Immunomodulatory compositions, formulations, and methods for use thereof
The invention provides new compositions and methods for immunomodulation of individuals. Immunomodulation is accomplished by administration of immunomodulatory polynucleotide/microcarrier (IMO/MC) complexes comprising 3-6mer immunomodulatory oligonucleotides. The IMO/MC complexes may be covalently or non-covalently bound. Also provided are immunomodulatory compositions comprising a 3-6mer IMO encapsulated in an MC.
1. A composition comprising a complex of an oligonucleotide three to six nucleotides in length bound to the surface of a solid phase microcarrier (MC), wherein said oligonucleotide consists of a sequence according to the formula 5′-X 1 TCGX 2 -3′ or 5′-X 1 UCGX 2 -3′, where X 1 is zero or one nucleotide and X 2 is zero to three nucleotides, and wherein the oligonucleotide alone induces interferon-α secretion at a level of no more than 20% of the complex.
2. The composition of claim 1 , wherein said oligonucleotide consists of a sequence according to the formula 5′-X 1 TCGX 2 -3′.
3. The composition according to claim 1 , wherein said oligonucleotide consists of a sequence according to the formula 5′-X 1 UCGX 2 -3′.
4. The composition of claim 1 , wherein said oligonucleotide is six nucleotides in length.
5. The composition of claim 1 , wherein said oligonucleotide is five nucleotides in length.
6. The composition of claim 1 , wherein said oligonucleotide is four nucleotides in length.
7. The composition of claim 1 , wherein said oligonucleotide is three nucleotides in length.
8. The composition of claim 1 , wherein said oligonucleotide comprises at least one phosphorothioate linkage.
9. The composition of claim 1 , wherein said oligonucleotide comprises at least one modified cytosine.
10. The composition of claim 1 , wherein the microcarrier is a biodegradable polymeric particle.
11. The composition of claim 10 , wherein the biodegradable polymeric particle is a biodegradable polyester particle.
12. The composition of claim 11 , wherein the biodegradable polyester particle comprises a polymer selected from the group consisting of poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid), poly(caprolactone), and polymethylidene malonate.
13. The composition of claim 1 , wherein said microcarrier comprises a cationic moiety.
14. The composition of claim 1 , wherein said microcarrier comprises an inorganic particle.
15. The composition of claim 14 , wherein said inorganic particle comprises an inorganic crystalline material.
16. The composition of claim 15 , wherein said inorganic crystalline material is selected from the group consisting of hydroxyapatite and calcium phosphate.
17. The composition of claim 1 , wherein said microcarrier is 10 nm to 10 μm in size.
18. The composition of claim 1 , wherein said microcarrier is 25 nm to 5 μm in size.
19. The composition of claim 1 , further comprising an antigen.
20. The composition of claim 19 , wherein said antigen is linked to said complex.
21. The composition of claim 20 , wherein said antigen is non-covalently linked to said complex.
22. The composition of claim 20 , wherein said antigen is covalently linked to said complex.
23. The composition of claim 22 , wherein said antigen is covalently linked to the MC of the complex.
24. The composition of claim 22 , wherein said antigen is covalently linked to the oligonucleotide of the complex.
25. The composition of claim 19 , wherein said antigen is not linked to said complex.
26. The composition of claim 1 , wherein said composition does not comprise an antigen.
27. The composition of claim 1 , wherein said complex does not comprise a further oligonucleotide greater than 6 nucleotides in length.
28. A pharmaceutical composition, comprising:
a complex of an oligonucleotide three to six nucleotides in length bound to the surface of a solid phase microcarrier (MC), wherein said has oligonucleotide consists of a sequence according to the formula 5′-X 1 TCGX 2 -3′ or 5′-X 1 UCGX 2 -3′, where X 1 is zero or one nucleotide and X 2 is zero to three nucleotides, and wherein the oligonucleotide alone induces interferon-α secretion at a level of no more than 20% of the complex; and a pharmaceutically acceptable excipient.
29. A method of modulating an immune response in an individual, comprising administering to said individual an amount of a complex of effective to modulate an immune response in said individual, wherein the complex comprises an oligonucleotide three to six nucleotides in length bound to the surface of a solid phase microcarrier (MC), wherein said oligonucleotide consists of a sequence according to the formula 5′-X 1 TCGX 2 -3′ or 5′-X 1 UCGX 2 -3′, where X 1 is zero or one nucleotide and X 2 is zero to three nucleotides, and wherein the oligonucleotide alone induces interferon-α secretion at a level of no more than 20% of the complex.
30. The composition of claim 1 , wherein the oligonucleotide is covalently bound to the surface of the MC.
31. The composition of claim 1 , wherein the oligonucleotide is non-covalently bound to the surface of the MC.
32. The composition of claim 1 , wherein said oligonucleotide does not comprise a palindromic sequence.
33. The method of claim 29 , wherein said oligonucleotide consists of a sequence according to the formula 5′-X TCGX 2 -3′.
34. The method of claim 29 , wherein said oligonucleotide consists of a sequence according to the formula 5′-X 1 UCGX 2 -3′.
35. The method of claim 29 , wherein said oligonucleotide comprises at least one phosphorothioate linkage.
36. The method of claim 29 , wherein said oligonucleotide does not comprise a palindromic sequence.
37. A method of increasing interferon-alpha (IFN-α) in an individual, comprising administering to said individual an amount of a complex effective to increase IFN-α in said individual, wherein the complex comprises an oligonucleotide three to six nucleotides in length bound to the surface of a solid phase microcarrier (MC), wherein said oligonucleotide consists of a sequence according to the formula 5′-X 1 TCGX 2 -3′ or 5′-X 1 UCGX 2 -3′, where X 1 is zero or one nucleotide and X 2 is zero to three nucleotides, and wherein the oligonucleotide alone induces interferon-α secretion at a level of no more than 20% of the complex.