Immunomodulatory interleukin-2 polypeptides and methods of treating melanoma
The present invention relates generally to polypeptides whose primary sequence has high sequence homology with human interleukin 2 (IL-2) with some punctual mutations in the sequence of native IL-2. The polypeptides of the present invention have an immunomodulatory effect on the immune system, which is selective/preferential on regulatory T cells. The present invention also relates to specific polypeptides whose amino acid sequence is disclosed herein. In another aspect the present invention relates to pharmaceutical compositions comprising as active ingredient the polypeptides disclosed. Finally, the present invention relates to the therapeutic use of the polypeptides and pharmaceutical compositions disclosed due to their immune modulating effect on diseases such as cancer and chronic infectious diseases.
1. An isolated immunomodulatory polypeptide derived from interleukin-2 (IL-2), which consists of several point mutations in respect to the sequence of human IL-2 and has the property of inhibiting IL-2 activity on regulatory T cells in vitro, wherein the polypeptide is selected from the group consisting of (i) said polypeptide consisting of mutations Q22V, Q126A, I129D, and S130G; (ii) said polypeptide consisting of mutations L18N, Q126Y and S130R; (iii) said polypeptide consisting of mutations Q13Y, Q126Y, I129D and S130R; (iv) said polypeptide consisting of mutations L18N, Q22V, T123A, I129D and S130R.
2. The polypeptide of claim 1 wherein said polypeptide has the ability to preferentially inhibit regulatory T cells in vivo.
3. A fusion protein comprising the immunomodulatory polypeptide of claim 1 coupled to a carrier protein.
4. The fusion protein of claim 3 wherein the carrier protein is albumin.
5. The fusion protein of claim 3 wherein the carrier protein is the Fc region of human immunoglobulin.
6. A pharmaceutical composition useful in the treatment of melanoma, comprising as an active ingredient the polypeptide of claim 1 .
7. A pharmaceutical composition useful in the treatment of melanoma, comprising as an active ingredient the fusion protein of claim 3 .
8. A pharmaceutical composition useful in the treatment of melanoma, comprising as an active ingredient the fusion protein of claim 4 .
9. A pharmaceutical composition useful in the treatment of melanoma, comprising as an active ingredient the fusion protein of claim 5 .
10. A method of treating melanoma in a patient in need of such treatment, comprising administering an effective amount of the polypeptide of claim 1 .
11. A method of treating melanoma in a patient in need of such treatment, comprising administering an effective amount of the fusion protein of claim 3 .
12. A method of treating melanoma in a patient in need of such treatment, comprising administering an effective amount of the fusion protein of claim 4 .
13. A method of treating melanoma in a patient in need of such treatment, comprising administering an effective amount of the fusion protein of claim 5 .