WO2000006588B1 - STEREOISOMERS OF CpG OLIGONUCLEOTIDES AND RELATED METHODS - Google Patents

STEREOISOMERS OF CpG OLIGONUCLEOTIDES AND RELATED METHODS

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Publication number
WO2000006588B1
WO2000006588B1 PCT/US1999/017100 US9917100W WO0006588B1 WO 2000006588 B1 WO2000006588 B1 WO 2000006588B1 US 9917100 W US9917100 W US 9917100W WO 0006588 B1 WO0006588 B1 WO 0006588B1
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Prior art keywords
nucleotides
composition
nucleic acid
chirality
subject
Prior art date
Application number
PCT/US1999/017100
Other languages
French (fr)
Other versions
WO2000006588A1 (en
Inventor
Arthur M Krieg
Original Assignee
Univ Iowa Res Found
Cpg Immunopharmaceuticals Inc
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Publication date
Application filed by Univ Iowa Res Found, Cpg Immunopharmaceuticals Inc filed Critical Univ Iowa Res Found
Priority to EP99938843A priority Critical patent/EP1100807A1/en
Priority to JP2000562385A priority patent/JP2002521489A/en
Priority to AU53238/99A priority patent/AU764532B2/en
Priority to CA002333854A priority patent/CA2333854A1/en
Publication of WO2000006588A1 publication Critical patent/WO2000006588A1/en
Publication of WO2000006588B1 publication Critical patent/WO2000006588B1/en

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    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P37/04—Immunostimulants
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • 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
    • C12N2310/312—Phosphonates

Abstract

The interactions of nucleic acids with proteins can be selective for the R stereoisomer, the S stereoisomer, or can be stereoindependent. The present invention demonstrates that the S stereoisomer of CpG containing DNA is active in mediating the immune stimulatory effects of CpG DNA. The invention provides methods of use of a pure stereoisomer or of DNA enriched for this form for clinical applications for CpG DNA, such as vaccine adjuvants, immune activators for the prevention or treatment of retroviral, viral, parasitic or fungal diseases, or cancer immunotherapy, immunotherapy of allergic and asthmatic diseases, etc. The invention also provides methods of use for R stereoisomer DNA to oppose the immune stimulatory effects of CpG DNA. Such R stereoisomers are useful in the treatment of diseases such as Sepsis syndrome, intestinal inflammatory diseases, psoriasis, gingivitis, systemic lupus erythematosus and other autoimmune diseases.

Claims

-65-AMENDED CLAIMS[received by the International Bureau on 24 January 2000 (24.01.00);Original claims 1, 29, 35-39, 46, 47, 50-52, 54-56, 60, 74, 80 and 82 amended; remaining claims unchanged (13 pages)]
1. A composition comprising:
an immunostimulatory nucleic acid having a sequence including at least the following formula:
5' X, X2CGX3 X4 3*
wherein C is unmethylated, wherein Xi, X2, X3 and > are nucleotides, wherein at least two nucleotides have a phosphate backbone modification forming a chiral center and wherein a plurality of the chiral centers have S chirality.
2. The composition of claim 1, wherein X|X2 are nucleotides selected from the group consisting of: TpA, ApA, ApC, ApG, and GpG.
3. The composition of claim 1, wherein X3X» are nucleotides selected from the group consisting of: TpT, TpA, TpG, ApA, ApG, GpA, and CpA.
4. The composition of claim 1, wherein XιX2 are nucleotides selected from the group consisting of: TpT, TpG, ApT, GpC, CpC, CpT, TpC, GpT and CpG; X3 is a nucleotide selected from the group consisting of A and T and X* is a nucleotide, but wherein when X]X is TpC, GpT, or CpG, X3X» is not TpC, ApT or ApC.
5. The composition of claim 1, wherein the immunostimulatory nucleic acid is double stranded.
6. The composition of claim 1, wherein less than all of the nucleotides have a backbone modification.
7. The composition of claim 1, wherein less than all of the chiral centers have S chirality.
8. The composition of claim 1, wherein at least 50% of the nucleotides have backbone modifications. -66-
9. The composition of claim 1, wherein at least 75% of the nucleotides have backbone modifications.
10. The composition of claim 1, wherein at least 90% of the nucleotides have backbone modifications.
11. The composition of claim 1, wherein at least 60% of the chiral centers have S chirality.
12. The composition of claim 1, wherein at least 75% of the chiral centers have S chirality.
13. The composition of claim 1, wherein at least 90% of the chiral centers have S chirality.
14. The composition of claim 1, wherein the immunostimulatory nucleic acid is single stranded.
15. The composition of claim 1, wherein the immunostimulatory nucleic acid has a sequence including at least the following formula:
5' TCNTXιX2CGX3X 3'
wherein N is a nucleic acid sequence composed of from about 0-25 nucleotides.
16. The composition of claim 1, wherein the composition includes immunostimulatory nucleic acids having identical sequences.
17. The composition of claim 1 , wherein the composition includes immunostimulatory nucleic acids having at least two different sequences.
18. The composition of claim 17, wherein the at least two sequences include a B-cell activating sequence and an NK cell activating sequence.
19. The composition of claim 1, wherein the nucleic acid has less than or equal to 100 nucleotides. -67-
20. The composition of claim 1, wherein the nucleic acid has between 8 and 40 nucleotides.
21. The composition of claim 1, further comprising an antigen.
22. The composition of claim 1, further comprising a cytokine.
23. The composition of claim 22, wherein the cytokine is selected from the group consisting of GM-CSF, IL-4, IL-18, IFNα, TNFα, Flt3 ligand, and IL-3.
24. The composition of claim 1, further comprising an antiviral.
25. The composition of claim 1, further comprising an antibacterial.
26. The composition of claim 1 , further comprising a non-nucleic acid adjuvant.
27. The composition of claim 1, wherein the composition is formulated as a sustained release device.
28. The composition of claim 1, wherein the CpG formula is a palindrome.
29. A composition comprising:
a double stranded immunostimulatory nucleic acid having a sequence on one strand including at least the following formula:
5' X, X2CGX3 X4 3'
wherein C is unmethylated, wherein Xi, X2, X3 and X are nucleotides, wherein at least two nucleotides have a phosphate backbone modification forming a chiral center and wherein a plurality of the chiral centers have S chirality.
30. The composition of claim 29, wherein XιX2 are nucleotides selected from the group consisting of: GpT, GpG, GpA, ApA, ApT, ApG, CpT, CpA, CpG, TpA, TpT, and TpG.
31. The composition of claim 29, X3X» are nucleotides selected from the group consisting of: TpT, CpT, ApT, TpG, ApG, CpG, TpC, ApC, CpC, TpA, ApA, and CpA.
32. The composition of claim 29, wherein XιX are nucleotides selected from the group consisting of: GpT, GpG, GpA and ApA; and X-3X4 are nucleotides selected from the group consisting of: TpT, CpT and ApT.
33. The composition of claim 29, wherein less than all of the nucleotides have a backbone modification.
34. The composition of claim 29, wherein less than all of the chiral centers have S chirality.
35. A method of inducing an antigen-specific immune response in a subject comprising:
administering to a subject an antigen and an immunostimulatory nucleic acid having a sequence including at least the following formula:
Figure imgf000006_0001
wherein C is unmethylated, wherein Xi, X2, X3 and X4 are nucleotides, wherein at least two nucleotides have a phosphate backbone modification forming a chiral center and wherein a plurality of the chiral centers have S chirality, in an amount effective to induce an antigen- specific immune response.
36. A method for redirecting a subject's immune response from a Th2 to a Thl comprising:
administering to a subject an immunostimulatory nucleic acid having a sequence including at least the following formula:
5' X, X2CGX3 X 3' -69-
wherein C is unmethylated, wherein Xi, X2, X3 and X4 are nucleotides, wherein at least two nucleotides have a phosphate backbone modification forming a chiral center and wherein a plurality of the chiral centers have S chirality, in an amount effective to redirecting the subject's immune response from a Th2 to a Thl .
37. A method for treating asthma in a subject, comprising:
administering to an asthmatic subject an effective amount for treating asthma in the subject of an immunostimulatory nucleic acid having a sequence including at least the following formula: 5' X, X2CGX3 X4 3'
wherein C is unmethylated, wherein Xi, X2, X3 and X4 are nucleotides, wherein at least two nucleotides have a phosphate backbone modification forming a chiral center and wherein a plurality of the chiral centers have S chirality.
38. A method for desensitizing a subject against the occurrence of an allergic reaction in response to contact with an allergen, comprising administering to a subject an immunostimulatory nucleic acid having a sequence including at least the following formula:
5' X, X2CGX3 XA
wherein C is unmethylated, wherein Xi, X2, X3 and X4 are nucleotides, wherein at least two nucleotides have a phosphate backbone modification forming a chiral center and wherein a plurality of the chiral centers have S chirality.
39. A method for activating an immune cell, comprising:
isolating an immune cell from a subject,
contacting the immune cell with an effective amount to activate the immune cell of an immunostimulatory nucleic acid having a sequence including at least the following formula: -70-
5' X, X2CGX3 X4 3'
wherein C is unmethylated, wherein Xi, X2, X3 and t are nucleotides, wherein at least two nucleotides have a phosphate backbone modification forming a chiral center and wherein a plurality of the chiral centers have S chirality, and
readministering the activated immune cells to the subject.
40. The method of claim 39, wherein the immune cell is a lymphocyte.
41. The method of claim 40, further comprising contacting the immune cell with an antigen.
42. The method of claim 41 , wherein the antigen is selected from the group consisting of: a tumor antigen, a viral antigen, a bacterial antigen, and a parasitic antigen.
43. The method of claim 39, wherein the immune cell is a dendritic cell.
44. The method of claim 43, wherein the dendritic cell expresses a cancer antigen.
45. The method of claim 44, wherein the dendritic cell is exposed to the cancer antigen ex vivo.
46. A method for activating a dendritic cell, comprising:
contacting a dendritic cell with an effective amount to activate a dendritic cell of an immunostimulatory nucleic acid having a sequence including at least the following formula:
5' X, X2CGX3 X4 3*
wherein C is unmethylated, wherein Xi, X2, X3 and X4 are nucleotides, wherein at least two nucleotides have a phosphate backbone modification forming a chiral center and wherein a plurality of the chiral centers have S chirality. -71-
47. A method for treating a cancer, comprising:
administering to a subject having a cancer an effective amount for treating the cancer of an immunostimulatory nucleic acid having a sequence including at least the following formula:
5' Xi X2CGX3 ( 3'
wherein C is unmethylated, wherein Xi, X2, X3 and X4 are nucleotides, wherein at least two nucleotides have a phosphate backbone modification forming a chiral center and wherein a plurality of the chiral centers have S chirality.
48. The method of claim 47, wherein the method is method for increasing the responsiveness of a cancer cell to a cancer therapy and wherein the immunostimulatory nucleic acid is administered in conjunction with an anti-cancer therapy.
49. The method of claim 48, wherein the anti-cancer therapy is an antibody.
50. A method for enhancing recovery of bone marrow in a cancer therapy subject, comprising:
administering to a subject undergoing or having undergone cancer therapy which damages the bone marrow an effective amount for enhancing the recovery of bone marrow of an immunostimulatory nucleic acid having a sequence including at least the following formula:
5' X, X2CGX3 X4 3'
wherein C is unmethylated, wherein Xi, X2, X3 and X4 are nucleotides, wherein at least two nucleotides have a phosphate backbone modification forming a chiral center and wherein a plurality of the chiral centers have S chirality.
51. In a method for stimulating an immune response in a subject having a cancer, the method of the type involving antigen dependent cellular cytotoxicity (ADCC), the improvement comprising: -72-
administering to the subject an immunostimulatory nucleic acid having a sequence including at least the following formula:
5' X, X2CGX3 X4 3'
wherein C is unmethylated, wherein Xi, X2, X and t are nucleotides, wherein at least two nucleotides have a phosphate backbone modification forming a chiral center and wherein a plurality of the chiral centers have S chirality.
52. A method for inducing cytokine production in a subject comprising
administering to the subject an effective amount to induce a cytokine in the subject of an immunostimulatory nucleic acid having a sequence including at least the following formula:
Figure imgf000010_0001
wherein C is unmethylated, wherein Xi, X2, X3 and X4 are nucleotides, wherein at least two nucleotides have a phosphate backbone modification forming a chiral center and wherein a plurality of the chiral centers have S chirality.
53. The method of claim 52, wherein the cytokine is selected from the group consisting of 11-6, 11-12, IL18 TNF, IFN α and IFN-γ.
54. A method of stimulating natural killer cell lytic activity comprising
exposing a natural killer cell to an immunostimulatory nucleic acid to stimulate natural killer cell lytic activity, the immunostimulatory nucleic acid having a sequence including at least the following formula:
5' X, X2CGX3 X4 3'
wherein C is unmethylated, wherein Xi, X2, X3 and X4 are nucleotides, wherein at least two nucleotides have a phosphate backbone modification forming a chiral center and wherein a plurality of the chiral centers have S chirality. -73-.
55. A method of inducing a Thl-type immune response in a subject, comprising:
administering to the subject in order to induce a Thl immune response a combination of adjuvants, wherein the combination of adjuvants includes at least one immunostimulatory nucleic acid having a sequence including at least the following formula:
5' X| X CGX3 t 3'
wherein C is unmethylated, wherein X], X2, X3 and X4 are nucleotides, wherein at least two nucleotides have a phosphate backbone modification forming a chiral center and wherein a plurality of the chiral centers have S chirality, and at least one non- nucleic acid adjuvant, and wherein the combination of adjuvants is administered in an effective amount for inducing a Thl-type immune response.
56. A method for inducing a mucosal immune response, comprising:
administering to a mucosal surface of a subject an effective amount for inducing a mucosal immune response of an immunostimulatory nucleic acid having a sequence including at least the following formula:
5' X, X2CGX3 X4 3'
wherein C is unmethylated, wherein Xi, X2, X3 and X4 are nucleotides, wherein at least two nucleotides have a phosphate backbone modification forming a chiral center and wherein a plurality of the chiral centers have S chirality, and
exposing the subject to an antigen to induce the mucosal immune response.
57. The method of claim 56, wherein the antigen is not encoded in a nucleic acid vector.
58. The method of claim 56, wherein the antigen is encoded by a nucleic acid vector.
59. The method of claim 56, wherein the mucosal surface is selected from the group consisting of an oral, nasal, rectal, vaginal, and ocular surface. -74-
60. A composition comprising:
an immunoinhibitory nucleic acid having a sequence including at least the following formula:
5' X, X2CGX3 4 3'
wherein C is unmethylated, wherein Xi, X2, X3 and X4 are nucleotides, wherein at least two nucleotides have a phosphate backbone modification forming a chiral center and wherein a plurality of the chiral centers have R chirality.
61. The composition of claim 60, wherein XιX2 are nucleotides selected from the group consisting of: TpA, ApA, ApC, ApG, and GpG.
62. The composition of claim 60, X3 t are nucleotides selected from the group consisting of: TpT, CpT, TpA, TpG, ApA, ApG, GpA, and CpA.
63. The composition of claim 60, wherein XιX2 are nucleotides selected from the group consisting of: TpT, TpG, ApT, GpC, CpC, CpT, TpC, GpT and CpG; X3 is a nucleotide selected from the group consisting of A and T and j is a nucleotide, but wherein when XjX2 is TpC, GpT, or CpG, X3X4 is not TpC, ApT or ApC.
64. The composition of claim 60, wherein the immunoinhibitory nucleic acid is double stranded.
65. The composition of claim 60, wherein less than all of the nucleotides have a backbone modification.
66. The composition of claim 60, wherein less than all of the chiral centers have R chirality.
67. The composition of claim 60, wherein at least 50% of the nucleotides have backbone modifications.
68. The composition of claim 60, wherein at least 75% of the nucleotides have backbone modifications. -75-
69. The composition of claim 60, wherein at least 90% of the nucleotides have backbone modifications.
70. The composition of claim 60, wherein at least 60% of the chiral centers have R chirality.
71. The composition of claim 60, wherein at least 75% of the chiral centers have R chirality.
72. The composition of claim 60, wherein at least 90% of the chiral centers have R chirality.
73. The composition of claim 60, wherein the immunoinhibitory nucleic acid is single stranded.
74. A composition comprising:
a double stranded immunoinhibitory nucleic acid having a sequence on one strand including at least the following formula:
5' X, X2CGX3 X4 3'
wherein C is unmethylated, wherein Xi, X2, X3 and j are nucleotides, wherein at least two nucleotides have a phosphate backbone modification forming a chiral center and wherein a plurality of the chiral centers have R chirality.
75. The composition of claim 74, wherein X|X2 are nucleotides selected from the group consisting of: GpT, GpG, GpA, ApA, ApT, ApG, CpT, CpA, CpG, TpA,
TpT, and TpG.
76. The composition of claim 74, X3X4 are nucleotides selected from the group consisting of: TpT, CpT, ApT, TpG, ApG, CpG, TpC, ApC, CpC, TpA, ApA, and CpA. -76-
77. The composition of claim 74, wherein XιX2 are nucleotides selected from the group consisting of: GpT, GpG, GpA and ApA; and X3X4 are nucleotides selected from the group consisting of: TpT, CpT and ApT.
78. The composition of claim 74, wherein less than all of the nucleotides have a backbone modification.
79. The composition of claim 74, wherein less than all of the chiral centers have R chirality.
80. A method of preventing an immune response in a subject comprising:
administering to a subject having an excessive immune response an immunoinhibitory nucleic acid having a sequence including at least the following formula:
5' X, X2CGX3 X4 3'
wherein C is unmethylated, wherein Xi, X2, X3 and X4 are nucleotides, wherein at least two nucleotides have a phosphate backbone modification forming a chiral center and wherein a plurality of the chiral centers have R chirality, in an amount effective to prevent an immune response.
81. The method of claim 80, wherein the subject having an excessive immune response is a subject who has received an immune stimulating compound.
82. A method for treating a subject comprising:
administering to a subject having or at risk of having an inflammatory disease an immunoinhibitory nucleic acid having a sequence including at least the following formula:
5' X, X2CGX3 X4 3'
wherein C is unmethylated, wherein Xi, X2, X3 and X4 are nucleotides, wherein at least two nucleotides have a phosphate backbone modification forming a chiral center -77-
and wherein a plurality of the chiral centers have R chirality, in an amount effective to prevent induction of an immune response.
83. The method of claim 82, wherein the inflammatory disease is selected form the group consisting of inflammatory bowel disease, autoimmune disease, gingivitis, psoriasis, and sepsis.
84. The method of claim 1, wherein the nucleic acid has a sequence including at least the formula GTCGTX4.
85. A method for inducing antigen non-specific innate immune activation and broad spectrum resistance to infectious challenge
PCT/US1999/017100 1998-07-27 1999-07-27 STEREOISOMERS OF CpG OLIGONUCLEOTIDES AND RELATED METHODS WO2000006588A1 (en)

Priority Applications (4)

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EP99938843A EP1100807A1 (en) 1998-07-27 1999-07-27 STEREOISOMERS OF CpG OLIGONUCLEOTIDES AND RELATED METHODS
JP2000562385A JP2002521489A (en) 1998-07-27 1999-07-27 Stereoisomers of CpG oligonucleotides and related methods
AU53238/99A AU764532B2 (en) 1998-07-27 1999-07-27 Stereoisomers of CpG oligonucleotides and related methods
CA002333854A CA2333854A1 (en) 1998-07-27 1999-07-27 Stereoisomers of cpg oligonucleotides and related methods

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US60/094,370 1998-07-27

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Cited By (7)

* 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
US8993542B2 (en) 2008-01-25 2015-03-31 Chimerix Inc. Methods of treating viral infections
US9006218B2 (en) 2010-02-12 2015-04-14 Chimerix Inc. Nucleoside phosphonate salts
US9028845B2 (en) 2001-06-21 2015-05-12 Dynavax Technologies Corporation Chimeric immunomodulatory compounds and methods of using the same-IV
US9278135B2 (en) 2010-04-26 2016-03-08 Chimerix Inc. Methods of treating retroviral infections and related dosage regimes
US9382545B2 (en) 2006-09-27 2016-07-05 Coley Pharmaceutical Gmbh CpG oligonucleotide analogs containing hydrophobic T analogs with enhanced immunostimulatory activity
US9528088B2 (en) 2002-06-28 2016-12-27 Life Technologies Corporation Methods for eliminating at least a substantial portion of a clonal antigen-specific memory T cell subpopulation

Families Citing this family (74)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6239116B1 (en) 1994-07-15 2001-05-29 University Of Iowa Research Foundation Immunostimulatory nucleic acid molecules
US6207646B1 (en) 1994-07-15 2001-03-27 University Of Iowa Research Foundation Immunostimulatory nucleic acid molecules
US20030026782A1 (en) 1995-02-07 2003-02-06 Arthur M. Krieg Immunomodulatory oligonucleotides
US7935675B1 (en) 1994-07-15 2011-05-03 University Of Iowa Research Foundation Immunostimulatory nucleic acid molecules
EP0855184A1 (en) 1997-01-23 1998-07-29 Grayson B. Dr. Lipford Pharmaceutical composition comprising a polynucleotide and an antigen especially for vaccination
US6406705B1 (en) 1997-03-10 2002-06-18 University Of Iowa Research Foundation Use of nucleic acids containing unmethylated CpG dinucleotide as an adjuvant
EP1067956B1 (en) 1998-04-03 2007-03-14 University Of Iowa Research Foundation Methods and products for stimulating the immune system using immunotherapeutic oligonucleotides and cytokines
DE69932717T2 (en) 1998-05-22 2007-08-09 Ottawa Health Research Institute, Ottawa METHODS AND PRODUCTS FOR INDUCING MUCOSAL IMMUNITY
EP1089751A4 (en) 1998-06-23 2001-07-25 Univ Leland Stanford Junior Adjuvant therapy
EP2204186B1 (en) 1999-02-17 2016-04-06 CSL Limited Immunogenic complexes and methods relating thereto
WO2000061151A2 (en) 1999-04-12 2000-10-19 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Oligodeoxynucleotide and its use to induce an immune response
JP2003510282A (en) 1999-09-25 2003-03-18 ユニバーシティ オブ アイオワ リサーチ ファウンデーション Immunostimulatory nucleic acids
EP1688147A1 (en) * 1999-09-27 2006-08-09 Coley Pharmaceutical Group, Inc. Methods Related to Immunostimulatory Nucleic Acid-Induced Interferon
ATE333284T1 (en) * 1999-09-27 2006-08-15 Coley Pharm Group Inc METHOD USING IMMUNOSTIMULATIVE INTERFERON INDUCED BY NUCLEIC ACIDS
US6949520B1 (en) 1999-09-27 2005-09-27 Coley Pharmaceutical Group, Inc. Methods related to immunostimulatory nucleic acid-induced interferon
US7030228B1 (en) 1999-11-15 2006-04-18 Miltenyi Biotec Gmbh Antigen-binding fragments specific for dendritic cells, compositions and methods of use thereof antigens recognized thereby and cells obtained thereby
WO2001051500A1 (en) 2000-01-14 2001-07-19 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Oligodeoxynucleotide and its use to induce an immune response
US7157437B2 (en) 2000-03-10 2007-01-02 Dynavax Technologies Corporation Methods of ameliorating symptoms of herpes infection using immunomodulatory polynucleotide sequences
US20020098199A1 (en) 2000-03-10 2002-07-25 Gary Van Nest Methods of suppressing hepatitis virus infection using immunomodulatory polynucleotide sequences
US7129222B2 (en) 2000-03-10 2006-10-31 Dynavax Technologies Corporation Immunomodulatory formulations and methods for use thereof
US20010046967A1 (en) 2000-03-10 2001-11-29 Gary Van Nest Methods of preventing and treating respiratory viral infection using immunomodulatory polynucleotide
US20030129251A1 (en) 2000-03-10 2003-07-10 Gary Van Nest Biodegradable immunomodulatory formulations and methods for use thereof
DE10032529A1 (en) * 2000-06-30 2002-02-07 Epigenomics Ag Diagnosis of major genetic parameters within the Major Histocompatibility Complex (MHC)
JP2005503320A (en) * 2000-08-25 2005-02-03 イエダ・リサーチ・アンド・デベロツプメント・カンパニー・リミテツド Methods for treating or preventing autoimmune diseases with CpG-containing polynucleotides
WO2002022809A2 (en) 2000-09-15 2002-03-21 Coley Pharmaceutical Gmbh PROCESS FOR HIGH THROUGHPUT SCREENING OF CpG-BASED IMMUNO-AGONIST/ANTAGONIST
JP2004509970A (en) * 2000-09-26 2004-04-02 ハイブリドン・インコーポレイテッド Regulation of immunostimulatory activity of immunostimulatory oligonucleotide analogues by positional chemical changes
US20030055014A1 (en) * 2000-12-14 2003-03-20 Bratzler Robert L. Inhibition of angiogenesis by nucleic acids
AU2002326561B2 (en) 2001-08-07 2008-04-03 Dynavax Technologies Corporation Immunomodulatory compositions, formulations, and methods for use thereof
WO2003015711A2 (en) 2001-08-17 2003-02-27 Coley Pharmaceutical Group, Inc. Combination motif immune stimulatory oligonucleotides with improved activity
DE60234375D1 (en) 2001-09-14 2009-12-24 Cytos Biotechnology Ag PACKAGING IMMUNSTIMULATING CpG IN VIRUS LIKE PARTICLES: PREPARATION METHOD AND USE
ES2543710T3 (en) 2002-04-04 2015-08-21 Zoetis Belgium S.A. Immunostimulatory oligonucleotides containing G and U
US20040053880A1 (en) 2002-07-03 2004-03-18 Coley Pharmaceutical Group, Inc. Nucleic acid compositions for stimulating immune responses
US7807803B2 (en) 2002-07-03 2010-10-05 Coley Pharmaceutical Group, Inc. Nucleic acid compositions for stimulating immune responses
AR040996A1 (en) 2002-08-19 2005-04-27 Coley Pharm Group Inc IMMUNE STIMULATING NUCLEIC ACIDS
JPWO2004028561A1 (en) * 2002-09-30 2006-01-19 アステラス製薬株式会社 Immune response induction method
CN1753687A (en) 2002-10-29 2006-03-29 科勒制药集团股份有限公司 Use of cpg oligonucleotides in the treatment of hepatitis c virus infection
JP4976653B2 (en) 2002-11-01 2012-07-18 ザ ガバメント オブ ザ ユナイテッド ステイツ オブ アメリカ アズ リプレゼンティッド バイ ザ セクレタリー オブ ザ デパートメント オブ ヘルス アンド ヒューマン サービシス Method for preventing infections caused by bioterrorism pathogens using immunostimulatory CpG oligonucleotides
US7956043B2 (en) 2002-12-11 2011-06-07 Coley Pharmaceutical Group, Inc. 5′ CpG nucleic acids and methods of use
DE60329223D1 (en) 2002-12-23 2009-10-22 Dynavax Tech Corp OLIGONUCLEOTIDES WITH AN IMMUNE SYSTEM STIMULATING SEQUENCE AND METHOD FOR THEIR APPLICATION
US8158768B2 (en) 2002-12-23 2012-04-17 Dynavax Technologies Corporation Immunostimulatory sequence oligonucleotides and methods of using the same
ES2385933T3 (en) 2003-02-20 2012-08-03 University Of Connecticut Health Center METHODS FOR THE PRODUCTION OF ALFA ANTIGEN MOLECULES COMPLEXES (2) MACROGLOBULIN.
US7537767B2 (en) 2003-03-26 2009-05-26 Cytis Biotechnology Ag Melan-A- carrier conjugates
RU2351362C2 (en) 2003-03-26 2009-04-10 Цитос Байотекнолоджи Аг CONJUGATES OF PEPTIDE Melan-A, VIRUS-LIKE PARTICLE ANALOGUE
JP4673217B2 (en) 2003-04-23 2011-04-20 由紀夫 佐藤 Methylated CpG polynucleotide
US8188254B2 (en) 2003-10-30 2012-05-29 Coley Pharmaceutical Gmbh C-class oligonucleotide analogs with enhanced immunostimulatory potency
JP2007531746A (en) * 2004-04-02 2007-11-08 コーリー ファーマシューティカル グループ，インコーポレイテッド Immunostimulatory nucleic acid for inducing an IL-10 response
EP1781325A2 (en) 2004-07-18 2007-05-09 CSL Limited Immuno stimulating complex and oligonucleotide formulations for inducing enhanced interferon-gamma responses
MY159370A (en) 2004-10-20 2016-12-30 Coley Pharm Group Inc Semi-soft-class immunostimulatory oligonucleotides
JP2008535862A (en) 2005-04-08 2008-09-04 キメリクス，インコーポレイテッド Compounds, compositions and methods for the treatment of poxvirus infections
AU2006266503B2 (en) 2005-07-01 2011-12-08 Index Pharmaceuticals Ab Immunostimulatory method
ES2435531T3 (en) 2005-07-01 2013-12-20 Index Pharmaceuticals Ab Modulation of steroid responsiveness
AU2006306805A1 (en) 2005-10-28 2007-05-03 Index Pharmaceuticals Ab Composition and method for the prevention, treatment and/or alleviation of an inflammatory disease
EP1957647B1 (en) 2005-11-25 2015-03-04 Zoetis Belgium S.A. Immunostimulatory oligoribonucleotides
JP5484732B2 (en) 2005-12-14 2014-05-07 サイトス バイオテクノロジー アーゲー Immunostimulatory nucleic acid package particles for the treatment of hypersensitivity
DK1991678T4 (en) 2006-02-15 2020-10-19 Rechtsanwalt Thomas Beck COMPOSITIONS AND PROCEDURES FOR OLIGONUCLEOTIDE FORMULATIONS
MX2008015529A (en) 2006-06-12 2009-01-13 Cytos Biotechnology Ag Processes for packaging oligonucleotides into virus-like particles of rna bacteriophages.
CN101820908A (en) 2007-10-09 2010-09-01 科利制药公司 The immune stimulatory oligonucleotide analogs that comprises modified sugar moieties
US9394333B2 (en) 2008-12-02 2016-07-19 Wave Life Sciences Japan Method for the synthesis of phosphorus atom modified nucleic acids
WO2011005761A1 (en) 2009-07-06 2011-01-13 Ontorii, Inc Novel nucleic acid prodrugs and methods use thereof
EA201290876A1 (en) 2010-03-05 2013-03-29 Президент Энд Феллоуз Оф Гарвард Колледж COMPOSITIONS OF INDUCED DENDRITIC CELLS AND THEIR USE
WO2012039448A1 (en) 2010-09-24 2012-03-29 株式会社キラルジェン Asymmetric auxiliary group
RU2014105311A (en) 2011-07-19 2015-08-27 Уэйв Лайф Сайенсес Пте. Лтд. METHODS FOR SYNTHESIS OF FUNCTIONALIZED NUCLEIC ACIDS
MX356830B (en) * 2012-07-13 2018-06-15 Shin Nippon Biomedical Laboratories Ltd Chiral nucleic acid adjuvant.
CN104684893B (en) 2012-07-13 2016-10-26 日本波涛生命科学公司 Asymmetric auxiliary group
RU2015104762A (en) 2012-07-13 2018-08-31 Уэйв Лайф Сайенсес Лтд. CHIRAL CONTROL
EP3095459A4 (en) 2014-01-15 2017-08-23 Shin Nippon Biomedical Laboratories, Ltd. Chiral nucleic acid adjuvant having antitumor effect and antitumor agent
US10322173B2 (en) 2014-01-15 2019-06-18 Shin Nippon Biomedical Laboratories, Ltd. Chiral nucleic acid adjuvant having anti-allergic activity, and anti-allergic agent
US10144933B2 (en) 2014-01-15 2018-12-04 Shin Nippon Biomedical Laboratories, Ltd. Chiral nucleic acid adjuvant having immunity induction activity, and immunity induction activator
ES2917473T3 (en) 2014-01-16 2022-07-08 Wave Life Sciences Ltd chiral design
EP3835312A1 (en) 2014-12-31 2021-06-16 Checkmate Pharmaceuticals, Inc. Combination tumor immunotherapy
WO2017210647A1 (en) 2016-06-03 2017-12-07 Wave Life Sciences Ltd. Oligonucleotides, compositions and methods thereof
AU2018288863A1 (en) * 2017-06-22 2020-01-30 Board Of Regents, The University Of Texas System Methods for producing regulatory immune cells and uses thereof
BR112020016876A2 (en) 2018-02-21 2020-12-15 Board Of Regents, The University Of Texas System UNIVERSAL ANTIGEN PRESENTING CELLS AND USES OF THE SAME
CN109865134A (en) * 2019-03-26 2019-06-11 斯潘思生命科技(武汉)有限公司 A kind of preparation method and applications of hybridization nanometer tumor vaccine

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2560114A1 (en) * 1994-07-15 1996-02-01 The University Of Iowa Research Foundation Immunomodulatory oligonucleotides
US6207646B1 (en) * 1994-07-15 2001-03-27 University Of Iowa Research Foundation Immunostimulatory nucleic acid molecules
CA2208528A1 (en) * 1994-12-22 1996-06-27 Hybridon, Inc. Synthesis of stereospecific oligonucleotide phosphorothioates
WO1996039154A1 (en) * 1995-06-06 1996-12-12 Isis Pharmaceuticals, Inc. Oligonucleotides having phosphorothioate linkages of high chiral purity

Cited By (10)

* 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
US9028845B2 (en) 2001-06-21 2015-05-12 Dynavax Technologies Corporation Chimeric immunomodulatory compounds and methods of using the same-IV
US9528088B2 (en) 2002-06-28 2016-12-27 Life Technologies Corporation Methods for eliminating at least a substantial portion of a clonal antigen-specific memory T cell subpopulation
US9382545B2 (en) 2006-09-27 2016-07-05 Coley Pharmaceutical Gmbh CpG oligonucleotide analogs containing hydrophobic T analogs with enhanced immunostimulatory activity
US8993542B2 (en) 2008-01-25 2015-03-31 Chimerix Inc. Methods of treating viral infections
US9006218B2 (en) 2010-02-12 2015-04-14 Chimerix Inc. Nucleoside phosphonate salts
US9765100B2 (en) 2010-02-12 2017-09-19 Chimerix, Inc. Nucleoside phosphonate salts
US9278135B2 (en) 2010-04-26 2016-03-08 Chimerix Inc. Methods of treating retroviral infections and related dosage regimes
US9694024B2 (en) 2010-04-26 2017-07-04 Chimerix, Inc. Methods of treating retroviral infections and related dosage regimes
US9956239B2 (en) 2010-04-26 2018-05-01 Chimerix, Inc. Methods of treating retroviral infections and related dosage regimes

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