Vault complexes for cytokine delivery
The invention relates to compositions of vault complexes containing recombinant cytokine fusion proteins that include a cytokine and a vault targeting domain, and methods of using the vault complexes to deliver the cytokines to a cell or subject, and methods for using the compositions to treat cancer, such as lung cancer.
1. A composition comprising a vault complex comprising a major vault protein and a fusion protein comprising a cytokine and a vault targeting domain, wherein the vault targeting domain is a vault poly ADP-ribose polymerase (VPARP) sequence or a portion thereof that interacts with the major vault protein, or a telomerase/vault associated protein 1 (TEP 1) sequence or a portion thereof that interacts with the major vault protein, wherein the fusion protein is non-covalently associated with the vault complex.
2. The composition of claim 1 , wherein the cytokine is a chemokine.
3. The composition of claim 1 , wherein the cytokine is a cysteine-cysteine chemokine.
4. The composition of claim 1 , wherein the cytokine is a CCL-21 chemokine.
5. The composition of claim 1 , wherein the cytokine comprises the amino acid sequence of SEQ ID NO:2.
6. The composition of claim 1 , wherein the vault targeting domain is a portion of the VPARP that is a major vault protein interaction (mINT) domain.
7. The composition of claim 6 , wherein the mINT domain comprises the amino acid sequence of SEQ ID NO:8.
8. The composition of claim 1 , wherein the fusion protein comprises the amino acid sequence of SEQ ID NO:13.
9. A method of delivering a cytokine to a cell, comprising introducing the composition of claim 1 to the cell.
10. The method of claim 9 , wherein the composition is introduced into the extracellular environment surrounding the cell.
11. A method for stimulating an immune response in a cell, the method comprising contacting the cell with the composition of claim 1 .
12. The method of claim 11 , wherein the cell is a human cell.
13. The method of claim 11 , wherein the immune response induces migration of T cells and dendritic cells.
14. The method of claim 11 , wherein contacting the cell with the composition of claim 2 increases T cell migration to the cell by at least 5% compared to administration of CCL-21 cytokine alone.
15. A method for stimulating an immune response in a subject, the method comprising administering the composition of claim 1 to the subject.
16. The method of claim 15 , wherein the subject is a human.
17. A method of treating or managing cancer in a subject in need of treatment or management of cancer, comprising administering to a subject a therapeutically effective amount of the composition of claim 1 .