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 whey acidic protein (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. A method of inhibiting or downregulating serine protease expression or activity in a subject in need thereof, the method comprising administering a 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:
amino acid position 5228 corresponding to amino acid residue 10 of SEQ ID NO: 60;
amino acid position L235 corresponding to amino acid residue 17 of SEQ ID NO: 60;
amino acid position M252 corresponding to amino acid residue 34 of SEQ ID NO: 60; and
amino acid position M428 corresponding to amino acid residue 210 of SEQ ID NO: 60,
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 method of claim 1 , wherein the subject in need thereof has a disease or disorder selected from the following: emphysema, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), allergic asthma, cystic fibrosis, cancers of the lung, ischemia-reperfusion injury, ischemia/reperfusion injury following cardiac transplantation, myocardial infarction, rheumatoid arthritis, septic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, psoriasis, type I and/or type II diabetes, pneumonia, sepsis, graft versus host disease (GVHD), wound healing, Systemic lupus erythematosus, and Multiple sclerosis.
3. The method of claim 2 , wherein the subject is a human.
4. The method of claim 1 , wherein the subject has an infection that is selected from bacterial infections, fungal infections, or viral infections.
5. The method 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.
6. The method of claim 1 , wherein the mutations at positions S228, L235, M252, and M428 comprise S228P, L235E, M252Y, and M428L.
7. A method of inhibiting or downregulating serine protease expression or activity in a subject in need thereof, the method comprising administering a 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.