IP Library › Granted Patent US 12,281,324
Granted Patent B2
US 12,281,324 · App. 17/852,891 · Granted Apr 22, 2025

Exogenous gene expression in recombinant adenovirus for minimal impact on viral kinetics

Inventors: Clodagh O'Shea (San Diego, CA); William Partlo (San Diego, CA); Colin Powers (San Diego, CA)
Assignee: Salk Institute for Biological Studies
C12N15/86C12N2710/10011C12N2710/10043C12N2710/10051C12N2840/00
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Quick Facts
Patent No.
US 12,281,324
App. No.
17/852,891
Granted
Apr 22, 2025
Kind
B2
Abstract

Recombinant adenovirus genomes that include an exogenous open reading frame (ORF) and a self-cleaving peptide coding sequence are described. Optimal placement of the exogenous genes for minimal impact on viral kinetics is further disclosed. Therapeutic applications of the recombinant adenoviruses are also described.

Claims (59)

1. A recombinant adenovirus genome, comprising a heterologous open reading frame (ORF) and a self-cleaving peptide coding sequence, both operably linked to and in the same reading frame as an endogenous adenovirus ORF, wherein the self-cleaving peptide coding sequence is located between the heterologous ORF and the endogenous ORF, and wherein:

the endogenous ORF is E1B-55k and the heterologous ORF is 3′ of E1B-55k;

the endogenous ORF is DNA polymerase and the heterologous ORF is 5′ of DNA polymerase;

the endogenous ORF is DNA-binding protein (DBP) and the heterologous ORF is 3′ of DBP;

the endogenous ORF is adenovirus death protein (ADP) and the heterologous ORF is 5′ of ADP;

the endogenous ORF is E3-14.7k and the heterologous ORF is 3′ of E3-14.7k;

the endogenous ORF is E4-ORF2 and the heterologous ORF is 5′ of E4-ORF2; or

the endogenous ORF is fiber and the heterologous ORF is 3′ of fiber.

2. The recombinant adenovirus genome of claim 1 , wherein the heterologous ORF encodes a therapeutic protein.

3. The recombinant adenovirus genome of claim 1 , wherein the self-cleaving peptide is a 2A peptide or variant thereof.

4. The recombinant adenovirus genome of claim 3 , wherein the 2A peptide comprises a porcine teschovirus-1 (PTV1) 2A (P2A) peptide, a foot and mouth disease virus (FMDV) 2A (F2A) peptide, an equine rhinitis A virus (ERAV) 2A (E2A) peptide or a Thosea asigna virus (TaV) 2A (T2A) peptide, or a variant thereof.

5. A composition comprising the recombinant adenovirus genome of claim 1 and a pharmaceutically acceptable carrier.

6. A recombinant adenovirus comprising the recombinant adenovirus genome of claim 1 .

7. A composition comprising the recombinant adenovirus of claim 6 and a pharmaceutically acceptable carrier.

8. A method of inhibiting tumor cell viability and/or tumor cell growth, comprising contacting the tumor cell with the recombinant adenovirus genome of claim 1 .

9. The method of claim 8 , wherein the method is an in vitro method.

10. The method of claim 8 , wherein the method is an in vivo method and contacting the tumor cell comprises administering the recombinant adenovirus genome to a subject with a tumor.

11. A method of inhibiting tumor progression or reducing tumor volume in a subject, comprising administering to the subject a therapeutically effective amount of the recombinant adenovirus genome of claim 1 , thereby inhibiting tumor progression or reducing tumor volume in the subject.

12. A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of the recombinant adenovirus genome of claim 1 , thereby treating cancer in the subject.

13. The method of claim 10 , further comprising administering an additional therapeutic agent to the subject.

14. The recombinant adenovirus genome of claim 3 , wherein the 2A peptide is a modified 2A peptide comprising Gly-Ser-Gly at the N-terminus.

15. The recombinant adenovirus genome of claim 1 , wherein the heterologous ORF encodes a fluorescent protein.

16. The recombinant adenovirus genome of claim 15 , wherein the fluorescent protein is a green fluorescent protein (GFP) a yellow fluorescent protein (YFP), a red fluorescent protein (RFP) or a blue fluorescent protein (BFP).

17. The recombinant adenovirus genome of claim 16 , wherein the YFP is YPet or the RFP is mCherry.

18. The recombinant adenovirus genome of claim 17 , comprising in the 40 to 3′ direction:

E1B-55K-P2A-YPet;

E1B-55K-P2A-mCherry;

YPet-P2A-(DNA polymerase);

DBP-P2A-YPet;

YPet-P2A-ADP;

E3-14.7k-P2A-YPet;

YPet-P2A-E4-ORF2; or

mCherry-P2A-E4-ORF2.

19. The recombinant adenovirus genome of claim 18 , comprising in the 5′ to 3′ direction:

E1B-55K-P2A-YPet sequence of adenovirus CMBT-456, wherein adenovirus CMBT-456 has a genome of SEQ ID NO: 3;

E1B-55K-P2A-mCherry sequence of adenovirus CMBT-499, wherein adenovirus CMBT-499 has a genome of SEQ ID NO: 4;

YPet-P2A-DNA polymerase sequence of adenovirus CMBT-530, wherein adenovirus CMBT-530 has a genome of SEQ ID NO: 5;

DBP-P2A-YPet sequence of adenovirus CMBT-886, wherein adenovirus CMBT-886 has a genome of SEQ ID NO: 6;

YPet-P2A-ADP sequence of adenovirus CMBT-403, wherein adenovirus CMBT-403 has a genome of SEQ ID NO: 7;

E 3 -14.7k-P2A-YPet sequence of adenovirus PCMN-887, wherein adenovirus PCMN-887 has a genome of SEQ ID NO: 9;

YPet-P2A-E4-ORF2 sequence of adenovirus CMBT-457, wherein adenovirus CMBT-457 has a genome of SEQ ID NO: 10;

mCherry-P2A-E4-ORF2 sequence of adenovirus CMBT-633, wherein adenovirus CMBT-633 has a genome of SEQ ID NO: 11; or

E3-14.7k-P2A-YPet sequence of adenovirus PCMN-889, wherein adenovirus PCMN-889 has a genome of SEQ ID NO: 23.

20. The recombinant adenovirus genome of claim 19 , wherein the genome codes for a chimeric fiber protein comprising a fiber shaft from Ad5 and a fiber knob from a second serotype of adenovirus.

21. The recombinant adenovirus genome of claim 20 , wherein the second serotype of adenovirus is Ad9 or Ad34.

22. The recombinant adenovirus genome of claim 20 , wherein the E4orf6/7 protein coding sequence is deleted.

23. The recombinant adenovirus genome of claim 19 , wherein the recombinant adenovirus genome is an Ad5 genome.

24. The recombinant adenovirus genome of claim 19 , wherein the recombinant adenovirus genome comprises the YPet-P2A-ADP sequence of adenovirus CMBT-403, wherein adenovirus CMBT-403 has a genome of SEQ ID NO: 7.

25. The recombinant adenovirus genome of claim 24 , wherein the genome codes for a chimeric fiber protein comprising a fiber shaft from Ad5 and a fiber knob from Ad9 or Ad34, and wherein the E4orf6/7 protein coding sequence is deleted.

26. The recombinant adenovirus genome of claim 19 , wherein the recombinant adenovirus genome is a chimeric adenovirus genome.

27. The recombinant adenovirus genome of claim 26 , wherein the recombinant adenovirus genome is a capsid-swapped adenovirus genome having capsid proteins derived from Ad34 and the remaining proteins derived from Ad5.

28. A composition comprising the recombinant adenovirus genome of claim 25 and a pharmaceutically acceptable carrier.

29. A recombinant adenovirus comprising the recombinant adenovirus genome of claim 25 .

30. A composition comprising the recombinant adenovirus of claim 29 and a pharmaceutically acceptable carrier.

31. A method of inhibiting tumor cell viability and/or tumor cell growth, comprising contacting the tumor cell with the recombinant adenovirus genome of claim 25 .

32. The method of claim 31 , wherein the method is an in vivo method and contacting the tumor cell comprises administering the recombinant adenovirus genome to a subject with a tumor.

33. A method of inhibiting tumor progression or reducing tumor volume in a subject, comprising administering to the subject a therapeutically effective amount of the recombinant adenovirus of claim 29 , thereby inhibiting tumor progression or reducing tumor volume in the subject.

34. A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of the recombinant adenovirus of claim 29 , thereby treating cancer in the subject.

35. The method of claim 32 , further comprising administering an additional therapeutic agent to the subject.

Assignments (3)
SECOND AMENDED AND RESTATED PATENT SECURITY AGREEMENT Recorded Mar 2, 2026
From: UROGEN PHARMA LTD.
To: BIOPHARMA CREDIT PLC, AS COLLATERAL AGENT
Reel/Frame 074994/0338 →
AMENDED AND RESTATED PATENT SECURITY AGREEMENT Recorded Mar 6, 2025
From: UROGEN PHARMA LTD.
To: BIOPHARMA CREDIT PLC [COLLATERAL AGENT]
Reel/Frame 070434/0319 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 29, 2022
From: O'SHEA, CLODAGH; PARTLO, WILLIAM; POWERS, COLIN
To: SALK INSTITUTE FOR BIOLOGICAL STUDIES
Reel/Frame 060359/0363 →
Continuity (5)
Continuation 16916764 · Jun 30, 2020
Continuation 16110207 · Aug 23, 2018
Continuation PCTUS2017019086 · Feb 23, 2017
Provisional Application 62298653 · Feb 23, 2016
Related Publication 20230088476A1 · Mar 23, 2023
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