WO1990000900A1 - Procede de traitement de troubles inflammatoires par reduction de l'activation phagocytaire - Google Patents

Procede de traitement de troubles inflammatoires par reduction de l'activation phagocytaire Download PDF

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Publication number
WO1990000900A1
WO1990000900A1 PCT/US1989/003096 US8903096W WO9000900A1 WO 1990000900 A1 WO1990000900 A1 WO 1990000900A1 US 8903096 W US8903096 W US 8903096W WO 9000900 A1 WO9000900 A1 WO 9000900A1
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WO
WIPO (PCT)
Prior art keywords
tgf
inflammatory
macrophages
composition
phagocytes
Prior art date
Application number
PCT/US1989/003096
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English (en)
Inventor
Carl F. Nathan
Michael A. Narachi
Original Assignee
Amgen Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Amgen Inc. filed Critical Amgen Inc.
Publication of WO1990000900A1 publication Critical patent/WO1990000900A1/fr

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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
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1841—Transforming growth factor [TGF]

Definitions

  • This invention is directed to methods of treatment of inflammatory disorders by reducing the level of activation of phagocytes. More particularly, this invention relates to treatment of these disorders with transforming growth factor-beta (TGF- ⁇ ).
  • TGF- ⁇ transforming growth factor-beta
  • Phagocytic cells (neutrophils, eosinophils, basophils, monocytes/macrophages) have among their functions the phagocytosis and destruction of
  • the phagocytes when activated by
  • cytotoxic agents which assist in the destruction and removal of the microorganisms, malignant cells and foreign particles.
  • Some of these cytotoxic agents include reactive oxygen intermediates, such as superoxide anion, hydrogen peroxide and hydroxyl radicals, and proteolytic and other digestive enzymes.
  • reactive oxygen intermediates such as superoxide anion, hydrogen peroxide and hydroxyl radicals, and proteolytic and other digestive enzymes.
  • tissue degradative enzymes are activated by oxidation or have enhanced activity in an environment where reactive oxygen intermediates are present.
  • protease inhibitors such as human ⁇ -1-proteinase inhibitor
  • oxidative pathways see Johnson et al., The oxidative inactivation of human ⁇ -1-proteinase inhibitor: further evidence for methionine at the reactive center. J. Biol. Chem., 254:4022-4026 (1979), and see Ossanna et al., Oxidative regulation of neutrophil elastase-alpha-1-proteinase inhibitor interactions. J. Clin. Invest., 77:1939-1951. Phagocytic cell activation is essential for host survival from infection and contributes to
  • Macrophages are essential to the healing of wounds and repair of damaged tissues. Yet the cytotoxic products of the activated macrophages can damage endothelium, fibroblasts, smooth muscle, and parenchymal cells, as described in Cross et al., Ann. Int. Med. 107, 526-545(1987). Thus, after an inflammatory site has been sterilized, the impact of phagocyte activation on the host can shift from benefit to detriment.
  • the subject invention relates to a method of treating an inflammatory disorder involving excessive phagocyte activation by administering to a patient a therapeutically effective amount of TGF- ⁇ .
  • inventions also relates to a pharmaceutical composition suitable for administration to a patient having an inflammatory disorder comprising a therapeutically effective amount of: TGF- ⁇ and at least one additional immunosuppressant.
  • Figure 1 shows suppression of macrophage H 2 O 2 releasing capacity following two days incubation in TGF- ⁇ 1 and TGF- ⁇ 2, but not any of the nine other polypeptide growth factors tested.
  • Figure 2 shows time course for suppression of H 2 O 2 releasing capacity by (A) TGF- ⁇ 1 or (3) TGF- ⁇ 2.
  • Figure 3 shows prevention of TGF- ⁇ 1-induced deactivation by coincubation in macrophage activating factors.
  • Figure 4 shows preservation of phagocytic function after deactivation of macrophage by TGF- ⁇ l or TGF- ⁇ 2.
  • TGF- ⁇ transforming growth factor-beta
  • TGF- ⁇ l transforming growth factor- ⁇ l
  • TGF- ⁇ 2 transforming growth factor- ⁇ l
  • TGF- ⁇ refers to TGF- ⁇
  • TGF- ⁇ 1, TGF- ⁇ 2, and/or TGF- ⁇ 1.2 produced, for example from natural source extraction and purification, or from recombinant cell culture systems.
  • the term likewise covers biologically active human TGF- ⁇ equivalents;
  • TGF- ⁇ is mature TGF- ⁇ from recombinant cell culture, see for example European Patent Application 200341, hereby incorporated by reference.
  • H 2 O 2 releasing capacity is a close biochemical correlate of macrophage activation, due to the prominent involvement of reactive oxygen
  • TGF- ⁇ tumor growth factor- ⁇
  • Prominent sources of natural TGF- ⁇ include degranulating platelets, endothelial cells, fibroblasts, keratinocytes, tumor cells, and T cells responding to antigen.
  • wounds, tumors, and T cells may all be able to restrain or reverse macrophage activation through the action of TGF- ⁇ .
  • Eukaryotic cells can deactivate macrophages by other routes as well, see Szuro-Sudol et al., J. Exp. Med. supra; Szuro-Sudol et al.,
  • chemotaxis EC 50 , 0.004 pM
  • EC 50 the concentration giving 50% of the maximum effect
  • release of fibroblast growth factors and accumulation of IL-1 mRNA (EC 50 , -40 pM) the concentration giving 50% of the maximum effect
  • release of fibroblast growth factors and accumulation of IL-1 mRNA (EC 50 , -40 pM) the concentration giving 50% of the maximum effect
  • IL-1 mRNA EC 50 , -40 pM
  • macrophages are recruited to scavenge debris and foster the growth of fibroblasts and endothelial cells, while being suppressed in their capacity for a respiratory burst that could be inimical to these cells.
  • TGF- ⁇ 1 and TGF- ⁇ 2 have a role in the treatment of inflammatory disorders involving excessive phagocyte activation.
  • TGF- ⁇ acute or chronic inflammatory responses are suppressed by reducing the degree of phagocytic cell activation, particularly by deactivating respiratory burst
  • Deactivating respiratory burst function can reduce tissue degradation caused by many digestive enzymes.
  • Inflammatory disorders involving excessive phagocyte activation include the following. Each of the following articles is hereby incorporated by reference.
  • the TGF- ⁇ is administered as a pharmaceutical composition comprising therapeutically effective amounts of TGF- ⁇ (i.e. amounts that provide a therapeutic effect by reducing the level of activation of phagocytes) together with suitable diluents, adjuvants and/or carriers useful in immunosuppressive therapy.
  • TGF- ⁇ compositions are administered by continuous infusion, sustained release formulation, or injection at
  • sustained release formulations can include biodegradable microcapsular particles or implantable articles.
  • TGF- ⁇ is optionally delivered as an aerosol to the activated phagocytic cells in inflammatory disorders of the lung and airways.
  • one or more additional immunosuppressants such as an additional phagocyte deactivator and/or an anti-inflammatory agent, are administered with TGF- ⁇ .
  • additional immunosuppressants such as an additional phagocyte deactivator and/or an anti-inflammatory agent.
  • anti-inflammatory substances are examples of anti-inflammatory substances.
  • nonsteroidal anti-inflammatory drugs salicylate, penicillamine, gold salts, and antagonists of: TNF ⁇ , ⁇ , IL-1, and ⁇ -interferon.
  • Therapeutic variables include the half-life of the TGF- ⁇ preparation, administration route, and the clinical condition of the patient.
  • Activated macrophages were collected 4 d after intraperitoneal injection of sodium caseinate and plated at 1.2-1.3x10 5 per well in 96-well trays in Eagle's minimum essential medium ( ⁇ -variant) with 10% horse serum (complete medium). Nonadherent cells were washed off at 2 h and test media added to triplicate wells for the times indicated before the media were flicked out and the plates washed in saline.
  • H 2 O 2 release was then measured in the absence of cytokines over 90 min in response to 167 nM phorbol myristate acetate (PMA) by the horseradish peroxidase catalyzed oxidation of fluorescent scopoletin, and related to the protein content in the same wells as described in de la Harpe et al., J. Immunolog. Meth. 78, 323-325(1985).
  • PMA phorbol myristate acetate
  • NGF natural mouse nerve growth factor
  • IL natural murine interleukin
  • PDGF natural porcine platelet derived growth factor
  • CSF mouse colony stimulating factor
  • CSF-GM granulocytes and macrophages
  • CSF-G recombinant human CSF for granulocytes
  • EGF epidermal growth factor
  • TGF- ⁇ 2 was purchased from R&D Systems, Minneapolis MN, see Marquandt et al., J. Biol. Chem. 262, 12127-12131 (1987). Time Course for Suppression
  • TGF- ⁇ did not deactivate macrophages by triggering their respiratory burst, since exhaustion of respiratory burst capacity by triggering agents is evident immediately after the burst ceases (-1.5-3.5 h).
  • TGF- ⁇ 1 at 1-100 ng/ml did not elicit H 2 O 2 release from macrophages when added directly to the scopoletin assay.
  • TNF ⁇ -mo interferon- ⁇
  • B tumor necrosis factor- ⁇ -hu
  • TNF ⁇ tumor necrosis factor- ⁇ -hu
  • TNF- ⁇ -hu TNF- ⁇ -hu
  • TGF- ⁇ 1 Suppression of H 2 O 2 releasing capacity caused by TGF- ⁇ 1 could be overcome by interferon- ⁇ , tumor necrosis factor (TNF)- ⁇ , or TNF- ⁇ , at concentrations similar to those required to activate resident peritoneal macrophages, see Ding et al., supra.
  • TNF tumor necrosis factor
  • macrophages took up -20-25 starch granules per cell ( each granule 2.6 u in diameter ) , marginally less than control cells , as assessed by a method optimized to detect dif ferences in maximal phagocytic capacity
  • Test media were added for 2 days as indicated: complete medium alone (open bar), or complete medium containing TGF- ⁇ 1 (solid bars) or TGF- ⁇ 2 (hatched bars) at the concentrations indicated in ng/ml. After 2 days, macrophages were washed and incubated in complete medium for 2 h with 2 mg/coverslip of

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Pour traiter des troubles associés à une activation excessive des phagocytes, on administre au patient un facteur de croissance bêta transformateur.
PCT/US1989/003096 1988-07-20 1989-07-20 Procede de traitement de troubles inflammatoires par reduction de l'activation phagocytaire WO1990000900A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US22257988A 1988-07-20 1988-07-20
US222,579 1988-07-20

Publications (1)

Publication Number Publication Date
WO1990000900A1 true WO1990000900A1 (fr) 1990-02-08

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AU (1) AU4056089A (fr)
WO (1) WO1990000900A1 (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991015223A1 (fr) * 1990-03-30 1991-10-17 Amgen Inc. Facteurs d'inhibition des bouffees respiratoires
EP0527283A1 (fr) * 1991-08-12 1993-02-17 Societe Des Produits Nestle S.A. Composition alimentaire
WO1993004692A1 (fr) * 1991-08-30 1993-03-18 Creative Biomolecules, Inc. Modulation, induite par morphogene, de reaction inflammatoire
US5449688A (en) * 1993-03-30 1995-09-12 The United States Of America As Represented By The Department Of Health And Human Services Method of treating chronic inflammatory diseases
US5462925A (en) * 1990-11-16 1995-10-31 Celtrix Pharmaceuticals, Inc. Transforming growth factor β2,3
EP0804181A1 (fr) * 1995-09-19 1997-11-05 Cellular Sciences, Inc. Methode et composition de traitement de maladies mammaliennes provoquees par une reaction inflammatoire
US5739107A (en) * 1991-03-11 1998-04-14 Creative Biomolecules, Inc. Morphogen treatment of gastrointestinal ulcers
WO1999003999A1 (fr) * 1997-07-17 1999-01-28 The Regents Of The University Of Michigan Procedes et compositions servant a inhiber la reaction proinflammatoire
US6077823A (en) * 1991-03-11 2000-06-20 Creative Biomolecules, Inc. Method for reducing tissue damage associated with ischemia-reperfusion or hypoxia injury
US6090776A (en) * 1991-03-11 2000-07-18 Creative Bio Molecules, Inc. Morphogen treatment of organ implants
US6194376B1 (en) * 1991-03-11 2001-02-27 Creative Biomolecules, Inc. Method for modulating inflammatory response comprising administering morphogen
US6407060B1 (en) 1996-03-22 2002-06-18 Curis, Inc. Method for enhancing functional recovery following central nervous system ischemia or trauma
EP2957634A1 (fr) * 2014-06-20 2015-12-23 Consejo Superior De Investigaciones Científicas Composés pour la prévention et/ou le traitement de maladies fibrotiques

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4806523A (en) * 1985-08-06 1989-02-21 Collagen Corporation Method of treating inflammation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4806523A (en) * 1985-08-06 1989-02-21 Collagen Corporation Method of treating inflammation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BRINCKERHOFF, CIBA FOUND SYMP., 113, 191-211, 1985, "Effect of Retinoids on Rheumatoid Arthritis, A Proliferative Invasive non-Malignant Disease", see the abstract. *
GOODMAN and GILMAN, THE PHARMACEUTICAL BASIS OF THERAPEUTICS, 3rd ed., The Macmillan Co. N.Y., 1965, pages 328-329, see page 329, middle of second paragraph. *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991015223A1 (fr) * 1990-03-30 1991-10-17 Amgen Inc. Facteurs d'inhibition des bouffees respiratoires
US5462925A (en) * 1990-11-16 1995-10-31 Celtrix Pharmaceuticals, Inc. Transforming growth factor β2,3
US6077823A (en) * 1991-03-11 2000-06-20 Creative Biomolecules, Inc. Method for reducing tissue damage associated with ischemia-reperfusion or hypoxia injury
US7060680B2 (en) 1991-03-11 2006-06-13 Curis, Inc. Morphogen treatments for limiting proliferation of epithelial cells
US6399569B1 (en) 1991-03-11 2002-06-04 Curis, Inc. Morphogen treatments for limiting proliferation of epithelial cells
US6288031B1 (en) 1991-03-11 2001-09-11 Curis, Inc. Method for reducing extravasation of effector cells
US6194376B1 (en) * 1991-03-11 2001-02-27 Creative Biomolecules, Inc. Method for modulating inflammatory response comprising administering morphogen
US5739107A (en) * 1991-03-11 1998-04-14 Creative Biomolecules, Inc. Morphogen treatment of gastrointestinal ulcers
US6090776A (en) * 1991-03-11 2000-07-18 Creative Bio Molecules, Inc. Morphogen treatment of organ implants
US5461033A (en) * 1991-08-12 1995-10-24 Nestec S.A. Modulation of class II antigen expression
EP0527283A1 (fr) * 1991-08-12 1993-02-17 Societe Des Produits Nestle S.A. Composition alimentaire
WO1993004692A1 (fr) * 1991-08-30 1993-03-18 Creative Biomolecules, Inc. Modulation, induite par morphogene, de reaction inflammatoire
US5449688A (en) * 1993-03-30 1995-09-12 The United States Of America As Represented By The Department Of Health And Human Services Method of treating chronic inflammatory diseases
EP0804181A1 (fr) * 1995-09-19 1997-11-05 Cellular Sciences, Inc. Methode et composition de traitement de maladies mammaliennes provoquees par une reaction inflammatoire
EP0804181A4 (fr) * 1995-09-19 2005-02-02 Cellular Sciences Inc Methode et composition de traitement de maladies mammaliennes provoquees par une reaction inflammatoire
US6407060B1 (en) 1996-03-22 2002-06-18 Curis, Inc. Method for enhancing functional recovery following central nervous system ischemia or trauma
WO1999003999A1 (fr) * 1997-07-17 1999-01-28 The Regents Of The University Of Michigan Procedes et compositions servant a inhiber la reaction proinflammatoire
EP2957634A1 (fr) * 2014-06-20 2015-12-23 Consejo Superior De Investigaciones Científicas Composés pour la prévention et/ou le traitement de maladies fibrotiques

Also Published As

Publication number Publication date
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