Granted Patent
B2
US 12,448,613 · App. 17/330,365 · Granted Oct 21, 2025
Genetically-modified T cells comprising a modified intron in the T cell receptor alpha gene
Inventors:
Derek Jantz (Durham, NC); James Jefferson Smith (Morrisville, NC); Clayton Beard (Durham, NC)
Assignee:
Precision Biosciences, Inc.
C12N9/22A61K40/11A61K40/31A61K40/32A61K40/40C07K14/7051C12N5/0636C12N15/86C12N15/907C12N2750/14143C12N2800/60C12N2800/80C12N2840/20
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Abstract
The present invention provides a genetically-modified T cell comprising in its genome a modified human T cell receptor alpha gene. The modified T cell receptor alpha gene comprises an exogenous sequence of interest inserted into an intron within the T cell receptor alpha gene that is positioned 5′ upstream of TRAC exon 1. The exogenous sequence of interest can comprise an exogenous splice acceptor site and/or a poly A signal, which disrupts expression of the T cell receptor alpha subunit. The sequence of interest can also include a coding sequence for a polypeptide, such as a chimeric antigen receptor. Additionally, the endogenous splice donor site and the endogenous splice acceptor site flanking the intron are unmodified and/or remain functional. The invention further provides compositions and methods for producing the genetically-modified cell, and populations of the cell, and methods for the treatment of a disease, such as cancer, using such cells.
Claims (20)
1. An isolated genetically-modified human T cell comprising in its genome a modified human T cell receptor alpha gene, wherein said modified human T cell receptor alpha gene comprises an exogenous sequence of interest inserted into an intron within the human T cell receptor alpha gene that is positioned 5′ upstream of the T cell receptor alpha constant region (TRAC) exon 1, and wherein said exogenous sequence of interest comprises an exogenous splice acceptor site or an exogenous splice acceptor site and a poly A signal, and wherein an endogenous splice donor site and an endogenous splice acceptor site flanking said intron are unmodified, and wherein said genetically-modified human T cell does not express an endogenous T cell receptor on the cell surface.
2. The isolated genetically-modified human T cell of claim 1 , wherein said intron comprises SEQ ID NO: 3.
3. The isolated genetically-modified human T cell of claim 1 , wherein said exogenous sequence of interest comprises, from 5′ to 3′, an exogenous splice acceptor site, a 2A element or IRES element, a coding sequence for a protein of interest, and a polyA signal.
4. The isolated genetically-modified human T cell of claim 3 , wherein said 2A element is a T2A element.
5. The isolated genetically-modified human T cell of claim 1 , wherein said sequence of interest comprises a coding sequence for a chimeric antigen receptor or an exogenous T cell receptor.
6. The isolated genetically-modified human T cell of claim 1 , wherein said exogenous sequence of interest is inserted into said intron at an engineered meganuclease recognition site.
7. The isolated genetically-modified human T cell of claim 1 , wherein said exogenous sequence of interest comprises, from 5′ to 3′, an exogenous splice acceptor site, a 2A element or IRES element, a coding sequence for a protein of interest, and a polyA signal, and wherein said sequence of interest comprises a coding sequence for a chimeric antigen receptor or an exogenous T cell receptor.
8. The isolated genetically-modified human T cell of claim 7 , wherein said exogenous sequence of interest is inserted into said intron at an engineered meganuclease recognition site.
9. An isolated population of genetically-modified human T cells comprising a plurality of said isolated genetically-modified human T cell of claim 1 .
10. An isolated population of genetically-modified human T cells comprising a plurality of said isolated genetically-modified human T cell of claim 3 .
11. An isolated population of genetically-modified human T cells comprising a plurality of said isolated genetically-modified human T cell of claim 5 .
12. An isolated population of genetically-modified human T cells comprising a plurality of said isolated genetically-modified human T cell of claim 7 .
13. A pharmaceutical composition useful for treatment of a disease in a subject in need thereof, wherein said pharmaceutical composition comprises a pharmaceutically-acceptable carrier and said isolated genetically-modified human T cell of claim 1 .
14. A pharmaceutical composition useful for treatment of a disease in a subject in need thereof, wherein said pharmaceutical composition comprises a pharmaceutically-acceptable carrier and said isolated genetically-modified human T cell of claim 3 .
15. A pharmaceutical composition useful for treatment of a disease in a subject in need thereof, wherein said pharmaceutical composition comprises a pharmaceutically-acceptable carrier and said isolated genetically-modified human T cell of claim 5 .
16. A pharmaceutical composition useful for treatment of a disease in a subject in need thereof, wherein said pharmaceutical composition comprises a pharmaceutically-acceptable carrier and said isolated genetically-modified human T cell of claim 7 .
17. A method of treating a disease in a subject in need thereof, said method comprising administering to said subject said isolated genetically-modified human T cell of claim 1 .
18. A method of treating a disease in a subject in need thereof, said method comprising administering to said subject said isolated genetically-modified human T cell of claim 3 .
19. A method of treating a disease in a subject in need thereof, said method comprising administering to said subject said isolated genetically-modified human T cell of claim 5 .
20. A method of treating a disease in a subject in need thereof, said method comprising administering to said subject said isolated genetically-modified human T cell of claim 7 .
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jan 18, 2023
From: JANTZ, DEREK; SMITH, JAMES JEFFERSON; BEARD, CLAYTON
To: PRECISION BIOSCIENCES, INC.
Reel/Frame 062404/0477 →
Continuity (4)
Continuation
16627052
Provisional Application
62579473
· Oct 31, 2017
Provisional Application
62527845
· Jun 30, 2017
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