CA2451974C - Chimeric immunomodulatory compounds and methods of using the same - Google Patents

Chimeric immunomodulatory compounds and methods of using the same Download PDF

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CA2451974C
CA2451974C CA2451974A CA2451974A CA2451974C CA 2451974 C CA2451974 C CA 2451974C CA 2451974 A CA2451974 A CA 2451974A CA 2451974 A CA2451974 A CA 2451974A CA 2451974 C CA2451974 C CA 2451974C
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heg
formula
cic
hexaethylene glycol
immunomodulatory molecule
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CA2451974A1 (en
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Karen L. Fearon
Dino Dina
Stephen F. Tuck
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Dynavax Technologies Corp
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Dynavax Technologies Corp
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Abstract

The invention provides for novel chimeric immunomodulatory compounds (CIC), which contain nucleic acid moieties and non-nucleic acid moieties as spacers connecting the nucleic acid moieties. CIC can be used to modulate the immune response in an individual, such as stimulating interferon-alpha, interferon-gamma and/or stimulating B
cell response in an individual. Such CIC are useful for treating diseases where a Th-1 type of immune response is helpful.

Claims (89)

CLAIMS:
1. A chimeric immunomodulatory compound (CIC) that comprises a core structure with the formula:
N1-S1-N2 or N1-S1-N2-S2-N3 wherein N1, N2, and N3 are nucleic acid moieties, S1 and S2 are non-nucleic acid spacer moieties, S1 and S2 are covalently bound to exactly two nucleic acid moieties, wherein at least one non-nucleic acid spacer moiety comprises oligoethylene glycol, glycerol, a C2-C10 alkyl, an abasic nucleotide, pentaerythritol, 1,3-diamino-2-propanol, 2-(hydroxymethyl)ethyl, a polysaccharide, or a dendrimerõ
wherein at least one nucleic acid moiety comprises the sequence 5'-TCG-3' at the prime position, wherein all the nucleic acid moieties that comprise the sequence 5'-CG-3' are less than 8 nucleotides in length and wherein the CIC has at least one immunomodulatory activity consisting of:
(a) the ability to stimulate IFN-gamma production by human peripheral blood mononuclear cells;
(b) the ability to stimulate IFN-alpha production by human peripheral blood mononuclear cells; or (c) the ability to stimulate B cell proliferation.
2. The CIC of claim 1 wherein at least one nucleic acid moiety comprising the sequence 5'-TCG-3' has a free 5' end.
3. A chimeric immunomodulatory compound (CIC) that comprises a core structure with the formula:[N v]x---S p wherein S p is a multivalent spacer covalently bonded to X
independently selected nucleic acid moieties, N v, and wherein X is at least 3, wherein at least one non-nucleic acid spacer moiety comprises oligoethylene glycol, glycerol, a C2-C10 alkyl, an abasic nucleotide, pentaerythritol, 1,3-diamino-2-propanol, 2-(hydroxymethyl)ethyl, a polysaccharide, or a dendrimer, wherein at least one nucleic acid moiety comprises the sequence 5'-TCG-3' at the 5 prime position, wherein all the nucleic acid moieties that comprise the sequence 5'-CG-3' are less than 8 nucleotides in length and wherein the CIC has at least one immunomodulatory activity consisting of:
(a) the ability to stimulate IFN-gamma production by human peripheral blood mononuclear cells;
(b) the ability to stimulate IFN-alpha production by human peripheral blood mononuclear cells; or (c) the ability to stimulate B cell proliferation.
4. The CIC of claim 3 wherein at least one nucleic acid moiety comprising the sequence 5'-TCG-3' has a free 5' end.
5. The CIC of claim 3 wherein X is from 3 to 50.
6. The CIC of claim 3 wherein X is from 50 to 500.
7. The CIC of claim 3 wherein Sp comprises a dendrimer or a polysaccharide.
8. The CIC of claim 7 wherein Sp comprises a crosslinked polysaccharide.
9. The CIC of claim 8 wherein the cross-linked polysaccharide comprises FicolI.TM.
10. The CIC of claim 9 wherein X is 25 to 150.
11. The CIC of claim 9 wherein X is 50 to 150.
12. The CIC of claim 9 wherein X is 100 to 150.
13. The CIC of claim 9 wherein X is 3 to 200.
14. The CIC of any one of claims 1 to 12 comprising a compound non-nucleotide spacer moiety.
15. The CIC of any one of claims 1 to 14 wherein the non-nucleotide spacer comprises a HEG subunit wherein HEG represents hexaethylene glycol.
16. The CIC of any one of claims 1 to 15 wherein the non-nucleotide spacer comprises phosphodiester or phosphorothioate linked oligoethylene glycol moiety.
17. The CIC of claim 14 comprising a first spacer subunit comprising a dendrimer, a polysaccharide, glycerol, pentaerythritol, or 2-(hydroxymethyl)ethyl and further comprising at least one HEG subunit, wherein said HEG subunit is covalently bound to the first spacer subunit and to a nucleic acid moiety and wherein HEG represents hexaethylene glycol.
18. The CIC of claim 17 wherein the linkage between the HEG subunit and the first spacer element is a phosphodiester linkage or a phosphorothioate ester linkage and the linkage between the HEG subunit and the nucleic acid moiety is a phosphodiester linkage or a phosphorothioate ester linkage.
19. The CIC of any one of claims 1 to 18 wherein at least one nucleic acid moiety comprises the sequence 5' -TCGA-3' .
20. The CIC of any one of claims 1 to 18 wherein at least one nucleic acid moiety comprises the sequence 5'-[(X)0-2]TCG[(X)2-4]-3, wherein each X is an independently selected nucleotide.
21. The CIC of claim 20 wherein at least one nucleic acid moiety consists of the sequence 5 ' -TCGR[(X)2.4]-3 ' ; 5' -TCG(A/T)[(X)1-3]-3' ; or 5 ' -TCG(A/T)CG(A/T)-3' wherein each X is an independently selected nucleotide.
22. The CIC of claim 21 wherein at least one nucleic acid moiety consists of the sequence 5'-TCGACGT-3' or 5'-TCGTCGA-3'.
23. The CIC of any one of claims 1 to 20 wherein all of the nucleic acid moieties in the CIC consist of a sequence of the formula 5'-TCG[(X)2-4]-3'; 5'-TCG(A/T)[(X)1-3]-3'; or 5'-TCG(A/T)CG(A/T)-3' wherein each X is an independently selected nucleotide.
24. The CIC of any one of claims 1 to 23 wherein all the nucleic acid moieties that comprise the sequence 5'-TCG-3' are 3-7 nucleotides in length.
25. The CIC of any one of claims 1 to 24 wherein all of the nucleic acid moieties are the same.
26. The CIC of any one of claims 1 to 25 wherein at least one nucleic acid moiety of the CIC (i) does not have isolated immunological activity or (ii) has inferior isolated immunological activity.
27. The CIC of claim 26, wherein no nucleic acid moiety of the CIC has isolated immunomodulatory activity.
28. A chimeric immunomodulatory molecule of the formula: 5'-TCGTCGA-3'-HEG-5'-ACGTTCG-3'-HEG-5'-AGATGAT-3' wherein HEG represents hexaethylene glycol.
29. A chimeric immunomodulatory molecule of the formula: 5'-TCGTCG-3'-HEG-5'-ACGTTCG-3'-HEG-5'-AGATGAT-3' wherein HEG represents hexaethylene glycol.
30. A chimeric immunomodulatory molecule of the formula: 5'-TCGTCGA-3'-HEG-5'-TCGTCGA-3'-HEG-5'-TCGTCGA-3' wherein HEG represents hexaethylene glycol.
31. A chimeric immunomodulatory molecule of the formula: 5'-TCGTCG-3'-HEG-5'-TCGTCG-3'-HEG-5'-TCGTCG-3' wherein HEG represents hexaethylene glycol.
32. A chimeric immunomodulatory molecule of the formula: 5'-TCGTCG-3'-HEG-5'-AACGTT-3'-HEG-5'-AGATGAT-3' wherein HEG represents hexaethylene glycol.
33. A chimeric immunomodulatory molecule of the formula: 5'-TCGTCG-3'-HEG-5'-ACGTTCG-3'-HEG-5'-AGATGAT-3'-TEG wherein HEG represents hexaethylene glycol and TEG represents triethylene glycol.
34. A chimeric immunomodulatory molecule of the formula: HEG-5'-TCGTCG-3'-HEG-5'-ACGTTCG-3'-HEG-5'-AGATGAT-3'-TEG wherein HEG represents hexaethylene glycol and TEG represents triethylene glycol.
35. A chimeric immunomodulatory molecule of the formula: 5'-TCGTTTT-3'-HEG-5'-TCGTTTT-3'-HEG-5'-TCGTTTT-3' wherein HEG represents hexaethylene glycol.
36. A chimeric immunomodulatory molecule of the formula: 5'-TCGTCGT-3'-HEG-5'-TCGTCGT-3'-HEG-5'-TCGTCGT-3' wherein HEG represents hexaethylene glycol.
37. A chimeric immunomodulatory molecule of the formula: 5'-TCGAGAT-3'-HEG-5'-TCGAGAT-3'-HEG-5'-TCGAGAT-3' wherein HEG represents hexaethylene glycol.
38. A chimeric immunomodulatory molecule of the formula: 5'-TCGTCGT-3'-HEG-5'-TGTCGTT-3'-HEG-5'-TGTCGTT-3' wherein HEG represents hexaethylene glycol.
39. A chimeric immunomodulatory molecule of the formula: 5'-TCGTCGA-3'-HEG-5'-ACGTTCG-3'-HEG-5'-TCGTCGA-3' wherein HEG represents hexaethylene glycol.
40. A chimeric immunomodulatory molecule of the formula: 5'-TCGTCGA-3'-HEG-5'-ACGTTCG-3'-HEG-5'-GGGGGG-3' wherein HEG represents hexaethylene glycol.
41. A chimeric immunomodulatory molecule of the formula: 5'-TCGAACG-3'-HEG-5'-TCGAACG-3'-HEG-5'-TCGAACG-3' wherein HEG represents hexaethylene glycol.
42. A chimeric immunomodulatory molecule of the formula: 5'-TCGACGT-3'-HEG-5'-TCGACGT-3'-HEG-5'-TCGACGT-3' wherein HEG represents hexaethylene glycol.
43. A chimeric immunomodulatory molecule of the formula: 5'-TCGTCGA-3'-HEG-5'-AACGTTC-3'-HEG-5'-AGATGAT-3' wherein HEG represents hexaethylene glycol.
44. A chimeric immunomodulatory molecule of the formula: 5'-TCGTCGA-3'-HEG-5' -AACGTTC-3'-HEG-5'-TCGTCGA-3' wherein HEG represents hexaethylene glycol.
45. A chimeric immunomodulatory molecule of the formula: 5'-TCGTCGA-3'-HEG-5'-AGATGAT-3'-HEG-5'-ACGTTCG-3' wherein HEG represents hexaethylene glycol.
46. A chimeric immunomodulatory molecule of the formula: 5'-TCGACTC-3'-HEG-5'-TCGAGCG-3'-HEG-5'-TTCTCTT-3' wherein HEG represents hexaethylene glycol.
47. A chimeric immunomodulatory molecule of the formula: 5'-TCGTCGA-3'-HEG-5'-TCGTCGA-3'-HEG-3'-AGCTGCT-5' wherein HEG represents hexaethylene glycol.
48. A chimeric immunomodulatory molecule of the formula: 5'-TCGAT-3'-HEG-5'-TCGAT-3'-HEG-5'-TCGAT-3'-HEG-5'-TCGAT-3' wherein HEG represents hexaethylene glycol.
49. A chimeric immunomodulatory molecule of the formula: 5'-TCGTCGA-3'-HEG-5'-TCGTCGA-3'-HEG-5'-AACGTTC-3'-HEG-5'-AGAT-3' wherein HEG represents hexaethylene glycol.
50. A chimeric immunomodulatory molecule of the formula: 5'-TCGACGT-3'-HEG-5'-TCGACGT-3'-HEG-5'-TCGACGT-3'-HEG-5'-TCGACGT-3' wherein HEG
represents hexaethylene glycol.
51. A chimeric immunomodulatory molecule of the formula: 5'-TCGATTT-3'-HEG-5'-TCGATTT-3'-HEG-5'-TCGATTT-3' wherein HEG represents hexaethylene glycol.
52. A chimeric immunomodulatory molecule of the formula: 5'-TCGCTTT-3'-HEG-5'-TCGCTTT-3'-HEG-5'-TCGCTTT-3' wherein HEG represents hexaethylene glycol.
53. A chimeric immunomodulatory molecule of the formula: 5'-TCGGTTT-3'-HEG-5'-TCGGTTT-3'-HEG-5'-TCGGTTT-3' wherein HEG represents hexaethylene glycol.
54. A chimeric immunomodulatory molecule of the formula: (5'-TCGTCGA-3'-HEG)2-glycerol-HEG-5'-TCGTCGA-3' wherein HEG represents hexaethylene glycol.
55. A chimeric immunomodulatory molecule of the formula: (5'-TCGTCGA-3'-HEG)2-glycerol-HEG-3'-AGCTGCT-5' wherein HEG represents hexaethylene glycol.
56. A chimeric immunomodulatory molecule of the formula: (5'-TCGTCGA-3'-HEG)2-glycerol-HEG-5'-AACGTTC-3' wherein HEG represents hexaethylene glycol.
57. A chimeric immunomodulatory molecule of the formula: (5'-TCGTCGA-3'-HEG)2-glycerol-HEG-5'-AACGTTC-3'-HEG-5'-TCGA-3' wherein HEG represents hexaethylene glycol.
58. A chimeric immunomodulatory molecule of the formula: (5'-TCGTCGA-3'-HEG)3-trebler-HEG-5'-AACGTTC-3'-HEG-5'-TCGA-3' wherein HEG represents hexaethylene glycol.
59. A chimeric immunomodulatory molecule of the formula: (5'-TCGTCGA-3'-HEG)2-glycerol-HEG-5'-AACGTTC-3'-HEG-5'-TCGACGT-3' wherein HEG represents hexaethylene glycol.
60. A chimeric immunomodulatory molecule of the formula: (5'-TCGACGT-3'-HEG) 2-glycerol-HEG-5'-TCGACGT-3' wherein HEG represents hexaethylene glycol.
61. A chimeric immunomodulatory molecule of the formula: (5'-TCGTCGA-3'-TEG)2-glycerol-TEG-5'-TCGTCGA-3' wherein HEG represents hexaethylene glycol.
62. A chimeric immunomodulatory molecule of the formula: (5'-TCGTCGA-3'-HEG-HEG)2-glycerol-HEG-HEG-5'-TCGTCGA-3' wherein HEG represents hexaethylene glycol.
63. A chimeric immunomodulatory molecule of the formula: (5'-TCGACGT-3'-HEG)2-symmetrical doubler-HEG-5'-TCGACGT-3' wherein HEG represents hexaethylene glycol.
64. A chimeric immunomodulatory molecule of the formula: (5 '-TCGACGT-3 '-HEG)3-trebler-HEG-5'-TCGACGT-3' wherein HEG represents hexaethylene glycol.
65. A chimeric immunomodulatory molecule of the formula: ((5'-TCGACGT-3'-HEG)2-glycerol-HEG)2-glycerol-HEG-5'-TCGACGT-3' wherein HEG represents hexaethylene glycol.
66. A chimeric immunomodulatory molecule of the formula: (5'-TCGACGT-3'-HEG)2-glycerol-HEG-5'-AACGTTC-3' wherein HEG represents hexaethylene glycol.
67. A chimeric immunomodulatory molecule of the formula: ((5'-TCGACGT-3'-HEG)2-glycerol-HEG)2-glycerol-HEG-5'-T-3' wherein HEG represents hexaethylene glycol.
68. A chimeric immunomodulatory molecule of the formula: (5'-TCGACGT-3'-HEG)3-trebler-HEG-5'-T-3'.
69. A chimeric immunomodulatory molecule of the formula: (5'-TCGACGT-3'-HEG)150-250-Ficoll.Tm.400.
70. The CIC of any one of claims 1 to 69 wherein the linkages between nucleotides of the nucleic acid moieties are phosphodiester linkages and phosphorothioate esters linkages.
71. The CIC of any one of claims 1 to 70 wherein the linkages between the nucleotides of the nucleic acid moieties, the nucleic acid moieties and spacer moieties, and between subunits of spacer moieties are phosphodiester or phosphorothioate ester.
72. A composition comprising a CIC described in any one of claims 1 to 71 and a pharmaceutically acceptable excipient.
73. The composition of claim 72 wherein the composition is endotoxin-free.
74. The composition of claim 72 or 73 further comprising an antigen.
75. The composition of claim 72 or 73 further comprising a cationic microsphere.
76. The composition of claim 75 wherein the microsphere comprises a polymer of lactic acid and glycolic acid.
77. Use of a CIC of any one of claims 1 to 71 or a composition of any one of claims 72 to 76 for modulating an immune response in an individual.
78. The use of claim 77 wherein said individual suffers from a disorder associated with a Th2-type immune response.
79. The use of claim 78 wherein said disorder associated with a Th2-type immune response is an allergy or allergy-induced asthma.
80. The use of claim 77 wherein said individual has an infectious disease.
81. Use of a CIC of any one of claims 1 to 71 or a composition of any one of claims 72 to 76 for increasing interferon-gamma (IFN-y) in an individual.
82. The use of claim 81 wherein said individual has idiopathic pulmonary fibrosis.
83. Use of a CIC of any one of claims 1 to 71 or a composition of any one of claims 72 to 76 for increasing interferon-alpha (IFN-.alpha.) in an individual.
84. The use of claim 83 wherein said individual has a viral infection.
85. Use of an effective amount of a CIC of any one of claims 1 to 71 or a composition of any one of claims 72 to 76 for ameliorating a symptom of allergy or allergy-induced asthma in an individual.
86. Use of an effective amount of a CIC of any one of claims 1 to 71 or a composition of any one of claims 72 to 76 for ameliorating an IgE-related disorder in an individual.
87. The use of claim 86 wherein said IgE-related disorder is an allergy.
88. The use of claim 86 wherein said IgE-related disorder is an allergy-related disorder.
89 Use of an effective amount of a CIC of any one of claims 1 to 71 or a composition of any one of claims 72 to 76 for treating cancer.
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