Method for treating cancer by administering IL-15 and IL-15Ralpha complexes

Patent metadata

Field	Value
Publication number	US-8940288-B2
Application number	US-201213368605-A
Country	US
Kind code	B2
Filing date	Feb 8, 2012
Priority date	May 17, 2005
Publication date	Jan 27, 2015
Grant date	Jan 27, 2015

Abstract

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.

First claim

We claim:

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.

Assignees

• Lefrancois Leo
• Stoklasek Thomas A
• Univ Connecticut

Inventors

• Lefrancois Leo
• Stoklasek Thomas A

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title