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WO2008114017A2 - Compositions et procédés associés à l'infection par le virus de l'influenza - Google Patents

Compositions et procédés associés à l'infection par le virus de l'influenza Download PDF

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Publication number
WO2008114017A2
WO2008114017A2 PCT/GB2008/000979 GB2008000979W WO2008114017A2 WO 2008114017 A2 WO2008114017 A2 WO 2008114017A2 GB 2008000979 W GB2008000979 W GB 2008000979W WO 2008114017 A2 WO2008114017 A2 WO 2008114017A2
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recited
influenza
mice
therapeutic composition
compound comprises
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PCT/GB2008/000979
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WO2008114017A3 (fr
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Tracy Hussell
Robert SNELGROVE
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Imperial Innovations Limited
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Publication of WO2008114017A2 publication Critical patent/WO2008114017A2/fr
Publication of WO2008114017A3 publication Critical patent/WO2008114017A3/fr

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    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/32—Tin compounds
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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

Definitions

  • compositions and Methods Relating to influenza infection are provided.
  • the present invention relates generally to therapeutic compositions comprising a compound mimetic of superoxide dismutase, and to methods for treating inflammation and/or influenza infection in a subject comprising administering such compounds to the subject.
  • ROS Reactive oxygen species
  • influenza virus causes death of the infected cell by cytopatliology, but a major part of the disease is attributed to an over-exuberant immune response that causes localized tissue damage and systemic illness via the induction of a "cytokine storm".
  • Current strategies to limit mortality include vaccination and the administration of antivirals. Vaccines, however, are only successful if they boost immunity to antigenic components present in the final infectious strain.
  • influenza variants have evolved resistance to antivirals. Since exaggerated T cell responses and the subsequent cytokine storm are strongly affiliated with pathology, weight loss and fever during influenza infection, strategies to modulate or prime an appropriate immune response irrespective of the infecting strain could have a significant clinical impact.
  • ROS represents an important component of the host's arsenal to combat invading microorganisms.
  • ROS also possess a significant cell-signaling role in biological systems, capable of regulating the phenotype and function of immune cells.
  • the extreme toxicity and lack of specificity means they are also capable of eliciting significant immunopathology to surrounding tissue.
  • the most abundant sources of ROS following infection are the NADPH oxidase of professional phagocytes and xanthine oxidase. Both potently induce superoxide, which can subsequently be converted into a host of other ROS.
  • the NADPH oxidase is a multimeric enzyme complex, composed of membrane-associated and cytosolic components that utilize molecular oxygen and NADPH to generate the superoxide radical (O2 ⁇ ).
  • the core of the enzyme contains the membrane bound flavocytochrome b558. This flavocytochrome is the site of the oxygen reduction and comprises two subunits, a 22-kDa protein (p22phox) and a 91-kDa glycoprotein (gp91phox).
  • cytosolic factors migrate to the membrane-associated components to form an active complex that catalyzes the formation of O2 ⁇ .
  • Influenza infection induces the production of superoxide from phagocyte NADPH oxidase and xanthine oxidase pathways that may have partial virucidal activity or limit viral propagation by inducing apoptosis of the infected cell.
  • ROS reactive oxygen species
  • ROS act as second messengers that activate redoxsensitive transcription factors implicated in the establishment of an inflammatory response, suggesting that they may add to the over-exuberance of the elicited immune response.
  • mice lacking a functional phagocyte NADPH oxidase (Cybb tml mice) or treated with the metalloporphyrin antioxidant manganese (III) tetrakis (N-ethyl pyridinium-2-yl) porpyhrin (MnTE-2-PyP) show heightened inflammatory infiltrates in their airways in response to pulmonary influenza infection, with augmented macrophage populations and a ThI -skewed T cell infiltrate. Underlying this exuberant macrophage response was a significant reduction in apoptosis and down-regulation of the myeloid inhibitory molecule CD200.
  • mice lacking a functional phagocyte NADPH oxidase offer a murine model of the autosomal genetic condition of chronic granulomatous disease (CGD). These mice lack the gp91phox subunit of the phagocyte NADPH oxidase, rendering them incapable of eliciting a respiratory burst and subsequent superoxide production. These mice demonstrate enhanced susceptibility to certain fungal and bacterial pathogens, but the effect on lung viral infection is not known.
  • MnTE-2-PyP offers protection in a variety of oxidative stress injuries, such as liver ischemia, diabetes, lung radiation injury and stroke, this is the first study to describe its use in the treatment of respiratory infection.
  • FIG. 1 Enhanced airway cellularity but reduced lung consolidation after influenza infection of Cybb tml mice.
  • A C57BL/6 and Cybb tml mice were infected with influenza; weight loss was recorded daily and is expressed as percent of original weight. Total viable cells were enumerated in the BAL fluid (B) and lung (C) on days O 5 1, 3 and 7 after influenza infection.
  • B BAL fluid
  • C lung
  • D Representative H&E-stained lung sections from C57BL/6 and Cybb tml mice 7 days after infection (magnification x200). Closed symbols, wild-type C57BL/6 mice; open symbols, Cybb tmlmice. Results represent mean values +/- SEM from five mice per group and are representative of three independent experiments. *, p ⁇ 0.05; **, p ⁇ 0.01.
  • Influenza-infected Cybb tml mice have expanded macrophage, neutrophil and T cell infiltrates in their airways.
  • the percentages of macrophages (A) and neutrophils (B) in the BAL fluid of wild-type (closed bars) and Cybb tml (open bars) mice at day 3 after influenza infection were determined from H&E-stained cytospin preparations, and the number of each population was calculated from total viable cell counts.
  • BAL was performed and lungs were removed from wild-type and Cybb tml mice 7 days after infection with influenza, and single-cell suspensions were stained with anti-CD45RB-FITC, anti-CD4-PerCP and anti-CD8-APC antibodies.
  • the number of CD4 + and CD8 + T cells in the BAL fluid (C) and lung (D) were determined by: % positive cells x total viable cells.
  • E The percentages of CD4 + and CD8 + T cells in the BAL fluid that were CD45RB 10 were determined by flow cytometry (each point represents an individual mouse). Results represent mean values +/- SEM from five mice per group and are representative of three independent experiments. *, p -" ⁇ 5; **, p ⁇ 0.01.
  • B 3 days after infection were determined using the BD mouse pro-inflammatory cytometric bead array.
  • BAL was performed on influenza-infected wild-type C57BL/6 (closed symbols) and Cybb tml (open symbols) mice, and single-cell suspensions were stained with anti-IFN- ⁇ -FITC, anti-CD8-PerCP and anti-CD4-APC antibodies.
  • FIG. 1 Representative plots of BAL CD4 + T cells versus IFN- ⁇ expression in wild-type (left) or Cybb tml (right) mice 3 days after influenza infection.
  • D The numbers of CD4 + and CD8 + T cells producing IFN- ⁇ in the BAL fluid at day 7 after infection were determined in wild-type (closed bars) and Cybb tml mice (open bars) by: % positive cells x total viable cells. Results represent mean values +/- SEM from five mice per group. Lungs were removed from influenza-infected wild-type and Cybb tml mice 7 days after infection.
  • E Proliferation of lung cells to UV-inactivated influenza was determined by [ 3 H]thymidine incorporation.
  • FIG. 4 Cybb tml mice exhibit increased viral clearance, reduced lung damage and improved lung function.
  • Viral titers were assessed in lung homogenates by plaque assay on days 1, 3 and 7 after infection. At day 7 after influenza infection, BAL fluid was removed and influenza-specific IgA (B), total protein (C) and LDH (D) were measured in the supernatant. Whole body plethysmography was utilized to assess the tidal volume (E) and peak expiratory flow (F) of influenza-infected wild-type and Cybb tail mice at day 7 after infection. Closed symbols, wild-type C57BL/6 mice; open symbols, Cybb tail mice. Results represent mean values +/-SEM from five mice per group. *, p ⁇ 0.05; **, p ⁇ 0.01.
  • FIG. 5 MnTE-2-PyP administration to influenza-infected mice provides a comparable immune profile to that seen in Cybb tail mice.
  • A Control (closed bars) and MnTE-2-PyP -treated (open bars) C57BL/6 mice were infected with influenza virus and the numbers of viable cells in the lung and BAL fluid after 7 days were determined by Trypan blue exclusion. Results are shown for treatment with 25 ⁇ g and 50 ⁇ g MnTE-2-PyP.
  • Viral titers were assessed in lung homogenates by plaque assay on day 7 after infection in mice treated with PBS (closed symbols) or MnTE-2- PyP (open symbols).
  • C Representative H&E-stained lung sections from PBS-treated and MnTE-2-PyP (25 ⁇ g)-treated C57BL/6 mice 7 days after infection (magnification x200).
  • D Cells from the BAL fluid of PBS- (closed bars) and MnTE-2-PyP (25 ⁇ g)- treated (open bars) mice were stained with anti-Gr-1-FITC, anti-CDl lb-PerCP and anti-CD 11 c-APC antibodies, and the numbers of CDlIb single-positive cells were determined by multiplying the percentages of positive cells by flow cytometry by the total numbers of viable cells.
  • BAL fluid and lungs were removed from PBS-treated (closed bars) and MnTE-2-PyP (25 ⁇ g)-treated (open bars) mice, and single-cell suspensions were stained with anti-CD4-PerCP and anti-CD8-APC antibodies.
  • the number of each population in the lung (E) and BAL fluid (F) was determined by: % positive cells x total viable cells. Results represent the mean +/- standard deviation of five individual mice and are representative of three independent experiments. *, p ⁇ n o5; **, p ⁇ 0.01. DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION
  • CGD chronic granulomatous disease
  • Cybb tml mice lacking a functional phagocyte NADPH oxidase
  • MCP-I monocyte chemoattractant protein- 1
  • MnTE-2-PyP manganese (III) tetrakis (N-ethyl pyridinium-2-yl) porpyhrin (metalloporphyrin antioxidant)
  • PerCP peridin chlorophyll a protein
  • Inflammatory cytokines are elevated during infection of Cybb tml mice.
  • TNF and IL-6 are derived largely from macrophages and have been implicated in the cachexia observed during an influenza infection. Production from these sources may therefore explain the enhanced weight loss in Cybb tml mice early in infection.
  • T lymphocytes are also a significant source of inflammatory cytokines, and considering their heightened activation state in the airways of Cybb tml mice, we were not surprised to see a greater percentage producing intracellular IFN- ⁇ (Fig. 3C) and TNF (data not shown) in CD4 + T cells 3 days after infection. The total number of both T cell subsets producing IFN- ⁇ was elevated in Cybb tml mice 7 days after infection (Fig. 3D). Furthermore, lung T cells from Cybb tml mice displayed enhanced proliferation to influenza virus compared to wild-type controls (Fig. 3E).
  • CD200 expression was also reduced on B and CD4 + and CD8 + T cells in the lung (data not shown) and airways (Fig. 3G) of influenza-infected Cybb tml mice. Binding of CD200 to CD200R on myeloid cells delivers an inhibitory signal. We therefore believe that soluble cytokines are enhanced due to a combination of (1) heightened T cell responses in the airways, (2) reduced apoptosis of cells producing inflammatory mediators and/or (3) a reduction of signals that negatively regulate myeloid cells, such as CD200.
  • the cell-permeable mimetic MnTE-2-PyP prevents pulmonary inflammation during influenza infection.
  • MnTE-2-PyP is a cell-permeable manganic porphyrin that acts as a potent antioxidant and superoxide mimic, and has previously been reported to confer protection in a variety of oxidative stress injuries.
  • Mice administered with 25 or 50 ⁇ g mimetic on days 0 and 3 of influenza infection showed a comparable immune response to Cybb tml mice, with heightened cellularity in the airways and reduced inflammation of the lung tissue (Fig. 5A).
  • Viral titers were reduced by administering 25 ⁇ g mimetic, similar to Cybb tml mice (data not shown), but actually heightened at a higher dose (Fig. 5B), which may reflect the scavenging of ROS from other sources (such as xanthine oxidase) than just the phagocyte NADPH oxidase disrupted in Cybb tail mice.
  • enhanced macrophage activity could also be explained by a reduction of inhibitory signals from other immune cells.
  • CD200 delivers an inhibitory signal on binding CD200R on the surface of myeloid cells
  • CD200 knockout mice display a similar phenotype to Cybb tml mice, with heightened macrophage numbers and a ThI bias.
  • CD200 is up-regulated on apoptosing cells to restrict the induction of inappropriate inflammatory sequelae by the phagocytosing macrophage. Therefore, a reduction in apoptosis and CD200 may in turn hinder the ability to switch off myeloid cells and explain their enhanced numbers in the absence of ROS.
  • NADPH oxidase knockout mice exhibit enhanced inflammatory gastritis, and sterile heat-killed fungal products cause excessive inflammation in the lungs.
  • Products of the phagocyte oxidase may therefore fulfill an anti-inflammatory role and, of significance, it has been implicated in oxidatively inactivating chemotactic factors, inducing anti-inflammatory cytokine production by neutrophils and macrophages, and in modulation of ThI cytokine production. It would therefore appear that in the absence of ROS, macrophages and neutrophils exist in a heightened state of activation such that replication of influenza virus is limited.
  • a limited viral load would reduce the chemotactic signals that usually induce lung consolidation.
  • the heightened ThI environment seen in the absence of ROS will act to further promote and activate resident macrophages. Indeed, we see elevated levels of TNF, IL-6, MCP-I and IL- 12 in the airways 3 days after influenza infection in Cybb tail mice, which may contain influenza, restrict dissemination into the lower airways and lung tissue and explain reduced parenchyma infiltrates.
  • ThI phenotype The dominant ThI phenotype observed in Cybb tml mice and mimetic-treated wild-type mice is likely to reflect heightened macrophage-derived IL- 12 production.
  • the mimetic used in this study reduces eosinophilia in a mouse model of asthma, implying a potential for ROS in defining the Thl/Th2 paradigm.
  • mice lacking a functional phagocyte oxidase exhibit compromised clearance of Escherichia coli, impaired NF-jB activation and host defense in Pseudomonas pneumonia, and a transient loss of resistance to pulmonary tuberculosis.
  • the divergent effects upon protection to different infections may depend on whether the pathogen has developed sophisticated strategies for avoiding the intracellular killing machinery.
  • reduced influenza titers are likely to reflect heightened macrophages in the airways, a ThI -dominated immune response and elevated mucosal IgA in the absence of ROS.
  • ROS HA receptor precursor
  • HAO HA receptor precursor
  • MnTE-2-PyP scavenges superoxide from sources other than the phagocyte NADPH oxidase, such as xanthine oxidase.
  • ROS may fulfill some virucidal role but the levels generated through xanthine oxidase are sufficient to deal with the virus, or the heightened macrophage response and ThI bias can compensate for the reduction in ROS.
  • ROS appear to play a homeostatic role in limiting macrophage activation.
  • An absence leads to a "poised” macrophage and subsequent development of ThI -mediated immunity that is better equipped to limit influenza virus replication, resulting in reduced lung consolidation and bystander tissue damage.
  • Raising the resting threshold of lung-resident antigen-presenting cells by modulating homeostatic negative feedback loops may therefore provide generic protection against viral infectious disease, irrespective of the infective strain.
  • mice 8-12 wk of age (Harlan Olac Ltd., Bicester, UK)were kept in pathogen-free conditions according to Home Office guidelines.
  • Cybb tml mice (back- crossed to the C57BL/6 background at least ten times) were originally purchased from The Jackson Laboratories (Bar Harbour, ME) but bred in-house thereafter.
  • Influenza A strain X31 (HA titer 1024) was a kind gift from Dr. Alan Douglas (NIMR, London, UK).
  • wild-type C57BL/6 and Cybb tml mice were anesthetized and infected i.n. with 50 HA units of influenza virus.
  • wild-type C57BL/6 mice were treated with the indicated doses of MnTE-2-PyP (Merck Biosciences AG, Switzerland) or PBS i.n. on days 0 and 3. Weight loss was monitored daily and the percent reduction was calculated from their original weight on day 0.
  • Mice were sacrificed various days after infection by injection of 3 mg pentobarbitone and exsanguinated via the femoral vessels. Some mice were challenged with 50 HA units of influenza virus 4 wk later and sacrificed on various days as indicated in the text.
  • CD45RBFITC anti-CD200-PE, anti-CD8- ⁇ eridin chlorophyll a protein (PerCP), anti- CD8-allophycocyanin (APC), anti-CDl lb-PerCP or anti-CDl Ic-APC, for 30 min at 4 0 C, and fixed with 2% paraformaldehyde (15 min at room temperature). All antibodies were purchased from BD Pharmingen (Heidelberg, Germany) except anti- CD200-PE (AMS Biotechnological Ltd., UK).
  • Excised lungs were inflation-fixed with 2% formalin in PBS 7 days after i.n. influenza virus infection.
  • the inflated lungs were excised and embedded in paraffin wax by Lorraine Lawrence, Leukocyte Biology, Imperial College, London. Sections (4 Im thick) from four to five mice were stained with H&E.
  • Lung Influenza Titer The titer of influenza virus was assessed in lung homogenates after 1 , 3 and 7 days. Homogenized cells were freeze-thawed three times, centrifuged at 4000 x g and supernatants were titrated in doubling dilutions on Madine Darby canine kidney cell monolayers in flat-bottom 96-well plates. After 3 h at room temperature, samples were overlaid with methylcellulose and incubated for 72 h at 37°C. Cell monolayers were washed and incubated with mouse anti-influenza antibody (Serotec, Oxford,
  • BAL fluid protein concentration was determined using the Pierce BSA protein assay kit. Working reagent was added to samples and standards at a 4 : 1 ratio and incubated at 37°C for 30 min. Absorbance was measured at 490 nm, and protein concentration calculated by comparison with an albumin standard.
  • LDH in the BAL was measured using an in vitro toxicology LDH- based assay kit (Sigma). Samples (tested in triplicate) were added to an equal volume of LDH assay mixture (assay dye, substrate and enzyme) and incubated at room temperature for 30 min. Absorbance was measured at 490 nm.
  • Lung function was measured in unrestrained animals by whole body plethysmography (Buxco Techologies, Petersfield, UK) as described.

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Abstract

Cette invention se rapporte à une composition thérapeutique permettant de moduler l'inflammation chez un sujet chez qui la variété réactive à l'oxygène du virus de l'influenza est un agent causal, pour traiter, améliorer ou empêcher l'infection, et pour traiter, améliorer ou empêcher une inflammation pulmonaire chez un sujet chez qui le virus de l'influenza est un agent causal; ladite composition thérapeutique comprend un composé imitant la superoxyde dismutase. L'invention concerne également des procédés permettant de moduler l'inflammation chez un sujet chez qui la variété réactive à l'oxygène du virus de l'influenza est un agent causal, pour traiter, améliorer ou empêcher une infection chez un hôte mammifère, et pour traiter, améliorer ou empêcher une inflammation pulmonaire chez un sujet chez qui le virus de l'influenza est un agent causal, les procédés comprenant l'administration de la composition thérapeutique chez le sujet.
PCT/GB2008/000979 2007-03-19 2008-03-19 Compositions et procédés associés à l'infection par le virus de l'influenza WO2008114017A2 (fr)

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ES2249784T3 (es) * 1995-06-07 2006-04-01 Duke University Antioxidantges de oxidantes.
US6214817B1 (en) * 1997-06-20 2001-04-10 Monsanto Company Substituted pyridino pentaazamacrocyle complexes having superoxide dismutase activity

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