IL-33 antagonists and uses thereof
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.
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.