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WO2007050059A2 - Oligonucleotides immunomodulateurs courts - Google Patents

Oligonucleotides immunomodulateurs courts Download PDF

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Publication number
WO2007050059A2
WO2007050059A2 PCT/US2005/038449 US2005038449W WO2007050059A2 WO 2007050059 A2 WO2007050059 A2 WO 2007050059A2 US 2005038449 W US2005038449 W US 2005038449W WO 2007050059 A2 WO2007050059 A2 WO 2007050059A2
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WO
WIPO (PCT)
Prior art keywords
ttctc
ctcttr
administering
immunostimulatory oligonucleotide
tcttr
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/US2005/038449
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English (en)
Other versions
WO2007050059A9 (fr
Inventor
Sudhir Agrawal
Ekambar R. Kandimalla
Dong Yu
Lakshmi Bhagat
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.)
Aceragen Inc
Original Assignee
Idera Pharmaceuticals Inc
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 Idera Pharmaceuticals Inc filed Critical Idera Pharmaceuticals Inc
Priority to PCT/US2005/038449 priority Critical patent/WO2007050059A2/fr
Publication of WO2007050059A2 publication Critical patent/WO2007050059A2/fr
Anticipated expiration legal-status Critical
Publication of WO2007050059A9 publication Critical patent/WO2007050059A9/fr
Ceased legal-status Critical Current

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Classifications

    • 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
    • C12N15/117—Nucleic acids having immunomodulatory properties, e.g. containing CpG-motifs
    • 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
    • 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
    • C12N2310/17—Immunomodulatory nucleic acids
    • 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
    • C12N2310/318—Chemical structure of the backbone where the PO2 is completely replaced, e.g. MMI or formacetal
    • C12N2310/3183—Diol linkers, e.g. glycols or propanediols
    • 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
    • C12N2310/32—Chemical structure of the sugar
    • 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
    • C12N2310/33—Chemical structure of the base
    • C12N2310/336—Modified G

Definitions

  • the invention relates to modulation of the immune system. More particularly, the invention relates to modulating the immune system through the use of oligonucleotide- derived compounds.
  • CpG dinucleotides in certain sequence contexts in bacterial and synthetic oligodeoxyribonucleotides (CpG DNAs) are known to activate vertebrate innate immune reaction, T-cells and B cells.
  • the invention provides immunostimulatory agents that are less expensive to make than existing immunostimulatory oligonucleotides.
  • the immunostimulatory agents according to the invention can, in preferred embodiments, cause immune stimulation across species lines.
  • the present inventors have discovered that short oligonucleotide-based agents that are linked together with appropriate linkers can be made inexpensively and can be designed to cause immune stimulation in multiple species.
  • the invention provides an immunostimulatory oligonucleotide having a structure from the group of 5'-TGTCR 5 TTCTC-X-CTCTTR 5 CTGT-S', 5'- GTCR'TTCTC-X-CTCTTR'CTG-5', 5'-TCR 5 TTCTC-X-CTCTTR'CT-5 5 , 5'- CRTCRTTG-X-GTTRCTRC-S 5 , S'-RTCRTTG-X-GTTRCTR-S', 5'-TCRTTG-X- GTTRCT-5', 5'-TGTCOR 5 TTCTC- X-CTCTTR'OCTGT-5', 5'-GTCORTTCTC-X- CTCTTR'OCTG-5 5 , S'-TCOR'TTCTC-X-CTCTTR'OCT-S', 5'-CRAACRTTCR-X- TCTTR 5 CTGTC-5 5 , S'-RAACRTTCR-X-TCTTR'CTGT-S
  • compositions comprise any one of the compositions disclosed in the first aspect of the invention and a pharmaceutically acceptable carrier.
  • the invention provides a method for generating an immune response in a vertebrate, the method comprising administering to the vertebrate an immunostimulatory oligonucleotide having a structure from the group of 5'- TGTCR'TTCTC-X-CTCTTR'CTGT-5', 5'-GTCR 5 TTCTC-X-CTCTTR 5 CTG-S', 5'- TCR'TTCTC-X-CTCTTR'CT-S 5 , 5 5 -CRTCRTTG-X-GTTRCTRC-5 5 , 5'-RTCRTTG-X- GTTRCTR-5', 5'-TCRTTG-X-GTTRCT-S 5 , 5' -TGTCOR' TTCTC-X-CTCTTR'OCTGT- 5', S'-GTCOR'TTCTC-X-CTCTTR'OCTG-S', 5'-TCOR 5 TTCTC-X-CTCTTROCT-S', 5'-CRAACRTTCR-X-TC
  • the invention provides a method for therapeutically treating a vertebrate having cancer, an autoimmune disorder, airway inflammation, inflammatory disorders, skin disorders, allergy, asthma or a disease caused by a pathogen, such method comprising administering to the patient an immunostimulatory oligonucleotide having a structure from the group of S'-TGTCR'TTCTC-X-CTCTTR'CTGT-S', 5'- GTCR'TTCTC-X-CTCTTR'CTG-5', 5'-TCR 5 TTCTC-X-CTCTTR 5 CT-S', 5'- CRTCRTTG-X-GTTRCTRC-5', 5'-RTCRTTG-X-GTTRCTR-S', 5'-TCRTTG-X- GTTRCT-5', S'-TGTCoR'TTCTC-X-CTCTTR'oCTGT-S', 5'-GTCORTTCTC-X- CTCTTR'oCTG-5', 5'-TCoR'TTCTCTCTC-X
  • the invention provides a method for preventing cancer, an autoimmune disorder, airway inflammation, inflammatory disorders, skin disorders, allergy, asthma or a disease caused by a pathogen in a vertebrate, such method comprising administering to the vertebrate an immunostimulatory oligonucleotide having a structure from the group of 5'-TGTCRTTCTC-X-CTCTTR 5 CTGT-S', 5'- GTCR , ⁇ c ⁇ c ⁇ _ CTCTTR , CTG _ 5 , ⁇ 5'. TCR ' TTCTCTC . ⁇ . CTCTTR ' CT _5' 5 5 '_
  • Figure 1 shows cytokine secretion profiles of IMO-I and its N-I, N-2, and N-3 analogs in mouse spleen cell cultures.
  • Figure 2 shows cytokine secretion profiles of IMO-5 and its N-I, N-2, and N-3 analogs in mouse spleen cell cultures.
  • Figure 3 shows cytokine secretion profiles of IMO-9 and its N-I, N-2, and N-3 analogs in mouse spleen cell cultures.
  • Figure 4 shows cytokine secretion profiles of IMO- 13 and its N-I, N-2, and N-3 analogs in mouse spleen cell cultures.
  • the invention relates to modulation of the immune system. More particularly, the invention relates to modulating the immune system through the use of oligonucleotide- derived compounds.
  • the patents and publications cited herein reflect the knowledge of those skilled in the art and are hereby incorporated by reference in their entirety. Any conflict between the teachings of such references and the instant specification shall be resolved in favor of the latter.
  • the invention provides immunostimulatory agents that are less expensive to make than existing immunostimulatory oligonucleotides.
  • the immunostimulatory agents according to the invention can, in preferred embodiments, cause immune stimulation across species lines.
  • the present inventors have discovered that short oligonucleotide-based agents that are linked together with appropriate linkers can be made inexpensively and can be designed to cause immune stimulation in multiple species.
  • the invention provides an immunostimulatory agent comprising two or more oligonucleotide branches linked together and having the structure: 5'-N n pYpRpN n p3'-L m -3'N n pRpYpN n -5'; wherein each N is independently selected from a nucleoside, a nucleoside analog; an arabinonucleoside, or an abasic sugar; each p is independently a natural or modified internucleoside linkage; at least one Y is selected from the group consisting of cytosine, 5-hydroxycytosine, N4-alkyl-cytosine, 4-thiouracil or other non-natural pyrimidine nucleoside or 2-oxo-7-deaza-8-methyl-purine, wherein when the base is 2-oxo-7-deaza-8-methyl-purine, it is covalently bound to the 1 '-position of a pentose via the 1 position of the base; at
  • Preferred internucleoside linkages include phosphodiester, phosphorothioate and methylphosphonate linkages.
  • sequences of specific short oligonucleotide-based agents within these general structures used in the present study include, but are not limited to, those shown in Table 1.
  • a “non-nucleotidic linker” includes, without limitation a linker selected from a linker having a length of from about 2 angstroms to about 200 angstroms, C2-C18 alkyl linker, ethylene glycol linker, poly(ethylene glycol) linker, 2-aminobutyl- 1 ,3 -propanediol linker, glyceryl linker and branched alkyl linkers, acyclic alkyl linker, cyclic alkyl linker, aryl or heteroaryl linker, heterocyclic linker, polyalcohol linker, peptide linker, lipid linker and carbohydrate linker, each of which may be substituted or non-substituted.
  • oligonucleotide refers to a polynucleoside formed from a plurality of linked nucleoside units. Such oligonucleotides can be obtained from existing nucleic acid sources, including genomic or cDNA, but are preferably produced by synthetic methods.
  • each nucleoside unit includes a heterocyclic base and a pentofuranosyl, 2'-deoxypentfuranosyl, trehalose, arabinose, 2'-deoxy-2'-substituted arabinose, 2'-0-substituted arabinose or hexose sugar group.
  • the nucleoside residues can be coupled to each other by any of the numerous known internucleoside linkages.
  • Such internucleoside linkages include, without limitation, phosphodiester, phosphorothioate, ' phosphorodithioate, alkylphosphonate, alkylphosphonothioate, phosphotriester, phosphoramidate, siloxane, carbonate, carboalkoxy, acetamidate, carbamate, morpholino, borano, thioether, bridged phosphoramidate, bridged methylene phosphonate, bridged phosphorothioate, and sulfone internucleoside linkages.
  • oligonucleotide also encompasses polynucleosides having one or more stereospecific internucleoside linkage (e.g., (Rp)- or (5p)-phosphorothioate, alkylphosphonate, or phosphotriester linkages).
  • the terms “oligonucleotide” and “dinucleotide” are expressly intended to include polynucleosides and dinucleosides having any such internucleoside linkage, whether or not the linkage comprises a phosphate group.
  • these internucleoside linkages may be phosphodiester, phosphorothioate, or phosphorodithioate linkages, or combinations thereof.
  • oligonucleotide also encompasses polynucleosides having additional substituents including, without limitation, protein groups, lipophilic groups, intercalating agents, diamines, folic acid, cholesterol and adamantane.
  • oligonucleotide also encompasses any other nucleobase containing polymer, including, without limitation, peptide nucleic acids (PNA), peptide nucleic acids with phosphate groups (PHONA), locked nucleic acids (LNA), morpholino-backbone oligonucleotides, and oligonucleotides having backbone sections with alkyl linkers or amino linkers.
  • PNA peptide nucleic acids
  • PONA peptide nucleic acids with phosphate groups
  • LNA locked nucleic acids
  • morpholino-backbone oligonucleotides oligonucleotides having backbone sections with alkyl linkers or amino linkers.
  • the oligonucleotides of the invention can include naturally occurring nucleosides, modified nucleosides, or mixtures thereof.
  • modified nucleoside is a nucleoside that includes a modified heterocyclic base, a modified sugar moiety, or a combination thereof.
  • the modified nucleoside is a non-natural pyrimidine or purine nucleoside, as herein described.
  • the modified nucleoside is a 2 ! -substituted ribonucleoside an arabinonucleoside or a 2'- deoxy-2' -substituted-arabinoside.
  • the term "2'-substituted ribonucleoside” or "2'- substituted arabinoside” includes ribonucleosides or arabinonucleoside in which the hydroxyl group at the 2' position of the pentose moiety is substituted to produce a 2'- substituted or 2'-0-substituted ribonucleoside.
  • substitution is with a lower alkyl group containing 1-6 saturated or unsaturated carbon atoms, or with an aryl group having 6-10 carbon atoms, wherein such alkyl, or aryl group may be unsubstituted or may be substituted, e.g., with halo, hydroxy, trifluoromethyl, cyano, nitro, acyl, acyloxy, alkoxy, carboxyl, carboalkoxy, or amino groups.
  • 2'-O-substituted ribonucleosides or 2'-O-substituted-arabinosides include, without limitation 2'-O- methylribonucleosides or 2'-O-methylarabinosides and 2'-O- methoxyethyMbonucleosides or 2'-O-methoxyethylarabinosides.
  • 2'-substituted ribonucleoside or "2 '-substituted arabinoside” also includes ribonucleosides or arabinonucleosides in which the 2'-hydroxyl group is replaced with a lower alkyl group containing 1-6 saturated or unsaturated carbon atoms, or with an amino or halo group.
  • Examples of such 2 '-substituted ribonucleosides or 2'- substituted arabinosides include, without limitation, 2'-amino, 2'-fluoro, 2'-allyl, and T- propargyl ribonucleosides or arabinosides.
  • oligonucleotide includes hybrid and chimeric oligonucleotides.
  • a "chimeric oligonucleotide” is an oligonucleotide having more than one type of internucleoside linkage.
  • One preferred example of such a chimeric oligonucleotide is a chimeric oligonucleotide comprising a phosphorothioate, phosphodiester or phosphorodithioate region and non-ionic linkages such as alkylphosphonate or alkylphosphonothioate linkages (see e.g., Pederson et al. U.S. Patent Nos. 5,635,377 and 5,366,878).
  • hybrid oligonucleotide is an oligonucleotide having more than one type of nucleoside.
  • One preferred example of such a hybrid oligonucleotide comprises a ribonucleotide or 2'-substituted ribonucleotide region, and a deoxyribonucleotide region (see, e.g., Metelev and Agrawal, U.S. Patent No. 5,652,355, 6,346,614 and 6,143,881).
  • compositions comprise any one of the compositions disclosed in the first aspect of the invention and a pharmaceutically acceptable carrier.
  • physiologically acceptable refers to a material that does not interfere with the effectiveness of the compositions of the first, third, fourth or fifth aspects of the invention and is compatible with a biological system such as a cell, cell culture, tissue, or organism, hi certain embodiments, the biological system is a living organism, such as a vertebrate.
  • carrier encompasses any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, or other material well known in the art for use in pharmaceutical formulations. It will be understood that the characteristics of the carrier, excipient, or diluent will depend on the route of administration for a particular application. The preparation of pharmaceutically acceptable formulations containing these materials is described in, e.g., Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, PA, 1990, ISBN: 0-912734-04-3.
  • compositions of the invention may be administered by any suitable route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, aerosol, intraocular, intratracheal, intrarectal, vaginal, by gene gun, dermal patch or in eye drop or mouthwash form.
  • Administration of the therapeutic compositions of immunostimulatory oligonucleotides can be carried out using known procedures at dosages and for periods of time effective to reduce symptoms or surrogate markers of the disease.
  • the therapeutic composition is preferably administered at a sufficient dosage to attain a blood level of immunostimulatory oligonucleotide from about 0.0001 micromolar to about 10 micromolar.
  • a total dosage of immunostimulatory oligonucleotide ranges from about 0.0001 mg per patient per day to about 200 mg per kg body weight per day. It may be desirable to administer simultaneously, or sequentially a therapeutically effective amount of one or more of the therapeutic compositions of the invention to an individual as a single treatment episode.
  • the invention provides a method for generating an immune response in a vertebrate.
  • the method according to this aspect of the invention comprises administering to the vertebrate an immunostimulatory oligonucleotide according to the first aspect of the invention.
  • the term "vertebrate” includes, without limitation, a fish, bird, or mammal.
  • the term “mammal” includes, without limitation rats, mice, cats, dogs, horses, cattle, cows, pigs, rabbits, non- human primates, and humans.
  • Modulating an immune response means causing an increase or decrease in, or activation of one or more of B-cell induction, T-cell induction, cytokine induction, natural killer cell induction, specific cell surface marker expression, chemokine induction and activation of antigen presenting cells, such as dendritic cells, monocytes and macrophages.
  • administration of the immunostimulatory oligonucleotide can be alone or in a pharmaceutical composition and can be by any suitable route as described previously.
  • the invention provides a method for treating a vertebrate having a disease or disorder.
  • the method according to this aspect of the invention comprises administering to the vertebrate an immunostimulatory oligonucleotide according to the first aspect of the invention.
  • the term "vertebrate" is as described previously.
  • administration of the immunostimulatory oligonucleotide can be alone or in a pharmaceutical composition and can be by any suitable route as described previously.
  • the disease or disorder to be treated is cancer, an autoimmune disorder, airway inflammation, inflammatory disorders, skin disorders, allergy, asthma or a disease caused by a pathogen.
  • Pathogens include bacteria, parasites, fungi, viruses, viroids and prions.
  • the invention provides a method for preventing cancer, an autoimmune disorder, airway inflammation, inflammatory disorders, skin disorders, allergy, asthma or a disease caused by a pathogen in a vertebrate.
  • the method according to this aspect of the invention comprises administering to the vertebrate an immunostimulatory oligonucleotide according to the first aspect of the invention.
  • the term "vertebrate" is as described previously.
  • administration of the immunostimulatory oligonucleotide can be alone or in a pharmaceutical composition and can be by any suitable route as described previously.
  • the immunostimulatory oligonucleotide can be administered in combination with any other agent useful for treating the disease or condition that does not diminish the immunostimulatory effect of the oligonucleotide.
  • the term "in combination with” means in the course of treating the same disease in the same patient, and includes administering the oligonucleotide and an agent in any order, including simultaneous administration, as well as any temporally spaced order, for example, from sequentially with one immediately following the other to up to several days apart.
  • Such combination treatment may also include more than a single administration of the oligonucleotide, and independently the agent.
  • the administration of the oligonucleotide and agent may be by the same or different routes.
  • the agent useful for treating the disease or condition includes, but is not limited to, vaccines, antigens, antibodies, cytotoxic agents, allergens, antibiotics, antisense oligonucleotides, chemotherapeutic agents, peptides, proteins, gene therapy vectors, DNA vaccines and/or adjuvants to enhance the specificity or magnitude of the immune response, or co-stimulatory molecules such as cytokines, chemokines, protein ligands, trans-activating factors, peptides and peptides comprising modified amino acids.
  • the agent can include DNA vectors encoding for antigen or allergen.
  • the oligonucleotides of the invention can variously act as adjuvants and/or produce direct immunostimulatory effects.
  • oligomers Immunostimulatory oligonucleotides were synthesized on a 1 to 2 ⁇ mole scale using ⁇ -cyanoethylphosphoramidites on a PerSeptive Biosystem' s 8990 Expedite DNA synthesizer according to the manufacturer's directions.
  • the phosphoramidites of dA, dG, dC, and T were obtained from PE Biosystems (Foster City, CA).
  • C3 -linker phosphoramidite was obtained from Glen Research Corporation (Sterling, VA).
  • Immunostimulatory oligonucleotides were synthesized on solid supports carrying DiDMT protected glyceryl linker obtained from ChemGenes (Wilmington, MA) using a parallel synthesis. Beaucage reagent (RJ.Chemicals, Orange, CA) was used as an oxidant to obtain the phosphorothioate backbone modification. Immunostimulatory oligonucleotides were deprotected using standard protocols, purified by HPLC, and dialyzed against USP quality sterile water for irrigation (Braun, Irving, CA). The Immunostimulatory oligonucleotides were lyophilized and dissolved again in distilled water and the concentrations were determined from UV absorbance at 260 nm.
  • All immunostimulatory oligonucleotides were characterized by CGE and MALDI-TOF mass spectrometry (Applied Biosystem's Voyager-DE STR Biospectrometry Workstation, Foster City, CA) for purity and molecular mass, respectively.
  • the purity of full-length immunostimulatory oligonucleotides ranged from 89-95% with the rest being shorter by one or two nucleotides (n-1 and n-2) as determined by CGE and/or denaturing PAGE.
  • All immunostimulatory oligonucleotides contained less than 0.075 EU/mL of endotoxin as determined by the Limulus assay (Bio-Whittaker, Walkersville, MD).
  • C57/BL6 spleen cells were cultured with indicated concentrations of compounds. After 24 hours the supernatants were collected and the levels of IL-12 and IL-6 were determined by ELISA. All immunostimulatory oligonucleotides showed a concentration- dependent induction of two typical cytokines, IL- 12 and IL-6 ( Figures 1-4).

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Abstract

L'invention concerne la modulation du système immunitaire et, plus particulièrement, la modulation du système immunitaire au moyen de composés dérivés d'oligonucléotides. L'invention concerne également des agents immunostimulants existants, lesdits agents immunostimulants de l'invention peuvent, dans des modes de réalisation préférés, entraîner une stimulation immunitaire dans des lignées d'espèces.
PCT/US2005/038449 2005-10-25 2005-10-25 Oligonucleotides immunomodulateurs courts Ceased WO2007050059A2 (fr)

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PCT/US2005/038449 WO2007050059A2 (fr) 2005-10-25 2005-10-25 Oligonucleotides immunomodulateurs courts

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WO2007050059A2 true WO2007050059A2 (fr) 2007-05-03
WO2007050059A9 WO2007050059A9 (fr) 2009-01-29

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11213593B2 (en) 2014-11-21 2022-01-04 Northwestern University Sequence-specific cellular uptake of spherical nucleic acid nanoparticle conjugates
US11433131B2 (en) 2017-05-11 2022-09-06 Northwestern University Adoptive cell therapy using spherical nucleic acids (SNAs)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11213593B2 (en) 2014-11-21 2022-01-04 Northwestern University Sequence-specific cellular uptake of spherical nucleic acid nanoparticle conjugates
US11433131B2 (en) 2017-05-11 2022-09-06 Northwestern University Adoptive cell therapy using spherical nucleic acids (SNAs)

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