Granted Patent B2

US 12,514,887 · App. 15/468,565 · Granted Jan 6, 2026

Inventors: Clodagh O'Shea (La Jolla, CA); Shigeki Miyake-Stoner (La Jolla, CA)

Assignee: Salk Institute for Biological Studies

A61K35/761A61K31/436C07K14/005C12N15/86A61K35/00A61K38/00C12N2710/10322C12N2710/10332C12N2710/10343C12N2810/6018C12N2810/855

Abstract

Claims (44)

1 . A recombinant adenovirus, comprising:

an adenovirus E1A promoter;

an adenovirus E4 promoter; and

a genome:

encoding a modified E1A protein comprising a deletion of the LXCXE motif or a C124G substitution; and

encoding a modified E4orf6/7 protein, wherein the function of the modified E4orf6/7 is impaired or abolished, or comprising a complete or partial deletion that results in the absence of E4orf6/7 protein expression;

wherein the genome comprises a deletion of the entirety of each of the E3-RIDα/RIDβ and E3-14.7k coding sequences,

wherein the recombinant adenovirus exhibits replication defects in normal cells compared to tumor cells and replicates to wild-type adenovirus levels in tumor cells.

2 . The recombinant adenovirus of claim 1 , wherein the genome encodes an adenovirus fiber protein fused to the wild-type FKBP-rapamycin binding (FRB) protein or a mutant FRB protein comprising a T2098L substitution.

3 . The recombinant adenovirus of claim 2 , wherein the genome further encodes a targeting ligand fused to FK506 binding protein (FKBP).

4 . The recombinant adenovirus of claim 3 , wherein the targeting ligand is a single domain antibody.

5 . The recombinant adenovirus of claim 1 , wherein the genome comprises a deletion of the entirety of each of the E3-RIDα/RIDβ and E3-14.7k coding sequences and the coding sequences are not replaced with a sequence coding an adenovirus fiber protein fused to the wild-type FKBP-rapamycin binding (FRB) protein or a mutant FRB protein comprising a T2098L substitution.

6 . The recombinant adenovirus of claim 1 , wherein the genome further encodes a modified hexon protein.

7 . The recombinant adenovirus virus of claim 6 , wherein the modified hexon protein comprises an E451Q substitution.

8 . The recombinant adenovirus of claim 2 , wherein the adenovirus fiber protein is fused to the mutant FRB protein comprising the T2098L substitution.

9 . The recombinant adenovirus of claim 1 , wherein the genome further comprises one or more binding sites for a liver-specific microRNA.

10 . The recombinant adenovirus of claim 9 , wherein the liver-specific microRNA is miR-122.

11 . The recombinant adenovirus of claim 1 , wherein the genome further encodes a modified penton protein.

12 . The recombinant adenovirus of claim 11 , wherein the modified penton protein comprises a mutation in the integrin-binding RGD motif.

13 . A composition comprising the recombinant adenovirus of claim 1 , and a pharmaceutically acceptable carrier.

14 . The recombinant adenovirus of claim 2 , wherein the genome of the recombinant adenovirus virus:

encodes a modified E1A protein comprising a deletion of the LXCXE motif;

comprises a complete or partial deletion that results in the absence of E4orf6/7 protein expression; and

encodes an adenovirus fiber protein fused to the mutant FRB protein comprising the T2098L substitution.

15 . The recombinant adenovirus of claim 2 , wherein the genome of the recombinant adenovirus virus:

encodes a modified E1A protein comprising a deletion of the LXCXE motif;

comprises a complete or partial deletion that results in the absence of E4orf6/7 protein expression; and

encodes an adenovirus fiber protein fused to the wild-type FRB protein.

16 . The recombinant adenovirus of claim 1 , wherein the adenovirus is a capsid-swapped chimeric adenovirus, wherein the E1, E3 and E4 modules are derived from a first adenovirus serotype and the E2B, L1, L2, L3, E2A and L4 modules are derived from a second adenovirus serotype.

17 . The recombinant adenovirus of claim 16 , wherein the first adenovirus serotype is Ad5 and the second adenovirus serotype is selected from Ad3, Ad9, Ad11, Ad12, and Ad34.

18 . The recombinant adenovirus of claim 1 , wherein the genome of the recombinant adenovirus further:

encodes a modified hexon protein comprising the E451Q substitution;

encodes a chimeric fiber protein comprising the fiber shaft from a first adenovirus serotype and the fiber knob from a second adenovirus serotype; and

does not encode an adenovirus fiber protein fused to the wild-type FKBP-rapamycin binding (FRB) protein or a mutant FRB protein comprising the T2098L substitution.

19 . The recombinant adenovirus of claim 18 , wherein the first adenovirus serotype is Ad5 and the second adenovirus serotype is Ad3, Ad9, Ad11, Ad12, Ad34 or Ad37.

20 . The recombinant adenovirus of claim 18 , wherein the first adenovirus serotype is Ad5 and the second adenovirus serotype is Ad34.

21 . The recombinant adenovirus of claim 1 , wherein the adenovirus is a capsid-swapped chimeric adenovirus.

22 . The recombinant adenovirus of claim 21 , wherein the adenovirus is a capsid-swapped chimeric adenovirus, wherein the E1, E3 and E4 modules are derived from a first adenovirus serotype and the E2B, L1, L2, L3, E2A and L4 modules are derived from a second adenovirus serotype.

23 . The recombinant adenovirus of claim 22 , herein the first adenovirus serotype is Ad5 and the second adenovirus serotype is Ad3, Ad9, Ad11, Ad12, Ad34 or Ad37.

24 . The recombinant adenovirus of claim 22 , wherein:

the E1 region of the first adenovirus serotype is modified to encode the pIX protein from the second adenovirus serotype; and/or

the E3 region of the first adenovirus serotype is modified to encode the Uexon and fiber proteins from the second adenovirus serotype.

25 . The recombinant adenovirus of claim 24 , herein the first adenovirus serotype is Ad5 and the second adenovirus serotype is Ad3, Ad9, Ad11, Ad12, Ad34 or Ad37.

26 . A composition comprising the recombinant adenovirus of claim 18 , and a pharmaceutically acceptable carrier.

Assignments (3)

Continuity (3)

References Cited (400)