Immunostimulatory regimen comprising administering type 1 interferon and agonistic anti-CD40 antibody
View Patent ↗A synergistic adjuvant is provided comprising synergistically effective amounts of at least one type 1 interferon and at least one CD40 agonist, wherein these moieties may be in the same or separate compositions. In addition, fusion proteins and DNA conjugates which contain a type 1 interferon/CD40 agonist/antigen combination are provided. The use of these compositions, protein and DNA conjugates as immune adjuvants for treatment of various chronic diseases such as HIV infection and for enhancing the efficacy of vaccines (prophylactic and therapeutic) is also provided.
1. An immunostimulatory regimen for inducing CD70 expression on dendritic cells in a human subject in need thereof comprising administering type 1 interferon and an immune agonist polypeptide other than said type 1 interferon, and further including the administration of a tumor antigen, wherein said regimen does not include the administration of a TLR agonist and further requires that the only immune agonist polypeptide other than said type 1 interferon administered in said immunostimulatory regimen consists of a CD40 agonistic antibody or a CD40 agonistic antibody fragment polypeptide, and further wherein said CD40 agonistic antibody or CD40 agonistic antibody fragment and said type 1 interferon are administered in amounts that in combination, but not separately, result in the synergistic induction of CD70 expression on dendritic cells and expansion of CD8 + T cells.
2. An immunostimulatory regimen for inducing the expansion of CD8 + T cells in a human subject in need thereof by administering a type 1 interferon and an immune agonist polypeptide other than said type 1 interferon and further including the administration of a tumor antigen, wherein said regimen does not include the administration of a TLR agonist and further requires that the only immune agonist polypeptide administered in said immunostimulatory regimen other than said type 1 interferon consists of a CD40 agonistic antibody or a CD40 agonistic antibody fragment polypeptide and wherein said CD40 agonistic antibody or said CD40 agonistic antibody fragment and said type 1 interferon are administered in amounts that in combination, but not separately, result in the synergistic expansion of CD8 + T cells.
3. An immunostimulatory therapeutic regimen for inducing primary and memory T cell responses in a human subject in need thereof by administering type 1 interferon and an immune agonist polypeptide other than said type 1 interferon and another further including a tumor antigen, wherein said regimen does not include the administration of a TLR agonist and further requires that the only immune agonist polypeptide used in said immunostimulatory regimen other than said type 1 interferon consists of a CD40 agonistic antibody or a CD40 agonistic antibody fragment polypeptide and wherein said CD40 agonistic antibody or said CD40 agonistic antibody fragment and said type 1 interferon are administered in amounts that in combination, but not separately, result in a synergistic effect on immunity resulting in synergistically enhanced primary and memory CD8 + T cell responses specific to the tumor antigen.
4. The immunostimulatory regimen of claim 1 wherein the CD40 agonistic antibody or antibody fragment, type 1 interferon and tumor antigen are administered as discrete polypeptides.
5. The immunostimulatory regimen of claim 2 wherein the CD40 agonistic antibody or antibody fragment, type 1 interferon and tumor antigen are administered as discrete polypeptides.
6. The immunostimulatory regimen of claim 3 wherein the CD40 agonistic antibody or antibody fragment, type 1 interferon and tumor antigen are administered as discrete polypeptides.
7. The immunostimulatory regimen of claim 1 wherein the CD40 agonistic antibody or antibody fragment, type 1 interferon and tumor antigen are administered as discrete polypeptides in combination.
8. The immunostimulatory regimen of claim 2 wherein the CD40 agonistic antibody or antibody fragment, type 1 interferon and tumor antigen are administered as discrete compounds in combination.
9. The immunostimulatory regimen of claim 3 wherein the CD40 agonistic antibody or antibody fragment, type 1 interferon and tumor antigen are administered as discrete polypeptides in combination.
10. The immunostimulatory regimen of claim 1 wherein the CD40 agonistic antibody or antibody fragment, type 1 interferon and tumor antigen are separately administered as discrete polypeptides.
11. The immunostimulatory regimen of claim 2 wherein the CD40 agonistic antibody or antibody fragment, type 1 interferon and tumor antigen are separately administered as discrete polypeptides.
12. The immunostimulatory regimen of claim 3 wherein the CD40 agonistic antibody or antibody fragment, type 1 interferon and tumor antigen are separately administered as discrete polypeptides compounds in combination.
13. The immunostimulatory regimen of claim 1 wherein the tumor antigen is one expressed by a cancer selected from breast, prostate, lung, ovarian, cervical, skin, melanoma, colon, stomach, liver, esophageal, kidney, throat, thyroid, pancreatic, testicular, brain, and bone cancer, leukemia, chronic lymphocytic leukemia, basal cell carcinoma, biliary tract cancer, bladder cancer, bone cancer, brain and central nervous system (CNS) cancer, cervical cancer, choriocarcinoma, colorectal cancer, connective tissue cancer, endometrial cancer, esophageal cancer, eye cancer, head and neck cancer, gastric cancer, intraepithelial neoplasm, kidney cancer, larynx cancer, lymphoma; melanoma; neuroblastoma; lip, tongue, mouth and pharynx cancer; ovarian cancer; pancreatic cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; sarcoma; skin cancer; stomach cancer; thyroid cancer; and uterine cancer.
14. The immunostimulatory regimen of claim 2 wherein the tumor antigen is one expressed by a cancer selected from breast, prostate, lung, ovarian, cervical, skin, melanoma, colon, stomach, liver, esophageal, kidney, throat, thyroid, pancreatic, testicular, brain, and bone cancer, leukemia, chronic lymphocytic leukemia, basal cell carcinoma, biliary tract cancer, bladder cancer, bone cancer, brain and central nervous system (CNS) cancer, cervical cancer, choriocarcinoma, colorectal cancer, connective tissue cancer, endometrial cancer, esophageal cancer, eye cancer, head and neck cancer, gastric cancer, intraepithelial neoplasm, kidney cancer, larynx cancer, lymphoma; melanoma; neuroblastoma; lip, tongue, mouth and pharynx cancer; ovarian cancer; pancreatic cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; sarcoma; skin cancer; stomach cancer; thyroid cancer; and uterine cancer.
15. The immunostimulatory regimen of claim 3 wherein the tumor antigen is one expressed by a cancer selected from breast, prostate, lung, ovarian, cervical, skin, melanoma, colon, stomach, liver, esophageal, kidney, throat, thyroid, pancreatic, testicular, brain, and bone cancer, leukemia, chronic lymphocytic leukemia, basal cell carcinoma, biliary tract cancer, bladder cancer, bone cancer, brain and central nervous system (CNS) cancer, cervical cancer, choriocarcinoma, colorectal cancer, connective tissue cancer, endometrial cancer, esophageal cancer, eye cancer, head and neck cancer, gastric cancer, intraepithelial neoplasm, kidney cancer, larynx cancer, lymphoma; melanoma; neuroblastoma; lip, tongue, mouth and pharynx cancer; ovarian cancer; pancreatic cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; sarcoma; skin cancer; stomach cancer; thyroid cancer; and uterine cancer.
16. The immunostimulatory regimen of claim 1 wherein the type 1 interferon is an alpha or beta interferon.
17. The immunostimulatory regimen of claim 2 wherein the type 1 interferon is an alpha or beta interferon.
18. The immunostimulatory regimen of claim 3 wherein the type 1 interferon is an alpha or beta interferon.
19. The immunostimulatory regimen of claim 1 wherein the type 1 interferon is a human alpha or beta interferon.
20. The immunostimulatory regimen of claim 2 wherein the type 1 interferon is a human alpha or beta interferon.
21. The immunostimulatory regimen of claim 3 wherein the type 1 interferon is a human alpha or beta interferon.
22. The immunostimulatory regimen of claim 1 wherein the type 1 interferon is PEGylated.
23. The immunostimulatory regimen of claim 1 wherein the type 1 interferon is PEGylated.
24. The immunostimulatory regimen of claim 1 wherein the type 1 interferon is PEGylated.
25. The immunostimulatory regimen of claim 1 wherein the CD40 agonistic antibody or fragment is an agonistic chimeric, human, or humanized anti-CD40 antibody or an agonistic CD40 antibody fragment which is selected from a Fab, F(ab′) 2 , Fd, and a Fv.
26. The immunostimulatory regimen of claim 2 wherein the CD40 agonist is an agonistic chimeric, human, or humanized anti-CD40 antibody or an agonistic CD40 antibody fragment which is selected from a Fab, F(ab′) 2 , Fd, and a Fv.
27. The immunostimulatory regimen of claim 3 wherein the CD40 agonist is an agonistic chimeric, human, or humanized anti-CD40 antibody or an agonistic CD40 antibody fragment which is selected from a Fab, F(ab′) 2 , Fd, and a Fv.
28. The immunostimulatory regimen of claim 1 wherein said type 1 interferon is selected from alpha interferon, beta interferon, omega interferon, tau interferon, zeta interferon and epsilon interferon.
29. The immunostimulatory regimen of claim 2 wherein said type 1 interferon is selected from alpha interferon, beta interferon, omega interferon, tau interferon, zeta interferon and epsilon interferon.
30. The immunostimulatory regimen of claim 3 wherein said type 1 interferon is selected from alpha interferon, beta interferon, omega interferon, tau interferon, zeta interferon and epsilon interferon.
31. The immunostimulatory regimen of claim 1 wherein the agonistic CD40 antibody or antibody fragment and the type 1 interferon are administered within 24 hours of each other.
32. The immunostimulatory regimen of claim 2 wherein the agonistic CD40 antibody or antibody fragment and the type 1 interferon are administered within 24 hours of each other.
33. The immunostimulatory regimen of claim 3 wherein the agonistic CD40 antibody or antibody fragment and the type 1 interferon are administered within 24 hours of each other.
34. The immunostimulatory regimen of claim 1 wherein the agonistic CD40 antibody or antibody fragment and the type 1 interferon are administered within 1-8 hours of each other.
35. The immunostimulatory regimen of claim 2 wherein the agonistic CD40 antibody or antibody fragment and the type 1 interferon are administered within 1-8 hours of each other.
36. The immunostimulatory regimen of claim 3 wherein the agonistic CD40 antibody or antibody fragment and the type 1 interferon are administered within 1-8 hours of each other.
37. The immunostimulatory regimen of claim 1 wherein the CD40 agonist and the type 1 interferon are administered at the same time.
38. The immunostimulatory regimen of claim 2 wherein the CD40 agonist and the type 1 interferon are administered at the same time.
39. The immunostimulatory regimen of claim 3 wherein the CD40 agonist and the type 1 interferon are administered at the same time.
40. The immunostimulatory regimen of claim 1 wherein the tumor antigen is a lung tumor antigen or a lymphoma antigen.
41. The immunostimulatory regimen of claim 2 wherein the tumor antigen is a lung tumor antigen or a lymphoma antigen.
42. The immunostimulatory regimen of claim 3 wherein the tumor antigen is a lung tumor antigen or a lymphoma antigen.
43. The immunostimulatory regimen of claim 1 wherein the CD40 agonistic antibody or antibody fragment, the type 1 interferon and the tumor antigen are comprised in the same or different compositions.
44. The immunostimulatory regimen of claim 2 wherein the CD40 agonistic antibody or antibody fragment, the type 1 interferon and the tumor antigen are comprised in the same or different compositions.
45. The immunostimulatory regimen of claim 3 wherein the CD40 agonistic antibody or antibody fragment, the type 1 interferon and the tumor antigen are comprised in the same or different compositions.
46. The immunostimulatory regimen of claim 1 wherein the CD40 agonistic antibody or antibody fragment, the type 1 interferon and the tumor antigen are comprised in the same or different compositions.
47. The immunostimulatory regimen of claim 2 wherein the CD40 agonistic antibody or antibody fragment, the type 1 interferon and the tumor antigen are comprised in the same or different compositions.
48. The immunostimulatory regimen of claim 3 wherein the CD40 agonistic antibody or antibody fragment, the type 1 interferon and the tumor antigen are comprised in the same or different compositions.
49. The immunostimulatory regimen of claim 1 wherein the CD40 agonistic antibody or antibody fragment, the type 1 interferon and the tumor antigen are comprised in the same or different compositions.
50. The immunostimulatory regimen of claim 2 wherein the CD40 agonistic antibody or antibody fragment, the type 1 interferon and the tumor antigen are comprised in the same or different compositions.
51. The immunostimulatory regimen of claim 3 wherein the CD40 agonistic antibody or antibody fragment, the type 1 interferon and the tumor antigen are comprised in the same or different compositions.
52. The immunostimulatory regimen of claim 1 which is effected in a cancer patient.
53. The immunostimulatory regimen of claim 2 which is effected in a cancer patient.
54. The immunostimulatory regimen of claim 3 which is effected in a cancer patient.
55. The immunostimulatory regimen of claim 52 wherein the CD40 agonistic antibody or antibody fragment, the type 1 interferon and the tumor antigen are administered mucosally, topically, orally, intravenously, intramuscularly, intranasally, vaginally, rectally, intratumorally, intrathecally, or intraocularly.
56. The immunostimulatory regimen of claim 53 wherein the CD40 agonistic antibody or antibody fragment, the type 1 interferon and the tumor antigen are administered mucosally, topically, orally, intravenously, intramuscularly, intranasally, vaginally, rectally, intratumorally, intrathecally, or intraocularly.
57. The immunostimulatory regimen of claim 54 wherein the CD40 agonistic antibody or antibody fragment, the type 1 interferon and the tumor antigen are administered mucosally, topically, orally, intravenously, intramuscularly, intranasally, vaginally, rectally, intratumorally, intrathecally, or intraocularly.
58. The immunostimulatory regimen of claim 1 wherein the tumor antigen is a melanoma antigen and the human subject has melanoma.
59. The immunostimulatory regimen of claim 2 wherein the tumor antigen is a melanoma antigen and the human subject has melanoma.
60. The immunostimulatory regimen of claim 1 wherein the tumor antigen is a melanoma antigen and the human subject has melanoma.