IL-37 variants

• US 11,084,855 B2
• Filed: 06/15/2016
• Issued: 08/10/2021
• Est. Priority Date: 06/15/2015
• Status: Active Grant

• Current Assignee: Monash University
• Original Assignee: Monash University
• Inventors: Nold, Marcel, Nold, Claudia, Ellisdon, Andrew, Whisstock, James
• Primary Examiner(s): Ford, Vanessa L.
• Assistant Examiner(s): Hissong, Bruce D.
• Application Number:
  US15/737,204
• Publication Number:
  US 20180162918A1
• Time in Patent Office: 1,882 Days
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: C07K 14/54 Interleukins [IL]

Abstract

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.

Claims

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 β

3 and β

4 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.