Method for treating cancer by administering IL-15 and IL-15Ralpha complexes
The present invention relates to a therapeutic polypeptide and methods for its creation and use for modulating an immune response in a host organism in need thereof. In particular, the invention relates to the administration to an organism in need thereof, of an effective amount of a pre-coupled polypeptide complex comprising a lymphokine polypeptide portion, for example IL-15 (SEQ ID NO: 5, 6), IL-2 (SEQ ID NO: 10, 12) or combinations of both, and an interleukin receptor polypeptide portion, for example IL-15Ra (SEQ ID NO: 7, 8), IL-2Ra (SEQ ID NO: 9, 11) or combinations of both, for augmenting the immune system in, for example, cancer, SCID, AIDS, or vaccination; or inhibiting the immune system in, for example, rheumatoid arthritis, or Lupus. The therapeutic complex of the invention surprisingly demonstrates increased half-life, and efficacy in vivo.
1. A method for treating cancer, comprising administering to a human in need thereof a composition, wherein the composition comprises:
(a) a purified interleukin-15 (IL-15) polypeptide and a purified soluble form of an interleukin-15 receptor alpha (IL-15Ra) polypeptide; or
(b) a purified complex comprising an IL-15 polypeptide bound to a soluble form of an IL-15Ra polypeptide,
wherein said administration results in treating cancer.
2. The method of claim 1 , wherein the composition comprises a purified IL-15 polypeptide and a purified soluble form of an IL-15Ra polypeptide.
3. The method of claim 1 , wherein the composition comprises a purified complex comprising an IL-15 polypeptide bound to a soluble form of an IL-15Ra polypeptide.
4. The method of claim 1 , wherein the IL-15polypeptide is:
(i) (a) encoded by a nucleic acid that is at least 80% identical to SEQ ID NO: 2over the entire length of SEQ ID NO: 2; or (b) at least 95% identical to the amino acid sequence of SEQ ID NO: 6over the length of the mature form of SEQ ID NO: 6; and
(ii) capable of forming a complex with IL-15Ra polypeptide.
5. The method of claim 4 , wherein the soluble form of the IL-15Ra polypeptide is:
(i) a soluble form of an IL-15Ra polypeptide and the IL-15Ra polypeptide is (a) encoded by a nucleic acid that is at least 80% identical to SEQ ID NO: 4over the entire length of SEQ ID NO: 4; or (b) at least 95% identical to the amino acid sequence of SEQ ID NO: 8over the length of the mature form of SEQ ID NO: 8; and
(ii) capable of forming a complex with IL-15 polypeptide.
6. The method of claim 4 , wherein the soluble form of the IL-15Ra polypeptide:
(i) has the amino acid sequence of the extracellular domain of an IL-15Ra polypeptide and the IL-15Ra polypeptide is (a) encoded by a nucleic acid that is at least 80% identical to SEQ ID NO: 4 over the entire length of SEQ ID NO: 4; or (b) at least 95% identical to the amino acid sequence of SEQ ID NO: 8 over the length of the mature form of SEQ ID NO: 8; and
(ii) is capable of forming a complex with IL-15 polypeptide.
7. The method of claim 6 , wherein the IL-15Ra polypeptide has the amino acid sequence of SEQ ID NO: 8.
8. The method of claim 2 or 3 , wherein the IL-15 polypeptide is:
(i) (a) encoded by a nucleic acid that is at least 80% identical to SEQ ID NO: 2 over the entire length of SEQ ID NO: 2; or (b) at least 95% identical to the amino acid sequence of SEQ ID NO: 6 over the length of the mature form of SEQ ID NO: 6; and
(ii) capable of forming a complex with IL-15Ra polypeptide.
9. The method of claim 8 , wherein the soluble form of the IL-15Ra polypeptide:
(i) has the amino acid sequence of the extracellular domain of an IL-15Ra polypeptide and the IL-15Ra polypeptide is (a) encoded by a nucleic acid that is at least 80% identical to SEQ ID NO: 4 over the entire length of SEQ ID NO: 4; or (b) at least 95% identical to the amino acid sequence of SEQ ID NO: 8 over the length of the mature form of SEQ ID NO: 8; and
(ii) is capable of forming a complex with IL-15 polypeptide.
10. The method of claim 2 or 3 , wherein the soluble form of the IL-15Ra polypeptide is:
(i) a soluble form of an IL-15Ra polypeptide and the IL-15Ra polypeptide is (a) encoded by a nucleic acid that is at least 80% identical to SEQ ID NO: 4over the entire length of SEQ ID NO: 4; or (b) at least 95% identical to the amino acid sequence of SEQ ID NO: 8over the length of the mature form of SEQ ID NO: 8; and
(ii) capable of forming a complex with IL-15 polypeptide.
11. The method of claim 2 or 3 , wherein the soluble form of the IL-15Ra polypeptide:
(i) has the amino acid sequence of the extracellular domain of an IL- l5 Ra polypeptide and the IL-15Ra polypeptide is (a) encoded by a nucleic acid that is at least 80% identical to SEQ ID NO: 4 over the entire length of SEQ ID NO: 4; or (b) at least 95% identical to the amino acid sequence of SEQ ID NO: 8 over the length of the mature form of SEQ ID NO: 8; and
(ii) is capable of forming a complex with IL-15polypeptide.
12. The method of claim 1 , wherein the IL-15polypeptide has the amino acid sequence of SEQ ID NO:6.
13. The method of claim 12 , wherein the soluble form of the IL- l5 Ra polypeptide:
(i) has the amino acid sequence of the extracellular domain of an IL- l5 Ra polypeptide and the IL-15Ra polypeptide is (a) encoded by a nucleic acid that is at least 80% identical to SEQ ID NO: 4 over the entire length of SEQ ID NO: 4; or (b) at least 95% identical to the amino acid sequence of SEQ ID NO: 8 over the length of the mature form of SEQ ID NO: 8; and
(ii) is capable of forming a complex with IL-15 polypeptide.
14. The method of claim 12 or 13 , wherein the IL-15Ra polypeptide has the amino acid sequence of SEQ ID NO:8.
15. The method of claim 1 , wherein the soluble form of the IL- l5 Ra polypeptide is:
(i) a soluble form of an IL-15Ra polypeptide and the IL-15Ra polypeptide is (a) encoded by a nucleic acid that is at least 80% identical to SEQ ID NO: 4 over the entire length of SEQ ID NO: 4; or (b) at least 95% identical to the amino acid sequence of SEQ ID NO: 8 over the length of the mature form of SEQ ID NO: 8; and
(ii) capable of forming a complex with IL-15 polypeptide.
16. The method of claim 1 , wherein the soluble form of the IL- l5 Ra polypeptide:
(i) has the amino acid sequence of the extracellular domain of an IL- l5 Ra polypeptide and the IL-15Ra polypeptide is (a) encoded by a nucleic acid that is at least 80% identical to SEQ ID NO: 4 over the entire length of SEQ ID NO: 4; or (b) at least 95% identical to the amino acid sequence of SEQ ID NO: 8 over the length of the mature form of SEQ ID NO: 8; and
(ii) is capable of forming a complex with IL-15 polypeptide.
17. The method of claim 16 , wherein the IL-15Ra polypeptide has the amino acid sequence of SEQ ID NO:8.
18. The method of claim 1 , wherein the composition is administered by a parenteral route.
19. The method of claim 1 , wherein the composition is administered by an intravenous route, subcutaneous route or intramuscular route.
20. The method of claim 1 , wherein the cancer is lymphoma.
21. The method of claim 1 , wherein the cancer is leukemia.
22. The method of claim 1 , wherein the cancer is prostate cancer, uterus cancer, liver cancer, melanoma, neoplasm, adenocarcinoma, lung cancer, kidney cancer or pancreatic cancer.
23. The method of claim 1 , wherein the human is lymphopenic.
24. The method of claim 1 , which increases proliferation of immune cells as measured in an in vitro assay with CFSE-labeled immune cells, wherein CFSE dilution is measured by flow cytometry.
25. The method of claim 1 , wherein said purified IL-15 or said purified complex demonstrates an in vivo half-life of greater than an hour.
26. The method of claim 1 , which further comprises administering another active ingredient to the human.
27. The method of claim 26 , wherein the active ingredient is anti-oncogenic.