TLR9 agonist and CD40 agonist immunostimulatory combinations
View Patent ↗The present invention provides immunostimulatory combinations. Generally, the immunostimulatory combinations include a TLR agonist and a TNF/R agonist. Certain immunostimulatory combinations also may include an antigen.
1. An immunostimulatory composition suitable for administration to a human subject in need of immunotherapy comprising:(i) at least one Toll-Like Receptor 9 (TLR9) agonist, and (ii) at least one anti-CD40 agonistic antibody or agonistic anti-CD40 antibody fragment; and (iii) a pharmaceutically acceptable carrier, wherein (i) and (ii) are each comprised in an amount such that, in combination with the other, is effective to produce a synergistic increase in a human subject on either or both the generation of activated CD8 + T cells or the generation of memory CD8 + T cells in response to an antigen upon administration to a human subject in need of immunotherapy.
2. The immunostimulatory composition of claim 1 wherein the at least one TLR9 agonist comprises CpG or a CpG containing compound.
3. The immunostimulatory composition of claim 1 which in addition comprises another TLR agonist selected from a TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7 or TLR8 agonist.
4. The immunostimulatory composition of claim 3 wherein the another TLR agonist comprises an IRM compound, MALP-2, Pam3cys, LPS, polyIC or a combination of the foregoing.
5. The immunostimulatory composition of claim 3 wherein the another TLR agonist is selected from an imidazoquinoline amine, a tetrahydroimidazoquinoline amine, an imidazopyridine amine, a 1,2-bridged imidazoquinoline amine, a 6,7-fused cycloalkylimidazopyridine amine, an imidazonaphthyridine amine, a tetrahydroimidazonaphthyridine amine, an oxazoloquinoline amine, a thiazoloquinoline amine, an oxazolopyridine amine, a thiazolopyridine amine, an oxazolonaphthyridine amine, or a thiazolonaphthyridine amine.
6. The immunostimulatory composition of claim 1 which is suitable for administration to a human subject in need of immunotherapy by a route selected from the group consisting of oral, nasal, topical, and injection.
7. The immunostimulatory composition of claim 6 which is suitable for injection to a human subject in need of immunotherapy.
8. The immunostimulatory composition of claim 7 wherein injection is selected from the group consisting of subcutaneous, intravenous, intraperitoneal, intramuscular and intravenous.
9. A method of human immunotherapy which comprises administering to a human subject in need thereof an immunostimulatory composition according to claim 1 under conditions that elicit a synergistic effect on an immune response to an antigen, wherein said synergistic effect comprises either or both of a synergistic increase in the generation of activated CD8 + T cells or the generation of memory CD8 + T cells in response to an antigen upon administration of said immunostimulatory composition to said human subject.
10. The method of claim 9 wherein the antigen comprises a microbial antigen.
11. The method of claim 9 wherein the antigen comprises a viral antigen.
12. The method of claim 9 wherein the antigen comprises a bacterial, yeast, parasite or fungal antigen.
13. The method of claim 9 wherein the immunostimulatory composition is administered via injection.
14. The method of claim 13 wherein injection is selected from the group consisting of intraperitoneal, intramuscular, intravenous, and subcutaneous.
15. The method of claim 9 wherein the administered immunostimulatory composition comprises an agonistic anti- CD40 antibody.
16. The method of claim 9 wherein the administered immunostimulatory composition comprises an agonistic anti-CD40 antibody fragment.
17. The method of claim 9 wherein the administered immunostimulatory composition comprises an additional TLR agonist selected from the group consisting of a TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, and TLR8 agonist.
18. The method of claim 17 wherein the administrated immunostimulatory composition comprises at least one TLR7 or TLR8 agonist.
19. The method of claim 9 wherein the antigen is a cancer or tumor antigen.
20. The method of claim 19 wherein the antigen is a melanoma antigen.
21. The composition of claim 20 wherein the melanoma antigen is selected from the group consisting of p5 protein, gp75, oncofetal antigen, GM2 ganglioside, GD2 ganglioside, Melan-A/MART-1, cdc27, MAGE-3, p21ras, and gp100.
22. A vaccine composition suitable for administration to a human subject in need thereof comprising:(i) at least one TLR9 agonist which is a TLR9 agonist and ;(ii) at least one CD40 agonistic antibody or agonistic CD40 antibody fragment; (iii) at least one antigen; and(iv) at least one pharmaceutically acceptable carrier; wherein (i) and (ii) are each comprised in an amount that, in combination with the other, is effective for inducing a synergistic immune response to the (iii) antigen in a human subject upon administration of the vaccine wherein said synergistic response comprises a synergistic increase in the generation of activated CD8 + T cells or the generation of memory CD8 + T cells in response to an antigen upon administration of said immunostimulatory composition to a human subject.
23. The vaccine composition of claim 22 which further comprises another TLR agonist selected from the group consisting of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, and TLR8 agonists.
24. The vaccine composition of claim 23 wherein the another TLR agonist comprises an immune response modifier (IRM) compound or an agonist of TLR2, TLR7 or TLR8.
25. The vaccine composition of claim 23 wherein the another TLR agonist comprises an IRM compound, MALP-2, Pam3cys, LPS, polyIC, or a combination of the foregoing.
26. The vaccine composition of claim 23 wherein the another TLR agonist comprises an imidazoquinoline amine, a tetrahydroimidazoquinoline amine, an imidazopyridine amine, a 1,2-bridged imidazoquinoline amine, a 6,7-fused cycloalkylimidazopyridine amine, an imidazonaphthyridine amine, a tetrahydroimidazonaphthyridine amine, an oxazoloquinoline amine, a thiazoloquinoline amine, an oxazolopyridine amine, a thiazolopyridine amine, an oxazolonaphthyridine amine, or a thiazolonaphthyridine amine.
27. The vaccine composition of claim 22 wherein the TLR9 agonist comprises CpG or a CpG containing compound.
28. The vaccine composition of claim 23 wherein the another TLR agonist comprises an agonist of TLR7.
29. The vaccine composition of claim 23 wherein the another TLR agonist comprises an agonist of TLR8.
30. The vaccine composition of claim 22 which is suitable for administration to a human subject in need of immunotherapy by a route selected from the group consisting of oral, nasal, topical, and injection.
31. The vaccine composition of claim 30 which is suitable for injection to a human subject in need of immunotherapy.
32. The vaccine composition of claim 31 wherein injection is selected from the group consisting of subcutaneous, intravenous, intraperitoneal, intramuscular and intravenous.
33. The vaccine composition of claim 22 wherein the antigen is a microbial antigen.
34. The vaccine composition of claim 22 wherein the antigen is a viral antigen.
35. The vaccine composition of claim 22 wherein the antigen is a bacterial or yeast or fungal antigen.
36. A method of immunotherapy which comprises administering to a human subject in need thereof a vaccine composition according to claim 22 under conditions that elicit a synergistic increase in an immune response to said antigen wherein said synergistic response comprises either or both of a synergistic increase in the generation of activated CD8 + T cells or the generation of memory CD8 + T cells in response to said antigen upon administration of said immunostimulatory composition to said human subject.
37. The method of claim 36 wherein the vaccine composition is administered via an injection route.
38. The method of claim 37 wherein injection route is selected from the group consisting of intraperitoneal, intramuscular, intravenous, and subcutaneous.
39. The method of claim 36 wherein the administered vaccine composition comprises an agonistic anti-CD40 antibody.
40. The method of claim 36 wherein the vaccine composition comprises an agonistic anti-CD40 antibody fragment.
41. The method of claim 36 wherein the administered vaccine composition comprises another TLR agonist selected from the group consisting of a TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, and a TLR8 agonist.
42. The method of claim 41 wherein the another TLR agonist is a TLR7 or TLR8 agonist.
43. The method of claim 36 wherein the TLR9 agonist comprised in the administered vaccine composition comprises CpG or a CpG containing compound.
44. The method of claim 36 wherein the administered vaccine composition comprises a microbial antigen.
45. The method of claim 44 wherein the microbial antigen in the administered vaccine composition comprises a viral antigen, a bacterial antigen, a yeast antigen, a fungal antigen, or a parasitic antigen.
46. The method of claim 36 wherein the antigen is a cancer or tumor antigen.
47. The method of claim 46 wherein the antigen is a melanoma antigen.
48. The method of claim 47 wherein the melanoma antigen is selected from the group consisting of p5 protein, gp75, oncofetal antigen, GM2 ganglioside, GD2 ganglioside, Melan-A/MART-1, cdc27, MAGE-3, p21ras, and gp100.
49. The vaccine composition of claim 22 which contains a cancer or tumor antigen.
50. The vaccine composition of claim 49 wherein the cancer or tumor antigen is a melanoma antigen.
51. The method of claim 50 wherein the melanoma antigen is selected from the group consisting of p5 protein, gp75, oncofetal antigen, GM2 ganglioside, GD2 ganglioside, Melan-A/MART-1, cdc27, MAGE-3, p21ras, and gp100.