Methods of using OX40 ligand encoding polynucleotides
View Patent ↗The disclosure relates to compositions and methods for the preparation, manufacture and therapeutic use of polynucleotide molecules comprising an mRNA encoding an OX40L polypeptide. Also provided is a method for activating T cells or increasing the number of NK cells in a subject in need thereof.
1. A method for treating cancer in a subject by increasing the number of NK cells in vivo, comprising administering to the subject a lipid nanoparticle (LNP) encapsulated messenger RNA (mRNA) encoding a human OX40L polypeptide, thereby increasing the number of NK cells in vivo, to treat cancer in the subject.
2. The method of claim 1 , wherein increasing NK cells results in one or more of: reduction or decrease in the size of a tumor, and inhibition of growth of a tumor.
3. The method of claim 1 , wherein the mRNA comprises a 3′ untranslated region (UTR) comprising at least one microRNA-122 (miR-122) binding site, wherein the miR-122 binding site is a miR-122-3p binding site or a miR-122-5-binding site.
4. The method of claim 3 , wherein the miR-122-5p binding site comprises the nucleotide sequence as set forth in SEQ ID NO: 26.
5. The method of claim 1 , wherein the human OX40L polypeptide comprises the amino acid sequence as set forth in SEQ ID NO: 1.
6. A method for treating cancer in a subject by increasing the number of NK cells in vivo, comprising administering to the subject a lipid nanoparticle (LNP) encapsulated messenger RNA (mRNA) encoding a human OX40L polypeptide, wherein the mRNA comprises an open reading frame comprising a nucleotide sequence at least 90% identical to SEQ ID NO: 4, thereby increasing the number of NK cells in vivo, to treat cancer in the subject.
7. The method of claim 6 , wherein increasing NK cells results in one or more of: reduction or decrease in the size of a tumor, and inhibition of growth of a tumor.
8. The method of claim 6 , wherein the open reading frame comprises the nucleotide sequence set forth in SEQ ID NO: 4.
9. The method of claim 6 , wherein the mRNA comprises the nucleotide sequence as set forth in SEQ ID NO: 65 or a nucleotide sequence at least 90% identical to SEQ ID NO: 65.
10. The method of claim 6 , wherein the lipid nanoparticle is administered intratumorally.
11. The method of claim 6 , wherein the mRNA is fully modified with chemically-modified uridines.
12. The method of claim 6 , wherein the mRNA comprises a 5′ UTR comprising the nucleotide sequence as set forth in SEQ ID NO: 27, and a 3′ UTR comprising the nucleotide sequence as set forth in SEQ ID NO: 63.
13. The method of claim 6 , wherein the mRNA comprises a 3′ UTR comprising at least one microRNA-122 (miR-122) binding site, wherein the miR-122 binding site is a miR-122-3p binding site or a miR-122-5-binding site.
14. The method of claim 13 , wherein the miR-122-5p binding site comprises the nucleotide sequence as set forth in SEQ ID NO: 26.
15. A method for treating cancer in a subject by increasing the number of NK cells in vivo, comprising administering to the subject a lipid nanoparticle (LNP) encapsulated messenger RNA (mRNA) encoding a human OX40L polypeptide, wherein the mRNA comprises a nucleotide sequence at least 90% identical to SEQ ID NO: 65, thereby increasing the number of NK cells in vivo, to treat cancer in the subject.
16. The method of claim 15 , wherein increasing NK cells results in one or more of: reduction or decrease in the size of a tumor, and inhibition of growth of a tumor.
17. The method of claim 15 , wherein the mRNA comprises the nucleotide sequence as set forth in SEQ ID NO: 65.
18. The method of claim 15 , wherein the lipid nanoparticle is administered intratumorally.
19. The method of claim 15 , wherein the mRNA is fully modified with chemically-modified uridines.
20. The method of claim 15 , wherein the mRNA comprises a 5′ UTR comprising the nucleotide sequence as set forth in SEQ ID NO: 27, and a 3′ UTR comprising the nucleotide sequence as set forth in SEQ ID NO: 63.
21. The method of claim 11 , wherein the chemically-modified uridines are N1-methylpseudouridines (m1ψ).
22. The method of claim 19 , wherein the chemically-modified uridines are N1-methylpseudouridines (m1ψ).