Chemokine mutants acting as chemokine antagonists
View Patent ↗Mutants of specific CC-chemokines containing a non-conservative substitution in a conserved consensus sequence act as CC-chemokine antagonists, and can be effectively used in the treatment of autoimmune and inflammatory diseases, cancers, and viral or bacterial infections. Particularly preferred are the RANTES/CCL5 mutants having the amino acid sequence of SEQ ID NO: 1, 2, 3, or 4.
1. An isolated mutant of CCL5 (RANTES) comprising SEQ ID NO: 1, 4, 5, 6 or 7, wherein said mutant antagonizes in vivo cellular recruitment caused by CCL5.
2. An isolated polypeptide comprising a heterologous polypeptide sequence and a polypeptide selected from the group consisting of SEQ ID NO: 1, 4, 5, 6 and 7.
3. The polypeptide according to claim 2 , wherein said heterologous polypeptide sequence comprises an amino acid sequence selected from one or more of the following protein sequences: extracellular domains of membrane-bound protein, immunoglobulin constant regions, multimerization domains, extracellular proteins, signal peptide-containing proteins, or export signal-containing proteins.
4. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a mutant of CCL5 (RANTES) comprising SEQ ID NO: 1, 4, 5, 6 or 7, wherein said mutant antagonizes in vivo cellular recruitment caused by CCL5.
5. A method of making a pharmaceutical composition comprising combining a pharmaceutically acceptable excipient and a mutant of CCL5 (RANTES) according to claim 1 .
6. The isolated mutant according to claim 1 , wherein said mutant comprises SEQ ID NO: 1.
7. The isolated mutant according to claim 1 , wherein said mutant comprises SEQ ID NO: 4.
8. The isolated mutant according to claim 1 , wherein said mutant comprises SEQ ID NO: 5.
9. The isolated mutant according to claim 1 , wherein said mutant comprises SEQ ID NO: 6.
10. The isolated mutant according to claim 1 , wherein said mutant comprises SEQ ID NO: 7.
11. The isolated polypeptide according to claim 2 , wherein said isolated polypeptide comprises a heterologous polypeptide sequence and SEQ ID NO: 1.
12. The isolated polypeptide according to claim 2 , wherein said isolated polypeptide comprises a heterologous polypeptide sequence and SEQ ID NO: 4.
13. The isolated polypeptide according to claim 2 , wherein said isolated polypeptide comprises a heterologous polypeptide sequence and SEQ ID NO: 5.
14. The isolated polypeptide according to claim 2 , wherein said isolated polypeptide comprises a heterologous polypeptide sequence and SEQ ID NO: 6.
15. The isolated polypeptide according to claim 2 , wherein said isolated polypeptide comprises a heterologous polypeptide sequence and SEQ ID NO: 7.
16. The pharmaceutical composition according to claim 4 , wherein said mutant comprises SEQ ID NO: 1.
17. The pharmaceutical composition according to claim 4 , wherein said mutant comprises SEQ ID NO: 4.
18. The pharmaceutical composition according to claim 4 , wherein said mutant comprises SEQ ID NO: 5.
19. The pharmaceutical composition according to claim 4 , wherein said mutant comprises SEQ ID NO: 6.
20. The pharmaceutical composition according to claim 4 , wherein said mutant comprises SEQ ID NO: 7.