Serpin fusion polypeptides and methods of use thereof
This invention relates to molecules, particularly polypeptides, more particularly fusion proteins that include a serpin polypeptide or an amino acid sequence that is derived from a serpin and second polypeptide comprising of at least one the following: an Fc polypeptide or an amino acid sequence that is derived from an Fc polypeptide; a cytokine targeting polypeptide or a sequence derived from a cytokine targeting polypeptide; a WAP domain containing polypeptide or a sequence derived from a WAP containing polypeptide; and an albumin polypeptide or an amino acid sequence that is derived from a serum albumin 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 serpin polypeptide operably linked to a modified human immunoglobulin Fc polypeptide, wherein the modified human immunoglobulin Fc polypeptide comprises the amino acid sequence of SEQ ID NO: 60, wherein the immunoglobulin Fc polypeptide comprises mutations at positions S228, L235, M252, and M428, and wherein the human serpin polypeptide is a human alpha-1 antitrypsin (AAT) polypeptide comprising the amino acid sequence of SEQ ID NO: 80.
2. The isolated fusion protein of claim 1 , wherein the fusion protein further comprises an additional polypeptide selected from the group consisting of:
a cytokine targeting polypeptide;
a whey acidic protein (WAP) domain containing polypeptide; or
an albumin polypeptide.
3. The isolated fusion protein of claim 1 , wherein the AAT polypeptide comprises a mutated reactive site loop of AAT comprising the amino acid sequence of SEQ ID NO: 32.
4. The isolated fusion protein of claim 1 , wherein the mutations at positions S228, L235, M252, and M428 comprise S228P, L235E, M252Y, and M428L.
5. The isolated fusion protein of claim 1 , wherein the AAT polypeptide and the immunoglobulin Fc polypeptide are operably linked via a hinge region, a linker region, or both a hinge region and linker region.
6. The isolated fusion protein of claim 5 , wherein the hinge region, the linker region or both the hinge region and the linker region comprise a peptide sequence.
7. An isolated fusion protein comprising at least one human serpin polypeptide operably linked to a modified human immunoglobulin Fc polypeptide, wherein the modified human immunoglobulin Fc polypeptide comprises the amino acid sequence of SEQ ID NO:73, and wherein the human serpin polypeptide is a human alpha-1 antitrypsin (AAT) polypeptide comprising the amino acid sequence of SEQ ID NO: 80.