IP Library › Granted Patent US 12,220,456
Granted Patent B2
US 12,220,456 · App. 18/436,426 · Granted Feb 11, 2025

Compositions and methods for organ-protective expression and modulation of coding ribonucleic acids

Inventors: Romain Micol (Wilmington, DE); Valerie Duval (Wilmington, DE)
Assignee: Combined Therapeutics, Inc.
A61K39/215C12N15/113A61K2039/53
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Quick Facts
Patent No.
US 12,220,456
App. No.
18/436,426
Granted
Feb 11, 2025
Kind
B2
Abstract

Compositions are provided comprising messenger RNA constructs having at least one open reading frame (ORF), wherein the ORF is operatively linked to at least one untranslated region (UTR), wherein the UTR comprises at least one organ protection sequence (OPS), wherein the OPS sequence comprises at least a first, a second and a third micro-RNA (miRNA) target sequence, and wherein each of the at least a first, second and third the miRNA target sequences are optimised to hybridise with a corresponding miRNA sequence. The compositions and molecules provided are useful in therapies such as for the treatment of cancer, in immunotherapies, and in vaccines.

Claims (36)

1. A composition comprising:

at least a first mRNA construct comprising at least a first open reading frame (ORF), wherein the first ORF encodes a tumor antigen;

at least a second mRNA construct comprising at least a second open reading frame (ORF), wherein the second ORF encodes a product associated with vaccine induced immunity selected from the group consisting of: IL-1; IL-2; IL-3; IL-4; IL-5; IL-6; IL-7; IL-8; IL-9; IL-10; IL-11; IL-12; IL-15; IL-17; IL-21; TGF-beta; IFNγ; IFNα; IFNβ; TNFα; M-CSF; G-CSF; GM-CSF; CCL2; CCL3; CCL4; CCL5; CCL20; CCL22; CCL28; CXCL8; CXCL9; CXCL10; CXCL11; CXCL12; and XCL1 and wherein the second ORF is operatively linked to at least one untranslated region (UTR), wherein the UTR comprises at least a first, second, and a third micro-RNA (miRNA) target sequence, and wherein each of the at least first, second, and third miRNA target sequences are optimised to each hybridise with a different corresponding miRNA sequence; and

an in vivo delivery composition;

wherein the first and second mRNA constructs are comprised within or adsorbed to the delivery composition.

2. The composition of claim 1 , wherein the second ORF codes for an IL-7 protein, or a derivative, agonist or homologue thereof.

3. The composition of claim 1 , wherein the second ORF codes for an IL-12 protein, or a derivative, agonist or homologue thereof.

4. The composition of claim 3 , wherein the IL-12 protein comprises a human recombinant IL-12 from a single chain (hscIL-12).

5. The composition of claim 1 , wherein the second ORF codes for an IL-15 protein, or a derivative, agonist or homologue thereof.

6. The composition of claim 1 , wherein the second ORF codes for an IL-17 protein, or a derivative, agonist or homologue thereof.

7. The composition of claim 1 , wherein the second ORF codes for a GM-CSF protein, or a derivative, agonist or homologue thereof.

8. The composition of claim 1 , wherein the at least a first, second and third miRNA target sequences include one or more sequences that bind with an miRNA selected from the group consisting of miRNA-122; miRNA-125; miRNA-199; miRNA-124a; miRNA-126; Let7 miRNA family; miRNA-375; miRNA-141; miRNA-142; miRNA-148a/b; miRNA-143; miRNA-145; miRNA-194; miRNA-200c; miRNA-203a; miRNA-205; miRNA-1; miRNA-133a; miRNA-206; miRNA-34a; miRNA-192; miRNA-194; miRNA-204; miRNA-215; miRNA-30 a,b,c; miRNA-877; miRNA-4300; miRNA-4720; and miRNA-6761.

9. The composition of claim 1 , wherein the at least a first and second miRNA target sequences are selected from one or more of the sequences of SEQ ID NOs: 44-57.

10. The composition of claim 1 , wherein the UTR comprises at least a fourth, a fifth and/or a sixth miRNA target sequence, and wherein each of the at least a fourth, fifth and/or sixth miRNA target sequences are optimised to each hybridise with a different corresponding miRNA sequence.

11. The composition of claim 10 , wherein the at least a fourth, fifth and/or sixth miRNA target sequences include one or more sequences that bind with an miRNA selected from the group consisting of miRNA-122; miRNA-125; miRNA-199; miRNA-124a; miRNA-126; Let7 miRNA family; miRNA-375; miRNA-141; miRNA-142; miRNA-148a/b; miRNA-143; miRNA-145; miRNA-194; miRNA-200c; miRNA-203a; miRNA-205; miRNA-1; miRNA-133a; miRNA-206; miRNA-34a; miRNA-192; miRNA-194; miRNA-204; miRNA-215; miRNA-30 a,b,c; miRNA-877; miRNA-4300; miRNA-4720; and miRNA-6761.

12. The composition of claim 10 , wherein the at least a fourth, fifth and/or sixth miRNA target sequences are selected from one or more of the sequences of SEQ ID NOs: 44-57.

13. The composition of claim 1 , wherein the first ORF encodes a tumor antigen comprising all or part of a cancer specific or associated antigen.

14. The composition of claim 13 , wherein cancer specific or associated antigen comprises a neoantigen.

15. The composition of claim 1 , wherein the first mRNA construct comprises at least one additional open reading frame (ORF).

16. The composition of claim 15 , wherein the at least one additional ORF encodes a product associated with vaccine induced immunity.

17. The composition of claim 16 , wherein the product associated with vaccine induced immunity is selected from the group consisting of: IL-1; IL-2; IL-3; IL-4; IL-5; IL-6; IL-7; IL-8; IL-9; IL-10; IL-11; IL-12; IL-15; IL-17; IL-21; TGF-beta; IFNγ; IFNα; IFNβ; TNFα; M-CSF; G-CSF; GM-CSF; CCL2; CCL3; CCL4; CCL5; CCL20; CCL22; CCL28; CXCL8; CXCL9; CXCL10; CXCL11; CXCL12; and XCL1.

18. The composition of claim 17 , wherein the first mRNA construct is polycistronic and comprises at least three open reading frames (ORFs).

19. The composition of claim 1 , wherein the delivery composition is selected from the group consisting of: a lipid nanoparticle; a polymeric particle; a liposome; a lipidoid particle; and a viral vector.

20. The composition of claim 1 , wherein the delivery composition comprises a lipid, phospholipid, cholesterol and a polyethylene glycol (PEG).

21. The composition of claim 1 , wherein the composition comprises at least a third mRNA construct comprising at least a third open reading frame (ORF), wherein the third ORF encodes a further tumor antigen.

22. The composition of claim 1 , wherein the composition comprises at least a third mRNA construct comprising at least a third open reading frame (ORF), wherein the third ORF encodes an immunomodulator.

23. The composition of claim 22 , wherein the immunomodulator is an IL-12 protein, or a derivative, agonist or homologue thereof.

24. The composition of claim 23 , wherein the IL-12 protein comprises a human recombinant IL-12 from a single chain (hscIL-12).

25. The composition of claim 22 , wherein the immunomodulator is a GM-CSF protein, or a derivative, agonist or homologue thereof.

26. The composition of claim 1 , wherein the first mRNA construct comprises at least one UTR and wherein the first ORF is operatively linked to the at least one UTR, and wherein the at least one UTR comprises at least one micro-RNA target sequence that is optimised to hybridise with a miRNA sequence.

27. The composition of claim 26 , wherein the at least one miRNA target sequence includes a sequence that binds with an miRNA selected from the group consisting of:

miRNA-122; miRNA-125; miRNA-199; miRNA-124a; miRNA-126; Let7 miRNA family; miRNA-375; miRNA-141; miRNA-142; miRNA-148a/b; miRNA-143; miRNA-145; miRNA-194; miRNA-200c; miRNA-203a; miRNA-205; miRNA-1; miRNA-133a; miRNA-206; miRNA-34a; miRNA-192; miRNA-194; miRNA-204; miRNA-215; miRNA-30 a,b,c; miRNA-877; miRNA-4300; miRNA-4720; and miRNA-6761.

28. The composition of claim 27 , wherein the at least one miRNA target sequence is selected from one or more of the sequences of SEQ ID NOs: 44-57.

29. A method of stimulating an anti-tumor immune response in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition according to claim 1 .

30. The method of claim 29 , wherein the composition is administered intravenously, subcutaneously, intra-muscularly, intranasally, intra-arterially and/or through inhalation.

31. The method of claim 29 , wherein the method is personalised to a specific cancer associated antigen in the subject.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 7, 2024
From: MICOL, ROMAIN; DUVAL, VALERIE
To: COMBINED THERAPEUTICS, INC.
Reel/Frame 066685/0796 →
Continuity (6)
Continuation 18108248 · Feb 10, 2023
Continuation 17689908 · Mar 8, 2022
Continuation PCTUS2021019028 · Feb 22, 2021
Provisional Application 63059458 · Jul 31, 2020
Provisional Application 62979619 · Feb 21, 2020
Related Publication 20240252618A1 · Aug 1, 2024
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