Chimeric immunomodulatory compounds and methods of using the same-II

• US 8,222,398 B2
• Filed: 10/01/2008
• Issued: 07/17/2012
• Est. Priority Date: 06/21/2001
• Status: Expired due to Term

• Current Assignee: Dynamax Technologies Limited
• Original Assignee: Dynamax Technologies Limited
• Inventors: Fearon, Karen L., Dina, Dino, Tuck, Stephen F.
• Primary Examiner(s): Minnifield, Nita M
• Application Number:
  US12/243,915
• Publication Number:
  US 20090317480A1
• Time in Patent Office: 1,385 Days
• Field of Search: None
• US Class Current: 536/25.6
• CPC Class Codes: A61K 2039/55561 CpG containing adjuvants; Oligonucleotide containing adjuvants
• CPC Class Codes: A61K 39/12 Viral antigens
• CPC Class Codes: A61K 39/292 Serum hepatitis virus, hepatitis B virus, e.g. Australia antigen
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: C07H 15/18 Acyclic radicals, substituted by carbocyclic rings
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C12N 15/117 Nucleic acids having immunomodulatory properties, e.g. containing CpG-motifs
• CPC Class Codes: C12N 2310/17 Immunomodulatory nucleic acids
• CPC Class Codes: C12N 2310/315 : Phosphorothioates
• CPC Class Codes: C12N 2310/332 : Abasic residue
• CPC Class Codes: C12N 2310/351 : Conjugate
• CPC Class Codes: C12N 2310/3519 : Fusion with another nucleic acid
• CPC Class Codes: C12N 2310/52 : branched
• CPC Class Codes: C12N 2730/10134 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Abstract

The invention provides immunomodulatory compounds and methods for immunomodulation of individuals using the immunomodulatory compounds.

Claims

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.

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.

21. A chimeric immunomodulatory compound (CIC) having a structure selected from the group consisting of

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.