or water for injections; buffer system such as phosphate buffer to maintain pH values from 3.0 to 8.5, preferably of about 6.5; ionic, non-ionic, and amphiphilic surfactant or combinations thereof; suitable osmotically active inorganic agent such as chlorides, sulfates or phosphates of sodium, calcium or magnesium; suitable osmotically active organic agent such as sugars and sugar alcohols, in particular trehalose, mannitol, and sorbitol; preservatives and antioxidants.
  • pharmaceutical water such as purified water or water for injections
  • buffer system such as phosphate buffer to maintain pH values from 3.0 to 8.5, preferably of about 6.5
  • ionic, non-ionic, and amphiphilic surfactant or combinations thereof suitable osmotically active inorganic agent such as chlorides, sulfates or phosphat
  • the excipient is selected from the group consisting of polysorbate 80, sucrose, disodium phosphate dodecahydrate, sodium dihydrogen phosphate dehydrate, L-histidine, L-histidine monohydrochloride, L-arginine, L-arginine hydrochloride, and L-methionine.
  • aqueous pharmaceutical composition means that a pharmaceutical water, e.g. purified water or water for injections, is the essential excipient of the composition of the invention.
  • the aqueous pharmaceutical composition may be in a unit dosage form suitable for a single pulmonary administration of a precise dose.
  • unit dosage form refers to a physically discrete unit of the composition of the invention suitable for a mammal to be treated by pulmonary route of administration.
  • the level of a particular effective dose for any particular mammal depends on many factors, including the kind of the mammal; disorder being treated and the severity of the disorder; the particular composition used; age, weight, general health, gender and diet of the subject; time of administration; duration of treatment; drugs and/or additional therapies combined with or in combination with the composition of the present invention, and similar factors well known in medical technology.
  • the unit dosage form contains tocilizumab in amount of 1.0 to 400.0 mg.
  • the composition of the invention can be prepared by procedures well-known from the art. Such procedures include, but are not limited to, mixing tocilizumab with other ingredients of the composition in conventional manner.
  • Guidance for the preparation of compositions of the invention can be found in "Remington: The science and practice of pharmacy” 20th ed. Mack Publishing, Easton PA, 2000 ISBN 0-912734-04-3 and " Encyclopaedia of Pharmaceutical Technology", edited by Swarbrick, J. & J. C. Boylan, Marcel Dekker, Inc., New York, 1988 ISBN 0-8247-2800-9 or a newer edition.
  • the present invention provides a method of treating an interleukin-6 related respiratory disease, which comprises a step of pulmonary administration of tocilizumab to a mammal in need thereof in an amount of 0.1 to 100.0 mg per kg body weight of the mammal.
  • tocilizumab or pharmaceutical compositions thereof can be administered pulmonary for one day or longer.
  • tocilizumab or pharmaceutical compositions thereof can be administered pulmonary once per four weeks.
  • the amount of tocilizumab to be administered pulmonary depends on the kind of mammals. Equivalent doses for humans can be calculated from doses for other mammals, and vice versa, as described in, e.g. Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), 2005, Pharmacology and Toxicology. The guidance teaches that a human equivalent dose can be obtained by dividing an animal dose by certain factor, e.g. by 12.3, 6.2, and 1.1 for mouse, rat, and mini-pig, respectively.
  • CDER Drug Evaluation and Research
  • tocilizumab may be administered as an active pharmaceutical ingredient of an aqueous pharmaceutical composition comprising tocilizumab and a pharmaceutically acceptable excipient.
  • inhaled tocilizumab of the present invention have an advantage over conventional tocilizumab injections in that inhaled tocilizumab is more effective in the treatment of interleukin-6 related respiratory diseases.
  • this invention provides particularly advantageous composition and methods for achieving the therapeutic effect in a mammal suffering from an interleukin-6 related respiratory disease.
  • This example shows the aqueous pharmaceutical composition for pulmonary administration.
  • the ingredients are mixed in the conventional manner in amounts as indicated in Table 1 to prepare a sterile, preservative-free solution for further dilution prior to pulmonary administration.
  • Single-dose vials for pulmonary administration contains 80 mg/4 ml_, 200 mg/10 mL, or 400 mg/20 mL of tocilizumab.
  • the aqueous pharmaceutical composition is administered in recommended dose to a mammal in need thereof by inhalation using nebulizer for 30 to 90 min, once a period of four weeks.
  • This example illustrates advantages of inhaled tocilizumab over conventional tocilizumab injections in the treatment of interleukin-6 related respiratory diseases.
  • mice received intratracheal LPS (E.coli; 300 pg/mouse) with addition of 10 pL/mouse Freund's complete adjuvant and 100 pg/mouse muramyl peptide.
  • E.coli Espineal LPS
  • 10 pL/mouse Freund's complete adjuvant 10 pL/mouse Freund's complete adjuvant
  • 100 pg/mouse muramyl peptide 100 pg/mouse muramyl peptide.
  • This model is characterized by dramatic overproduction of interleukin-6 in lung tissue and acute rise of lung IL-6 levels up to 5150 pg/mL that is by 43-times higher than IL-6 levels in the lungs of healthy mice (119 pg/ml).
  • the IL-6 overproduction in this model is associated with acute lung injury, pulmonary edema, acute respiratory disitress-syndrome, and pneumonia.
  • FIG.1 shows hematoxylin-eosin stained histological preparations of healthy lung tissue before LPS administration (0 h) and lung preparations obtained from animals after 24, 72, and 120 h of administering lipopolysaccharide (LPS).
  • the healthy lung preparations are characterized by moderate blood supply, the absence of pathological changes in the stroma and parenchyma, as well as in the walls of the bronchi and bronchioles.
  • the preparations obtained from lungs after intraracheal administration of LPS show characteristic signs of acute lung injury caused by inflammation.
  • this model reproduces the essential signs of interleukin-6 related respiratory diseases in humans such as acute respiratory distress syndrome, pulmonary edema, and pneumonia.
  • mice with LPS-induced lung injury were randomized into three groups of 20 animals each and received treatments 30 min after the LPS injection.
  • mice received once saline s.c. (control).
  • mice received once tocilizumab subcutaneously at dose of 28 mg/kg (“LPS+T sc”) in form of aqueous composition of example 1.
  • mice received once tocilizumab by inhalation at dose of 28 mg/kg (“LPS+T inh”) in form of aqueous composition of example 1.
  • the LPS-induced acute lung injury resulted in death of most animals in control group.
  • FIG.2 shows the Kaplan-Meyer survival curves for 456 hours in four groups. There was a statistically significant difference between the groups (Mantel-Cox logrank test; p ⁇ 0.0001). The median survival, i.e. the time during which half of the animals were still alive, was 72, 48, and 72 hours in control, “LPS+T sc”, and “LPS+T inh”, respectively. After 456 hours, 15% (3/20), 30% (6/20), and 40% (8/20) animals survived in control group, “LPS+T sc” group, and “LPS+T inh” group, respectively. For reference, all animals in “Inact” group were still alive at 456 h.
  • inhaled tocilizumab have an advantage over conventional tocilizumab injection in that the inhaled tocilizumab was more effective in the improvement of survival of mammals with IL-6 related acute lung injury compared to tocilizumab injection in the same dose.
  • This example illustrates advantages of inhaled tocilizumab over conventional tocilizumab injections in reducing excessive IL-6 levels in lungs of mammals suffering from interleukin-6 related respiratory disease.
  • mice with LPS-induced acute lung injury as described in example 2 were randomized into three groups of 10 animals each and received treatments 30 min after the LPS injection.
  • Table 2 shows that LPS induced an acute rise of IL-6 levels at 2 h with subsequent gradual decrease in IL-6 levels at 12 day in mice that were still alive (control group).
  • levels of IL-6 in lungs of non-treated healthy mice were 119 pg/mL.
  • Tocilizumab injection resulted in a significant acute increase in lung IL-6 levels in LPS-induced mice compared even to control (p ⁇ 0.05).
  • IL-6 levels in lungs at 2 hours after the tocilizumab injection were 3-fold higher than in contol group that is a serious adverse effect of tocilizumab injection.
  • lung IL-6 levels in tocilizumab-treated mice were significantly lower than in mice of control group (p ⁇ 0.05).
  • the pulmonary administration of tocilizumab by inhalation in the same dose did not result in the undesirable acute rise of IL-6 in lungs compared to control (p>0.05).
  • the lung levels of IL-6 at 2 hours were 3 times less in mice who received inhaled tocilizumab (p ⁇ 0.05) compared to mice treated with tocilizumab injection. This provide a serious advantage of pulmonary route of tocilizumab administration as more safe over tocilizumab injection in the treatment of a respiratory disease.
  • inhaled tocilizumab decreased IL-6 in lungs to levels significantly less than those observed after tocilizumab injection (p ⁇ 0.05). It means that inhaled tocilizumab more effectively reduces the levels of IL-6 in the lungs of mammals suffering from the IL-6 related respiratory disease than tocilizumab injection in the same dose.
  • pulmonary administration of tocilizumab provides more effective and safe treatment of IL-6 related respiratory diseases than tocilizumab injections.
  • Table 3 shows that LPS-induced respiratory disease is accompanied by an increase in the levels of IL-1 b in the lungs (control group).
  • Tocilizumab injection resulted in signficant transient increase of lung IL-1 b at 2 hours and delayed increase in IL-1 b at 12 day compared to control (p ⁇ 0.05).
  • the acute and delayed increase in lung IL-1 b levels represent an adverse effect of tociliumab injection.
  • the pulmonary administration of tocilizumab did not cause both acute and delayed significant increase in IL-1 b compared to control (p>0.05).
  • Table 4 shows that tocilizumab injection resulted in signficant transient increase of lung IL-17A at 2 hours and dramatic delayed increase in IL-17A at 12 day compared to control (p ⁇ 0.05).
  • the acute and delayed increase in lung IL-17A levels represent an adverse effect of tociliumab injection.
  • the pulmonary administration of tocilizumab did not cause both acute and delayed significant increase in IL-17A compared to control (p>0.05).
  • Table 5 shows that that tocilizumab injection resulted in signficant transient increase of lung TNFa at 2 hours and delayed increase in TNFa at 12 day compared to control (p ⁇ 0.05).
  • the acute and delayed increase in lung TNFa levels represent an adverse effect of tociliumab injection.
  • the pulmonary administration of tocilizumab did not cause both acute and delayed significant increase in TNFa compared to control (p>0.05).
  • Table 6 shows that pulmonary administration of tocilizumab as well as tocilizumab injection decreased significantly lung IFNg levels at 12 day compared to control (p ⁇ 0.05).
  • pulmonary administration of tocilizumab provides more effective treatment of IL-6 related respiratory disease compared to tocilizumab injection in the same dose with respect to reducing lung IL-6 levels. Moreover, pulmonary administration of tocilizumab is more safe than tocilizumab injection, since inhaled tocilizumab does not induced the acute or delayed increase in the production of pro-inflammatory cytokines such as IL-1 b, IL-17A, and TNFa in the lung.
  • This example illustrates the dose-response of inhaled tocilizumab in the treatment interleukin-6 related respiratory disease.
  • mice with LPS-induced acute lung injury as described in example 2 were randomized into six groups of 6 animals each and received treatments 30 min after the LPS injection. In the first group, mice received once saline s.c. (control). In other groups, mice received once tocilizumab by pulmonary administration in form of aqueous composition of example 1 in doses 0.01, 0.1, 1.0, 10.0, and 100.0 mg/kg. After 12 hours, concentrations of IL-6 in lung homogenates were measured with the Bio-Plex ProTM Mouse Cytokine Th17 Panel A 6-Plex immunoassay using Bio-Plex® MAGPIXTM Multiplex Reader (Bio-Rad, SN: 12250707). Results are presented in table 7 as mean ⁇ SEM of IL-6 concentrations (pg/ml). [0067] Table 7.
  • Table 7 shows that pulmonary administration of tocilizumab in doses of 0.1 to 100.0 mg/kg decreases overproduction of IL-6 in the lung of mammals suffering from IL-6 related respiratory disease in a dose-dependent manner.

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Abstract

La présente invention se rapporte au domaine des soins de santé. Plus particulièrement, l'invention concerne l'utilisation de tocilizumab inhalé et de compositions pharmaceutiques aqueuses associées dans le traitement de maladies respiratoires liées à l'interleukine-6. L'invention concerne du tocilizumab destiné à être utilisé dans le traitement d'une maladie respiratoire liée à l'interleukine-6 chez un mammifère par administration pulmonaire en une quantité de 0,1 à 100,0 mg par kg de poids corporel du mammifère, la maladie étant choisie dans le groupe constitué par l'asthme, la pneumonie, l'œdème pulmonaire, la bronchopneumopathie chronique obstructive et le syndrome de détresse respiratoire aiguë. En outre, l'invention concerne une méthode de traitement d'une maladie respiratoire liée à l'interleukine-6, qui comprend une étape d'administration pulmonaire de tocilizumab à un mammifère en ayant besoin dans une quantité de 0,1 à 100,0 mg par kg de poids corporel du mammifère.
PCT/RU2020/000316 2020-06-29 2020-06-29 Tocilizumab inhalé pour traiter des maladies respiratoires liées à l'interleukine-6 Ceased WO2022005321A1 (fr)

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Citations (4)

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