WO2008104200A1 - Utilisation d'apyrase pour le traitement d'une pathologie résultant de l'activité d'une endotoxine - Google Patents

Utilisation d'apyrase pour le traitement d'une pathologie résultant de l'activité d'une endotoxine Download PDF

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Publication number
WO2008104200A1
WO2008104200A1 PCT/EP2007/001986 EP2007001986W WO2008104200A1 WO 2008104200 A1 WO2008104200 A1 WO 2008104200A1 EP 2007001986 W EP2007001986 W EP 2007001986W WO 2008104200 A1 WO2008104200 A1 WO 2008104200A1
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Prior art keywords
apyrase
lps
phosphohydrolase
ecto
nucleoside
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PCT/EP2007/001986
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English (en)
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Rudi Brands
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Gelato Corporation N.V.
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Priority to PCT/EP2007/001986 priority Critical patent/WO2008104200A1/fr
Publication of WO2008104200A1 publication Critical patent/WO2008104200A1/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
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y306/00—Hydrolases acting on acid anhydrides (3.6)
    • C12Y306/01—Hydrolases acting on acid anhydrides (3.6) in phosphorus-containing anhydrides (3.6.1)
    • C12Y306/01005—Apyrase (3.6.1.5), i.e. ATP diphosphohydrolase

Definitions

  • the present invention relates to the use of Ecto- nucleoside phosphohydrolase 1 (apyrase) for the preparation of a medicament for the treatment or prophylaxis of pathological conditions resulting from endotoxic activity such as acute or chronic systemic inflammation or a disruption of the vascular endothelial homeostasis.
  • apyrase Ecto- nucleoside phosphohydrolase 1
  • pathological conditions may result from exposure to agents like bacterial toxins, e.g., endotoxin, being the most potent pro-inflammation inducer.
  • the present invention also relates to a pharmaceutical composition comprising apyrase for the treatment of pathological conditions resulting from endotoxic activity.
  • Endotoxins are a component of the cell wall of Gram negative bacteria.
  • the term endotoxin refers to the lipopolysaccharide (LPS) complex associated with the outer membrane of all Gram negative bacteria.
  • LPS lipopolysaccharide
  • These bacteria include commensal and/or opportunistic pathogenic species, such as E. coli, Salmonella, Shigella, Pseudomonas, Neisseria, Helicobacter and Haemophilus, as well as many other common species .
  • Lipopolysaccharides comprise a lipid portion and a polysaccharide portion. The lipid portion, also denoted as lipid A, is highly conserved amongst Gram negative bacterial species.
  • the lipid A portion of LPS in most of these species is substantially or completely identical.
  • the polysaccharide portion of lipopolysaccharides differs however amongst the various Gram negative species and even between different strains of the same species.
  • the lipid A portion of LPS is not generally antigenic, i.e. it does not usually provoke the production of antibodies and immune defenses specific to it. Despite its low antigenicity, it is the lipid A portion which is essentially responsible for the toxicity of LPS. Lipid A, if stripped from LPS and injected intravenously, will produce all the effects of an intact LPS injection and almost all the effects of injecting the corresponding live bacteria themselves .
  • Lipid A portion is highly conserved across species of bacteria, the reaction to different varieties of LPS from different bacteria is roughly similar (in the same host) , however the Lipid A of some species is considerably more toxic than that of others.
  • the polysaccharide portion of LPS is quite antigenic, i.e. it provokes a specific immune response.
  • the polysaccharide portion contains a core and an "O-specific chain" .
  • the O-specific chain is the portion of LPS most responsible for its immune recognition. Minor variations in the structure of the O-polysaccharide make enormous differences to the virulence of bacterial infections, i.e. the capacity of the bacteria to multiply, infect and virulence .
  • Lipid A While it is the function of the immune system to recognize the O-polysaccharide and to mount defenses against the invading bacteria or their toxins, it is the Lipid A fragments that produces the harmful and potentially lethal effects of an infection. Paradoxically, destroying the microbe increases the harm it does because of cell death and subsequent disintegration, LPS is released in large quantities from the destroyed pathogen. Lipid A, once released into, for example, the vascular system and tissue spaces, invokes a powerful non-specific immune reaction.
  • the endothelial barrier is the primary defense against LPS although other mechanisms such as scavengers and detoxifying molecules are known. From this, it follows that any condition affecting the integrity of the endothelial barrier such as severe burns, antibiotic use/abuse, severe trauma, intense or endurance exercise, ischemia, reperfusion damage of the gut (and other organs) and several common gastrointestinal pathologies are potentially dangerous by readily allowing LPS to cross the gut barrier into the blood.
  • LPS exposure leads to an increase in circulating levels of nitrate and nitrite, which are stable by-products of nitric oxide.
  • LPS induces inducible nitric oxide synthase (iNOS) expression leading to an increased synthesis of nitric oxide (NO) .
  • NO is a potent vasodilator and its continuous overproduction during inflammation, along with the production of various cytokines, leads to vasodilation.
  • Inhaled endotoxin inevitably affects the lungs first, and gut-derived endotoxin inevitably affects the liver first.
  • LPS is a potent initiator of immune responses.
  • the production of NO, TNF-alpha and other interleukins after pro-inflammatory exposure to even picograms amounts of LPS can literally cause the vascular collapse, inflammation, coagulation and multiple organ failure being characteristic of severe sepsis.
  • LPS depletes membrane glutathione (GSH) and severely depletes ascorbate, as well as other key antioxidants. Drastic reductions in antioxidant concentrations in multiple tissues are characteristic of sepsis. Still today, despite advances in sepsis care, approximately 400,000-500,000 people develop sepsis in Europe and the USA each year. Half of these people show signs of shock. Over half of the people who develop shock will die despite all treatment efforts. LPS is a potent initiator of immune cascades.
  • LPS may also be derived from blood-borne bacteria or from some other tissue infection. Efforts to control infection with antibiotics are documented to increase LPS loads, leading to the paradoxical tension between controlling the infection and limiting the damage it does from LPS release .
  • the present invention has as object to provide such alternative for the treatment of endotoxin induced conditions.
  • This object of the present invention is met by providing the use of ecto-nucleoside phosphohydrolase (apyrase) for the preparation of a medicament for the treatment and/or prophylaxis of an pathological condition in a mammal resulting from endotoxic activity.
  • apyrase ecto-nucleoside phosphohydrolase
  • Ecto-nucleoside Triphosphate Diphosphohydrolase 1 or apyrase which terms are interchangeably used herein, is a nucleotide metabolizing enzyme belonging to a family of acid anhydride hydrolases. Examples of other enzymes belonging to this family are GTP phosphohydrolase, pyrophosphatase and thiamin-triphosphatase .
  • the ecto-enzyme was first identified in 1949 and in 1963 partially purified from potato.
  • the enzyme is also known under its registry number EC 3.6.1.5. or as CD39.
  • Apyrases are naturally occurring transmembrane glycoproteins that can activate intracellular pathways upon activation. Apyrases are found in a large number of microbial species such as E.coli, Aspergillus fumigatus and Kluyveromyces lactis, plants such as Arabidopsis thaliana, Glycine max and Oryza sativa, insects such as Drosophila melanogaster and mammals like Rattus norvegicus, Mus musculus and Homo sapiens.
  • An apyrase enzyme comprises three domains, an extracelluar, a transmembrane and an intracellular domain. The extracellular domain comprises a conserved catalytic region responsible for the catalytic activity of the extracellular enzyme.
  • the catalytical domain catalyzes the hydrolysis of ATP to yield AMP and orthophosphate .
  • Such activity can thus be characterized as an ATP-diphosphatase or ATP diphosphohydrolase. It can also act on ADP, again yielding AMP and orthophosphate.
  • This activity can be characterized as an ADPase or ADP phosphohydrolase .
  • the enzyme can also be regarded as an ATP-ADPase.
  • Reported physiological functions of apyrases address their possible involvement in maintenance of hemostasis and inhibition of platelet aggregation through hydrolysis of extracellular ADP, which is released from activated thrombocytes upon vascular injury.
  • This ADP is known to function in recruitment and induction of platelet aggregation if not cleared by endothelial cell plasma membrane apyrase.
  • the present invention is based on the discovery that apyrase, and specifically exogenous apyrase, i.e., non- membrane associated apyrase, is also capable of providing inactivation or attenuation of a bacterial endotoxin and/or its provoked effects.
  • apyrase and preferably exogenous apyrase, is used for the treatment and/or prophylaxis of an endotoxin induced inflammatory reaction which can be acute or chronic.
  • inflammatory diseases which can preferably be treated using apyrase, and specifically exogenous apyrase, are LPS-mediated diseases amongst which sepsis, peritonitis, pancreatitis, pneumonia, inflammatory bowel disease, rheumatoid arthritis, vascular diseases, atherosclerosis, fibrosis, asthma, barrier-integrity loss, acute myocardial infarction, wound healing and Alzheimer' s disease.
  • (bacterial) toxins have an aggravating effect on the disease conditions.
  • the apyrase according to the present invention can be a naturally occurring apyrase such as an apyrase found in microbial species such as E.coli, Aspergillus fumigatus and Kluyveromyces lactis, in plants species such as Arabidopsis thaliana, Glycine max and Oryza sativa, in insects species such as Drosophila melanogaster and in mammals like Rattus norvegicus, Mus musculus and Homo sapiens.
  • microbial species such as E.coli, Aspergillus fumigatus and Kluyveromyces lactis
  • plants species such as Arabidopsis thaliana, Glycine max and Oryza sativa
  • insects species such as Drosophila melanogaster and in mammals like Rattus norvegicus, Mus musculus and Homo sapiens.
  • a preferred source of apyrase is Homo sapiens. This source is preferred since the use of human apyrase will inherently prevent or reduce adverse immune reactions triggered after administrating the apyrase during prophylaxis and/or treatment.
  • apyrase Another preferred source of apyrase is potato.
  • Potato, and preferably genetically modified potato producing a non-membrane bound apyrase (ecto-apyrase) allows the isolation of large quantities of apyrase using a relative simple and economic method.
  • the present invention relates to the use of an apyrase having 70%, preferably 80%, more preferably 90%, most preferably 95% sequence identity with the amino acid sequence depicted SEQ ID No: 1 (Fig. 1) .
  • the present invention also relates to the use of a nucleic acid sequence encoding 70%, preferably 80%, more preferably 90%, most preferably 95% of the amino acid sequence as depicted in SEQ ID No: 1.
  • apyrase can be a recombinant apyrase and preferably a non-membrane associated apyrase.
  • apyrase can readily be obtained using well known cloning methods using for example the known apyrase sequence depicted in SEQ ID no: 1.
  • a coding sequence of apyrase can be identified and isolated from different sources using probes derived from known apyrase DNA sequences, preferably of human origin, to screen cDNA or genomic libraries.
  • nucleic acid amplification techniques can be used for the identification, isolation and cloning of the coding sequence of an apyrase.
  • the coding sequence can be placed under the control of appropriate regulation signals and transformed in a suitable host allowing the expression and isolation of the enzyme.
  • Appropriate regulation signals are a promoter, one or more enhancer sequences, a transcription and/or translation initiation site and a transcription and/or translation termination site.
  • the present apyrase is a soluble or exogenous apyrase. In most cases, this would mean a deletion of the transmembrane and intracellular domain while leaving the catalytic part of the extracellular part of the enzyme functionally in tact. But also an other construction yielding a soluble recombinant protein comprising the catalytic domain of apyrase can be envisaged such as a fusion protein, in frame deletion of only the transmembrane domain, amino acid modifications such as substituting hydrophobic amino acids for hydrophilic ones, etc.
  • the present invention relates to a pharmaceutical composition for treatment or prophylaxis of an pathological condition in a mammal resulting from endotoxic (LPS) activity comprising a therapeutically effective amount of ecto-nucleoside phosphohydrolase (apyrase) and one ore more pharmaceutically acceptable excipients .
  • LPS endotoxic
  • apyrase ecto-nucleoside phosphohydrolase
  • Preferred therapeutically effective amounts of ecto- nucleoside phosphohydrolase are between 10 to 400 IU/kg body weight.
  • One IU unit is defined as the amount of apyrase capable of liberating 1 micromole of inorganic phosphate from ATP or ADP per minute at pH 6.5 at 30 0 C.
  • Fig. 1 shows the amino acid sequence of the GDA1/CD39 catalytic domain (aa 86 to 540) of human apyrase
  • Fig. 2 shows attenuation of a LPS insult in mice after administration of apyrase
  • Fig. 3 shows attenuation of proinflammatory MCP-I induction in a mouse myocardial unsult model after adminsitration of apyrase
  • Fig. 4 shows attenuation of a LPS insult in mice after administration of recombinant human apyrase.
  • Apyrase is capable of in vivo attenuation of LPS mediated inflammation
  • mice C57B16 were i.p. administered both CD39 (apyrase) (4.5 units) and alkaline phosphatase (rec IAP 0502, 1.5 units) and LPS (5 micrograms).
  • apyrase 4.5 units
  • alkaline phosphatase rec IAP 0502, 1.5 units
  • LPS 5 micrograms
  • apyrase or alkaline phosphatase resulted in a comparable attenuation of inflammation as demonstrated by a stabilization of body temperature.
  • LPS (5 micrograms) administered i.p. alone, resulted in lower body temperature which recovered after 5 hours.
  • Both alkaline phosphatase and apyrase (potato-apyrase) injected mice show normalized body temperatures .
  • AMI acute myocardial infarction
  • apyrase was obtained from Sigma (Sigma Aldrich, St. Louis, MO) .
  • One IU unit is defined as the amount of apyrase capable of liberating 1 micromole of inorganic phosphate from ATP or ADP per minute at pH 6.5 at 30 0 C.
  • BIAP Clinical grade bovine intestinal alkaline phosphatase
  • mice Specific pathogen free female BALB/c mice (23-27 gram) were purchased from Charles River (Sulzfeld, Germany) . Mice were acclimatized for 1 week under barrier conditions in filter-topped macrolon cages with drinking water and standard food pellets ad libitum.
  • BIAP and apyrase was injected into the tail vein just before anaesthezation as a single intravenous dose of 5 IU in 100 ⁇ l PBS (approximately 100 times above plasma levels) .
  • mice were injected with an equal volume of PBS. The study was approved by the animal ethics committee of the Faculty of Veterinary Medicine, University Utrecht.
  • mice were anaesthetized by inhalation of a mixture of O 2 air and 4% isoflurane, endotracheally intubated, and mechanically ventilated.
  • Myocardial infarction was induced as described previously (Salto-Tellez, M., et al . , Myocardial infarction in the C57BL/6J mouse: A quantifiable and highly reproducible experimental model. Cardiovascular Pathology, 2004. 13(2) : p. 91-97.)
  • the LAD coronary artery was exposed via a left thoractomy and double ligated with an 8.0 prolene suture. Animals were sacrificed 4 hours after myocardial infarction after which blood was collected. Heart, lung, liver and kidneys were removed and fixed in 4% paraformaldehyde in PBS .
  • MMCP-I mice mast cell protease-1
  • MMCP-I mouse mast cell protease-1
  • NTPase-1 Recombinant human apyrase (NTPase-1 , CD-39-1) has inflammatory activity in a LPS challenge model
  • mice (C57B16) were i.p. administered recombinant human apyrase (NTPase-1, CD39-1) , recombinant human placental alkaline phosphatase or bovine intestinal alkaline phosphatase and were subsequently challenged with LPS. Mice only injected with the carrier served as control group. As shown in fig. 4, administration of recombinant human apyrase (NTPase-1, CD39-1), recombinant human placental alkaline phosphatase or bovine intestinal alkaline phosphatase resulted in a comparable attenuation of inflammation as demonstrated by a stabilization of body temperature.
  • mice LPS administered alone, resulted in lower body temperature which recovered after 5 hours. (In mice reduced body temp is generally observed after LPS administration) .
  • recombinant human apyrase NTPase-1, CD39-1
  • recombinant human placental alkaline phosphatase or bovine intestinal alkaline phosphatase injected mice show comparable normalized body temperatures .

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Abstract

La présente invention concerne l'utilisation d'ectonucléoside phosphohydrolase 1 (apyrase) pour la préparation d'un médicament destiné au traitement ou à l prophylaxie d'états pathologiques tels qu'une exposition à des agents tels que des toxines bactériennes, par ex., une endotoxine, qui est le plus puissant inducteur de pro-inflammation, résultant d'une activité endotoxique telle qu'une inflammation aiguë ou systémique chronique ou une rupture de l'homéostase endothéliale vasculaire.
PCT/EP2007/001986 2007-03-01 2007-03-01 Utilisation d'apyrase pour le traitement d'une pathologie résultant de l'activité d'une endotoxine WO2008104200A1 (fr)

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Cited By (7)

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EP2533802A2 (fr) * 2010-02-12 2012-12-19 The General Hospital Corporation Procédés de réduction ou d'inhibition des effets toxiques associés à une infection bactérienne par utilisation de phosphatase alcaline
EP3345614A1 (fr) * 2017-01-05 2018-07-11 Amrif B.V. Composition comprenant de la phosphatase alcaline destinée à être utilisée dans le traitement des arthrites
US10987410B2 (en) 2017-03-21 2021-04-27 Synthetic Biologics, Inc. Alkaline phosphatase formulations
US11338020B2 (en) 2018-01-09 2022-05-24 Synthetic Biologics, Inc. Alkaline phosphatase agents for treatment of neurodevelopmental disorders
WO2022178214A1 (fr) * 2021-02-19 2022-08-25 Dupont Nutrition Biosciences Aps Compositions pour la santé intestinale
US11638699B2 (en) 2018-03-20 2023-05-02 Theriva Biologics, Inc. Intestinal alkaline phosphatase formulations
US11654184B2 (en) 2018-03-20 2023-05-23 Theriva Biologics, Inc. Alkaline phosphatase agents for treatment of radiation disorders

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2533802A2 (fr) * 2010-02-12 2012-12-19 The General Hospital Corporation Procédés de réduction ou d'inhibition des effets toxiques associés à une infection bactérienne par utilisation de phosphatase alcaline
EP2533802A4 (fr) * 2010-02-12 2013-07-10 Gen Hospital Corp Procédés de réduction ou d'inhibition des effets toxiques associés à une infection bactérienne par utilisation de phosphatase alcaline
US8932587B2 (en) 2010-02-12 2015-01-13 The General Hospital Corporation Methods of reducing or inhibiting toxic effects associated with a bacterial infection using alkaline phosphatase
EP3345614A1 (fr) * 2017-01-05 2018-07-11 Amrif B.V. Composition comprenant de la phosphatase alcaline destinée à être utilisée dans le traitement des arthrites
WO2018127363A1 (fr) * 2017-01-05 2018-07-12 Amrif Bv Composition comprenant de la phosphatase alcaline destinée à être utilisée dans le traitement des arthrites
US11103562B2 (en) 2017-01-05 2021-08-31 Amrif Bv Composition comprising alkaline phosphatase for use in the treatment of arthritides
US10987410B2 (en) 2017-03-21 2021-04-27 Synthetic Biologics, Inc. Alkaline phosphatase formulations
US11338020B2 (en) 2018-01-09 2022-05-24 Synthetic Biologics, Inc. Alkaline phosphatase agents for treatment of neurodevelopmental disorders
US11638699B2 (en) 2018-03-20 2023-05-02 Theriva Biologics, Inc. Intestinal alkaline phosphatase formulations
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