Chimeric immunomodulatory compounds and methods of using the same—IV
The invention provides immunomodulatory compounds and methods for immunomodulation of individuals using the immunomodulatory compounds.
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.