Polynucleotides encoding immune modulating polypeptides

Abstract

The invention relates to compositions and methods for the preparation, manufacture and therapeutic use of polynucleotide molecules encoding at least one polypeptide of interest to modulate the immune response.

1 .- 16 . (canceled) 
     
     
         17 . A method for modulating the activity of the immune system in a subject in need thereof comprising administering to said subject a lipid nanoparticle (LNP) comprising a modified mRNA molecule:
 (a) a first region of linked nucleosides, said first region encoding a cytokine or growth factor;   (b) a first flanking region located 5′ relative to said first region comprising a 5′ untranslated region (5′UTR) and at least one 5′ terminal cap; and   (c) a second flanking region located 3′ relative to said first region comprising a 3′ untranslated region (3′UTR) and a 3′ tailing sequence of linked nucleosides;   wherein when said LNP is administered to said subject, said cytokine or growth factor is expressed and the immune system is modulated in the subject.   
     
     
         18 . The method of  claim 17 , wherein the activity of the immune system is increased. 
     
     
         19 . The method of  claim 17 , wherein the activity of the immune system is decreased. 
     
     
         20 . The method of  claim 17 , wherein the first region encodes the cytokine. 
     
     
         21 . The method of  claim 20 , wherein the cytokine is selected from the group consisting of: interferon-gamma (IFN-γ), interleukin 4 (IL-4), interleukin 10 (IL-10), and interleukin 13 (IL-13). 
     
     
         22 . The method of  claim 17 , wherein the first region encodes the growth factor. 
     
     
         23 . The method of  claim 22 , wherein the growth factor is selected from the group consisting of: transforming growth factor, beta 1 (TGF-beta 1), transforming growth factor, beta 2 (TGF-beta 2) and transforming growth factor, beta 3 (TGF-beta 3). 
     
     
         24 . The method of  claim 17 , wherein the 3′UTR is selected from the group consisting of SEQ ID NOs: 20-36 and the native 3′ UTR of any of the nucleic acids that encode any of SEQ ID NOs: 39, 40, 115-178, 510-519, 847-854, 963-1014, 1283-1290, 1368-1404 and 1599-1605. 
     
     
         25 . The method of  claim 17 , wherein the 3′UTR is heterologous to the 5′UTR. 
     
     
         26 . The method of  claim 17 , wherein the modified mRNA comprises a uridine modification. 
     
     
         27 . The method of  claim 26 , wherein the uridine modification is selected from the group consisting of pseudouridine and 1-methylpseudouridine. 
     
     
         28 . The method of  claim 17 , wherein the modified mRNA comprises a cytidine modification. 
     
     
         29 . The method of  claim 28 , wherein the cytidine modification is 5-methylcytosine. 
     
     
         30 . The method of  claim 17 , wherein the modified mRNA comprises a uridine modification and a cytidine modification. 
     
     
         31 . The method of  claim 30 , wherein the uridine modification is selected from the group consisting of pseudouridine and 1-methylpseudouridine, and the cytidine modification is 5-methylcytosine. 
     
     
         32 . The method of  claim 17 , wherein the administration is parenteral.