Modified polynucleotides for the production of oncology-related proteins and peptides

Abstract

The invention relates to compositions including polynucleotides encoding polypeptides which have been chemically modified by replacing the uridines with 1-methyl-pseudouridine to improve one or more of the stability and/or clearance in tissues, receptor uptake and/or kinetics, cellular access by the compositions, engagement with translational machinery, mRNA half-life, translation efficiency, immune evasion, protein production capacity, secretion efficiency, accessibility to circulation, protein half-life and/or modulation of a cell's status, function, and/or activity.

1 . A pharmaceutical composition comprising:
 a plurality of lipid nanoparticles comprising a cationic lipid, a non-cationic lipid, a cholesterol, and a PEG lipid, wherein the plurality of lipid nanoparticles has a mean particle size of between 80 nm and 150 nm; and  1     wherein the lipid nanoparticles comprise an mRNA encoding an oncology-related polypeptide, wherein the mRNA comprises:   (i) a 5′-cap structure;   (ii) a 5′-UTR;   (iii) an open reading frame encoding the oncology-related polypeptide and consisting of nucleotides including uracil, cytosine, adenine, and guanine;   (iv) a 3′-UTR; and   (v) a poly-A region of least 100 nucleotides in length.   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the cationic lipid is a biodegradable cationic lipid. 
     
     
         3 . The pharmaceutical composition of  claim 2 , wherein the biodegradable cationic lipid comprises an ester linkage. 
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein the biodegradable cationic lipid comprises DLin-DMA with an internal ester, DLin-DMA with a terminal ester, DLin-MC3-DMA with an internal ester, or DLin-MC3-DMA with a terminal ester. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the non-cationic lipid is a phospholipid. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the 5′-cap structure is cap0, cap1, ARCA, inosine, N1-methyl-guanosine, 2′-fluoro-guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, or 2-azido-guanosine. 
     
     
         7 . The pharmaceutical composition of  claim 5 , wherein the 5′-cap structure is cap0, cap1, or ARCA. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the mRNA comprises at least two stop codons. 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the 3′-UTR comprises at least one miR binding site. 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein the 3′-UTR comprises a miR-122 binding site.