IL-37 variants
This invention relates to polypeptides, including variants of interleukin-37 (IL-37), and related therapeutics and compositions. The invention also relates to the use of the polypeptides and compositions in methods of treating inflammatory diseases or conditions. The present invention provides a monomeric anti-inflammatory polypeptide comprising an amino acid sequence of an IL-37 monomer, the amino acid sequence having a mutation or modification for preventing the anti-inflammatory peptide from forming a homodimer.
1. An anti-inflammatory polypeptide comprising an amino acid sequence of an IL-37 polypeptide,
wherein the anti-inflammatory polypeptide has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 1 over the full length of SEQ ID NO: 1;
wherein the anti-inflammatory polypeptide comprises a mutation or modification that reduces the capacity of the anti-inflammatory polypeptide to form a dimer, compared to a polypeptide comprising the amino acid sequence of SEQ ID NO: 1; and
wherein the mutation or modification in the anti-inflammatory polypeptide is at any one or more residues, or residues equivalent to, 71 to 74, 78, 80, 83 to 88 and 184 in SEQ ID NO: 1,
wherein the amino acid residue at, or equivalent to:
position 71 in SEQ ID NO: 1 is not a Val;
position 72 in SEQ ID NO: 1 is not an Leu;
position 73 in SEQ ID NO: 1 is not a Asp;
position 74 in SEQ ID NO: 1 is not a Ser;
position 78 in SEQ ID NO: 1 is not an Ile;
position 80 in SEQ ID NO: 1 is not a Val;
position 83 in SEQ ID NO: 1 is not a Lys;
position 84 in SEQ ID NO: 1 is not an Asn;
position 85 in SEQ ID NO: 1 is not a Tyr;
position 86 in SEQ ID NO: 1 is not an Ile;
position 87 in SEQ ID NO: 1 is not an Arg;
position 88 in SEQ ID NO: 1 is not a Pro; and/or
position 184 in SEQ ID NO: 1 is not an Asn.
2. The anti-inflammatory polypeptide of claim 1 , wherein the mutation prevents the anti-inflammatory polypeptide from forming a dimerization interface that enables dimerization of IL-37 monomers.
3. The anti-inflammatory polypeptide of claim 2 , wherein the mutation is located in a region of the anti-inflammatory polypeptide that has the same amino acid sequence as the amino acid sequence that forms the dimerization interface of an IL-37 monomer.
4. The anti-inflammatory polypeptide of claim 3 , wherein the mutation is located in the loop between the β3 and β4 strands that form the dimerization interface of an IL-37 monomer.
5. The anti-inflammatory polypeptide of claim 1 , wherein the mutation or modification is located within a region, or a region equivalent to, residues 83 to 88 in SEQ ID NO:1.
6. The anti-inflammatory polypeptide according to claim 1 , wherein the mutation or modification occurs at a residue at a position, or at a position equivalent to, D73, K83, N84, Y85, 186, R87 or P88 in SEQ ID NO: 1.
7. The anti-inflammatory polypeptide according to claim 1 , wherein the mutation is a replacement with a non-conservative amino acid.
8. The anti-inflammatory polypeptide according to claim 1 , wherein the mutation is replacement with alanine or an amino acid with an opposite charge.
9. The anti-inflammatory polypeptide according to claim 1 , wherein the anti-inflammatory polypeptide has an amino acid sequence having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 1.
10. The anti-inflammatory polypeptide according to claim 1 , wherein the mutation is any one or more of D73A, D73K, K83E and Y85A.
11. The anti-inflammatory polypeptide according to claim 1 , wherein the mutation is D73A.
12. The anti-inflammatory polypeptide according to claim 1 , wherein the mutation is D73K.
13. The anti-inflammatory polypeptide according to claim 1 , wherein the mutation is K83E.
14. The anti-inflammatory polypeptide according to claim 1 , wherein the mutation is Y85A.
15. The anti-inflammatory polypeptide according to claim 1 , wherein one or more residues at a position, or position equivalent to, residues 83 to 88 of SEQ ID NO: 1 is deleted.
16. A pharmaceutical composition comprising the anti-inflammatory polypeptide according to claim 1 and a pharmaceutically acceptable diluent, excipient or carrier.
17. An anti-inflammatory polypeptide comprising an amino acid sequence of an IL-37 polypeptide,
wherein the polypeptide has an N terminal truncation of, or equivalent to, residues 1 to 20 or 1 to 45 of SEQ ID NO: 1,
wherein the polypeptide has at least 95% sequence identity to the amino acid sequence of 21 to 218 or 46 to 218 of SEQ ID NO: 1,
wherein the polypeptide comprises a mutation or modification that reduces the capacity of the anti-inflammatory polypeptide to form a dimer, compared to a polypeptide comprising the amino acid sequence of SEQ ID NO: 1; and
wherein the mutation or modification in the polypeptide is, or is equivalent to, any one or more of D73A, D73K, K83E and Y85A.
18. The anti-inflammatory polypeptide of claim 17 , wherein the anti-inflammatory polypeptide has an amino acid sequence having at least 96% sequence identity to the amino acid sequence of 21 to 218 or 46 to 218 of SEQ ID NO: 1.
19. The anti-inflammatory polypeptide of claim 17 , wherein the anti-inflammatory polypeptide has an amino acid sequence having at least 97% sequence identity to the amino acid sequence of 21 to 218 or 46 to 218 of SEQ ID NO: 1.
20. The anti-inflammatory polypeptide of claim 17 , wherein the anti-inflammatory polypeptide has an amino acid sequence having at least 98% sequence identity to the amino acid sequence of 21 to 218 or 46 to 218 of SEQ ID NO: 1.
21. The anti-inflammatory polypeptide of claim 17 , wherein the anti-inflammatory polypeptide has an amino acid sequence having at least 99% sequence identity to the amino acid sequence of 21 to 218 or 46 to 218 of SEQ ID NO: 1.
22. The anti-inflammatory polypeptide of claim 17 , wherein the anti-inflammatory polypeptide has an amino acid sequence having at least 100% sequence identity to the amino acid sequence of 21 to 218 or 46 to 218 of SEQ ID NO: 1.