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EP-4735479-A1 - MOLECULES AND METHODS FOR ACTIVATING CAR T CELLS

EP4735479A1EP 4735479 A1EP4735479 A1EP 4735479A1EP-4735479-A1

Abstract

The present invention relates to molecules comprising a heterodimer consisting of a first portion comprising a first Fab arm of an antibody and a second portion comprising a second Fab arm of an antibody, wherein the first and second Fab arms each comprise an antigen binding domain for binding to a cell surface molecule on a target cell, wherein the first Fab arm comprises at least one moiety capable of being bound by the exogenous immune cell receptor, and wherein the second Fab arm does not comprise any moieties capable of being bound by the exogenous immune cell receptor. Methods for activating immune cells expressing chimeric antigen receptors and for the prevention and/or treatment of various conditions, including cancer, are also contemplated.

Inventors

  • Schlegel, Patrick
  • LI, Ziduo
  • WERBROUCK, Coralie

Assignees

  • Biosceptre (Aust) Pty Ltd

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. 1 . A molecule capable of simultaneously binding to a target cell and to an immune cell expressing an exogenous cell surface receptor comprising an intracellular signalling domain, the molecule comprising: a heterodimer consisting of a first portion comprising a first Fab arm of an antibody and a second portion comprising a second Fab arm of an antibody, wherein the first and second Fab arms each comprise an antigen binding domain for binding to a cell surface molecule on a target cell, wherein the first Fab arm comprises at least one moiety capable of being bound by the exogenous immune cell receptor, wherein the second Fab arm does not comprise any moieties capable of being bound by the exogenous immune cell receptor and wherein the first and second portions of the heterodimer comprise amino acid sequences for enabling heterodimerisation via pairing of distinct heavy chains and/or pairing of cognate light chains to the heavy chains.
  2. 2. A molecule capable of simultaneously binding to a target cell and to an immune cell expressing an exogenous cell surface receptor comprising an intracellular signalling domain, the molecule comprising: a heterodimer consisting of a first portion comprising a first Fab arm of an antibody and a second portion comprising a second Fab arm of an antibody, wherein the first and second Fab arms each comprise an antigen binding domain for binding to a cell surface molecule on a target cell, wherein the first Fab arm comprises at least two moieties capable of being bound by the exogenous immune cell receptor, and wherein the second Fab arm does not comprise any moieties capable of being bound by the exogenous immune cell receptor.
  3. 3. The molecule of claim 2, wherein the first and second portions of the heterodimer comprise amino acid sequences for enabling heterodimerisation via pairing of distinct heavy chains and/or pairing of cognate light chains to the heavy chains.
  4. 4. A two-component therapeutic comprising: (a) an immune cell or progenitor thereof, expressing an exogenous receptor comprising an intracellular signalling domain; and (b) a bridging molecule comprising: a heterodimer consisting of a first portion comprising a first Fab arm of an antibody and a second portion comprising a second Fab arm of an antibody, wherein the first and second Fab arms each comprise an antigen binding domain for binding to a cell surface molecule on a target cell, wherein the first Fab arm comprises at least one moiety capable of being bound by the exogenous immune cell receptor, wherein the second Fab arm does not comprise any moieties capable of being bound by the exogenous immune cell receptor, and wherein the first and second portions of the heterodimer comprise amino acid sequences for enabling heterodimerisation via pairing of distinct heavy chains and/or pairing of cognate light chains to the heavy chains.
  5. 5. A composition comprising: (a) an immune cell or progenitor thereof, expressing an exogenous receptor comprising and an intracellular signalling domain; and (b) a bridging molecule comprising: a heterodimer consisting of a first portion comprising a first Fab arm and a second portion comprising a second Fab arm, wherein the first and second Fab arms comprise an antigen binding domain for binding to a cell surface molecule on a target cell, wherein the first Fab arm comprises at least one moiety capable of being bound by the exogenous immune cell receptor, wherein the second Fab arm does not comprise any moieties capable of being bound by the exogenous immune cell receptor, and wherein the first and second portions of the heterodimer comprise amino acid sequences for enabling heterodimerisation via pairing of distinct heavy chains and/or pairing of cognate light chains to the heavy chains.
  6. 6. A kit comprising: (a) an immune cell or progenitor thereof, expressing an exogenous receptor comprising an intracellular signalling domain; and (b) a bridging molecule comprising: a heterodimer consisting of a first portion comprising a first Fab arm and a second portion comprising a second Fab arm, wherein the first and second Fab arms comprise an antigen binding domain for binding to a cell surface molecule on a target cell, wherein the first Fab arm comprises at least one moiety capable of being bound by the exogenous immune cell receptor, wherein the second Fab arm does not comprise any moieties capable of being bound by the exogenous immune cell receptor, and wherein the first and second portions of the heterodimer comprise amino acid sequences for enabling heterodimerisation via pairing of distinct heavy chains and/or pairing of cognate light chains to the heavy chains.
  7. 7. The molecule of claim 1 to 3 or the bridging molecule defined in any one of claims 4 to 6, wherein the first and second portions comprise an Fc region of an antibody.
  8. 8. The molecule of claim 7 wherein the Fc region of an antibody is a CH2 region of an antibody.
  9. 9. The molecule of claim 7 wherein the Fc region of an antibody is a CH3 region of an antibody.
  10. 10. The molecule of claim 7 wherein the Fc region of an antibody comprises a CH2 and a CH3 region of an antibody.
  11. 11 . The molecule of any one of claims 7 to 10 wherein the antigen binding domains of the first and second Fab arms of the heterodimeric molecule are identical in amino acid sequence.
  12. 12. The molecule of any one of claims 7 to 10, wherein the antigen binding domains are non-identical but bind to the same epitope of an antigen, or bind to different epitopes of the same antigen.
  13. 13. The molecule of any one of claims 7 to 10 wherein the antigen binding domains of the first and second Fab arms of the heterodimeric molecule are for binding to different antigens.
  14. 14. The molecule of any one of claims 7 to 13, wherein the first and second Fab arms are capable of specifically binding to an antigen on a cancer cell.
  15. 15. The molecule of any one of claims 7 to 14, wherein the first Fab arm of the heterodimeric molecule comprises 3 or 4 or 5.
  16. 16. The molecule of any one of claims 7 to 15, wherein the moieties capable of being bound by the exogenous immune cell receptor are selected from: a peptide, polysaccharide, dye, lipid, or small molecule.
  17. 17. The molecule of any one of claims 7 to 16, wherein the moieties capable of being bound by the exogenous immune cell receptor are peptides.
  18. 18. The molecule of claim 17, wherein the moieties capable of being bound by the exogenous immune cell receptor are peptides comprising the amino acid sequence of a neo-epitope.
  19. 19. The molecule of claim 17, wherein the moieties capable of being bound by the exogenous immune cell receptor are peptides comprising the amino acid sequence of a tumour-specific or tumour-associated antigen.
  20. 20. The molecule of claim 19, wherein the antigen is selected from an antigen of P2X?, EGFRvlll or CLDN6 and the moieties capable of being bound by the exogenous immune cell receptor are peptides comprising the amino acid sequence an epitope derived from P2X 7 , EGFRvlll or CLDN6.

Description

Molecules and methods for activating CAR T cells Field of the invention [0001] The present invention relates to molecules and methods for activating immune cells expressing an exogenous cell surface receptor comprising an intracellular signalling domain (eg chimeric antigen receptors), for the prevention and/or treatment of various conditions, including cancer. Related application [0002] This application claims priority from Australian provisional application AU 2023902090, the entire contents of which are hereby incorporated by reference. Background of the invention [0003] Cancer immunotherapy is a rapidly growing field. The development of T cells expressing chimeric antigen receptors (CARs) has revolutionised adoptive cell therapies. [0004] The potential of this approach has been demonstrated in clinical trials, wherein CAR T cells were infused into adult and paediatric patients with B-cell malignancies, neuroblastoma, and sarcoma. To date, over 500 clinical trials have emerged worldwide, designed at testing the efficacy of CAR T cells targeted to bind 64 different tumour associated antigens. Among these, three CD19-specific CAR T cell products have been approved for the treatment of acute lymphoblastic leukaemia (ALL), large B cell lymphoma and mantle cell lymphoma. To date, most of the success with CAR T therapies has been observed in the context of so-called “liquid” tumours, or where the CARs are directed to CD19, CD22 or the B cell maturation antigen (BCMA). [0005] Several challenges remain in the clinical application of CAR T cell therapies. These include difficulties with achieving sufficient therapeutic responses in the context of solid tumours, which may be due to insufficient activation, expansion and persistence of CAR T cells and/or the immunosuppressive tumour microenvironment. In addition, the long-term clinical application of CAR T therapies can be negatively impacted by the selective pressure of mono-specific CAR T cells, antigen-negative escape variants, and antigen depletion. Moreover, low levels of target antigen expression in healthy tissues can result in severe “on-target, off-tumour” toxicities. Finally, cytokine release syndrome (CRS) and CAR T cell-related encephalopathy syndrome (CRES) are frequently observed side effects of CAR T cell therapy. [0006] There is consequently a need for new and improved approaches to CAR, preferably CAR-T, therapies. [0007] Reference to any prior art in the specification is not an acknowledgment or suggestion that this prior art forms part of the common general knowledge in any jurisdiction or that this prior art could reasonably be expected to be understood, regarded as relevant, and/or combined with other pieces of prior art by a skilled person in the art. Summary of the invention [0008] The present invention is based on the surprising finding by the inventors that molecules having a particular architecture are especially useful for activating immune cells expressing an exogenous cell surface receptor comprising an intracellular signalling domain (eg chimeric antigen receptors, including expressed on T cells). These molecules may be referring to herein as “bridging molecules” (or may also be referred to as adapter molecules). [0009] Accordingly, in a first aspect, the invention provides a molecule capable of simultaneously binding to a target cell (such as a tumour cell) and to an immune cell expressing an exogenous cell surface receptor comprising an intracellular signalling domain, the molecule comprising: a heterodimer consisting of a first portion comprising a first Fab arm of an antibody and a second portion comprising a second Fab arm of an antibody, wherein the first and second Fab arms each comprise an antigen binding domain for binding to a cell surface molecule on a target cell, wherein the first Fab arm comprises at least one moiety capable of being bound by the exogenous immune cell receptor, wherein the second Fab arm does not comprise any moieties capable of being bound by the exogenous immune cell receptor and wherein the first and second portions of the heterodimer comprise amino acid sequences for enabling heterodimerisation via pairing of distinct heavy chains and/or pairing of cognate light chains to the heavy chains. [0010] In a further aspect, the invention provides a molecule capable of simultaneously binding to a target cell (such as a tumour cell) and to an immune cell expressing an exogenous cell surface receptor comprising an intracellular signalling domain, the molecule comprising: a heterodimer consisting of a first portion comprising a first Fab arm of an antibody and a second portion comprising a second Fab arm of an antibody, wherein the first and second Fab arms each comprise an antigen binding domain for binding to a cell surface molecule on a target cell, wherein the first Fab arm comprises at least two moieties capable of being bound by the exogenous immune cell receptor, and wherein the second Fab arm does n