Genetically-modified cells comprising a modified human T cell receptor alpha constant region gene

Patent metadata

Field	Value
Publication number	US-9993502-B1
Application number	US-201815865055-A
Country	US
Kind code	B1
Filing date	Jan 8, 2018
Priority date	Oct 5, 2015
Publication date	Jun 12, 2018
Grant date	Jun 12, 2018

Abstract

Disclosed herein is a genetically-modified cell comprising in its genome a modified human T cell receptor alpha constant region gene, wherein the cell has reduced cell-surface expression of the endogenous T cell receptor. The present disclosure further relates to methods for producing such a genetically-modified cell, and to methods of using such a cell for treating a disease in a subject.

First claim

The invention claimed is:

1. A pharmaceutical composition comprising a population of genetically-modified human T cells and a pharmaceutically acceptable carrier, wherein between 20% and 65% of cells in said population express a cell-surface chimeric antigen receptor and exhibit reduced cell-surface expression of the endogenous T cell receptor (TCR) when compared to unmodified control cells, wherein said cells expressing said chimeric antigen receptor comprise in their genome a modified human TCR alpha constant region gene, wherein said modified human TCR alpha constant region gene comprises from 5′ to 3′:
(a) a 5′ region of a human TCR alpha constant region gene which is endogenous to said T cell;
(b) an exogenous nucleic acid sequence encoding said chimeric antigen receptor; and
(c) a 3′ region of said human TCR alpha constant region gene which is endogenous to said T cell;
wherein said chimeric antigen receptor comprises a ligand-binding domain having specificity for an antigen present on a cancer cell.

2. The pharmaceutical composition of claim 1 , wherein between 35% and 65% of cells in said population express said chimeric antigen receptor and exhibit reduced cell-surface expression of said endogenous TCR when compared to unmodified control cells.

3. The pharmaceutical composition of claim 1 , wherein between 50% and 65% of cells in said population express said chimeric antigen receptor and exhibit reduced cell-surface expression of said endogenous TCR when compared to unmodified control cells.

4. The pharmaceutical composition of claim 1 , wherein between 20% and 83% of cells in said population exhibit reduced cell-surface expression of said endogenous TCR when compared to unmodified control cells.

5. The pharmaceutical composition of claim 1 , wherein between 50% and 83% of cells in said population exhibit reduced cell-surface expression of said endogenous TCR when compared to unmodified control cells.

6. The pharmaceutical composition of claim 1 , wherein said exogenous nucleic acid sequence encoding said chimeric antigen receptor is inserted into said TCR alpha constant region gene which is endogenous to said T cell at a position within SEQ ID NO: 3.

7. The pharmaceutical composition of claim 1 , wherein said exogenous nucleic acid sequence comprises a promoter sequence that drives expression of said chimeric antigen receptor.

8. The pharmaceutical composition of claim 1 , wherein said chimeric antigen receptor comprises an intracellular cytoplasmic signaling domain.

9. The pharmaceutical composition of claim 1 , wherein said chimeric antigen receptor comprises an intracellular co-stimulatory signaling domain.

10. The pharmaceutical composition of claim 1 , wherein said chimeric antigen receptor comprises a signal peptide.

11. The pharmaceutical composition of claim 1 , wherein said chimeric antigen receptor comprises a hinge domain.

12. The pharmaceutical composition of claim 1 , wherein said chimeric antigen receptor comprises a transmembrane domain.

13. The pharmaceutical composition of claim 1 , wherein said ligand-binding domain of said chimeric antigen receptor is specific for CD19.

Assignees

• Prec Biosciences Inc

Inventors

• Jantz Derek
• Smith James Jefferson
• Nicholson Michael G
• Macleod Daniel T
• Antony Jeyaraj
• Bartsevich Victor

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07K2319/40

  containing a tag for immunodetection, or an epitope for immunisation · CPC title

• C07K2319/02

  containing a signal sequence · CPC title

• C07K14/7051

  T-cell receptor (TcR)-CD3 complex · CPC title

• A61K48/0008

  characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition · CPC title