WO1998055495B1 - Immunostimulatory oligonucleotides, compositions thereof and methods of use thereof - Google Patents

Immunostimulatory oligonucleotides, compositions thereof and methods of use thereof

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Publication number
WO1998055495B1
WO1998055495B1 PCT/US1998/011578 US9811578W WO9855495B1 WO 1998055495 B1 WO1998055495 B1 WO 1998055495B1 US 9811578 W US9811578 W US 9811578W WO 9855495 B1 WO9855495 B1 WO 9855495B1
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WO
WIPO (PCT)
Prior art keywords
immunomodulatory
immune response
immunomodulatory composition
iss
antigen
Prior art date
Application number
PCT/US1998/011578
Other languages
French (fr)
Other versions
WO1998055495A2 (en
WO1998055495A3 (en
Inventor
David Schwartz
Mark Roman
Dino Dina
Original Assignee
Dynavax Tech Corp
David Schwartz
Mark Roman
Dino Dina
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=21956478&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO1998055495(B1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Dynavax Tech Corp, David Schwartz, Mark Roman, Dino Dina filed Critical Dynavax Tech Corp
Priority to AT98926311T priority Critical patent/ATE252596T1/en
Priority to AU78178/98A priority patent/AU753172B2/en
Priority to CA2291483A priority patent/CA2291483C/en
Priority to EP98926311A priority patent/EP0986572B2/en
Priority to JP50288499A priority patent/JP4101888B2/en
Priority to DE69819150T priority patent/DE69819150T3/en
Publication of WO1998055495A2 publication Critical patent/WO1998055495A2/en
Publication of WO1998055495A3 publication Critical patent/WO1998055495A3/en
Publication of WO1998055495B1 publication Critical patent/WO1998055495B1/en
Priority to HK00102617A priority patent/HK1024701A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4702—Regulators; Modulating activity
    • C07K14/4703—Inhibitors; Suppressors
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    • 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
    • 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
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
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    • 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
    • C12N2310/11—Antisense
    • C12N2310/111—Antisense spanning the whole gene, or a large part of it
    • 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
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    • 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
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/315—Phosphorothioates
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    • C12N2310/00—Structure or type of the nucleic acid
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    • C12N2310/334—Modified C
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/35—Nature of the modification
    • C12N2310/351—Conjugate
    • C12N2310/3513—Protein; Peptide
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention relates to immunostimulatory oligonucleotide compositions. These oligonucleotides comprise an immunostimulatory octanucleotide sequence. These oligonucleotides can be administered in conjunction with an immunostimulatory peptide or antigen. Methods for modulating an immune response upon administration of the oligonucleotide are also disclosed. In addition, an in vitro screening method to identify oligonucleotides with immunostimulatory activity is provided.

Claims

AMENDED CLAIMS[received by the International Bureau on 26 May 1999 (26.05.99); original claims 1-70 replaced by amended claims 1-80 (7 pages)]
1. An immunomodulatory oligonucleotide comprising an immunostimulatory sequence
(ISS), wherein the ISS comprises an octanucleotide sequence selected from the group consisting of GACGCTCC; GACGCCC; AGCGTTCC; AGCGCTCC; AGCGTCCC; AGCGCCCC; AACGTCCC AACGCCCC; GGCGTTCC; GGCGCTCC; GGCGTCCC; GGCGCCCC; GACGCTCG; GACGTCCG GACGCCCG; AGCGTTCG; AGCGTCCG; AGCGCCCG; AACGTCCG; AACGCCCG; GGCGTTCG GGCGCTCG; GGCGTCCG; GGCGCCCG.
2. An immunomodulatory oligonucleotide comprising the sequence of SEQ ID NO:2.
3. An immunomodulatory oligonucleotide comprising the sequence of SEQ ID NO:4.
4. An immunomodulatory oligonucleotide comprising the sequence of SEQ ID NO:1.
5. An immunomodulatory oligonucleotide comprising the sequence of SEQ ID NO:6.
6. An immunomodulatory oligonucleotide comprising the sequence of SEQ ID NO:7.
7. An immunomodulatory oligonucleotide comprising the sequence of SEQ ID NO: 12.
8. An immunomodulatory oligonucleotide comprising the sequence of SEQ ID NO: 15.
9. An immunomodulatory oligonucleotide comprising the sequence of SEQ ID NO:16.
10. The immunomodulatory oligonucleotide of claim 1 , wherein at least one cytosine of the octanucleotide sequence is substituted with a modified cytosine.
11. An immunomodulatory oligonucleotide of claim 10, wherein the modified cytosine comprises an addition of an electron-withdrawing group at least to C-5.
12. An immunomodulatory oligonucleotide of claim 10, wherein the modified cytosine comprises an addition of an electron-withdrawing group at least to C-6.
13. An immunomodulatory oligonucleotide of claim 10, wherein the modified cytosine is a 5'-bromocytidine.
14. An immunomodulatory oligonucleotide of claim 10, wherein the C at the third position from the 5' end of the octanucleotide is substituted with a 5'-bromocytidine.
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15. An immunomodulatory oligonucleotide of claim 10, wherein the C at the third position from the 5' end of the ISS octanucleotide is substituted with a 5'-bromocytidine and the C at the seventh position from the 5' end of the ISS octanucleotide is substituted with a 5'-bromocytidine.
16. An immunomodulatory composition comprising an immunomodulatory oligonucleotide according to claim 1 ;
and further comprising an antigen.
17. An immunomodulatory composition of claim 16, wherein the antigen is selected from the group consisting of peptides, glycoproteins, polysaccharides, and lipids.
18. An immunomodulatory composition of claim 16, wherein the antigen is conjugated to the immunomodulatory oligonucleotide.
19. An immunomodulatory composition comprising an immunomodulatory oligonucleotide according to claim 1; and further comprising a facilitator selected from the group consisting of co-stimulatory molecules, cytokines, chemokines, targeting protein ligand, a trans-activating factor, a peptide, and a peptide comprising a modified amino acid.
20. An immunomodulatory composition of claim 19, wherein the facilitator is conjugated to the immunomodulatory oligonucleotide.
21. An immunomodulatory composition comprising an immunomodulatory oligonucleotide according to claim 1; and further comprising an antigen; and further comprising an adjuvant.
22. An immunomodulatory composition of claim 21, wherein the antigen is selected from the group consisting of peptides, glycoproteins, polysaccharides, and lipids.
23. An immunomodulatory composition of claim 21, wherein the antigen is conjugated to the immunomodulatory oligonucleotide.
24. An immunomodulatory composition comprising a polynucleotide comprising an immunostimulatory sequence (ISS) and an antigen, wherein the ISS comprises 5'-cytosine, guanine-3', and wherein the ISS and the antigen are not conjugated and are proximately associated at a distance effective to enhance an immune response compared to co-administration of the ISS and antigen in solution.
25. The immunomodulatory composition of claim 24, wherein the ISS comprises a palindromic region, and wherein the palindromic region comprises the sequence 5'-cytosine, guanine-3'.
26. The immunomodulatory composition of claim 25, wherein the ISS comprises 5'-purine, purine, cytosine, guanine, pyrimidine, pyrimidine-3'.
27. The immunomodulatory composition of claim 26, wherein the ISS comprises a sequence selected from the group consisting of AACGTT, AGCGTT, GACGTT, GGCGTT, AACGTC, AGCGTC, GACGTC, GGCGTC, AACGCC, AGCGCC, GACGCC, GGCGCC, AACGCT, AGCGCT, GACGCT, and GGCGCT.
28. The immunomodulatory composition of claim 26, wherein the ISS is selected from the group consisting of GACGCTCC; GACGCCC; AGCGTTCC; AGCGCTCC; AGCGTCCC AGCGCCCC; AACGTCCC; AACGCCCC; GGCGTTCC; GGCGCTCC; GGCGTCCC; GGCGCCCC GACGCTCG; GACGTCCG; GACGCCCG; AGCGTTCG; AGCGTCCG; AGCGCCCG; AACGTCCG AACGCCCG; GGCGTTCG; GGCGCTCG; GGCGTCCG; GGCGCCCG.
29. The immunomodulatory composition of claim 24, wherein the ISS and antigen are proximately associated by encapsulation.
30. The immunomodulatory composition of claim 29, wherein the encapsulation is within liposomes.
31. The immunomodulatory composition of claim 24, wherein the ISS and antigen are proximately associated by linkage to a platform molecule.
32. The immunomodulatory composition of claim 24, wherein the ISS and antigen are proximately associated at a distance from about 0.04 μm to about 100 μm.
33. The immunomodulatory composition of claim 32, wherein the distance is from about 0.1 μm to about 20 μm.
34. The immunomodulatory composition of claim 33, wherein the distance is from about 0.15 μm to about 10 μm.
35. The immunomodulatory composition of claim 24, wherein the ISS and antigen are proximately associated such that the ISS and the antigen are co-delivered to an immune target.
36. The immunomodulatory composition of claim 35, wherein the immune target is a lymphatic structure.
37. An immunomodulatory composition of claim 35, wherein the immune target is a antigen presenting cell.
38. An immunomodulatory composition of claim 37, wherein the antigen presenting cell is a dendritic cell.
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39. An immunomodulatory composition of claim 37, wherein the antigen presenting cell is a macrophage cell.
40. An immunomodulatory composition of claim 37, wherein the antigen presenting cell is a lymphocyte.
41. The immunomodulatory composition of claim 24, further comprising an adjuvant.
42. The immunomodulatory composition of claim 40, wherein the ISS and antigen are proximately associated by encapsulation.
43. The immunomodulatory composition of claim 40, wherein the ISS and antigen are proximately associated by linkage to a platform molecule.
44. A method of modulating an immune response in an individual comprising administering the immunomodulatory oligonucleotide of claim 1 to the individual in an amount sufficient to modulate the immune response.
45. The method of claim 44, wherein the modulating of an immune response comprises induction of a Th1 response.
46. A method of modulating an immune response in an individual comprising administering to the individual the immunomodulatory oligonucleotide of SEQ ID NO:2 in an amount sufficient to modulate the immune response.
47. The method of claim 46, wherein the modulating of an immune response comprises induction of a Th1 response.
48. A method of modulating an immune response in an individual comprising administering the immunomodulatory composition of claim 16 to the individual in an amount sufficient to modulate the immune response.
49. The method of claim 48, wherein the modulating of an immune response comprises induction of a Th1 response.
50. A method of modulating an immune response in an individual comprising the administration of an immunomodulatory composition according to claim 18 in an amount sufficient to modulate the immune response.
51. The method of claim 50, wherein the modulating of an immune response comprises induction of a Th1 response.
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52. A method of modulating an immune response in an individual comprising the administration of an immunomodulatory composition according to claim 21 in an amount sufficient to modulate the immune response.
53. The method of claim 52, wherein the modulating of an immune response comprises induction of a Th1 response.
54. A method of modulating an immune response in an individual comprising the administration of an immunomodulatory composition according to claim 24 in an amount sufficient to modulate the immune response.
55. The method of claim 54, wherein the modulating of an immune response comprises induction of a Th1 response.
56. A method of modulating an immune response in an individual comprising the administration of an immunomodulatory composition according to claim 28 in an amount sufficient to modulate the immune response.
57. The method of claim 56 wherein the modulating of an immune response comprises induction of a Th1 response.
58. A method of modulating an immune response in an individual comprising the administration of an immunomodulatory composition according to claim 41 in an amount sufficient to modulate the immune response.
59. The method of claim 58 wherein the modulating of an immune response comprises induction of a Th1 response.
60. A method according to claim 44, wherein the individual is suffering from a disorder selected from the group consisting of cancer, allergic disease, asthma and an infectious disease.
61. A method according to claim 60, wherein the infectious disease is caused by a virus selected from the group consisting of hepatitis B virus, papillomavirus and human immunodeficiency virus.
62. A method of preventing an infectious disease in an individual comprising administration of an immunomodulatory composition according to claim 16.
63. A method according to claim 62, wherein the infectious disease is due to a viral infection.
64. A method according to claim 63, wherein the virus is selected from the group consisting of hepatitis B virus, influenza virus, herpes virus, human immunodeficiency virus and papillomavirus.
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65. A method according to claim 62, wherein the infectious disease is due to a bacterial infection.
66. A method according to claim 65, wherein the bacteria is selected from the group consisting of Hemophilus influenza, Mycobacterium tuberculosis and Bordetella pertussis.
67. A method according to claim 62, wherein the infectious disease is due to a parasitic infection.
68. A method according to claim 67, wherein the parasitic agent is selected from a group consisting of malarial plasmodia, Leishmania species, Trypanosoma species and Schistosoma species.
69. A method of preventing an infectious disease in an individual comprising administration of an immunomodulatory composition according to claim 2.
70. A method of preventing an infectious disease in an individual comprising administration of an immunomodulatory composition according to claim 18.
71. A method of preventing an infectious disease in an individual comprising administration of an immunomodulatory composition according to claim 21.
72. A method of preventing an infectious disease in an individual comprising administration of an immunomodulatory composition according to claim 24.
73. A method of modulating an immune response comprising the administration of an immunomodulatory composition according to claim 28.
74. A method to screen for human immunostimulatory activity of oligonucleotides comprising the steps of:
(a) providing macrophage cells and an aliquot of an oligonucleotide to be tested;
(b) incubating the cells and oligonucleotide of step a) for an appropriate length of time;
(c) determining the relative amount of Th1 -biased cytokines in the cell culture supernatant.
75. A method to screen for human immunostimulatory activity of oligonucleotides according to claim 74, wherein the cells are selected from the 90196B cell line and the P388D1 cell line.
76. A method to screen for human immunostimulatory activity of oligonucleotides according to claim 74, wherein at least one of the Th1-biased cytokines determined is interferon-gamma.
77. A method to screen for human immunostimulatory activity of oligonucleotides according to claim 74, wherein at least one of the Th1-biased cytokines determined is interleukin-12.
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78. An immunomodulatory composition comprising a polynucleotide comprising (a) an immunostimulatory sequence (ISS); (b) an antigen; and (c) an adjuvant other than alum, wherein the ISS comprises 5'-cytosine, guanine-3', wherein the ISS and antigen are not conjugated, and wherein the adjuvant is in an amount sufficient to enhance an immune response compared to co- administration of the ISS and antigen without adjuvant.
79. The immunomodulatory composition of claim 78, wherein the ISS comprises a palindromic region, and wherein the palindromic region comprises the sequence 5'-cytosine, guanine-3'.
80. A method of modulating an immune response in an individual, comprising administering the composition of claim 78 in an amount sufficient to modulate the immune response.
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PCT/US1998/011578 1997-06-06 1998-06-05 Immunostimulatory oligonucleotides, compositions thereof and methods of use thereof WO1998055495A2 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
AT98926311T ATE252596T1 (en) 1997-06-06 1998-06-05 IMMUNO-STIMULATING OLIGONUCLEOTIDES, COMPOSITIONS THEREOF, AND METHODS OF USE THEREOF
AU78178/98A AU753172B2 (en) 1997-06-06 1998-06-05 Immunostimulatory oligonucleotides, compositions thereof and methods of use thereof
CA2291483A CA2291483C (en) 1997-06-06 1998-06-05 Immunostimulatory oligonucleotides, compositions thereof and methods of use thereof
EP98926311A EP0986572B2 (en) 1997-06-06 1998-06-05 Immunostimulatory oligonucleotides, compositions thereof and methods of use thereof
JP50288499A JP4101888B2 (en) 1997-06-06 1998-06-05 Immunostimulatory oligonucleotides, compositions thereof and methods of use thereof
DE69819150T DE69819150T3 (en) 1997-06-06 1998-06-05 IMMUNOSTIMULATING OLIGONUCLEOTIDES, COMPOSITIONS THEREOF, AND METHOD OF USE THEREOF
HK00102617A HK1024701A1 (en) 1997-06-06 2000-04-29 Immunostimulatory oligonucleotides, compositions thereof and methods of use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US4879397P 1997-06-06 1997-06-06
US60/048,793 1997-06-06

Publications (3)

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WO1998055495A2 WO1998055495A2 (en) 1998-12-10
WO1998055495A3 WO1998055495A3 (en) 1999-05-27
WO1998055495B1 true WO1998055495B1 (en) 1999-07-22

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PCT/US1998/011391 WO1998055609A1 (en) 1997-06-06 1998-06-05 Inhibitors of dna immunostimulatory sequence activity

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PCT/US1998/011391 WO1998055609A1 (en) 1997-06-06 1998-06-05 Inhibitors of dna immunostimulatory sequence activity

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US (4) US6225292B1 (en)
EP (3) EP1003850B1 (en)
JP (2) JP4280309B2 (en)
AT (2) ATE252596T1 (en)
AU (2) AU755322B2 (en)
CA (2) CA2291483C (en)
CY (1) CY1109287T1 (en)
DE (2) DE69819150T3 (en)
DK (1) DK1003850T3 (en)
ES (1) ES2326848T3 (en)
HK (1) HK1024701A1 (en)
PT (1) PT1003850E (en)
WO (2) WO1998055495A2 (en)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8372413B2 (en) 2000-12-27 2013-02-12 Dynavax Technologies Corporation Immunomodulatory polynucleotides and methods of using the same
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