CHIMERIC ANTIGEN RECEPTOR
The present disclosure relates to a chimeric antigen receptor (CAR) which comprises an antigen-binding domain which selectively binds TCR beta constant region 1 (TRBC1) or TRBC2; cells; such a T cells comprising such a CAR; and the use of such cells for the treatment of a T-cell lymphoma or leukaemia in a subject.
1 . A chimeric antigen receptor (CAR) which comprises an antigen-binding domain which selectively binds TCR beta constant region 1 (TRBC1) or TRBC2.
2 . A CAR according o claim 1 which selectively binds TRBC1.
3 . A CAR according to claim 2 , wherein the antigen-binding domain has a variable heavy chain (VH) and a variable light chain (VL) which comprise the following complementarity determining regions (CDRs):
VH CDR1: SEQ ID No. 7;
VH CDR2: SEQ ID No. 8;
VH CDR3: SEQ ID No. 9;
VL CDR1: SEQ ID No. 10;
VL CDR2: SEQ ID No. 11; and
VL CDR3: SEQ ID No. 12.
4 . A CAR according to claim 2 , wherein the antigen-binding domain comprises a variable heavy chain (VH) having the sequence shown as SEQ ID No. 1 and a variable light chain (VL) having the sequence shown as SEQ ID No. 2.
5 . A CAR according to claim 2 . wherein the antigen-binding domain comprises an scFv having the amino acid sequence shown as SEQ ID No. 3.
6 . A CAR according o claim 2 , which comprises an amino acid sequence selected from SEQ ID No. 4, 5 and 6
7 . A CAR according to claim 1 which selectively binds TRBC2.
8 . A nucleic acrid sequence encoding a CAR according to claim 1 .
9 . A vector which comprises a nucleic acid sequence according to claim 8 .
10 . A cell which comprises a CAR according to claim 1 .
11 . A T cell according to claim 10 .
12 . A method for making a cell according to claim 10 which comprises the step of transducing or transfecting a cell with a nucleic acid sequence according to claim 8 or a vector according to claim 9 .
13 . A method for treating a T-cell lymphoma or leukaemia in a subject which method comprises the step of
administrating a cell according to claim 10 comprising the TCRB1 or TCRB2 selective CAR to the subject, thereby causing selective depletion of the malignant T-cells together with normal T-cells expressing the same TRBC as the malignant T-cells, but not causing depletion of normal T-cells expressing the TRBC not expressed by the malignant T-cells.
14 . A method according to claim 13 , which also comprises the step of investigating the TCR beta constant region (TCRB) of a malignant T cell from the subject to determine whether it expresses TRBC1 or TRBC2.
15 . A method according to claim 13 , wherein the T-cell lymphoma or leukaemia is selected from peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS); angio-immunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (AL(L), enteropathy-associated T-cell lymphoma (EATL), hepatosplenic T-cell lymphoma (HSTL), extranodal NKIT-cell lymphoma nasal type, cutaneous T-cell lymphoma, primary cutaneous ALCL, T cell prolymphocytic leukaemia and T-cell acute lymphoblastic leukaemia.
16 . A method for diagnosing a T-cell lymphoma or leukaemia in a subject which comprises the step of determining the percentage of total T-cells in a sample isolated from the subject which are TRBC1 or TRBC2 positive.
17 . A method according to claim 16 wherein a percentage of TRBC1 or TRBC2 positive T-cells which is greater than about 80% indicates the presence of a T-cell lymphoma or leukaemia.
18 . A method according to claim 16 wherein the sample is a peripheral blood sample or a biopsy.
19 . A method according to claim 16 wherein total T cells are identified in or isolated from the sample using an agent which binds CD3.