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WO1999015198A2 - Agents pour lutter contre la meningite purulente - Google Patents

Agents pour lutter contre la meningite purulente Download PDF

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Publication number
WO1999015198A2
WO1999015198A2 PCT/EP1998/006069 EP9806069W WO9915198A2 WO 1999015198 A2 WO1999015198 A2 WO 1999015198A2 EP 9806069 W EP9806069 W EP 9806069W WO 9915198 A2 WO9915198 A2 WO 9915198A2
Authority
WO
WIPO (PCT)
Prior art keywords
iga
composition according
protease
iga protease
preparation
Prior art date
Application number
PCT/EP1998/006069
Other languages
German (de)
English (en)
Other versions
WO1999015198A3 (fr
Inventor
Dirk Lorenzen
Frank DÜX
Thomas Meyer
Gaby Haas
Original Assignee
MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V.
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 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. filed Critical MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V.
Priority to CA002304615A priority Critical patent/CA2304615A1/fr
Priority to EP98952634A priority patent/EP1015021A2/fr
Priority to JP2000512567A priority patent/JP2001517637A/ja
Publication of WO1999015198A2 publication Critical patent/WO1999015198A2/fr
Publication of WO1999015198A3 publication Critical patent/WO1999015198A3/fr

Links

Classifications

    • 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
    • A61K39/02—Bacterial antigens
    • A61K39/09—Lactobacillales, e.g. aerococcus, enterococcus, lactobacillus, lactococcus, streptococcus
    • A61K39/092—Streptococcus
    • 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
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1774—Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)
    • 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
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/482—Serine endopeptidases (3.4.21)
    • 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
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
    • 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
    • A61K39/02—Bacterial antigens
    • A61K39/095—Neisseria
    • 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
    • A61K39/02—Bacterial antigens
    • A61K39/102—Pasteurellales, e.g. Actinobacillus, Pasteurella; Haemophilus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21—Serine endopeptidases (3.4.21)
    • C12Y304/21072—IgA-specific serine endopeptidase (3.4.21.72)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/24—Metalloendopeptidases (3.4.24)
    • C12Y304/24013—IgA-specific metalloendopeptidase (3.4.24.13)

Definitions

  • the invention relates to new agents against bacterial meningitis.
  • Bacterial meningitis is an infectious disease with high morbidity and mortality, especially in young children.
  • a characteristic feature of meningitis is an inflammatory reaction, which is characterized by a massive infiltration of activated leukocytes.
  • the patient's immune response to the bacteria is associated with the release of large amounts of cytokines such as TNF- ⁇ , IL-1 ⁇ and IL-6 (Waage et al., J. Exp. Med. 1 69 (1 989), 333 -338).
  • cytokines The release of these cytokines enhances the inflammatory reactions in the subarachnoid space, mediates adherence of leukocytes to the endothelial tissue and their transmigration by upregulating the expression of adherence molecules such as ICAM-1 (CD54) and thus leads to damage to epithelial barriers, e.g. the blood-brain barrier (Mc Gee et al., Microb. Path. 1 2 (1 992), 333). It is also believed that the release of the cytokines is responsible for increased production of reactive oxygen species during meningial inflammation.
  • Antibiotics have reduced the mortality rate of acute bacterial menigitides to approximately 1 0% in early cases. However, if meningitis is diagnosed late or if it affects newborns or the elderly, it is often fatal. There is therefore a need to further elucidate the pathogenic mechanism of bacterial meningitis and to provide new therapeutic and diagnostic agents (Kornelisse et al., Eur. J. Pediatr. 1 54 (1 995), 85-96). The inflammatory immune reactions in gram-negative bacterial meningitis are essentially caused by bacterial lipopolysaccharides (endotoxins).
  • IgA proteases from Gram-negative bacteria are able to stimulate the production and secretion of cytokines such as TNF- ⁇ , IL-1 ⁇ , IL-6 and IL-8, in peripheral blood monocytes and as a result thereof To increase expression of adhesion molecules such as ICAM-1.
  • cytokines such as TNF- ⁇ , IL-1 ⁇ , IL-6 and IL-8
  • adhesion molecules such as ICAM-1.
  • the IgA protease is involved as a possible factor in the damage to the blood-brain barrier and is of considerable importance in the development or progression of bakerial meningitis.
  • IgA proteases are exoenzymes that are generated by various pathogens, including the three pathogens that are primarily responsible for the development of bacterial meningitis, namely Haemophilus influenzae, Neisseria meningitidis and Streptococcus pneumoniae (see e.g. EP-A-0 254 090).
  • the IgA proteases are sequence-specific endopeptidases that specifically cleave individual peptide bonds in certain proline-rich consensus sequences within the hinge region of human IgA1 but not IgA2 (Pohlner et al., Bio / Technology 10 (1,992), 779-804; Lomholt, APMIS Supl. 62, vol. 104 (1 996), 3-28).
  • IgA proteases cause the formation of antibodies in humans.
  • a new The therapeutic approach in the treatment of bacterial meningitis is therefore to reduce or completely suppress the stimulation of the release of cytokines caused by the IgA protease.
  • a first aspect of the present invention therefore relates to a pharmaceutical composition which contains at least one IgA protease or an immunologically active fragment thereof as an active ingredient, optionally together with customary pharmaceutical carriers and auxiliaries.
  • composition is suitable as an active vaccine for immunization against bacterial meningitis.
  • active ingredient in one or more injections, optionally together with known immunological adjuvants, the formation of antibodies against IgA protease is induced in the organism, whereby the risk of a disease of bacterial infections, in particular bacterial meningitis, can be reduced or the course of such diseases can be reduced .
  • the IgA protease can be a natural or recombinant IgA protease or a fragment thereof which causes the formation of neutralizing antibodies in the organism.
  • suitable IgA proteases are IgA proteases from bacteria of the genus Neisseria, in particular from N.meningitidis, Haemophilus, in particular H.influenzae and Streptococcus, in particular S.pneumoniae.
  • a chemically or genetically modified IgA protease (by changing the amino acid sequence in the active center or by complete or partial deletion of the active center) is used for the injection, which has an at least partially reduced biological activity, ie proteolytic activity and / or ability to Has binding to a surface receptor.
  • the pharmaceutical composition can contain not only an IgA protease, but also a mixture of several different IgA proteases or protease fragments, for example from different organisms.
  • Another aspect of the present invention relates to a pharmaceutical composition which effects a direct inhibition of the IgA protease activity and is suitable for combating acute bacterial meningitis.
  • this composition contains at least one inhibitor of IgA proteases, optionally together with conventional pharmaceutical carriers and auxiliaries.
  • An inhibitor of IgA proteases is a substance which at least partially suppresses the stimulation of the secretion of cytokines mediated by IgA protease.
  • suitable inhibitors are antibodies directed against IgA proteases, e.g. polyclonal antisera, monoclonal antibodies, antibody fragments etc., which partially or completely inhibit the cytokine-stimulating effect of the IgA protease.
  • suitable inhibitors are inhibitors of the proteolytic activity of IgA proteases, e.g. Serine protease inhibitors.
  • the agents according to the invention which bring about direct inhibition of the IgA proteases, can also be used in the late stage of the disease when successful therapy with antibiotics alone is no longer possible.
  • compositions according to the present invention are suitable for the preparation of an agent against bacterial infections, in particular for the preparation of an agent against bacterial meningitis.
  • the administration of these agents leads to a reduction in Secretion of cytokines and thus to reduce damage to epithelial barriers, especially the blood-brain barrier.
  • compositions according to the invention can be prepared in a known manner, e.g. to be administered introperitoneally by injection.
  • intracerebrospinal administration or administration together with an aid for penetration of the blood-brain barrier can be useful.
  • Fig. 1 The dose-dependent release of the cytokines TNF- ⁇ , IL-1 ß, IL-
  • Fig. 3 The stimulation of cytokine release in mononuclear
  • MNC Cells by IgA protease compared to stimulation with the T cell mitogen PHA.
  • the individual values represent the content of the corresponding cytokine in the culture supernatant of MNC from different donors after 1 8
  • the box blot charts present the median value, 1. and 3rd quartille (boxes) and the 90% leeway (whisker Limits) of all values from different experiments.
  • the cytokine release after stimulation with IgA protease differs significantly from the cytokine release from the control (medium) (p ⁇ 0.01), but not from that after stimulation with PH A (determined according to the distribution-independent procedure with the Mann-Whitney U-Test).
  • Fig. 4 The increase in expression of ICAM in monocytes after stimulation with IgA protease differs significantly from the cytokine release from the control (medium) (p ⁇ 0.01), but not from that after stimulation with PH A (determined according to the distribution-independent procedure with the Mann-Whitney U-Test).
  • Fig. 4 The increase in expression of ICAM in monocytes after stimulation with PH A (determined according to the distribution-independent procedure with the Mann-Whitney U-Test).
  • PBMC Peripheral mononuclear blood cells
  • the PBMC were cultured in RPMI medium supplemented with 5% heat-inactivated pooled human AB serum ( ⁇ 1 ng / ml endotoxin; Sigma).
  • a total of 1 x 10 5 cells / well in 0.5 ml of culture medium were cultivated in aliquots in 96-well round-bottom plates at 37 ° C. in 5% CO 2 .
  • Purified IgA protease was added to the cultures in the concentrations indicated or as positive controls 30 ng / ml lipopolysaccharide (LPS) of E.
  • LPS lipopolysaccharide
  • the cells were cultured with the culture medium alone or in the presence of a low endotoxin concentration (0.03 ng / ml LPS) corresponding to the maximum possible endotoxin concentration in 30 ⁇ g / ml IgA protease. After 18 hours, cell-free supernatants were collected and the cytokines contained therein were quantified by commercially available sandwich ELISA tests (quantum set, Pharmigen). In some cases, the cells were harvested, washed and labeled with fluorescent dye-labeled monoclonal antibodies directed against monocyte and lymphocyte markers. These labeled cells were analyzed by flow cytometry (FACScalibur, Becton Dickinson) using FSC / SSC gates for monocytes or lymphocytes.
  • the cell line MonoMac ⁇ (1 x 10 6 cells / ml) was cultivated in RPMI medium supplemented with 5% heat-inactivated AB serum, 1% non-essential amino acids, 1% sodium pyruvate and 1% bovine serum albumin.
  • the MonoMac6 cell cultures showed no clumping, which indicates that there was no significant endotoxin contamination in the culture medium (Löms-Ziegler-Heitbrock et al., Immunbiology 1 93 (1 995), 21 7-223).
  • the MonoMac6 cells expressed CD14 as determined by a fluorescent dye-labeled monoclonal anti-CD 14 antibody (Becton Dickinson) and measured by flow cytometry.
  • IgA protease stimulates the release of the cytokines TNF- ⁇ , IL-1 ⁇ , IL-6 and IL-8 by PBMC in a dose-dependent manner (FIG. 1).
  • the greatest amounts of these cytokines in the supernatant of PBMC were measured at an IgA protease concentration between 3 to 30 ⁇ g / ml comparable to the cytokine production induced by 33 to 100 ng / ml LPS (FIG. 2).
  • the IgA protease contains less than 1 pg / ⁇ g protein endotoxin (limulus test).
  • the ability of the IgA synthesis to activate the cytokines IL-1 ⁇ , TNF- ⁇ and IL-6 derived from monocytes depends on the presence of T-lymphocytes.
  • Purified monocytes (adherent cells) and the monocytic cell line MonoMac6 showed no production of significant amounts of IL-1 ⁇ , IL-6 and TNF- ⁇ , but detectable amounts of IL-8 in response to IgA protease, while LPS (30 ng / ml) stimulates the release of all four cytokines mentioned in purified monocytes and in the cell line MonoMac6 (FIG. 2). In contrast, large amounts of these cytokines were released from unseparated PBMC after stimulation by IgA protease.
  • the polyclonal activator PHA requires the presence of T lymphocytes to produce cytokines derived from monocytes.
  • the amounts of the cytokines TNF- ⁇ , IL-1 ⁇ , IL6 and IL8 released in the supernatants from PHA-stimulated PBMC were comparable to the amounts of these cytokines after stimulation with IgA protease (Fig. 3).
  • Fig. 3 The amounts of the cytokines TNF- ⁇ , IL-1 ⁇ , IL6 and IL8 released in the supernatants from PHA-stimulated PBMC were comparable to the amounts of these cytokines after stimulation with IgA protease (Fig. 3).
  • PHA 1 7-20% IL2R + or CD25 + cells after 24 hours
  • no noteworthy T-cell stimulation by IgA protease was found (1% IL2R + positive cells / 24h).
  • ICAM-1 (CD54) in particular, but not, for example, of HLA-DR in monocytes was significantly increased (FIG. 4). ICAM-1 expression was stable in lymphocytes. The IgA protease had no influence on the expression of LFA-1 (CD 1 1 a / CD1 8) in monocytes or in lymphocytes. 3. Conclusion
  • IgA-1 protease from bacteria of the Neisseria genus is an effective stimulator of peripheral blood mononuclear cells for the production and secretion of the cytokines TNF- ⁇ , IL-1 ⁇ , IL-6 and IL-8, which leads to an increase in ICAM- 1 expression on monocytes leads.
  • the TNF- ⁇ , IL-1 ⁇ and IL-6 production induced by IgA protease required the presence of T cells, which were not activated by the IgA protease.
  • the IgA protease plays an important role in the inflammatory response that occurs in bacterial meningitis and is believed to be directly involved in the increased cytokine production.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Gastroenterology & Hepatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Genetics & Genomics (AREA)
  • General Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
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  • Molecular Biology (AREA)
  • Cell Biology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux agents pour lutter contre la méningite purulente.
PCT/EP1998/006069 1997-09-23 1998-09-23 Agents pour lutter contre la meningite purulente WO1999015198A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CA002304615A CA2304615A1 (fr) 1997-09-23 1998-09-23 Agents pour lutter contre la meningite purulente
EP98952634A EP1015021A2 (fr) 1997-09-23 1998-09-23 Agents pour lutter contre la meningite purulente
JP2000512567A JP2001517637A (ja) 1997-09-23 1998-09-23 細菌性髄膜炎に対する薬剤

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19741955.0 1997-09-23
DE19741955A DE19741955A1 (de) 1997-09-23 1997-09-23 Mittel gegen bakterielle Meningitis

Publications (2)

Publication Number Publication Date
WO1999015198A2 true WO1999015198A2 (fr) 1999-04-01
WO1999015198A3 WO1999015198A3 (fr) 1999-06-17

Family

ID=7843345

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1998/006069 WO1999015198A2 (fr) 1997-09-23 1998-09-23 Agents pour lutter contre la meningite purulente

Country Status (5)

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EP (1) EP1015021A2 (fr)
JP (1) JP2001517637A (fr)
CA (1) CA2304615A1 (fr)
DE (1) DE19741955A1 (fr)
WO (1) WO1999015198A2 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2020043814A (ja) * 2018-09-19 2020-03-26 東ソー株式会社 無活性アルカリホスファターゼ

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK130889A (da) * 1989-03-17 1990-09-18 Mogens Kilian Immunoglobulin a1-proteaser (iga1-proteaser), fremgangsmaade til genteknologisk fremstilling af saadanne enzymer samt vaccine indeholdende enzymerne og fragmenter deraf til immunisering mod bakteriel meningitis og andre sygdomme fremkaldt af iga1-protease-producerende bakterier
WO1993010818A1 (fr) * 1991-12-04 1993-06-10 New England Medical Center Hospitals, Inc. Preparation lactee pour nouveau-nes et additif pour cette preparation

Also Published As

Publication number Publication date
DE19741955A1 (de) 1999-04-01
EP1015021A2 (fr) 2000-07-05
JP2001517637A (ja) 2001-10-09
CA2304615A1 (fr) 1999-04-01
WO1999015198A3 (fr) 1999-06-17

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