WO2002018593A2 - Modulation de l'expression de fas et de fasl - Google Patents

Modulation de l'expression de fas et de fasl Download PDF

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Publication number
WO2002018593A2
WO2002018593A2 PCT/CA2001/000845 CA0100845W WO0218593A2 WO 2002018593 A2 WO2002018593 A2 WO 2002018593A2 CA 0100845 W CA0100845 W CA 0100845W WO 0218593 A2 WO0218593 A2 WO 0218593A2
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Prior art keywords
fas
human
composition
animal
fasl
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Ceased
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PCT/CA2001/000845
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WO2002018593A3 (fr
Inventor
Nigel C. Phillips
Mario C. Filion
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Telesta Therapeutics Inc
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Bioniche Life Sciences Inc
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Publication date
Priority claimed from US09/735,363 external-priority patent/US7157436B2/en
Priority to DK01947067.3T priority Critical patent/DK1313853T3/da
Priority to CA002420103A priority patent/CA2420103A1/fr
Priority to ES01947067T priority patent/ES2383671T3/es
Priority to JP2002522500A priority patent/JP2004507469A/ja
Priority to EP01947067A priority patent/EP1313853B1/fr
Application filed by Bioniche Life Sciences Inc filed Critical Bioniche Life Sciences Inc
Priority to MXPA03001812A priority patent/MXPA03001812A/es
Priority to AU6886301A priority patent/AU6886301A/xx
Priority to AU2001268863A priority patent/AU2001268863B2/en
Priority to AT01947067T priority patent/ATE550428T1/de
Publication of WO2002018593A2 publication Critical patent/WO2002018593A2/fr
Publication of WO2002018593A3 publication Critical patent/WO2002018593A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • 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
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • 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
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1138—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against receptors or cell surface proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/18—Type of nucleic acid acting by a non-sequence specific mechanism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/315—Phosphorothioates

Definitions

  • the present invention relates compositions useful for modulating Fas and Fas ligand expression on cells and for modulating efficacy of therapeutic agents.
  • Fas is a type-I membrane protein abundantly expressed by cells in various tissues and particularly on activated T cells, heart cells, kidney cells and hepatocytes.
  • FasL is a type-II transmembrane protein expressed particularly on activated T cells and natural killer cells (Nagata, S. Ann. Rev. Genet. 33:29, 1999), and is expressed constitutively in immune- privileged sites as, for example, the eye and testis (Griffith et al. Science 270:630, 1995).
  • Fas and FasL interactions play an essential role in the regulation of immune cells and in the elimination of autoreactive cells (Sabelko- Downes et al. Curr. Opin. Immunol. 12:330, 2000).
  • Fas/FasL mediates the killing of cancer cells and of virus-infected cells (Famularo et al. Med. Hypoth. 53:50, 1999; Owen-Schaub et al. Int. J. Oncol. 17:5, 2000).
  • FasL expressed on cancer cells, may attack cells of the immune system (O'Connell, J. Exp. Med.
  • FasL expressed on activated T cells, may also participate in tissue damage in fulminant hepatitis and in graft- versus-host disease (Kondo et al. Nature Med. 3:409, 1997; Braun et al. J. Exp. Med. 183:657, 1996).
  • Apoptosis is an active cellular death process characterized by distinctive morphological changes that include condensation of nuclear chromatin, cell shrinkage, nuclear disintegration, plasma membrane blebbing, and the formation of membrane-bound apoptotic bodies (Wyllie et al. Int. Rev. Cytol. 68:251, 1980).
  • a molecular hallmark of apoptosis is degradation of cellular nuclear DNA into oligonucleosomal-length fragments as the result of activation of endogenous endonucleases (Wyllie A. Nature 284:555, 1980).
  • Caspases cyste-aspartyl- specific proteases
  • the binding of FasL to Fas activates a cascade of caspases via a FADD adaptor (Fas-associated protein with death domain), which leads to the cleavage of various cellular substrates and to DNA fragmentation (Nagata, S. Ann. Rev. Genet. 33:29, 1999).
  • Synthetic oligonucleotides are polyanionic sequences that can be internalized by cells (Nlassov et al. Biochim. Biophys. Acta 1197:95, 1994) and bind selectively to nucleic acids (Wagner, R. Nature: 372:333, 1994), to specific cellular proteins (Bates et al. J. Biol. Chem. 274:26369, 1999) and to specific nuclear proteins (Scaggiante et al. Eur. J. Biochem. 252:207, 1998), and inhibit cell proliferation. Proliferation is the culmination of the progression of a cell through the cell cycle, resulting in the division of one cell into two cells. Alterations in cell cycle progression occur in all cancers and may result from over-expression of genes, mutation of regulatory genes, or abrogation of DNA damage checkpoints (Hochhauser D. Anti-Cancer Chemotherapeutic Agents 8:903, 1997).
  • Synthetic phosphorothioate oligonucleotides containing unmethylated CpG dinucleotides flanked by two 5' purine and two 3' pyrimidine are reported to induce the synthesis of cytokines by macrophages and B cells, to increase the activity of NK cells and cytotoxic T lymphocytes, and to enhance T- Natl. Acad. Sci. USA93:2879, 1996; Lipford et al. Eur. J. Immunol. 27:2340, 1997).
  • a 20 base synthetic CpG motif is reported to block Fas expression on activated B cells and to block apoptosis induced by anti-Fas monoclonal antibodies (Wang et al. Cell.
  • Fas/FasL The ability to modulate the Fas/FasL system has many clinical applications for use in diseases including, but not limited to, neoplastic autoimmune, degenerative and cardiovascular diseases.
  • Fas/FasL modulating agents have proven to be less than adequate in clinical applications.
  • many of these agents are inefficient, toxic or have significant adverse effects.
  • the present invention fulfills these needs by providing a novel method, employing new compositions comprising a synthetic phosphodiester oligodeoxynucleotide (hereinafter, "sequence") selected from the group consisting of (GG) n , (GT) n , a(GT) n b, a(GA) n b, and a(GC) n b, wherein n is an integer between 1 and 3, and a and b are independently either none or one or more As, Cs, Gs, or Ts, or combinations thereof, wherein the total number of bases in the composition is between 2 and 10, preferably 4 to 8, more preferably 5 to 7, and most preferably 6.
  • the present invention provides new uses for these compositions.
  • This composition is combined with a pharmaceutically acceptable carrier, and is FasL expression in the animal or the human.
  • This composition is also combined with a pharmaceutically acceptable carrier, and is administered to an animal or a human having a disease in an amount effective to modulate Fas and FasL expression in order to treat the disease in the animal or the human.
  • This composition is also administered to an animal or human to modulate the efficacy of Fas and FasL modulatory agents, comprising administration of the composition in an amount effective to modulate efficacy of Fas and FasL modulatory agents to modulate Fas and FasL, or to treat an animal or a human having a disease.
  • compositions of the present invention are to modulate, and preferentially potentiate, the efficacy of a therapeutic agent to treat a disease, comprising administration of the composition in a pharmaceutically acceptable carrier, optionally in combination with a therapeutic agent, in an amount effective to modulate efficacy of the therapeutic agent administered to an animal or a human.
  • the compositions of the present invention may be administered at any time before, during, or after administration of the therapeutic agent, in order to modulate the efficacy of the therapeutic agent.
  • the compositions of the present invention may also be administered in vitro, for example to animal or human cells or tissues.
  • the composition of the present invention comprises a sequence selected from the group consisting of (GG) n , (GT) n , a(GT) n b, a(GA) n b, and a(GC) n b, wherein n is an integer between 1 and 3, and a and b are independently either none or one or more As, Cs, Gs, or Ts, or combinations thereof provided the total number of bases in the composition is 6.
  • the composition of the present invention comprises this sequence of 6 bases in combination with a pharmaceutically acceptable carrier.
  • the composition of the present invention comprises this sequence of 6 bases in combination with a therapeutic agent and a pharmaceutically acceptable carrier.
  • an object of the present invention is to provide a new composition
  • a synthetic phosphodiester oligodeoxynucleotide (hereinafter, "sequence") selected from the group consisting of (GG) n , (GT) n , a(GT) n b, a(GA) n b, and a(GC) utilizatb, wherein n is an integer between 1 and 3, and a and b are independently either none or one or more As, Cs, Gs, or Ts, or combinations thereof, wherein the total number of bases in the composition is 2 to 10.
  • sequence synthetic phosphodiester oligodeoxynucleotide
  • Another object of the present invention is to provide a new composition
  • a synthetic phosphodiester oligodeoxynucleotide (hereinafter, "sequence") selected from the group consisting of (GG) n , (GT) n , a(GT) n b, a(GA) n b, and a(GC) n b, wherein n is an integer between 1 and 3, and a and b are independently either none or one or more As, Cs, Gs, or Ts, or combinations thereof, wherein the total number of bases in the composition is 4 to 8.
  • sequence synthetic phosphodiester oligodeoxynucleotide
  • Yet another object of the present invention is to provide a new composition
  • a synthetic phosphodiester oligodeoxynucleotide (hereinafter, "sequence") selected from the group consisting of (GG) n , (GT) n , a(GT) n b, a(GA) n b, and a(GC) n b, wherein n is an integer between 1 and 3, and a and b are independently either none or one or more As, Cs, Gs, or Ts, or combinations thereof, wherein the total number of bases in the composition is 5 to 7.
  • sequence synthetic phosphodiester oligodeoxynucleotide
  • Another object of the present invention is to provide a new composition
  • a new composition comprising a synthetic phosphodiester oligodeoxynucleotide (hereinafter, "sequence") selected from the group consisting of (GG) n , (GT) n , a(GT) n b, a(GA) repeatb, and a(GC) n b, wherein n is an integer between 1 and 3, and a and b are independently either none or one or more As, Cs, Gs, or Ts, or combinations thereof, wherein the total number of bases in the composition is 6.
  • sequence synthetic phosphodiester oligodeoxynucleotide
  • Yet another object of the present invention is to provide for the use of any of the novel compositions described herein for the manufacture of a medicament.
  • Still another object of the present invention is to provide new uses for the compositions of the present invention.
  • Still another object of the present invention is to provide a method to modulate the Fas expression on immune cells.
  • Another object of the present invention is to provide a method to modulate FasL expression on immune cells.
  • Yet another object of the present invention is to provide a method to modulate Fas expression on cancer cells.
  • Yet another object of the present invention is to provide a method to treat a neoplastic disease.
  • Still another object of the present invention is to provide a method to treat an autoimmune disease.
  • Another object of the present invention is to provide a method to treat an inflammatory disease.
  • Yet another object of the present invention is to provide a method to treat a proliferative disease
  • Another object of the present invention is to provide a method to treat a lymphoproliferative disease.
  • Yet another object of the present invention is to provide a method to treat a degenerative disease.
  • Yet another object of the present invention is to provide a method to treat a graft rejection.
  • Another object of the present invention is to provide a method effective to treat an infection.
  • Yet another object of the present invention is to provide a method that modulates the effect of a therapeutic agent to treat disease.
  • Another object of the present invention is to provide a method that potentiates the effect of a FasL modulating agent.
  • Yet another object of the present invention is to provide a method that potentiates the effect of an anti-neoplastic agent.
  • Another object of the present invention is to provide a method that potentiates the effect of an immunostimulatory agent.
  • Still another object of the present invention is to provide a method that potentiates the effect of an immunosuppressive agent.
  • Another object of the present invention is to provide a method that potentiates the effect of an anti-inflammatory agent.
  • Another object of the present invention is to provide a composition that is minimally toxic to the recipient.
  • the present invention fulfills these needs by providing new compositions and new methods of using these compositions.
  • the present compositions comprise a synthetic phosphodiester oligodeoxynucleotide (hereinafter, "sequence") selected from the group consisting of (GG) n , (GT) n , a(GT) complicatb, a(GA) n b, and a(GC) n b, wherein n is an integer between 1 and 3, and a and b are independently either none or one or more As, Cs, Gs, or Ts, or combinations thereof, wherein the total number of bases in the composition is between 2 and 10, preferably 4 to 8, more preferably 5 to 7, and most preferably 6.
  • the compositions of the present invention further comprise any of the sequences described herein in combination with a pharmaceutically acceptable carrier.
  • the compositions of the present invention further comprise any of the sequences described herein in combination with a therapeutic agent and a pharmaceutically acceptable carrier.
  • the present invention provides new uses for these novel compositions.
  • This composition is combined with a pharmaceutically acceptable carrier, and is administered to an animal or a human an amount effective to modulate Fas and FasL expression in the animal or the human.
  • This composition is also combined with a pharmaceutically acceptable carrier, and is administered to an animal or a human having a disease in an amount effective to modulate Fas and FasL expression in order to treat the disease in the animal or the human.
  • This composition is also administered to an animal or human to modulate the efficacy of Fas and FasL modulatory agents, comprising administration of the composition in an amount effective to modulate efficacy of Fas and FasL modulatory agents to modulate Fas and FasL, or to treat an animal or a human having a disease.
  • composition of the present invention is to modulate, and preferentially potentiate, the efficacy of a therapeutic agent to treat a disease, carrier, optionally in combination with a therapeutic agent, in an amount effective to modulate efficacy of the therapeutic agent administered to an animal or a human.
  • the composition of the present invention may be administered at any time before, during, or after administration of the therapeutic agent, in order to modulate the efficacy of the therapeutic agent.
  • the composition of the present invention comprises a sequence selected from the group consisting of (GG) n , (GT) n , a(GT) n b, a(GA) n b, and a(GC) n b, wherein n is an integer between 1 and 3, and a and b are independently either none or one or more As, Cs, Gs, or Ts, or combinations thereof provided the total number of bases in the composition is 6.
  • the composition of the present invention comprises this sequence of 6 bases in combination with a pharmaceutically acceptable carrier.
  • the composition of the present invention comprises this sequence of 6 bases in combination with a therapeutic agent and a pharmaceutically acceptable carrier.
  • sequence refers to a synthetic phosphodiester oligodeoxynucleotide comprised of adenine (A), cytosine (C), guanine (G) and thymine (T), with a total number of bases of 2 to 10, preferably 4 to 8, more preferably 5 to 7 and most preferably 6.
  • the word "expression” refers to the cell surface concentration of Fas or of FasL.
  • the words “response” refers to upregulation (increase) or downregulation (decrease) of Fas or of Fas L expression.
  • the word “modulates” refers to changes in the expression of Fas or of FasL. Such changes include upregulation and downregulation of Fas or of FasL expression.
  • the word modulate is also employed to describe the ability of the novel sequences of the present invention to modulate the efficacy of therapeutic agents, including Fas and FasL modulating agents, to treat disease or to modulate Fas or FasL expression.
  • the phrases “therapeutically effective”, “effective amount” and “amount effective to” refer to an amount of a sequence effective to modulate the expression of Fas or of FasL.
  • disease refers to a condition wherein bodily health is impaired.
  • the phrase "therapeutic agent” is any agent approved by a regulatory agency of a country or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use to treat a disease in an animal, including a human.
  • the word “antineoplastic” refers to preventing the development, maturation, proliferation or spread of cancer cells
  • the word “potentiates” refers to a degree of synergism that is greater than additive.
  • the word “synergism” refers to the coordinated action of two or more agents.
  • Administration of an effective amount of a sequence of the present invention to an animal, including a human, is a therapeutic treatment that prevents, treats or eliminates a disease including, but not limited to, neoplastic, autoimmune, proliferative, lymphoproliferative, degenerative, and cardiovascular disease; infection; inflammation; and, graft, tissue and cell rejection.
  • a disease including, but not limited to, neoplastic, autoimmune, proliferative, lymphoproliferative, degenerative, and cardiovascular disease; infection; inflammation; and, graft, tissue and cell rejection.
  • compositions comprising one or more sequences and a pharmaceutically acceptable carrier are prepared by uniformly and intimately bringing into association the sequence and the pharmaceutically acceptable carrier.
  • compositions comprising one or more sequences, a therapeutic agent and a pharmaceutically acceptable carrier are prepared by uniformly and intimately bringing into association the sequence, the therapeutic agent and the pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers include liquid carriers, solid carriers or both. Liquid carriers are aqueous carriers, non- aqueous carriers or both and include, but are not limited to, solutions, suspensions and emulsions.
  • Emulsions include, but are not limited to, oil emulsions, water in oil emulsions, water-in-oil-in-water emulsions, site-specific emulsions, long- carriers are biological carriers, chemical carriers or both and include, but are not limited to, viral vector systems, plasmids, particles, microparticles, nanoparticles, microspheres, nanospheres, bacterial cell walls, minipumps, and biodegradable or non-biodegradable natural or synthetic polymers that allow for sustained release of the sequences.
  • Preferred aqueous carriers include, but are not limited to, water, saline and pharmaceutically acceptable buffers.
  • Preferred non-aqueous carriers include, but are not limited to, a mineral oil or a neutral oil including, but not limited to, a diglyceride, a triglyceride, a phospholipid, a lipid, an oil and mixtures thereof, wherein the oil contains an appropriate mix of polyunsaturated and saturated fatty acids.
  • stabilizing agents and excipients may be included regardless of the pharmaceutically acceptable carrier used to present the sequence to the cells.
  • the therapeutic effectiveness of a sequence may be increased by methods including, but not limited to, chemically modifying the base, sugar or phosphate backbone, chemically supplementing or biotechnologically amplifying the sequences using bacterial plasmids containing the appropriate sequences, complexing the sequences to biological or chemical carriers or coupling the sequences to tissue-type or cell-type directed ligands or antibodies.
  • composition of the present invention further comprises a composition comprising a sequence and a therapeutic agent, wherein, when the sequence and the therapeutic agent are combined with a pharmaceutically acceptable carrier and administered to an animal or human having a disease.
  • the sequence modulates and preferentially potentiates the effect of the therapeutic agent on the disease.
  • Therapeutic agents include, but not limited to, anti-neoplastic, anti-inflammatory, anti-autoimmune, anti-degenerative, Fas modulating and FasL modulating agents, or any combination thereof, and radiation therapy, or a combination of radiation therapy with therapeutic agents.
  • These therapeutic agents include, but are not limited to, biologicals, drugs, chemotherapeutic drugs, immunostimulants, immunomodulators, immunotherapeutics, anti-virals, anti- infectives, antibiotics, cytokines, antigens, antibodies, nucleic acids, vaccines, aptabases, nucleic acids, antisense nucleic acids, telomerase inhibitors, caspase biologically engineered and chemically synthesized agents, and agents that target cell death molecules for activation or inactivation.
  • Chemotherapeutic drugs include, but are not limited to, DNA damaging, DNA-alkylating, DNA-cross-linking, anti-tumor antibiotic, topoisomerase inhibiting, purine inhibiting, pyrimidine inhibiting, microtubule stabilizing, microtubule destabilizing, anti-metabolic, hormone antagonist, protein kinase inhibiting, HMG-CoA inhibiting, metaloproteinase inhibiting, CDK inhibiting, cyclin inhibiting, angiogenesis inhibiting, differentiation enhancing and molecular biologically modified viral, bacterial and extotoxic agents.
  • Routes of administration include, but are not limited to, oral, topical, subcutaneous, transdermal, subdermal, intra-muscular, intra-peritoneal, intra- vesical, intra-articular, intra-prostatic, intra-arterial, intra-venous, intra-dermal, intra-cranial, intra-lesional, intra-tumoral, intra-ocular, intra-pulmonary, intra- spinal, placement within cavities of the body, nasal inhalation and impression into skin. It is to be understood that administration of the compositions of the present invention may occur in vivo, ex vivo or in vitro. For example, the compositions of the present invention may be administered to animal or human cells or tissues in vitro.
  • Appropriate doses for in vitro administration are about 1 nM to 1 mM, preferably about 10 nM to 100 ⁇ M, and more preferably about 100 nM to 10 ⁇ M.
  • the volume per dose is preferably about 0.001 to 100 ml per dose, more preferably about 0.01 to 50 ml per dose and most preferably about 0.1 to 30 ml per dose.
  • a sequence in a pharmaceutically acceptable carrier, or sequence plus therapeutic agent in a pharmaceutically acceptable carrier can be administered in a single dose treatment, in multiple dose treatments or continuously infused on a schedule and over a period of time appropriate to the disease being treated, the condition of the recipient and the route of admimstration.
  • the therapeutic agent can be administered before, concurrently with, or after administration of the sequence.
  • the amount of sequence administered per dose is from about 0.001 to 100 mg/kg, more preferably from about 0.01 to 10 mg/ml and most preferably from about 0.1 to 5 mg/kg.
  • the amount of therapeutic agent administered per dose is from about 0.001 to 1000 mg/m 2 or from about 0.01 to 1000 mg/kg, more preferably from about 0.01 to 500 mg/m 2 or about 0.01 to 500 mg/kg and most preferably from about 0.1 to 100 mg/m 2 or about 0.1 to 100 mg/kg.
  • anti- Fas antibodies are employed and are administered in a dose of from about 0.003 to about 0.3 mg/kg, preferably 0.01 to about 0.1 mg/kg.
  • sequence and the particular therapeutic agent administered should be decided by the practitioner using methods known to those skilled in the art and will depend on the type of disease, the severity of the disease, the location of the disease and other clinical factors such as the size, weight and physical condition of the recipient.
  • in vitro assays may optionally be employed to help identify optimal ranges for sequence and for sequence plus therapeutic agent administration.
  • PBMCs Peripheral blood mononuclear cells
  • Ficoll-Hypaque Amersham Pharmacia Biotech, Baie d'Urfee, Quebec, Canada
  • Cancer cells and PBMCs were seeded in 6 well flat-bottom microplates and were maintained at 37°C in a 5% CO 2 atmosphere. Unless stated otherwise, 2 X 10 5 cells/ml were incubated for 48 h with 0 ⁇ g/ml (control) or 100 ⁇ g/ml (5.5 ⁇ M) (treated) of the sequences.
  • Fas and FasL expression were measured by flow cytometry using anti-Fas FITC-conjugated monoclonal antibodies and anti-FasL PE-conjugated monoclonal antibodies in a FACScalibur Flow Cytometer (Becton Dickinson, San Jose, CA, USA) using the CELLQuest program (Becton Dickinson).
  • Results are expressed as percentage (%) increase in the expression of Fas Example 4 Modulation of Fas and FasL on Jurkat leukemia T cells
  • Jurkat human leukemia T cells are an atypical multi-drug resistant human suspension tumor cell model.
  • Jurkat T cells were incubated with the 6 base sequences shown in Table 2.
  • PBMCs were incubated with the 6 base sequences shown in Table 3.
  • T-24 bladder cancer cells are a p53 mutated human cell line T-24 cells
  • UMUC-3 bladder cancer cells are a P-glycoprotein overexpressing human cell line.
  • UMUC-3 cells 1.0 X 10 ⁇ cells/ml were incubated with the 6 base sequences shown in Table 5.
  • Table 5 Percentage increase of Fas and of FasL on UMUC-3 bladder cancer cells
  • OVCAR-3 ovarian cancer cells are a p53 mutated, p21/waf-l/Cip deleted, metastatic human solid tumor model. OVCAR-3 cells were incubated with the 6 base sequences shown in Table 6. Table 6 Percentage increase of Fas and of FasL on OVCAR-3 ovarian cancer cells
  • SK-OV-3 ovarian cancer cells are a p53 mutated, p21/waf-l/Cip deleted, pl5 ink4B ,pl6 ink4 deleted metastatic human solid tumor model.
  • SK-OV 3 cells (1.0
  • LNCaP prostate cancer cells are a TGF-beta 1 receptor negative, androgen-independent, metastatic human solid tumor model. LNCaP cells were incubated with the 6 base sequences shown in Table 8. Table 8 Percentage increase of Fas and of FasL on LNCaP prostate cancer cells
  • MCF-7 human breast cancer cells are a caspase-3 negative, estrogen-dependent human solid tumor model.
  • MCF-7 cells (1 x 10 5 cells/ml) were incubated with the 6 base sequences shown in Table 9.
  • Jurkat human leukemia T cells were pre-incubated with 0.0 ⁇ g/ml (- CHX) or with 0.1 ⁇ g/ml of cycloheximide (+ CHX) for 1 h.
  • Ten ⁇ g/ml or 100 ⁇ g/ml of 6 base SEQ ID NO:5 (GGGTGG) was added to both the - CHX and + CHX cells and the incubation was continued for 24 hours and for 48 hours (Table 10).
  • SEQ ID NO:5 upregulated Fas expression on Jurkat T cells.
  • cycloheximide decreased Fas expression 92% after 24 h and 44% after 48 h.
  • cycloheximide decreased Fas expression 65% after 24 h and 23% after 48 h.
  • Example 13 Synergistic effect of SEQ ID No: 5 (GGGTGG) and agonistic anti-Fas antibodies on inhibition of UMUC-3 bladder cancer cell proliferation
  • UMUC-3 bladder cancer cells were incubated for 48 hours with 0.00, 0.02 and 0.20 ⁇ g/ml of agonistic anti-Fas monoclonal antibodies (clone CH-11 : Coulter-Immunotech, Marseille, France) + 0 or 10 ⁇ g/ml of SEQ ID NO:5.
  • Cell proliferation was measured using dimethylthiazol-diphenyltetrazolium (MTT) reduction (Mosman et al. J. Immunol. Methods 65:55, 1983). MTT was measured at a wavelength of 570 nm using a multiplate spectrophotometer reader (ELX800, Bio-TEK Instruments Inc., Winooski, VT). Table 11 Inhibition of UMUC-3 bladder cancer cell proliferation
  • 6 base SEQ ID NO: 5 potentiated the inhibitory activity of 0.02 and 0.2 ⁇ g/ml of agonistic anti-Fas antibodies on UMUC-3 cell proliferation.
  • Example 14 Additive effect of SEQ ID NO: 5 (GGGTGG) and agonistic anti-Fas antibodies on inhibition of Jurkat leukemia T cell proliferation.
  • Jurkat T leukemia cells were incubated for 48 hours with 0.00, 0.02 and 0.20 ⁇ g/ml of agonistic anti-Fas monoclonal antibodies (clone CH-11) + 0 and 10 ⁇ g/ml of SEQ ID NO:5.
  • Cell proliferation was measured as in Example 13.
  • mice Effect of 6 base sequences and agonistic anti-Fas antibodies on EL-4 murine T EL-4 murine T lymphoma cells are implanted into C57/BL6 lpr/lpr (Fas negative mice). The mice are divided into 30 groups of 10 mice. On day 0, group 1 mice receive saline, group 2 mice receive 1, 10 or 100 mg/kg of SEQ. ID NO:5, group 3 mice receive 1, 10 or 100 mg/kg of SEQ. ID NO:16, group 4 receive 1, 10 or 100 mg/kg of SEQ. ID NO: 17, group 5 mice receive 1, 10 or 100 mg/kg of SEQ. ID NO: 18, group 6 mice receive anti-Fas antibodies, group 7 mice receive 1, 10 or 100 mg/kg of SEQ.
  • anti-Fas antibodies are administered at any dose in the range of about 0.003 to about 0.3 mg/kg.
  • Group 1 mice have the most tumor mass
  • groups 2, 3, 4, 5 and 6 mice have less tumor mass than group 1 mice
  • group 7, 8, 9 and 10 mice have the least tumor mass.
  • the efficacy of the SEQ. ID NO:5, the SEQ. ID NO:16 and the SEQ. ID NO:17 is dose-dependent.
  • Example 16 Female (SJL/J x PL/J) FI mice are injected subcutaneously in both femoral regions with an emulsion containing 0.5 mg of myelin basic protein (MBP) mixed with complete Freund's adjuvant. After 24 h, 400 ng of Bordetella pertussis toxin is administered intraperitoneally. On the day of onset (day 0), group 1 mice receive saline, group 2 mice receive 1, 10 or 100 mg/kg of SEQ. ID NO:5, group 3 mice receive 1, 10 or 100 mg/kg of SEQ. ID NO:16, group 4 mice receive 1, 10 or 100 mg/kg of SEQ. ID NO: 17, group 5 mice receive 1, 10 or 100 mg/kg of SEQ.
  • MBP myelin basic protein
  • group 6 mice receive anti-Fas antibodies
  • group 7 mice receive 1, 10 or 100 mg/kg of SEQ. ID NO:5 + anti-Fas antibodies
  • group 8 mice receive 1, 10 or 100 mg/kg of SEQ. ID NO:16 + anti-Fas antibodies
  • group 9 receive 1, 10 or 100 mg/kg of SEQ. ID NO: 17 + anti-Fas antibodies
  • group 10 mice receive 1, 10 or 100 mg/kg of SEQ. ID NO: 18 + anti-Fas antibodies for 3 days by intracisternal administration (20 ⁇ g/day).
  • anti- Fas antibodies are administered at any dose in the range of about 0.003 to about group 1, 2, 3, 4 and 5 mice.
  • Group 7, 8, 9 and 10 mice show the least progression of EAE.
  • the efficacy of the SEQ. ID NO:5, the SEQ. ID NO:16 and the SEQ. ID NO: 17 is dose-dependent

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Abstract

La présente invention concerne un procédé faisant intervenir l'utilisation d'une composition comprenant de 2 à 10 séquences oligonucléotidiques synthétiques de base choisies parmi le groupe comprenant (GG)n, (GT)n, a(GT)nb, a(GA)nb, et a(GC)nb, où n est un entier de 1 à 3, et a et b sont indépendamment zéro, un ou plusieurs des éléments As, Cs, Gs, ou Ts, ou de leurs combinaisons, ladite composition étant utilisée pour moduler l'expression de Fas et de FasL ou pour moduler l'efficacité d'agents thérapeutiques. La composition est administrée à un animal ou à un être humain avec un excipient pharmaceutiquement acceptable, et éventuellement avec un agent thérapeutique, en une quantité efficace pour moduler l'expression de Fas et de FasL, pour traiter la maladie, ou pour moduler l'efficacité de l'agent thérapeutique.
PCT/CA2001/000845 1999-12-13 2001-06-12 Modulation de l'expression de fas et de fasl Ceased WO2002018593A2 (fr)

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AT01947067T ATE550428T1 (de) 2000-08-29 2001-06-12 Modulierung der fas und fasl expression durch ein synthetisches oligonukleotid und einen anti-fas antikörper
AU6886301A AU6886301A (en) 2000-08-29 2001-06-12 Modulation of fas and fasl expression
ES01947067T ES2383671T3 (es) 2000-08-29 2001-06-12 Modulación de la expresión de Fas y FasL por un oligonucleótido-fosfodiéster sintético y un anticuerpo anti-Fas
JP2002522500A JP2004507469A (ja) 2000-08-29 2001-06-12 Ｆａｓおよびｆａｓｌ発現の調整
EP01947067A EP1313853B1 (fr) 2000-08-29 2001-06-12 Modulation de l'expression de fas et fasl par un oligonucléotide phosphodiester synthétique et un anticorps anti-fas
DK01947067.3T DK1313853T3 (da) 2000-08-29 2001-06-12 Modulering af Fas- og Fasl-ekspression med et syntetisk phosphodiesteroligonucleotid og et anti-Fas-antistof
MXPA03001812A MXPA03001812A (es) 2000-08-29 2001-06-12 Modulacion de la expresion del sindrome de alcohol fetal y del ligando del sindrome de alcohol fetal..
CA002420103A CA2420103A1 (fr) 2000-08-29 2001-06-12 Modulation de l'expression de fas et de fasl
AU2001268863A AU2001268863B2 (en) 1999-12-13 2001-06-12 Modulation of FAS and FASL expression

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US22892500P 2000-08-29 2000-08-29
US60/228,925 2000-08-29
US09/735,363 2000-12-12
US09/735,363 US7157436B2 (en) 1999-12-13 2000-12-12 Therapeutically useful synthetic oligonucleotides
CAPCT/CA00/01467 2000-12-12
PCT/CA2000/001467 WO2001044465A2 (fr) 1999-12-13 2000-12-12 Oligonucleotides synthetiques utiles du point de vue therapeutique
US26622901P 2001-02-02 2001-02-02
US60/266,229 2001-02-02

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002085340A3 (fr) * 2001-04-24 2003-10-30 Bioniche Life Sciences Inc Compositions oligonucleotidiques et leur utilisation dans la differentiation cellulaire

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001044465A2 (fr) 1999-12-13 2001-06-21 Bioniche Life Sciences Inc. Oligonucleotides synthetiques utiles du point de vue therapeutique

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5523389A (en) * 1992-09-29 1996-06-04 Isis Pharmaceuticals, Inc. Inhibitors of human immunodeficiency virus
US5643890A (en) * 1995-01-31 1997-07-01 The Board Of Regents Of The University Of Nebraska Synthetic oligonucleotides which mimic telomeric sequences for use in treatment of cancer and other diseases
IT1277025B1 (it) * 1995-12-04 1997-11-04 Cooperativa Centro Ricerche Po Classe di oligonucleotidi fosfodiesterici ad attivita' citotossica composizioni farmaceutiche che li contengono e loro uso
WO1999003998A1 (fr) * 1997-07-17 1999-01-28 The Regents Of The University Of Michigan Procedes et compositions servant a reduire une tumeur

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001044465A2 (fr) 1999-12-13 2001-06-21 Bioniche Life Sciences Inc. Oligonucleotides synthetiques utiles du point de vue therapeutique

Non-Patent Citations (22)

* Cited by examiner, † Cited by third party
Title
BATES ET AL., J. BIOL. CHEM., vol. 274, 1999, pages 26369
BRAUN ET AL., J. EXP. MED., vol. 183, 1996, pages 657
FAMULARO ET AL., MED. HYPOTH., vol. 53, 1999, pages 50
GRIFFITH ET AL., SCIENCE, vol. 270, 1995, pages 630
HOCHHAUSER D., ANTI-CANCER CHEMOTHERAPEUTIC AGENTS, vol. 8, 1997, pages 903
KONDO ET AL., NATURE MED., vol. 3, 1997, pages 409
LIPFORD ET AL., BUR. J. IMMUNOL., vol. 27, 1997, pages 2340
MOSMAN ET AL., J. IMMUNOL. METHODS, vol. 65, 1983, pages 55
NAGATA, S., ANN. REV. GENET., vol. 33, 1999, pages 29
NATL. ACAD. SCI. USA, vol. 93, 1996, pages 2879
NISHIOKA ET AL., INT. J. MOL. MED., vol. 3, 1999, pages 275
O'CONNELL, J. EXP. MED., vol. 184, 1996, pages 1075
OWEN-SCHAUB ET AL., INT. J. ONCOL., vol. 17, 2000, pages 5
SABELKO-DOWNES ET AL., CURR. OPIN. IMMUNOL., vol. 12, 2000, pages 330
SCAGGIANTE ET AL., EUR. J. BIOCHEM., vol. 252, 1998, pages 207
SHEARD ET AL., INT J. CANCER, vol. 73, 1997, pages 757
VLASSOV ET AL., BIOCHIM. BIOPHYS. ACTA, vol. 1197, 1994, pages 95
WAGNER, R., NATURE, vol. 372, 1994, pages 333
WANG ET AL., CELL. IMMUNOL., vol. 180, 1997, pages 162
WYLLIE A., NATURE, vol. 284, 1980, pages 555
WYLLIE ET AL., INT. REV. CYTOL., vol. 68, 1980, pages 251
YOONG ET AL., AM. J. PATHOL., vol. 154, 1999, pages 693

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002085340A3 (fr) * 2001-04-24 2003-10-30 Bioniche Life Sciences Inc Compositions oligonucleotidiques et leur utilisation dans la differentiation cellulaire
AU2002252891B2 (en) * 2001-04-24 2007-09-20 Bioniche Life Sciences, Inc. Oligonucleotide compositions and their use to induce differentiation of cells
KR100913860B1 (ko) * 2001-04-24 2009-08-26 바이오니취 라이프 사이언시즈 인코포레이티드 올리고뉴클레오타이드 조성물 및 세포 분화 유도시 이의용도

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