WAP domain fusion polypeptides and methods of use thereof
This invention relates to fusion proteins that include a whey acidic protein (WAP) domain-containing polypeptide and a second polypeptide. Additionally, the invention relates to fusion proteins that include a WAP domain-containing polypeptide, a second polypeptide, and a third polypeptide. The second and/or third polypeptides of the fusion proteins of the invention are an Fc polypeptide; an albumin polypeptide; a cytokine targeting polypeptide; or a serpin polypeptide. This invention also relates to methods of using such molecules in a variety of therapeutic and diagnostic indications, as well as methods of producing such molecules.
1. An isolated fusion protein comprising at least one human whey acidic protein (WAP) domain-containing polypeptide comprising a human secretory leukocyte proteinase inhibitor (SLPI) polypeptide comprising the amino acid sequence of SEQ ID NO: 3 or a human elafin polypeptide comprising the amino acid sequence of SEQ ID NO: 6 operably linked to
an immunoglobulin Fc polypeptide comprising the amino acid sequence of SEQ ID NO: 10.
2. The isolated fusion protein of claim 1 , wherein the WAP domain containing polypeptide and the immunoglobulin Fc polypeptide are operably linked via a hinge region, a linker region, or both a hinge region and linker region.
3. The isolated fusion protein of claim 2 , wherein the hinge region, the linker region or both the hinge region and the linker region comprise an amino acid sequence selected from the group consisting of SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, and SEQ ID NO: 51.
4. The isolated fusion protein of claim 1 , wherein the fusion protein further comprises a serpin polypeptide comprising the amino acid sequence of SEQ ID NO: 13 or SEQ ID NO: 38.
5. The isolated fusion protein of claim 1 , wherein the Fc polypeptide is modified to enhance FcRn binding.
6. The isolated fusion protein of claim 1 , wherein the immunoglobulin Fc polypeptide comprises at least one of the following mutations: Met252Tyr, Ser254Thr, Thr256Glu or Met428Leu or Asn434Ser.
7. The isolated fusion protein of claim 1 , wherein the immunoglobulin Fc polypeptide comprises at least one mutation at a position selected from the group consisting of: Met252, Ser254, Thr256, Met428, and Asn434.
8. An isolated fusion protein comprising at least one human secretory leukocyte proteinase inhibitor (SLPI) polypeptide comprising the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 39 operably linked to
an immunoglobulin Fc polypeptide comprising the amino acid sequence of SEQ ID NO: 10.
9. The isolated fusion protein of claim 8 , wherein the SLPI polypeptide and the immunoglobulin Fc polypeptide are operably linked via a hinge region, a linker region, or both a hinge region and linker region.
10. The isolated fusion protein of claim 9 , wherein the peptide sequence comprises the amino acid sequence of SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, or SEQ ID NO: 51.
11. The isolated fusion protein of claim 8 , wherein the fusion protein further comprises an AAT polypeptide comprising the amino acid sequence of SEQ ID NO: 13 or SEQ ID NO: 38.
12. The isolated fusion protein of claim 8 , wherein the immunoglobulin Fc polypeptide is modified to enhance FcRn binding.
13. The isolated fusion protein of claim 8 , wherein the immunoglobulin Fc polypeptide comprises at least one mutation at a position selected from the group consisting of: Met252, Ser254, Thr256, Met428, and Asn434.
14. The isolated fusion protein of claim 8 , wherein the immunoglobulin Fc polypeptide comprises at least one of the following mutations: Met252Tyr, Ser254Thr, Thr256Glu, Met428Leu or Asn434Ser.
15. An isolated fusion protein comprising human at least one human Elafin polypeptide comprising the amino acid sequence of SEQ ID NO: 4, SEQ ID NO: 5 or SEQ ID NO: 6 operably linked to
an immunoglobulin Fc polypeptide comprising the amino acid sequence of SEQ ID NO: 10.
16. The isolated fusion protein of claim 15 , wherein the Elafin polypeptide and the immunoglobulin Fc polypeptide are operably linked via a hinge region, a linker region, or both a hinge region and linker region.
17. The isolated fusion protein of claim 16 , wherein the peptide sequence comprises the amino acid sequence of SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, or SEQ ID NO: 51.
18. The isolated fusion protein of claim 15 , wherein the immunoglobulin Fc polypeptide is modified to enhance FcRn binding.
19. The isolated fusion protein of claim 15 , wherein the immunoglobulin Fc polypeptide comprises at least one mutation at a position selected from the group consisting of: Met252, Ser254, Thr256, Met428, and Asn434.
20. The isolated fusion protein of claim 15 , wherein the immunoglobulin Fc polypeptide comprises at least one of the following mutations: Met252Tyr, Ser254Thr, Thr256Glu, Met428Leu or Asn434Ser.
21. A method of treating or alleviating a symptom of a disease or disorder associated with aberrant serine protease expression or activity in a subject in need thereof, the method comprising administering a fusion protein according to claim 1 , claim 8 , or claim 15 .
22. The method of claim 21 , wherein the subject is a human.
23. A method of treating or alleviating a symptom of an inflammatory disease or disorder in a subject in need thereof, the method comprising administering a fusion protein according to claim 1 , claim 8 , or claim 15 .
24. A method of treating or alleviating a symptom of an infectious disease or disorder in a subject in need thereof, the method comprising administering a fusion protein according to claim 1 , claim 8 , or claim 15 .