Cytokine derived treatment with reduced vascular leak syndrome

Patent metadata

Field	Value
Publication number	US-11401312-B2
Application number	US-201414785536-A
Country	US
Kind code	B2
Filing date	Apr 22, 2014
Priority date	Apr 19, 2013
Publication date	Aug 2, 2022
Grant date	Aug 2, 2022

Abstract

The present invention relates to a pharmaceutical composition for treating a cancer or an infection in a subject by administrating an amount of an interleukin 15 (IL-15) derivative conjugate so as to induce a proliferation of natural killer cells (NK cells) which is the same or higher than the one obtained with high dose of interleukin-2 (HDIL-2); eventually associated with a pharmaceutically acceptable carrier.

First claim

We claim:

1. A method for inducing proliferation of natural killer cells (NK cells), in a human, comprising:
administering to the human a pharmaceutical composition consisting of a conjugate in an amount sufficient to induce a proliferation of NK cells that is the same or higher than the one obtained with High Dose of interleukin-2 (HDIL-2) and a pharmaceutically acceptable carrier, wherein said conjugate consists of:
a) a polypeptide consisting of the amino acid sequence of interleukin 15 of SEQ ID NO: 3;
b) a polypeptide consisting of the the amino acid sequence of the sushi domain of IL-15Rα selected from the group consisting of SEQ ID NO:8, SEQ ID NO:9 and SEQ ID NO:12; and
c) separated by a linker amino acid sequence having a length of 5-30 amino acids, said linker comprising near neutral amino acids selected from the group consisting of Gly (G), Asn (N), Ser (S), Thr (T), Ala (A), Leu (L), and Gln (Q);
wherein the conjugate is a fusion protein; and wherein the amount of conjugate is between 2 to 200 pmol/kg, and wherein the amount of conjugate induces a proliferation of Treg cells that is at least 5% less than the one obtained with HDIL-2.

2. The method of claim 1 , wherein said conjugate is administered in an amount that also induces a proliferation of CD8 + T cells higher than the one obtained with HDIL-2.

3. The method of claim 1 , wherein said amount of conjugate induces a proliferation of NK cells that is higher than the one obtained with HDIL-2.

4. The method of claim 1 , wherein said human has a grade IV cancer according to TNM Classification of Malignant tumors or a metastatic cancer.

5. The method of claim 1 , wherein said conjugate is administered in an amount that induces proliferation of NK cells that is at least 20% higher than the one obtained with HDIL-2.

6. The method of claim 1 , wherein said conjugate is administered in an amount that induces proliferation of CD8 + T cells that is at least 20% higher than the one obtained with HDIL-2.

7. The method of claim 1 , wherein the amount of conjugate induces a proliferation of FoxP3 + CD4 + CD25 high Treg cells that is less than the one obtained with HDIL-2.

8. The method of claim 1 , wherein the amount of conjugate results in a ratio of induced proliferating NK cells to induced proliferating Treg cells that is at least 25% higher than the one obtained with HDIL-2.

9. The method of claim 1 , wherein the amount of conjugate results in a ratio of induced proliferating CD8 + T cells to proliferating Treg cells that is at least 25% higher than the one obtained with HDIL-2.

10. The method of claim 1 , wherein said conjugate consists of the amino acid sequence of the interleukin 15 in a C-terminal position relative to the amino acid sequence of the sushi domain of the IL-15Rα.

11. The method according to claim 1 , wherein the amount of conjugate corresponds to a daily administration amount.

12. The method of claim 1 , wherein said composition is administered parenterally or intravenously.

13. The method of claim 1 , wherein the amount of conjugate is between 8 and 200 pmol/kg.

14. The method of claim 1 , wherein the amount of conjugate is between 20 and 80 pmol/kg.

15. The method of claim 1 , wherein the amount of conjugate is between 50 and 5,000 ng/kg.

16. The method of claim 1 , wherein the amount of conjugate is between 200 and 5,000 ng/kg.

17. The method of claim 1 , wherein the amount of conjugate is between 500 and 2,000 ng/kg.

18. The method of claim 1 , wherein said conjugate is administered in an amount that induces proliferation of NK cells that is at least 25% higher the one obtained with HDIL-2.

19. The method of claim 1 , wherein said conjugate is administered in an amount that induces proliferation of NK cells that is at least 30% higher than the one obtained with HDIL-2.

20. The method of claim 1 , wherein said conjugate is administered in an amount that induces proliferation of CD8 + T cells that is at least 25% higher than the one obtained with HDIL-2.

21. The method of claim 1 , wherein said conjugate is administered in an amount that induces proliferation of CD8 + T cells that is at least 30% higher than the one obtained with HDIL-2.

22. The method of claim 7 , wherein the amount of conjugate induces a proliferation of Treg cells that is at least 10 or 20% less than the one obtained with HDIL-2.

23. The method of claim 7 , wherein the amount of conjugate induces a proliferation of Treg cells that is at least 50% less than the one obtained with HDIL-2.

24. The method of claim 1 , wherein said linker amino acid sequence is set forth in SEQ ID NO: 13-14.

25. The method of claim 1 , wherein the interleukin 15 has the amino acid sequence of SEQ ID NO:3, the sushi domain of IL-15Rα has the amino acid sequence SEQ ID NO:12, and the linker sequence has the amino acid sequence SEQ ID NO:14.

26. The method of claim 1 , wherein the linker amino acid sequence length is 15-30 amino acids.

27. The method of claim 1 , wherein the linker amino acid sequence length is 15-25 amino acids.

28. The method of claim 1 , wherein the linker amino acid sequence length is 18-22 amino acids.

Assignees

• Cytune Pharma
• Roussy Inst Gustave
• Inst Gustave Roussy Igr

Inventors

• Bechard David
• Chaput Nathalie
• Desbois Melanie

Classifications

• A61K47/642

  the peptide or protein in the drug conjugate being a cytokine, e.g. IL2, chemokine, growth factors or interferons being the inactive part of the conjugate · CPC title

• G01N33/5011

  for testing antineoplastic activity · CPC title

• C07K14/7155

  for interleukins [IL] · CPC title

• A61P37/04

  Immunostimulants · CPC title

• A61P37/02

  Immunomodulators · CPC title