IP Library › Granted Patent US 10,881,730
Granted Patent B2
US 10,881,730 · App. 16/279,372 · Granted Jan 5, 2021

Immunomodulatory therapeutic MRNA compositions encoding activating oncogene mutation peptides

Inventors: Eric Yi-Chun Huang (Boston, MA); Sze-Wah Tse (Cambridge, MA); Jared Iacovelli (Waltham, MA); Kristine McKinney (Cambridge, MA); Nicholas Valiante (Cambridge, MA)
Assignee: ModernaTX, Inc.
A61K39/39A61K9/0019A61K9/5015A61K9/5123A61K39/0011A61K39/001164A61P35/00C07K14/7051A61K2039/53A61K2039/55561A61K2039/572A61K2039/575
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Quick Facts
Patent No.
US 10,881,730
App. No.
16/279,372
Granted
Jan 5, 2021
Kind
B2
Abstract

The disclosure features immunomodulatory therapeutic compositions of an mRNA encoding an activating oncogene mutation peptide and an mRNA encoding a polypeptide that enhances immune responses to the activating oncogene mutation peptide, for example an mRNA encoding an immune potentiator. The disclosure also features methods of using the same, for example, to stimulate anti-cancer immune responses.

Claims (49)

1. An immunomodulatory therapeutic composition comprising an mRNA formulated in a lipid nanoparticle (LNP), wherein:

the mRNA comprises an open reading frame encoding a concatemer of four KRAS activating oncogene mutation peptides, each of the KRAS activating oncogene mutation peptides having an amino acid sequence independently selected from the group consisting of SEQ ID NOs: 121, 36, 39, 122, 37, 40, 123, 38, 41, 124, 125, and 72.

2. The immunomodulatory therapeutic composition of claim 1 , wherein the concatemer comprises the KRAS activating oncogene mutation peptides having SEQ ID NOs: 39, 40, 41, and 72.

3. The immunomodulatory therapeutic composition of claim 1 , wherein the concatemer comprises, from N- to C-terminus, the KRAS activating oncogene mutation peptides having respectively the amino acid sequences of SEQ ID NOs: 39, 40, 41, and 72.

4. The immunomodulatory therapeutic composition of claim 1 , wherein the concatemer comprises amino acid sequence SEQ ID NO: 137.

5. The immunomodulatory therapeutic composition of claim 1 , wherein the open reading frame comprises nucleotide sequence SEQ ID NO: 169.

6. The immunomodulatory therapeutic composition of claim 5 , wherein all uridine nucleosides in the mRNA are N1-methylpseudouridine.

7. The immunomodulatory therapeutic composition of claim 1 , wherein the mRNA comprises nucleotide sequence SEQ ID NO: 167.

8. The immunomodulatory therapeutic composition of claim 7 , wherein all uridine nucleosides in the mRNA are N1-methylpseudouridine.

9. The immunomodulatory therapeutic composition of claim 1 , wherein the LNP comprises a molar ratio of about 20-60% ionizable amino lipid: about 5-25% phospholipid: about 25-55% sterol: about 0.5-15% PEG-modified lipid.

10. The immunomodulatory therapeutic composition of claim 1 , wherein the LNP comprises a molar ratio of about 20-60% Compound 25: about 5-25% DSPC: about 25-55% cholesterol: about 0.5-15% PEG-DMG.

11. The immunomodulatory therapeutic composition of claim 1 , wherein the LNP comprises a molar ratio of about 50% Compound 25: about 10% DSPC: about 38.5% cholesterol: about 1.5% PEG-DMG.

12. An immunomodulatory therapeutic composition, comprising: an mRNA comprising an open reading frame encoding a concatemer of 3-10 KRAS activating oncogene mutation peptides, wherein each peptide is about 10-30 amino acids in length, and wherein each peptide comprises a mutation independently selected from the group consisting of G12D, G12V, G12C, G12S, G12A, G12R and G13D mutations in human KRAS of SEQ ID NO: 166.

13. The immunomodulatory therapeutic composition of claim 12 , wherein the mutations are independently selected from the group consisting of the G12D, G12V, G12C and G13D mutations.

14. The immunomodulatory therapeutic composition of claim 12 , wherein the concatemer comprises peptides.

15. The immunomodulatory therapeutic composition of claim 12 , wherein each peptide is about 15-25 amino acids in length.

16. The immunomodulatory therapeutic composition of claim 12 , wherein at least two of the peptides are linked directly to one another without a linker.

17. The immunomodulatory therapeutic composition of claim 12 , wherein the mRNA comprises 200, 300, 400, 500, 600, 700, 800, or 900 nucleotides.

18. The immunomodulatory therapeutic composition of claim 12 , wherein the concatemer is a 100-mer concatemer.

19. The immunomodulatory therapeutic composition of claim 12 , wherein all uridine nucleosides in the mRNA are N1-methylpseudouridine.

20. The immunomodulatory therapeutic composition of claim 12 , wherein the mRNA is formulated in a lipid nanoparticle.

21. The immunomodulatory therapeutic composition of claim 20 , wherein the lipid nanoparticle comprises a molar ratio of about 20-60% ionizable amino lipid: about 5-25% phospholipid: about 25-55% sterol: about 0.5-15% PEG-modified lipid.

22. The immunomodulatory therapeutic composition of claim 20 , wherein the LNP comprises a molar ratio of about 20-60% Compound 25: about 5-25% DSPC: about 25-55% cholesterol: about 0.5-15% PEG-DMG.

23. The immunomodulatory therapeutic composition of claim 20 , wherein the LNP comprises a molar ratio of about 50% Compound 25: about 10% DSPC: about 38.5% cholesterol: about 1.5% PEG-DMG.

24. An immunomodulatory therapeutic composition, comprising: an mRNA comprising an open reading frame encoding a concatemer of four KRAS activating oncogene mutation peptides, wherein each peptide is about 10-30 amino acids in length, wherein each peptide comprises a mutation independently selected from the group consisting of G12D, G12V, G12C, and G13D mutations in human KRAS of SEQ ID NO: 166, and wherein the peptides are linked directly to one another without a linker.

25. The immunomodulatory therapeutic composition of claim 24 , wherein the peptides are about 15-25 amino acids in length.

26. The immunomodulatory therapeutic composition of claim 24 , wherein the mRNA comprises 200, 300, 400, 500, 600, 700, 800, or 900 nucleotides.

27. The immunomodulatory therapeutic composition of claim 24 , wherein the concatemer is a 100-mer concatemer.

28. The immunomodulatory therapeutic composition of claim 24 , wherein all uridine nucleosides in the mRNA are N1-methylpseudouridine.

29. The immunomodulatory therapeutic composition of claim 24 , wherein the mRNA is formulated in a lipid nanoparticle.

30. The immunomodulatory therapeutic composition of claim 29 , wherein the lipid nanoparticle comprises a molar ratio of about 20-60% ionizable amino lipid: about 5-25% phospholipid: about 25-55% sterol: about 0.5-15% PEG-modified lipid.

31. The immunomodulatory therapeutic composition of claim 29 , wherein the LNP comprises a molar ratio of about 20-60% Compound 25: about 5-25% DSPC: about 25-55% cholesterol: about 0.5-15% PEG-DMG.

32. The immunomodulatory therapeutic composition of claim 29 , wherein the LNP comprises a molar ratio of about 50% Compound 25: about 10% DSPC: about 38.5% cholesterol: about 1.5% PEG DMG.

33. An immunomodulatory therapeutic composition comprising an mRNA formulated in a lipid nanoparticle (LNP), wherein:

the mRNA comprises an open reading frame encoding a concatemer of four KRAS activating oncogene mutation peptides, the concatemer comprising amino acid sequence SEQ ID NO: 137;

the LNP comprises a molar ratio of about 20-60% Compound 25: about 5-25% DSPC: about 25-55% cholesterol: about 0.1-15% PEG-DMG; and

wherein one or more uridine nucleosides in the mRNA are N1-methylpseudouridine.

34. The immunomodulatory therapeutic composition of claim 33 , wherein the open reading frame comprises nucleotide sequences SEQ ID NO: 169.

35. The immunomodulatory therapeutic composition of claim 33 , wherein the mRNA comprises nucleotide sequences SEQ ID NO: 167.

36. The immunomodulatory therapeutic composition of claim 33 , wherein the LNP comprises the molar ratio of about 50% Compound 25: about 10% DSPC: about 38.5% cholesterol: about 1.5% PEG-DMG.

37. The immunomodulatory therapeutic composition of claim 36 , wherein the open reading frame comprises nucleotide sequence SEQ ID NO: 169.

38. The immunomodulatory therapeutic composition of claim 36 , wherein the mRNA comprises nucleotide sequences SEQ ID NO: 167.

39. The immunomodulatory therapeutic composition of claim 36 , wherein all uridine nucleosides in the mRNA are N1-methylpseudouridine.

40. An immunomodulatory therapeutic composition comprising an mRNA formulated in a lipid nanoparticle (LNP), wherein:

the mRNA comprises an open reading frame encoding a concatemer of four KRAS activating oncogene mutation peptides, each of the KRAS activating oncogene mutation peptides having an amino acid sequence independently selected from the group consisting of SEQ ID NOs: 39, 40, 41, and 72.

41. The immunomodulatory therapeutic composition of claim 40 , wherein all uridine nucleosides in the mRNA are N1-methylpseudouridine.

42. The immunomodulatory therapeutic composition of claim 40 , wherein the LNP comprises a molar ratio of about 20-60% ionizable amino lipid: about 5-25% phospholipid: about 25-55% sterol: about 0.5-15% PEG-modified lipid.

43. The immunomodulatory therapeutic composition of claim 40 , wherein the LNP comprises a molar ratio of about 20-60% Compound 25: about 5-25% DSPC: about 25-55% cholesterol: about 0.5-15% PEG-DMG.

44. The immunomodulatory therapeutic composition of claim 40 , wherein the LNP comprises a molar ratio of about 50% Compound 25: about 10% DSPC: about 38.5% cholesterol: about 1.5% PEG-DMG.

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 Mar 1, 2019
From: HUANG, ERIC YI-CHUN; TSE, SZE-WAH; IACOVELLI, JARED; MCKINNEY, KRISTINE; VALIANTE, NICHOLAS
To: MODERNATX, INC.
Reel/Frame 048475/0476 →