IL-15 mutant polypeptides as IL-15 antagonists and encoding nucleic acids
The present relates to interleukin 15 (IL-15) antagonists and uses thereof, in particular for the treatment of autoimmune diseases and inflammatory diseases. In particular, the present invention relates to an IL-15 mutant polypeptide having the amino acid sequence as set forth in SEQ ID NO:1 wherein the leucine residue at position 45 is substituted by an aspartic acid residue, the asparagines residue at position 65 is substituted by a lysine residue and the leucine residue at position 69 is substituted by an arginine residue.
1. An IL-15 mutant polypeptide which amino acid sequence is identical to the sequence in SEQ ID NO:1 except the leucine residue at position 45 is substituted by an aspartic acid residue, the asparagine residue at position 65 is substituted by a lysine residue, and the leucine residue at position 69 is substituted by an arginine residue.
2. A fusion protein comprising the IL-15 mutant polypeptide according to claim 1 fused to a heterologous polypeptide.
3. The fusion protein of claim 2 wherein the heterologous polypeptide is an immunoglobulin constant domain.
4. The fusion protein of claim 3 wherein the immunoglobulin constant domain is obtained from an immunoglobulin selected from the group consisting of IgG-1, IgG-2, IgG-3, IgG-4, IgA, IgE, IgD and IgM.
5. The fusion protein of claim 4 , wherein said IgA is IgA-1 or IgA-2.
6. The fusion protein of claim 3 wherein the IL-15 mutant polypeptide and the immunoglobulin constant domain are linked by a linker.
7. The fusion protein of claim 6 wherein the linker has 4; 5; 6; 7; 8; 9; 10; 11; 12; 13; 14; 15; 16; 17; 18; 19; 20; 21; 22; 23; 24; 25; 26; 27; 28; 29; or 30 amino acid residues.
8. The fusion protein of claim 6 wherein the linker is selected from the group consisting of SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14 and SEQ ID NO:15.
9. The fusion protein of claim 3 wherein the immunoglobulin constant domain is a Fc region.
10. The fusion protein according to claim 3 which has an amino acid sequence selected from the group consisting of SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:7, SEQ ID NO:8 and SEQ ID NO:9.
11. An IL-15 antagonist consisting of a dimer of the fusion protein according to claim 2 .
12. A pharmaceutical composition comprising the IL-15 mutant polypeptide of claim 1 , a fusion protein comprising the IL-15 mutant polypeptide and a heterologous polypeptide, or an IL-15 antagonist consisting of a dimer of the fusion protein.
13. An isolated nucleic acid encoding the IL-15 mutant polypeptide of claim 1 or a fusion protein comprising said IL-15 mutant polypeptide and a heterologous polypeptide.
14. A vector comprising the nucleic acid according to claim 13 .
15. An isolated cell comprising the nucleic acid of claim 13 , or a vector comprising said nucleic acid.
16. A method of producing the IL-15 mutant polypeptide of claim 1 , or a fusion protein comprising said IL-15 mutant polypeptide and a heterologous polypeptide, which method comprises the steps of: (i) culturing a host cell transformed or transfected with an expression vector comprising a nucleic acid encoding said IL-15 mutant polypeptide or fusion protein under conditions suitable to allow expression of said IL-15 mutant polypeptide or fusion protein; and (ii) recovering the expressed IL-15 mutant polypeptide or fusion protein.