Methods of using OX40 ligand encoding polynucleotides
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 having a solid tumor, the method comprising administering to the subject a lipid nanoparticle (LNP) encapsulated messenger RNA (mRNA) encoding a human OX40L polypeptide, thereby treating cancer in the subject.
2. The method of claim 1 , wherein the OX40L polypeptide comprises the amino acid sequence as set forth in SEQ ID NO: 1.
3. The method of claim 1 , wherein the mRNA comprises an open reading frame (ORF), and wherein the ORF comprises a nucleotide sequence at least 90% identical to SEQ ID NO: 4.
4. The method of claim 3 , wherein the ORF comprises the nucleotide sequence as set forth in SEQ ID NO: 4.
5. The method of claim 1 , wherein the mRNA is fully modified with chemically-modified nucleotides.
6. The method of claim 5 , wherein the chemically-modified nucleotides are N1-methylpseudouridines (m1ψ).
7. The method of claim 5 , wherein the mRNA is fully modified with 5-methylcytosine or is fully modified with m1ψ and 5-methylcytosine.
8. The method of claim 1 , comprising administering an effective amount of a PD-1 antagonist, a PD-L1 antagonist or a CTLA-4 antagonist.
9. The method of claim 8 , wherein the PD-1 antagonist is an antibody or antigen binding portion thereof that specifically binds to PD-1, wherein the PD-L1 antagonist is an antibody or antigen binding portion thereof that specifically binds to PD-L1, and wherein the CTLA-4 antagonist is an antibody or antigen binding portion thereof that specifically binds to CTLA-4.
10. The method of claim 9 , wherein the PD-1 antagonist is selected from the group consisting of nivolumab, pembrolizumab, and pidilizumab, wherein the PD-L1 antagonist is selected from the group consisting of durvalumab, avelumab, and atezolizumab, and wherein the CTLA-4 antagonist is selected from the group consisting of ipilimumab and tremelimumab.
11. The method of claim 1 , wherein the mRNA comprises at least one microRNA-122 (miR-122) binding site.
12. The method of claim 11 , wherein the miR-122 binding site is a miR-122-3p binding site or a miR-122-5p binding site.
13. The method of claim 12 , wherein the miR-122-5p binding site comprises the nucleotide sequence as set forth in SEQ ID NO: 26.
14. The method of claim 11 , wherein the mRNA comprises a 3′ untranslated region (UTR) and a 5′ UTR, and wherein the miR-122 binding site is located within the 3′ UTR of the mRNA, the 5′ UTR of the mRNA, or a combination thereof.
15. The method of claim 14 , wherein the 3′ UTR comprises the nucleotide sequence as set forth in SEQ ID NO: 63.
16. The method of claim 1 , wherein the mRNA comprises a 5′ UTR comprising the nucleotide sequence as set forth in SEQ ID NO: 27.
17. The method of claim 1 , wherein the mRNA comprises a nucleotide sequence at least 90% identical to SEQ ID NO: 65.
18. The method of claim 17 , wherein the mRNA comprises the nucleotide sequence as set forth in SEQ ID NO: 65.
19. The method of claim 1 , wherein the solid tumor is a sarcoma, a melanoma or a carcinoma.
20. A method for treating cancer in a subject having a solid tumor, the method comprising administering to the subject a LNP encapsulated mRNA encoding a human OX40L polypeptide comprising the amino acid sequence as set forth in SEQ ID NO: 1, wherein the mRNA is fully modified with N1-methylpseudouridines (m1ψ), and wherein the mRNA comprises at least one miR-122 binding site, thereby treating cancer in the subject.
21. The method of claim 20 , wherein the mRNA comprises a 3′ UTR, and wherein the miR-122 binding site is located within the 3′ UTR of the mRNA.
22. The method of claim 20 , wherein the solid tumor is a sarcoma, a melanoma or a carcinoma.
23. A method for treating cancer in a subject having a solid tumor, the method comprising administering to the subject a LNP encapsulated mRNA comprising an ORF encoding a human OX40L polypeptide, wherein the ORF comprises a nucleotide sequence at least 90% identical to SEQ ID NO: 4, wherein the mRNA is fully modified with N1-methylpseudouridines (m1ψ), and wherein the mRNA comprises at least one miR-122 binding site, thereby treating cancer in the subject.
24. The method of claim 23 , wherein the ORF comprises the nucleotide sequence as set forth in SEQ ID NO: 4.
25. The method of claim 23 , wherein the mRNA comprises a 3′ UTR, and wherein the miR-122 binding site is located within the 3′ UTR of the mRNA.
26. The method of claim 23 , wherein the solid tumor is a sarcoma, a melanoma or a carcinoma.
27. A method for treating cancer in a subject having a solid tumor, the method comprising administering to the subject a LNP encapsulated mRNA encoding a human OX40L polypeptide, wherein the mRNA comprises a nucleotide sequence at least 90% identical to SEQ ID NO: 65, and wherein the mRNA is fully modified with N1-methylpseudouridines (m10, thereby treating cancer in the subject.
28. The method of claim 27 , wherein the mRNA comprises the nucleotide sequence as set forth in SEQ ID NO: 65.
29. The method of claim 27 , wherein the solid tumor is a sarcoma, a melanoma or a carcinoma.