Enhancement of immune responses by 4-1BB-binding agents
View Patent ↗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.
1. A method of generating an enhanced immune response in a subject, the method comprising administering to the subject:
(a) an immunogenic stimulus, wherein the immunogenic stimulus is
(i) 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,
(ii) a dendritic cell that has been incubated with tumor cells, a tumor cell lysate, a tumor-associated antigen (TAA), a peptide-epitope of a TAA, or a heat shock protein bound to a peptide-epitope expressed by a tumor cell,
(iii) a tumor cell that is transfected with or transformed with a nucleic acid encoding a cytokine or a growth factor, or
(iv) a hybrid cell; and
(b) an agonistic antibody, or antibody fragment, that binds to 4-1BB.
2. The method of claim 1 , wherein the immune response is a response of a T cell.
3. The method of claim 1 , wherein the cytokine is granulocyte macrophage-colony stimulating factor (GM-CSF).
4. 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, wherein the immunogenic stimulus is
(i) 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 tumor associated antigen (TAA) or a fragment of a polypeptide produced by an infectious microorganism,
(ii) 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,
(iii) a tumor cell that is transfected with or transformed with a nucleic acid encoding a cytokine or a growth factor, or
(iv) a hybrid cell; and
(b) an agonistic antibody, or antibody fragment, that binds to 4-1BB.
5. The method of claim 4 , wherein the cytokine is granulocyte macrophage-colony stimulating factor (GM-CSF).
6. The method of claim 1 , wherein the subject is a human.
7. The method of claim 1 , wherein the MHC molecule is a MHC class I molecule.
8. The method of claim 1 , wherein the MHC molecule is a MHC class II molecule.
9. The method of claim 2 , wherein the T cell is a CD8+ T cell.
10. The method of claim 2 , wherein the T cell is a CD4+ T cell.
11. The method of claim 1 , wherein the hybrid cell is a fusion product of a tumor cell and a dendritic cell.
12. The method of claim 4 , wherein the contacting is in vitro.
13. The method of claim 4 , wherein the T cell is in a mammal.
14. The method of claim 13 , wherein the mammal is a human.
15. The method of claim 4 , wherein the MHC molecule is a MHC class I molecule.
16. The method of claim 4 , wherein the MHC molecule is a MHC class II molecule.
17. The method claim 4 , wherein the T cell is a CD8+ T cell.
18. The method of claim 4 , wherein the T cell is a CD4+ T cell.
19. The method of claim 4 , wherein the hybrid cell is a fusion product of a tumor cell and a dendritic cell.