Enhancement of immune responses by 4-1bb-binding agents

• US 20050013811A1
• Filed: 10/09/2002
• Published: 01/20/2005
• Est. Priority Date: 10/09/2001
• Status: Active Grant

• Current Assignee: Mayo Foundation For Medical Education And Research (Mayo Clinic)
• Original Assignee: Mayo Foundation For Medical Education And Research (Mayo Clinic)
• Inventors: Strome, Scott E., Chen, Lieping
• Granted Patent: US 7,651,686 B2
• Time in Patent Office: Days
• US Class Current: 424/144.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/55516 Proteins; Peptides
• CPC Class Codes: A61K 2039/55522 Cytokines; Lymphokines; Interferons
• CPC Class Codes: A61K 2039/585 wherein the target is cancer
• CPC Class Codes: A61K 2239/31 characterized by the route of administration
• CPC Class Codes: A61K 39/12 Viral antigens
• CPC Class Codes: A61K 39/39 characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: A61K 39/4611 T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
• CPC Class Codes: A61K 39/4615 Dendritic cells
• CPC Class Codes: A61K 39/4622 Antigen presenting cells
• CPC Class Codes: A61K 39/464499 Undefined tumor antigens, e.g. tumor lysate or antigens targeted by cells isolated from tumor
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/2878 against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• CPC Class Codes: C12N 2710/20034 Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Abstract

This invention features methods of enhancing immune responses in mammalian subjects and in vitro methods of enhancing the response of a T cell. Also embodied by the invention are methods of receiving and preventing the induction of energy in T cells.

Claims

1. A method of generating an enhanced immune response in a subject, the method comprising administering to the subject:

(a) an immunogenic stimulus; and

(b) an agonistic 4-1BB-binding agent.

2. The method of claim 1, wherein the agonistic 4-1BB binding agent is an antibody that binds to 4-1BB.

3. The method of claim 1, wherein the agonistic 4-1BB binding agent is 4-1BB ligand (4-1BBL) or a functional fragment thereof.

4. The method of claim 1, wherein the immunogenic stimulus is (a) a tumor-associated antigen (TAA) or (b) a functional fragment of a TAA.

5. The method of claim 1, wherein the immunogenic stimulus is a polypeptide.

6. The method of claim 4, wherein the TAA is a molecule produced by a cancer cell selected from the group consisting of a leukemia, a lymphoma, a neurological cancer, a melanoma, a breast cancer, a lung cancer, a head and neck cancer, a gastrointestinal cancer, a liver cancer, a pancreatic cancer, a genitourinary cancer, a prostate cancer, a renal cell cancer, a bone cancer, and a vascular cancer cell.

7. The method of claim 1, wherein the immunogenic stimulus is a molecule produced by an infectious microorganism.

8. The method of claim 7, wherein the infectious microorganism is a virus.

9. The method of claim 8, wherein the virus is a retrovirus.

10. The method of claim 7, wherein the infectious microorganism is selected from the group consisting of a bacterium, a fungus, and a protozoan parasite.

11. The method of claim 1, wherein the subject is a human.

12. The method of claim 1, wherein the immunogenic stimulus is a dendritic cell comprising a major histocompatibility complex (MHC) molecule with a peptide-epitope bound thereto, wherein the peptide-epitope is a fragment of a TAA or a fragment of a polypeptide produced by an infectious microorganism.

13. The method of claim 12, wherein the MHC molecule is a MHC class I molecule.

14. The method of claim 12, wherein the MHC molecule is a MHC class II molecule.

15. The method of claim 1, wherein the immune response is a response of a T cell.

16. The method of claim 15, wherein the T cell is a CD8+ T cell.

17. The method of claim 15, wherein the T cell is CD4+ T cell.

18. The method of claim 1, wherein the immunogenic stimulus is a hybrid cell.

19. The method of claim 18, wherein the hybrid cell is a fusion product of a tumor cell and a dendritic cell.

20. The method of claim 1, wherein the immunogenic stimulus is a tumor cell, a tumor cell lysate, a TAA, a peptide-epitope of a TAA, or a heat shock protein bound to peptide-epitope of protein expressed by a tumor cell.

21. The method of claim 1, wherein the immunogenic stimulus is a dendritic cell that has been incubated with tumor cells, a tumor cell lysate, a TAA, a peptide-epitope of a TAA, or a heat shock protein bound to a peptide-epitope expressed by a tumor cell.

22. The method of claim 20, wherein the tumor cell is transfected with or transformed with a nucleic acid encoding a cytokine or a growth factor.

23. The method of claim 22, wherein the cytokine is granulocyte macrophage-colony stimulating factor (GM-CSF).

24. An in vitro method of activating a T cell, the method comprising:

(a) providing a cell sample comprising a T cell; and

(b) culturing the cell sample with an immunogenic stimulus and an agonistic 4-1BB-binding agent.

46. The method of claim 24, wherein the immunogenic stimulus is a hybrid cell.

47. The method of claim 46, wherein the hybrid cell is a fusion product of a tumor cell and a dendritic cell.

25. A method of preventing induction of anergy or of reversing anergy in a T cell, the method comprising contacting the T cell with:

(a) an immunogenic stimulus; and

(b) an agonistic 4-1BB-binding agent.

26. The method of claim 25, wherein the contacting is in vitro.

27. The method of claim 25, wherein the T cell is in a mammal.

28. The method of claim 27, wherein the mammal is a human.

29. The method of claim 25, wherein the contacting comprises administering to the mammal:

(a) the immunogenic stimulus and the agonistic 4-1BB-binding agent;

(b) a nucleic acid encoding the immunogenic stimulus and the agonistic 4-1BB-binding agent;

(c) the immunogenic stimulus and a nucleic acid encoding the agonistic 4-1BB binding agent;

or

(d) a nucleic acid encoding the immunogenic stimulus and a nucleic acid encoding the agonistic 4-1BB binding agent.

30. The method of claim 29, wherein the contacting comprises administering to the mammal a nucleic acid encoding the immunogenic stimulus and a nucleic acid encoding the 4-1BB binding agent, wherein the nucleic acid encoding the immunogenic stimulus and the nucleic acid encoding the 4-1BB binding agent are in the same nucleic acid molecule.

31. The method of claim 29, wherein the method comprises administering a cell transfected or transduced with a nucleic acid encoding the immunogenic stimulus or the 4-1BB-binding agent to the mammal, wherein the cell is a cell, or a progeny of a cell, that prior to the transfection or the transduction, was obtained from the mammal.

32. The method of claim 25, wherein the agonistic 4-1BB binding agent is an antibody that binds to 4-1BB.

33. The method of claim 25, wherein the agonistic 4-1BB binding agent is 4-1BB ligand (4-1BBL) or a functional fragment thereof.

34. The method of claim 25, wherein the immunogenic stimulus is (a) a tumor-associated antigen (TAA) or (b) a functional fragment of a TAA.

35. The method of claim 25, wherein the immunogenic stimulus is a polypeptide.

36. The method of claim 34, wherein the TAA is a molecule produced by a cancer cell selected from the group consisting of a leukemia, a lymphoma, a neurological cancer, a melanoma, a breast cancer, a lung cancer, a head and neck cancer, a gastrointestinal cancer, a liver cancer, a pancreatic cancer, a genitourinary cancer, a prostate cancer, a renal cell cancer, a bone cancer, and a vascular cancer cell.

37. The method of claim 25, wherein the immunogenic stimulus is a molecule produced by an infectious microorganism.

38. The method of claim 37, wherein the infectious microorganism is a virus.

39. The method of claim 38, wherein the virus is a retrovirus.

40. The method of claim 37, wherein the infectious microorganism is selected from the group consisting of a bacterium, a fungus, and a protozoan parasite.

41. The method of claim 25, wherein the immunogenic stimulus is a dendritic cell comprising a major histocompatibility complex (MHC) molecule with a peptide-epitope bound thereto, wherein the peptide-epitope is a fragment of a TAA or a fragment of a polypeptide produced by an infectious microorganism.

42. The method of claim 41, wherein the MHC molecule is a MHC class I molecule.

43. The method of claim 42, wherein the MHC molecule is a MHC class II molecule

44. The method of claim 25, wherein the T cell is a CD8+ T cell.

45. The method of claim 25, wherein the T cell is CD4+ T cell.

48. The method of claim 25, wherein the immunogenic stimulus is a tumor cell, a tumor cell lysate, a TAA, a peptide-epitope of a TAA, or a heat shock protein bound to peptide-epitope of protein expressed by a tumor cell.

49. The method of claim 25, wherein the immunogenic stimulus is a dendritic cell that has been incubated with tumor cells, a tumor cell lysate, a TAA, a peptide-epitope of a TAA, or a heat shock protein bound to a peptide-epitope expressed by a tumor cell.

50. The method of claim 48, wherein the tumor cell is transfected with or transformed with a nucleic acid encoding a cytokine or a growth factor.

51. The method of claim 49, wherein the cytokine is granulocyte macrophage-colony stimulating factor (GM-CSF).