Compositions and Methods of Use for Alpha-1 Antitrypsin Fusion Polypeptides

Abstract

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

What is claimed: 
     
         1 . A method for treating a subject in need of alpha-1 antitrypsin (AAT) therapy comprising, administering to the subject an isolated fusion polypeptide comprising a first polypeptide comprising an AAT polypeptide or a carboxyterminal fragment thereof, wherein the AAT polypeptide or carboxyterminal fragment thereof comprises SEQ ID NO: 1, SEQ ID NO: 33, SEQ ID NO: 24 and SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 34, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 52, SEQ ID NO: 53 or SEQ ID NO: 54 and a second polypeptide comprising an immunoglobulin Fc polypeptide, wherein the isolated fusion polypeptide is part of a pharmaceutical composition. 
     
     
         2 . The method according to  claim 1 , wherein the first polypeptide of AAT consists of SEQ ID NO:1 or SEQ ID NO:33. 
     
     
         3 . The method according to  claim 1 , wherein the composition is administered by inhalation, intranasally, intraperitoneally, intravaginally, orally, topically, by implant, intravenously, intramolecularly, subcutaneously or by another method of administration. 
     
     
         4 . The method according to  claim 1 , wherein the alpha antitrypsin (AAT) therapy comprises treating AAT deficiency, transplant rejection; graft versus host disease (GvHD), a cardiac condition and wherein administering the isolated fusion polypeptide reduces cardiac remodeling; ischemia-reperfusion injury (IR), side effects of reconstructive or plastic surgery; emphysema; chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS); cystic fibrosis, pulmonary fibrosis, bronchiocytis, asthma, cancers of the lung; arthritis, rheumatoid arthritis, septic arthritis, psoriatic arthritis, Crohn's disease, inflammatory bowel disease (IBD) or irritable bowel disease (IBD), ulcerative colitis, systemic inflammatory response syndrome (SIRS), Systemic lupus erythematosus (SLE), stroke, Multiple sclerosis, lupus erythematosus, Sjogren's syndrome, scleroderma, dermatomyositis, polymyositis, gout, Reiter's syndrome, and Behcet's disease, myasthenia gravis, or encephalomyelitis, Celiac disease, Celiac sprue-dermatitis, Hashimoto's thyroiditis, Graves' Disease, ulveitis; Alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune diseases of the adrenal gland, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune oophoritis and orchitis, autoimmune thrombocytopenia, Bullous pemphigoid, chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, Cicatrical pemphigoid, Discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Glomerulonephritis, Guillain-Barre, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), Juvenile arthritis, Meniere's disease, Pemphigus vulgaris, Pernicious anemia, Polyarteritis nodosa, Polychrondritis, Polyglandular syndromes, Polymyalgia rheumatic, Polymyositis and dermatomyositis, Primary agammaglobulinemia, Primary biliary cirrhosis, psoriasis, psoriatic arthritis, Raynauld's phenomenon, Scleroderma, Sjogren's syndrome, Stiff-man syndrome, Takayasu arteritis, Temporal arteristis/giant cell arteritis, wound healing, Vitiligo, Wegener's granulomatosis, and a side effect of radiation exposure, wherein the composition reduces the side effect of radiation exposure. 
     
     
         5 . The method according to  claim 1 , wherein the subject has AAT deficiency. 
     
     
         6 . The method according to  claim 1 , wherein the subject has a lung condition and the pharmaceutical composition increases AAT levels in pulmonary and lymphatic tissues of the subject. 
     
     
         7 . The method according to  claim 1 , wherein the subject has a lung condition selected from an infection of the lungs or a respiratory condition. 
     
     
         8 . The method according to  claim 1 , wherein the respiratory condition comprises one or more of asthma, chronic obstructive pulmonary disease (COPD), emphysema, cystic fibrosis acute respiratory distress syndrome (ARDS), pulmonary fibrosis, or bronchiocytis. 
     
     
         9 . The method according to  claim 1 , wherein the subject has an inflammatory condition of the gastrointestinal tract. 
     
     
         10 . The method according to  claim 9 , wherein the subject has Crohn's disease, inflammatory bowel disease (IBD) or irritable bowel disease (IBD), ulcerative colitis or other inflammatory-related gastrointestinal tract condition. 
     
     
         11 . The method according to  claim 1 , wherein the subject has undergone a transplant and is at risk of transplant rejection. 
     
     
         12 . The method according to  claim 1 , wherein the subject has graft versus host disease (GVHD) or is at risk of developing graft versus host disease (GVHD). 
     
     
         13 . The method according to  claim 1 , wherein the subject has rheumatoid arthritis. 
     
     
         13 . The method according to  claim 1 , comprising administering the pharmaceutical composition to the subject by one or more of intravenous, intratracheal, intradermal, intranasally, by inhalation, subcutaneous, topical, vaginal or other mode of administration. 
     
     
         14 . The method according to  claim 1 , wherein the subject is further administered at least one of a macrolide or non-macrolide antibiotics, anti-bacterial agents, anti-fungicides, anti-viral agents, anti-parasitic agents, anti-inflammatory or immunomodulatory agent. 
     
     
         15 . The method according to  claim 1 , wherein the subject is human or other mammal. 
     
     
         16 . The method according to  claim 1 , further comprising an immunoglobulin Fc polypeptide from IgG1, IgG2, IgG3, IgG4 or IgGD. 
     
     
         17 . The method according to  claim 1 , further comprising an immunoglobulin Fc polypeptide fused to the carboxyterminal end of the AAT polypeptide or the carboxyterminal fragment thereof. 
     
     
         18 . A method for reducing the risk of developing or treating graft versus host disease (GVHD) comprising, administering to the subject an isolated fusion polypeptide comprising a first polypeptide comprising an AAT polypeptide or a carboxyterminal fragment thereof, wherein the AAT polypeptide or carboxyterminal fragment thereof comprises SEQ ID NO: 1, SEQ ID NO: 33, SEQ ID NO: 24 and SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 34, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 52, SEQ ID NO: 53 or SEQ ID NO: 54 and a second polypeptide comprising an immunoglobulin Fc, wherein the isolated fusion polypeptide is part of a pharmaceutical composition. 
     
     
         19 . The method according to  claim 18 , wherein the first polypeptide comprising mammalian AAT is represented by SEQ ID NO:1 or SEQ ID NO:33. 
     
     
         20 . A method for treating AAT deficiency comprising administering to the subject an isolated fusion polypeptide comprising a first polypeptide comprising an AAT polypeptide or a carboxyterminal fragment thereof, wherein the AAT polypeptide or carboxyterminal fragment thereof comprises SEQ ID NO: 1, SEQ ID NO: 33, SEQ ID NO: 24 and SEQ ID NO: 25, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 34, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 52, SEQ ID NO: 53 or SEQ ID NO: 54 and a second polypeptide comprising an immunoglobulin Fc, wherein the isolated fusion polypeptide is part of a pharmaceutical composition and treats AAT deficiency in the subject. 
     
     
         21 . The method according to  claim 20 , wherein the first polypeptide comprising mammalian AAT is represented by SEQ ID NO:1 or SEQ ID NO:33. 
     
     
         22 . A polypeptide comprising an amino acid sequence represented by SEQ ID NO:32, SEQ ID NO:47 or SEQ ID NO:49. 
     
     
         23 . An isolated cell comprising the polypeptide according to  claim 22 . 
     
     
         24 . An isolated vector comprising a nucleic acid construct encoding a polypeptide according to  claim 22 .