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WO1992008474A2 - Traitement des maladies pulmonaires - Google Patents

Traitement des maladies pulmonaires Download PDF

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Publication number
WO1992008474A2
WO1992008474A2 PCT/GB1991/002049 GB9102049W WO9208474A2 WO 1992008474 A2 WO1992008474 A2 WO 1992008474A2 GB 9102049 W GB9102049 W GB 9102049W WO 9208474 A2 WO9208474 A2 WO 9208474A2
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treatment
immunosuppressive agent
response
lymphocytes
cyclosporin
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PCT/GB1991/002049
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English (en)
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WO1992008474A3 (fr
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Anthony Barry Kay
Neil Christopher Barnes
Peter John Cole
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The National Heart & Lung Institute
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Priority claimed from GB909025154A external-priority patent/GB9025154D0/en
Application filed by The National Heart & Lung Institute filed Critical The National Heart & Lung Institute
Publication of WO1992008474A2 publication Critical patent/WO1992008474A2/fr
Publication of WO1992008474A3 publication Critical patent/WO1992008474A3/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5091—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing the pathological state of an organism
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • 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
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2812—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD4
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
    • G01N33/5047—Cells of the immune system
    • G01N33/505—Cells of the immune system involving T-cells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/10—Screening for compounds of potential therapeutic value involving cells

Definitions

  • the present invention relates to the treatment of asthma and other diseases characterised by airflow obstruction, and to .in vitro tests for use in connection with such treatment.
  • Asthma is a disease of unknown aetiology in which the bronchi (or airways) are inflamed and, as a con ⁇ sequence, obstructed. This narrowing results from a combination of bronchial smooth muscle contraction, mucosal oedema, inflammatory cell infiltrate and partial or total occlusion of the lumen with mucus, cells and cell debris. Bronchial obstruction is either partially or totally reversible and this important feature distin ⁇ guishes asthma from chronic bronchitis (sometimes called Chronic Obstructive Airways Disease - COAD) which is caused by smoking and where there is fixed airway narrowing.
  • chronic bronchitis sometimes called Chronic Obstructive Airways Disease - COAD
  • Asthma is an extremely common disease with a prevalence world-wide of between 5% and 8%. In the developed world it is the commonest chronic illness and, for reasons which are unclear, the disease is on the increase. It is now widely accepted that inflammation is an important component of the disease, but there remain many theories as to its aetiology and mechanism. The illness has a wide clinical spectrum ranging from mild episodic bronchospas (easily controlled by the - 2 -
  • COPD chronic obstructive pulmonary disease
  • COPD and chronic bronchitis or chronic mucus hypersecretion
  • chronic bronchitis with emphysema are sometimes used interchange- ably.
  • Emphysema occasionally occurs alone. These conditions are essentially smoking-related.
  • COPD and asthma are generally believed to be separate disorders, but some patients may exhibit both diseases (this is then sometimes called "chronic asthmatic bronchitis”) .
  • chronic asthmatic bronchitis In COPD there is bronchial hyperresponsiveness (although this is less marked than in asthma) .
  • the pathology of the bronchi in COPD is not fully elucidated, but features include hypertrophy of mucus-secreting glands, inflamma ⁇ tion (including infiltration with lymphocytes) and goblet cell hyperplasia.
  • COPD chronic obstructive pulmonary disease
  • bronchiectasis and chronic sinusitis are final common pathways of a number of known and unknown causes of inflammation in which the first-line mucus clearance mechanism (common to both the lower respiratory bronchial airways and the upper respiratory nasal airways and para-nasal sinuses) is impaired, allowing chronic bacterial colonisation of these airways and sinuses.
  • This colonisation stimulates chronic inflammation, resulting in progressive tissue damage, airflow obstruction and bronchial hyper-responsiveness.
  • Treatment of bronchiectasis and sinusitis is similar to that of COPD but with more emphasis on the use of antibiotics, to modify the bacterial colonisation, and physiotherapy to eliminate infected secretions.
  • Cystic fibrosis is an autosomally recessively inherited condition affecting 1 in 2,500 in the U.K.. Excess viscid mucus is produced. This leads to recurrent chest infections and progressive bronchiectasis. Approximately 50% of cystic fibrosis sufferers have - 4 -
  • Treatment of asthma can be broadly divided into (a) drugs for relief and (b) drugs for prevention.
  • Anti- asthma drugs have a huge market world-wide which is increasing.
  • the most widely used drugs for relief are the selective beta2-agonists, which when administered by the inhaled route usually give rapid relief of acute whez episodes. These drugs may be used regularly or on an "as required" basis, i.e. to relieve acute symptoms.
  • Drugs for prevention have to be taken on a continuous basis and "titrated" to the patient's individual requirement.
  • the chromone-like substances are effective in children but only in a minority of adults. Their great advantage is safety and the fact that they are "non- steroid" agents.
  • the mast cell stabiliser drugs include ketotifen (Zaditen (Trade Mark)) and 3,4-dimethoxycinnamoyl- anthranilic acid (Tranilast (Trade Mark) ) . They have the great advantage of being administered by the oral route. They may have some efficacy in mild asthma in children but have to be taken for at least four to six weeks to show effect. Corticosteroids are the mainstay of treatment of chronic asthma and they revolutionised the treatment of this disease when they were fist introduced in the 1950's. Oral corticosteroids have today been largely replaced by inhaled corticosteroids (first marketed in the late 1960's) , although severe asthmatics still require medication by mouth.
  • Inhaled corticosteroids are relatively safe and extremely effective in most patients, although at high doses side-effects include occasional oral pharyngeal candidiasis and aphonia.
  • the cor ⁇ ticosteroids have improved the quality of life for millions of asthmatic sufferers world-wide. For those with severe asthma, however, oral therapy with corticosteroids is required. When taken for more than a few days oral corticosteroids have a number of serious side-effects. These include growth retardation in children, severe osteoporosis (especially in old age) , reduced responsiveness of the pituitary adrenal axis to stress, fluid retention, diabetes and precipitation of psychosis.
  • corticosteroids are the single most effective drug for prevention in chronic asthma, they are by no means the ideal drug, since many asthmatics are dependent on a combination of high-dose inhaled and oral steroids; even with this regime many patients have a poor quality of life and poor lung function.
  • Corticosteroids are both anti-inflammatory and immunosuppressive.
  • asthma doctors have occasionally used immunosuppressive agents (which can also be called cytotoxic agents if they are used to treat cancer) as adjuncts to corticosteroids in patients with extremely severe disease, i.e. those requiring very large doses of oral prednisolone, or equivalent, for long periods of time.
  • immunosuppressive agent does not include corticosteroids.
  • One drug, azathioprine has been used since the 60's. Clinical studies of azathioprine in asthma have shown the drug to be of limited or little benefit. Like other mercapto- purine derivatives, bone marrow depression is a serious side-effect. About four years ago considerable interest was expressed in the use of the anti-inflammatory and immunosuppressant drug methotrexate in chronic asthma since this was shown to reduce steroid requirements in chronic asthmatics. However, there is no evidence that methotrexate improves lung function, and its major side- effect, liver toxicity, probably precludes its widespread use. Increasing numbers of other side-effects with methotrexate are now being reported, i.e. opportunist infections and bone marrow suppression.
  • the drug produced dramatic improvements in lung function in patients with severe asthma after treatment for as little as 2 to 3 weeks at a dose 1/2 to 1/3 of that employed in organ transplantation. At such doses the drug was surprisingly effective and there was no evidence of the major side- effects associated with the use of the drug.
  • Cyclosporin A has been in widespread use for immunosuppression in organ transplantation since the early 1980's.
  • This compound a natural product of a fungus, is a lipophilic cyclic peptide composed of 11 amino acids.
  • the drug has been remarkably successful in increasing the survival of organ grafts. Doses greater than 7.5 mg/kg/day, however, are likely to be associated with reversible renal toxicity and hypertension, and this has been a particular problem in, for example, kidney transplantation.
  • cyclosporin A is effective in asthmatic patients at substantially lower doses and that, provided patients are carefully selected, the risk/benefit ratio for cyclosporin A may be no worse than (and quite possibly better than) oral prednisolone; furthermore, patients previously insufficiently con ⁇ trolled by existing therapy have shown an unexpectedly dramatic response.
  • Our clinical trial of cyclosporin A was carried out in documented steroid-dependent chronic asthmatics who were poorly controlled by even oral corticosteroid therapy. Subjects were life-long non-smokers, demonstra ⁇ ted reversibility to beta 2 -agonists, required maintenance prednisolone of 5 mg or more per day and had an FEV- ⁇ (forced expired volume) of less than 70% predicted.
  • cyclosporin A restores the PEFR almost to predicted normal values in some of the individuals.
  • the drug was well-tolerated for the 12 week treat ⁇ ment period; thus it has been found, at least so far, to be safe at effective dosages. Changes in renal function and blood pressure could be readily controlled by monitoring the blood levels of cyclosporin A and adjust- ing the oral dose accordingly.
  • cyclosporin may be preferable to oral prednisolone and may prove suitable as sole therapy for severe asthma.
  • the drug could further ⁇ more be considered as an addition to, or alternative to, treatment even in milder disease (i.e. those taking inhaled steroids) ; even lower doses may be appropriate in such cases.
  • cyclosporin A is an anti- inflammatory agent (as well as an immunosuppressant) since it is successful in the treatment of a chronic inflammatory disease.
  • the present invention provides the use of cyclosporin A or other immunosuppressant (i.e. non- corticosteroidal immunosuppressant) with the same or a - 12 -
  • the present invention also provides a method for the treatment of diseases characterised by airflow obstruc ⁇ tion and/or of chronic sinusitis, which comprises administering a therapeutically effective dose of cyclosporin A or other immunosuppressant with the same or a similar mode of action.
  • diseases characterised by airflow obstruc ⁇ tion are, in general, characterised by shortness of breath, wheeze, an obstructive pattern of lung function or chest tightness or by two or more such features.
  • asthma can, we believe, be regarded as an im unological disorder with many features in common with autoimmune disease.
  • cyclosporin is known to have a much more specific mode of action, i.e. it suppresses the production of interleukin 2 (IL-2) by T lymphocytes (and thereby inhibits the elaboration of the essential T cell growth factor) .
  • IL-2 interleukin 2
  • CD4+ T lymphocytes are involved.
  • cyclosporin has been shown to have other modes of action on, for example, macrophages (and other antigen-presenting cells) , basophils and mast cells, CD4 T lymphocytes appear to be its principal target.
  • the chronic inflammatory response in this disease consists of a bronchial intra ⁇ mural cell mediated immune response and traffic of neutrophil polymorphonuclear leucocytes through the bronchial wall to the bronchial lumen.
  • the cell-mediated immune response consists of increased numbers (and activation) of T-lymphocytes of CD4 and CDS lineage (the latter being present in large numbers in all compartments of the bronchial wall, the former present in follicles) and of antigen processing and mature macrophages.
  • immunosuppressants such as cyclosporin A also have potential in the treatment of bronchiectasis and sinusitis, and trial results to date bear this out.
  • the present invention also provides the use of cyclosporin or other immunosuppressive agent which prevents the release of cytokines from T cells, for the manufacture of a medicament for the treatment of diseases characterised by airflow obstruction and/or of chronic sinusitis.
  • the present invention also provides the use of a T cell-selective immunosuppressive agent for the manufac- ture of a medicament for the treatment of diseases characterised by airflow obstruction and/or of chronic sinusitis.
  • the present invention also provides the use of an immunosuppressive agent that inhibits the elaboration of cytokines such as IL-2, for the manufacture of a medica ⁇ ment for the treatment of diseases characterised by airflow obstruction and/or of chronic sinusitis.
  • an immunosuppressive agent that inhibits the elaboration of cytokines such as IL-2, for the manufacture of a medica ⁇ ment for the treatment of diseases characterised by airflow obstruction and/or of chronic sinusitis.
  • the present invention further especially provides a method for the treatment of diseases characterised by airflow obstruction and/or of chronic sinusitis, which comprises administering a therapeutically effective dose of cyclosporin or other immunosuppressive agent which prevents the release of cytokines from T cells.
  • the present invention further especially provides a method for the treatment of diseases characterised by airflow obstruction and/or of chronic sinusitis, which comprises administering a therapeutically effective dose of a T cell-selective immunosuppressive agent.
  • the present invention also provides a method for the treatment of diseases characterised by airflow obstruc ⁇ tion and/or of chronic sinusitis, which comprises administering a therapeutically effective dose of an immunosuppressive agent that inhibits the elaboration of cytokines such as IL-2.
  • atopic asthma that is, extrinsic or allergic asthma
  • TNF cytokines of the "IL-4 family” (IL- 3, IL-4, IL-5 and GM-CSF)
  • IL-4 family IL-4, IL-5 and GM-CSF
  • TNF is also released and has importance in the asthma process; IL-8 is probably also released and may have importance in the process.
  • cytokines include IL-2, IL-3, IL-4, IL-5, GM-CSF (granulocyte/macrophage- colony stimulating factor) , TNF (Tissue Necrosis Factor) , IL-6 and IL-8.
  • IL-5 because that produces local eosinophils.
  • the immunosuppressive agent used accord ⁇ ing to the present invention is specifically targeted at the CD4 + T helper cell.
  • the agent is preferably selective for the IL-4 family of cytokines, especially IL-5.
  • Suitable immunosup ⁇ pressive agents include, for example, FK 506 and rapamycin.
  • anti-T cell antibody especially anti-CD4 antibody, anti-IL-2 receptor monoclonal antibody and antibodies designed in a similar fashion to CAMPATH- 1H (reshaped by genetic engineering to resemble more closely a human antibody ("humanised")) is also contemplated.
  • the product FK506, manufactured by the Fujisawa Company, Japan is, like cyclosporin, a natural by ⁇ product of a soil fungus and is a potent inhibitor of interleukin-2 production.
  • FK506 is a macrolide antibiotic (like erythro ycin) .
  • calcineurin a protein phosphatase
  • cyclosporin and FK506 might inhibit the phosphatase activity of calcineurin, thereby preventing an essential dephosphorylation step in cytosolic NF-AT (nuclear factor of activated T cells) processing, which in turn might prevent both translocation of cytosolic NF-AT to the nucleus and subsequent interleukin-2 gene transcription.
  • the present invention further provides the use of FK506 or other immunosuppressive agent with the same or similar principle of action (or same or similar mode and/or site of action) , for the manufacture of a medica ⁇ ment for the treatment of diseases characterised by airflow obstruction and/or of chronic sinusitis.
  • the present invention further provides the use of cyclosporin or FK506 or other immunosuppressive agent with a principle (or mode and/or site) of action in common with either or both, for the manufacture of a medicament for the treatment of diseases characterised by airflow obstruction and/or of chronic sinusitis.
  • FK506 also called FR-900506
  • EP 0184162 A that European patent applica ⁇ tion also describes and claims other compounds, their preparation and use as immunosuppressants.
  • the present invention also includes the use of those compounds, of the general formula I described in EP 0184162 A and their salts, more especially the compounds specifically mentioned (FR-900520, FR-900523 and FR-900525) , for the treatment of asthma and other diseases characterised by airflow obstruction and/or of chronic sinusitis.
  • Another compound, the antifungal product rapamycin (Calne R.Y. et al., Rapamycin for immunosuppression in organ allografting. Lancet 1989; 2:227), is structurally similar to FK506 and has also been found to have immuno ⁇ suppressive effects.
  • the present invention further provides the use of cyclosporin or rapamycin or other immunosuppressive agent with a principle (or mode and/or site) of action in - 20 -
  • Antibodies directed against the CD4 subset of T lymphocytes are, for example, VIT4 and M-T151. Such antibodies have been found to be effective in rheumatoid arthritis. Reiter C. et al (Arthritis & Rheumatism 1991 34. 525) and Walker C. et al (J. of Autoimmunity 1989, 2., 643-649) describe the use of the CD4 monoclonal antibody M-T151 and Herzog C. et al (J. of Autoimmunity 1989 2 , 627-642) describe the use of M-T151 and VIT4. More recently a chimeric IgG monoclonal anti-CD4 antibody (M-T412) manufactured by Centocor, Inc. has become available, and there is also a similar murine-human chimeric antibody (chimeric 17-1A) (LoBuglio A.F.,
  • the present invention further provides the use of an antibody directed against the IL-2 receptor and/or against one or more cytokines selected from the IL-5, IL- 4, IL-3 and GM-CSF family of cytokines (i.e. the IL-4 family of cytokines), IL-6, TNF, IL-8 and IL-10 and/or against IFN-gamma, for the manufacture of a medicament for the treatment of diseases characterised by airflow obstruction and/or of chronic sinusitis.
  • the antibody is preferably humanised.
  • Another antibody effective in the reversal of rejection and directed only against T lymphocytes is anti-CD3 (Cosi i A.B. et al. , N. Engl. J. Med. 1981, 305: 308-314), now licensed as Orthoclone OKT3, which is a monoclonal antibody to T cells expressing the CD3 antigen. This is less specific than the antibodies mentioned above, but may be suitable in certain cases.
  • US Patent 4,117,118 describes and claims cyclosporin A and cyclosporin B and their use inter alia as anti ⁇ biotics and as immunosuppressants.
  • the present invention also includes the use of cyclosporin B for treatment of asthma and other diseases characterised by airflow obstruction and/or of chronic sinusitis.
  • prostaglandin E j _ analogue misoprostol in conjunction with cyclosporin or other appropriate immunosuppressive drug should also be mentioned.
  • the drug when used in appropriate combination therapy, for example with cyclosporin, the drug will potentiate the effect of the immunosuppressant.
  • "local immunosuppression" produced by the various immunosuppres ⁇ sive drugs mentioned above may be highly effective in the treatment of asthma, particularly chronic asthma, and other diseases characterised by airflow obstruction and/or of chronic sinusitis.
  • Suitable cyclosporin- containing preparations for oral administration contain the active ingredient, for example in an amount of 25 to 250 mg per dosage unit.
  • Suitable oral dosage forms containing FK506 contain the active ingredient, for example in an amount of 2.5 to 5 mg per dosage unit.
  • Pharmaceutical preparations suitable for immunosuppres ⁇ sant use containing FK506 are described in EP 0184162 A; as mentioned above, for the present invention dosages will generally be 1/3 to 1/2 of such dosages.
  • Pharma ⁇ ceutical preparations containing FK506 as a solid dispersion to achieve solubilisation of the drug and improve bioavailability are described in EP 0240773 A.
  • DE 1491715 in particular, is said to be suitable for inhalation therapy intended for bronchial or lung diseases.
  • the present invention provides the use of cyclosporin A or other immunosuppressant with the same or a similar mode and/or site of action, for example
  • FK506 or rapamycin or other immunosuppressive agent with a common principle of action especially a T cell- selective immunosuppressive agent or an immunosuppressive agent that inhibits cytokine, e.g. IL-2, production, for the manufacture of a topical preparation for the treat ⁇ ment, with or without concurrent use of other drugs, of diseases characterised by airflow obstruction and/or of chronic sinusitis.
  • cytokine e.g. IL-2
  • the present invention further provides a pharma- ceutical preparation for the treatment of diseases characterised by airflow obstruction and/or of chronic sinusitis, which comprises cyclosporin A or other immunosuppressant with the same or a similar mode and/or site of action, for example FK506 or rapamycin or other immunosupprssive agent with a common principle of action,especially a T cell-selective immunosuppressive agent or an immunosuppressive agent that inhibits cytokine, e.g.IL-2 production, if desired together with a further agent, for example misoprostol, in admixture or conjunction with a pharmaceutically suitable carrier, and which is in a form suitable for inhalation.
  • a pharma- ceutical preparation for the treatment of diseases characterised by airflow obstruction and/or of chronic sinusitis which comprises cyclosporin A or other immunosuppressant with the same or a similar mode and/or site of action, for example FK506 or rapamycin or
  • the immunosuppressive agent may - 25 -
  • IL-4 family of cytokines, for example IL-5.
  • Dosages for the topical preparation will in general be one tenth to one hundredth, for example one twenty- fifth, of the dose required for oral preparations.
  • patients with cortico- steroid-dependent asthma can be divided into cortico- steroid responders and corticosteroid-resistant subjects.
  • the clinical response to oral prednisolone is reflected by the behaviour of the T-lymphocytes in vitro.
  • T-lympho- cytes are incubated with a lectin (phytohae agglutinin - PHA) they proliferate and incorporate tritiated thymidine.
  • the proposed tests include not only inhibition of proliferation by PHA (and other lymphocyte itogens) but also measurements of the degree of inhibition of the cytokines they release, i.e. IL-1, IL-2, IL-3, IL-4,
  • cytokine production after stimulation can be used as the end-point.
  • Variants of the above-described tests include inhibition of proliferation of lymphocytes stimulated by immobilised anti-CD3 and stimulation with common antigens to which most of the population are sensitive (i.e.. purified protein derivative from M tuberculosis, Candida and mumps antigens) and also stimulation of T lymphocyte blasts with interleukin-2.
  • the present invention provides a method of predicting clinical response to a corticosteroid or an immunosuppressive agent in a treatment for asthma or other disease characterised by airflow obstruction and/or of chronic sinusitis, which comprises ascertaining the effect of a corticosteroid or immunosuppressive agent on the response of T-lymphocytes or T-lymphocyte blasts in vitro to treatment with a stimulant or mitogen, an inhibitory effect by the corticosteroid or immunosuppres ⁇ sive agent on the response of the T-lymphocytes or T- lymphocyte blasts to the stimulant or mitogen being indicative of a positive response in vivo to therapy by one such compound and/or an absence of such inhibitory effect being indicative of a negative response in vivo to therapy by one such compound.
  • Suitable immunosuppressive agents for the test are cyclosporin A and other immunosuppressive agents with a common principle (or mode and/or site) of action; they may be immunosuppressive agents that inhibit cytokine elaboration. T cell-selective immunosuppressive agents and immunosuppressive agents that are selective for the IL-4 family of cytokines should especially be mentioned.
  • suitable immunosuppressive agents may be, for example, humanised antibodies directed against the IL-2 - 28 -
  • Suitable corticosteroids are, for example, prednisolone and dexamethasone.
  • dexametha- sone, prednisolone, cyclosporin A, rapamycin, CAMPATH-H, VIT4, M-T151, M-T412 or FK-506 or an analogue thereof or of misoprostol together with cyclosporin or one of the other agents should especially be mentioned.
  • the compound or mixture of compounds used in vitro in the T- ly phocyte test may, for example, be the same as that (those) for which prediction of response to therapy is sought.
  • the in vitro test may be used to establish the prima facie suitability or lack of suitability of a particular patient for treatment by a corticosteroid or immunosup- pressive agent.
  • a patient who is unresponsive to one particular therapy may be responsive to treatment with a different agent; for example a corticosteroid non- responder may be shown to be likely to respond to treatment by an immunosuppressive agent.
  • clinical treatment is carried out with a compound used in the test that gives the inhibitory effect in vitro or with a related compound or one known to have similar action; if more than one compound is tested, the compound that gives the greatest inhibition or a related compound or compound having similar action may be selected.
  • the test may be used to give an indication of dose for clinical treatment. In such cases the in vitro test may be used to establish the most effective therapy for a particular subject.
  • the test may be used to screen potential immunosuppressive agents, for example by carrying out the in vitro test on T-lymphocytes from a normal subject or proven immunosuppressant responder and/or by carrying out tests on T-lymphocytes from a number of subjects.
  • cortico- steroid-resistant asthmatics clinically respond to cyclosporin A.
  • corticosteroid- resistance be identified by an in vitro test (T cell proliferation) , but it appears that corticosteroid- resistant patients thus identified will respond clinically to cyclosporin A.
  • the primary outcome measures were variations in mean morning and evening PEFR and the number of disease exacerbations requiring a temporary increase in pred ⁇ nisolone dose. Secondary outcome measures were altera ⁇ tions in FEV l7 forced vital capacity (FVC) and slow VC measured at clinic visits, and diurnal variation in PEFR, subjective symptom scores and inhaled bronchodilator consumption as recorded on asthma diary cards.
  • FVC forced vital capacity
  • the trial was designed to detect an improvement in lung function rather than a corticosteroid-sparing effect.
  • the crossover design allows direct intra-subject comparisons with each patient acting as his/her own control. For this reason all treatment except inhaled bronchodilator usage was kept constant during the trial, although prednisolone dosage was increased according to standard clinical practice where necessary for exacerba- tions.
  • An exacerbation was defined as an increase in asthma symptoms and/or a decrease in PEFR, taking into account individual features. Exacerbations were treated along standard clinical lines tailored to each patient according to previous experience. Patients who had exacerbations requiring an increase in prednisolone above 40mg at any time, 40mg daily for more than two weeks or hospital admission were withdrawn from study.
  • Clinical protocol
  • Cyclosporin A dosage Cyclosporin A concentrations and renal function were monitored by an open investigator, who took no part in patient management during the trial. The blinded trial physician received instructions prior to patients' visits to increase or decrease the dose of trial medication by a certain percentage or to leave the dose unchanged. To maintain blindness, changes were also made when patients were taking placebo. Whole blood trough concentrations of CsA between 100-250 ⁇ g/l were deemed satisfactory and dosage was adjusted to achieve levels within this range. In addition, the dose of CsA was decreased if serum creatinine rose above 130% of baseline or above the upper limit of the normal range, if serum potassium rose above the upper limit of the normal range or if hypertension developed.
  • the within-patient differences between treatments (active minus placebo) for each of the diary and visit variables were summarised as above.
  • the treatment effect was calculated combining a paired Student's t test on each group as recommended by Pocock for crossover data.
  • the period and differential carryover effects were calculated following the same method.
  • the duration of sustained d_rug effect on morning PEFR after cessation of CsA therapy was calculated using a simple paired t test of the diferences between the mean run-in value and each week from tiie end of CsA treatment.
  • the number of exacerbatiors requiring an increase in prednisolone dose was summarised for each patient (placebo minus active) and analysed by the Wilcoxon matched pairs signed rank test.
  • Fig. 1 shows the percentage change from baseline in mean weekly morning PEFR for the
  • FEV lf FVC and slow VC increased significantly above placebo with CsA treatment (Table 2) .
  • the increases in FEV-L and FVC did not appear to have reached a plateau by the end of the 12 week period.
  • the variability in individual response was large, with a range of -10% to 100%.
  • Cyclosporin A therapy caused a significant mean (SE) decrease in GFR of 5.7 (2.6)% compared to placebo (p ⁇ 0.02). There was no difference between baseline GFR values and measurements at the end of the second
  • the larger number of rescue courses of prednisolone required by the patients on placebo therapy acts to increase PEFR more than in the CsA group, thus further decreasing the observed effect of CsA on lung function as compared to placebo.
  • improvements in lung function with CsA therapy reverted rapidly in some patients on cessation of treatment, there was no evidence of rebound exacerbations with PEFR levels below run-in values after cessation of CsA.
  • Four patients achieved improvements in pulmonary function which were greater than those recorded since becoming oral corticosteroid-dependent, even during periods of high doses of prednisolone. This improvement was in airflow obstruction which would previously have been considered to be "irreversible".
  • %diff percentage difference between CsA and placebo
  • diff absolute difference
  • 95% CI 95% confidence intervals for the %diff or diff
  • p probability.
  • Systolic b.p. (mm Hg) Diastolic b.p. (mm Hg) Total wbc (xl0 9 /l) Neutrophils (xl0 9 /l) Potassium (mmol/1) Urea (mmol/1) Creatinine ( ⁇ mol/1) Globulin (g/1) ALP (IU/ml)
  • SE standard error of the mean
  • b.p. blood pressure
  • wbc white blood count
  • ALP alkaline phosphatase
  • CYCLOSPORIN A USE IN BRONCHIECTASIS AND SINUSITIS
  • bronchiectasis was set up in the apical lobe of the rat by partial ligation of the apical lobe bronchus and distal intra-bronchial injection of viable bacteria. This model allowed for testing the pathogenetic mechanisms underlying bronchiectasis and for testing efficacy of treatment.
  • the immunohistology in the experimental model closely resembled that of the human bronchiectasis, particularly with respect to evolution of a florid intra-mural cell-mediated immune response.
  • the rationale for treatment was that the drug could reduce the T lymphocyte intra-mural bronchial infiltra ⁇ tion, as seen in the cyclosporin A-treated experimental animals, and possibly also reduce cytokine-driven recruitment of neutrophils to the bronchial lumen. Blood levels of cyclosporin were monitored regularly, as was renal function and blood pressure.
  • the present study compared the ability of dexametha- sone (Dex) and cyclosporin A (CsA) to inhibit prolifera ⁇ tion of T lymphocytes from clinically corticosteroid- resistant and -sensitive asthmatic patients.
  • PHA PHA-P, L9017, Sigma, Poole, England
  • Disodium dexamethasone was dissolved directly in RPMI-1640 to produce a concentration of 10 ⁇ 4 M.
  • Cyclosporin A the oily suspension (lOOmg/ml) was diluted in ethanol, then in RPMI-1640 to produce a final concentration of 10"" 4 M.
  • PBMC Peripheral blood mononuclear cell
  • PBMC isolated as described above were resuspended in RPMI-1640 at 4 x 10 6 /ml. 80 ⁇ l aliquots of this cell suspension with or without added PHA (5 ⁇ g) were added to 80 ⁇ l aliquots of drug solution or medium control in triplicate in sterile 96 well round bottomed culture plates (Cel-cult, Sterilin) . Culture plates were incubated for 48 hours in a humidified atmosphere with 5% C0 2 . Cell proliferation was measured by uptake of tritiated methylthymidine.
  • PBMC peripheral blood mononuclear cells
  • 80 ⁇ l aliquots of this cell suspension with or without added PHA were added to 20 ⁇ l aliquots of drug solution or medium control in triplicate in sterile 96 well U- bottomed culture plates as described above.
  • 60 ⁇ l of medium were added to give a total volume of 160 ⁇ l and final concentrations of the cell suspension (2xl0 6 cell/ml) ; PHA (5 ⁇ g/ml) ; and the drug solutions listed above.
  • Culture plates were incubated for 48 hours and the proliferation was measured as described above.
  • Statistical methods All results are expressed as Mean ⁇ standard error of the mean (SEM) . Significance levels were calculated using Mann-Whitney test.
  • T-lymphocytes from clinically corticosteroid- resistant asthmatic patients were significantly more resistant to the inhibitory action of dexamethasone in vitro as compared to those of corticosteroid-sensitive patients.
  • CsA inhibited lymphocyte proliferation in both groups of patients.
  • IMMUNOHISTOLOGICAL STUDY OF BRONCHIAL MUCOSA IN ASTHMA Fibre-optic bronchial biopsies were obtained from 5 intrinsic asthmatics (I) , 9 occupational (5 toluene and 4 ethylene diisocyanate sensitive) asthmatics (0) not exposed in the previous 4 weeks, 6 extrinsic asthmatics (E) and 12 normal control subjects (N) .
  • I intrinsic asthmatics
  • E extrinsic asthmatics
  • N normal control subjects
  • IL-2R interleukin 2 receptor
  • Bronchoalveolar lavage cells from 10 mild atopic asthmatics (methacholine PC2 0 0.25-16.0 mg/ml) and 10 normal control subjects (PC 2 o > 32mg/ml) were assessed for expression of mRNA for IL-2, IL-3, IL-4, IL-5, GM- CSF, and interferon-gamma (IFN-gamma ) by in situ hybridization using 3 P-labelled riboprobes.
  • Localisa- tion of mRNA to bronchoalveolar lavage (BAL) T-cells was assessed by simultaneous in situ hybridization and immunofluorescence and by in situ hybridization after immunomagnetic enrichment or depletion of T-cells.
  • GM-CSF 38.0 (27-55) 8.5 (0-15) ⁇ 0.001 IFN-gamma 2.5 (0-19) 0 (0-10) ns
  • asthmatics had sig ⁇ nificantly higher numbers of bronchoalveolar cells per 1000 positive for mRNA for IL-2, IL-3, IL-4, IL-5 and GM-CSF. There was no difference between the two groups in numbers of cells expressing mRNA for IFN-gamma. In asthmatic subjects mRNA for IL-4 and IL-5 was predominantly expressed by T lymphocytes. There was increased expression of CD25 (IL-2R) on CD4+ BAL lympho ⁇ cytes in asthmatics (median 13.6% vs 8.7%, p ⁇ 0.001) and an increased percentage of eosinophils in BAL (4.0% vm 0.4%, p ⁇ 0.001).
  • Atopic asthma is associated with activation of the IL-3, IL-4, IL-5 and GMCSF gene cluster. This may be due to predominant activation of a Tjj2 equivalent T- cell population.
  • Blocks of lung tissue were or had been fixed in neutral buffered formalin for several days, processed in graded alcohols by standard methods and embedded in paraffin wax.
  • Three to five micron paraffin sections of formalin-fixed segmental and subsegmental airways were cut using a sledge or rotary microtome, and retrieved on albumin-coated slides, dried at 60°C for 1 hour, and then stored until stained.
  • mice monoclonal antibody Ab
  • MT1 Bionuclear Services, Reading, Berks, UK
  • sialophorin ie staining T cells with little B cell or macrophage specificity
  • MAb staining was detected using a modification of the immunogold silver staining (IGSS) technique, originally described by Holgate et al. Quantification
  • FIG. 3 The mean results ( ⁇ SEM) of cell counts following application of each antibody are shown in Figure 3.
  • This figure shows the number of immuno-positive leukocytes (MT-1 positive (T) cells) detected by the IGSS technique expressed per mm length epithelial basement membrane in a zone 115 ⁇ m deep to the lamina reticularis in the asthmatic (A) , cystic fibrosis (CF) and control (C) groups. Horizontal bars denote the median values.
  • Lymphocyte infiltration of the airway mucosa by MT-1 positive (T) lymphocytes was found in all three groups, being significantly higher than the controls in both the asthma and CF groups.
  • the asthma and CF groups had mean and median values for the group more than twice that of the non-asthma sudden death group (p ⁇ 0.05 and p ⁇ 0.0l respectively) .

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Abstract

Le ciblage pharmacologique spécifique des lymphocytes T constitue une nouvelle approche pour le traitement de l´asthme chronique (à la fois chez les patients relativement sensibles aux effets des corticoïdes et chez les patients résistant à leurs effets) et pour le traitement d'autres maladies pulmonaires telles que la bronchestasie et la mucovicidose, ainsi que la sinusite. Dans cette invention, on utilise de la cyclosporine A et d'autres agents immunosuppresseurs suivant le même mode ou lieu d'action ou suivant un mode ou un lieu d'action similaire, pour traiter des maladies se caractérisant par l'obstruction de l'écoulement de l'air et/ou une sinusite chronique. D'autres agents appropriés comprennent le FK 506, la répamicyne et des anticorps anti-CD4 rendus assimilables pour l'homme. Cette invention concerne également un test in vitro permettant de prédire la réponse clinique aux corticoïdes et aux agents immunosuppresseurs. A l'aide du test in vitro on peut détecter la résistance aux corticoïdes et on peut ainsi identifier les patients résistant aux corticoïdes qui peuvent être traités avec de la cyclosporine A ou un autre agent immunosuppresseur approprié.
PCT/GB1991/002049 1990-11-20 1991-11-20 Traitement des maladies pulmonaires WO1992008474A2 (fr)

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EP0573584A1 (fr) * 1991-02-22 1993-12-15 American Home Products Corporation Procede de traitement de l'inflammation pulmonaire
WO1994008619A1 (fr) * 1992-10-08 1994-04-28 The Kennedy Institute Of Rheumatology Traitement d'affections auto-immunes et inflammatoires
WO1995035375A1 (fr) * 1994-06-17 1995-12-28 Celltech Therapeutics Limited Anticorps de recombinaison specifiques contre l'interleukine-5
WO1997010806A1 (fr) * 1995-09-19 1997-03-27 Fujisawa Pharmaceutical Co., Ltd. Compositions en aerosol
US5677426A (en) * 1994-03-03 1997-10-14 Genentech, Inc. Anti-IL-8 antibody fragments
WO1998036061A2 (fr) * 1997-02-13 1998-08-20 The Victoria University Of Manchester Reduction de la fibrose et/ou de la cicatrisation par inhibition de l'activite induite par le recepteur de l'interleukine 6
US5874080A (en) * 1994-03-03 1999-02-23 Genentech, Inc. Anti-IL-8 monoclonal antibodies for treatment of asthma
EP0942959A1 (fr) * 1996-12-02 1999-09-22 GenPharm International Animaux transgeniques non humains capables de produire des anticorps heterologues
WO2000006153A1 (fr) * 1998-07-28 2000-02-10 Smithkline Beecham Corporation Propenamides tenant lieu de modulateurs de ccr5
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WO2000051637A1 (fr) * 1999-03-02 2000-09-08 Centocor, Inc. ANTICORPS ANTI-TNF$G(a) UTILISES DANS LA THERAPIE DE L'ASTHME
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WO2004069267A1 (fr) * 2003-02-10 2004-08-19 Novartis Ag Combinaisons pharmaceutiques contenant des corticoides et des immunodepresseurs pour traiter des maladies resistant aux inhibiteurs de corticoides et/ou de la calcineurine
WO2005030252A1 (fr) * 2003-09-23 2005-04-07 Pdl Biopharma, Inc. Traitement de maladies respiratoires avec des anticorps diriges contre le recepteur de l'interleukine-2
WO2005063242A1 (fr) * 2003-12-30 2005-07-14 Astellas Pharma Inc. Utilisation de macrolides pour le traitement ou la prevention de l'obstruction bronchique
EP1599212A2 (fr) * 2003-02-14 2005-11-30 Combinatorx, Incorporated Polytherapie servant au traitement de troubles immuno-inflammatoires
WO2006116716A3 (fr) * 2005-04-27 2007-05-10 Univ Florida Materiaux et methodes permettant d'ameliorer la degradation de proteines mutantes associees avec une maladie humaine
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US7910798B2 (en) 2006-03-31 2011-03-22 Medarex, Inc. Transgenic animals expressing chimeric antibodies for use in preparing human antibodies
US8398972B2 (en) 2006-11-21 2013-03-19 Kalobios Pharmaceuticals, Inc. Methods of treating dementia using a GM-CSF antagonist
US8679502B2 (en) 2007-11-13 2014-03-25 Evec Inc. Monoclonal antibodies that bind to HGM-CSF and medical compositions comprising same

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EP0573584A4 (fr) * 1991-02-22 1994-02-16 American Home Products Corporation
EP0573584A1 (fr) * 1991-02-22 1993-12-15 American Home Products Corporation Procede de traitement de l'inflammation pulmonaire
US7501552B2 (en) 1991-08-28 2009-03-10 Medarex, Inc. Transgenic non-human animals for producing chimeric antibodies
US5741488A (en) * 1992-10-08 1998-04-21 The Kennedy Institute For Rheumatology Treatment of rheumatoid arthritis with anti-CD4 antibodies in conjunction with anti-TNF antibodies
WO1994008619A1 (fr) * 1992-10-08 1994-04-28 The Kennedy Institute Of Rheumatology Traitement d'affections auto-immunes et inflammatoires
US6770279B1 (en) 1992-10-08 2004-08-03 The Kennedy Institute Of Rheumatology TNFα antagonists and cyclosporin in therapy of rheumatoid arthritis
US6270766B1 (en) 1992-10-08 2001-08-07 The Kennedy Institute Of Rheumatology Anti-TNF antibodies and methotrexate in the treatment of arthritis and crohn's disease
US7846442B2 (en) 1992-10-08 2010-12-07 The Mathilda And Terence Kennedy Institute Of Rheumatology Trust Methods of treating rheumatoid arthritis with an anti-TNF-alpha antibodies and methotrexate
US5874080A (en) * 1994-03-03 1999-02-23 Genentech, Inc. Anti-IL-8 monoclonal antibodies for treatment of asthma
US5707622A (en) * 1994-03-03 1998-01-13 Genentech, Inc. Methods for treating ulcerative colitis
US5702946A (en) * 1994-03-03 1997-12-30 Genentech, Inc. Anti-IL-8 monoclonal antibodies for treatment of inflammatory disorders
US5686070A (en) * 1994-03-03 1997-11-11 Genentech, Inc. Methods for treating bacterial pneumonia
US5677426A (en) * 1994-03-03 1997-10-14 Genentech, Inc. Anti-IL-8 antibody fragments
US8158419B2 (en) 1994-03-09 2012-04-17 Medarex, Inc. Transgenic non-human animals for producing chimeric antibodies
US8293480B2 (en) 1994-03-09 2012-10-23 Genpharm International Transgenic non-human animals for producing chimeric antibodies
WO1995035375A1 (fr) * 1994-06-17 1995-12-28 Celltech Therapeutics Limited Anticorps de recombinaison specifiques contre l'interleukine-5
US6524556B2 (en) 1995-09-19 2003-02-25 Fujisawa Pharmaceutical Co., Ltd. Aerosol compositions
US6361760B1 (en) 1995-09-19 2002-03-26 Fujisawa Pharmaceutical Co., Ltd. Aerosol compositions
WO1997010806A1 (fr) * 1995-09-19 1997-03-27 Fujisawa Pharmaceutical Co., Ltd. Compositions en aerosol
US8383120B2 (en) 1996-08-01 2013-02-26 The Mathilda And Terence Kennedy Institute Of Rheumatology Trust Concomitant treatment of rheumatoid arthritis with anti-TNF-alpha antibodies and methotrexate
US7838489B2 (en) 1996-08-01 2010-11-23 The Mathilda And Terence Kennedy Institute Of Rheumatology Trust Methods of treating rheumatoid arthritis with p75 TNF-alpha receptor and methotrexate
US8298537B2 (en) 1996-08-01 2012-10-30 The Mathilda And Terence Kennedy Institute Of Rheumatology Trust Concomitant treatment of rheumatoid arthritis with anti-TNF-α antibodies and methotrexate
EP0942959A4 (fr) * 1996-12-02 2005-04-13 Genpharm Internat Animaux transgeniques non humains capables de produire des anticorps heterologues
EP0942959A1 (fr) * 1996-12-02 1999-09-22 GenPharm International Animaux transgeniques non humains capables de produire des anticorps heterologues
WO1998036061A3 (fr) * 1997-02-13 1998-11-12 Univ Manchester Reduction de la fibrose et/ou de la cicatrisation par inhibition de l'activite induite par le recepteur de l'interleukine 6
WO1998036061A2 (fr) * 1997-02-13 1998-08-20 The Victoria University Of Manchester Reduction de la fibrose et/ou de la cicatrisation par inhibition de l'activite induite par le recepteur de l'interleukine 6
US6333334B1 (en) * 1998-03-06 2001-12-25 Fujisawa Pharmaceutical Co., Ltd. Use of macrolide compounds for the treatment of ARDS
WO2000006153A1 (fr) * 1998-07-28 2000-02-10 Smithkline Beecham Corporation Propenamides tenant lieu de modulateurs de ccr5
WO2000010592A2 (fr) * 1998-08-22 2000-03-02 The Victoria University Of Manchester Medicaments permettant de prevenir ou de reduire la cicatrisation
WO2000010592A3 (fr) * 1998-08-22 2000-06-08 Univ Manchester Medicaments permettant de prevenir ou de reduire la cicatrisation
AU756677B2 (en) * 1999-03-02 2003-01-23 Centocor Inc. Anti-TNFalpha antibodies in therapy of asthma
WO2000051637A1 (fr) * 1999-03-02 2000-09-08 Centocor, Inc. ANTICORPS ANTI-TNF$G(a) UTILISES DANS LA THERAPIE DE L'ASTHME
JP2006517217A (ja) * 2003-02-10 2006-07-20 ノバルティス アクチエンゲゼルシャフト コルチコイドおよび／またはカルシニューリン阻害剤耐性疾患を処置するための、コルチコイドおよび免疫抑制剤を含んでなる医薬組合せ剤
WO2004069267A1 (fr) * 2003-02-10 2004-08-19 Novartis Ag Combinaisons pharmaceutiques contenant des corticoides et des immunodepresseurs pour traiter des maladies resistant aux inhibiteurs de corticoides et/ou de la calcineurine
EP1599212A4 (fr) * 2003-02-14 2006-02-08 Combinatorx Inc Polytherapie servant au traitement de troubles immuno-inflammatoires
EP1599212A2 (fr) * 2003-02-14 2005-11-30 Combinatorx, Incorporated Polytherapie servant au traitement de troubles immuno-inflammatoires
JP2007506681A (ja) * 2003-09-23 2007-03-22 ピーディーエル バイオファーマ，インコーポレイティド 抗ｉｌ−２受容体抗体による呼吸器疾患の治療
WO2005030252A1 (fr) * 2003-09-23 2005-04-07 Pdl Biopharma, Inc. Traitement de maladies respiratoires avec des anticorps diriges contre le recepteur de l'interleukine-2
WO2005063242A1 (fr) * 2003-12-30 2005-07-14 Astellas Pharma Inc. Utilisation de macrolides pour le traitement ou la prevention de l'obstruction bronchique
WO2006116716A3 (fr) * 2005-04-27 2007-05-10 Univ Florida Materiaux et methodes permettant d'ameliorer la degradation de proteines mutantes associees avec une maladie humaine
US7910798B2 (en) 2006-03-31 2011-03-22 Medarex, Inc. Transgenic animals expressing chimeric antibodies for use in preparing human antibodies
US8232449B2 (en) 2006-03-31 2012-07-31 Medarex, Inc. Transgenic animals expressing chimeric antibodies for use in preparing human antibodies
US9220244B2 (en) 2006-03-31 2015-12-29 E. R. Squibb & Sons, L.L.C. Transgenic animals expressing chimeric antibodies for use in preparing human antibodies
US8398972B2 (en) 2006-11-21 2013-03-19 Kalobios Pharmaceuticals, Inc. Methods of treating dementia using a GM-CSF antagonist
US8679502B2 (en) 2007-11-13 2014-03-25 Evec Inc. Monoclonal antibodies that bind to HGM-CSF and medical compositions comprising same

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