IP Library › Granted Patent US 11,311,602
Granted Patent B2
US 11,311,602 · App. 17/308,686 · Granted Apr 26, 2022

Polynucleotides encoding interleukin-12 (IL12) and uses thereof

Inventors: Joshua Frederick (Charlestown, MA); Susannah Hewitt (Jamaica Plain, MA); Ailin Bai (Newton, MA); Stephen Hoge (Brookline, MA); Vladimir Presnyak (Manchester, NH); Iain McFadyen (Arlington, MA); Kerry Benenato (Sudbury, MA); Ellalahewage Sathyajith Kumarasinghe (Harvard, MA)
Assignee: ModernaTX, Inc.
A61K38/208A61K9/0019A61K9/5123A61K31/7088A61K31/7115A61K48/005A61K48/0008A61K48/0025A61P35/00C07K14/5434C12N15/62A61K48/00
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Quick Facts
Patent No.
US 11,311,602
App. No.
17/308,686
Granted
Apr 26, 2022
Kind
B2
Abstract

The present disclosure relates to polynucleotides comprising an open reading frame of linked nucleosides encoding human interleukin-12 (IL12), functional fragments thereof, and fusion proteins comprising IL12. In some embodiments, the open reading frame is sequence-optimized. In particular embodiments, the disclosure provides sequence-optimized polynucleotides comprising nucleotides encoding the polypeptide sequence of human IL12, or sequences having high sequence identity with those sequence optimized polynucleotides.

Claims (44)

1. A lipid nanoparticle (LNP) comprising a messenger RNA (mRNA) comprising an open reading frame (ORF) encoding a fusion protein comprising a human IL-12B polypeptide fused directly or by a linker to a human IL-12A polypeptide, wherein the IL-12B polypeptide comprises the amino acid sequence of SEQ ID NO: 1, wherein the IL-12A polypeptide comprises the amino acid sequence of SEQ ID NO: 3, and wherein the LNP comprises an ionizable amino lipid; a phospholipid; a sterol; and a PEG-modified lipid.

2. The LNP of claim 1 , wherein the IL-12B polypeptide is fused directly to the IL-12A polypeptide without a linker.

3. The LNP of claim 1 , wherein the IL-12B polypeptide is fused directly to the IL-12A polypeptide with a peptide linker.

4. The LNP of claim 1 , wherein the fusion protein comprises a heterologous signal peptide.

5. The LNP of claim 1 , wherein the fusion protein comprises a human IL-12B signal peptide or a human IL-12A signal peptide.

6. The LNP of claim 5 , wherein the human IL-12B signal peptide comprises the amino acid sequence of SEQ ID NO: 45.

7. The LNP of claim 1 , wherein the ORF comprises from 5′ to 3′ a nucleotide sequence selected from the group consisting of:

(i) a nucleotide sequence encoding the IL-12B polypeptide, a nucleotide sequence encoding a peptide linker, and a nucleotide sequence encoding the IL-12A polypeptide;

(ii) a nucleotide sequence encoding the IL-12B polypeptide, and a nucleotide sequence encoding the IL-12A polypeptide;

(iii) a nucleotide sequence encoding the IL-12A polypeptide, a nucleotide sequence encoding a peptide linker, and a nucleotide sequence encoding the IL-12B polypeptide; and

(iv) a nucleotide sequence encoding the IL-12A polypeptide, and a nucleotide sequence encoding the IL-12B polypeptide.

8. The LNP of claim 7 , wherein the ORF comprises a nucleotide sequence encoding a signal peptide located at the 5′ terminus of the ORF.

9. The LNP of claim 7 , wherein the peptide linker is a Gly/Ser linker.

10. The LNP of claim 1 , wherein the fusion protein comprises the amino acid sequence of SEQ ID NO: 48.

11. The LNP of claim 1 , wherein the mRNA comprises (i) a 3′ UTR; (ii) a 5′ UTR and (iii) a polyA tail.

12. The LNP of claim 11 , wherein the 3′ UTR comprises a microRNA binding site, and wherein the microRNA binding site is a miR-122-3p or a miR-122-5p binding site.

13. The LNP of claim 1 , wherein the mRNA comprises a chemically modified nucleotide.

14. The LNP of claim 13 , wherein the mRNA is fully modified with chemically modified uridines.

15. A LNP comprising a mRNA comprising an ORF comprising from 5′ to 3′:

(i) a nucleotide sequence encoding a signal peptide;

(ii) a nucleotide sequence encoding a human IL-12B polypeptide comprising the amino acid sequence of SEQ ID NO: 1;

(iii) a nucleotide sequence encoding a peptide linker;

(iv) a nucleotide sequence encoding a human IL-12A polypeptide comprising the amino acid sequence of SEQ ID NO: 3,

wherein the LNP comprises an ionizable amino lipid; a phospholipid; a sterol; and a PEG-modified lipid.

16. The LNP of claim 15 , wherein the signal peptide is selected from: (i) a heterologous signal peptide; (ii) a human IL-12A signal peptide; and (iii) a human IL-12B signal peptide.

17. The LNP of claim 16 , wherein the human IL-12B signal peptide comprises the amino acid sequence of SEQ ID NO: 45.

18. The LNP of claim 15 , wherein the mRNA comprises (i) a 3′ UTR; (ii) a 5′ UTR and (iii) a polyA tail.

19. The LNP of claim 18 , wherein the 3′ UTR comprises a microRNA binding site, and wherein the microRNA binding site is a miR-122-3p or a miR-122-5p binding site.

20. The LNP of claim 15 , wherein the mRNA comprises a chemically modified nucleotide.

21. The LNP of claim 20 , wherein the mRNA is fully modified with chemically modified uridines.

22. A LNP comprising a mRNA comprising an ORF comprising from 5′ to 3′:

(i) a nucleotide sequence encoding a signal peptide;

(ii) a nucleotide sequence encoding a human IL-12B polypeptide comprising the amino acid sequence of SEQ ID NO: 1;

(iii) a nucleotide sequence encoding a human IL-12A polypeptide comprising the amino acid sequence of SEQ ID NO: 3,

wherein the LNP comprises an ionizable amino lipid; a phospholipid; a sterol; and a PEG-modified lipid.

23. The LNP of claim 22 , wherein the signal peptide is selected from: (i) a heterologous signal peptide; (ii) a human IL-12A signal peptide; and (iii) a human IL-12B signal peptide.

24. The LNP of claim 23 , wherein the human IL-12B signal peptide comprises the amino acid sequence of SEQ ID NO: 45.

25. The LNP of claim 22 , wherein the mRNA comprises (i) a 3′ UTR; (ii) a 5′ UTR and (iii) a polyA tail.

26. The LNP of claim 25 , wherein the 3′ UTR comprises a microRNA binding site, and wherein the microRNA binding site is a miR-122-3p or a miR-122-5p binding site.

27. The LNP of claim 22 , wherein the mRNA comprises a chemically modified nucleotide.

28. The LNP of claim 27 , wherein the mRNA is fully modified with chemically modified uridines.

29. The LNP of claim 1 , wherein the mRNA comprises a 3′ UTR comprising a microRNA binding site, wherein the microRNA binding site is a miR-122-3p or a miR-122-5p binding site, and wherein the mRNA is fully modified with chemically modified uridines.

30. The LNP of claim 15 , wherein the mRNA comprises a 3′ UTR comprising a microRNA binding site, wherein the microRNA binding site is a miR-122-3p or a miR-122-5p binding site, and wherein the mRNA is fully modified with chemically modified uridines.

31. The LNP of claim 22 , wherein the mRNA comprises a 3′ UTR comprising a microRNA binding site, wherein the microRNA binding site is a miR-122-3p or a miR-122-5p binding site, and wherein the mRNA is fully modified with chemically modified uridines.

Assignments (2)
SECURITY INTEREST Recorded Nov 19, 2025
From: MODERNATX, INC.
To: ARES CAPITAL CORPORATION, AS AGENT
Reel/Frame 073634/0354 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 10, 2021
From: FREDERICK, JOSHUA; HEWITT, SUSANNAH; BAI, AILIN; HOGE, STEPHEN; PRESNYAK, VLADIMIR; MCFADYEN, IAIN; BENENATO, KERRY; KUMARASINGHE, ELLALAHEWAGE SATHYAJITH
To: MODERNATX, INC.
Reel/Frame 056184/0942 →