IL-37 VARIANTS

• US 20180162918A1
• Filed: 06/15/2016
• Published: 06/14/2018
• Est. Priority Date: 06/15/2015
• Status: Active Grant

• Current Assignee: Monash University
• Original Assignee: Hudson Institute of Medical Research, Monash University
• Inventors: Nold, Marcel, Nold, Claudia, Ellisdon, Andrew, Whisstock, James
• Granted Patent: US 11,084,855 B2
• Time in Patent Office: 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, the amino acid sequence having a mutation or modification that reduces the capacity of the anti-inflammatory polypeptide to form a dimer.

2. The polypeptide of claim 1, wherein the mutation prevents the peptide from forming a dimerization interface that enables dimerization of IL-37 monomers.

3. The polypeptide of claim 2, wherein the mutation is located in a region of the peptide that has the same amino acid sequence as the amino acid sequence that forms the dimerization interface of an IL-37 monomer.

4. The polypeptide of claim 3, wherein the mutation is located in the β

3 or β

4 loops that form the dimerization interface of an IL-37 monomer.

5. The polypeptide of any one of claims 1 to 4, wherein the amino acid sequence has at least 50% identity with SEQ ID NO:

1 and the mutation or modification is at any one or more residues, or residues equivalent to, 71 to 74, 78, 80, 83 to 91 and 184 in SEQ ID NO;

1.

6. The polypeptide of claim 5, wherein the mutation or modification is located within a region, or a region equivalent to, residues 83 to 91 in SEQ ID NO:

1.

7. A polypeptide according to claim 5 or 6, wherein the mutation or modification occurs at a residue at a position, or at a position equivalent to, D73, K83, N84, Y85, I86, R87 or P88 in SEQ ID NO:

1.

8. A polypeptide according to any one of claims 5 to 7, 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.

9. A polypeptide according to any one of claims 5 to 8, wherein the mutation is a replacement with a non-conservative amino acid.

10. A polypeptide according to any one of claims 5 to 9, wherein the mutation is replacement with alanine or an amino acid with an opposite charge.

11. A polypeptide according to any one of claims 5 to 10, wherein the polypeptide has an amino acid sequence having at least 60%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with SEQ ID NO:

1.

12. A polypeptide according to any one of claims 5 to 11, wherein the mutation is any one or more of D73A, D73K, K83E and Y85A.

13. A polypeptide according to any one of claims 5 to 2, wherein the mutation is D73A.

14. A polypeptide according to any one of claims 5 to 12, wherein the mutation is D73K.

15. A polypeptide according to any one of claims 5 to 12, wherein the mutation is K83E.

16. A polypeptide according to any one of claims 5 to 12, wherein the mutation is Y85A.

17. A polypeptide according to any one of claims 1 to 8, wherein one or more residues at a position, or position equivalent to, residues 83 to 91 of SEQ ID NO:

1 are deleted.

18. A polypeptide according to any one of preceding claims wherein the peptide has an N terminal truncation.

19. A polypeptide according to claim 18, wherein the N terminal truncation is of, or equivalent to, residues 1 to 25 or 1 to 45.

20. A polypeptide according to any one of the preceding claims wherein the polypeptide inhibits the production or function of an inflammatory cytokine.

21. A polypeptide according to claim 20, wherein the peptide reduces the production of IL-1.

22. A pharmaceutical composition for treating or preventing an inflammatory disease or condition comprising a polypeptide according to any one of claims 1 to 21 and a pharmaceutically acceptable diluent, excipient or carrier.

23. A method of inhibiting inflammation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a polypeptide according to any one of claims 1 to 21, or a pharmaceutical composition according to claim 22, thereby inhibiting inflammation.

24. A method of treating or preventing an inflammatory disease or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a polypeptide according to any one of claims 1 to 21, or a pharmaceutical composition according to claim 22, thereby treating or preventing an inflammatory disease or condition in a subject.

25. A method of alleviating or ameliorating a symptom of an inflammatory disease or condition in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a polypeptide according to any one of claims 1 to 21, or a pharmaceutical composition according to claim 22, thereby alleviating or ameliorating a symptom of an inflammatory disease or condition in the subject.

26. Use of a therapeutically effective amount of a polypeptide according to any one of claims 1 to 21 in the manufacture of a medicament for the treatment or prevention of an inflammatory disease or condition in a subject in need thereof.

27. A method of any one of claims 23 to 25, or a use according to claim 26, wherein the inflammatory disease is predominantly mediated by activation of TLR2 or TLR4.

28. A method of any one of claims 23 to 25, or a use according to claim 26, wherein the inflammatory disease is predominantly mediated by activation of TLR7, 8 or 9.

29. A method of any one of claims 23 to 25, or a use according to claim 26, wherein the inflammatory disease is an autoimmune disease.

30. A method of any one of claims 23 to 25, or a use according to claim 26, wherein the inflammatory disease is endotoxic shock.

31. A method or a use according to claim 30, wherein the endotoxic shock is caused by bacteria.

32. A nucleic acid molecule encoding an a polypeptide according to any one of claims 1 to 21.

33. A vector comprising a nucleic acid molecule according to claim 32.

34. A cell comprising a vector according to claim 33 or nucleic acid molecule according to claim 32.

35. An animal or tissue derived therefrom comprising a cell according to claim 34.