Title:
IMMUNOSTIMULATORY OLIGONUCLEOTIDES WITH MODIFIED BASES AND METHODS OF USE THEREOF
Document Type and Number:
WIPO Patent Application WO/1999/062923
Kind Code:
A2
Abstract:
Immunomodulatory oligonucleotide compositions are disclosed. These oligonucleotides comprise an immunostimulatory hexanucleotide sequence comprising a modified cytosine. These oligonucleotides can be administered in conjunction with an immunomodulatory peptide or antigen. Methods of modulating an immune response upon administration of the oligonucleotide comprising a modified immunostimulatory sequence are also disclosed.
Inventors:
SCHWARTZ DAVID (US)
Application Number:
PCT/US1999/012538
Publication Date:
December 09, 1999
Filing Date:
June 04, 1999
Export Citation:
Assignee:
DYNAVAX TECH CORP (US)
SCHWARTZ DAVID (US)
SCHWARTZ DAVID (US)
International Classes:
A61K39/39; A61K47/48; A61P37/04; C07H21/00; C12N15/117; (IPC1-7): C07H21/00; A61K31/70; A61K31/715; A61K38/00; A61K39/00; C07K2/00; C07K14/52
Domestic Patent References:
| WO1989009779A1 | 1989-10-19 | |||
| WO1998055495A2 | 1998-12-10 |
Foreign References:
| US4948882A | 1990-08-14 |
Other References:
HARDIN, CHARLES C. ET AL: "Characterization of anti-Z-RNA polyclonal antibodies: epitope properties and recognition of Z-DNA" BIOCHEMISTRY (1988), 27(11), 4169-77, XP002129945
BRENNAN, CATHERINE A. ET AL: "The effects of base analog substitutions on the methylation by the EcoRI modification methylase of octadeoxyribonucleotides containing modified EcoRI recognition sequences" J. BIOL. CHEM. (1986), 261(16), 7279-86, XP002143307
JEAN, YUCH CHENG ET AL: "Z-DNA structure of a modified DNA hexamer at 1,4-.ANG. resolution: aminohexyl-5'-d(pCpGp[Br5C]pGpCpG)" BIOCHEMISTRY (1993), 32(1), 381-8 , XP002143308
NGUYEN H ET AL: "Studies Towards the Design of a Modified GC Base Pair With Stability Similar to that of the AT Base Pair" TETRAHEDRON LETTERS,NL,ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, vol. 38, no. 23, 9 June 1997 (1997-06-09), pages 4083-4086, XP004065032 ISSN: 0040-4039
FERRER, ELISENDA ET AL: "Preparation and Properties of Oligodeoxynucleotides Containing 5-Iodouracil and 5-Bromo- and 5-Iodocytosine" BIOCONJUGATE CHEM. (1997), 8(5), 757-761 , XP002143309
DUTTA, RATNA ET AL: "Binding of the modified daunorubicin WP401 adjacent to a T-G base pair induces the reverse Watson-Crick conformation: crystal structures of the WP401-TGGCCG and WP401-CGG[br5C]CG complexes" NUCLEIC ACIDS RES. (1998), 26(12), 3001-3005, XP002143310
THERIAULT, N. Y. ET AL: "Studies on the base pair binding specificity of CC-1065 to oligomer duplexes" CHEM.-BIOL. INTERACT. (1988), 65(2), 187-201 , XP000929239
YOON, CHUN ET AL: "Structure of an alternating-B DNA helix and its relationship to A-tract DNA" PROC. NATL. ACAD. SCI. U. S. A. (1988), 85(17), 6332-6, XP002143311
KRIEG A M ET AL: "CPG MOTIFS IN BACTERIAL DNA TRIGGER DIRECT B-CELL ACTIVATION" NATURE,GB,MACMILLAN JOURNALS LTD. LONDON, vol. 374, 6 April 1995 (1995-04-06), pages 546-549, XP000197060 ISSN: 0028-0836
GODDARD, AMANDA J. ET AL: "Synthesis of a phosphoramidite of 2'-deoxy-5,6-dihydro-5-azacytidine. It potential application in the synthesis of DNA containing dihydro-5-aza an 5-azacytosine bases" TETRAHEDRON LETT. (1988), 29(15), 1767-70, XP002129946
See also references of EP 1121373A2
BRENNAN, CATHERINE A. ET AL: "The effects of base analog substitutions on the methylation by the EcoRI modification methylase of octadeoxyribonucleotides containing modified EcoRI recognition sequences" J. BIOL. CHEM. (1986), 261(16), 7279-86, XP002143307
JEAN, YUCH CHENG ET AL: "Z-DNA structure of a modified DNA hexamer at 1,4-.ANG. resolution: aminohexyl-5'-d(pCpGp[Br5C]pGpCpG)" BIOCHEMISTRY (1993), 32(1), 381-8 , XP002143308
NGUYEN H ET AL: "Studies Towards the Design of a Modified GC Base Pair With Stability Similar to that of the AT Base Pair" TETRAHEDRON LETTERS,NL,ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, vol. 38, no. 23, 9 June 1997 (1997-06-09), pages 4083-4086, XP004065032 ISSN: 0040-4039
FERRER, ELISENDA ET AL: "Preparation and Properties of Oligodeoxynucleotides Containing 5-Iodouracil and 5-Bromo- and 5-Iodocytosine" BIOCONJUGATE CHEM. (1997), 8(5), 757-761 , XP002143309
DUTTA, RATNA ET AL: "Binding of the modified daunorubicin WP401 adjacent to a T-G base pair induces the reverse Watson-Crick conformation: crystal structures of the WP401-TGGCCG and WP401-CGG[br5C]CG complexes" NUCLEIC ACIDS RES. (1998), 26(12), 3001-3005, XP002143310
THERIAULT, N. Y. ET AL: "Studies on the base pair binding specificity of CC-1065 to oligomer duplexes" CHEM.-BIOL. INTERACT. (1988), 65(2), 187-201 , XP000929239
YOON, CHUN ET AL: "Structure of an alternating-B DNA helix and its relationship to A-tract DNA" PROC. NATL. ACAD. SCI. U. S. A. (1988), 85(17), 6332-6, XP002143311
KRIEG A M ET AL: "CPG MOTIFS IN BACTERIAL DNA TRIGGER DIRECT B-CELL ACTIVATION" NATURE,GB,MACMILLAN JOURNALS LTD. LONDON, vol. 374, 6 April 1995 (1995-04-06), pages 546-549, XP000197060 ISSN: 0028-0836
GODDARD, AMANDA J. ET AL: "Synthesis of a phosphoramidite of 2'-deoxy-5,6-dihydro-5-azacytidine. It potential application in the synthesis of DNA containing dihydro-5-aza an 5-azacytosine bases" TETRAHEDRON LETT. (1988), 29(15), 1767-70, XP002129946
See also references of EP 1121373A2
Attorney, Agent or Firm:
Polizzi, Catherine M. (CA, US)
GOLDIN, DOUGLAS MICHAEL J.A. KEMP & CO. (London WC1R 5LX, GB)
GOLDIN, DOUGLAS MICHAEL J.A. KEMP & CO. (London WC1R 5LX, GB)
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Claims:
CLAIMS We claim:
| 1. | An immunomodulatory oligonucleotide comprising an immunostimulatory sequence (ISS) comprising a modified cytosine. |
| 2. | An immunomodulatory oligonucleotide of claim 1, wherein the modified cytosine comprises an addition of an electronwithdrawing group to at least position C5. |
| 3. | An immunomodulatory oligonucleotide of claim 1, wherein the modified cytosine comprises an addition of an electronwithdrawing group to at least position C6. |
| 4. | An immunomodulatory oligonucleotide of claim 1, wherein the ISS comprises a modified cytosine selected from the group consisting of azacytosine, 5bromocytosine, bromouracil, 5chlorocytosine, chlorinated cytosine, cyclocytosine, cytosine arabinoside, fluorinated cytosine, fluoropyrimidine, fluorouracil, 5,6dihydrocytosine, halogenated cytosine, halogenated pyrimidine analogue, hydroxyurea, iodouracil, 5nitrocytosine, 5trifluoromethylcytosine, uracil, 5fluorocytosine, 5trifluoromethylcytosine, and 5,6dihydrocytosine. |
| 5. | An immunomodulatory oligonucleotide of claim 1, wherein the modified cytosine is a 5'bromocytidine. |
| 6. | An immunomodulatory oligonucleotide of claim 1, wherein the ISS comprises the sequence 5'Purine, Purine, Cytosine, Guanine, Pyrimidine, Pyrimidine3'. |
| 7. | An immunomodulatory oligonucleotide of claim 6, wherein the modified cytosine comprises an addition of an electronwithdrawing group to at least position C5. |
| 8. | An immunomodulatory oligonucleotide of claim 6, wherein the modified cytosine comprises an addition of an electronwithdrawing group to at least position C6. |
| 9. | An immunomodulatory oligonucleotide of claim 6, wherein the modified cytosine is a 5'bromocytidine. |
| 10. | An immunomodulatory oligonucleotide of claim 9, wherein the cytosine at the third position from the 5'end of the ISS octanucleotide is substituted with a 5'bromocytidine. |
| 11. | An immunomodulatory oligonucleotide of claim 1, wherein the ISS comprises the sequence 5'Purine, Purine, Cytosine, Guanine, Pyrimidine, Pyrimidine, Cytosine, Cytosine3'. |
| 12. | An immunomodulatory oligonucleotide of claim 11, wherein the modified cytosine comprises an addition of an electronwithdrawing group to at least position C5. |
| 13. | An immunomodulatory oligonucleotide of claim 11, wherein the modified cytosine comprises an addition of an electronwithdrawing group to at least position C6. |
| 14. | An immunomodulatory oligonucleotide of claim 11, wherein the modified cytosine is a 5'bromocytidine. |
| 15. | An immunomodulatory oligonucleotide of claim 11, wherein the cytosine at the third position from the 5'end of the ISS is substituted with a 5' bromocytidine. |
| 16. | An immunomodulatory oligonucleotide of claim 11, wherein the cytosine at the third position from the 5'end of the ISS is substituted with a 5' bromocytidine and the cytosine at the seventh position from the 5'end of the ISS is substituted with a 5'bromocytidine. |
| 17. | An immunomodulatory oligonucleotide of claim 1, wherein the ISS comprises the sequence 5'Purine, Purine, Cytosine, Guanine, Pyrimidine, Pyrimidine, Cytosine, Guanine3'. |
| 18. | An immunomodulatory oligonucleotide of claim 17, wherein the modified cytosine comprises an addition of an electronwithdrawing group to at least position C5. |
| 19. | An immunomodulatory oligonucleotide of claim 17, wherein the modified cytosine comprises an addition of an electronwithdrawing group to at least position C6. |
| 20. | An immunomodulatory oligonucleotide of claim 17, wherein the modified cytosine is a 5'bromocytidine. |
| 21. | An immunomodulatory oligonucleotide of claim 17, wherein the Cytosine at the third position from the 5'end of the ISS octanucleotide is substituted with a 5'bromocytidine. |
| 22. | An immunomodulatory oligonucleotide of claim 17, wherein the cytosine at the third position from the 5'end of the ISS is substituted with a 5' bromocytidine and the cytosine at the seventh position from the 5'end of the ISS is substituted with a 5'bromocytidine. |
| 23. | An immunomodulatory oligonucleotide of claim 1, wherein the ISS comprises a phosphorothioate group. |
| 24. | An immunomodulatory oligonucleotide of claim 1, wherein the ISS comprises a sequence selected from the group consisting of AACGTT, GACGTT, AACGTTCC, AACGTTCG, GACGTTCC, and GACGTTCG, wherein at least one C is substituted with a modified cytosine. |
| 25. | An immunomodulatory oligonucleotide of claim 24, wherein the ISS further comprises a second modified cytosine. |
| 26. | An immunomodulatory oligonucleotide of claim 1, wherein the oligonucleotide portion further comprises an RNA sequence. |
| 27. | An immunomodulatory oligonucleotide of claim 26, wherein the ISS is an RNA sequence comprising a singlestranded or doublestranded sequence selected from the group consisting of AACGUU, GACGUU, AACGUUCC, AACGUUCG, GACGUUCC, and GACGUUCG, wherein at least one C is substituted with a modified cytosine. |
| 28. | An immunomodulatory oligonucleotide of claim 27, wherein the ISS further comprises a second modified cytosine. |
| 29. | An immunomodulatory oligonucleotide comprising the sequence SEQ ID NO: 2. |
| 30. | An immunomodulatory oligonucleotide comprising the sequence SEQ ID NO:5. |
| 31. | An immunomodulatory oligonucleotide comprising the sequence SEQ ID NO: 6. |
| 32. | An immunomodulatory composition comprising an immunomodulatory oligonucleotide according to claim 1; and further comprising an antigen. |
| 33. | An immunomodulatory composition of claim 32, wherein the antigen is selected from the group consisting of peptides, glycoproteins, polysaccharides, and lipids. |
| 34. | An immunomodulatory composition of claim 32, wherein the antigen is conjugated to the immunomodulatory oligonucleotide. |
| 35. | An immunomodulatory composition comprising an immunomodulatory oligonucleotide according to claim 1; and further comprising a facilitator selected from the group consisting of costimulatory molecules, cytokines, chemokines, targeting protein ligand, a transactivating factor, a peptide, and a peptide comprising a modified amino acid. |
| 36. | An immunomodulatory composition of claim 35, wherein the facilitator is conjugated to the immunomodulatory oligonucleotide. |
| 37. | An immunomodulatory composition comprising an immunomodulatory oligonucleotide according to claim 1; and further comprising an antigen; and further comprising an adjuvant. |
| 38. | An immunomodulatory composition of claim 37, wherein the antigen is selected from the group consisting of peptides, glycoproteins, polysaccharides, and lipids. |
| 39. | An immunomodulatory composition of claim 37, wherein the antigen is conjugated to the immunomodulatory oligonucleotide. |
| 40. | A method of modulating an immune response comprising co administration of an immunomodulatory composition comprising an antigen and an immunomodulatory oligonucleotide according to claim 1. |
| 41. | The method of claim 40, wherein the modulating of an immune response comprises induction of a Thltype response. |
| 42. | A method of modulating an immune response comprising administration of an immunomodulatory composition according to claim 34. |
| 43. | The method of claim 42, wherein the modulating of an immune response comprises induction of a Thltype response. |
| 44. | A method of modulating an immune response comprising the co administration of an antigen, an adjuvant and an immunomodulatory oligonucleotide according to claim 1. |
| 45. | The method of claim 44, wherein the modulating of an immune response comprises induction of a Thltype response. |
| 46. | A method of modulating an immune response comprising the administration of an immunomodulatory composition according to claim 35, wherein the components of the composition are coadministered. |
| 47. | A method of modulating an immune response comprising administration of an immunomodulatory composition according to claim 39. |
| 48. | A method of treating an individual in need of immune modulation comprising administration of a composition comprising an immunomodulatory oligonucleotide of claim 1. |
Description:
INTERNATIONAL SEARCH EPORT |In ItionalApplicationNo PCT/US 99/12538 C.(Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT Category ° Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X BRENNAN, CATHERINE A. ET AL:"The effects 1,2,4,5 of base analog substitutions on the methylation by the EcoRI modification methylase of octadeoxyribonucleotides containing modified EcoRI recognition sequences" J. BIOL. CHEM. (1986), 261 (16), 7279-86, XP002143307 page 7279 page 7284, right-hand column, paragraph 3 see RN 103549-62-8 X JEAN, YUCH CHENG ET AL:"Z-DNA structure 1,2,4,5 of a modified DNA hexamer at 1,4-. ANG. resolution: aminohexyl-5'-d (pCpGp'Br5C ! pGpCpG)" BIOCHEMISTRY (1993), 32 (1), 381-8, XP002143308 page 381-page 382, left-hand column, paragraph 1 see RN 145586-04-5 X NGUYEN H ET AL:"Studies Towards the 1,2,4,5 Design of a Modified GC Base Pair With Stability Similar to that of the AT Base Pair" TETRAHEDRON LETTERS, NL, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, vol. 38, no. 23,9 June 1997 (1997-06-09), pages 4083-4086, XP004065032 ISSN: 0040-4039 the whole document X FERRER, ELISENDA ET AL:"Preparation and 1,2,4,5 Properties of Oligodeoxynucleotides Containing 5-Iodouracil and 5-Bromo-and 5-Iodocytosine" BIOCONJUGATE CHEM. (1997), 8 (5), 757-761, XP002143309 page 757, right-hand column, paragraph 1 page 760, left-hand column see RN 194096-69-0 X DUTTA, RATNA ET AL:"Binding of the 1,2,4,5 modified daunorubicin WP401 adjacent to a T-G base pair induces the reverse Watson-Crick conformation: crystal structures of the WP401-TGGCCG and WP401-CGG'br5C ! CG complexes" NUCLEIC ACIDS RES. (1998), 26 (12), 3001-3005, XP002143310 page 3001-page 3002, left-hand column see RN 211176-10-2 2 2 INTERNATIONAL SEARCH REPORT | In'tionalApplicationNo PCT/US99/12538 C. (Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT Category ° Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X THERIAULT, N. Y. ET AL:"Studies on the 1,2,4,5 base pair binding specificity of CC-1065 to oligomer duplexes" CHEM.-BIOL. INTERACT. (1988), 65 (2), 187-201, XP000929239 page 188-page 189 table I, entry 10 see RN 116193-94-3 X YOON, CHUN ET AL:"Structure of an 1,2,4,5 alternating-B DNA helix and its relationship to A-tract DNA" PROC. NATL. ACAD. SCI. U. S. A. (1988), 85 (17), 6332-6, XP002143311 page 6336, left-hand column, paragraph 1 figure 6 see RN 117978-22-0 A KRIEG A M ET AL:"CPG MOTIFS IN BACTERIAL 1,40 DNA TRIGGER DIRECT B-CELL ACTIVATION" NATURE, GB, MACMILLAN JOURNALS LTD. LONDON, vol. 374,6 April 1995 (1995-04-06), pages 546-549,XP000197060 ISSN: 0028-0836 page 546, right-hand column, paragraph 2- paragraph 3 page 549, left-hand column, paragraph 1 table 1 A GODDARD, AMANDA J. ET AL:"Synthesis of a 1,40 phosphoramidite of 2'-deoxy-5,6-dihydro-5-azacytidine. It potential application in the synthesis of DNA containing dihydro-5-aza an 5-azacytosine bases" TETRAHEDRON LETT. (1988), 29 (15), 1767-70, XP002129946 page 1767, paragraph 1 page1770 A WO 89 09779 A (US GOVERNMENT) 1,40 19 October 1989 (1989-10-19) page 1, line 4-line 9 scheme 1 A US 4 948 882 A (RUTH JERRY L) 1,40 14 August 1990 (1990-08-14) column 4, line 22-line 58 column 7 2 2 INTERNATIONAL SEARCH REPORT n, tional Application No PCT/US 99/12538 C. (Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT Category ° Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. P, X WO 98 55495 A (DYNAVAX TECHNOLOGIES CORP 1,2,4-7, ; DINA DINO (US); ROMAN MARK (US); SCHWAR) 9,11,12, 10 December 1998 (1998-12-10) 14,17, 18,20, 23-48 page 1, line 10-line 16 claims SEQ ID No 12,15 and 16 2 2 ternational application No. INTERNATIONAL SEARCH REPORT PCT/US 99/12538 Box I Observations where certain claims were found unsearchable (Continuation of item 1 of first sheet) This international Search Report has not been established in respect of certain claims under Article 17 (2) (a) for the following reasons: 1. i Claims Nos. : because they relate to subject matter not required to be searched by this Authority, namely : Although claims 40-48 are directed to a method of treatment of the human/animal body, the search has been carried out and based on the alleged effects of the compound/composition. 2. Claims Nos.: because they relate to parts of the International Application that do not comply with the prescribed requirements to such an extent that no meaningful International Search can be carried out, specifically : 3. Claims Nos. : because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4 (a). Box 11 Observations where unity of invention is lacking (Continuation of item 2 of first sheet) This International Searching Authority found multiple inventions in this international application, as follows : see additional sheet 1. n As all required additional search fees were timely paid by the applicant, this International Search Report covers all searchable claims. 2. as ait searchable claims could be searched without effort justifying an additional fee, this Authority did not invite payment of any additional fee. 3.1 As only some of the required additional search fees were timely paid by the applicant, this International Search Report covers only those claims for which fees were paid, specifically claims Nos.: 1-4 (partially), 5,6-8 (partially), 9,10,11-13 (partially), 14-16,17-19 (partially), 20-22,23-28 (partially), 29-31,32-48 (partially) 4. No required additional search fees were timely paid by the applicant. Consequently, this International Search Report is restricted to the invention first mentioned in the claims; it is covered by claims Nos.: Remark on Protest g The additional search fees were accompanied by the applicant's protest. u FXI No protest accompanied the payment of additional search fees. u FURTHER INFORMATION CONTINUED FROM PCTIFSAI 210 This International Searching Authority found multiple (groups of) inventions in this international application, as follows: 1. Claims: 1 (partially), 4 (partially), 6 (partially), 11 (partially), 17 (partially), 23-28 (partially), 32-48 (partially) An immunomodulatory oligonucleotide comprising an immunostimulatory sequence comprising a modified cytosine characterized in that the modified cytosine is an azacytosine, in so far as it is neither a cyclocytosine nor a cytosine arabinoside; a composition containing such an oligonucleotide as well as the use of such a composition to modulate an immune response 2. Claims: 1 (partially), 4 (partially), 6 (partially), 11 (partially), 17 (partially), 23-28 (partially), 32-48 (partially) An immunomodulatory oligonucleotide comprising an immunostimulatory sequence comprising a modified cytosine characterized in that the"modified cytosine"is an azapyrimidine (not an azacytosine), in so far as it is neither a cyclocytosine nor a cytosine arabinoside; a composition containing such an oligonucleotide as well as the use of such a composition to modulate an immune response 3. Claims: 1-4 (partially), 5,6-8 (partially), 9,10, 11-13 (partially), 14-16,17-19 (partially), 20-22,23-28 (partially), 29-31,32-48 (partially) An immunomodulatory oligonucleotide comprising an immunostimulatory sequence comprising a modified cytosine characterized in that the modified cytosine is 5-bromocytosine, in so far as it is neither a cyclocytosine nor a cytosine arabinoside; a composition containing such an oligonucleotide as well as the use of such a composition to modulate an immune response 4. Claims: 1-4 (partially), 6-8 (partially), 11-13 (partially), 17-19 (partially), 23-28 (partially), 32-48 (partially) An immunomodulatory oligonucleotide comprising an immunostimulatory sequence comprising a modified cytosine characterized in that the"modified cytosine"is bromouracil, in so far as it is neither a cyclocytosine nor a cytosine arabinoside; a composition containing such an FURTHER INFORMATION CONTINUED FROM PCT/ISA/210 oligonucleotide as well as the use of such a composition to modulate an immune response 5. Claims: 1-4 (partially), 6-8 (partially), 11-13 (partially), 17-19 (partially), 23-28 (partially), 32-48 (partially) An immunomodulatory oligonucleotide comprising an immunostimulatory sequence comprising a modified cytosine characterized in that the"modified cytosine"is a bromopyrimidine (not a cytosine or an uracil), in so far as it is neither a cyclocytosine nor a cytosine arabinoside; a composition containing such an oligonucleotide as well as the use of such a composition to modulate an immune response 6. Claims: 1-4 (partially), 6-8 (partially), 11-13 (partially), 17-19 (partially), 23-28 (partially), 32-48 (partially) An immunomodulatory oligonucleotide comprising an immunostimulatory sequence comprising a modified cytosine characterized in that the"modified cytosine"is a chloropyrimidine, in so far as it is neither a cyclocytosine nor a cytosine arabinoside; a composition containing such an oligonucleotide as well as the use of such a composition to modulate an immune response 7. Claims: 1-4 (partially), 6-8 (partially), 11-13 (partially), 17-19 (partially), 23-28 (partially), 32-48 (partially) An immunomodulatory oligonucleotide comprising an immunostimulatory sequence comprising a modified cytosine characterized in that the"modified cytosine"is a fluoropyrimidine, in so far as it is neither a cyclocytosine nor a cytosine arabinoside; a composition containing such an oligonucleotide as well as the use of such a composition to modulate an immune response 8. Claims: 1-4 (partially), 6-8 (partially), 11-13 (partially), 17-19 (partially), 23-28 (partially), 32-48 (partially) An immunomodulatory oligonucleotide comprising an immunostimulatory sequence comprising a modified cytosine characterized in that the"modified cytosine"is a 5-trifluoromethylpyrimidine, in so far as it is neither a FURTHER INFORMATION CONTINUED FROM PCT/lSA/210 cyclocytosine nor a cytosine arabinoside; a composition containing such an oligonucleotide as well as the use of such a composition to modulate an immune response 9. Claims: 1-4 (partially), 6-8 (partially), 11-13 (partially), 17-19 (partially), 23-28 (partially), 32-48 (partially) An immunomodulatory oligonucleotide comprising an immunostimulatory sequence comprising a modified cytosine characterized in that the"modified cytosine"is a 5,6-dihydropyrimidine, in so far as it is neither a cyclocytosine nor a cytosine arabinoside; a composition containing such an oligonucleotide as well as the use of such a composition to modulate an immune response 10. Claims: 1-4 (partially), 6-8 (partially), 11-13 (partially), 17-19 (partially), 23-28 (partially), 32-48 (partially) An immunomodulatory oligonucleotide comprising an immunostimulatory sequence comprising a modified cytosine characterized in that the"modified cytosine"is a iodopyrimidine, in so far as it is neither a cyclocytosine nor a cytosine arabinoside; a composition containing such an oligonucleotide as well as the use of such a composition to modulate an immune response 11. Claims: 1-4 (partially), 6-8 (partially), 11-13 (partially), 17-19 (partially), 23-28 (partially), 32-48 (partially) An immunomodulatory oligonucleotide comprising an immunostimulatory sequence comprising a modified cytosine characterized in that the"modified cytosine"is a nitropyrimidine, in so far as it is neither a cyclocytosine nor a cytosine arabinoside; a composition containing such an oligonucleotide as well as the use of such a composition to modulate an immune response 12. Claims: 1-4 (partially), 6-8 (partially), 11-13 (partially), 17-19 (partially), 23-28 (partially), 32-48 (partially) An immunomodulatory oligonucleotide comprising an immunostimulatory sequence comprising a modified cytosine characterized in that the"modified cytosine"is a FURTHER INFORMATION CONTINUED FROM PCT/ISA/210 hydroxyurea, in so far as it is neither a cyclocytosine nor a cytosine arabinoside; a composition containing such an oligonucleotide as well as the use of such a composition to modulate an immune response 13. Claims: 1-4 (partially), 6-8 (partially), 11-13 (partially), 17-19 (partially), 23-28 (partially), 32-48 (partially) An immunomodulatory oligonucleotide comprising an immunostimulatory sequence comprising a modified cytosine characterized in that the modified cytosine is a cyclocytosine ; a composition containing such an oligonucleotide as well as the use of such a composition to modulate an immune response 14. Claims: 1-4 (partially), 6-8 (partially), 11-13 (partially), 17-19 (partially), 23-28 (partially), 32-48 (partially) An immunomodulatory oligonucleotide comprising an immunostimulatory sequence comprising a modified cytosine characterized in that the modified cytosine is a cytosine arabinoside; a composition containing such an oligonucleotide as well as the use of such a composition to modulate an immune response 15. Claims: 1-4 (partially), 6-8 (partially), 11-13 (partially), 17-19 (partially), 23-28 (partially), 32-48 (partially) An immunomodulatory oligonucleotide comprising an immunostimulatory sequence comprising a modified cytosine characterized in that the"modified cytosine"is uracil; a composition containing such an oligonucleotide as well as the use of such a composition to modulate an immune response 16. Claims : 1-4 (partially), 6-8 (partially), 11-13 (partially), 17-19 (partially), 23-28 (partially), 32-48 (partially) An immunomodulatory oligonucleotide comprising an immunostimulatory sequence comprising a modified cytosine characterized in that the"modified cytosine"is a pyrimidine not belonging to the groups of compounds mentioned in subjects 1-15; composition containing such an oligonucleotide as well as the use of such a composition to FURTHER INFORMATION CONTINUED FROM PCT/ISAI 210 modulate an immune response INTERNATIONAL SEARCH REPORT | Int tionaiApplicationNO nformation on patent tamily members PCT/US 99/12538 Patent document Publication Patent family Pubiication cited in search report datemember (s) date WO 8909779 A 19-10-1989 US 5324831 A 28-06-1994 AU 625295 B 09-07-1992 AU 3368189 A 03-11-1989 CA 1330960 A 26-07-1994 JP 6092435 B 16-11-1994 JP 3502577 T 13-06-1991 US 4948882 A 14-08-1990 US 5541313 A 30-07-1996 US 5668266 A 16-09-1997 US 5817786 A 06-10-1998 AU 596068 B 26-04-1990 AU 2813984 A 10-09-1984 DE 3482113 D 07-06-1990 DK 502184 A 19-12-1984 EP 0135587 A 03-04-1985 JP 2542453 B 09-10-1996 JP 3086897 A 11-04-1991 NO 844196 A 19-10-1984 WO 8403285 A 30-08-1984 WO 9855495 A 10-12-1998 AU 7811398 A 21-12-1998 AU 7817898 A 21-12-1998 EP 1003850 A 31-05-2000 EP 0986572 A 22-03-2000 WO 9855609 A 10-12-1998