IL-2 derivative polypeptides
The present invention relates to polypeptides which share primary sequence with human IL-2, except for several amino acids that have been mutated. The mutations introduced substantially reduce the ability of these polypeptides to stimulate in vitro and in vivo regulatory T cells (T CD4+CD25+FoxP3+) and make them more effective in the therapy of murine transplantable tumors. Also includes therapeutic uses of these mutated variants, used alone or in combination with vaccines for the therapy of diseases such as cancer or infections where the activity of regulatory T cells (Tregs) is relevant. In another aspect the present invention relates to pharmaceutical compositions comprising as active principle the polypeptides disclosed. Finally, the present invention relates to the therapeutic use of the polypeptides and pharmaceutical compositions disclosed due to their modulating effect of the immune system on diseases like cancer and chronic infectious diseases.
1. An agonist polypeptide of IL-2, characterized by 95% homology with the sequence of native wild-type human IL-2 and wherein said polypeptide is at least 1000 times less effective in stimulating in vitro and/or in vivo regulatory T cells and shows greater in vivo therapeutic efficacy, wherein the polypeptide is selected from the group consisting of: (i) the polypeptide comprising the sequence of SEQ ID NO 1; (ii) the polypeptide comprising the sequence of SEQ ID NO 2; (iii) the polypeptide comprising the sequence of SEQ ID NO 3; (iv) the polypeptide comprising the sequence of SEQ ID NO 4; (v) the polypeptide comprising the sequence of SEQ ID NO 5; (vi) the polypeptide comprising the sequence of SEQ ID NO 6.
2. The agonist polypeptide of claim 1 , wherein said polypeptide comprises the amino acid sequence of SEQ ID NO: 1.
3. The agonist polypeptide of claim 1 , wherein said polypeptide comprises the amino acid sequence of SEQ ID NO: 2.
4. The agonist polypeptide of claim 1 , wherein said polypeptide comprises the amino acid sequence of SEQ ID NO: 3.
5. The agonist polypeptide of claim 1 , wherein said polypeptide comprises the amino acid sequence of SEQ ID NO: 4.
6. The agonist polypeptide of claim 1 , wherein said polypeptide comprises the amino acid sequence of SEQ ID NO: 5.
7. The agonist polypeptide of claim 1 , wherein said polypeptide comprises the amino acid sequence of SEQ ID NO: 6.
8. A fusion protein comprising the immunomodulatory polypeptide of claim 1 , coupled to a carrier protein.
9. The fusion protein of claim 8 wherein the carrier protein is albumin.
10. The fusion protein of claim 8 wherein the carrier protein is the Fc region of a human immunoglobulin.
11. A pharmaceutical composition useful in the treatment of melanoma, comprising as an active ingredient the polypeptide of claim 1 and a pharmaceutically acceptable carrier or diluent.
12. The pharmaceutical composition of claim 11 , characterized by comprising as an active ingredient at least two polypeptides described in claim 1 .
13. A pharmaceutical composition useful in the treatment of melanoma, which comprises as an active principle the fusion protein described in claim 8 .
14. A method of treating in a patient in need of such treatment, comprising administering an effective amount of the polypeptide of claim 1 .
15. A method of treating in a patient in need of such treatment, comprising administering an effective amount of the polypeptide of claim 2 .
16. A method of treating in a patient in need of such treatment, comprising administering an effective amount of the polypeptide of claim 3 .
17. A method of treating in a patient in need of such treatment, comprising administering an effective amount of the polypeptide of claim 4 .
18. A method of treating in a patient in need of such treatment, comprising administering an effective amount of the polypeptide of claim 5 .
19. A method of treating in a patient in need of such treatment, comprising administering an effective amount of the polypeptide of claim 6 .
20. A method of treating in a patient in need of such treatment, comprising administering an effective amount of the polypeptide of claim 7 .
21. A method of treating in a patient in need of such treatment, comprising administering an effective amount of the fusion protein of claim 8 .
22. A method of treating in a patient in need of such treatment, comprising administering an effective amount of the fusion protein of claim 9 .
23. A method of treating in a patient in need of such treatment, comprising administering an effective amount of the fusion protein of claim 10 .
24. A method of treating in a patient in need of such treatment, comprising administering an effective amount of the polypeptide of claim 1 in combination with a cancer vaccine.
25. A method of treating in a patient in need of such treatment, comprising administering an effective amount of the polypeptide of claim 2 in combination with a cancer vaccine.
26. A method of treating in a patient in need of such treatment, comprising administering an effective amount of the polypeptide of claim 3 in combination with a cancer vaccine.
27. A method of treating in a patient in need of such treatment, comprising administering an effective amount of the polypeptide of claim 4 in combination with a cancer vaccine.
28. A method of treating in a patient in need of such treatment, comprising administering an effective amount of the polypeptide of claim 5 in combination with a cancer vaccine.
29. A method of treating in a patient in need of such treatment, comprising administering an effective amount of the polypeptide of claim 6 in combination with a cancer vaccine.
30. A method of treating in a patient in need of such treatment, comprising administering an effective amount of the polypeptide of claim 7 in combination with a cancer vaccine.
31. A method of treating in a patient in need of such treatment, comprising administering an effective amount of the fusion protein of claim 8 in combination with a cancer vaccine.
32. A method of treating in a patient in need of such treatment, comprising administering an effective amount of the fusion protein of claim 9 in combination with a cancer vaccine.
33. A method of treating in a patient in need of such treatment, comprising administering an effective amount of the fusion protein of claim 10 in combination with a cancer vaccine.