Chimeric immunomodulatory compounds and methods of using the same—IV

• US 8,114,418 B2
• Filed: 10/30/2006
• Issued: 02/14/2012
• Est. Priority Date: 06/21/2001
• Status: Active Grant

• 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:
  US11/590,150
• Publication Number:
  US 20070049550A1
• Time in Patent Office: 1,933 Days
• Field of Search: None
• US Class Current: 424/278.1
• 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 branched chimeric immunomodulatory compound (CIC) comprising a core structure with the formula [N_v]_A—

S_p wherein;

(a) A is at least 3;

(b) S_p is a multivalent spacer moiety covalently bonded to A independently selected nucleic acid moieties (N_v);

(c) at least one of the nucleic acid moieties

comprises a sequence 5′

-TCGY in the 5′

position of the nucleic acid moiety, where Y is selected from the group consisting of XCGX, XTCG, XXCG, and CGXX, where X is any nucleotide, and

(d) said CIC stimulates production of interferon alpha from human peripheral blood mononuclear cells.

2. The CIC of claim 1 comprising at least one multivalent nonnucleic acid spacer moiety.

3. The CIC of claim 1 wherein at least one nonnucleic acid spacer moiety comprises hexaethylene glycol, triethylene glycol, propyl, butyl, hexyl, pentaerythritol, 2-(hydroxymethyl)ethyl, glycerol, a polysaccharide, 1,3-diamino-2-propanol, or a dendrimer.

4. The CIC of claim 1 wherein the CIC stimulates production of IFN-α

from human peripheral blood mononuclear cells but does not stimulate human B cell proliferation.

5. The CIC of claim 1 wherein the nucleic acid moiety comprising the sequence 5′

CGAX_N, where X is any nucleotide and N is an integer from 4 to 9.

6. The CIC of claim 1 comprising a nucleic acid moiety comprising the sequence 5′

-TCGACGX_N, where X is any nucleotide and N is 1, 2, 3, or an integer from 4 to 7.

7. The CIC of claim 6 wherein N is 1.

8. The CIC of claim 7 wherein X is T.

9. The CIC of claim 8 having the structure (5′

-TCGACGT-HEG)₂-glycerol-HEG-5′

-TCGACGT or (5′

-TCGACGT-HEG)₃-trebler-HEG-5′

-TCGACGT.

10. The CIC of claim 1 wherein the CIC stimulates production of IFN-α

from human peripheral blood mononuclear cells and stimulates little human B cell proliferation.

11. A composition comprising a CIC of claim 1, 4, or 10 and a pharmaceutically acceptable excipient.

12. A composition comprising a CIC of claim 11 and further comprising an antigen.

13. A composition comprising a CIC of claim 11 and further comprising a cationic microsphere.

14. A method of modulating an immune response in an individual comprising administering to an individual a CIC of claim 1 in an amount sufficient to modulate an immune response in said individual.

15. A method of modulating an immune response in an individual comprising administering to an individual a CIC of claim 4 in an amount sufficient to modulate an immune response in said individual.