Cells expressing chimeric activating receptors and chimeric stimulating receptors and uses thereof

Patent metadata

Field	Value
Publication number	US-11965021-B2
Application number	US-201816608366-A
Country	US
Kind code	B2
Filing date	Apr 24, 2018
Priority date	Apr 26, 2017
Publication date	Apr 23, 2024
Grant date	Apr 23, 2024

Abstract

The present application provides immune cells (such as T cells) comprising a chimeric antibody-T cell receptor (TCR) construct (caTCR) and a chimeric signaling receptor (CSR) construct. The caTCR comprises an antigen-binding module that specifically binds to a target antigen and a T cell receptor module (TCRM) capable of recruiting at least one TCR-associated signaling molecule, and the CSR comprises a ligand-binding domain that specifically binds to a target ligand and a co-stimulatory signaling domain capable of providing a stimulatory signal to the immune cell. Also provided are methods of making and using these cells.

First claim

What is claimed is:

1. An immune cell comprising:
a) a chimeric antibody-T cell receptor (TCR) construct (caTCR) comprising:
i) an antigen binding module that specifically binds to a target antigen; and
ii) a TCR module (TCRM), wherein the TCRM comprises a first TCR domain (TCRD) comprising a first TCR transmembrane domain (TCR-TM) and a second TCRD comprising a second TCR-TM,
wherein the TCRM facilitates recruitment of at least one TCR-associated signaling molecule; and
wherein the caTCR further comprises a stabilization module comprising a first stabilization domain and a second stabilization domain, wherein the stabilization module is selected from the group consisting of a C H 1-C L module, a C H 2-C H 2 module, a C H 3-C H 3 module, and a C H 4-C H 4 module;
and

b) a chimeric signaling receptor (CSR) comprising:
i) a ligand-binding module that is capable of binding or interacting with a target ligand;
ii) a transmembrane module; and
iii) a co-stimulatory immune cell signaling module that is capable of providing a co-stimulatory signal to the immune cell,
wherein the ligand-binding module and the co-stimulatory immune cell signaling module are not derived from the same molecule, wherein the CSR lacks a functional primary immune cell signaling domain, and wherein the co-stimulatory immune cell signaling module is derived from CD30;
wherein the immune cell is a T cell.

2. The immune cell of claim 1 , wherein the CSR lacks any primary immune cell signaling sequences.

3. The immune cell of claim 1 , wherein the target antigen is a cell surface antigen.

4. The immune cell of claim 1 , wherein the first TCR-TM is derived from one of the transmembrane domains of a TCR and the second TCR-TM is derived from the other transmembrane domain of the TCR.

5. The immune cell of claim 1 , wherein at least one of the TCR-TMs is non-naturally occurring.

6. The immune cell of claim 4 , wherein the TCR is a γ/δ TCR.

7. The immune cell of claim 6 , wherein the immune cell is an αβ T cell.

8. The immune cell of claim 1 , wherein the target antigen and the target ligand are the same.

9. The immune cell of claim 1 , wherein the target antigen and the target ligand are different.

10. The immune cell of claim 1 , wherein the target ligand is a ligand expressed on the surface of a cell presenting the target antigen.

11. The immune cell of claim 1 , where the target ligand is a disease-associated ligand.

12. The immune cell of claim 1 , wherein the ligand-binding module of the CSR is an antibody moiety.

13. The immune cell of claim 1 , wherein the transmembrane module of the CSR comprises a transmembrane domain derived from CD28, CD3ε, CD3ζ, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD30, CD33, CD37, CD64, CD80, CD86, CD134, CD137, or CD154.

14. The immune cell of claim 1 , wherein the target antigen is a complex comprising a peptide and a major histocompatibility complex (MHC) protein.

15. The immune cell of claim 1 , wherein the antigen binding module of the caTCR is multispecific.

16. The immune cell of claim 1 , wherein the target ligand is a cancer-associated ligand.

17. The immune cell of claim 1 , wherein the ligand-binding module of the CSR comprises an scFv.

18. The immune cell of claim 1 , wherein the immune cell is selected from the group consisting of a cytotoxic T cell, a helper T cell, a natural killer T cell, and a suppressor T cell.

19. The immune cell of claim 1 , wherein the transmembrane module and the co-stimulatory signaling module of the CSR are derived from the same molecule.

20. The immune cell of claim 1 , wherein the transmembrane module and the co-stimulatory signaling module of the CSR are derived from different molecules.

21. A T cell comprising one or more nucleic acids encoding:
a) a chimeric antibody-T cell receptor (TCR) construct (caTCR) comprising:
i) an antigen binding module that specifically binds to a target antigen; and
ii) a TCR module (TCRM), wherein the TCRM comprises a first TCR domain (TCRD) comprising a first TCR transmembrane domain (TCR-TM) and a second TCRD comprising a second TCR-TM,
wherein the TCRM facilitates recruitment of at least one TCR-associated signaling molecule;
wherein the caTCR further comprises a stabilization module comprising a first stabilization domain and a second stabilization domain, and wherein the stabilization module is selected from the group consisting of a C H 1-C L module, a C H 2-C H 2 module, a C H 3-C H 3 module, and a C H 4-C H 4 module;
and

b) a chimeric signaling receptor (CSR) comprising:
i) a ligand-binding module that is capable of binding or interacting with a target ligand;
ii) a transmembrane module; and
iii) a co-stimulatory immune cell signaling module that is capable of providing a co-stimulatory signal to the T cell,
wherein the ligand-binding module and the co-stimulatory immune cell signaling module are not derived from the same molecule, wherein the CSR lacks a functional primary immune cell signaling domain, and wherein the co-stimulatory immune cell signaling module is derived from CD30; and
wherein the caTCR and CSR each consists of one or more polypeptide chains encoded by the one or more nucleic acids.

22. A method of killing a target cell presenting a target antigen, comprising contacting the target cell with the immune cell of claim 1 , wherein the caTCR specifically binds to the target antigen.

23. A method of treating a target antigen-associated disease in an individual in need thereof, comprising administering to the individual an effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises the immune cell of claim 1 and a pharmaceutically acceptable carrier, wherein the caTCR specifically binds to the target antigen.

Assignees

• Eureka Therapeutics Inc

Inventors

• Liu Hong
• Zhang Pengbo
• Horan Lucas
• Xu Yiyang
• Staley Binnaz K
• Liu Lianxing
• Yun Hongruo

Classifications

• C12N5/0636 Primary

  T lymphocytes · CPC title

• A61K40/4261

  Proteoglycans, e.g. glypican, brevican or CSPG4 · CPC title

• A61K40/32

  T-cell receptors [TCR] · CPC title

• A61K40/4211

  CD19 or B4 · CPC title

• A61K40/11

  T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells · CPC title