IL-15-based fusions to IL-12 and IL-18
The invention features multi-specific fusion protein complexes with one domain comprising IL-15 or a functional variant and a binding domain specific to IL-12 or IL-18.
1. A method of activating Natural Killer (NK) cells, the method comprising exposing NK cells to an isolated soluble fusion protein complex comprising a first soluble protein comprising an interleukin-15 (IL-15) polypeptide domain and an IL-12 polypeptide domain, and a second soluble protein comprising a soluble IL-15 receptor alpha sushi (IL-15RαSu) polypeptide domain and an IL-18 polypeptide domain, wherein the IL-15 polypeptide domain binds to the IL-15RαSu polypeptide domain to form the soluble fusion protein complex, wherein the NK cells are activated.
2. The method of claim 1 , wherein the activated NK cells have increased expression of one or more activation markers, wherein the activation markers comprise CD25 and/or CD69.
3. The method of claim 1 , wherein the activated NK cells have increased cytotoxicity against cancerous or virally infected cells.
4. The method of claim 1 , wherein the activated NK cells have increased production of Interferon gamma (IFNγ).
5. The method of claim 1 , wherein the activated NK cells are primary NK cells.
6. The method of claim 5 , wherein the primary NK cells are comprised of Cytokine Induced Memory Like (CIML) NK cells.
7. The method of claim 1 , wherein the activated NK cells comprise an NK cell line.
8. The method of claim 7 , wherein the NK cell line is an NK-92 cell line.
9. A method of stimulating an immune response in a mammal, the method comprising administering to the mammal an effective amount of an isolated soluble fusion protein complex comprising a first soluble protein comprising an interleukin-15 (IL-15) polypeptide domain and an IL-12 polypeptide domain, and a second soluble protein comprising a soluble IL-15 receptor alpha sushi (IL-15RαSu) polypeptide domain and an IL-18 polypeptide domain, wherein the IL-15 polypeptide domain binds to the IL-15RαSu polypeptide domain to form the soluble fusion protein complex and wherein NK cells are activated in the mammal.
10. The method of claim 9 , wherein the activated NK cells have increased cytotoxicity against cancerous or virally infected cells.
11. The method of claim 9 , wherein the activated NK cells have increased production of Interferon gamma (IFNγ).
12. The method of claim 9 , wherein the activated NK cells are comprised of Cytokine Induced Memory Like (CIML) NK cells.
13. The method of claim 9 , wherein the activated NK cells have increased proliferation.
14. The method of claim 9 , wherein CD8 + cells proliferation is induced.