COMPOSITIONS OF, AND METHODS FOR, ALPHA-1 ANTITRYPSIN Fc FUSION MOLECULES

Abstract

A novel method of treating and preventing bacterial diseases is provided. In particular, the present invention relates to compositions and methods for inhibition of Gram negative, Gram positive and acid fast bacilli in general and tuberculosis (TB), mycobacterium avium complex (MAC), and anthrax in particular. Thus, the invention relates to modulation of cellular activities, including macrophage activity, and the like. More particularly, the present invention relates to the inhibitory compounds comprising naturally occurring and man-made inhibitors of serine protease.

What is claimed: 
     
         1 . A construct comprising a nucleic acid sequence encoding a fusion polypeptide
 comprising:   a first nucleic acid sequence encoding mammalian alpha-1 antitrypsin (AAT), wherein the first nucleic acid sequence comprises SEQ ID NO: 68 or SEQ ID NO:78; and   a second nucleic acid sequence encoding an IgG1 Fc.   
     
     
         2 . The construct according to  claim 1 , wherein the construct comprises an encoded fusion protein of mammalian alpha-1 antitrypsin (AAT) fused to the amino-terminus or carboxy-terminus of Fc. 
     
     
         3 . The construct according to  claim 1 , wherein the encoded fusion polypeptide is part of a pharmaceutical composition that further comprises a pharmaceutically acceptable carrier or excipient. 
     
     
         4 . The construct according to  claim 1 , wherein the second nucleic acid sequence encoding the IgG1 Fc is represented by SEQ ID NO: 64. 
     
     
         5 . The construct according to  claim 1 , wherein the construct encoding a fusion polypeptide comprises the nucleic acid sequence represented by SEQ ID NO: 86 or SEQ ID NO: 88. 
     
     
         6 . The construct according to  claim 1 , wherein the construct encodes a fusion polypeptide represented by SEQ ID NO: 87 or SEQ ID NO: 89. 
     
     
         7 . A vector comprising the nucleic acid construct of  claim 1 . 
     
     
         8 . An expression vector comprising the nucleic acid construct of  claim 1  and a promoter operatively linked thereto. 
     
     
         9 . A transformed cell comprising the expression vector of  claim 8 . 
     
     
         10 . An isolated preparation of expressed inclusion bodies comprising an encoded fusion polypeptide of the construct of  claim 1 . 
     
     
         11 . A method for treating a subject in need of α-1 antitrypsin (AAT) therapy, the method comprising administering to the subject a therapeutically effective amount of a composition comprising an AAT fusion polypeptide in an amount effective to treat the subject. 
     
     
         12 . The method according to  claim 11 , wherein the AAT fusion polypeptide comprises a fusion molecule comprising a first polypeptide comprising mammalian alpha-1 antitrypsin (AAT), wherein the first polypeptide comprising mammalian AAT is represented by SEQ ID NO:69 or SEQ ID NO:79; and a second polypeptide comprising an IgG1 Fc, an immunoglobulin constant region; and a pharmaceutically acceptable excipient thereof. 
     
     
         13 . The method according to  claim 11 , wherein the second polypeptide comprising an IgG1 Fc is represented by SEQ ID NO:65. 
     
     
         14 . The method according to  claim 11 , wherein the AAT fusion polypeptide comprises a fusion molecule comprising a first polypeptide comprising mammalian alpha-1 antitrypsin (AAT); and a second polypeptide comprising an IgG1 Fc, an immunoglobulin constant region, wherein the second polypeptide comprising an IgG1 Fc is represented by SEQ ID NO:65; and a pharmaceutically acceptable excipient thereof. 
     
     
         15 . The method according to  claim 11 , wherein the subject has a pathogenic infection. 
     
     
         16 . The method according to  claim 15 , wherein the pathogenic infection is caused by a bacterial organism. 
     
     
         17 . The method according to  claim 15 , wherein the pathogenic infection is caused by a viral organism. 
     
     
         18 . The method according to  claim 11 , wherein the subject has a lung condition. 
     
     
         19 . The method according to  claim 18 , wherein the lung condition comprises an infection of the lungs. 
     
     
         20 . The method according to  claim 19 , wherein the lung condition comprises a lung disease. 
     
     
         21 . The method according to  claim 11 , wherein the subject has a genetic deficiency in AAT. 
     
     
         22 . The method according to  claim 20 , wherein the subject has an inflammatory condition. 
     
     
         23 . The method according to  claim 22 , wherein the inflammatory condition comprises modulation of proinflammatory cytokines. 
     
     
         24 . The method according to  claim 11 , wherein the subject has an immune condition. 
     
     
         25 . The method according to  claim 11 , wherein the composition is administered by inhalation, intranasally, intravenously, intramolecular or subcutaneously. 
     
     
         26 . A kit comprising:
 one or more containers; and   at least one composition comprising a fusion polypeptide construct comprising: a first polypeptide comprising mammalian alpha-1 antitrypsin (AAT), wherein the first polypeptide comprising mammalian AAT is represented by SEQ ID NO:69 or SEQ ID NO:79; a second polypeptide comprising an IgG1 Fc, an immunoglobulin constant region; and a pharmaceutically acceptable excipient thereof