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

Patent metadata

Field	Value
Publication number	US-2021107976-A1
Application number	US-201816608366-A
Country	US
Kind code	A1
Filing date	Apr 24, 2018
Priority date	Apr 26, 2017
Publication date	Apr 15, 2021
Grant date	—

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

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 T cell receptor module (TCRM) comprising 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 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, and wherein the CSR lacks a functional primary immune cell signaling domain.

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, or a complex comprising a peptide and a major histocompatibility complex (MHC) protein.

4 . (canceled)

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

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

7 . The immune cell of claim 5 , wherein the first T cell receptor is a γ/δ T cell receptor.

8 . (canceled)

9 . The immune cell of claim 1 , wherein the caTCR further comprises a stabilization module comprising a first stabilization domain and a second stabilization domain, wherein the first and second stabilization domains have a binding affinity for each other that stabilizes the caTCR.

10 . The immune cell of claim 9 , wherein the stabilization module is selected from the group consisting of a CH1-CL module, a CH2-CH2 module, a CH3-CH3 module, and a CH4-CH4 module.

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

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

13 . The immune cell of claim 12 , wherein the target ligand is a ligand expressed on the surface of a cell presenting the target antigen.

14 . The immune cell of claim 1 , where the target ligand is a disease-associated ligand, a virus-associated ligand, an immunomodulatory molecule, or an apoptotic molecule.

15 - 22 . (canceled)

23 . The immune cell of claim 1 , wherein the ligand-binding module is an antibody moiety or derived from the extracellular domain of a receptor.

24 . (canceled)

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

26 . The immune cell of claim 1 , wherein the co-stimulatory immune cell signaling module is derived from the intracellular domain of a co-stimulatory receptor of a TCR.

27 - 32 . (canceled)

33 . One or more nucleic acids encoding the caTCR and CSR of claim 1 , wherein the caTCR and CSR each consist of one or more polypeptide chains encoded by the one or more nucleic acids.

34 . (canceled)

35 . An immune cell comprising the one or more nucleic acids of claim 33 .

36 - 37 . (canceled)

38 . A method of killing a target cell presenting a target antigen, comprising contacting the target cell with the immune cell of claim 1 .

39 . 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.

40 . A method of providing a co-stimulatory signal to an immune cell comprising a caTCR or transduced with a nucleic acid encoding a caTCR, comprising introducing into said cell the one or more nucleic acids of claim 33 .

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