Chimeric immunomodulatory compounds and methods of using the same-II
The invention provides immunomodulatory compounds and methods for immunomodulation of individuals using the immunomodulatory compounds.
1. A chimeric immunomodulatory compound (CIC) comprising a core structure with the formula [N v ] x —S p , wherein S p is a multivalent spacer moiety covalently bonded to X independently selected nucleic acid moieties (N v ), wherein the nucleic acid moieties are between 3 and 7 nucleotides, wherein X is at least 3, wherein said multivalent spacer moiety is selected from the group consisting of a polysaccharide, glycerol, substituted glycerol, tetraaminobenzene, heptaaminobetacyclodextrin, 1,3,5-trihydroxycyclohexane, pentaerythritol, 1,3-diamino-2-propanol, substituted derivatives of 1,3,-diamino-2-propanol, [propyloxymethyl]ethyl compounds, tetraaminopentaerythritol, 1,4,8,11-tetraazacyclotetradecane, 1,4,7,10-tetraazacyclododecane, polyethyleneimino, or a 2-(hydroxymethyl)ethyl moiety, and wherein said CIC further comprises at least one additional non-nucleic acid spacer moiety.
2. The CIC of claim 1 wherein the multivalent spacer moiety comprises a polysaccharide, glycerol, pentaerythritol, 1,3-diamino-2-propanol, or a 2-(hydroxymethyl)ethyl moiety.
3. The CIC of claim 1 wherein the multivalent spacer moiety comprises crosslinked polysaccharide.
4. The CIC of claim 1 , wherein said at least one additional nonnucleic acid spacer moiety comprises hexaethylene glycol (HEG), wherein said HEG is covalently bound to said multivalent spacer moiety and to at least one of said nucleic acid moieties.
5. The CIC of claim 4 wherein the linkage between said HEG and said multivalent spacer moiety is a phosphodiester linkage or a phosphorothioate ester linkage, and wherein the linkage between said HEG and said nucleic acid moiety is a phosphodiester linkage or a phosphorothioate ester linkage.
6. The CIC of claim 1 wherein at least one nucleic acid moiety has the sequence 5′-[(X) 0-2 ]TCG[(X) 2-4 ]-3′, wherein each X is an independently selected nucleotide.
7. The CIC of claim 6 wherein said at least one nucleic acid moiety has the sequence 5′-TCG[(X) 2-4 ]-3′.
8. The CIC of claim 7 wherein said at least one nucleic acid moiety has the sequence 5′-TCG(A/T)[(X) 1-3 ]-3′.
9. The CIC of claim 8 wherein said at least one nucleic acid moiety has the sequence 5′-TCG(A/T)CG(A/T)-3′.
10. The CIC of claim 9 wherein said at least one nucleic acid moiety has the sequence 5′-TCGACGT-3′.
11. The CIC of claim 6 comprising at least 3 nucleic acid moieties having the sequence 5′-TCG[(X) 2-4 ]-3′.
12. The CIC of claim 11 comprising at least 30 nucleic acid moieties having the sequence 5′-TCG[(X) 2-4 ]-3′.
13. The CIC of claim 1 , where the linkages between the nucleic acid moieties and the nonnucleic acid spacer moieties are selected from phosphodiester linkages, phosphorothioate esters linkages, or a combination of phosphodiester linkages and phosphorothioate esters linkages.
14. A composition comprising a CIC of claim 1 and a pharmaceutically acceptable excipient.
15. A composition comprising a CIC of claim 1 and further comprising an antigen.
16. A composition comprising a CIC of claim 1 and further comprising a cationic microsphere.
17. The composition of claim 16 wherein the microsphere comprises a polymer of lactic acid and glycolic acid.
18. A CIC of claim 1 comprising a thioether group.
19. A CIC of claim 1 linked to a polypeptide.
20. The CIC of claim 1 , wherein at least one additional nonnucleic acid spacer moiety comprises HEG, triethylene glycol (TEG), propyl, butyl, or hexyl.
21. A chimeric immunomodulatory compound (CIC) having a structure selected from the group consisting of
(5′-TCGTCGA-3′-hexaethylene glycol (HEG)) 2 -
glycerol-HEG-5′-TCGTCGA-3′
(5′-TCGTCGA-3′-HEG) 2 -glycerol-HEG-3′-AGCTGCT-5′
(5′-TCGTCGA-3′-HEG) 2 -glycerol-HEG-5′-AACGTTC-3′
(5′-TCGTCGA-3′-HEG) 2 -glycerol-HEG-5′-AACGTTC-
3′-HEG-5′-TCGA-3′
(5′-TCGTCGA-3′-HEG) 3 -trebler-HEG-5′-AACGTTC-
3′-HEG-5′-TCGA-3′
(5′-TCGTCGA-3′-HEG) 2 -glycerol-HEG-5′-AACGTTC-
3′-HEG-5′-TCGACGT-3′
(5′-TCGACGT-3′-HEG) 2 -glycerol-HEG-5′-TCGACGT-3′
(5′-TCGTCGA-3′-TEG) 2 -glycerol-TEG-5′-TCGTCGA-3′
(5′-TCGTCGA-3′-HEG-HEG) 2 -glycerol-HEG-HEG-
5′-TCGTCGA-3′
(5′-TCGACGT-3′-HEG) 2 -symmetrical doubler-HEG-
5′-TCGACGT-3′
(5′-TCGACGT-3′-HEG) 3 -trebler-HEG-5′-TCGACGT-3′
((5′-TCGACGT-3′-HEG) 2 -glycerol-HEG) 2 -
glycerol-HEG-5′-TCGACGT-3′
(5′-TCGACGT-3′-HEG) 2 -glycerol-HEG-5′-AACGTTC-3′
((5′-TCGACGT-3′-HEG) 2 -glycerol-HEG) 2 -
glycerol-HEG-5′-T-3′
(5′-TCGACGT-3′-HEG) 3 -trebler-HEG-5′-T-3′
(5′-TCGACGT-3′-HEG) x -epichlorohydrin-
crosslinked sucrose (x = 150-250).
22. A composition comprising a CIC of claim 21 and a pharmaceutically acceptable excipient.
23. A composition comprising a CIC of claim 21 and further comprising an antigen.
24. A composition comprising a CIC of claim 21 and further comprising a cationic microsphere.
25. The composition of claim 24 wherein the microsphere comprises a polymer of lactic acid and glycolic acid.
26. A CIC of claim 21 further comprising a thioether group.
27. A CIC of claim 21 linked to a polypeptide.
28. The CIC of claim 3 wherein the cross-linked polysaccharide comprises epichlorohydrin-crosslinked sucrose (Ficoll®).
29. The CIC of claim 1 wherein X is 3 to 400.
30. The CIC of claim 1 wherein X is 3 to 200.
31. The CIC of claim 1 wherein X is 25 to 150.
32. The CIC of claim 1 wherein X is 50 to 150.
33. The CIC of claim 1 wherein X is 100 to 150.
34. The CIC of claim 1 , where the linkages between the nucleotides of the nucleic acid moieties are selected from phosphodiester linkages, phosphorothioate esters, phosphorodithioate ester linkages, or any combination thereof.