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US-12624088-B2 - Chimeric receptor comprising a ligand binding domain and an endodomain comprising a cytokine receptor endodomain and an intracellular T cell signalling domain

US12624088B2US 12624088 B2US12624088 B2US 12624088B2US-12624088-B2

Abstract

The present invention provides a chimeric receptor which comprises: a ligand-binding exodomain; and an endodomain which comprises: (i) a cytokine receptor endodomain; and (ii) an intracellular T cell signalling domain.

Inventors

  • Martin Pulé
  • Shaun Cordoba
  • Matteo Righi

Assignees

  • Autolus Limited

Dates

Publication Date
20260512
Application Date
20211222
Priority Date
20151023

Claims (20)

  1. 1 . A chimeric receptor comprising: a ligand-binding exodomain that comprises an antigen binding domain of an antibody; a transmembrane domain; and an endodomain which comprises: (i) a cytokine receptor endodomain, wherein the cytokine receptor endodomain comprises or consists of an IL-2 receptor β-chain endodomain; and (ii) an intracellular T cell signalling domain that includes a CD3 zeta endodomain.
  2. 2 . The chimeric receptor according to claim 1 , wherein the antigen binding domain binds to a tumor-secreted factor or a tumor-associated antigen.
  3. 3 . The chimeric receptor according to claim 1 , wherein the intracellular T cell signalling domain further includes a CD28 endodomain, an OX40 endodomain, a 4-1BB endodomain, a CD2 endodomain, a CD27 endodomain, an ICOS endodomain, and/or a CD40 endodomain.
  4. 4 . A cell which comprises a chimeric receptor according to claim 1 .
  5. 5 . A pharmaceutical composition comprising a plurality of cells according to claim 4 .
  6. 6 . A method for treating cancer, which comprises the step of administering a pharmaceutical composition according to claim 5 to a subject with cancer, wherein the cells comprise cells from a cell-containing sample isolated from a subject and that comprise the chimeric receptor.
  7. 7 . A method according to claim 6 , wherein the sample is a T-cell containing sample.
  8. 8 . A method according to claim 6 , wherein the cancer is bladder cancer, breast cancer, colon cancer, endometrial cancer, kidney cancer, leukaemia, lung cancer, melanoma, non-Hodgkin lymphoma, pancreatic cancer, prostate cancer or thyroid cancer.
  9. 9 . A chimeric receptor system which comprises first and second chimeric receptors; wherein the first chimeric receptor comprises a chimeric receptor according to claim 1 , and wherein the second chimeric receptor comprises a ligand-binding exodomain that comprises an antigen binding domain of an antibody; a transmembrane domain; and an endodomain that comprises (i) a cytokine receptor endodomain that comprises or consists of a type I cytokine receptor common y-chain endodomain; and (ii) an intracellular T cell signalling domain that includes a CD3 zeta endodomain.
  10. 10 . A chimeric receptor system according to claim 9 , wherein the antigen binding domain of the first chimeric receptor and the antigen binding domain of the second chimeric receptor bind to different epitopes of the same antigen.
  11. 11 . A cell that comprises a chimeric receptor system according to claim 9 .
  12. 12 . A pharmaceutical composition comprising a plurality of cells according to claim 11 .
  13. 13 . A method for treating cancer, which comprises the step of administering a pharmaceutical composition according to claim 12 to a subject with cancer, wherein the cells comprise cells from a cell-containing sample isolated from a subject and that comprise the chimeric receptor.
  14. 14 . A chimeric receptor system comprising a chimeric receptor according to claim 1 , and an intracellular fusion protein, wherein the intracellular fusion protein comprises a ZAP70 SH2 domain and a cytokine receptor endodomain that is complementary to the cytokine receptor endodomain of the chimeric receptor according to claim 1 .
  15. 15 . A cell that comprises a chimeric receptor system according to claim 14 .
  16. 16 . A pharmaceutical composition comprising a plurality of cells according to claim 15 .
  17. 17 . A method for treating cancer, which comprises the step of administering a pharmaceutical composition according to claim 16 to a subject with cancer, wherein the cells comprise cells from a cell-containing sample isolated from a subject and that comprise the chimeric receptor.
  18. 18 . A chimeric receptor system comprising a chimeric receptor according to claim 1 , and a transmembrane protein, wherein the transmembrane protein comprises a type I cytokine receptor common γ-chain endodomain.
  19. 19 . A cell that comprises a chimeric receptor system according to claim 18 .
  20. 20 . A pharmaceutical composition comprising a plurality of cells according to claim 19 .

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 15/770,110, filed on Apr. 20, 2018, which is a U.S. National Phase of International Patent Application No. PCT/GB2016/053290, filed on Oct. 21, 2016, which claims priority benefit of United Kingdom Patent Application No. 1518816.2, filed on Oct. 23, 2015. INCORPORATION BY REFERENCE OF MATERIALS SUBMITTED ELECTRONICALLY This application contains, as a separate part of the disclosure, a sequence listing in computer readable form (filename: 52926A_Seqlisting.txt; size: 40,172 bytes; created: Dec. 22, 2021), which is incorporated by reference in its entirety. FIELD OF THE INVENTION The present invention relates to a chimeric receptor (CR), and a cell which expresses such a chimeric receptor. BACKGROUND TO THE INVENTION Chimeric Antigen Receptors (CARs) A number of immunotherapeutic agents have been described for use in cancer treatment, including therapeutic monoclonal antibodies (mAbs), bi-specific T-cell engagers and chimeric antigen receptors (CARs). Chimeric antigen receptors are proteins which graft the specificity of a monoclonal antibody (mAb) to the effector function of a T-cell. Their usual form is that of a type I transmembrane domain protein with an antigen recognizing amino terminus, a spacer, a transmembrane domain all connected to a compound endodomain which transmits T-cell survival and activation signals. The most common form of these molecules are fusions of single-chain variable fragments (scFv) derived from monoclonal antibodies which recognize a target antigen, fused via a spacer and a trans-membrane domain to a signaling endodomain. Such molecules result in activation of the T-cell in response to recognition by the scFv of its target. When T cells express such a CAR, they recognize and kill target cells that express the target antigen. Several CARs have been developed against tumour associated antigens, and adoptive transfer approaches using such CAR-expressing T cells are currently in clinical trial for the treatment of various cancers. There has been some success to date for the application of CAR T cells in the treatment of liquid tumours, such as leukemia and lymphoma. However, the use of CAR T cells for the treatment of solid tumours is more challenging, due to the immunosuppressive microenvironment which is hostile to T cells. CAR T-cell persistence and activity can be enhanced by administration of cytokines, or by the CAR T-cells producing cytokines constitutively. However, these approaches have limitations: systemic administration of cytokines can be toxic; constitutive production of cytokines may lead to uncontrolled proliferation and transformation (Nagarkatti et al (1994) PNAS 91:7638-7642; Hassuneh et al (1997) Blood 89:610-620). There is therefore a need for alternative CAR T-cell approaches, which facilitate engraftment and expansion of T cells, which are not associated with the disadvantages mentioned above. DESCRIPTION OF THE FIGURES FIG. 1: Schematic diagram summarising the structure of various cytokine receptors, the cell types which produce the cytokines and the cell types which express the cytokine receptors. FIG. 2: Schematic diagram of a dual chimeric receptor system of the invention The first CR has an endodomain which comprises a cytokine receptor endodomain (the common gamma chain) and an intracellular T cell signalling domain (CD3 zeta). The second CR has an endodomain which comprises a cytokine receptor endodomain (the IL2 receptor beta chain) and an intracellular T cell signalling domain (comprising both CD28 and OX40 co-stimulatory domains). The antigen-binding exodomains of the two chimeric receptors bind different epitopes on the same ligand. When the CRs bind the ligand, the cytokine endodomains on each molecule are brought into approximation, so that they can associate and lead to cytokine-like cell activation. Cell activation also occurs via the T-cell activating endodomains providing signal 1 and signal 2 to the cell. Note: Although only one chain is shown, the CRs in this system are homodimers. FIG. 3: Schematic diagram of an alternative dual CR system of the invention In this system, the first and second CRs have a similar structure to the ones shown in FIG. 2 in terms of endodomains etc. The difference is that the antigen-binding exodomains of the two chimeric receptors bind the same epitopes on the ligand. They may comprise identical antigen-binding portions. Where there is a tight synapse, the independent binding of an antigen by two chimeric receptors may bring the endodomains into close enough proximity for the cytokine endodomains to asscoiate, leading to activation. Note: Although only one chain is shown, the CRs in this system are homodimers. FIG. 4: Schematic diagram of a CR:ZAP70 system of the invention In this system, a single CR recognizes the cognate antigen and its endodomain comprises not only of T-cell signalling (which at a mini