Uti fusion proteins

Abstract

The present invention provides UTI fusion proteins, DNA sequences for producing the same, and pharmaceutical compositions and methods of using the same.

1 - 9 . (canceled) 
     
     
         10 . An isolated human urinary trypsin inhibitor (hUTI) fusion protein comprising:
 (a) hUTI or a hUTI variant that retains hUTI functional activity,   (b) a flexible peptide linker (L) selected from the group consisting of SEQ ID Nos: 33-42, and   (c) an IgG Fc domain that lacks the first constant region immunoglobulin domain, or fragment thereof that retains wild type IgG Fc functional activity.   
     
     
         11 . The hUTI fusion protein of  claim 10 , wherein the hUTI fusion protein demonstrates greater thermal stability than the UTI fusion proteins described in Chinese patent application CN103044554A. 
     
     
         12 . The hUTI fusion protein of  claim 10 , wherein the hUTI variant is a hUTI fragment. 
     
     
         13 . The hUTI fusion protein of  claim 10 , wherein the hUTI variant is a hUTI analogue. 
     
     
         14 . The hUTI fusion protein of  claim 10 , wherein the Fc domain binds to an Fc receptor on a human cell. 
     
     
         15 . The hUTI fusion protein of  claim 10 , wherein the Fc domain is an analogue of an Fc domain. 
     
     
         16 . The hUTI fusion protein of  claim 10 , wherein the Fc domain is a fragment of an Fc domain. 
     
     
         17 . The hUTI fusion protein of  claim 10 , further comprising signal peptide MGWSCIILFLVATATGVHS (SEQ ID NO:49). 
     
     
         18 . The hUTI fusion protein of  claim 10 , wherein the hUTI fusion protein is a monomer. 
     
     
         19 . The hUTI fusion protein of  claim 10 , wherein the hUTI fusion protein is a multimer. 
     
     
         20 . The hUTI fusion protein of  claim 10 , wherein the hUTI fusion protein is a dimer. 
     
     
         21 . The hUTI fusion protein of  claim 19  or  20 , wherein the multimer or dimer comprises polypeptide chains that are associated covalently. 
     
     
         22 . The hUTI fusion protein of  claim 19  or  20 , wherein the multimer or dimer comprises polypeptide chains that are associated non-covalently. 
     
     
         23 . The hUTI fusion protein of  claim 10 , wherein the hUTI fusion protein comprises an amino acid sequence selected from the group consisting of SEQ ID Nos: 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, and 29. 
     
     
         24 . The hUTI fusion protein of  claim 10 , wherein the hUTI protein is a variant human UTI protein that retains hUTI functional activity. 
     
     
         25 . A dimer comprising two isolated hUTI fusion proteins of  claim 10 , wherein the Fc domains, or fragments thereof, are associated covalently. 
     
     
         26 . A pharmaceutical composition comprising the UTI fusion protein of  claim 10  or the dimer of  claim 25 , and a pharmaceutically acceptable excipient. 
     
     
         27 . A nucleic acid encoding the UTI fusion protein of any one of  claim 10  or the dimer of  claim 25 . 
     
     
         28 . An expression vector comprising the nucleic acid of  claim 27 . 
     
     
         29 . A recombinant host cell comprising the expression vector of  claim 28 . 
     
     
         30 . The recombinant host cell of  claim 29 , wherein the cell is selected from the group consisting of a mammalian cell, an insect cell, an  E. coli  cell, a yeast cell, and a plant cell. 
     
     
         31 . The recombinant host cell of  claim 30 , wherein the mammalian cell is selected from the group consisting of a Chinese hamster ovary (CHO) cell, an HEK 293 cell, an NSO cell, a HeLa cell, a baby hamster kidney (BHK) cell, a monkey kidney cell (COS) and a human hepatocellular carcinoma cell. 
     
     
         32 . A method of producing a hUTI fusion protein, the method comprising the step of placing the recombinant host cell of  claim 31  in a growth medium such that a-recombinant fusion protein is expressed, and isolating the recombinant fusion protein from the cell or growth medium. 
     
     
         33 . A method of producing a UTI fusion protein, wherein the UTI fusion protein of  claim 10  or the dimer of  claim 25 , is produced in a transgenic animal. 
     
     
         34 . The isolated UTI fusion protein of  claim 10  or the dimer of  claim 25 , wherein the Fc domain is selected from the group consisting of an IgG1, an IgG2 and an IgG4 Fc domain. 
     
     
         35 . The isolated UTI fusion protein of  claim 10  or the dimer of  claim 25 , wherein the Fc domain is an IgG1 Fc domain. 
     
     
         36 . A method of treating a UTI-related condition comprising administering to a patient in need thereof an effective amount of the UTI fusion protein of  claim 10  or the dimer of  claim 25 . 
     
     
         37 . The method of  claim 36 , wherein the UTI-related condition is selected from the group consisting of pancreatitis, endoscopy-induced pancreatitis, acute pancreatitis, arthritis, severe acute respiratory syndrome, systemic inflammatory response syndrome, acute circulatory failure, sepsis, hepatitis, appendicitis, colitis, organ failure, organ damage, pancreas damage, kidney damage, lung damage, reperfusion injury, Stevens-Johnson syndrome, toxic epidermal necrolysis, shock, ischemic injury, acute lung injury, lung injury caused by acute aortic dissection, asthma, lung inflammation, pneumonia, ventilator-associated pneumonia, disseminated intravascular coagulation, and acute respiratory distress syndrome. 
     
     
         38 . The method of  claim 36 , wherein the UTI-related condition is acute pancreatitis.