Cytokine derived treatment with reduced vascular leak syndrome
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.
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.