Adjuvant formulations comprising TLR4 agonists and methods of using the same
Formulations and methods, including vaccines and pharmaceutical compositions for inducing or enhancing an immune response are disclosed. The formulations generally comprise a TLR4 agonist and a metabolizable oil at a concentration of about 0.01%-1% v/v, wherein the hydrophobic:lipophilic balance (HLB) of the emulsion is greater than about 9.
1. An oil-in-water emulsion comprising a TLR4 agonist, 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), and a metabolizable oil, wherein the TLR4 agonist comprises synthetic GLA, wherein the metabolizable oil is present in the oil-in-water emulsion at a concentration of 0.01%-1% v/v, wherein the DMPC is present in the oil-and-water emulsion at a concentration of 0.002% to 2% w/v, and wherein the hydrophobic:lipophilic balance (HLB) of the oil-in-water emulsion is greater than about 9.
2. The oil-in-water emulsion of claim 1 , wherein the metabolizable oil is present in the oil-in-water emulsion at a concentration of 0.01%- 0.5% v/v.
3. The oil-in-water emulsion of claim 1 , wherein the emulsion does not comprise egg phosphatidyl choline (PC).
4. The oil-in-water emulsion of claim 3 , wherein the emulsion does not comprise an antioxidant.
5. The oil-in-water emulsion of claim 1 , wherein the HLB of the emulsion is greater than about 10.
6. The oil-in-water emulsion of claim 1 , wherein the HLB of the emulsion is between about 9-12.
7. The oil-in-water emulsion of claim 1 , wherein the synthetic GLA has the following structure:
where: R 1 , R 3 , R 5 , and R 6 are C 11 -C 20 alkyl; and R 2 and R 4 are C 12 -C 20 alkyl.
8. The oil-in-water emulsion of claim 7 , wherein R 1 , R 3 , R 5 , and R 6 are C 11 alkyl; and R 2 and R 4 are C 13 alkyl.
9. The oil-in-water emulsion of claim 1 , wherein the synthetic GLA has the following structure:
wherein R 1 , R 3 , R 5 , and R 6 are C 10 alkyl; and R 2 and R 4 are C 8 alkyl.
10. The oil-in-water emulsion of claim 1 , wherein the emulsion further comprises a surfactant.
11. The oil-in-water emulsion of claim 10 , wherein the surfactant is pluronic F68.
12. The oil-in-water emulsion of claim 1 , wherein the metabolizable oil is squalene.
13. The oil-in-water emulsion of claim 1 , wherein the emulsion further comprises an antioxidant.
14. The oil-in-water emulsion of claim 13 , wherein the antioxidant is vitamin E.
15. The oil-in-water emulsion of claim 1 , wherein the emulsion further comprises at least one antigen.
16. An oil-in-water emulsion comprising a synthetic GLA, a metabolizable oil at a concentration of 0.01%-1% v/v, and DMPC at a concentration of 0.002%-2% w/v, wherein the HLB of the emulsion is greater than about 10.
17. The oil-in-water emulsion of claim 16 , wherein the synthetic GLA has the following structure:
where: R 1 , R 3 , R 5 , and R 6 are C 11 -C 20 alkyl; and R 2 and R 4 are C 12 -C 20 alkyl.
18. The oil-in-water emulsion of claim 17 , wherein R 1 , R 3 , R 5 , and R 6 are C 11 alkyl; and R 2 and R 4 are C 13 alkyl.
19. The oil-in-water emulsion of claim 16 , wherein the synthetic GLA has the following structure:
or a pharmaceutically acceptable salt thereof, wherein:
L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 are the same or different and independently -O-, -NH- or -(CH 2 )-L 7 ,
L 8 , L 9 , and L 10 are the same or different and independently absent or -C(═O)—; Y 1 is an acid functional group;
Y 2 and Y 3 are the same or different and independently —OH, —SH, or an acid functional group;
Y 4 is —OH or —SH;
R 1 , R 3 , R 5 , and R 6 are the same or different and independently C 8-13 alkyl; and
R 2 and R 4 are the same or different and independently C 6-11 alkyl.
20. The oil-in-water emulsion of claim 19 , wherein R 1 , R 3 , R 5 , and R 6 are C 11 alkyl; and R 2 and R 4 are C 8 alkyl.
21. A method of stimulating an immune response in a subject comprising administering an oil-in-water emulsion of claim 1 to the subject and thereby stimulating an immune response in the subject.
22. The method of claim 21 , wherein the immune response is a non- specific immune response.
23. The method of claim 21 , wherein the immune response is an antigen-specific immune response.
24. The method of claim 21 , wherein the oil-in-water emulsion is administered intradermally.
25. The oil-in-water emulsion of claim 1 , wherein the synthetic GLA has the following structure:
or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 3 , R 5 , and R 6 are C 11-20 alkyl; and R 2 and R 4 are C 9-20 alkyl.
26. The oil-in-water emulsion of claim 1 , wherein the synthetic GLA has the following structure:
or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 3 , R 5 , and R 6 are C 11 -C 20 alkyl; and R 2 and R 4 are C 9 -C 20 alkyl.
27. The oil-in-water emulsion of claim 1 , wherein the synthetic GLA has the following structure:
or a pharmaceutically acceptable salt thereof.
28. The oil-in-water emulsion of claim 16 , wherein the synthetic GLA has the following structure:
or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 3 , R 5 , and R 6 are C 11-20 alkyl; and R 2 and R 4 are C 9-20 alkyl.
29. The oil-in-water emulsion of claim 16 , wherein the synthetic GLA has the following structure:
or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 3 , R 5 , and R 6 are C 11 -C 20 alkyl; and R 2 and R 4 are C 9 -C 20 alkyl.
30. The oil-in-water emulsion of claim 16 , wherein the synthetic GLA has the following structure:
or a pharmaceutically acceptable salt thereof.
31. An oil-in-water emulsion comprising a metabolizable oil and DMPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine), wherein the DMPC is present in the oil-and-water emulsion at a concentration of 0.002% to 2% w/v and wherein the emulsion does not comprise egg phosphatidyl choline (PC).
32. The oil-in-water emulsion of claim 31 , wherein the metabolizable oil is present in the oil-in-water emulsion at a concentration of 0.01%-4% v/v.
33. The oil-in-water emulsion of claim 31 , wherein the emulsion does not comprise an antioxidant.
34. The oil-in-water emulsion of claim 31 , wherein a hydrophobic:lipophilic balance (HLB) of the emulsion is greater than about 10.
35. The oil-in-water emulsion of claim 31 , wherein a hydrophobic:lipophilic balance (HLB) of the emulsion is between about 9-12.
36. The oil-in-water emulsion of claim 31 , further comprising a TLR4 agonist.
37. The oil-in-water emulsion of claim 36 , wherein the TLR4 agonist comprises MPL, 3D-MPL, or synthetic GLA.
38. The oil-in-water emulsion of claim 37 , wherein the synthetic GLA has the following structure:
where: R 1 , R 3 , R 5 , and R 6 are C 11 -C 20 alkyl; and R 2 and R 4 are C 12 -C 20 alkyl.
39. The oil-in-water emulsion of claim 38 , wherein R 1 , R 3 , R 5 , and R 6 are C 11 alkyl; and R 2 and R 4 are C 13 alkyl.
40. The oil-in-water emulsion of claim 37 , wherein the synthetic GLA has the following structure:
or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 3 , R 5 , and R 6 are C 11-20 alkyl; and R 2 and R 4 are C 12-20 alkyl.
41. The oil-in-water emulsion of claim 31 , wherein the emulsion further comprises a surfactant.
42. The oil-in-water emulsion of claim 41 , wherein the surfactant is pluronic F68.
43. The oil-in-water emulsion of claim 31 , wherein the metabolizable oil is squalene.
44. The oil-in-water emulsion of claim 31 , wherein the emulsion further comprises an antioxidant.
45. The oil-in-water emulsion of claim 44 , wherein the antioxidant is vitamin E.
46. The oil-in-water emulsion of claim 31 , wherein the emulsion further comprises at least one antigen.
47. A method of stimulating an immune response in a subject comprising administering an oil-in-water emulsion of claim 31 to the subject and thereby stimulating an immune response in the subject.
48. The method of claim 47 , wherein the immune response is a non- specific immune response.
49. The method of claim 47 , wherein the immune response is an antigen-specific immune response.
50. The method of claim 47 , wherein the oil-in-water emulsion is administered intradermally.
51. The oil-in-water emulsion of claim 31 , wherein the DMPC is present in the oil-in-water emulsion at a concentration of 0.015% to 0.25% w/v.
52. The oil-in-water emulsion of claim 32 , wherein the metabolizable oil is squalene.
53. The oil-in-water emulsion of claim 36 , wherein the metabolizable oil is squalene.
54. The oil-in-water emulsion of claim 51 , wherein the metabolizable oil is squalene.
55. The oil-in-water emulsion of claim 16 , wherein the metabolizable oil is squalene.
56. A method of stimulating an immune response in a subject comprising administering an oil-in-water emulsion of claim 16 to the subject and thereby stimulating an immune response in the subject.
57. The method of claim 56 , wherein the immune response is a non-specific immune response.
58. The method of claim 56 , wherein the immune response is an antigen-specific immune response.
59. The method of claim 56 , wherein the oil-in-water emulsion is administered intradermally.
60. The oil-in-water emulsion of claim 37 , wherein the TLR4 agonist comprises synthetic GLA.
61. The oil-in-water emulsion of claim 31 , wherein a hydrophobic:lipophilic balance (HLB) of the emulsion is greater than about 9.