Compositions, methods and uses for alpha-1 antitrypsin fusion molecules

Abstract

Embodiments herein report compositions of and methods for making and using alpha-1 antitrypsin (AAT) fusion molecules or peptide derivatives thereof. In certain embodiments, compositions and methods relate to generating an AAT fusion molecule of use in pharmaceutically acceptable compositions to treat a subject in need of AAT therapy or treatment. In other embodiments, compositions and methods disclosed herein concern linking AAT or derivative thereof to an immune fragment.

What is claimed is: 
     
         1 . A construct comprising:
 a nucleic acid encoding an alpha-1 antitrypsin (AAT) polypeptide or fragment or peptide cleavage molecule thereof; and   a nucleic acid encoding an immunoglobulin Fc fragment, the nucleic acid further manipulated to truncate or eliminate the immune fragment hinge region.   
     
     
         2 . The construct of  claim 1 , wherein the nucleic acid encoding AAT comprises a nucleic acid encoding naturally occurring AAT (SEQ ID NO:1). 
     
     
         3 . The construct of  claim 1  wherein the nucleic acid encoding the AAT peptide cleavage molecule comprises a nucleic acid encoding one or more carboxyterminal fragments cleavage products of naturally occurring AAT. 
     
     
         4 . The construct of  claim 3 , wherein the carboxyterminal fragment comprises the last 80 amino acids of SEQ ID NO:1 or 10 or more consecutive amino acids thereof 
     
     
         5 . The construct of  claim 1 , wherein the immunoglobulin Fc comprises a nucleic acid encoding an Fc fragment from IgG1, IgG2, IgG3 or IgG4. 
     
     
         6 . The construct of  claim 1 , wherein the nucleic acid encoding AAT or fragment thereof comprises a nucleic acid represented by SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 50, SEQ ID NO: 52, or SEQ ID NO: 54. 
     
     
         7 . The construct of  claim 1 , wherein the encoded AAT polypeptide is represented by the amino acid sequence of SEQ ID NO: 54. 
     
     
         8 . The construct of  claim 1 , wherein the nucleic acid encoding the AAT or fragment or peptide cleavage molecule thereof comprises a nucleic acid encoding a mutant having a mutation at the reactive center loop (RCL). 
     
     
         9 . The construct of  claim 1 , further comprising a linker between the alpha-1 antitrypsin (AAT) polypeptide or fragment or peptide cleavage molecule thereof and the immunoglobulin Fc fragment. 
     
     
         10 . A composition comprising a fusion polypeptide encoded by the nucleic acid of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         11 . A vector comprising the nucleic acid construct of  claim 1 . 
     
     
         12 . A transformed cell comprising the vector of  claim 11 . 
     
     
         13 . An isolated preparation of expressed inclusion bodies comprising the fusion protein of  claim 12 . 
     
     
         14 . A method for treating a subject in need of AAT therapy, the method comprising administering to the subject a therapeutically effective amount of the composition comprising  claim 10  in an amount effective to initiate an anti-inflammatory response, wherein the administration reduces the inflammatory response in the subject. 
     
     
         15 . A method for treating a subject in need of AAT therapy, the method comprising administering to the subject a therapeutically effective amount of the composition comprising  claim 10  in an amount effective to achieve an immune modulatory response. 
     
     
         16 . A method for treating AAT deficiency in a subject, the method comprising administering to the subject a therapeutically effective amount of the composition comprising  claim 10  in an amount effective to treat AAT deficiency in the subject. 
     
     
         17 . A method for treating a subject undergoing an organ or non-organ transplant, the method comprising administering to the subject a therapeutically effective amount of the composition comprising  claim 10  in an amount effective to treat the subject, wherein the administration modulates transplant rejection in the subject. 
     
     
         18 . A method for treating a subject having gout, the method comprising administering to the subject a therapeutically effective amount of the composition comprising  claim 10  in an amount effective to treat the subject, wherein the administration modulates gout in the subject. 
     
     
         19 . A method for treating a a subject having a lung condition, the method comprising administering to the subject a therapeutically effective amount of the composition comprising  claim 10  in an amount effective to treat the subject, wherein the administration modulates the lung condition in the subject. 
     
     
         20 . A kit comprising, at least one container and a nucleic acid construct according to  claim 1 .