Polynucleotides encoding immune modulating polypeptides
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. A method for stimulating T cells in a subject in need thereof comprising administering to said subject a lipid nanoparticle (LNP) comprising a modified mRNA molecule, the modified mRNA molecule comprising:
(a) a first region of linked nucleosides, said first region encoding a polypeptide comprising the amino acid sequence of SEQ ID NO:1368;
(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; and
(d) at least one chemically modified nucleoside, and wherein when said LNP is administered to said subject, said polypeptide is expressed, such that T cells are stimulated in the subject.
2. The method of claim 1 , wherein administration is parenteral.
3. The method of claim 1 , wherein the first region of linked nucleosides comprises a nucleic acid sequence having at least 80% identity to any one of SEQ ID NOs: 1405-1409.
4. The method of claim 1 , 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.
5. The method of claim 1 , wherein the 3′UTR is heterologous to the 5′UTR.
6. The method of claim 1 , wherein the modification is a uridine modification.
7. The method of claim 6 , wherein the uridine modification is selected from the group consisting of pseudouridine and 1-methylpseudouridine.
8. The method of claim 1 , wherein the modification is a cytidine modification.
9. The method of claim 1 , wherein the cytidine modification is 5-methylcytosine.
10. The method of claim 1 , wherein the polynucleotide comprises a first chemically modified nucleoside and a second chemically modified nucleoside.
11. The method of claim 10 , wherein the first chemically modified nucleoside is a uridine modification.
12. The method of claim 11 , wherein the uridine modification is selected from the group consisting of pseudouridine and 1-methylpseudouridine.
13. The method of claim 10 , wherein the second chemically modified nucleoside is a cytidine modification.
14. The method of claim 13 , wherein the cytidine modification is 5-methylcytosine.
15. The method of claim 10 , wherein the first and second chemically modified nucleosides are selected from the group consisting of pseudouridine, 1-methylpseudouridine and 5-methylcytosine.