Methods for regulating hematopoiesis using CpG-oligonucleotides

• US 20040030118A1
• Filed: 02/24/2003
• Published: 02/12/2004
• Est. Priority Date: 05/14/1998
• Status: Abandoned Application

• Current Assignee: Coley Pharmaceutical GmbH (Pfizer Inc.)
• Original Assignee: Coley Pharmaceutical GmbH (Pfizer Inc.)
• Inventors: Wagner, Hermann, Lipford, Grayson
• Application Number:
  US10/373,381
• Publication Number:
  US 20040030118A1
• Time in Patent Office: Days
• US Class Current: 536/23.72
• CPC Class Codes: A61K 2039/55555 Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
• CPC Class Codes: A61K 2039/55561 CpG containing adjuvants; Oligonucleotide containing adjuvants
• CPC Class Codes: A61K 2039/55566 Emulsions, e.g. Freund's adjuvant, MF59
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 39/39 characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: C12N 15/117 Nucleic acids having immunomodulatory properties, e.g. containing CpG-motifs
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/345 having at least two different backbone modifications
• CPC Class Codes: Y02A 50/30 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 methods for regulating hematopoiesis using CpG containing oligonucleotides. In particular, the invention relates to methods of treating thrombopoiesis and anemia by regulating hematopoiesis. The invention also relates to methods of regulating immune system remodeling by administering CpG oligonucleotides to control hematopoiesis.

Claims

1. A method for treating a subject at risk of infection with an infectious virus, comprising:

administering to a subject at risk of infection with an infectious virus an oligonucleotide having a sequence including at least the following formula;

5′

X₁CGX₂ 3′

wherein the oligonucleotide includes at least 8 nucleotides, C is unmethylated, X₁ and X₂ are nucleotides, and the subject is exposed to the infectious virus at least 2 days after the oligonucleotide is administered to the subject to produce an immune response against the virus.

2. The method of claim 1, wherein the subject is exposed to the infectious virus at least 4 days after the oligonucleotide is administered to the subject.

3. The method of claim 1, wherein the subject is exposed to the infectious virus at least 7 days after the oligonucleotide is administered to the subject.

4. The method of claim 1, wherein the subject is exposed to the infectious virus at least 15 days after the oligonucleotide is administered to the subject.

5. The method of claim 1, wherein the subject is exposed to the infectious virus at least 30 days after the oligonucleotide is administered to the subject.

6. The method of claim 1, wherein the oligonucleotide is 8 to 100 nucleotides in length.

7. The method of claim 1, wherein the oligonucleotide includes a phosphate backbone modification which is a phosphorothioate or phosphorodithioate modification.

8. The method of claim 7, wherein the phosphate backbone modification occurs at the 5′

end of the oligonucleotide.

9. The method of claim 7, wherein the phosphate backbone modification occurs at the 3′

end of the oligonucleotide.

10. The method of claim 1, wherein the oligonucleotide has a sequence including at least the following formula:

5′

′

X₁X₂CGX₃X₄ 3′

wherein X₁X₂ are nucleotides selected from the group consisting of;

GpT, GpG, GpA, and ApA; and

wherein X₃X₄ are nucleotides selected from the group consisting of;

TpT, CpT, and GpT.

11. The method of claim 1, wherein the oligonucleotide has a sequence including at least the following formula:

5′

TCNTX₁X₂CGX₃X₄ 3′

 

 

(SEQ ID NO;

89)

wherein X₁, X₂, X₃, and X₄ are nucleotides and N is a nucleic acid sequence composed of from about 0-25 nucleotides.

12. The method of claim 11, wherein X₁X₂ are nucleotides selected from the group consisting of:

GpT, GpG, GpA, and ApA; and

wherein X₃X₄ are nucleotides selected from the group consisting of;

TpT, CpT, and GpT.

13. The method of claim 1, wherein the infectious virus is selected from the group consisting of Retroviridae, Picomaviridae, Caliciviridae, Togaviridae, Flaviviridae, Coronaviridae, Rhabdoviridae, Filoviridae, Paramyxoviridae, Orthomyxoviridae, Bunyaviridae, Arenaviridae, Reoviridae, Hepadnaviridae, Parvoviridae, Papovaviridae, Adenoviridae, Herpesviridae, Poxyiridae, and Iridoviridae.

14. The method of claim 1, wherein the subject is actively exposed to the infectious virus.

15. The method of claim 1, wherein the subject is passively exposed to the infectious virus.

16. The method of claim 1, wherein the oligonucleotide is administered to the subject on a regular basis.

17. The method of claim 16, wherein the regular basis is weekly.

18. The method of claim 16, wherein the regular basis is monthly.

19. A method for treating a subject at risk of infection with respiratory syncytial virus (RSV), comprising:

administering to a subject at risk of infection with RSV an oligonucleotide having a sequence including at least the following formula;

5′

X₁CGX₂ 3′

wherein the oligonucleotide includes at least 8 nucleotides, C is unmethylated, X₁ and X₂ are nucleotides, and the subject is exposed to RSV at least 2 days after the oligonucleotide is administered to the subject to produce an immune response against RSV.

20. The method of claim 19, wherein the subject is exposed to RSV at least 4 days after the oligonucleotide is administered to the subject.

21. The method of claim 19, wherein the subject is exposed to RSV at least 7 days after the oligonucleotide is administered to the subject.

22. The method of claim 19, wherein the subject is exposed to RSV at least 15 days after the oligonucleotide is administered to the subject.

23. The method of claim 19, wherein the subject is exposed to RSV at least 30 days after the oligonucleotide is administered to the subject.

24. The method of claim 19, wherein the oligonucleotide is 8 to 100 nucleotides in length.

25. The method of claim 19, wherein the oligonucleotide includes a phosphate backbone modification which is a phosphorothioate or phosphorodithioate modification.

26. The method of claim 25, wherein the phosphate backbone modification occurs at the 5′

end of the oligonucleotide.

27. The method of claim 25, wherein the phosphate backbone modification occurs at the 3′

end of the oligonucleotide.

28. The method of claim 19, wherein the oligonucleotide has a sequence including at least the following formula:

5′

X₁X₂CGX₃X₄ 3′

wherein X₁X₂ are nucleotides selected from the group consisting of;

GpT, GpG, GpA, and ApA; and

wherein X₃X₄ are nucleotides selected from the group consisting of;

TpT, CpT, and GpT.

29. The method of claim 19, wherein the oligonucleotide has a sequence including at least the following formula:

5′

TCNTX₁X₂CGX₃X₄ 3′

 

 

(SEQ ID NO;

89)

wherein X₁, X₂, X₃, and X₄ are nucleotides and N is a nucleic acid sequence composed of from about 0-25 nucleotides.

30. The method of claim 29, wherein X₁X₂ are nucleotides selected from the group consisting of:

GpT, GpG, GpA, and ApA; and

wherein X₃X₄ are nucleotides selected from the group consisting of;

TpT, CpT, and GpT.

31. The method of claim 19, wherein the subject is actively exposed to RSV.

32. The method of claim 19, wherein the subject is passively exposed to RSV.

33. The method of claim 19, wherein the oligonucleotide is administered to the subject on a regular basis.

34. The method of claim 33, wherein the regular basis is weekly.

35. The method of claim 33, wherein the regular basis is monthly.

36. The method of claim 19, wherein the administering is via a route selected from the group consisting of intranasal, intratracheal, and mucosal.

37. A method for treating a subject at risk of infection with hepatitis B virus (HBV), comprising:

administering to a subject at risk of infection with HBV an oligonucleotide having a sequence including at least the following formula;

5′

X₁CGX₂ 3′

wherein the oligonucleotide includes at least 8 nucleotides, C is unmethylated, X₁ and X₂ are nucleotides, and the subject is exposed to HBV at least 2 days after the oligonucleotide is administered to the subject to produce an immune response against HBV.

38. The method of claim 37, wherein the subject is exposed to HBV at least 4 days after the oligonucleotide is administered to the subject.

39. The method of claim 37, wherein the subject is exposed to HBV at least 7 days after the oligonucleotide is administered to the subject.

40. The method of claim 37, wherein the subject is exposed to HBV at least 15 days after the oligonucleotide is administered to the subject.

41. The method of claim 37, wherein the subject is exposed to HBV at least 30 days after the oligonucleotide is administered to the subject.

42. The method of claim 37, wherein the oligonucleotide is 8 to 100 nucleotides in length.

43. The method of claim 37, wherein the oligonucleotide includes a phosphate backbone modification which is a phosphorothioate or phosphorodithioate modification.

44. The method of claim 43, wherein the phosphate backbone modification occurs at the 5′

end of the oligonucleotide.

45. The method of claim 43, wherein the phosphate backbone modification occurs at the 3′

end of the oligonucleotide.

46. The method of claim 37, wherein the oligonucleotide has a sequence including at least the following formula:

5′

X₁X₂CGX₃X₄ 3′

wherein X₁X₂ are nucleotides selected from the group consisting of;

GpT, GpG, GpA, and ApA; and

wherein X₃X₄ are nucleotides selected from the group consisting of;

TpT, CpT, and GpT.

47. The method of claim 37, wherein the oligonucleotide has a sequence including at least the following formula:

5′

TCNTX₁X₂CGX₃X₄ 3′

 

 

(SEQ ID NO;

89)

wherein X₁, X₂, X₃, and X₄ are nucleotides and N is a nucleic acid sequence composed of from about 0-25 nucleotides.

48. The method of claim 47, wherein X₁X₂ are nucleotides selected from the group consisting of:

GpT, GpG, GpA, and ApA; and

wherein X₃X₄ are nucleotides selected from the group consisting of;

TpT, CpT, and GpT.

49. The method of claim 37, wherein the subject is actively exposed to HBV.

50. The method of claim 37, wherein the subject is passively exposed to HBV.

51. The method of claim 37, wherein the oligonucleotide is administered to the subject on a regular basis.

52. The method of claim 51, wherein the regular basis is weekly.

53. The method of claim 51, wherein the regular basis is monthly.

54. The method of claim 37, wherein the administering is via a route selected from the group consisting of intranasal, intratracheal, and mucosal.

55. A method for treating a subject at risk of infection with hepatitis A virus (HAV), comprising:

administering to a subject at risk of infection with HAV an oligonucleotide having a sequence including at least the following formula;

5′

X₁CGX₂ 3′

wherein the oligonucleotide includes at least 8 nucleotides, C is unmethylated, X₁ and X₂ are nucleotides, and the subject is exposed to HAV at least 2 days after the oligonucleotide is administered to the subject to produce an immune response against HAV.

56. The method of claim 55, wherein the subject is exposed to HAV at least 4 days after the oligonucleotide is administered to the subject.

57. The method of claim 55, wherein the subject is exposed to HAV at least 7 days after the oligonucleotide is administered to the subject.

58. The method of claim 55, wherein the subject is exposed to HAV at least 15 days after the oligonucleotide is administered to the subject.

59. The method of claim 55, wherein the subject is exposed to HAV at least 30 days after the oligonucleotide is administered to the subject.

60. The method of claim 55, wherein the oligonucleotide is 8 to 100 nucleotides in length.

61. The method of claim 55, wherein the oligonucleotide includes a phosphate backbone modification which is a phosphorothioate or phosphorodithioate modification.

62. The method of claim 61, wherein the phosphate backbone modification occurs at the 5′

end of the oligonucleotide.

63. The method of claim 61, wherein the phosphate backbone modification occurs at the 3′

end of the oligonucleotide.

64. The method of claim 55, wherein the oligonucleotide has a sequence including at least the following formula:

5′

X₁X₂CGX₃X₄ 3′

wherein X₁X₂ are nucleotides selected from the group consisting of;

GpT, GpG, GpA, and ApA; and

wherein X₃X₄ are nucleotides selected from the group consisting of;

TpT, CpT, and GpT.

65. The method of claim 55, wherein the oligonucleotide has a sequence including at least the following formula:

5′

TCNTX₁X₂CGX₃X₄ 3′

 

 

(SEQ ID NO;

89)

wherein X₁, X₂, X₃, and X₄ are nucleotides and N is a nucleic acid sequence composed of from about 0-25 nucleotides.

66. The method of claim 65, wherein X₁X₂ are nucleotides selected from the group consisting of:

GpT, GpG, GpA, and ApA; and

wherein X₃X₄ are nucleotides selected from the group consisting of;

TpT, CpT, and GpT.

67. The method of claim 55, wherein the subject is actively exposed to HAV.

68. The method of claim 55, wherein the subject is passively exposed to HAV.

69. The method of claim 55, wherein the oligonucleotide is administered to the subject on a regular basis.

70. The method of claim 69, wherein the regular basis is weekly.

71. The method of claim 69, wherein the regular basis is monthly.

72. The method of claim 55, wherein the administering is via a route selected from the group consisting of intranasal, intratracheal, and mucosal.