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WO1993021953A1 - Composition destinee a la prophylaxie et au traitement de la fibrose pulmonaire - Google Patents

Composition destinee a la prophylaxie et au traitement de la fibrose pulmonaire Download PDF

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Publication number
WO1993021953A1
WO1993021953A1 PCT/GB1993/000886 GB9300886W WO9321953A1 WO 1993021953 A1 WO1993021953 A1 WO 1993021953A1 GB 9300886 W GB9300886 W GB 9300886W WO 9321953 A1 WO9321953 A1 WO 9321953A1
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WIPO (PCT)
Prior art keywords
pulmonary fibrosis
bleomycin
silica
treatment
lung
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Ceased
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PCT/GB1993/000886
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English (en)
Inventor
Pierre François PIGUET
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Individual
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Individual
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Publication of WO1993021953A1 publication Critical patent/WO1993021953A1/fr
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    • 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
    • C07K16/2839—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 integrin superfamily
    • C07K16/2845—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 integrin superfamily against integrin beta2-subunit-containing molecules, e.g. CD11, CD18
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to a method of prophylaxis and treatment of pulmonary fibrosis. Furthermore, it relates to a pharmaceutical composition for the prophylaxis and treatment of pulmonary fibrosis. More generally it relates to the facilitation of wound repair- Pulmonary fibrosis is any one of a group of diseases characterised by an increase in the deposition of proteins of the extra-cellular matrix (ECM), notably collagens, generally associated with the growth of interstitial cells. These diseases respond poorly to current therapy, ⁇ and are responsible for about 5% of annual deaths in the USA (see Bitter an and Hen e in Chest, 1991, 99, 81s).
  • ECM extra-cellular matrix
  • cytokines have been characterized recently which might be involved in pulmonary fibrosis, notably tumor necrosis factor- ⁇ (TNF- ⁇ ), interleukin-1 ' (IL-1), transforming growth factor (TGF- ⁇ ) or platelet derived growth factor (PDGF) (see E. J. ova ⁇ s, Immunology Today, 1991, _12_, 17). Macrophages are known to produce several of these factors.
  • the lung contains various leukocytes (i. e. lymphocytes, macrophages and polynuclear leukocytes), in three distinct compartments - alveolar, interstitial and intra-vascular (see Abraham et al, J. Immunol. , 1990, 144, 2117), which may also play some role in the development of pulmonary fibrosis instead of normal healing of lesions.
  • pulmonary fibrosis The two most commonly used experimental models in the study of pulmonary fibrosis are the pulmonary fibrosis elicited by the instillation of either bleo ycin or silica (see D. H. Bowden, Laboratory I vestigation, 1984, 50, 487, and E. M. Lugano et al, Am. J. Pathol. , 1982, 109, 27). It has been shown that development of bleomycin-induced pulmonary fibrosis can be prevented by a depletion of T lymphocytes (Piguet et al, J. Exp. Med. , 1989, 170, 655), the presence of T-lymphocytes being necessary for both increased lung TNF RNA levels and the development of " fibrosis.
  • Sili ⁇ osis has been shown not to be markedly affected by the absence of T-lymphocytes. .It has also been shown that administration of anti-TNF antibodies to mice during instillation of silica almost completetly prevents deposition of collagen due to silica-induced pulmonary fibrosis (P. F. Piguet et al, Nature, 1990, 344, 245). Administration of anti-TNF antibdies, however, is much less effective in the prevention of pulmonary fibrosis induced by bleomycin (P. F. Piguet et al, J. Exp. Med. , 1989, 170, 655). Thus, although much research interest has centered on the possible development of the work with T-lympho ⁇ ytes and anti-TNF antibodies, it has become clear that neither approach is likely to provide a viable method of treatment of the complete range of pulmonary fibrosis.
  • a pharmaceutical composition is sought that may be' administered both as a means of preventing the onset of pulmonary fibrosis, and treating the condition after its onset.
  • the leukocytes of the lung may have some role to play in the evolution of pulmonary fibrosis.
  • the interactions and state of activation of leukocytes is known to be modulated by various surface proteins.
  • One such class of surface proteins is the leukocytic integrins.
  • leukocytic integrins There are " three leukocytic integrins, all of which are non-covalently linked heterodimers sharing a common ⁇ -subunit (CD-18) and different but homologous a-subunits: the CD-lla (or the LFA-1), the CD-lib (or Mac-1 or C 3), and the CD-llc (or the pl50, 95) (see Anderson and Springer in Ann. Rev. Med. , 1987, 38, 175).
  • the CD-ll/CD-18 family also known as the leukocytic or ⁇ -2 integrins, are believed to be involved in various immune and inflammatory responses on the basis of two pieces of evidence.
  • CD-18 congenital deficiencies in humans lead to a severe disease, known as Leukocyte Adhesion Deficiency (LAD), which is characterised by recurrent bacterial infections, and impaired pus formation and wound healing (see Anderson and Springer in Ann. Rev. Med., 1987, 3J3, 175).
  • LAD can be treated by bone marrow transplantation, donor rejection of HLA-mismatched bone marrow being overcome by administration of anti CD-lla mAbs to the patient from about 3 to 5 days before the graft.
  • pulmonary fibrosis may be elicited by the intratracheal instillation of bleomycin or silica in mice, significant increases in the lung hydroxyproline content being observed after 15 days.
  • simultaneous administration of either or both of anti CD-lla or anti CD-lib mAb during the period of instillation has been found to prevent excessive lung collagen deposition for both bleomycin and silica instillation, i. e. administration of the antibodies completely prevents the onset of both bleomycin and silica induced pulmonary fibrosis.
  • collagen levels in the lung are slightly lower after administration of anti CD-11 mAbs following the instillation of silica or bleomycin, than those in normal lungs in which no fibrosis have been elicited.
  • pulmonary fibrosis including idiopathi ⁇ pulmonary fibrosis, drug-induced pulmonary fibrosis, silicosis, pneumoconiosis (e.g. asbestosis, berylliosis), and acute respiratory distress syndrome (ARDS).
  • a monoclonal antibody to either or both of the leukocytic a sub-units CD-lla and CD-Ilb for the manufacture of a composition for the prophylaxis and treatment of pulmonary fibrosis in mammals.
  • the invention may be further illustrated by consideration of the Examples below.
  • the animals, materials and methods used in the Examples are as follows:
  • mice CBA/Ca and C57BL/10 (BIO) mice were purchased from OLAC Ltd. (Blackthorn, UK), and bred for 3-4 generations. Experiments were performed with 2-4 month old male mice.
  • Bleomycin (Lundbeck, AVA, Copenhagen, Denmark) was dissolved in HBSS and 0.08 U in 0.1 ml was injected intra-tracheally. This procedure induced some morbidity, manifested by a loss in body weight and death by the 15th day after the injection in 5-20% of the mice. About 2 mg silica particles (DQ 12, size ⁇ 5 micron) were suspended in 0.1 ml of saline, and injected intra-tracheally. This treatment did not induce detectable loss of body weight or mortality.
  • the alveolae were lavaged with saline instilled within the trachea by a 25 cm hydrostatic pressure.
  • Lung interstitial cells were isolated as described by Abraham et al, J. Immunol. , 1990, 144, 2117.
  • the lungs were fixed by the intra-tracheal administration of formol sublimate or glutaraldehyde (2% in 0.1M cacodylate buffer, pH 7.4) for paraffin or methacrylate and epon embedding respectively.
  • Four sections from paraffin embedded material for each individual mouse were stained with hematoxilin and eosin, and a modified trichrome stain was used for the identification of platelet aggregates.
  • RNAs denatured with glyoxal, were separated on 1.2% agarose gels (4 ⁇ g per lane), and transferred onto nylon membranes. . Filters were hybridised with 32P-labelled cRNA probes (see Collart et al, J. Exp. Med., 1986, 163, 2113).
  • Example 1
  • Pulmonary fibrosis were elicited in groups of mice by the instillation of bleomycin or silica as decribed above.
  • 500 ⁇ g of the anti CD-lla or anti CD-Ilb mAbs were injected every 5 days after instillation, and the mice were sacrificed on the 15th day after instillation.
  • Control tests were run in which saline was injected intra-tracheally at the beginning of the experiment, and in which saline was injected into the mice at 5 day intervals instead of the antibodies after instillation by bleomycin or silica.
  • Cells from the broncho-alveolar lavage (BAL) were recovered after an intra-tracheal instillation of saline.
  • the lung hydroxyproline as an evaluation of the lung collagen, was determined after lung hydrolysis. The results were as shown in Table 1 below.
  • silica saline 18 (4) 144 (48) silica anti CD-lla 10 (4) 89 (30)* silica anti CD-lib 16 (3) 80 (39)*
  • Results are the mean (+sd) of the values obtained with 7-10 mice.
  • the significance of the difference with the saline treated group was evaluated by the Mann and ithney non-parametric U test; *p ⁇ 0.02, **p ⁇ 10 -2
  • Pulmonary fibrosis was elicited in mice using bleomycin or silica as in Example 1.
  • Anti CD-lla mAbs 500 ⁇ g were administered to the mice on day 20 and day 25 and the mice were sacrificed on day 30 after silica or bleomycin instillation.
  • Control tests were run in which saline was injected at days 20 and 25 after instillation with silica or bleomycin instead of the mAbs. Mice, to which nothing had been administered throughout the period of the tests, were also sacrificed after 30 days. The results were as shown below in Table II. Table II
  • silica saline 120 (22 ) silica anti CD-lla 63 ( 10 ) *
  • Results are the mean (_+sd) of groups of 5 mice. Difference with the saline injected group; *p ⁇ 10 -3
  • the lung hydroxyproline content is approximately the same as the value for mice in which no fibrosis have been elicited, while in the case of silica induced fibrosis, the lung hydroxyproline content is actually below that of the value obtained for mice in which no fibrosis have been elicited.
  • Pulmonary fibrosis was elicited using silica or bleomycin in groups of 4-8 mice as described in Example 1. On day 15 the lungs were fixed by an intra-tracheal instillation of formol sublimate, and 3-4 sections across the hilus of the major lobes were prepared for each individual mouse. Sections were scored semi-quantitatively as follows:
  • Lymphoid infiltration was evaluated as the number of lymphoid foci (i.e. lymphoid formation of >20) per section.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

On utilise un anticorps monoclonal destiné à l'une ou l'autre des sous-unités leucocytaires α CD-11a et CD-11b pour fabriquer une composition destinée à la prophylaxie et au traitement de la fibrose pulmonaire chez les mammifères. L'invention concerne également un procédé de prophylaxie et de traitement de la fibrose pulmonaire chez les mammifères qui consiste à administrer une quantité efficace d'un anticorps monoclonal à l'une ou l'autre des sous-unités leucocytaires α CD-11a et CD-11b ou aux deux.
PCT/GB1993/000886 1992-04-28 1993-04-28 Composition destinee a la prophylaxie et au traitement de la fibrose pulmonaire Ceased WO1993021953A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9209177A GB2266664A (en) 1992-04-28 1992-04-28 Monoclonal antibodies for prophylaxis and treatment of pulmonary fibrosis
GB9209177.6 1992-04-28

Publications (1)

Publication Number Publication Date
WO1993021953A1 true WO1993021953A1 (fr) 1993-11-11

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PCT/GB1993/000886 Ceased WO1993021953A1 (fr) 1992-04-28 1993-04-28 Composition destinee a la prophylaxie et au traitement de la fibrose pulmonaire

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GB (1) GB2266664A (fr)
WO (1) WO1993021953A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7396530B2 (en) 2004-06-09 2008-07-08 Genentech, Inc. Method of treating granuloma annulare or sarcoid
WO2016138538A3 (fr) * 2015-02-27 2016-10-20 The General Hospital Corporation Utilisation thérapeutique d'anticorps de liaison à l'intégrine

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
AMERICAN REVIEW OF RESPIRATORY DISEASE vol. 145, no. 4(2), April 1992, NEW YORK, USA page A190 P. PIGUET ET AL. 'Antibody to the leukocyte integrins CD11a or b prevent or cure pulmonary fibrosis elicited in mice by bleomycin or silica.' *
AMERICAN REVIEW OF RESPIRATORY DISEASE vol. 147, no. 2, February 1993, NEW YORK, USA pages 435 - 441 P. PIGUET ET AL. 'Effective treatment of the pulmonary fibrosis elicited in mice by bleomycin or silica with anti-CD11 antibodies.' *
BIORHEOLOGY vol. 27, no. 3-4, 1990, OXFORD, GB pages 425 - 432 J. WAUTIER ET AL. 'Leukocyte adhesion to endothelial cells.' *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7396530B2 (en) 2004-06-09 2008-07-08 Genentech, Inc. Method of treating granuloma annulare or sarcoid
WO2016138538A3 (fr) * 2015-02-27 2016-10-20 The General Hospital Corporation Utilisation thérapeutique d'anticorps de liaison à l'intégrine
US10738121B2 (en) 2015-02-27 2020-08-11 The General Hospital Corporation Therapeutic use of integrin-binding antibodies

Also Published As

Publication number Publication date
GB2266664A (en) 1993-11-10
GB9209177D0 (en) 1992-06-10

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