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WO2001051083A2 - Compositions de stimulation de l'immunite naturelle a base de cpg et de saponine et procedes correspondants - Google Patents

Compositions de stimulation de l'immunite naturelle a base de cpg et de saponine et procedes correspondants Download PDF

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Publication number
WO2001051083A2
WO2001051083A2 PCT/US2001/001046 US0101046W WO0151083A2 WO 2001051083 A2 WO2001051083 A2 WO 2001051083A2 US 0101046 W US0101046 W US 0101046W WO 0151083 A2 WO0151083 A2 WO 0151083A2
Authority
WO
WIPO (PCT)
Prior art keywords
composition
saponin
cpg
oligonucleotide
administered
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2001/001046
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English (en)
Other versions
WO2001051083A3 (fr
Inventor
Charlotte R. Kensil
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aquila Biopharmaceuticals Inc
Agenus Inc
Original Assignee
Aquila Biopharmaceuticals Inc
Antigenics LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aquila Biopharmaceuticals Inc, Antigenics LLC filed Critical Aquila Biopharmaceuticals Inc
Priority to JP2001551506A priority Critical patent/JP2003527352A/ja
Priority to EP01902032A priority patent/EP1250150A2/fr
Priority to AU27877/01A priority patent/AU781812B2/en
Priority to CA002397374A priority patent/CA2397374A1/fr
Publication of WO2001051083A2 publication Critical patent/WO2001051083A2/fr
Publication of WO2001051083A3 publication Critical patent/WO2001051083A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • 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
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
    • 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
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55561—CpG containing adjuvants; Oligonucleotide containing adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55577—Saponins; Quil A; QS21; ISCOMS

Definitions

  • the present invention is in the field of immune enhancers.
  • compositions of the invention stimulate innate immunity.
  • Adjuvant saponins have been identified and purified from an aqueous
  • purified saponins have been identified as QS-7, QS-17, QS-18, and QS-21, also
  • HPLC high pressure liquid silica chromatography
  • HILIC hydrophilic interactive chromatography
  • saponins have been found to be useful as immune adjuvants when used with
  • CpG guanine
  • CpG motifs can stimulate monocytes, macrophages, and dendritic cells
  • Th 1 T helper 1
  • IL interleukin
  • NK cells natural killer cells
  • DNA motif consisting of an unmethylated CpG dinucleotide flanked by two 5'
  • At least one unmethylated CpG dinucleotide may affect the immune response of a subject (Davis, et al., WO 98/40100). Kensil, et al., previously showed that
  • vaccine antigen can protect a mouse against an otherwise lethal infection with
  • an intracellular bacteria such as Listeria monocytogenes or Francisella tularensis, if
  • the CpG is administered between 2-3 days prior or no earlier than 2 weeks
  • agents may be potentially incorporated in future therapeutic agents.
  • oligonucleotide comprising at least one
  • NK cell activity was significantly higher for a composition comprising a CpG-
  • composition comprising saponin alone and a composition comprising an oligonucleotide
  • the invention covers a composition
  • composition provides that the
  • saponin is derived from Quillaja sapona ⁇ a, and more preferably, the saponin is
  • the substantially pure saponin comprises QS-7,
  • composition is further directed to one in which the oligonucleotide is
  • oligonucleotide is modified with
  • a preferred embodiment of the first aspect encompasses the composition wherein the
  • oligonucleotide comprises a CpG motif having the formula 5'X.CGX-3',
  • X 2 is cytosine, thymine, or adenine. More
  • the CpG motif comprises TCTCCCAGCGTGCGCC AT or
  • composition according to the first aspect of the invention, preferably increases
  • composition enhances a natural killer cell response, preferably in a positive
  • the invention is directed to a method for stimulating
  • composition comprising: (a) a saponin; and (b) an oligonucleotide comprising
  • saponin is derived from Quillaja saponaria, and more
  • the saponin is chemically modified or comprises a substantially
  • substantially pure saponin comprises QS-7, QS-17, QS-18, or QS-21, and more
  • the substantially pure saponin comprises QS-21.
  • the method is further directed to
  • the oligonucleotide is chemically modified. More particularly, the
  • oligonucleotide is modified with at least one phosphorothioate internucieotide
  • a preferred embodiment of the second aspect encompasses the method wherein the oligonucleotide comprises a CpG motif having the
  • the CpG motif comprises
  • a third aspect of the invention provides for methods for stimulating
  • composition comprising a saponin only to an individual.
  • saponin a saponin only to an individual.
  • the saponin is derived from Quillaja sa ⁇ onaria, and more
  • the saponin is chemically modified or comprises a substantially
  • pure saponin comprises QS-7, QS-17, QS-18, or QS-21, and more preferably, the
  • substantially pure saponin comprises QS-21.
  • third aspect of the invention preferably further increases an innate immune
  • Figure 1 is a graphic representation showing the enhancement of the
  • Figure 2 is a graphic representation showing the optimal timing of
  • Figure 3 is a graphic representation depicting the NK activating activity
  • Figure 4 is a graphic representation depicting the NK activating activity
  • Figure 5 is a graphic representation illustrating protection of Balb/c
  • saponin as used herein includes glycosidic triterpenoid
  • the invention encompasses the saponin per se, as well as natural and pharmaceutically acceptable salts and pharmaceutically
  • the saponins of the present invention may be obtained from the tree
  • a partially purified saponin enriched extract prepared as described by
  • QS-21 also known as QA-7, QA-17, QA-18, and QA-21, respectively.
  • QS-21 designates the mixture of components QS-21-V1 and QS-21-V2
  • the present invention may also employ chemically modified saponins.
  • QS-21 can be reduced with a mild reducing agent, such as sodium or
  • QS-21 can be subjected to reductive amidation with a primary amine and a
  • glucuronic acid of saponins from Quillaja saponaria Molina can be conjugated to
  • a protein a peptide, or a small molecule containing a primary amine.
  • Quillaja saponaria may be deacylated by alkaline-catalyzed hydrolysis.
  • lipid may be conjugated to a lipid, fatty acid, polyethylene glycol, or terpene.
  • the present invention relates to a chemically modified saponin or a biologically
  • Adjuvant-active saponins and adjuvant-inactive saponins fall within the scope
  • the term "saponin" covers
  • the mixture of saponins comprises two or
  • the two or more substantially pure saponins More preferably, the two or more substantially pure saponins. More preferably, the two or more substantially pure saponins.
  • substantially pure saponins are from Quillaja saponaria in doses that are
  • the combination of saponins consists essentially of substantially
  • the saponin is QS-21 and the
  • excipients are selected from nonionic surfactants, polyvinyl pyrolidone, human
  • the nonionic surfactants are selected from Polysorbate 20,
  • Polysorbate-40, Polysorbate-60, and Polysorbate-80 The polyvinyl pyrolidone
  • Plasdone C15 a pharmaceutical grade of polyvinyl
  • the agent having anesthetic action preferably is benzyl alcohol.
  • Preferred cyclodextrins are hydroxypropyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -
  • the present invention may also employ saponins isolated from other
  • the invention provides a method for stimulating an
  • nucleic acid or oligonucleotide refers to a
  • nucleotides at least five bases in length.
  • the invention can be deoxyribonucleotides, ribonucleotides, or modified forms
  • the nucleic acid molecule can include the use of phosphorothioate or
  • backbone modification may occur at the 3' end of the nucleic acid, for example
  • Nontraditional bases such as
  • adenine, cytidine, guanine, thymine, and uridine can also be included, which are not as easily recognized by endogenous endonucleases.
  • nucleic acid molecules include: nonionic DNA analogs, such as alkyl- and aryl-
  • oligonucleotide includes
  • CpG or “CpG motif” refers to a nucleic acid having a cytosine
  • CpG refers to the methylation of the cytosine on the pyrimidine ring, usually
  • oligonucleotide of the invention is believed to reduce its effect. Methylation or
  • the CpG motif is an
  • the CpG oligonucleotide is in the range of about 5 to 40 bases
  • nucleic acids can be synthesized de
  • CpG dinucleotides can be produced on
  • Oligonucleotides can be prepared from existing nucleic acid sequences (e.g.,
  • genomic or cDNA using known techniques, such as those employing
  • restriction enzymes enzymes, exonucleases or endocucleases.
  • nucleic acids are preferably relatively resistant to
  • stem loops can stabilize nucleic acids against degradation.
  • nucleic acid stabilization can be accomplished via phosphate backbone
  • a preferred stabilized nucleic acid has at least a partial
  • Phosphorothioates may be synthesized
  • Aryl- and alkyl-phosphonates can be made, e.g., as
  • Patent No. 5,023,243 and Tullis, EP 092574B1 can be prepared by automated
  • nucleic acids may be associated with a
  • target cell e.g., B-cell
  • NK natural killer
  • nucleic acids uptake by target cells to form a "nucleic acid delivery complex.”
  • linking agents can be used, e.g., protein A, carbodiimide, and N-succinimidyl-3-
  • the CpG motif may be part of a monomer or part of a multimer.
  • the CpG motif may be part of a monomer or part of a multimer.
  • nucleotide separates consecutive CpGs, and wherein X, is adenine, guanine, or
  • X 2 is cytosine, thymine, or adenine.
  • X j is adenine
  • guanine, or thymidine guanine, or thymidine
  • X is cytosine or thymine
  • N is any nucleotide and N j +
  • N 2 is from about 0-26 bases. In a preferred embodiment, N. and N 2 do not
  • sequence is from about 8-30 bases in length.
  • nucleic acids of any size (even may kb long) can be used in the invention if CpGs are present, as larger
  • nucleic acids are degraded into oligonucleotides inside cells.
  • synthetic oligonucleotides do not include a CCGG quadmer or more than one
  • mitogenic CpG motif is not a palindrome.
  • palindrome means an inverted repeat (i.e., a sequence such as
  • the method of the invention includes the
  • N is any nucleotide and N.+N 2 is
  • N. and N 2 do not contain a
  • oligodeoxynucleotides are also preferably in the range of 8 to 30 bases in
  • CCGG quadmer or more than one CCG or CGG trimer at or near the
  • 5' and/or 3' terminals and/or the consensus mitogenic CpG motif is not a
  • CpG oligonucleotides can be assayed for efficacy using methods described herein.
  • the CpG motif comprises
  • TCTCCCAGCGTGCGCCAT also known as “CpG sequence 1758"
  • TCCATGACGTTCCTGACGTT also known as “CpG sequence 1826"
  • TCGTCGTTTTGTCGTTTTGTCGTT also known as "CpG sequence 2006”.
  • oligonucleotides of the invention may be chemically modified in a
  • a phosphate backbone modification e.g., a phosphorothioate or
  • the oligonucleotides may be any suitable phosphorodithioate modification.
  • the oligonucleotides may be any suitable phosphorodithioate modification.
  • the oligonucleotides may be any suitable phosphorodithioate modification.
  • the oligonucleotides may be any suitable phosphorodithioate modification.
  • non-traditional bases or chemical groups such as phosphorothioate. More
  • the phosphate backbone modification occurs at the 5' end of the
  • nucleic acid for example, at the first two nucleotides of the 5' end of the nucleic
  • phosphate backbone modification may occur at the 3'end of
  • the nucleic acid for example, at the last five nucleotides of the 3' end of the
  • the oligonucleotide comprising at least one unmethylated CpG
  • dinucleotide may preferably be modified with at least one such
  • Oligonucleotides with phosphorothioate linkages may be prepared
  • alkylphosphonates include alkylphosphonates, phosphorodithioates, alkylphosphorothioates,
  • monocyte, and/or NK cell responses For example, as assayed by induction of
  • cytokines proliferative responses
  • lytic responses the stimulation of the
  • innate immunity refers to an immune
  • monocytes include monocytes, macrophages, natural killer cells, and polymorphonuclear cells, such as monocytes, macrophages, natural killer cells, and polymorphonuclear cells, such as monocytes, macrophages, natural killer cells, and polymorphonuclear cells, such as monocytes, macrophages, natural killer cells, and polymorphonuclear cells, such as monocytes, macrophages, natural killer cells, and others.
  • neutrophils neutrophils.
  • nonspecific immunostimulator refers to compounds
  • mammals and more preferably, the mammals are humans, however, the
  • nonspecific immunostimulator may enhance the immune response of the
  • interleukin-12 IL-12
  • IFN ⁇ interleukin-12
  • compositions to enhance innate immunity may be any composition that enhance innate immunity.
  • composition may be used as a criterion for stimulation of
  • one such method involves injecting Balb/c mice at
  • day 3 can be tested for a natural killer cell lytic activity against a natural killer
  • cell sensitive-cell line such as YAC-1 cells.
  • determining innate immunity is to administer a test composition to a suitable vehicle
  • mice such as Balb/c mice. These mice can be challenged with an infectious agent.
  • agent e.g., a bacterium such as Listeria monocytogenes after the administration of
  • test compound The ability of the test compound to stimulate the innate immune system.
  • immune response can be tested, for example, by measuring protection against infection with the infectious agent. For example, as described herein, three
  • the spleens can be removed and tested for
  • composition comprising a saponin
  • an oligonucleotide comprising at least one unmethylated CpG dinucleotide
  • Such a composition may be administered. More preferably, such a composition may increase the
  • the composition is administered.
  • the saponin is a saponin from Quillaja
  • the saponin is a partially pure or
  • substantially pure saponin from Quillaja saponaria Molina Preferably, the
  • partially pure saponin may comprise QS-7, QS-17, QS-18, and/or QS-21 and
  • the substantially pure saponin is QS-
  • the substantially pure saponin is
  • composition may comprise more than one saponin
  • oligonucleotide comprising at least one unmethylated CpG
  • the saponin may
  • chemically modified saponin or biologically active fraction thereof comprises at least
  • the oligonucleotide comprises at least one of QS-17, QS-18, QS-21, QS-21-V1, and QS-21-V2.
  • CpG dinucleotide comprising at least one unmethylated CpG dinucleotide is preferably a monomer or multimer.
  • Another preferred embodiment of the CpG motif is as
  • oligonucleotide comprising at least one unmethylated CpG dinucleotide
  • oligonucleotide is modified.
  • the particular modification may
  • oligonucleotide having at least one unmethylated CpG dinucleotide may
  • nucleotide separates consecutive CpGs, and wherein X. is adenine, guanine, or
  • X 2 is cytosine, thymine, or adenine.
  • the CpG motif may
  • TCCATGACGTTCCTGACGTT TCGTCGTTTTGTCGTTTTGTCGTT.
  • composition refers to a composition capable of
  • a composition according to the
  • composition comprising a saponin and an oligonucleotide comprising at least
  • one unmethylated CpG dinucleotide of the present invention may be any unmethylated CpG dinucleotide of the present invention.
  • the composition stimulates
  • composition enhances a protective agent.
  • composition of the invention comprising both saponin and CpG-
  • containing oligonucleotide may enhance the immune response, e.g., the innate
  • the innate immune response is natural killer cell response.
  • positive immune response is natural killer cell response.
  • the inventive composition e.g., a saponin plus a CpG-containing
  • composition of oligonucleotide plus saponin described herein may be
  • the invention is directed to a method for increasing
  • oligonucleotide comprising at least one unmethylated CpG
  • the saponin is a saponin from Quillaja saponaria
  • the saponin is a partially pure or a substantially pure
  • the method may also embody a
  • composition comprising more than one substantially pure saponin and an
  • oligonucleotide comprising at least one unmethylated CpG dinucleotide.
  • substantially pure saponin is preferably QS-7, QS-17, QS-18, or QS-21.
  • the substantially pure saponin is QS-21.
  • the substantially pure saponin is QS-21.
  • the saponin may cover a chemically modified saponin or a
  • the oligonucleotide In a preferred embodiment of the method, the oligonucleotide
  • CpG motif is preferably a monomer or a multimer.
  • Another preferred embodiment of the method includes the CpG motif as a part
  • Yet another embodiment is directed to the method
  • oligonucleotide comprises at least one unmethylated CpG
  • oligonucleotide may be chemically
  • the modification may comprise at least one phosphorothioate internucieotide
  • the method may be directed, in part, to the oligonucleotide
  • X. is adenine, guanine, or thymine, and X 2 is
  • CpG motif is TCTCCCAGCGTGCGCCAT, TCCATGACGTTCCTGACGTT, or
  • a third aspect of the invention provides for methods for stimulating
  • composition comprising a saponin to an individual.
  • saponin is derived from Quillaja saponaria, and more
  • the saponin is chemically modified or comprises a substantially
  • pure saponin comprises QS-7, QS-17, QS-18, or QS-21, and more preferably, the
  • substantially pure saponin comprises QS-21.
  • third aspect of the invention preferably further increases an innate immune
  • Still another preferred embodiment is directed to the method for further enhancing a natural killer cell
  • inventions include, but are not limited to, those caused by hepatitis type A,
  • hepatitis type B hepatitis type B
  • hepatitis type C feline leukemia virus
  • immunodeficiency virus influenza, varicella, adenovirus, herpes simplex type
  • HSV-I herpes simplex type II
  • rinderpest herpes simplex type II
  • vhinovirus echovirus
  • rotavirus respiratory syncytial virus
  • papilloma virus papova virus
  • cytomegalovirus echinovirus
  • arbovirus huntavirus
  • coxsachie virus mumps
  • virus measles virus, rubella virus, polio virus, human immunodeficiency virus
  • H ⁇ V-I human immunodeficiency virus type II
  • HIV-II human immunodeficiency virus type II
  • rabies virus
  • Bacterial diseases than can be treated or prevented by methods of the
  • present inventions are caused by bacteria including, but not limited to,
  • mycobacteria rickettsia mycoplasma, neisseria, legionella, Yersinia, Helobacter
  • the present invention are caused by protozoa including, but not limited to,
  • present invention are caused by parasites including, but not limited to,
  • cancers may include
  • sarcomas include, but not limited to, human sarcomas and carcinomas, e.g.,
  • fibrosarcoma myxosarcoma, liposarcoma, chondrosarcoma, osteogenic
  • sarcoma chordoma
  • angiosarcoma endotheliosarcoma
  • lymphangiosarcoma lymphangiosarcoma
  • lymphangioendotheliosarcoma synovioma
  • mesothelioma mesothelioma
  • Ewing's tumor
  • breast cancer ovarian cancer, prostate cancer, squamous cell carcinoma, basal
  • carcinoma papillary carcinoma
  • papillary adenocarcinomas
  • cystadenocarcinoma medullary carcinoma, bronchogenic carcinoma, renal cell
  • carcinoma hepatoma, bile duct carcinoma, choriocarcinoma, seminoma,
  • carcinoma small cell lung carcinoma, bladder carcinoma, epithelial carcinoma,
  • glioma astrocytoma, medulloblastoma, craniopharyngioma, ependymoma,
  • pinealoma pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma,
  • lymphocytic leukemia and acute myelocytic leukemia (myeloblastic,
  • leukemia chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia
  • polycythemia vera lymphoma
  • the cancer is metastatic. In another specific embodiment the cancer is metastatic. In another specific
  • the patient having a cancer is immunosuppressed by reason of
  • anticancer therapy e.g., chemotherapy radiation
  • compositions of the invention administration of the compositions of the invention.
  • administration of the compositions of the invention administration of the compositions of the invention.
  • the cancer is a tumor.
  • the saponins and oligonucleotides comprising at least one
  • compositions suitable for administration Such compositions typically include
  • oligonucleotide comprising at least one
  • antifungal agent isotonic and absorption delaying agents, and the like,
  • compositions can also be incorporated into the compositions.
  • a pharmaceutical composition of the invention is formulated to be
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous,
  • oral e.g., inhalation
  • transdermal topical
  • transmucosal transmucosal
  • subcutaneous application can include the following components: a sterile
  • diluent such as water for injection, saline solution, fixed oils, polyethylene
  • glycols glycerine, propylene glycol or other synthetic solvents
  • antibacterial antibacterial
  • antioxidants such as ascorbic
  • chelating agents such as ethylenediaminetetraacetic
  • buffers such as acetates, citrates or phosphates and agents for the
  • tonicity such as sodium chloride or dextrose. pH can be adjusted
  • acids or bases such as hydrocholoric acid or sodium hydroxide.
  • parenteral preparation can be enclosed in ampoules, disposable syringes or
  • compositions suitable for injectable use include sterile
  • suitable carriers include physiological saline,
  • PBS buffered saline
  • microorganisms such as bacteria and fungi.
  • carrier also can be a solvent or dispersion medium containing, for example,
  • polyvinyl pyrolidone polyvinyl pyrolidone
  • calcium carbonate carbohydrates such as lactose
  • PEG polyethylene glycol
  • antifungal agents for example, paragens, chlorobutanol, phenol, ascorbic acid,
  • agents for example, sugars, polyalcohols such as manitol, sorbitol, sodium
  • compositions can be brought about by including in the composition an agent
  • Sterile injectable solutions can be prepared by incorporating the active
  • dispersions are prepared by incorporating the active
  • Oral compositions generally include an inert diluent or an edible carrier.
  • the active compound can be any substance purpose of oral therapeutic administration.
  • the active compound can be any substance purpose of oral therapeutic administration.
  • Oral compositions can also be prepared using a fluid carrier for use
  • binding agents and /or adjuvant materials can be included as part of the
  • composition The tablets, pills, capsules, troches and the like can contain any of
  • a binder such as
  • microcrystalline cellulose cellulose, gum tragacanth or gelatin
  • excipient such as
  • starch or lactose a disintegrating agent such as alginic acid, Primogel, or corn
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as
  • colloidal silicon dioxide a sweetening agent such as sucrose or saccharin; or a
  • flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • the compounds are delivered in the
  • a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
  • Systemic administration can also be by transmucosal or transdermal
  • penetrants for transmucosal or transdermal administration, penetrants
  • penetrants are generally known in the art, and include, for example, for
  • transmucosal administration detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compounds for transdermal administration, the active compounds
  • the compounds can also be prepared in the form of suppositories (e.g.
  • suppository bases such as cocoa butter and other glycerides
  • the active compounds are prepared with carriers
  • Biodegradable, biocompatible polymers can be used, such as
  • Liposomal suspensions including liposomes targeted to infected cells
  • Dosage unit form as used herein refers to physically discrete units
  • each unit containing a
  • Toxicity and therapeutic efficacy of such compounds can be determined
  • mice e.g., for determining the LD50 (the dose lethal to 50% of the
  • the ED50 the dose therapeutically effective in 50% of the
  • therapeutic index and it can be expressed as the ratio LD50/ED50.
  • the dosage may vary within this
  • the therapeutically effective dose can be estimated initially from
  • dosage required to effectively treat a subject including, but not limited to, the severity of the disease or disorder, previous treatments, the general health
  • booster dosages may also be included.
  • inert acceptable carrier may preferably be used or any such acceptable carrier
  • compositions of the present invention have suitable solubility
  • composition will be dependent on a number of factors, including the route of
  • the drug is an amount which elicits or boosts an innate immune response.
  • Dosages for a particular individual may be determined by a person of ordinary
  • the invention also provides kits for carrying out the therapeutic
  • kits comprise in one or more containers
  • inventions may be in the form of a pharmaceutically acceptable solution, e.g., in
  • composition may be any pharmaceutically acceptable sterile fluid.
  • the composition may be any pharmaceutically acceptable sterile fluid.
  • the composition may be any pharmaceutically acceptable sterile fluid.
  • the composition may be any pharmaceutically acceptable sterile fluid.
  • kit optionally further
  • a pharmaceutically acceptable solution e.g., saline
  • dextrose solution preferably sterile
  • a kit of the invention further comprises a needle
  • composition preferably packaged in sterile form, for injecting the composition
  • composition administration of the composition by a clinician or by a patient.
  • cytokines Various cytokines, antibiotics, and other bioactive agents also may be co-reactive agents.
  • compositions described herein are administered with the compositions described herein.
  • various combinations of the compounds described herein are administered with the compositions described herein.
  • various combinations of the compounds described herein are administered with the compositions described herein.
  • interleukin-l ⁇ IL-l
  • IL-l ⁇ interleukin-l ⁇
  • IL-l ⁇ interleukin-l ⁇
  • IL-l ⁇ interleukin-l ⁇
  • IL-2 interleukin-3
  • IL-4 interleukin-4
  • IL-5 interleukin-5
  • interleukin-6 interleukin-6
  • interleukin-7 interleukin-7
  • interleukin-8 interleukin-8
  • interleukin-9 interleukin-9
  • interleukin-10 interleukin-10
  • IL-11 inter leukin- 11
  • INF ⁇ interferon- ⁇
  • interferon- ⁇ interferon- ⁇
  • INF ⁇ interferon- ⁇
  • tumor necrosis factor a tumor necrosis factor a
  • necrosis factor ⁇ TNF ⁇
  • G-CSF granulocyte colony stimulating factor
  • GM-CSF granulocyte/macrophage colony stimulating factor
  • TGF- ⁇ transforming growth factor ⁇
  • composition in order to maximize the physiological response.
  • immunostimulatory CpG sequence e.g., 1826
  • oligodeoxynucleotides included the phosphorothiate-modified sequences 1826
  • ATCC American Type Culture Collection
  • mice (4 per group, female, 8-10 weeks of age) were tested.
  • compositions evaluated were (1) saline (negative control), (2) 10 ug QS-21, (3)
  • test compositions were administered subcutaneously except for
  • YAC-1 cells loaded with 51 Cr were used as target cells. The lysis of this NK
  • mice 5 per group, female, 8-10
  • mice at day 0 for use as effector cells in the natural killer cell assay.
  • YAC-1 cells loaded with 51 Cr were used as target cells.
  • mice (5 per group, female, 8-10 weeks of age) were administered
  • compositions evaluated were (1) saline (negative control), (2)
  • QS-21, QS-7, and CpG sequence 1826 enhance NK activity in a dose
  • mice (5 per group, female, 8-10 weeks of age) were administered
  • Group 2 10 ug QS-21 and 10 ug of CpG sequence 1826, subcutaneous route.
  • Group 3 10 ug QS-21, subcutaneous route.
  • Group 4 10 ug CpG sequence
  • Group 5 0.5 ug recombinant murine IL-12,
  • mice were challenged by the intraperitoneal route with 10 5 colonies of Listeria monocytogenes strain 10403s. Spleens were removed at 96 hours after challenge,
  • Figure 5 is a graphic representation showing the results of the challenge.
  • the group with the highest spleen colony count was the group receiving saline

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Abstract

L'invention se rapporte à des compositions comportant des oligonucléotides comprenant au moins un dinucléotide de CpG (cytosine-guanine) non méthylé et une saponine, ainsi qu'à l'utilisation de ces compositions pour stimuler l'immunité naturelle et renforcer l'activité des cellules tueuses naturelles.
PCT/US2001/001046 2000-01-13 2001-01-12 Compositions de stimulation de l'immunite naturelle a base de cpg et de saponine et procedes correspondants Ceased WO2001051083A2 (fr)

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JP2001551506A JP2003527352A (ja) 2000-01-13 2001-01-12 Ｃｐｇおよびサポニンの自然免疫刺激化合物、ならびにそれらの方法
EP01902032A EP1250150A2 (fr) 2000-01-13 2001-01-12 Compositions de stimulation de l'immunite naturelle a base de cpg et de saponine et procedes correspondants
AU27877/01A AU781812B2 (en) 2000-01-13 2001-01-12 Innate immunity-stimulating compositions of CPG and saponin and methods thereof
CA002397374A CA2397374A1 (fr) 2000-01-13 2001-01-12 Compositions de stimulation de l'immunite naturelle a base de cpg et de saponine et procedes correspondants

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WO2001051083A3 (fr) 2002-01-03
AU781812B2 (en) 2005-06-16

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