Method of inducing a CTL response

• US 20060153858A1
• Filed: 12/19/2005
• Published: 07/13/2006
• Est. Priority Date: 07/10/1997
• Status: Active Grant

• Current Assignee: Mannkind Corporation
• Original Assignee: Mannkind Corporation
• Inventors: Simard, John J.L., Kundig, Thomas M.
• Granted Patent: US 7,364,729 B2
• Time in Patent Office: Days
• US Class Current: 424/184.100
• CPC Class Codes: A61K 2039/53 DNA (RNA) vaccination
• CPC Class Codes: A61K 2039/54 characterised by the route of administration
• CPC Class Codes: A61K 2039/55522 Cytokines; Lymphokines; Interferons
• CPC Class Codes: A61K 2039/57 characterised by the type of response, e.g. Th1, Th2
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 39/0011 Cancer antigens
• CPC Class Codes: A61K 39/12 Viral antigens
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 14/005 from viruses
• CPC Class Codes: C12N 2760/10022 New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
• CPC Class Codes: C12N 2760/10034 Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Abstract

Disclosed herein are methods for inducing an immunological CTL response to an antigen by sustained, regular delivery of the antigen to a mammal so that the antigen reaches the lymphatic system. Antigen is delivered at a level sufficient to induce an immunologic CTL response in a mammal and the level of the antigen in the mammal'"'"'s lymphatic system is maintained over time sufficient to maintain the immunologic CTL response. Also disclosed is an article of manufacture for delivering an antigen that induces a CTL response in an animal.

Claims

1. A method of treating a mammal having or being predisposed to a disease to which the mammal'"'"'s immune system mounts a cell-mediated response to a disease-related antigen to attack the disease, which method comprises:

delivering means for inducing an antigen-specific CTL response to said disease-related antigen to the lymphatic system of the mammal; and

maintaining said means for inducing an antigen-specific CTL response in the mammal'"'"'s lymphatic system over time sufficient to treat the disease.

3. The method of claim 1, wherein the CTL response induced is an increase in a pre-existing CTL response.

4. The method of claim 1, further comprising obtaining a sustained CTL response in the mammal.

5. The method of claim 4, further comprising detecting the sustained antigen-specific effector CTL response in the mammal, wherein the detecting comprises an assay selected from the group consisting of a cytokine assay, a chromium release assay, an antiviral protection assay, virus titer, an immunofluorescence assay, a tumor growth inhibition assay, tumor size reduction, a CTL assay, inhibition of tumor metastasis, increase in life expectancy, infectious disease recovery, inflammatory reaction assay, and observation of the health of the mammal.

6. The method of claim 1, wherein treating the disease comprises inhibition of tumor growth, reduction in tumor size, reduction of a rate of growth of a tumor, improvement in the overall health of the mammal, or prevention or reduction of risk of developing said disease.

7. The method of claim 1, wherein the disease is cancer.

8. The method of claim 7, wherein the antigen is a tumor-associated antigen.

9. The method of claim 7, wherein the cancer is a carcinoma.

10. The method of claim 1, wherein the disease is an infectious disease.

11. The method of claim 10, wherein the infectious disease is a viral disease.

12. The method of claim 1, wherein the antigen is a microbial antigen.

13. The method of claim 1, wherein delivering the means for inducing an antigen-specific CTL response comprises delivery to a lymph node or a lymph vessel of the mammal.

14. The method of claim 13, wherein delivering the means for inducing an antigen-specific CTL response comprises delivery to an inguinal or axillary lymph node.

15. The method of claim 1, wherein delivering the means for inducing an antigen-specific CTL response comprises delivery to an area of high lymphatic drainage in the mammal.

16. The method of claim 1, wherein delivering the means for inducing an antigen-specific CTL response comprises delivery as a single bolus.

17. The method of claim 1, wherein delivering the means for inducing an antigen-specific CTL response comprises delivery in a sustained, repeated, or continuous manner.

18. The method of claim 1, wherein delivering the means for inducing an antigen-specific CTL response comprises delivery from a device external to the mammal.

19. The method of claim 1, wherein delivering the means for inducing an antigen-specific CTL response comprises delivery from an implantable, sustained-release pump.

20. The method of claim 19, wherein the pump is an osmotic pump.

21. The method of claim 1, wherein the means for inducing an antigen-specific CTL response comprises a single antigen.

22. The method of claim 1, wherein the means for inducing an antigen-specific CTL response comprises multiple antigens.

23. The method of claim 1, wherein the means for inducing an antigen-specific CTL response comprises a patient-matched antigen.

24. The method of claim 1, wherein the means for inducing an antigen-specific CTL response is a liquid comprising the antigen.

25. The method of claim 1, wherein the means for inducing an antigen-specific CTL response comprises a cytokine, adjuvant, or potentiator.

26. The method of claim 1, wherein the means for inducing an antigen-specific CTL response is free of an immunopotentiator.

27. The method of claim 1, wherein the means for inducing an antigen-specific CTL response comprises a non-peptide antigen.

28. The method of claim 1, wherein the means for inducing an antigen-specific CTL response is selected from a peptide, a polypeptide, a polyepitope sequence, and a protein.

29. The method of claim 28, wherein the means for inducing an antigen-specific CTL response comprises a polypeptide consisting of 8-10 amino acids.

30. The method of claim 1, wherein the means for inducing an antigen-specific CTL response comprises a component or lysate of a microorganism or mammalian cell.

31. The method of claim 1, wherein the means for inducing an antigen-specific CTL response comprises a microorganism.

32. The method of claim 31, wherein the microorganism is selected from a protozoan, a bacterium, and a virus.

33. The method of claim 31, wherein the microorganism comprises an exogenous antigen.

34. The method of claim 31, wherein the microorganism expresses a microbial antigen native to a second microbial species.

35. The method of claim 31, wherein the microorganism expresses a tumor-associated antigen.

36. The method of claim 31, wherein the microorganism comprises a recombinant nucleic acid encoding or promoting expression of said antigen.

37. The method of claim 1, wherein the means for inducing an antigen-specific CTL response comprises a mammalian cell.

38. The method of claim 37, wherein the mammalian cell is an antigen presenting cell.

39. The method of claim 38, wherein the antigen presenting cell is a dendritic cell.

40. The method of claim 1, wherein the means for inducing an antigen-specific CTL response comprises a recombinant nucleic acid encoding or promoting expression of a disease-related antigen.

41. The method of claim 40, wherein nucleic acid encodes a tumor-associated antigen.

42. The method of claim 40, wherein nucleic acid encodes a microbial antigen.

43. The method of claim 42, wherein the antigen is selected from the group consisting of a viral antigen, a bacterial antigen, and a protozoal antigen.

44. The method of claim 1, wherein the means for inducing an antigen-specific CTL response comprises a vector carrying and/or conferring expression of the antigen.

45. The method of claim 44, wherein the vector is a cell.

46. The method of claim 45, wherein the cell is a tumor cell.

47. The method of claim 44, wherein the vector comprises a plasmid.

48. The method of claim 47, wherein the vector further comprises a bacterium.

49. The method of claim 48, wherein the bacterium is selected from the group consisting of Listeria, Shigella, Samonella, and Escherichia.

50. The method of claim 44, wherein the vector comprises a virus.

51. The method of claim 50, wherein the virus is selected from the group consisting of pox viruses, adenoviruses, adeno-associated viruses, retroviruses, and herpesviruses.

52. The method of claim 44, wherein the vector is a professional antigen-presenting cell.

53. The method of claim 44, wherein the vector is a dendritic cell.

2. A method of inducing an immune response in a mammal having or being predisposed to a disease, to which the mammal'"'"'s immune system mounts a cell-mediated response to a disease-related antigen to attack the disease, which method comprises:

delivering means for inducing an antigen-specific CTL response to said disease-related antigen in the mammal to an area of high lymphatic drainage or directly to the lymphatic system of the mammal; and

maintaining said means for inducing an antigen-specific CTL response in the mammal'"'"'s lymphatic system over time sufficient to induce a CTL response.

54. A method of inducing a CTL response in a mammal, which method comprises:

delivering a liquid comprising an antigen directly to an area of high lymphatic drainage or a lymphatic system of the mammal at a level sufficient to induce an antigen-specific CTL response in the mammal; and

maintaining the antigen in the mammal'"'"'s lymphatic system over time sufficient to induce the CTL response.

55. The method of claim 54, wherein the CTL response induced is an increase in a preexisting CTL response.

56. The method of claim 54, further comprising obtaining a sustained CTL response in the mammal.

57. The method of claim 56, further comprising detecting the sustained antigen-specific effector CTL response in the mammal, wherein the detecting comprises an assay selected from the group consisting of a cytokine assay, a chromium release assay, an antiviral protection assay, virus titer, an immunofluorescence assay, a tumor growth inhibition assay, tumor size reduction, a CTL assay, inhibition of tumor metastasis, increase in life expectancy, infectious disease recovery, inflammatory reaction assay, and observation of the health of the mammal.

58. The method of claim 54, wherein delivering the liquid comprising the antigen comprises delivery to an inguinal or axillary lymph node

59. The method of claim 54, wherein delivering the liquid comprising the antigen comprises delivery to an area of high lymphatic drainage in the mammal.

60. The method of claim 54, wherein delivering the liquid comprising the antigen comprises delivery in a single bolus.

61. The method of claim 54, wherein delivering the liquid comprising the antigen comprises delivery in a sustained, repeated, or continuous manner

62. The method of claim 54, wherein delivering the liquid comprising the antigen comprises delivery from an external or implantable, sustained-release pump.

63. The method of claim 54, wherein the antigen is a disease-matched antigen.

64. The method of claim 54, wherein the antigen is a patient-matched antigen.

65. The method of claim 54, wherein the antigen is a non-peptide antigen.

66. The method of claim 54, wherein the antigen is selected from a peptide, a polypeptide, a polyepitope sequence, and a protein.

67. The method of claim 66, wherein the polypeptide consists of 8-10 amino acids.

68. The method of claim 66, wherein the antigen is a polypeptide derived from a tumor-associated antigen.

69. The method of claim 66, wherein the antigen is a polypeptide derived from a microbial antigen.

70. The method of claim 54, wherein the antigen is provided as a vector carrying and/or conferring expression of the antigen.

71. The method of claim 70, wherein the vector is a cell.

72. The method of claim 70, wherein the vector comprises a plasmid.

73. The method of claim 72, wherein the vector further comprises a bacterium.

74. The method of claim 73, wherein the bacterium is selected from the group consisting of Listeria, Shigella, Samonella, and Escherichia.

75. The method of claim 72, wherein the vector comprises a virus.

76. The method of claim 70, wherein the virus is selected from the group consisting of pox viruses, adenoviruses, adeno-associated viruses, retroviruses, and herpesviruses.

77. The method of claim 70, wherein the vector is a professional antigen-presenting cell.

78. The method of claim 70, wherein the vector is a dendritic cell.