WO2001028533A2 - TRAITEMENT DE LA MALARIA PAR ACTIVATION DU PPARη-RXR ET REMONTEE DU CD36 DES MONOCYTES/MACROPHAGES, ET PRODUITS A CET EFFET - Google Patents

TRAITEMENT DE LA MALARIA PAR ACTIVATION DU PPARη-RXR ET REMONTEE DU CD36 DES MONOCYTES/MACROPHAGES, ET PRODUITS A CET EFFET Download PDF

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WO2001028533A2
WO2001028533A2 PCT/CA2000/001209 CA0001209W WO0128533A2 WO 2001028533 A2 WO2001028533 A2 WO 2001028533A2 CA 0001209 W CA0001209 W CA 0001209W WO 0128533 A2 WO0128533 A2 WO 0128533A2
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pparγ
malaria
members
composition
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PCT/CA2000/001209
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WO2001028533A3 (fr
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Kevin C. Kain
Lena Serghides
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Kain Kevin C
Lena Serghides
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Publication of WO2001028533A3 publication Critical patent/WO2001028533A3/fr

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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/193—Colony stimulating factors [CSF]
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    • A61P33/06—Antimalarials
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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    • G01N2333/445—Plasmodium
    • G—PHYSICS
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    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to compositions and methods for treating Plasmodium falciparum malaria.
  • this invention relates to compositions and methods for activating PPAR ⁇ -RXR and up-regulating monocyte/macrophage CD36 for treating Plasmodium falciparum malaria.
  • BACKGROUND OF THE INVENTION Plasmodium falciparum malaria is the world's most important parasitic infection accounting for an estimated 300 to 500 million cases and 1.5 to 2.7 million deaths annually (WHO Bull. 1990, Miller 1994, Kain 1998).
  • P. falciparum infection accounts for over 90% of the morbidity and mortality associated with malaria.
  • the central pathophysiologic events in falciparum malaria are the sequestration of parasitized erythrocytes ("PEs") in the microvascular beds of vital organs and the release of pro-inflammatory cytokines from cells of the monocytes/macrophage lineage. Collectively these processes may result in the disruption of local circulation and the manifestation of cerebral or severe malaria (Warrell 1987, MacPherson 1985, Howard 1989, Turner 1994, Miller 1994).
  • endothelial receptors have been implicated in the sequestration of PEs to endothelial cells including ICAM-1 (Ockenhouse 1991, Berendt 1989), VCAM (Ockenhouse 1992), E-selectin (Ockenhouse 1992), chondroitin sulfate A (Robert 1995, Rogerson 1997), thrombospondin (TSP; Roberts 1985), ⁇ v ⁇ 3 (Siano 1998), PECAM-1/CD31 (Treutiger 1997) and CD36 (Oquendo 1989, Ockenhouse 1989, Panton 1987, Barnwell 1985).
  • CD36 is an 88kD cell surface glycoprotein, expressed on endothelial cells, platelets, monocytes and macrophages (Oquendo 1989). CD36 is a major sequestration receptor, preferentially recognized by almost all wild isolates of P. falciparum (Ockenhouse 1991, Udomsangpetch 1997, Newbold 1997).
  • TNF ⁇ pro-inflammatory cytokines
  • TNF ⁇ pro-inflammatory cytokines
  • a strong correlation has been observed between elevated TNF ⁇ levels and disease severity and poor prognosis in falciparum malaria (Grau 1989, Allan 1994, Kwiatkowski 1990).
  • the host's genetic predisposition to over secrete TNF ⁇ in response to falciparum malaria may determine an individuals susceptibility to cerebral malaria (Turner 1994, Berendt 1989, McGuire 1994). Phagocytic cells are an essential first line of defense against malaria, facilitating the control and resolution of the infection by clearing PEs (Shear 1989, Urquhart 1994).
  • Phagocytes of the monocyte/macrophage lineage are also the primary source of parasite- induced TNF ⁇ (Grau 1989, Allan 1994, Kwiatkowski 1990, Miller 1994).
  • Several studies have concentrated on the phagocytosis of opsonized PEs (Cappadaro, Staunton 1992, Turrini 1992).
  • the relevance of opsonic clearance of PEs in the non- immune individual is unclear.
  • monocytes bind PEs in the absence of antibody (Ruangjirachuporn 1992, Ockenhouse 1989, Staunton 1992) and engulf PEs even when complement and Fc-receptor pathways are blocked (Turrini 1992).
  • CD36 is the major sequestration receptor preferentially recognized by almost all wild isolates of P. falciparum and its gene promoter contains a PPAR ⁇ -RXR binding site.
  • PPAR ⁇ is a member of the nuclear hormone receptor superfamily, and as a heterodimer with the retinoid X receptor (RXR) activates transcription of target genes by binding to DR-1 (direct repeat with 1 nucleotide spacer) type hormone response elements (Kliewer 1992, Tontonoz 1994, Shao 1998).
  • PPAR ⁇ is primarily expressed in adipose tissue, mammary and colonic epithelium and in myelomonocytic cells (Torontoz 1998).
  • the PPAR ⁇ -RXR complex can modulate CD36 gene expression through direct promoter interaction with the PPAR ⁇ -RXR binding site (Torontoz 1998).
  • PPAR ⁇ agonists have been shown to suppress monocyte secretion of pro-inflammatory cytokines induced by phorbol esters but not be LPS (Jiang 1998).
  • Several PPAR ⁇ -RXR ligands are now known.
  • CD36 as a major sequestration receptor
  • ICAM-1 interleukin-1
  • CD36 is known to be well-expressed in microvascular endothelial cells from non-vital sites such as skin, muscle and sites rich in resident macrophages such as liver and spleen (Turner 1994).
  • Virtually all natural P. falciparum isolates bind CD36, but only a small proportion of infected individuals develop severe or cerebral malaria.
  • WO 9306849 Olet al
  • the inventors blocked the binding of malarially infected erythrocyte to CD36 by using an agent capable of binding to the CD36 binding site.
  • the inventors suggested that by blocking CD36 binding, the complications arising from malaria can be ameliorated.
  • WO 9306848 the inventors inhibited CD36 binding by malaria infected erythrocytes by administering an antibody covalently attached to CD36 or CD36 fragment. Binding was alleged to bring the antibody into close proximity to the malaria infected erythrocytes to promote cell death by stimulating phagocytosis via the Fc receptor.
  • CD36 plays a beneficial role during infection by aiding in the clearance of parasites as a phagocytic receptor on monocytes/macrophages and that CD36-mediated phagocytosis does not lead to the release of pro-inflammatory cytokines such as TNF ⁇ , which contribute to severe malaria and adverse clinical outcomes.
  • TNF ⁇ pro-inflammatory cytokines
  • current strategies to disrupt CD36-PE interactions may be deleterious if they inhibit CD36-mediated PE phagocytosis and displace PEs from CD36 in non-vital sites, to the receptors of the cerebral vasculature.
  • compositions and methods for the treatment of P. falciparum malaria which result in increased phagocytic clearance of PEs and which do not result in elevated levels of TNF ⁇ .
  • the inventors have determined the molecular mechanisms of P. falciparum phagocytosis.
  • Monocyte/macrophage CD36 participates in a novel phagocytic pathway for PEs that is distinct from that utilized in the clearance of apoptotic cells.
  • monocyte/macrophage CD36 with PPAR ⁇ -RXR agonists or ligands results in increased phagocytic clearance of PEs, and decreased secretion of pro- inflammatory cytokines (such as TNF ⁇ ) by monocytes and macrophages in response to malaria glycosylphosphatidylinositol (GPI) toxins.
  • pro-inflammatory cytokines such as TNF ⁇
  • the present invention relates to products which can be used to upregulate the monocyte/macrophage CD36, contributing to the phagocytosis of P. falciparum-mfected erythrocytes, and to downregulate pro-inflammatory responses to malaria toxins. These products can be used to treat or prevent severe P. falciparum malaria.
  • a composition for the treatment of malaria comprises one or more members of a group consisting of a PPAR ⁇ agonist, a RXR agonist and natural or synthetic ligands thereof. Included within the group are prostaglandin A, prostaglandin D, prostanoid 15-deoxy- ⁇ 12 ' 14 -prostaglandin J2 (15d-PGJ2), thiazolidinedione (TZD) class of antidiabetic drugs, non-steroidal-anti-inflammatory drugs, L-tyrosine-based agonists, cytokines, lipoproteins and their components, polyunsaturated fatty acids, methoprene acid, vitamin A, and vitamin A metabolites, and compounds which are inhibitors of antagonists of PPAR ⁇ or RXR and a mimetic of any of the foregoing.
  • thiazolidinedione class of antidiabetic drugs
  • ciglitazone troglitazone, pioglitazone, rosiglitazone, englitazone, and a mimetic of any of the foregoing.
  • NSAIDS non-steroidal-anti-inflammatory drugs
  • the L-tyrosine-based agonist could be GW1929.
  • Cytokines would include IL-4, GM-CSF, M-CSF.
  • Lipoproteins and their components used could be selected from one or more members of a group consisting of oxidized LDL, 13- hydroxyoctadecadienoic acid [13-HODE], 15-hydroxyeicosatetraenoic acid [15-HETE].
  • the vitamin A metabolite could be selected from one or more members of a group consisting of 9-cis-retinoic acid, BRL49653, LG100268, LG 1069, LGD49653 and a mimetic of any of the foregoing.
  • the PPAR ⁇ -RXR agonist could be derived from natural or engineered ligands.
  • Another aspect of the invention is a method for treating or preventing severe infection by P. falciparum malaria in a person comprising administering to a patient in need thereof a composition as described above..
  • Yet another aspect of the invention is a method for identifying a product for the treatment or prevention of malaria, the method comprising the steps of:
  • kits for the treatment of malaria comprising a product which activates PPAR ⁇ -RXR or upregulates monocyte/m ⁇ CD36 in admixture with a pharmaceutically acceptable carrier, excipient or diluent.
  • the kit would include the products described above.
  • Fetal calf serum was from Wisent (Mississauga, Canada) and was heat inactivated at 55C for 30 minutes prior to use.
  • FA6-152 was from Immunotech (Marseille, France)
  • the anti- ⁇ v ⁇ 3 monoclonal 23C6 was from Serotec (Raleigh, NC)
  • the anti-TSP monoclonal C6.7 was from Medicorp (Montreal, Canada)
  • the anti-ICAM monoclonal 15.2 was from Santa Cruz Biotech (Balthesa, CA).
  • Recombinant human TNF ⁇ and monoclonal anti-human TNF ⁇ were from Genzyme (Mississauga, Canada).
  • Ciglitazone, 15d- ⁇ 12 ' 14 -PGJ2, and methoprene acid were from BIOMOL (Plymouth, PA).
  • E. coli 0111.B4 endotoxin (LPS), PMA, DMSO, 9-cis-retinoic acid, saline, trypsin, and sterile water were from Sigma-Aldrich (Oakville, Canada).
  • Ficoll-Paque, Percol, and Dextran T500 were from Pharmacia (Peapack, NJ).
  • Human IgG Fc fragments were from Calbiochem (San Diego, CA).
  • Lipids were purchased from Avanti Polar Lipids (Alabaster, AL).
  • PC liposomes were made at 100 mol % PC.
  • PI and PS liposomes were made at 70 mol % PC and 30 mol % PS or PI.
  • Parasite Cultures Parasite cultures were maintained in erythrocytes from A+ donors and RPMI-
  • Monocyte Isolation Human monocytes were isolated from the blood of healthy volunteers as previously described (McGilvray 2000). Briefly, the buffy coat fraction from whole blood in sodium heparin was brought up to an osmolality of 360mOsm by the addition of sterile 9% saline. The buffy coat was then centrifuged over a 40/55 Percoll gradient, the monocyte layer was collected and washed 3 times with cold RPMI. This procedure yields a platelet-free population of non-activated monocytes >80% CD 14 positive by flow cytometry, minimal baseline TNF ⁇ secretion, >98% viability by trypan blue exclusion. Detection ofCD36 expression by flow cytometry:
  • Human monocytes treated for 22-24 hours with PPAR ⁇ and RXR agonists (initially dissolved in DMSO) or controls containing the same concentration of DMSO but without a PPAR ⁇ or RXR agonist, were stained with 1: 100 dilution of the mAb FA6- 152 (anti-CD36) for 30 min on ice followed by a 1: 100 dilution of a secondary anti- mouse IgG-FITC conjugated antibody. Unstained and a secondary antibody only stained controls were also performed The monocytes were fixed in 1% paraformaldehyde PBS and analyzed using the EPICS ELITE flow cytometer (Beckman-Coulter) for CD36 expression. Flow data was analyzed using the ELITE software (Beckman-Coulter).
  • Purified human monocytes suspended in RPMI-10 were plated on round glass coverslips in a 24 well polystyrene plate (250,000 monocytes per well), and allowed to adhere for 1 hour. Non-adherent cells were washed away, the supernatant was removed and replaced with RPMI-10 containing 5 ⁇ M 15d-PGJ2 plus 30 ⁇ M methoprene acid, or 5 ⁇ M 15d-PGJ2 plus 5 ⁇ M 9-cis-retinoic acid, or 30 ⁇ M ciglitazone alone, or appropriate concentrations of DMSO as a control, and incubated at 37°C 5% C0 2 for 22-24 hours.
  • the monocytes were then washed and incubated with 20 ⁇ g/mL Fc fragments for 30 min at room temperature (in order to block Fc receptors) followed by a 30 min incubation with 5-lO ⁇ g/mL FA6-152 when appropriate.
  • the monocytes were washed and 500 ⁇ l of 2% Hct, 5-8% parasitemia of carefully synchronised parasites in RPMI-10 prepared as described (McGilvray 2000), were layered on top. The assay was allowed to continue for 4 hours, at 37°C with gentle rotation.
  • Purified human monocytes were seeded in 24 well polystyrene plates at 200,000 cells per well, and allowed to adhere for 1 hour. Unattached cells were washed away, and the remaining cells were treated with PPAR ⁇ and RXR agonists, or DMSO controls as described above, followed by the addition of l ⁇ g/ml LPS, 50nM PMA, 1:10 dilution of various falciparum culture supematants, or no additions. Following a 18-24 hour incubation at 37°C, the supematants were collected and cells spun down and removed.
  • the cleared supematants were subjected to a sandwich ELISA for the detection of human
  • TNF ⁇ assays were also performed as above using THP-1 cells, kept in suspension at a concentration of 500,000 cells/ml, in place of purified human monocytes.
  • Phagocytic index represents the number of monocytes with at least one internalized PE divided by the total number of monocytes counted. Experiments were performed in duplicate and repeated at least three times. The variation in phagocytic index between experiments is due to different donors and day to day parasite variation. The phagocytic index within experiments was very consistent.
  • Monocytes were treated with the combination of 15d-PGJ2 and methoprene acid or 15d-PGJ2 and 9-cis-retinoic acid led to an ⁇ 40% to 60% increase in CD36 and an ⁇ 40% to 60% increase in the phagocytic clearance of non-opsonized falciparum infected erythrocytes over control monocytes (P ⁇ 0.05).
  • Treatment with ciglitazone resulted in an - 60% increase in phagocytic clearance of PEs over controls ( P ⁇ 0.05).
  • phagocytosis was inhibited (40 to 70%) by pre-incubation with the anti-CD36 monoclonal antibody FA6-152.
  • Fc receptors were blocked by pre-treating monocytes with Fc fragments (20 ⁇ g/mL) and complement mediated phagocytosis was avoided by using heat-inactivated serum.
  • Adherent monocytes were treated for 24 hours with 30 ⁇ M ciglitazone alone, a combination of 5 ⁇ M 15d-PGJ2 (PG) and 30 ⁇ M methoprene acid (MA), a combination of 5 ⁇ M 15d-PGJ2 and l ⁇ M 9-cis-retinoic acid (9RA), or vehicle alone (DMSO).
  • CD36 was blocked by incubation with FA6-152.
  • Treatment with 15d-PGJ2 and methoprene acid or 9-cis-retinoic acid resulted in a significant increase in the phagocytic clearance of PEs over control. This phagocytosis was blocked by incubating monocytes with FA6-152 prior to the assay.
  • Treatment with the TZD drug ciglitazone also resulted in increased phagocytic clearance of PEs which was inhibited by CD36 blockade.
  • Non-opsonic phagocytic clearance of P. falciparum infected erythrocytes is CD36 dependent but does not utilize the cCy ⁇ j -TSP-CD36 phagocytic mechanism.
  • CD36 on monocytes was blocked by incubation with lO ⁇ g/mL of FA6-152 (anti-CD36 monoclonal antibody) prior to the addition of PEs. Incubation with FA6 resulted in a 40- 70% inhibition of phagocytosis of PEs by PPAR ⁇ -RXR agonist-treated monocytes.
  • CD36 receptor blockade with FA6 inhibited phagocytosis of PEs in both control and PPAR ⁇ - RXR agonist-treated monocytes to similar levels.
  • the anti-0Cv ⁇ 3 and anti-TSP antibodies had no effect on phagocytosis of PE, alone or in combination. Furthermore no synergistic inhibition was observed since treatment with a combination of all three antibodies, FA6-152, 23C6 and C6.7, inhibited phagocytosis to the same level as treatment with FA6-152 alone .
  • Blocking CD36 on monocytes by pre-treatment with lOug/mL FA6-152 resulted in a 60% decrease in phagocytosis of PEs over controls.
  • Blockade of the vitronectin receptor, and TSP with 23C6 (anti- ⁇ v ⁇ 3 ) and C6.7 (anti-TSP) had no effect on the level of phagocytosis of PEs.
  • Co-treatment with all three antibodies resulted in a decrease in phagocytosis that was similar to blockade by FA6-152 alone.
  • PPAR ⁇ -RXR agonists Treatment of monocytes and THP-1 cells with PPAR ⁇ -RXR agonists inhibits P. falciparum-induced TNF secretion. Elevated levels of TNF ⁇ have been consistently correlated with severity of disease and a poor prognosis leading to the conclusion that excessive secretion of TNF ⁇ by monocyte/m ⁇ s in response to parasite products may promote severe and cerebral malaria (Grau 1989; McGuire 1994; Allan 1995). Jiang and colleagues have previously demonstrated that PPAR ⁇ agonists can reduce PMA-induced but not LPS-induced pro- inflammatory cytokine secretion from monocytes. We examined whether PPAR ⁇ agonists would also inhibit P. falciparum-m ' Jerusalem TNF ⁇ secretion from monocytes and THP-1 cells.
  • TNF ⁇ levels produced by THP-1 cells exposed to lug/ml LPS, 50nM/ml PMA, or a 1: 10 dilution of various P. falciparum culture supematants (see methods for details) were observed.
  • the decrease in TNF ⁇ levels seen in the PPAR ⁇ -RXR-treated cells exposed to PMA and the culture supematants were significant.
  • TNF ⁇ levels produced by human monocytes treated as the THP-1 cells above were observed.
  • a significant decrease in TNF ⁇ levels was seen in monocytes treated with PPAR ⁇ agonists and exposed to PMA, and P. falciparum culture supematants.
  • An increase in CD36 expression seen in human monocytes treated with l ⁇ M 9- cis-RA for 48 hours was observed.
  • CD36 expression was determined by flow cytometric analysis of FA6-152 stained monocytes.
  • An increase in CD36 expression seen in THP-1 cells treated with 9-cis-RA as above was also observed.
  • CD36 is the major receptor on freshly isolated human monocytes mediating the uptake of non-opsonised PEs (McGilvray 2000).
  • McGilvray 2000 Tissue resident macrophages (m ⁇ s) in the liver, spleen and reticuloendothelial system that mediate the uptake of PEs would be expected to behave more like culture- derived m ⁇ s which have been reported to express increased levels of CD36 (Huh 1996).
  • CD36 surface levels increased on monocytes aged in culture for 5 days.
  • phagocytosis of non-opsonised PEs increased approximately 4-fold. Phagocytosis occurred in a complement-free environment, with Fc receptor blockade and with no prior opsonization of PEs. Monoclonal antibody (mAb) blockade of CD36 (FA6-152, lO ⁇ g ml) resulted in a 50%-70% inhibition of phagocytosis in both day 0 and day 5 monocytes (P ⁇ 0.05). There was no phagocytosis of uninfected erythrocytes (UEs) by monocytes or culture- derived m ⁇ s.
  • UEs uninfected erythrocytes
  • Macrophage phagocytosis of non-opsonised PEs is a CD36 specific process.
  • CD36 has previously been reported to participate, in co-operation with ⁇ v ⁇ 3 and thrombospondin (TSP), in the phagocytic removal of apoptotic cells (Savill. 1989, Ren 1995).
  • TSP thrombospondin
  • Blocking 0Cv ⁇ 3 , TSP and CD36 in combination resulted in a decrease in PE phagocytosis similar to that observed with CD36 blockade alone.
  • Receptor blockade of ICAM-1, an important sequestration receptor for PEs had no significant inhibitory effect on PE phagocytosis.
  • CD36 has been shown to interact with phosphatidyl-serine (PS) and PS-containing liposomes have been reported to inhibit CD36-mediated apoptotic cell phagocytosis
  • PS phosphatidyl-serine
  • the ligand for CD36 on the PE is a trypsin sensitive protein, PfEMP-1 (Baruch 1996). Removal of the CD36 ligand by mild trypsinization of the PEs prior to phagocytosis resulted in a decrease in phagocytosis similar to that observed with CD36 receptor blockade Fc-receptor blocked culture-derived macrophages were pre-treated for 30 minutes with lO ⁇ g/ml of the monoclonal antibodies FA6-152 (anti-CD36), 15.2 (anti-ICAM- 1), 23C6 (anti- ⁇ v ⁇ 3), C6.7 (anti-TSP), or a combination of FA6-152, 23C6, and C6.7.
  • PfEMP-1 trypsin sensitive protein
  • Receptor blockade was followed by a standard phagocytosis assay (see methods). Phagocytic index was quantitated microscopically. P ⁇ 0.01 (Student's t) comparing control to FA6-152 treated, and control to FA6-152 plus 23C6 plus C6.7 treated. There was no significant difference in phagocytosis between CD36 blockade alone and combination blockade of CD36, ⁇ v ⁇ 3 and TSP.
  • Fc-receptor blocked culture-derived macrophages were pre-treated for 30 minutes with O.lmM PS containing liposomes, PC containing liposomes or PI containing liposomes, or with lO ⁇ g/ml of monoclonal antibody FA6-152 prior to exposure to non- opsonised PEs (see methods). Phagocytic index was quantitated microscopically. Liposome preparations did not inhibited phagocytosis of PEs.
  • CD36 is a major phagocytic receptor for non-opsonized PEs (McGilvray ., 2000) and that monocyte-derived m ⁇ s express more CD36 and have increased phagocytic capacity for PEs, prompted us to determine whether pharmacologic up-regulation of CD36 would increase phagocytic removal of non-opsonised PEs.
  • CD36-independent phagocytosis did not differ significantly between treated and control monocytes.
  • PPAR ⁇ and RXR agonists up-regulate CD36 expression in human monocytes and increase their phagocytic capacity for non-opsonised PEs.
  • Adherent human monocytes were treated with increasing doses of ciglitazone (3- lOO ⁇ M), or appropriate controls for 24 hours.
  • CD36 surface levels were analysed by flow cytometry following staining with FA6-152. Mean fluorescence of ciglitazone- treated was compared to control-treated monocytes. Phagocytic index was determined as described in the methods. Phagocytic index of ciglitazone-treated was compared to control-treated monocytes.
  • Increases in monocyte surface levels of CD36 and non-opsonic phagocytosis demonstrated a dose-response relationship to treatment with ciglitazone (3-100 ⁇ M).
  • CD36 expression was determined by staining the macrophages with the monoclonal FITC conjugated anti-CD36 antibody FA6-152, followed by flow cytometric analysis. Control and 9-cis-RA treated macrophages were exposed to a 20: 1 ratio of non- opsonised P. falciparum parasitised erythrocytes for 4 hours at 37C. Fc receptors were blocked using Fc fragments. All serum used was heat inactivated to remove complement. In some cases CD36 was blocked using lOug/ml of the anti-CD36 monoclonal antibody FA6-152. Following the 4 hours incubation, non-intemalised PEs were removed by hypotonic lysis, and the coverslips were fixed and stained.
  • Phagocytosis was quantitated microscopically.
  • P. falciparum-m ' Jerusalem-RA treated macrophages P. falciparum-m ' Jerusalem TNF ⁇ secretions were also reduced by 9-cis-retinoic acid.
  • Freshly isolated monocytes were co-treated for 24 hours with luM 9-cis-RA or appropriate controls plus either lOOnM PMA, or lOOul/ml of culture supematants of the P. falciparum clone ITG or of a patient isolate. Supematants were collected and analysed for TNF ⁇ by ELISA. Treatment with 9-cis-RA significantly reduced the level of TNF ⁇ secreted in response to culture supematants as compared to controls.
  • PPAR ⁇ and RXR agonists to increase CD36 expression and phagocytic capacity was not limited to freshly isolated monocytes.
  • Monocyte-derived m ⁇ s treated with 15d-PGJ2 plus 9-cis-RA had increased CD36 surface levels and a corresponding increase in non-opsonic phagocytosis with a -70% increase in ingested PEs in treated macrophages. Similar to untreated m ⁇ s, phagocytosis of non-opsonized
  • PEs by PPAR ⁇ -RXR-treated m ⁇ s was inhibited by mAb blockade of CD36 and by cleaving the CD36 ligand from the PEs and not by receptor blockade of ⁇ v ⁇ 3, TSP, and ICAM-1, or by pre-incubation with PS, PC, or PI containing liposomes.
  • Culture-derived macrophages were treated with 5 ⁇ M 15d-PGJ2 plus l ⁇ M 9-cis- retinoic acid or DMSO controls for 24 hours, and then were used in PE phagocytosis assays.
  • P ⁇ 0.01 (Student's t) comparing phagocytic index in control vs. treated macrophages.
  • PPAR ⁇ agonists reduce P. falciparum-induced TNF from human monocytes.
  • THP-1 cells were exposed to l ⁇ g/ml LPS, 50nM/ml PMA, or a 1: 10 dilution of various P. falciparum culture supematants (ITG, PI and P2) and TNF ⁇ production was assayed (see methods for details).
  • Cells included DMSO treated controls and cells treated with 5 ⁇ M 15d-PGJ2 plus l ⁇ M 9-cis-retinoic acid.
  • Significant decreases in TNF ⁇ secretion were observed in the PPAR ⁇ -RXR treated cells exposed to PMA and the culture supematants (P ⁇ 0.05; Student's t). Experiments were performed in triplicate and data obtained was representative of at least 3 independent experiments.
  • 0_v ⁇ 3 and TSP have been shown to cooperate with CD36 in the phagocytic clearance of apoptotic cells (Savill 1989).
  • antibodies against ⁇ v ⁇ 3 and TSP do not inhibit the phagocytosis of PEs, either singly or in combination.
  • these antibodies synergistically inhibit PE phagocytosis when used together with anti-CD36 antibodies.
  • CD36-mediated phagocytosis of PEs is distinct from that mediating phagocytosis of apoptotic cells.
  • Our data support a protective role for CD36 in the host-parasite interaction.
  • CD36 expression in the brain is very low to absent (Turner 1994) and thus cytoadherence to CD36 is unlikely to account for cerebral sequestration.
  • ICAM-1 and CD31 are expressed on brain endothelium and their expression is up-regulated by exposure to pro-inflammatory cytokines such as TNF ⁇ .
  • TNF ⁇ secretion during falciparum malaria infection has been associated with a parasite-derived glycosylphosphatidylinositol (GPI) "toxin" which stimulates TNF ⁇ from monocytes/m ⁇ s by a pathway that differs from that of LPS-induced TNF ⁇ production.
  • GPI glycosylphosphatidylinositol
  • CD36 is primarily expressed by monocytes and by m ⁇ s of the reticuloendothelial system (RES), especially the liver and spleen, where the majority of tissue resident macrophages reside and by endothelial cells of the RES and such organs as the skin, muscle, and heart. Sequestration of PEs in the RES should enhance their clearance. Similarly, up-regulating CD36 in microvascular beds of non-vital organs such as skin or muscle would not endanger a patient.
  • RES reticuloendothelial system
  • TZD drugs are currently in clinical trials for the management of type II diabetes. These agents have been well tolerated in these studies.
  • the commercial availability of TZD compounds will expedite the in-vivo testing of their effectiveness in enhancing phagocytic clearance of parasitized erythrocytes and reducing TNF ⁇ levels.
  • TZDs and or other PPAR ⁇ -RXR ligands will represent a new adjunctive short term therapy for severe falcipamm infection (Vamecq 1999, Henke 1998).
  • CD36 may also been implicated in the outcome of malaria in pregnancy. Semi- immune women who become pregnant often have poor clinical outcomes with falcipamm malaria despite having controlled many previous falcipamm infections with minimal symptoms (Duffy 1996). This has been attributed to the presence of parasite isolates which bind chondroitin sulfate A (CSA), a sequestration receptor primarily found in the placenta. Of note, parasite lines which bind CSA are unique among falcipamm isolates in that they do not also bind CD36. Our data demonstrates that the inability to control CSA-binding parasites may be attributable, in part, because they do not adhere to CD36 and thus avoid CD36-mediated phagocytic clearance and decreased pro-inflammatory cytokine responses.
  • CSA chondroitin sulfate A
  • CD36 is the major receptor mediating the phagocytosis of non-opsonized parasitized erythrocytes (PEs) by monocytes and culture- derived macrophages (m ⁇ s).
  • PEs non-opsonized parasitized erythrocytes
  • m ⁇ s culture- derived macrophages
  • This clearance mechanism is of potential relevance to those at greatest risk of severe disease including non-immune patient populations and semi- immune individuals infected with a falcipamm PfEMP-1 variant to which they lack an opsonizing or specific immune response.
  • CD36-PE uptake occurs via a novel phagocytic pathway that is distinct from the co-operative ⁇ v ⁇ 3-TSP-CD36 mechanism involved in the uptake of apoptotic cells and does not appear to involve phosphatidyl-serine recognition.
  • CD36-PE interactions may be deleterious to the host.
  • CD36 expression in the brain is low to absent (Turner 1994) and cytoadherence to CD36 is unlikely to account for cerebral sequestration.
  • CD36 is however well-expressed in microvascular endothelial cells from sites such as skin and muscle (Turner 1994).
  • CD36- mediated cytoadherence directs parasites to these non-vital sites and away from cerebral microvasculature. Sequestration in peripheral sites such as skin facilitates transmission
  • ICAM-1 and CD31 are expressed on brain endothelium and are up-regulated by pro-inflammatory cytokines such as TNF ⁇ (Berendt 1989, Treutiger 1997, Schofield 1996, Kwiatkowski 1990, Brown 1999, Day 1999, Dobbie 1999).
  • TNF ⁇ secretion during infection has been associated with a parasite-derived GPI "toxin" which stimulates TNF ⁇ release from monocytes and m ⁇ s.
  • PPAR ⁇ -RXR agonists inhibit parasite-induced TNF ⁇ secretion by monocytes and THP-1 cells.
  • PPAR ⁇ agonists inhibit pro-inflammatory cytokine secretion from PMA-activated but not LPS-activated monocytes (Jiang 1998) GPI induces TNF ⁇ secretion by a similar pathway.
  • PPAR ⁇ agonists also inhibit TNF ⁇ -induced ICAM-1 expression (Pasceri 2000).
  • Adjunctive therapy with PPAR ⁇ -RXR agonists reduces excessive pro-inflammatory cytokine secretion and ICAM- 1 up-regulation associated with severe malaria.
  • CD36 is primarily expressed by monocytes, macrophages, adipocytes, myocytes, and endothelial cells of the skin and reticuloendothelial system, especially the liver and spleen (Turner 1994). Increased sequestration in these sites would not be expected to endanger infected patients, since binding within the reticuloendothelial system should theoretically enhance clearance and binding to CD36 in non-vital sites might confer protection against severe and cerebral disease (Newbold 1999, Aitman 2000, McGilvray 2000.).
  • vitamin A metabolites activating the PPAR ⁇ -RXR heterodimer increase CD36-mediated clearance and decrease pro-inflammatory cytokine release, providing a putative mechanism for the protective role of vitamin A in malaria.
  • this invention establishes that CD36 is a major receptor mediating non-opsonic clearance of PEs, which is important in non-immune hosts who are at greatest risk of severe and cerebral malaria.
  • up-regulation of monocyte/m ⁇ CD36 via PPAR ⁇ -RXR activation resulted in an increase in the CD36- mediated phagocytosis of PEs and a decrease in parasite-induced TNF ⁇ production.
  • Pharmacologic up-regulation of monocyte/m ⁇ CD36 represents a novel way to immunomodulate host defense and a new strategy to prevent or treat severe falciparum- malaria. Since several PPAR ⁇ agonists are approved for human use, and can be used in clinical trials for this purpose (Torontoz 1998, Kersten 2000)
  • Treatment trials will examine consecutive patients with severe falcipamm malaria (as defined by the World Health Organization [Warrell 1990]) randomized to standard therapy plus placebo or standard therapy plus rosiglitazone (once daily for 5 days) or other suitable orally or parenterally administered PPAR ⁇ -RXR agonist (reviewed in Vamecq 1999, Henke 1998, Brown 1999).
  • Primary endpoint will be survival rates in each of the treatment arms. Secondary endpoints will be fever and parasite clearance times, TNF ⁇ levels, and long term morbidity in survivors.
  • products which activate PPAR ⁇ -RXR or upregulate monocyte/m ⁇ CD36 can be selected and designed in the manufacture of pharmaceutical compositions for the treatment of malaria.
  • the pharmaceutical compositions can be administered to patients by methods known to those skilled in the art, such as oral administration, aerosol administration, direct lavage and parenteral injection. Dosages to be administered depend on patient needs, on the desired effect and on the chosen route of administration.
  • Synthetic or natural ligands of PPAR ⁇ -RXR or genes (DNA) encoding these products or CD36 may also be introduced using in vivo delivery vehicles such as liposomes, infection or transfection with live or plasmid recombinant vectors, and cationic lipids. They may also be introduced into these cells using physical techniques such as microinjection and electroporation or chemical methods such as coprecipitation and incorporation of DNA into liposomes.
  • compositions can be prepared by known methods for the preparation of pharmaceutically acceptable compositions which can be administered to patients, and such that an effective quantity of the products are combined in a mixture with a pharmaceutically acceptable vehicle.
  • Suitable vehicles are described, for example in Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA 1990).
  • the pharmaceutical compositions could include an active ingredient, in association with one or more pharmaceutically acceptable vehicles, such as carriers, excipients or diluents, and contained in buffered solutions with a suitable pH and isoosmotic with the physiological fluids.
  • suitable products such as carriers, excipients or diluents
  • the methods of combining suitable products with the vehicles is well known to those skilled in the art.
  • the composition could include a targeting agent for the transport of the active compound to specified sites within tissue.
  • peptides or vectors may be administered by infection, microinjection, electroporation and by other methods known in the art.
  • compositions of the present invention may be formulated in a variety of ways.
  • Aqueous solutions of composition of the present invention may be encapsulated in polymeric beads, liposomes, nanoparticles or other injectable depot formulations known to those of skill in the art.
  • Doses are selected to provide effective activation of PPAR ⁇ -RXR and upregulation of monocyte/m ⁇ CD36.
  • compositions including a liquid pharmaceutically inert carrier such as water may also be considered for both parenteral and oral administration.
  • a liquid pharmaceutically inert carrier such as water
  • Other pharmaceutically compatible liquids may also be used.
  • the use of such liquids is well known to those of skill in the art. (Examples thereof may be found, for example, in Remington's Pharmaceutical Sciences, 18th Edition, 1990.)
  • the dose level and schedule of administration may vary depending on the particular product used, the method of administration, and such factors as the age and condition of the patient.
  • parenteral administration is preferred for ill patients, but formulations may also be considered for other means of administration such as orally, per rectum, and transdermally.
  • the usefulness of these formulations may depend on the particular compound used and the particular patient receiving the compound.
  • Oral formulations of products may optionally and conveniently be used in compositions containing a pharmaceutically inert carrier, including conventional solid carriers, which are conveniently presented in tablet or capsule form.
  • Formulations for rectal or transdermal use may contain a liquid carrier that may be oily, aqueous, emulsified or contain certain solvents suitable to the mode of administration. Suitable formulations are known to those of skill in the art. (Examples thereof may be found, for example, in Remington's Pharmaceutical Sciences, 18th Edition, 1990.) Having illustrated and described the principles of the invention in a preferred embodiment, it should be appreciated to those skilled in the art that the invention can be modified in arrangement and detail without departure from such principles. All modifications coming within the scope of the following claims are claimed. All publications, patents and patent applications referred to in this application are incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
  • G6PD glucose-6-phosphate dehydrogenase
  • 1/CD31 an endothelial receptor for binding Plasmodium falcipamm-infected erythrocytes. Nat. Med. 3, 1405-8 (1997). 76. Turner G.D. et al. An immunohistochemical study of the pathology of fatal malaria.

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Abstract

La présente invention concerne des produits thérapeutiques pour le traitement de la malaria par Plasmodium falciparum. L'invention concerne principalement une composition pour le traitement de la malaria. Le principe actif de cette composition est un agoniste de PPARη et/ou de RXR qui fait remonter le CD36 des monocytes/macrophages, mélangé à un vecteur, un excipient ou un diluant pharmaceutiquement acceptable. L'invention concerne également le traitement ou la prévention de l'infection sévère d'un sujet par P. falciparum. Ce traitement consiste d'abord (a) à former une composition combinant un agoniste de PPARη et/ou de RXR avec un vecteur, un excipient ou un diluant pharmaceutiquement acceptable, puis (b) à administrer une quantité efficace de la composition au sujet infecté par P. falciparum ou risquant de le devenir.
PCT/CA2000/001209 1999-10-19 2000-10-18 TRAITEMENT DE LA MALARIA PAR ACTIVATION DU PPARη-RXR ET REMONTEE DU CD36 DES MONOCYTES/MACROPHAGES, ET PRODUITS A CET EFFET WO2001028533A2 (fr)

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Citations (4)

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WO1997013525A1 (fr) * 1995-10-11 1997-04-17 Schering Corporation Utilisation d'il-4 pour traiter le psoriasis
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US5192264A (en) * 1989-10-06 1993-03-09 The Beth Israel Hospital Association Methods and apparatus for treating disease states using oxidized lipoproteins
US5457129A (en) * 1993-05-17 1995-10-10 Research Development Foundation Inhibition of nitric oxide production by retinoic acid
US5658949A (en) * 1993-05-17 1997-08-19 Research Development Foundation Inhibition of tumor necrosis factor by retinoic acid
WO1997013525A1 (fr) * 1995-10-11 1997-04-17 Schering Corporation Utilisation d'il-4 pour traiter le psoriasis
WO1998052540A1 (fr) * 1997-05-22 1998-11-26 The Boots Company Plc Compositions pharmaceutiques

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FENG J. ET AL: "Expression of CD36 is dependent on PKC and PPAR-Gamma." FASEB JOURNAL, vol. 13, no. 4, - 12 March 1999 (1999-03-12) pages A200-A200, XP000994810 *
LENHARD J.M. ET AL: "The RXR agonist LG100268 causes hepatomegaly, improves glycaemic control and decreases cardiovascular risk and cachexia in diabetic mice suffering from pancreatic beta-cell dysfunction." DIABETOLOGICA, vol. 42, - 1 May 1999 (1999-05-01) pages 545-554, XP000985788 *
YESNER L.M. ET AL: "Regulation of monocyte CD36 and thrombospondin-1 expression by soluble mediators." ARTERIOSCLEROSIS, THROMBOSIS, AND VASCULAR BIOLOGY, vol. 16, no. 8, 1996, pages 1019-1025, XP000985327 *

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