IL-33 antagonists and uses thereof

Patent metadata

Field	Value
Publication number	US-9637535-B2
Application number	US-201414210599-A
Country	US
Kind code	B2
Filing date	Mar 14, 2014
Priority date	Mar 15, 2013
Publication date	May 2, 2017
Grant date	May 2, 2017

Abstract

The present invention provides interleukin-33 (IL-33) antagonists comprising one or more IL-33-binding domains and one or more multimerizing domains and methods of using the same. According to certain embodiments of the invention, the IL-33-binding domains can comprise an IL-33-binding portion of an ST2 protein and/or an extracellular portion of an IL-1RAcP protein. The IL-33 antagonists of the invention are useful for the treatment of diseases and disorders associated with IL-33 signaling and/or IL-33 cellular expression, such as infectious diseases, inflammatory diseases, allergic diseases and fibrotic diseases.

First claim

What is claimed is:

1. An interleukin-33 (IL-33) antagonist comprising a first IL-33 binding domain (D1), a second IL-33 binding domain (D2), and a multimerizing domain (M), wherein D1, or D2, or both D1 and D2 are attached to the multimerizing domain (M), wherein D1 comprises an extracellular portion of a suppression of tumorigenicity (ST2) protein, D2 comprises an extracellular portion of an interleukin-1 receptor accessory protein (IL-1RAcP), and M comprises an Fc portion of an immunoglobulin.

2. The IL-33 antagonist of claim 1 , wherein D2 is attached to the N-terminus of D1, and wherein D1 is attached to the N-terminus of M.

3. The IL-33 antagonist of claim 1 , wherein D1 is attached to the N-terminus of M, and D2 is attached to the C-terminus of M.

4. The IL-33 antagonist of claim 1 , wherein D2 is attached to the N-terminus of M, and D1 is attached to the C-terminus of M.

5. The IL-33 antagonist of claim 1 , wherein D1 is attached to the C-terminus of M, and D2 is attached to the C-terminus of D1.

6. The IL-33 antagonist of claim 1 , wherein D2 is attached to the C-terminus of M, and D1 is attached to the C-terminus of D2.

7. The IL-33 antagonist of claim 1 , wherein D1 is attached to the N-terminus of D2, and wherein D2 is attached to the N-terminus of M.

8. The IL-33 antagonist of claim 1 , wherein the IL-33 antagonist binds human interleukin 33 (IL-33) with a binding dissociation equilibrium constant (KD) of less than about 80 pM as measured in a surface plasmon resonance assay at 25° C., and/or a binding dissociation equilibrium constant (KD) of less than about 400 pM as measured in a surface plasmon resonance assay at 37° C.

9. The IL-33 antagonist of claim 1 , wherein the IL-33 antagonist binds monkey interleukin 33 (IL-33) with a binding dissociation equilibrium constant (KD) of less than about 60 pM as measured in a surface plasmon resonance assay at 25° C., and/or a binding dissociation equilibrium constant (KD) of less than about 200 pM as measured in a surface plasmon resonance assay at 37° C.

10. The IL-33 antagonist of claim 1 , wherein the IL-33 antagonist binds mouse interleukin 33 (IL-33) with a binding dissociation equilibrium constant (KD) of less than about 110 pM as measured in a surface plasmon resonance assay at 25° C., and/or a binding dissociation equilibrium constant (KD) of less than about 100 pM as measured in a surface plasmon resonance assay at 37° C.

11. The IL-33 antagonist of claim 1 , wherein the IL-33 antagonist binds human interleukin 33 (IL-33) with a dissociative half-life (t½) of greater than or equal to about 9 minutes as measured in a surface plasmon resonance assay at 25° C., and/or a dissociative half-life (t½) of greater than or equal to about 4 minutes as measured in a surface plasmon resonance assay at 37° C.

12. The IL-33 antagonist of claim 1 , wherein the IL-33 antagonist binds monkey interleukin 33 (IL-33) with a dissociative half-life (t½) of greater than about 40 minutes as measured in a surface plasmon resonance assay at 25° C., and/or a dissociative half-life (t½) of greater than or equal to about 10 minutes as measured in a surface plasmon resonance assay at 37° C.

13. The IL-33 antagonist of claim 1 , wherein the IL-33 antagonist binds mouse interleukin 33 (IL-33) with a dissociative half-life (t½) of greater than about 25 minutes as measured in a surface plasmon resonance assay at 25° C., and/or a dissociative half-life (t½) of greater than about 30 minutes as measured in a surface plasmon resonance assay at 37° C.

14. The IL-33 antagonist of claim 1 , wherein the IL-33 antagonist blocks the interaction of IL-33 and ST2.

15. The IL-33 antagonist of claim 14 , wherein the IL-33 antagonist blocks the interaction of IL-33 and ST2 with an IC50 value of less than about 115 pM as measured in an in vitro receptor/ligand binding assay at 25° C.

16. The IL-33 antagonist of claim 1 , wherein D1 comprises the amino acid sequence of SEQ ID NO: 5 or 6, or an amino acid sequence having at least 90% identity thereto.

17. The IL-33 antagonist of claim 1 , wherein D2 comprises the amino acid sequence of SEQ ID NO: 7 or 8, or an amino acid sequence having at least 90% identity thereto.

18. An IL-33 antagonist comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 2, 3, 4 and 13.

19. A pharmaceutical composition comprising the IL-33 antagonist of claim 1 , and a pharmaceutically acceptable carrier or diluent.

20. The IL-33 antagonist of claim 1 , wherein the immunoglobulin is human IgG.

21. The IL-33 antagonist of claim 20 , wherein the immunoglobulin is human IgG1.

22. The IL-33 antagonist of claim 1 , wherein the immunoglobulin is murine IgG.

23. The IL-33 antagonist of claim 22 , wherein the immunoglobulin is murine IgG2a.

24. The IL-33 antagonist of claim 18 , comprising the amino acid sequence of SEQ ID NO: 1.

25. The IL-33 antagonist of claim 18 , comprising the amino acid sequence of SEQ ID NO: 2.

26. The IL-33 antagonist of claim 18 , comprising the amino acid sequence of SEQ ID NO: 3.

27. The IL-33 antagonist of claim 18 , comprising the amino acid sequence of SEQ ID NO: 4.

28. The IL-33 antagonist of claim 18 , comprising the amino acid sequence of SEQ ID NO: 13.

29. A pharmaceutical composition comprising the IL-33 antagonist of claim 24 , and a pharmaceutically acceptable carrier or diluent.

30. A pharmaceutical composition comprising the IL-33 antagonist of claim 25 , and a pharmaceutically acceptable carrier or diluent.

31. A pharmaceutical composition comprising the IL-33 antagonist of claim 26 , and a pharmaceutically acceptable carrier or diluent.

32. A pharmaceutical composition comprising the IL-33 antagonist of claim 27 , and a pharmaceutically acceptable carrier or diluent.

33. A pharmaceutical composition comprising the IL-33 antagonist of claim 28 , and a pharmaceutically acceptable carrier or diluent.

Assignees

• Regeneron Pharma

Inventors

• Murphy Andrew J
• Papadopoulos Nicholas J
• Orengo Jamie

Classifications

• C07K14/54

  Interleukins [IL] · CPC title

• C07K19/00

  Hybrid peptides {, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes} · CPC title

• A61K38/20

  Interleukins [IL] · CPC title

• A61K38/17

  from animals; from humans {(enzyme inhibitors A61K38/005)} · CPC title

• A61P11/02

  Nasal agents, e.g. decongestants · CPC title