Haematopoietic-restricted minor histocompatibility antigens and uses thereof

Abstract

Novel nucleic acid compositions, vector systems, modified cells, isolated peptides, isolated nucleic acid sequences and pharmaceutical compositions that encode or express T cell receptor components directed against haematopoietic-restricted minor histocompatibility antigens (MiHAs) are provided herein. These novel components may be used in the treatment of a subject having a haematological malignancy, particularly after the subject has undergone allogeneic stem cell transplantation (alloSCT). Associated methods for treating such subjects are also provided herein.

Description

[0001] Haematopoietic-restricted Minor Histocompatibility Antigens and uses thereof

[0002] Novel nucleic acid compositions, vector systems, modified cells, isolated peptides, isolated nucleic acid sequences and pharmaceutical compositions that encode or express T cell receptor components directed against haematopoietic-restricted minor histocompatibility antigens (MiHAs) are provided herein. These novel components may be used in the treatment of a subject having a haematological malignancy, particularly after the subject has undergone allogeneic stem cell transplantation (alloSCT). Associated methods for treating such subjects are also provided herein.

[0003] Haematological malignancies are cancers that affect the cellular components of blood or immune system. The cancer may begin in blood-forming tissue (e.g. bone marrow), or in the cells of the immune system.

[0004] In the Netherlands, 600-700 allogeneic haematopoietic stem cell transplantations are performed each year. This number is rising due to a continuing increase in elderly patients that are treated with allogeneic stem cell transplantation (alloSCT). Allogeneic stem cell transplantation is necessary in up to two thirds of adult patients with a disease of myeloid origin, most often acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), and in one third of adult patients with a malignancy of lymphoid origin, i.e. multiple myeloma (MM), non-Hodgkin’s lymphoma (NHL), chronic lymphocytic leukemia (CLL) or acute lymphoblastic leukemia (ALL).

[0005] In allogeneic stem cell transplantation, the blood forming stem cells in the bone marrow of the patient are replaced by a new haematopoietic system from a healthy donor. Due to genetic differences between patient and donor, the transplanted immune system of the donor is exposed to a large variety of foreign structures. As a consequence, a strong immune response is induced against structures on patient cells that are absent on donor cells. Allogeneic stem cell transplantation poses a curative treatment for haematologic malignant diseases, but often involves Graft-versus-Host Disease (GvHD) or relapse of disease in case of an insufficient Graft- versus-Leukemia effect (GvL).

[0006] Human Leukocyte Antigens (HLA) are molecules on the surface of almost all body cells. HLA molecules present small protein fragments, so-called peptides, to the immune system. In allogeneic stem cell transplantation, HLA molecules are preferably matched between patient and donor to prevent severe side effects. Due to SNPs in the genome, however, peptides that are presented by matched HLA molecules can still be different between patient and donor. Peptides presented on patient cells by matched HLA that are recognized by donor T cells after allogeneic stem cell transplantation are known as minor histocompatibility antigens. These antigens, which are intracellularly processed peptides presented in the groove of cell surface HLA molecules, are foreign to the donor T cell repertoire due to genetic differences between patient and donor. Studies sequencing patient and donor genomes counted on average 10000 mismatches of nonsynonymous SNPs per donor-recipient pair, i.e. the donor is homozygous for the allelic variant, while the patient is either heterozygous or homozygous for the minor histocompatibility antigen. However, not every SNP difference leads to a polymorphic peptide that is processed and presented by HLA surface molecules. On average, 50-150 minor histocompatibility antigens have been predicted per HLA class I allele of transplanted patients. In contrast, only 70 HLA class I- restricted minor histocompatibility antigens in total have been reported since the discovery of the first antigen in 1995.

[0007] Most minor histocompatibility antigens are broadly expressed on haematopoietic as well as non- haematopoietic cells. Donor T lymphocytes targeting antigens on non-haematopoietic tissues of the patient may induce undesired side effects potentially leading to a life-threating complication known as Graft-versus-Host Disease. For mitigation of GvHD, T cell depletion of the graft can be performed, followed by delayed pre-emptive donor lymphocyte infusion (DLI) for the benefit of GvL, which is, however, still often accompanied by GvHD. In an HLA-matched setting, both immune responses are orchestrated by alloreactive donor T cells recognizing patient cells of non- haematopoietic or haematopoietic origin. Only a few minor histocompatibility antigens are exclusively expressed on cells of haematopoietic origin, but not on non-haematopoietic tissues. These haematopoietic restricted minor histocompatibility antigens are relevant for immunotherapy, since T cells for these antigens destroy the malignant haematopoietic cells of the patient, but not healthy tissues of non-haematopoietic origin. Donor T cells for haematopoietic restricted minor histocompatibility antigens also spare healthy haematopoietic cells of the patient, since these cells are of donor origin after transplantation. Haematopoietic restricted minor histocompatibility antigens are thus excellent targets for immunotherapy to induce anti-tumor immunity after allogeneic stem cell transplantation without severe side effects.

[0008] T cells recognize H LA-binding peptides with specific receptors. The genetic information for a T cell receptor (TOR) can be transferred and used to modify T cells from other individuals. TCR gene therapy enables production of large numbers of T cells for a defined antigen, which can be infused in patients to stimulate anti-tumor immunity. T cells can also be genetically modified with artificial receptors targeting surface antigens in an H LA-independent manner. T cells genetically engineered with these artificial chimeric antigen receptors are successfully used in the clinic to treat B-cell malignancies, but are not standard therapy for myeloid malignancies due to lack of appropriate surface antigens that can be targeted. In contrast to surface antigens, myeloid malignancies express various H LA-binding peptides that can be targeted by TCR gene therapy.

[0009] HA-1 H is a haematopoietic restricted minor histocompatibility antigen that is used as target for immunotherapy to treat patients with a haematological malignancy after they have undergone allogeneic stem cell transplantation. The HA-1 H peptide VLHDDLLEA (SEQ ID NO: 75) is encoded by SNP rs1801284 (allele frequency 36%; population frequency 59%) and presented by HLA-A*02:01 (population frequency 50%). The HA-1 H peptide or nucleic acids encoding the antigen can be used for vaccination to stimulate anti-tumor immunity after allogeneic stem cell transplantation. In addition, TCRs for HA-1 H are used in clinical trials to treat or prevent relapse of blood cancer after allogeneic stem cell transplantation. The TCRs can be introduced into donor T cells or patient T cells obtained after transplantation, and large numbers of antigen specific T cells are produced and infused in patients to stimulate anti-tumor immunity after allogeneic stem cell transplantation. Patients can be treated with TCRs or other immunotherapies targeting HA- 1 H if they are positive for HLA-A*02:01 (50% of European people) and HA-1 H (59% of European people) and have been transplanted with an HI_A-A*02:01 positive donor who is negative for HA- 1 H, which are 12% of patients treated with HI_A-matched allogeneic stem cell transplantation. In addition, HLA-A*02:01 and HA-1 H positive patients can also be treated with HA-1 H targeting immunotherapy after transplantation with HLA-A*02:01 negative donors. Besides more elderly patients, the number of allogeneic stem cell transplantations that are performed each year is increasing due to optimized strategies that allow patients to be transplanted with donors that are mismatched for one or more HLA alleles or even a full HI_A haplotype. In haploidentical transplantation, patients receive stem cells from donors who share one HI_A haplotype with the recipient and are mismatched for a variable number of HLA genes on the unshared haplotype. Overall survival of patients with blood cancer after haploidentical or other types of HLA mismatched allogeneic stem cell transplantation significantly improved in the last decade.

[0010] The role of minor histocompatibility antigens in disease was first recognized when syngeneic transplantations or depletion of T cells from transplants not only led to amelioration GvHD, but also to an increase in relapses. Ubiquitously presented and recognized minor histocompatibility antigens increase the risk of GvHD, but also contribute to the beneficial Graft-versus-Leukaemia (GvL) effect due to their presence on malignant cells. Antigens that are exclusively expressed and presented on haematopoietic cells, however, constitute safe targets for a selective GvL response without GvHD. Therefore, potential immunotherapeutic clinical applications include adoptive T cell therapy and vaccine strategies targeting these haematopoietic-restricted antigens. Furthermore, haematopoietic-restricted minor histocompatibility antigens may serve as a biomarker for a more directed search for donors that are mismatched for these antigens in order to stimulate GvL reactivity while minimizing the risk for GvHD.

[0011] There is a need for an improved treatment of AM L and other types of blood cancer after allogeneic haematopoietic stem cell transplantation through expanding the repertoire of haematopoietic restricted minor histocompatibility antigens and TCRs for these antigens. A large repertoire of haematopoietic restricted minor histocompatibility antigens and TCRs for these antigens enables more transplanted patients to be treated and also allows for simultaneous targeting of multiple antigens thereby mimicking an effective natural immune response with a low risk for immune escape.

[0012] Brief summary of the disclosure

[0013] The inventors have screened 39 patients that underwent alloSCT and experienced an immune response after pre-emptive donor lymphocyte infusion in order to identify novel MiHAs and corresponding TCRs for use in the treatment of such patients. In total, 81 MiHAs were identified for the first time in these patients. Of the new MiHAs, eleven new antigens were identified that are haematopoietic-restricted minor histocompatibility antigens, including VSMNPYQEL (SEQ ID NO: 71 ; also referred to as “LB-MYO1G-2M / 3M” herein, more specifically as LB-MYO1G-2M for the peptide when presented by HLA-C*03:03 and as LB-MYO1G-3M for the peptide when presented by HLA-C*03:04), GPRPSPTRSV (SEQ ID NO: 72; also referred to as “LB-LILRB4- 1G” herein), and GPRWPPRMTH (SEQ ID NO: 73, 10-mer, also referred to as “LB-IL10RA-1 R” herein). In addition, a shorter haematopoietic-restricted minor histocompatibility antigen from LB- IL10RA-1 R was also identified herein (GPRWPPRMT (SEQ ID NO: 153); 9-mer, also referred to as “LB-IL10RA-1 R” herein). The new haematopoietic restricted minor histocompatibility antigens provided herein are presented by common HI_A class I alleles and encoded by genes with strong expression in AML and potentially also in other types of haematological malignancy. Advantageously, these new antigens and TCRs for these antigens can be used to treat patients with AM L or other types of haematological malignancy after they have undergone allogeneic stem cell transplantation. Expanding the repertoire of haematopoietic restricted minor histocompatibility antigens and TCRs for these antigens enables more transplanted patients to be treated and also allows for simultaneous targeting of multiple antigens thereby mimicking an effective natural immune response after allogeneic stem cell transplantation with a low risk for immune escape. These haematopoietic-restricted antigens may advantageously be used as targets for immunotherapies, or as peptide or nucleic acid based vaccines for the treatment or prevention of haematological malignancies.

[0014] In addition, a TCR was identified for the known ITGB2 haematopoietic-restricted minor histocompatibility antigen GQAGFFPSPF (SEQ ID NO: 74, also referred to as “LB - ITGB2- 1” herein).

[0015] Advantageously, the above mentioned peptides (e.g. SEQ ID NO:s 71 to 73, SEQ ID NO: 153) can be used as therapeutic agents (e.g. vaccines) to treat haematological malignancies (as described elsewhere herein). The peptides themselves therefore have utility e.g. in isolated form, or when formulated as a pharmaceutical composition. Alternatively, said peptides can be used as a target antigen for treatment of such patients with modified cells described herein (e.g. peripheral blood lymphocytes, bone marrow derived lymphocytes or tumour-infiltrating lymphocytes (TILs)) having T cell receptors or other binding proteins that specifically recognize one of the specified peptides, for example T cell receptors that specifically recognize one of the specified peptides in the context of a specific HLA as described herein). Further examples of the utility of the peptides described herein are provided in detail elsewhere herein.

[0016] Using the methods described herein, the inventors successfully isolated T cells with specific recognition of these peptides when presented in HLA-C*03:03, HI_A-C*03:04, HI_A-B*07:02, or HLA-B*15:01 (as appropriate).

[0017] The inventors have identified several TCRs that bind to a specific haematopoietic-restricted minor histocompatibility antigen presented in HLA-C*03:03, HI_A-C*03:04, HLA-B*07:02, or HLA- B*15:01. Specifically, the inventors identified the following haematopoietic-restricted MiHA- specific TCR clones:

[0018] (i) TCR clone VDL_3.1 F9 which interacts with VSMNPYQEL (SEQ ID NO: 71) in the context of HLA-C*03:03 or HLA-C*03:04;

[0019] (ii) TCR clone VDL_T1 which interacts with GPRPSPTRSV (SEQ ID NO: 72) in the context of HLA-B*07:02;

[0020] (iii) TCR clone AJV_1.32 (identical to TCR clone AJV_2.2) which interacts with GPRWPPRMT (SEQ ID NO: 153) in the context of HLA-B*07:02;

[0021] (iv) TCR clone EWO_4.1G7 which interacts with GPRWPPRMTH (SEQ ID NO: 73) in the context of HLA-B*07:02;

[0022] (v) TCR clone HJS_1-55 which interacts with GQAGFFPSPF (SEQ ID NO: 74) in the context of HLA-B*15:01;

[0023] (vi) TCR clone VDL_T3 which interacts with GPRPSPTRSV (SEQ ID NO: 72) in the context of HLA-B*07:02;

[0024] (vii) TCR clone EW0_18-22-23 which interacts with GPRWPPRMTH (SEQ ID NO: 73) and / or GPRWPPRMT (SEQ ID NO: 153) in the context of HLA-B*07:02;

[0025] (viii) TCR clone HJS_BLK_01 which interacts with GQAGFFPSPF (SEQ ID NO: 74) in the context of HLA-B*15:01 ;

[0026] (ix) TCR clone MBF_1-31 which interacts with GPRWPPRMTH (SEQ ID NO: 73) in the context of HLA-B*07:02.

[0027] Accordingly, provided herein are isolated nucleic acid compositions encoding haematopoietic- restricted minor histocompatibility antigen-specific binding proteins (as well as corresponding vector systems, modified cells, pharmaceutical compositions etc). The TCR components of clones (i) to (ix) form the basis of the haematopoietic-restricted minor histocompatibility antigen - specific binding proteins of the invention (e.g. the isolated nucleic acid compositions encoding haematopoietic-restricted minor histocompatibility antigen-specific binding proteins of the invention) and are described in more detail elsewhere herein.

[0028] Advantageously, cells expressing the haematopoietic-restricted minor histocompatibility antigen -specific binding proteins described herein can be used as an effective immunotherapy in the treatment of haematological malignancies, as described in more detail below.

[0029] Accordingly, in one aspect the invention provides an isolated nucleic acid composition that encodes a haematopoietic-restricted minor histocompatibility antigen (MiHA)-specific binding protein, the binding protein having a TCR a chain variable (Va) domain and a TCR p chain variable (VP) domain, the composition comprising:

[0030] (a) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence; and

[0031] (b) a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence; wherein the CDR3 amino acid sequences of (a) and (b) together bind (e.g. specifically bind) to an MiHA that comprises an amino acid sequence selected from the group consisting of: VSMNPYQEL (SEQ ID NO:71), GPRPSPTRSV (SEQ ID NO: 72), GPRWPPRMTH (SEQ ID NO: 73), GPRWPPRMT (SEQ ID NO: 153) and GQAGFFPSPF (SEQ ID NO: 74).

[0032] Suitably, the encoded binding protein may be capable of binding (e.g. specifically binding) to a peptide:HI_A complex selected from the group consisting of: a VSMNPYQEL:HLA-C*03:03 complex; a VSMNPYQEL:HLA-C*03:04 complex; a GPRPSPTRSV:HLA-B*07:02 complex; a GPRWPPRMTH:HLA-B*07:02 complex; a GPRWPPRMT:HLA-B*07:02 complex; and a GQAGFFPSPF:B*15:01 complex.

[0033] Suitably, the composition may comprise:

[0034] (i) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 3, or a functional fragment thereof; and a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6, or a functional fragment thereof, and the encoded binding protein is capable of binding (e.g. specifically binding) to a VSMNPYQEL:HLA-C*03:03 complex or a VSMNPYQEL:HLA-C*03:04 complex; or

[0035] (ii) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 17, or a functional fragment thereof; and a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 20, or a functional fragment thereof, and the encoded binding protein is capable of binding (e.g. specifically binding) to a GPRPSPTRSV:HLA-B*07:02 complex; or (iii) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 45, or a functional fragment thereof; and a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 48, or a functional fragment thereof, and the encoded binding protein is capable of binding (e.g. specifically binding) to a GPRWPPRMTH:HI_A-B*07:02 complex; or

[0036] (iv) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 31 , or a functional fragment thereof; and a nucleic acid sequence that encodes a TCR p domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 34, or a functional fragment thereof, and the encoded binding protein is capable of binding (e.g. specifically binding) to a GPRWPPRMT:HLA-B*07:02 complex; or

[0037] (v) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 59, or a functional fragment thereof; and a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 62, or a functional fragment thereof, and the encoded binding protein is capable of binding (e.g. specifically binding) to a GQAGFFPSPF:B*15:01 complex; or

[0038] (vi) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 99, or a functional fragment thereof; and a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 102, or a functional fragment thereof, and the encoded binding protein is capable of binding (e.g. specifically binding) to a GPRPSPTRSV:HLA-B*07:02 complex; or

[0039] (vii) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 113, or a functional fragment thereof; and a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 116, or a functional fragment thereof, and the encoded binding protein is capable of binding (e.g. specifically binding) to a GPRWPPRMTH:HLA-B*07:02 complex and / or a GPRWPPRMT:HLA-B*07:02 complex; or

[0040] (viii) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 127, or a functional fragment thereof; and a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 130, or a functional fragment thereof, and the encoded binding protein is capable of binding (e.g. specifically binding) to a GQAGFFPSPF:B*15:01 complex; or

[0041] (ix) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 141 , or a functional fragment thereof; and a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 144, or a functional fragment thereof, and the encoded binding protein is capable of binding (e.g. specifically binding) to a GPRWPPRMTH:HLA-B*07:02 complex.

[0042] Suitably:

[0043] (i) the CDR3 of the Va domain may comprise or consist of the amino acid sequence of SEQ ID NO: 3, and the CDR3 of the Vp domain may comprise or consist of the amino acid sequence of SEQ ID NO: 6, and the encoded binding protein may be capable of binding (e.g. specifically binding) to a VSMNPYQEL:HLA-C*03:03 complex or a VSMNPYQEL:HLA-C*03:04 complex; or

[0044] (ii) the CDR3 of the Va domain may comprise or consist of the amino acid sequence of SEQ ID NO: 17, and the CDR3 of the p domain may comprise or consist of the amino acid sequence of SEQ ID NO: 20, and the encoded binding protein may be capable of binding (e.g. specifically binding) to a GPRPSPTRSV:HLA-B*07:02 complex; or

[0045] (iii) the CDR3 of the Va domain may comprise or consist of the amino acid sequence of SEQ ID NO: 45, and the CDR3 of the Vp domain may comprise or consist of the amino acid sequence of SEQ ID NO: 48, and the encoded binding protein may be capable of binding (e.g. specifically binding) to a GPRWPPRMTH:HLA-B*07:02 complex; or

[0046] (iv) the CDR3 of the Va domain may comprise or consist of the amino acid sequence of SEQ ID NO: 31 , and the CDR3 of the Vp domain may comprise or consist of the amino acid sequence of SEQ ID NO: 34, and the encoded binding protein may be capable of binding (e.g. specifically binding) to a GPRWPPRMT:HLA-B*07:02 complex; or

[0047] (v) the CDR3 of the Va domain may comprise or consist of the amino acid sequence of SEQ ID NO: 59, and the CDR3 of the Vp domain may comprise or consist of the amino acid sequence of SEQ ID NO: 62, and the encoded binding protein may be capable of binding (e.g. specifically binding) to a GQAGFFPSPF:B*15:01 complex; or

[0048] (vi) the CDR3 of the Va domain may comprise or consist of the amino acid sequence of SEQ ID NO: 99, and the CDR3 of the Vp domain may comprise or consist of the amino acid sequence of SEQ ID NO: 102, and the encoded binding protein may be capable of binding (e.g. specifically binding) to a GPRPSPTRSV:HLA-B*07:02 complex; or

[0049] (vii) the CDR3 of the Va domain may comprise or consist of the amino acid sequence of SEQ ID NO: 113, and the CDR3 of the Vp domain may comprise or consist of the amino acid sequence of SEQ ID NO: 116, and the encoded binding protein may be capable of binding (e.g. specifically binding) to a GPRWPPRMTH:HLA-B*07:02 complex and / or a GPRWPPRMT:HLA-B*07:02 complex; or

[0050] (viii) the CDR3 of the Va domain may comprise or consist of the amino acid sequence of SEQ ID NO: 127, and the CDR3 of the Vp domain may comprise or consist of the amino acid sequence of SEQ ID NO: 130, and the encoded binding protein may be capable of binding (e.g. specifically binding) to a GQAGFFPSPF:B*15:01 complex; or

[0051] (ix) the CDR3 of the Va domain may comprise or consist of the amino acid sequence of SEQ ID NO: 141 , and the CDR3 of the Vp domain may comprise or consist of the amino acid sequence of SEQ ID NO: 144, and the encoded binding protein may be capable of binding (e.g. specifically binding) to a GPRWPPRMTH:HLA-B*07:02 complex.

[0052] Suitably:

[0053] (i) the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 7; and (ii) the p domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 9, and the encoded binding protein may be capable of binding (e.g. specifically binding) to a VSMNPYQEL:HLA-C*03:03 complex or a VSMNPYQEL:HLA-C*03:04 complex; or

[0054] (ii) the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 21 ; and (ii) the Vp domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 23, and the encoded binding protein may be capable of binding (e.g. specifically binding) to a GPRPSPTRSV:HLA-B*07:02 complex; or

[0055] (iii) the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 49; and (ii) the Vp domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 51 , and the encoded binding protein may be capable of binding (e.g. specifically binding) to a GPRWPPRMTH:HLA-B*07:02 complex; or

[0056] (iv) the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 35; and (ii) the Vp domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 37, and the encoded binding protein may be capable of binding (e.g. specifically binding) to a GPRWPPRMT:HLA-B*07:02 complex; or

[0057] (v) the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 63; and (ii) the Vp domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 65, and the encoded binding protein may be capable of binding (e.g. specifically binding) to a GQAGFFPSPF:B*15:01 complex; or

[0058] (vi) the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 103; and (ii) the Vp domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 105, and the encoded binding protein may be capable of binding (e.g. specifically binding) to a GPRPSPTRSV:HLA-B*07:02 complex; or (vii) the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 117; and (ii) the Vp domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 119, and the encoded binding protein may be capable of binding (e.g. specifically binding) to a GPRWPPRMTH:HLA-B*07:02 complex and / or a GPRWPPRMT:HLA-B*07:02 complex; or

[0059] (viii) the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 131 ; and (ii) the p domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 133, and the encoded binding protein may be capable of binding (e.g. specifically binding) to a GQAGFFPSPF:B*15:01 complex; or

[0060] (ix) the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 145; and (ii) the Vp domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 147, and the encoded binding protein may be capable of binding (e.g. specifically binding) to a GPRWPPRMTH:HLA-B*07:02 complex.

[0061] Suitably, the nucleic acid sequence may be codon optimised for expression in a host cell, optionally wherein the host cell is a human cell.

[0062] Suitably, the composition may further comprise a TCR a chain constant domain and / or a TCR p chain constant domain.

[0063] Suitably, the encoded binding protein may comprise a TCR, an antigen binding fragment of a TCR, a chimeric antigen receptor (CAR), or an ImmTAC.

[0064] Suitably, the antigen binding fragment of a TCR may be a single chain TCR (scTCR) or a chimeric TCR dimer in which the antigen binding fragment of the TCR is linked to an alternative transmembrane and intracellular signalling domain.

[0065] In another aspect, the invention provides a vector system comprising a nucleic acid composition according to the invention.

[0066] Suitably, the vector may be a plasmid, a viral vector, or a cosmid, optionally wherein the vector is selected from the group consisting of a retrovirus, lentivirus, adeno-associated virus, adenovirus, vaccinia virus, canary poxvirus, herpes virus, minicircle vector and synthetic DNA or RNA.

[0067] In another aspect, the invention provides a modified cell comprising a nucleic acid composition according to the invention, or a vector system according to the invention. Suitably, the modified cell may be selected from the group consisting of a CD8 T cell, a CD4 T cell, an NK cell, an NKT cell, a gamma-delta T cell, a hematopoietic stem cell, an inducible pluripotent stem cell, a progenitor cell, a T cell line and a NK-92 cell line.

[0068] Suitably, the modified cell may be a human cell.

[0069] In another aspect, the invention provides an isolated peptide comprising or consisting of an amino acid sequence selected from the group consisting of: VSMNPYQEL (SEQ ID NO:71), GPRPSPTRSV (SEQ ID NO: 72), GPRWPPRMTH (SEQ ID NO: 73) and GPRWPPRMT (SEQ ID NO: 153).

[0070] Suitably, the peptide may have no more than 30 amino acids, no more than 25 amino acids or no more than 20 amino acids.

[0071] In another aspect, the invention provides an isolated nucleic acid sequence encoding the peptide of the invention.

[0072] In another aspect, the invention provides a vector system comprising the nucleic acid sequence of the invention.

[0073] In another aspect, the invention provides a binding agent that binds (e.g. specifically binds) to a peptide:HLA complex, wherein the complex is selected from the group consisting of: a VSMNPYQEL:HLA-C*03:03 complex; a VSMNPYQEL:HLA-C*03:04 complex; a GPRPSPTRSV:HLA-B*07:02 complex; a GPRWPPRMTH :H LA- B*07:02 complex; a GPRWPPRMT:HLA- B*07:02 complex; and a GQAGFFPSPF:B*15:01 complex.

[0074] Suitably, the binding agent may be an antibody, an antibody fragment or a T cell receptor.

[0075] In another aspect, the invention provides a pharmaceutical composition comprising a nucleic acid composition according to the invention, a vector system according to the invention, a modified cell according to the invention, an isolated peptide according to the invention, a nucleic acid sequence according to the invention, or a binding agent according to the invention, and a pharmaceutically acceptable excipient, adjuvant, diluent and / or carrier.

[0076] In one aspect, the invention provides a pharmaceutical composition according to the invention for use in therapy. In another aspect, the invention provides a method for treating or preventing a relapse of a haematological malignancy after allogeneic stem cell transplantation (allo-SCT) in a human subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to the invention.

[0077] In another aspect, the invention provides a pharmaceutical composition according to the invention for use in treating or preventing a relapse of a haematological malignancy after allogeneic stem cell transplantation (allo-SCT) in a human subject.

[0078] In another aspect, the invention provides the use of a pharmaceutical composition according to the invention in the manufacture of a medicament for treating or preventing a relapse of a haematological malignancy after allogeneic stem cell transplantation (allo-SCT) in a human subject.

[0079] Suitably, the haematological malignancy may comprise a leukemia, a lymphoma, a myelodysplastic disorder, or a myeloma.

[0080] Suitably:

[0081] (i) the haematological malignancy may comprise a leukemia, optionally wherein the leukemia is selected from the group consisting of acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL) (such as T-ALL or B-ALL), mixed phenotype acute leukemia (MPAL), acute undifferentiated leukemia (AUL), chronic myeloid leukemia (CML), B cell prolymphocytic leukemia, hairy cell leukemia, or chronic lymphocytic leukemia (CLL); or

[0082] (ii) the haematological malignancy may comprise a lymphoma, optionally wherein the lymphoma is selected from the group consisting of Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL), a central nervous system lymphoma, small lymphocytic lymphoma (SLL), CD37+ dendritic cell lymphoma, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, B-cell lymphoma, extra- nodal marginal zone B-cell lymphoma of mucosa-associated (MALT) lymphoid tissue, nodal marginal zone B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, precursor B-lymphoblastic lymphoma, immunoblastic large cell lymphoma, intravascular large B- cell lymphoma, primary effusion lymphoma, or Burkitt's lymphoma; or

[0083] (iii) the hematological malignancy may comprise a multiple myeloma; or

[0084] (iv) the hematological malignancy may comprise a myelodysplastic disorder, optionally wherein the myelodysplastic disorder is selected from refractory cytopenia with unilineage dysplasia (refractory anemia, refractory neutropenia, and refractory thrombocytopenia), refractory anemia with ring sideroblasts (RARS), refractory anemia with ring sideroblasts - thrombocytosis (RARS- t), refractory cytopenia with multilineage dysplasia (RCMD), refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS), refractory anemia with excess blasts (RAEB), myelodysplasia unclassifiable, or refractory cytopenia of childhood.

[0085] Suitably, the subject may have previously received lymphodepleting chemotherapy.

[0086] Suitably, the lymphodepleting chemotherapy may comprise cyclophosphamide, fludarabine, antithymocyte globulin, or a combination thereof.

[0087] Suitably, one or more of the modified cells within the composition of the invention may be allogeneic to the subject.

[0088] Suitably:

[0089] (a) when the subject has haematopoietic cells comprising VSMNPYQEL:HLA-C*03:03 complexes, the composition may comprise (i) a peptide comprising the amino acid sequence of VSMNPYQEL, and / or a nucleic acid sequence, vector or cell encoding said peptide, and / or (ii) a nucleic acid composition, vector or modified cell encoding a binding protein that binds (e.g. specifically binds) said complex, optionally wherein the subject has a haematological malignancy that is selected from the group consisting of: AML, ALL (such as T-ALL or B-ALL), HL, NHL, CLL, MPN (such as CML), B-cell lymphoma, MDS, and multiple myeloma; or

[0090] (b) when the subject has haematopoietic cells comprising VSMNPYQEL:HLA-C*03:04 complexes, the composition may comprise (i) a peptide comprising the amino acid sequence of VSMNPYQEL, and / or a nucleic acid sequence, vector or cell encoding said peptide, and / or (ii) a nucleic acid composition, vector or modified cell encoding a binding protein that binds (e.g. specifically binds) said complex, optionally wherein the subject has a haematological malignancy that is selected from the group consisting of: AML, ALL (such as T-ALL or B-ALL), HL, NHL, CLL, MPN (such as CML), B-cell lymphoma, MDS, and multiple myeloma; or

[0091] (c) when the subject has haematopoietic cells comprising GPRPSPTRSV:HLA-B*07:02 complexes, the composition may comprise (i) a peptide comprising the amino acid sequence of GPRPSPTRSV, and / or a nucleic acid sequence, vector or cell encoding said peptide, and / or (ii) a nucleic acid composition, vector or modified cell encoding a binding protein that binds (e.g. specifically binds) said complex, optionally wherein the subject has a haematological malignancy further optionally wherein the haematological malignancy is selected from the group consisting of AML, MDS, MPN (such as CML), and multiple myeloma; or

[0092] (d) when the subject has haematopoietic cells comprising GPRWPPRMTH:HLA-B*07:02 complexes, the composition may comprise (i) a peptide comprising the amino acid sequence of GPRWPPRMTH, and / or a nucleic acid sequence, vector or cell encoding said peptide, and / or (ii) a nucleic acid composition, vector or modified cell encoding a binding protein that binds (e.g. specifically binds) said complex, optionally wherein the subject has a haematological malignancy that is selected from the group consisting of: AML, ALL, HL, NHL, CLL, MPN (such as CML), MDS and multiple myeloma; or

[0093] (e) when the subject has haematopoietic cells comprising GQAGFFPSPF:B*15:01 complexes, the composition may comprise (i) a nucleic acid composition, vector or modified cell encoding a binding protein that binds (e.g. specifically binds) said complex, optionally wherein the subject has a haematological malignancy selected from the group consisting of: AML, ALL (such as B- ALL or T-ALL), HL, NHL, CLL, MPN (such as CLM), MDS and multiple myeloma; or

[0094] (f) when the subject has haematopoietic cells comprising GPRWPPRMT:HLA-B*07:02 complexes, the composition may comprise (i) a peptide comprising the amino acid sequence of GPRWPPRMT, and / or a nucleic acid sequence, vector or cell encoding said peptide, and / or (ii) a nucleic acid composition, vector or modified cell encoding a binding protein that binds (e.g. specifically binds) said complex, optionally wherein the subject has a haematological malignancy that is selected from the group consisting of: AML, ALL, HL, NHL, CLL, MPN (such as CML), MDS and multiple myeloma.

[0095] In another aspect, the invention provides a method of generating a binding protein that is capable of binding (e.g. specifically binding) to a peptide containing a MiHA and does not bind to a peptide that does not contain the MiHA, comprising contacting a nucleic acid composition according to the invention with a cell under conditions in which the nucleic acid composition is incorporated and expressed by the cell.

[0096] Suitably, the method may be ex vivo.

[0097] In another aspect, the invention provides an isolated nucleic acid composition that encodes a T cell receptor (TOR), wherein the TCR comprises:

[0098] (i) TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 3, and a TCR Vp domain comprising a CDR3 amino acid sequence of SEQ ID NO: 6; or

[0099] (ii) a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 17; and a TCR p domain comprising a CDR3 amino acid sequence of SEQ ID NO: 20; or

[0100] (iii) a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 45; and a TCR Vp domain comprising a CDR3 amino acid sequence of SEQ ID NO: 48; or

[0101] (iv) a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 31 ; and a TCR Vp domain comprising a CDR3 amino acid sequence of SEQ ID NO: 34; or

[0102] (v) a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 59; and a TCR Vp domain comprising a CDR3 of SEQ ID NO: 62; or

[0103] (vi) a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 99; and a TCR Vp domain comprising a CDR3 amino acid sequence of SEQ ID NO: 102; or (vii) a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 113; and a TOR Vp domain comprising a CDR3 amino acid sequence of SEQ ID NO: 116; or

[0104] (viii) a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 127; and a TCR Vp domain comprising a CDR3 of SEQ ID NO: 130; or

[0105] (ix) a Va domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 7; and (ii) a Vp domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 9; or

[0106] (x) a Va domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 21 ; and (ii) a Vp domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 23; or

[0107] (xi) a Va domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 49; and (ii) a Vp domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 51 ,; or

[0108] (xii) a Va domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 35; and (ii) a Vp domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 37; or

[0109] (xiii) a Va domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 63; and (ii) a Vp domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 65; or

[0110] (xiv) a Va domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 103; and (ii) a Vp domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 105; or

[0111] (xv) a Va domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 117; and (ii) a Vp domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 119; or

[0112] (xvi) a Va domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 131 ; and (ii) a Vp domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 133; or

[0113] (xvii) a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 141 ; and a TCR Vp domain comprising a CDR3 of SEQ ID NO: 144; or

[0114] (xviii) a Va domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 145; and (ii) a Vp domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 147.

[0115] In another aspect, the invention provides an isolated nucleic acid composition according to the invention for use in therapy. Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of them mean “including but not limited to”, and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps.

[0116] Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0117] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.

[0118] Various aspects of the invention are described in further detail below.

[0119] Brief description of the Figures

[0120] Embodiments of the invention are further described hereinafter with reference to the accompanying drawings, in which:

[0121] Figure 1 shows MiHAs targeted by T cells in a cohort of 39 transplanted patients. In total, 137 of all 159 MiHAs were mismatched in at least one patient that was positive for the relevant HLA-restriction allele (white bars). MiHAs were targeted in single patients (light grey) or recurrently targeted in >2 patients either in the cohort (middle grey) or also outside the cohort (dark grey). Asterisks indicate two MiHAs (LB-SIK1-1A and LB-LINC02427-1G) for which T-cell clones were isolated but SNPs could not be genotyped because of insufficient coverage by whole exome sequencing and KASPar assays. Genotyping also failed for the SNP encoding LB- C16ORF-1 R.

[0122] Figure 2 shows that often the same MiHAs are targeted by T cells. In total, 174 T cell clones for 108 different MiHAs were isolated from 39 patients. Of the 174 T cell clones, 111 (63.8%) T cell clones were directed against recurrent MiHAs that were targeted in > 2 patients either in the inventor’s cohort (middle grey) or also outside the cohort (dark grey). The remaining 63 (36.2%) T cell clones were directed against MiHAs targeted in only one patient (light grey). Indicated are also the total number of MiHA mismatches for each patient with the relevant HI_A restriction allele (white bars).

[0123] Figure 3 shows the tissue distribution of MiHAs. Indicated is the number of targeted MiHAs in the 39 patients coloured based on their gene expression profile. Gene expression analysis was performed using single cell RNA sequencing data of the Human Protein Atlas. Gene expression was reported for 123 of 129 genes coding for 159 MiHAs. Gene expression was separately analyzed for hematopoietic and non-hematopoietic cells in GvHD tissues including skin, esophagus, stomach, small intestine, colon, rectum, liver, lung, bronchus, eye and thymus, and additionally for hematopoietic cells including B cells, plasma cells, T cells, NK cells, monocytes, dendritic cells, macrophages, Langerhans cells, Kupffer cells, granulocytes, erythroid cells, platelets and mixed immune cells in GvHD tissues as well as PBMC and spleen. The maximum expression value in hematopoietic cells was compared to the maximum value in non- hematopoietic tissues. MiHAs with gene expression levels that are at least 3-fold higher in hematopoietic than non-hematopoietic cells are indicated by light gray dots. MiHAs with gene expression levels that are at least 3-fold higher in non-hematopoietic than hematopoietic cells are shown by dark gray dots. The remaining MiHAs with gene expression levels varying less than 3- fold between hematopoietic and non-hematopoietic cells are represented by middle gray dots. MiHAs with lacking gene expression data are displayed by striped dots.

[0124] Figure 4 shows gene expression of MiHAs in acute myeloid leukemia using LUMC RNA- Seq data. Expression of HMHA1, MY01G, ITGB2, DOK2, F13A1, IL10RA, LILRB4, TXNDC11, APOBEC3H, SLAMF1 and LTA have been analyzed by RNA-Seq in 46 AML with >80% leukemic cells from the biobank of the department of Hematology of the LUMC. Indicated is the RPKM (reads per kilobase of transcript per million mapped reads).

[0125] Figure 5 shows pMHC tetramer staining of TCRs for hematopoietic-restricted MiHAs. (A) TCRs for hematopoietic-restricted MiHAs were cloned and transferred to CD8 T cells from healthy donors who are positive for the relevant HLA class I restriction allele but negative for the respective MiHA. TCRa and p variable regions were sequenced and cloned in the MP71-flex retroviral vector. In MP71-flex, human TCRa and variable regions are cloned in-frame with murine TCRa and p constant regions. For production of TCR-T cells, CD8 cells were stimulated with anti-CD3 / CD28 and IL-2. On day 2, CD8 cells were edited by CRISPR / Cas9 to knock out the endogenous TCRa and p genes followed by retroviral transduction of the TCR on day 3. On day 5-8, TCR-T cells that were positive for mouse TCR-Cp but negative for endogenous human TCRs were sorted by FACS. Purified TCR-T cells were restimulated and analyzed for staining with pMHC-tetramers containing the respective MiHAs (black). As controls, CD8 T cells transduced with the HLA-A*02:01 restricted TCR for CMVpp65 were stained with MiHA-containing pMHC- tetramers (gray). The TCR for LB-MY0O1G-2M expressed by T cell clone VDL_3.1 F9 from patient 6711 has been introduced in CD8 T cells from healthy donor 6904. The TCRs for LB-IL10RA-1 R expressed by T cell clone EWO_4.1G7 from patient 8490 and T cell clone AJV_1.32 from patient 8008 have been transferred to CD8 T cells from healthy donor 11295. The TCRs for LB-LILRB4- 1G expressed by T cell clones VDL_T1 and VDL_T3 from patient 6711 have been transferred to CD8 T cells from healthy donor 6904. The TCR for LB-ITGB2-1 expressed by T cell clone HJS_1.55 from patient 6940 has been transferred to CD8 T cells from healthy donor 6904. The TCRs for LB-LTA-1 R expressed by T cell clones HHS_2.004, HHS_2.043 and HHS_2.269 from patient 7952 have been transferred to CD8 T cells from donor 11295. The TCRs for LB-DOK2-1 L expressed by T cell clones PML_H.4G10 from patient 9528, FHA_1 H8 from patient 7956 and MHU_1 .052 from patient 5528 have been transferred to CD8 T cells from donor 6904. The TCRs for LB-SLAMF1-1 F expressed by T cell clones ORZ_003 and ORZ_2.231 from patient 9701 have been transferred to CD8 T cells from donor 10433. (B) TCRs for hematopoietic-restricted MiHAs were cloned and transferred to Jurkat-76 cells, which were transduced with the CD8 coreceptor. Jurkat-76 cells lack expression of endogenous TCRa and p genes. TCR-transduced Jurkat-76 cells with the CD8 coreceptor were stained with the pMHC-tetramer with the respective MiHA (black) or with a control HLA-B*07:02 tetramer with the CMVpp65 peptide (gray). The TCR for LB-TXNDC11-1 P has been isolated from T cell clone FHA_5E5 from patient 7956. The TCR for LB-F13A1-1 L has been isolated from T cell clone EBJ_1.195 from patient 7072. The TCR for LB- APOBEC3H-2R has been isolated from T cell clone USF_3.41 from patient 6325. The TCR for LB-ITGB2-1 has been isolated from T cell clone HJS_BLK_01 from patient 6940. The TCR for LB-IL10RA-1 R has been isolated from T cell clone EWO_18-22-23 from patient 8490.

[0126] Figure 6 shows T-cell reactivity against titrated peptides of MiHAs and allelic variants. (A) TCR-T cells for hematopoietic-restricted MiHAs as shown in Figure 5A were tested against titrated peptide concentrations of MiHAs (black symbols) and their allelic variants (gray symbols). Peptides were loaded on EBV-B cells that were positive for the relevant HI_A class I restriction allele but negative for the MiHA. After overnight coincubation, release of IFN-y was measured by ELISA. Polymorphic amino acids in the indicated peptide sequences are shown between brackets. TCR-T cells for LB-MYO1G-2M were tested against VSMNPYQEL (MiHA) and VSVNPYQEL (allelic variant). TCR-T cells for LB-LILRB4-1G were tested against GPRPSPTRSV (MiHA) and DPRPSPTRSV (allelic variant). TCR-T cells for LB-ITGB2-1 was tested against GQAGFFPSPF (MiHA). LB-ITGB2-1 is encoded by a polymorphic transcript and does not have an allelic variant. TCR-T cells for LB-IL10RA-1 R were tested against GPRWPPRMTH (MiHA) and GPRWPPQMTH (allelic variant). TCR-T cells for LB-LTA-1 R were tested against RVRGTTLHLLL (MiHA) and RVCGTTLHLLL (allelic variant). TCR-T cells for LB-DOK2-1 L were tested against LPRPDSPYSRL (MiHA) and LPRPDSPYSRP (allelic variant). TCR-T cells for LB-SLAMF1-1 F were tested against GLLSLTFVL (MiHA) and GLLSLTLVL (allelic variant). (B) T cell clones for hematopoietic-restricted MiHAs were tested against titrated peptide concentrations of MiHAs and their allelic variants. Peptides were loaded on EBV-B cells that were positive for the relevant HLA class I restriction allele, but negative for the MiHA. After overnight coincubation, release of IFN-y was measured by ELISA. T cell clone PML_074 for LB-APOBEC3H-1 K from patient 9528 was tested against KPQQKGLRLL (MiHA) and KPQQDGLRLL (allelic variant). T cell clone for LB- APOBEC3H-2R was tested against RIFASRLYY (MiHA) and GIFASRLYY (allelic variant). T cell clone for LB-F13A1-1 L against ITFYTGVLK (MiHA) and ITFYTGVPK (allelic variant) and T cell clone for LB-TXNDC11-1 P against RPRGLRLPQL (MiHA) and RLRGLRLPQL (allelic variant). Figure 7 shows T-cell reactivity against skin fibroblasts. (A) TCR-T cells for hematopoietic- restricted MiHAs (black bars) as shown in Figure 5A and Figure 6A and as controls TCR-T cells for CMVpp65 (gray bars) were tested against EBV-B cells from the patient from whom the T cell clone was isolated that expressed the TCR (pEBV), EBV-B cells from the corresponding stem cell donor (dEBV) and skin fibroblasts cultured from a patient who was positive for the relevant HI_A class I restriction allele and MiHA for three days in the absence or presence of 150 lll / ml IFN-y. After overnight coincubation, release of IFN-y was measured by ELISA. (B) T cell clones for hematopoietic-restricted MiHAs were tested against patient and donor EBV-B cells and skin fibroblasts. Release of IFN-y was measured by ELISA.

[0127] Figure 8 shows TCR-T cells for three new haematopoietic restricted minor histocompatibility antigens. (A) TCR-T cells for LB-MYO1G-2M / 3M (VDL_3.1 F9) in donor 9933 (upper), LB-LILRB4-1G (VDL_T1) in donor 8412 (middle) and LB-IL10RA-1 R (EWO_4.1G7) in donor 9530 (lower) and TCR-T cells for CMVpp65 were stained with pMHC-tetramers for the respective MiHA or CMVpp65. (B) TCR-T cells for LB-MYO1G-2M / 3M in donor 9933 (dark grey), LB-LILRB4-1G in donor 8412 (grey hatched) and LB-IL10RA-1 R in donor 9530 (light grey hatched) and control TCR-T cells for CMVpp65 from the same donors were co-incubated with three AML cases (AML 6711 , AML 5156 and AML 5092) with >80% malignant blasts. All three AML are positive for LB-LILRB4-1G and LB-IL10RA-1 R and HLA-B*07:02. Only AML 6711 is positive for LB-MYO1G-3M and HLA-C*03:04. Release of IFN-y was measured by ELISA.

[0128] Figure 9 shows pMHC-tetramer staining of TCR-T cells for hematopoietic-restricted MiHAs. TCRs for hematopoietic-restricted MiHAs were cloned and transferred to CD8 T cells from healthy donors who were positive for the relevant HLA class I restriction allele but negative for the respective MiHA. Human TCRa and p variable regions were sequenced and cloned in the MP71- flex retroviral vector in-frame with murine TCRa and constant regions. For production of TCR- T cells, CD8 cells were isolated by magnetic activated cell sorting (MACS) using anti-CD8 microbeads, stimulated with anti-CD3 / CD28 and IL-2. On day 2, CD8 cells were edited by CRISPR / Cas9 to knock out the endogenous TCRa and p genes followed by retroviral transduction of the MiHA-specific TCR on day 3. On day 8, TCR-T cells that were positive for mouse TCR-Cp and negative for endogenous human TCRs were sorted by FACS. Purified TCR-T cells were restimulated and stained with pMHC-tetramers containing the respective MiHAs (black). As controls, CD8 T cells transduced with the HLA-A*02:01 -restricted TCR for CMVpp65 or HLA- A*03:01 -restricted TCR for EBNA3A were stained with MiHA-containing pMHC-tetramers (gray). (A) The VDL_3.1 F9 TCR for LB-MYO1G-2M was introduced in CD8 T cells from healthy donor 6904. The VDL_T1 and VDL_T3 TCRs for LB-LILRB4-1G were transferred to CD8 T cells from healthy donor 6904. The EWO_4.1G7, EW0_18, and AJV_1.32 TCRs for LB-IL10RA-1 R as well as the TCR for LB-IL10RA-1 R from T cell clone MBF_1-31 from patient 5177 were introduced to CD8 T cells from healthy donor 11295. TCR-T cells for LB-IL10RA-1 R were stained with pMHC- tetramers containing the 10-mer MiHA peptide GPRWPPRMTH or 9-mer GPRWPPRMT peptide variants. The HJS_1-55 and HJS_bulk TCRs for LB-ITGB2-1 were transferred to CD8 T cells from healthy donor 6904. All TCR-T cells showed specific binding to pMHC-tetramers with the respective MiHA peptides. AJV_1.32 TCR-T cells for LB-IL10RA-1 R showed specific binding to the pMHC-tetramer with the 9-mer peptide, EWO_4.1G7 TCR-T cells to the pMHC-tetramer with the 10-mer peptide, EW0_18 TCR-T cells to both peptides but most strongly to the 9-mer peptide, and MBF_1.31 TCR-T cells to the 10-mer peptide. (B) The TCRs for LB-LTA-1 R expressed by T cell clones HHS_2.004, HHS_2.043, and HHS_2.269 from patient 7952 were introduced to CD8 T cells from healthy donor 11295. The TCRs for LB-DOK2-1 L expressed by T cell clones PML_H.4G10 from patient 9528, FHA_1 H8 from patient 7956, and MHU_1.052 from patient 5528 were transferred to CD8 T cells from healthy donor 6904. The TCRs for LB-SLAMF1-1 F expressed by T cell clones GRZ_003 and ORZ_2.321 from patient 9701 were transferred to CD8 T cells from healthy donor 10433. The TCR for LB-APOBEC3H-1 K, isolated from T cell clone PML_074 from patient 9528, was introduced into CD8 T cells from healthy donor 7073. The TCR for LB-APOBEC3H-2R, isolated from T cell clone USF_3.41 from patient 6325, was transferred to CD8 T cells from healthy donor 9278. The TCR for LB-TXNDC11-1 P, isolated from T cell clone FHA_5E5 from patient 7956, was transferred to CD8 T cells from healthy donor 7073. The TCR for LB-F13A1-1 L, isolated from T cell clone EBJ_1.195 from patient 7072, was introduced into CD8 T cells from healthy donor 11295. All TCR-T cells showed specific binding to pMHC- tetramers with the respective MiHA peptides.

[0129] Figure 10 shows reactivity of TCR-T cells against titrated MiHA peptides. TCR-T cells for hematopoietic-restricted MiHAs were tested against titrated peptide concentrations of identified MiHAs (black symbols) and length variants (gray symbols). Peptides were loaded on EBV-B cells that were positive for the relevant HI_A class I restriction allele and negative for the MiHA. After overnight coincubation, release of IFN-y was measured by ELISA. Polymorphic amino acids in the indicated peptide sequences are shown between brackets. TCR-T cells for LB-APOBEC3H- 1 K were tested against peptide KPQQKGLRLL, TCR-T cells for LB-APOBEC3H-2R against peptide RIFASRLYY, TCR-T cells for LB-F13A1-1 L against peptide ITFYTGVLK, TCR-T cells for LB-TXNDC11-1 P against peptide RPRGLRLPQL, and TCR-T cells for LB-IL10RA-1 R against peptides GPRWPPRMTH and GPRWPPRMT. All TCR-T cells recognize the specific MiHA peptide.

[0130] Figure 11 shows reactivity of MiHA-specific TCR-T cells against patient and donor EBV-B cells. TCR-T cells for hematopoietic restricted MiHAs (black bars) and control TCR-T cells (gray bars) were tested against EBV-B cells from a MiHA-positive patient (pEBV) and its corresponding MiHA-negative stem cell donor (dEBV). After overnight coincubation, release of IFN-y was measured in culture supernatants by ELISA. All TCR-T cells were reactive against patient EBV- B cells, but not donor EBV-B cells.

[0131] Figure 12 shows TCR-T cell reactivity against malignant cell lines of different hematopoietic origins. TCRs for hematopoietic-restricted MiHAs were introduced into CD8 T cells from healthy donors. The TCRs for LB-MYO1G-2M and LB-LILRB4-1G were introduced in CD8 T cells from healthy donor 6904, the TCRs for LB-IL10RA-1 R and LB-ITGB2-1 in CD8 T cells from healthy donor 11295, the TCR for LB-TXNDC11-1 P in CD8 T cells from healthy donor 6312, the TCR for LB-LTA-1 R in CD8 T cells from healthy donor 6282, and the TCR for LB- SLAMF1-1 F TCR in CD8 T cells from healthy donor 10433. TCR-T cells (black bars) were coincubated with malignant hematopoietic cell lines of different origins. The panel contains acute myeloid cell lines (AML) cell lines (OCI-AML2, OCI-AML3, MONOMAC-6, THP-1 , SIG-M5, NB4, MOLM13-RES-AC, Kasumi-6), multiple myeloma (MM) cell lines (UM6, UM8, UM9, U266, L363, OPM-2), B-cell lymphoma cell lines (OCI-Ly19, U937, U2932, Raji, Namalwa), B-cell acute lymphoblastic leukemia (B-ALL) cell lines (LeidenALL-BV, LeidenALL-RL, LeidenALL-VG, LeidenALL-BL), T-cell acute lymphoblastic leukemia (T-ALL) cell lines (LOUCY, ALL-SIL), chronic myelogenous leukemia (CML) cell line (LAMA-84) and chronic lymphocytic leukemia (CLL) cell lines (BV-173, EHEB). TCR-T cells were tested against malignant cell lines of different hematopoietic origins that were positive for the MiHA-encoding SNP and relevant HLA class I restriction allele. In addition, various cell lines were included that were positive for the MiHA- encoding SNP, but negative for the relevant HLA restriction allele. These cell lines were retrovirally transduced with the relevant HLA as indicated by +A2, +B7, +B15, +C3 after transduction with HLA-A*02:01 , B*07:02, B*15:01 , C*03:03, respectively. Release of IFN-y was measured by ELISA in co-culture supernatants after overnight incubation. TCR-T cells for LB- MYO1G-2M were reactive against lymphoid and myeloid cell lines including T-ALL, B-ALL, B-cell lymphoma, MM, and AML cell lines, TCR-T cells for LB-LILRB4-1G and TCR-T cells for LB- IL10RA-1 R against MM and AML cell lines, TCR-T cells for LB-ITGB2-1 against B-ALL, MM, and AML cell lines, TCR-T cells for LB-LTA-1 R against B-cell lymphoma and CML cell lines, TCR-T cells for LB-SLAMF1-1 F against CLL, B-cell lymphoma and MM cell lines, and TCR-T cells for LB-TXNDC11-1 P against MM cell lines.

[0132] Figure 13 shows TCR-T cell reactivity against hematopoietic MiHAs on patient-derived AML cases. TCR-T cells for LB-MYO1G-2M / 3M (dark grey), LB-ITGB2-1 (light grey), and control TCR-T cells for CMVpp65 (white bars) produced from CD8 T cells of donor 6904 were coincubated with four patient AML cases (AML 7503, AML 2250, AML 9559, AML 2467) each containing >80% malignant blasts. All four AML are positive for HLA-C*03:03 or HLA-C*03:04 and HLA-A*02:01. Three AML are positive for LB-MYO1G-2M (AML 7503, AML 2250, AML 9559), and one AML is negative for LB-MYO1G-2M (AML 2467). Only AML 7503 is positive for LB- ITGB2-1 and HLA-B*15:01. (A) Release of IFN-y was measured by ELISA in culture supernatants after overnight co-incubation. TCR-T cells for LB-MYO1G-2M and TCR-T cells for LB-ITGB2-1 were able to specifically recognize patient-derived AML cells. (B) Numbers of viable AML cells after 48 hrs of co-incubation with TCR-T cells were measured by quantitative flow cytometry. TCR-T cells for LB-MYO1G-2M and TCR-T cells for LB-ITGB2-1 were able to specifically kill patient-derived AML cells.

[0133] The patent, scientific and technical literature referred to herein establish knowledge that was available to those skilled in the art at the time of filing. The entire disclosures of the issued patents, published and pending patent applications, and other publications that are cited herein are hereby incorporated by reference to the same extent as if each was specifically and individually indicated to be incorporated by reference. In the case of any inconsistencies, the present disclosure will prevail.

[0134] Various aspects of the invention are described in further detail below.

[0135] Detailed Description

[0136] Nucleic acid compositions that encode binding protein components

[0137] An isolated nucleic acid composition that encodes a haematopoietic-restricted minor histocompatibility antigen (MiHA)-specific binding protein is provided herein, the binding protein having a TCR a chain variable (Va) domain and a TCR p chain variable (VP) domain, the composition comprising:

[0138] (a) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence; and

[0139] (b) a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence; wherein the CDR3 amino acid sequences of (a) and (b) together bind (e.g. specifically bind) to an MiHA that comprises an amino acid sequence selected from the group consisting of: VSMNPYQEL (SEQ ID NO:71), GPRPSPTRSV (SEQ ID NO: 72), GPRWPPRMTH (SEQ ID NO: 73), GPRWPPRMT (SEQ ID NO: 153) and GQAGFFPSPF (SEQ ID NO: 74).

[0140] As would be clear to a person of skill in the art, the CDR3 amino acid sequences described herein bind to their target (in this case a haematopoietic-restricted MiHA peptide), when the target (i.e. the appropriate haematopoietic-restricted MiHA peptide) is presented in the context of HLA. The binding proteins (and CDR3 sequences specifically described herein) are therefore capable of binding to a haematopoietic-restricted MiHA peptide:HLA complex. These complexes are described in more detail elsewhere herein.

[0141] Any of the permutations described below for (a) may be combined with the permutations described below for (b) (e.g. to form an appropriate nucleic acid composition that encodes a haematopoietic-restricted MiHA-specific binding protein having a TCR a chain variable (Va) domain and a TCR p chain variable (VP) domain).

[0142] The invention provides an isolated nucleic acid composition that encodes a binding protein comprising T cell receptor (TCR) components that specifically bind a haematopoietic-restricted MiHA. The encoded binding protein is therefore capable of specifically binding to a peptide containing a haematopoietic-restricted MiHA (e.g. a haematopoietic-restricted MiHA comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 71 to 74 and SEQ ID NO: 153) and does not bind to a peptide that does not contain a haematopoietic-restricted MiHA (e.g. it does not bind to a peptide that does not contain haematopoietic-restricted MiHA comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 71 to 74 and SEQ ID NO:153).

[0143] The nucleic acid composition comprises (a) a nucleic acid sequence that encodes a TCR Va domain with the specified features described herein and (b) a nucleic acid sequence that encodes a TCR Vp domain with the specified features described herein. The encoded TCR components form a haematopoietic- restricted MiHA-specific binding protein.

[0144] The nucleic acid sequences of (a) and (b) above may be distinct nucleic acid sequences within the nucleic acid composition. The TCR components of the binding protein may therefore be encoded by two (or more) nucleic acid sequences (with distinct nucleotide sequences) which, together, encode all of the TCR components of the binding protein. In other words, some of the TCR components may be encoded by one nucleic acid sequence in the nucleic acid composition, and others may be encoded by another (distinct) nucleic acid sequence within the nucleic acid composition.

[0145] Alternatively, the nucleic acid sequences of (a) and (b) may be part of a single nucleic acid sequence. The TCR components of the binding protein may therefore all be encoded by a single nucleic acid sequence (for example with a single open reading frame, or with multiple (e.g. 2 or more, three or more etc.) open reading frames).

[0146] Nucleic acid sequences described herein may form part of a larger nucleic acid sequence that encodes a larger component part of a functioning binding protein. For example, a nucleic acid sequence that encodes a TCR Va domain with the specified features described herein may be part of a larger nucleic acid sequence that encodes a functional TCR a chain (including the constant domain). As another example, a nucleic acid sequence that encodes a TCR Vp domain with the specified features described herein may be part of a larger nucleic acid sequence that encodes a functional TCR chain (including the constant domain). As a further example, both nucleic acid sequences (a) and (b) above may be part of a larger nucleic acid sequence that encodes a combination of a functional TCR a chain (including the constant domain) and a functional TCR p chain (including the constant domain), optionally wherein the sequence encoding the functional TCR a chain is separated from the sequence encoding the functional TCR P chain by a linker sequence that enables coordinate expression of two proteins or polypeptides in the same nucleic acid sequence. More details on this are provided below.

[0147] The nucleic acid sequences described herein may alternatively encode a small component of a T cell receptor e.g. a TCR Va domain, or a TCR Vp domain, only. The nucleic acid sequences may be considered as “building blocks” that provide essential components for peptide binding specificity. The nucleic acid sequences described herein may be incorporated into a distinct nucleic acid sequence (e.g. a vector) that encodes the other elements of a functional binding protein such as a TCR, such that when the nucleic acid sequence described herein is incorporated, a new nucleic acid sequence is generated that encodes e.g. a TCR a chain and / or a TCR p chain that specifically binds to a haematopoietic-restricted MiHA (e.g. wherein the haematopoietic-restricted MiHA comprises an amino acid sequence selected from the group consisting of: SEQ ID NO: 71 , SEQ ID NO: 72, SEQ ID NO:73, SEQ ID NO:74 and SEQ ID NO: 153). The nucleic acid sequences described herein therefore have utility as essential components that confer binding specificity for a haematopoietic-restricted MiHA, and thus can be used to generate a larger nucleic acid sequence encoding a binding protein with the required antigen binding activity and specificity.

[0148] The nucleic acid sequences described herein may be codon optimised for expression in a host cell, for example they may be codon optimised for expression in a human cell, such as a cell of the immune system, a inducible pluripotent stem cell (iPSC), a haematopoietic stem cell, a T cell, a primary T cell, a T cell line, a NK cell, or a natural killer T cell (Scholten et al, Clin. Immunol. 119: 135, 2006). The T cell can be a CD4+ or a CD8+ T cell. Codon optimisation is a well-known method in the art for maximizing expression of a nucleic acid sequence in a particular host cell. For instance, one or more cysteine residues may also be introduced into the encoded TCR alpha and beta chain components (e.g. to reduce the risk of mispairing with endogenous TCR chains).

[0149] In one example, the nucleic acid sequences described herein are codon optimised for expression in a suitable host cell, and / or are modified to introduce codons encoding one or more cysteine amino acids (e.g. into the constant domain of the encoded TCR alpha chain and / or the encoded TCR beta chain) to reduce the risk of mispairing with endogenous TCR chains. In one example, the nucleic acid sequences described herein are codon optimised for expression in a suitable host cell, optionally wherein the host cell is a human cell.

[0150] In certain examples, a TCR constant domain is modified to enhance pairing of desired TCR chains. For example, enhanced pairing between a heterologous TCR a chain and a heterologous TCR p chain due to a modification may result in the preferential assembly of a TCR comprising two heterologous chains over an undesired mispairing of a heterologous TCR chain with an endogenous TCR chain (see, e.g., Covers et al, Trends Mol. Med. 16(2):11 (2010)). Exemplary modifications to enhance pairing of heterologous TCR chains include the introduction of complementary cysteine residues in each of the heterologous TCR a chain and p chain.

[0151] A binding protein that is encoded by the nucleic acid compositions described herein is specific for a haematopoietic-restricted MiHA and comprises haematopoietic-restricted MiHA specific-TCR components. However, the encoded binding protein is not limited to being a TCR. Other appropriate binding proteins that comprise the specified haematopoietic-restricted MiHA specific -TCR components are also encompassed. For example, the encoded binding protein may comprise a TCR, an antigen binding fragment of a TCR, a chimeric antigen receptor (CAR), or an immTAC. TCRs, antigen binding fragments thereof, CARs and ImmTACs are well defined in the art. A non-limiting example of an antigen binding fragment of a TCR is a single chain TCR (scTCR) or a chimeric dimer composed of the antigen binding fragments of the TCR a and TCR chain linked to transmembrane and intracellular domains of a dimeric complex so that the complex is a chimeric dimer TCR (cdTCR). An ImmTAC comprises a TCR connected to an anti-CD3 antibody. ImmTACs are therefore bispecific, combining haematopoietic-restricted MiHA-recognizing TCR components with immune activating complexes.

[0152] In certain examples, an antigen-binding fragment of a TCR comprises a single chain TCR (scTCR), which comprises both the TCR Va and TCR Vp domains, but only a single TCR constant domain. In other examples, an antigen-binding fragment of a TCR comprises a chimeric TCR dimer in which the antigen binding fragment of the TCR is linked to an alternative transmembrane and intracellular signalling domain (where the alternative transmembrane and intracellular signalling domain are not naturally found in TCRs). In further examples, an antigen-binding fragment of a TCR or a chimeric antigen receptor is chimeric (e.g., comprises amino acid residues or motifs from more than one donor or species), humanized (e.g., comprises residues from a nonhuman organism that are altered or substituted so as to reduce the risk of immunogenicity in a human), or human.

[0153] "Chimeric antigen receptor" (CAR) refers to a fusion protein that is engineered to contain two or more amino acid sequences (which may or may not individually be naturally occurring amino acid sequences) linked together in a way that does not occur naturally or does not occur naturally in a host cell, which fusion protein can function as a receptor when present on a surface of a cell. CARs described herein include an extracellular portion comprising an antigen binding domain (i.e. , obtained or derived from an immunoglobulin or immunoglobulin-like molecule, such as an scFv derived from an antibody or TCR specific for an antigen (e.g. a cancer antigen etc), or an antigen binding domain derived or obtained from a killer immunoreceptor from an NK cell) linked to a transmembrane domain and one or more intracellular signalling domains (optionally containing co-stimulatory domain(s)) (see, e.g., Sadelain et al, Cancer Discov., 3(4):388 (2013); see also Harris and Kranz, Trends Pharmacol. Sci., 37(3):220 (2016), and Stone et al, Cancer Immunol. Immunother., 63(11): 1163 (2014)). Methods for producing engineered TCRs are described in, for example, Bowerman et al, Mol. Immunol, 5(15):3000 (2009). Methods for making CARs are well known in the art and are described, for example, in U.S. Patent No. 6,410,319; U.S. Patent No. 7,446,191 ; U.S. Patent Publication No. 2010 / 065818; U.S. Patent No. 8,822,647; PCT Publication No. WO 2014 / 031687; U.S. Patent No. 7,514,537; and Brentjens et al, 2007, Clin. Cancer Res. 73:5426.

[0154] The binding proteins described herein may also be expressed as part of a transgene construct that encodes additional accessory proteins, such as a safety switch protein, a tag, a selection marker, a CD8 co-receptor p-chain, a-chain or both, or any combination thereof.

[0155] A T cell receptor (TCR) is a molecule found on the surface of T cells (T lymphocytes) that is responsible for recognising a peptide that is bound to (presented by) a major histocompatibility complex (MHC) molecule on a target cell. The invention is directed to nucleic acid compositions that encode binding proteins comprising TCR components that interact with a particular peptide in the context of the appropriate subtype of MHC, i.e. a haematopoietic-restricted MiHA in the context of HI_A-C*03:03, HLA-C*03:04, HI_A-B*07:02, and / or HI_A-B*15:01 (in other words, the encoded binding protein is capable of specifically binding to a haematopoietic-restricted MiHA:specific HI_A complex). In an example, the invention is directed to nucleic acid compositions that encode binding proteins comprising TCR components that interact with a particular peptide in the context of the appropriate subtype of MHC, i.e. VSMNPYQEL (SEQ ID NO: 71) in the context of HLA-C*03:03; VSMNPYQEL (SEQ ID NO: 71) in the context of HLA-C*03:04; GPRPSPTRSV (SEQ ID NO: 72) in the context of HLA-B*07:02; GPRWPPRMTH (SEQ ID NO: 73) in the context of HLA-B*07:02; GPRWPPRMT (SEQ ID NO: 153) in the context of HLA- B*07:02; or GQAGFFPSPF (SEQ ID NO: 74) in the context HLA-B*15:01.

[0156] HLA-C*03:03 is a globally common human leukocyte antigen subtype within the HLA-C group. Peptides that are presented by HLA-C*03:03 to TCRs are described as being “HLA-C*03:03 restricted”.

[0157] HLA-C*03:04, HLA-B*07:02, and HLA-B*15:01 are also common human leukocyte antigen subtypes within the HLA-C and HLA-B groups. Peptides that are presented by HLA-C*03:04 to TCRs are described as being “HLA-C*03:04 restricted”. Similarly, peptides that are presented by HLA-B*07:02 to TCRs are described as being “HLA-B*07:02 restricted”. Similarly, peptides that are presented by HLA-B*15:01 to TCRs are described as being “HLA-B*15:01 restricted”.

[0158] HLA-C*03:03 and HLA-C*03:04 can both be referred to herein as HLA-C3. Similarly, HLA- B*07:02 is also referred to herein as HLA-B7; and HLA-B*15:01 is also referred to herein as HLA- B15.

[0159] As described herein, the inventors have identified several haematopoietic-restricted MiHA derived peptides presented on haematopoietic cells in HLA-C*03:03 and / or HLA-C*03:04 (HLA-C3), HLA- B*07:02 (HLA-B7), and HLA-B*15:01 (HLA-B15). Specifically, the inventors identified the haematopoietic-restricted MiHA derived peptides VSMNPYQEL (SEQ ID NO:71), GPRPSPTRSV (SEQ ID NO: 72), GPRWPPRMTH (SEQ ID NO: 73), GQAGFFPSPF (SEQ ID NO: 74) and GPRWPPRMT (SEQ ID NO: 153).

[0160] Accordingly, the haematopoietic-restricted MiHA bound (e.g. specifically bound) by a binding protein described herein may comprise an amino acid sequence selected from the group consisting of: VSMNPYQEL (SEQ ID NO:71), GPRPSPTRSV (SEQ ID NO: 72), GPRWPPRMTH (SEQ ID NO: 73), GPRWPPRMT (SEQ ID NO: 153) and GQAGFFPSPF (SEQ ID NO: 74). The antigen may be an antigenic fragment (i.e. a portion) of an amino acid sequence selected from the group consisting of: VSMNPYQEL (SEQ ID NO:71), GPRPSPTRSV (SEQ ID NO: 72), GPRWPPRMTH (SEQ ID NO: 73) GPRWPPRMT (SEQ ID NO: 153) and GQAGFFPSPF (SEQ ID NO: 74), it may consist of an amino acid sequence selected from the group consisting of: VSMNPYQEL (SEQ ID NO:71), GPRPSPTRSV (SEQ ID NO: 72), GPRWPPRMTH (SEQ ID NO: 73), GPRWPPRMT (SEQ ID NO: 153), and GQAGFFPSPF (SEQ ID NO: 74), or it may comprise (i.e. include within a longer sequence) an amino acid sequence selected from the group consisting of: VSMNPYQEL (SEQ ID NO:71), GPRPSPTRSV (SEQ ID NO: 72), GPRWPPRMTH (SEQ ID NO: 73), GPRWPPRMT (SEQ ID NO: 153), and GQAGFFPSPF (SEQ ID NO: 74).

[0161] Accordingly, in an example, the haematopoietic-restricted MiHA comprises an amino acid sequence selected from the group consisting of: VSMNPYQEL (SEQ ID NO:71), GPRPSPTRSV (SEQ ID NO: 72), GPRWPPRMTH (SEQ ID NO: 73), GPRWPPRMT (SEQ ID NO: 153), and GQAGFFPSPF (SEQ ID NO: 74).

[0162] In one example, the haematopoietic-restricted MiHA comprises the amino acid sequence VSMNPYQEL (SEQ ID NO:71). In another example, the haematopoietic-restricted MiHA comprises the amino acid sequence GPRPSPTRSV (SEQ ID NO: 72). In a further example, the haematopoietic-restricted MiHA comprises the amino acid sequence GPRWPPRMTH (SEQ ID NO: 73). In a further example, the haematopoietic-restricted MiHA comprises the amino acid sequence GQAGFFPSPF (SEQ ID NO: 74). In a further example, the haematopoietic-restricted MiHA comprises the amino acid sequence GPRWPPRMT (SEQ ID NO: 153).

[0163] The inventors identified that the haematopoietic-restricted MiHA derived peptide VSMNPYQEL (SEQ ID NO:71) is capable of being presented by HLA-C*03:03 or HLA-C*03:04; that the haematopoietic-restricted MiHA derived peptides GPRPSPTRSV (SEQ ID NO: 72), GPRWPPRMT (SEQ ID NO: 153) and GPRWPPRMTH (SEQ ID NO: 73) are capable of being presented by HLA-B*07:02; and that the haematopoietic-restricted MiHA peptide GQAGFFPSPF (SEQ ID NO: 74) is capable of being presented by HLA-B*15:01.

[0164] Accordingly, in one example, the encoded binding protein is capable of specifically binding to a peptide:HLA complex selected from the group consisting of: a VSMNPYQEL:HLA-C*03:03 complex; a VSMNPYQEL:HLA-C*03:04 complex; a GPRPSPTRSV:HLA-B*07:02 complex; a GPRWPPRMTH:HLA- B*07:02 complex; a GPRWPPRMT:HLA- B*07:02 complex, and a GQAGFFPSPF:B*15:01 complex.

[0165] In a further example, the encoded binding protein is capable of specifically binding to a VSMNPYQEL:HI_A-C*03:03 complex. In another example, the encoded binding protein is capable of specifically binding to a VSMNPYQEL:HI_A-C*03:04 complex. In another example, the encoded binding protein is capable of specifically binding to a GPRPSPTRSV:HLA-B*07:02 complex. In a further example, the encoded binding protein is capable of specifically binding to a GPRWPPRMTH:HI_A- B*07:02 complex. In a further example, the encoded binding protein is capable of specifically binding to a GQAGFFPSPF:B*15:01 complex. In a further example, the encoded binding protein is capable of specifically binding to a GPRWPPRMT:HI_A-B*07:02 complex. In a further example, the encoded binding protein is capable of specifically binding to a GPRWPPRMT:HLA- B*07:02 complex and / or a GPRWPPRMTH:HLA- B*07:02 complex.

[0166] In one example, the haematopoietic-restricted MiHA derived peptide of the peptide:HI_A complex comprises an antigenic fragment of an amino acid sequence selected from the group consisting of: SEQ ID NO: 71 to 74 and SEQ ID NO:153. In a further example, the haematopoietic-restricted MiHA derived peptide of the peptide:HLA complex comprises or consists of an amino acid sequence selected from the group consisting of: SEQ ID NO:71 to 74 and SEQ ID NO: 153.

[0167] The TCR is composed of two different polypeptide chains. In humans, 95% of TCRs consist of an alpha (a) chain and a beta (P) chain (encoded by TRA and TRB respectively). When the TCR engages with peptide in the context of HI_A (e.g. in the context of HLA-C*03:03, HI_A-C*03:04, HI_A-B*07:02, and / or HI_A-B*15:01 , as appropriate), the T cell is activated through signal transduction.

[0168] The alpha and beta chains of the TCR are highly variable in sequence. Each chain is composed of two extracellular domains, a variable domain (V) and a constant domain (C). The constant domain is proximal to the T cell membrane followed by a transmembrane region and a short cytoplasmic tail while the variable domain binds to the peptide / HLA complex.

[0169] An isolated nucleic acid composition that encodes a haematopoietic-restricted MiHA antigenspecific binding protein is provided herein having a TCR a chain variable (Va) domain and a TCR chain variable (VP) domain. In one example the nucleic acid composition described herein may comprise a TCR a chain constant domain and / or a TCR p chain constant domain.

[0170] The variable domain of each chain has three hypervariable regions (also called complementarity determining regions (CDRs)). Accordingly, the TCR alpha variable domain (referred to herein as a TCR Va domain, TCR V alpha domain, Va domain or V alpha domain, alpha variable domain etc) comprises a CDR1 , a CDR2 and CDR3 region. Similarly, the TCR beta variable domain (referred to herein as a TCR Vp domain, TCR V beta domain, Vp domain or V beta domain, beta variable domain etc) also comprises a (different) CDR1 , CDR2, and CDR3 region. In each of the alpha and beta variable domains it is CDR3 that is mainly responsible for recognizing the peptide being presented by the HLA molecules.

[0171] As will be clear to a person of skill in the art, the phrase “TCR a chain variable domain” refers to the variable (V) domain (extracellular domain) of a TCR alpha chain, and thus includes three hypervariable regions (CDR1 , CDR2 and the specified CDR3), as well as the intervening sequences, but does not include the constant (C) domain of the alpha chain, which does not form part of the variable domain.

[0172] As will be clear to a person of skill in the art, the phrase “TCR p chain variable domain” refers to the variable (V) domain (extracellular domain) of a TCR beta chain, and thus includes three hypervariable regions (CDR1 , CDR2 and the specified CDR3), as well as the intervening sequences, but does not include the constant (C) domain of the beta chain, which does not form part of the variable domain.

[0173] Components of the TCR a chain variable (Va) domain

[0174] The isolated nucleic acid composition described herein encodes a haematopoietic-restricted MiHA-specific binding protein. As discussed herein, the inventors have identified several TCRs that bind (e.g. specifically bind) to a haematopoietic-restricted MiHA selected from: VSMNPYQEL (SEQ ID NO:71), GPRPSPTRSV (SEQ ID NO: 72), GPRWPPRMTH (SEQ ID NO: 73), GPRWPPRMT (SEQ ID NO: 153) and GQAGFFPSPF (SEQ ID NO: 74).

[0175] (i) Va domains that interact with VSMNPYQEL (SEQ ID NO: 71)

[0176] As provided elsewhere herein, the inventors identified TCR clone VDL_3.1 F9 which interacts with VSMNPYQEL (SEQ ID NO: 71) in the context of HLA-C*03:03 (or HLA-C*3:04). The sequences provided herein that correspond to TCR clone VDL_3.1 F9 are SEQ ID NO:s 1 to 14.

[0177] As discussed above, an isolated nucleic acid composition that encodes a haematopoietic- restricted MiHA-specific binding protein having a TCR a chain variable (Va) domain and a TCR p chain variable (Vp) domain is provided, the composition comprising: (a) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence; and (b) a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence; wherein the CDR3 amino acid sequences of (a) and (b) together bind (e.g. specifically bind) to an MiHA that comprises the amino acid sequence VSMNPYQEL (SEQ ID NO:71).

[0178] An example of an appropriate TCR Va domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to VSMNPYQEL (SEQ ID NO:71) is shown in SEQ ID NO:3. As would be clear to a person of skill in the art, variants of the amino acid sequence shown in SEQ ID NO:3 may also be functional (i.e. retain their ability to confer (specific) binding to the peptide VSMNPYQEL (SEQ ID NO:71)) when the CDR3 is part of TCR Va domain). Such functional variants are therefore encompassed herein.

[0179] For example, appropriate (functional) Va domain CDR3 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 3, i.e. they may have at least 80%, at least 94%, or 100% sequence identity to SEQ ID NO: 3. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO:3). In other words, appropriate (functional) Va domain CDR3 amino acid sequences may vary from the sequence shown in SEQ ID NO:3 by one or several (e.g. two etc) amino acids.

[0180] As stated above, functional variants of SEQ ID NO:3 retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO:71 when the CDR3 is part of TCR Va domain.

[0181] Functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO:3. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one, two or more amino acids of SEQ ID NO:3, or substitution, deletion or insertion of non-critical amino acids in non- critical regions of the CDR3.

[0182] Non-functional variants are amino acid sequence variants of SEQ ID NO: 3 that do not bind to the peptide shown in SEQ ID NO:71. Non-functional variants will typically contain a non-conservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO:3 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0183] In one example, the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 3. In examples where the TCR Va domain CDR3 has the amino acid sequence of SEQ ID NO:3, the CDR3 may be encoded by any appropriate nucleic acid sequence.

[0184] The encoded TCR Va domain may comprise, in addition to the specified CDR3, a CDR1 comprising an amino acid sequence of SEQ ID NO: 1 , or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO:71). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO:1. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO:1 , or substitution, deletion or insertion of non-critical amino acids in non- critical regions of the protein.

[0185] Non-functional variants are amino acid sequence variants of SEQ ID NO: 1 that do not bind to the peptide shown in SEQ ID NO:71. Non-functional variants will typically contain a non-conservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO:1 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0186] For example, appropriate functional Va domain CDR1 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 1 , i.e. it may have at least 80%, or 100% sequence identity to SEQ ID NO: 1. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO:1). In other words, appropriate functional Va domain CDR1 amino acid sequences may vary from the sequence shown in SEQ ID NO: 1 by one or several amino acids. As stated previously, the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO:1. As stated above, functional variants of SEQ ID NO: 1 retain the ability to (specifically) bind to the peptide shown in SEQ ID NO:71 when the CDR1 is part of TCR Va domain.

[0187] In one example, the CDR1 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO:1. In examples where the TCR Va domain CDR1 has the amino acid sequence of SEQ ID NO:1 , the CDR1 may be encoded by any appropriate nucleic acid sequence.

[0188] The encoded TCR Va domain may also comprise, in addition to the specified CDR3 (and optionally the specified CDR1 above), a CDR2 comprising an amino acid sequence of SEQ ID NO:2, or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HI_A-C*03:03 and / or HLA-C*03:04). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO:2. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO:2, or substitution, deletion or insertion of non-critical amino acids in non-critical regions of the protein.

[0189] Non-functional variants are amino acid sequence variants of SEQ ID NO: 2 that do not specifically bind to HI_A-C*03:03 and / or HI_A-C*03:04. Non-functional variants will typically contain a nonconservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 2 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0190] For example, appropriate functional Va domain CDR2 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 2, i.e. it may have at least 80%, at least 85%, or 100% sequence identity to SEQ ID NO: 2. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO:2). In other words, appropriate (functional) Va domain CDR2 amino acid sequences may vary from the sequence shown in SEQ ID NO:2 by one or several amino acids. As stated previously, the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO:2. As stated above, a functional variant of SEQ ID NO: 2 retains the ability to specifically bind to HLA-C*03:03 and / or HI_A-C*03:04.

[0191] In one example, the CDR2 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 2. In examples where the TCR Va domain CDR2 has the amino acid sequence of SEQ ID NO:2, the CDR2 may be encoded by any appropriate nucleic acid sequence.

[0192] The encoded TCR Va domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NO:3, SEQ ID NO: 1 and SEQ ID NO: 2, or functional variants thereof), with appropriate intervening sequences between the CDRs.

[0193] The encoded TCR Va domain may comprise an amino acid sequence of SEQ ID NO:7, or a functional variant thereof (i.e. wherein the variant TCR Va domain retains the ability to (specifically) bind to the peptide shown in SEQ ID NO:71 when part of a binding protein described herein). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO:7. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO:7, or substitution, deletion or insertion of non-critical amino acids in non-critical regions of the protein.

[0194] Non-functional variants are amino acid sequence variants of SEQ ID NO: 7 that do not bind to the peptide shown in SEQ ID NO:71. Non-functional variants will typically contain a non-conservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO:7 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0195] In one example, the encoded TCR Va domain may have an amino acid sequence having at least 75%, at least 80%, at least 85% or at least 90% (or at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) sequence identity to the amino acid sequence of SEQ ID NO: 7, whilst retaining the ability to (specifically) bind to the peptide shown in SEQ ID NO:71. In other words, a functional TCR Va domain with one or several amino acid substitutions compared to the sequence of SEQ ID NO:7 is also encompassed. As stated previously, the amino acid substitution may be a conservative amino acid substitution. The variability in sequence compared to SEQ ID NO:7 may all be in regions of the TCR Va domain that do not form CDRs (i.e. the variant may have the CDRs of SEQ ID NO: 3, SEQ ID NO: 1 and / or SEQ ID NO: 2, and still have 25% (or less) sequence variability compared to SEQ ID NO:7). In other words, the sequence of the CDRs of SEQ ID NO: 7 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above. Suitably, percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 7).

[0196] As an example, the encoded TOR Va domain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 7, wherein the TOR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 3. In this example, the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 1 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 2.

[0197] As another example, the encoded TCR Va domain may comprise an amino acid sequence with 0 to 10 (or 0 to 5) amino acid substitutions, insertions or deletions compared to SEQ ID NO:7, wherein the TCR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 3. In this example, the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 1 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 2.

[0198] In examples where the TCR Va domain has the amino acid sequence of SEQ ID NO:7, the TCR Va domain may be encoded by the nucleic acid sequence of SEQ ID NO:8, or a genetically degenerate sequence thereof (i.e. other nucleic acid sequences that encode the same protein as a result of the degeneracy of the genetic code).

[0199] The phrase “genetically degenerate sequence thereof” is used interchangeably with “derivative thereof” herein.

[0200] For the avoidance of doubt, the nucleic acid sequence encoding the TCR Va domain may also encode a TCR a chain constant domain. An example of a suitable constant domain (for either a TCR a chain or a TCR p chain) is encoded in the MP71-TCR-flex retroviral vector. However, the invention is not limited to this specific constant domain, and encompasses any appropriate TCR a chain constant domain. The constant domain may be murine derived, human derived or humanised. Methods for identifying or generating appropriate constant domains are well known to a person of skill in the art and are well within their routine capabilities.

[0201] By way of example only, the constant domain may be encoded by or derived from a vector, such as a lentiviral, retroviral or plasmid vector but also adenovirus, adeno-associated virus, vaccinia virus, canary poxvirus or herpes virus vectors in which murine or human constant domains are pre-cloned. Recently, minicircles have also been described for TCR gene transfer (non-viral Sleeping Beauty transposition from minicircle vectors as published by R Monjezi, et al., 2017). Moreover, naked (synthetic) DNA / RNA can also be used to introduce the TCR. As an example, a pMSGV retroviral vector with pre-cloned TCR-Ca and Cp genes as described in LV Coren et al., BioTechniques 2015 may be used to provide an appropriate constant domain. Alternatively, single stranded or double stranded DNA or RNA can be inserted by homologous directed repair into the TCR locus (see Roth et al 2018 Nature vol 559; page 405). As a further option, non - homologous end joining is possible.

[0202] An example of a specific TCR a chain amino acid sequence that includes a TCR Va domain described herein with an appropriate constant domain is shown in SEQ ID NO: 11. Appropriate functional variants of SEQ ID NO:11 are also encompassed (e.g. variants having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 11 , wherein the variant TCR a chain amino acid sequence retains its ability to (specifically) bind to the peptide shown in SEQ ID NO:71 when part of a binding protein described herein). In other words, a functional TCR a chain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 11 is also encompassed. As stated previously, the amino acid substitution may be a conservative amino acid substitution. The variability in sequence compared to SEQ ID NO: 11 may all be in regions of the TCR a chain that do not form CDRs (i.e. the variant may have the CDRs of SEQ ID NO: 3, SEQ ID NO: 1 and / or SEQ ID NO: 2, and still have 25% (or less) sequence variability compared to SEQ ID NO:11). In other words, the sequence of the CDRs of SEQ ID NO: 11 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above. Suitably, percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 11).

[0203] As an example, the encoded TCR a chain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 11 , wherein the TCR a chain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 3. In this example, the TCR a chain CDR1 may have an amino acid sequence of SEQ ID NO:1 and the TCR a chain CDR2 may have an amino acid sequence of SEQ ID NO: 2.

[0204] In examples where the TCR a chain has the amino acid sequence of SEQ ID NO:11 , the TCR a chain may be encoded by the nucleic acid sequence of SEQ ID NO: 12, or a genetically degenerate sequence thereof (i.e. other nucleic acid sequences that encode the same protein as a result of the degeneracy of the genetic code). It is noted that SEQ ID NO: 12 is the nucleic acid sequence for TCR a chain of clone VDL_3.1 F9.

[0205] In one example, the nucleic acid composition provided herein comprises a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO:3, or a functional fragment thereof.

[0206] In another example, the CDR3 of the Va domain of a nucleic acid composition provided herein comprises or consists of the amino acid sequence of SEQ ID NO: 3. In another example, the Va domain of a nucleic acid composition provided herein comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 7.

[0207] (ii) Va domains that interact with GPRPSPTRSV (SEQ ID NO:72)

[0208] As provided elsewhere herein, the inventors have also identified TOR clone VDL_T1 which interacts with GPRPSPTRSV (SEQ ID NO:72) in the context of HLA-B*07:02. The sequences provided herein that correspond to TCR clone VDL_T1 are SEQ ID NO:s 15 to 28.

[0209] As discussed above, an isolated nucleic acid composition that encodes a haematopoietic- restricted MiHA-specific binding protein having a TCR a chain variable (Va) domain and a TCR p chain variable (VP) domain is provided, the composition comprising: (a) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence; and (b) a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence; wherein the CDR3 amino acid sequences of (a) and (b) together bind (e.g. specifically) bind to an MiHA that comprises the amino acid sequence GPRPSPTRSV (SEQ ID NO:72).

[0210] Accordingly, an example of an appropriate TCR Va domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to GPRPSPTRSV (SEQ ID NO:72) is shown in SEQ ID NO: 17. As would be clear to a person of skill in the art, variants of the amino acid sequence shown in SEQ ID NO: 17 may also be functional (i.e. retain their ability to confer (specific) binding to the peptide GPRPSPTRSV (SEQ ID NO:72)) when the CDR3 is part of TCR Va domain). Such functional variants are therefore encompassed herein.

[0211] For example, appropriate (functional) Va domain CDR3 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 17, i.e. they may have at least 80%, at least 92%, or 100% sequence identity to SEQ ID NO: 17. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO:17). In other words, appropriate (functional) Va domain CDR3 amino acid sequences may vary from the sequence shown in SEQ ID NO: 17 by one or several (e.g. two etc) amino acids.

[0212] As stated above, functional variants of SEQ I D NO: 17 retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO:72 when the CDR3 is part of TCR Va domain.

[0213] Functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 17. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one, two or more amino acids of SEQ ID NO: 17, or substitution, deletion or insertion of non-critical amino acids in non- critical regions of the CDR3. Non-functional variants are amino acid sequence variants of SEQ ID NO: 17 that do not bind to the peptide shown in SEQ ID NO:72. Non-functional variants will typically contain a nonconservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 17 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0214] In one example, the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 17. In examples where the TCR Va domain CDR3 has the amino acid sequence of SEQ ID NO: 17, the CDR3 may be encoded by any appropriate nucleic acid sequence.

[0215] The encoded TCR Va domain may comprise, in addition to the specified CDR3, a CDR1 comprising an amino acid sequence of SEQ ID NO: 15, or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO:72. Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 15. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 15, or substitution, deletion or insertion of non-critical amino acids in non- critical regions of the protein.

[0216] Non-functional variants are amino acid sequence variants of SEQ ID NO: 15 that do not bind to the peptide shown in SEQ ID NO:72. Non-functional variants will typically contain a nonconservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 15 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0217] For example, appropriate functional Va domain CDR1 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 15, i.e. it may have at least 80%, at least 85%, or 100% sequence identity to SEQ ID NO: 15. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO:15). In other words, appropriate functional Va domain CDR1 amino acid sequences may vary from the sequence shown in SEQ ID NO: 15 by one or several amino acids. As stated previously, the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO: 15. As stated above, functional variants of SEQ ID NO: 15 retain the ability to (specifically) bind to the peptide shown in SEQ ID NO:72 when the CDR1 is part of TCR Va domain).

[0218] In one example, the CDR1 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO:15. In examples where the TCR Va domain CDR1 has the amino acid sequence of SEQ ID NO: 15, the CDR1 may be encoded by any appropriate nucleic acid sequence. The encoded TCR Va domain may also comprise, in addition to the specified CDR3 (and optionally the specified CDR1 above), a CDR2 comprising an amino acid sequence of SEQ ID NO: 16, or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HLA-B*07:02). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 16. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 16, or substitution, deletion or insertion of non-critical amino acids in non-critical regions of the protein.

[0219] Non-functional variants are amino acid sequence variants of SEQ ID NO: 16 that do not specifically bind to HLA-A*01 :01. Non-functional variants will typically contain a non-conservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO:16 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0220] For example, appropriate functional Va domain CDR2 amino acid sequences may have at least 80% sequence identity to SEQ ID NO:16, i.e. it may have at least 80%, or 100% sequence identity to SEQ ID NO: 16. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO:16). In other words, appropriate (functional) Va domain CDR2 amino acid sequences may vary from the sequence shown in SEQ ID NO: 16 by one or several amino acids. As stated previously, the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO:16). As stated above, a functional variant of SEQ ID NO:16 retains the ability to specifically bind to HLA-B*07:02.

[0221] In one example, the CDR2 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 16. In examples where the TCR Va domain CDR2 has the amino acid sequence of SEQ ID NO: 16, the CDR2 may be encoded by any appropriate nucleic acid sequence.

[0222] The encoded TCR Va domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NO: 17, SEQ ID NO: 15 and SEQ ID NO: 16, or functional variants thereof), with appropriate intervening sequences between the CDRs.

[0223] The encoded TCR Va domain may comprise an amino acid sequence of SEQ ID NO:21 , or a functional variant thereof (i.e. wherein the variant TCR Va domain retains the ability to (specifically) bind to the peptide shown in SEQ ID NO:72 when part of a binding protein described herein). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO:21. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO:21 , or substitution, deletion or insertion of non-critical amino acids in non-critical regions of the protein.

[0224] Non-functional variants are amino acid sequence variants of SEQ ID NO:21 that do not bind to the peptide shown in SEQ ID NO:72. Non-functional variants will typically contain a nonconservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO:21 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0225] In one example, the encoded TCR Va domain may have an amino acid sequence having at least 75%, at least 80%, at least 85% or at least 90% (or at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) sequence identity to the amino acid sequence of SEQ ID NO:21 , whilst retaining the ability to (specifically) bind to the peptide shown in SEQ ID NO:72. In other words, a functional TCR Va domain with one or several amino acid substitutions compared to the sequence of SEQ ID NO:21 is also encompassed. As stated previously, the amino acid substitution may be a conservative amino acid substitution. The variability in sequence compared to SEQ ID NO:21 may all be in regions of the TCR Va domain that do not form CDRs (i.e. the variant may have the CDRs of SEQ ID NO: 17, SEQ ID NO:15 and / or SEQ ID NO:16, and still have 25% (or less) sequence variability compared to SEQ ID NO:21). In other words, the sequence of the CDRs of SEQ ID NO: 21 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above. Suitably, percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 21).

[0226] As an example, the encoded TCR Va domain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 21 , wherein the TCR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 17. In this example, the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 15 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 16.

[0227] As another example, the encoded TCR Va domain may comprise an amino acid sequence with 0 to 10 (or 0 to 5) amino acid substitutions, insertions or deletions compared to SEQ ID NO:21 , wherein the TCR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 17. In this example, the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 15 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 16.

[0228] In examples where the TCR Va domain has the amino acid sequence of SEQ ID NO:21 , the TCR Va domain may be encoded by the nucleic acid sequence of SEQ ID NO: 22, or a genetically degenerate sequence thereof (i.e. other nucleic acid sequences that encode the same protein as a result of the degeneracy of the genetic code).

[0229] For the avoidance of doubt, the nucleic acid sequence encoding the TCR Va domain may also encode a TCR a chain constant domain. Examples of suitable constant domains are generally discussed above.

[0230] An example of a specific TCR a chain amino acid sequence that includes a TCR Va domain described herein with an appropriate constant domain is shown in SEQ ID NO: 25. Appropriate functional variants of SEQ ID NO: 25 are also encompassed (e.g. variants having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 25, wherein the variant TCR a chain amino acid sequence retains its ability to (specifically) bind to the peptide shown in SEQ ID NO:72 when part of a binding protein described herein). In other words, a functional TCR a chain with one or several amino acid substitutions compared to the sequence of SEQ ID NO:25 is also encompassed. As stated previously, the amino acid substitution may be a conservative amino acid substitution. The variability in sequence compared to SEQ ID NO:25 may all be in regions of the TCR a chain that do not form CDRs (i.e. the variant may have the CDRs of SEQ ID NO: 17, SEQ ID NO: 15 and / or SEQ ID NO: 16, and still have 25% (or less) sequence variability compared to SEQ ID NO:25). In other words, the sequence of the CDRs of SEQ ID NO: 25 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above. Suitably, percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 25).

[0231] As an example, the encoded TCR a chain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 25, wherein the TCR a chain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 17. In this example, the TCR a chain CDR1 may have an amino acid sequence of SEQ ID NO: 15 and the TCR a chain CDR2 may have an amino acid sequence of SEQ ID NO: 16.

[0232] In examples where the TCR a chain has the amino acid sequence of SEQ ID NO:25, the TCR a chain may be encoded by the nucleic acid sequence of SEQ ID NO:26, or a genetically degenerate sequence thereof (i.e. other nucleic acid sequences that encode the same protein as a result of the degeneracy of the genetic code). It is noted that SEQ ID NO:26 is the nucleic acid sequence for TCR a chain of clone VDL_T 1.

[0233] In one example, the nucleic acid composition provided herein comprises a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 17, or a functional fragment thereof. In another example, the CDR3 of the Va domain of a nucleic acid composition provided herein comprises or consists of the amino acid sequence of SEQ ID NO: 17.

[0234] In another example, the Va domain of a nucleic acid composition provided herein comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 21.

[0235] (iii) Va domains that interact with GPRWPPRMTH (SEQ ID NO:73) and / or GPRWPPRMT (SEQ ID NO:153)

[0236] As discussed above, an isolated nucleic acid composition that encodes a haematopoietic- restricted MiHA-specific binding protein having a TCR a chain variable (Va) domain and a TCR p chain variable (VP) domain is provided, the composition comprising: (a) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence; and (b) a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence; wherein the CDR3 amino acid sequences of (a) and (b) together bind (e.g. specifically bind) to an MiHA that comprises the amino acid sequence GPRWPPRMT (SEQ ID NO:153).

[0237] As provided elsewhere herein, the inventors identified TCR clone AJV_1.32 which interacts with GPRWPPRMT (SEQ ID NO:153) in the context of HI_A-B*07:02. The sequences provided herein that correspond to TCR clone AJV_1 .32 are SEQ ID NO:s 29 to 42.

[0238] An example of an appropriate TCR Va domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to GPRWPPRMT (SEQ ID NO:153) is shown in SEQ ID NO:31. As would be clear to a person of skill in the art, variants of the amino acid sequence shown in SEQ ID NO:31 may also be functional (i.e. retain their ability to confer (specific) binding to the peptide GPRWPPRMT (SEQ ID NO: 153)) when the CDR3 is part of TCR Va domain). Such functional variants are therefore encompassed herein.

[0239] For example, appropriate (functional) Va domain CDR3 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 31 , i.e. they may have at least 80%, at least 92%, or 100% sequence identity to SEQ ID NO: 31. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO:31). In other words, appropriate (functional) Va domain CDR3 amino acid sequences may vary from the sequence shown in SEQ ID NO:31 by one or several (e.g. two etc) amino acids.

[0240] As stated above, functional variants of SEQ ID NO: 31 retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO: 153) when the CDR3 is part of TCR Va domain.

[0241] Functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 31. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one, two or more amino acids of SEQ ID NO: 31 , or substitution, deletion or insertion of non-critical amino acids in non- critical regions of the CDR3.

[0242] Non-functional variants are amino acid sequence variants of SEQ ID NO: 31 that do not bind to the peptide shown in SEQ ID NO: 153. Non-functional variants will typically contain a nonconservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 31 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0243] In one example, the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 31. In examples where the TCR Va domain CDR3 has the amino acid sequence of SEQ ID NO: 31 , the CDR3 may be encoded by any appropriate nucleic acid sequence.

[0244] The encoded TCR Va domain may comprise, in addition to the specified CDR3, a CDR1 comprising an amino acid sequence of SEQ ID NO: 29, or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 153). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 29. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 29, or substitution, deletion or insertion of non-critical amino acids in non- critical regions of the protein.

[0245] Non-functional variants are amino acid sequence variants of SEQ ID NO: 29 that do not bind to the peptide shown in SEQ ID NO: 153. Non-functional variants will typically contain a nonconservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 29 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0246] For example, appropriate functional Va domain CDR1 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 29, i.e. it may have at least 80%, at least 83%, or 100% sequence identity to SEQ ID NO: 29. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 29). In other words, appropriate functional Va domain CDR1 amino acid sequences may vary from the sequence shown in SEQ ID NO: 29 by one or several amino acids. As stated previously, the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO: 29. As stated above, functional variants of SEQ ID NO: 29 retain the ability to (specifically) bind to the peptide shown in SEQ ID NO: 153 when the CDR1 is part of TCR Va domain). In one example, the CDR1 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 29. In examples where the TOR Va domain CDR1 has the amino acid sequence of SEQ ID NO: 29, the CDR1 may be encoded by any appropriate nucleic acid sequence.

[0247] The encoded TOR Va domain may also comprise, in addition to the specified CDR3 (and optionally the specified CDR1 above), a CDR2 comprising an amino acid sequence of SEQ ID NO: 30, or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HLA-B*07:02). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 30. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 30, or substitution, deletion or insertion of non-critical amino acids in non-critical regions of the protein.

[0248] Non-functional variants are amino acid sequence variants of SEQ ID NO: 30 that do not specifically bind to HLA-B*07:02. Non-functional variants will typically contain a non-conservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 30 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0249] For example, appropriate functional Va domain CDR2 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 30, i.e. it may have at least 80%, at least 85%, or 100% sequence identity to SEQ ID NO: 30. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NQ:30). In other words, appropriate (functional) Va domain CDR2 amino acid sequences may vary from the sequence shown in SEQ ID NQ:30 by one or several amino acids. As stated previously, the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO: 30). As stated above, a functional variant of SEQ ID NO: 30 retains the ability to specifically bind to HLA-B*07:02.

[0250] In one example, the CDR2 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 30. In examples where the TCR Va domain CDR2 has the amino acid sequence of SEQ ID NQ:30, the CDR2 may be encoded by any appropriate nucleic acid sequence.

[0251] The encoded TCR Va domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NO: 31 , SEQ ID NO: 29 and SEQ ID NO: 30, or functional variants thereof), with appropriate intervening sequences between the CDRs.

[0252] The encoded TCR Va domain may comprise an amino acid sequence of SEQ ID NO: 35, or a functional variant thereof (i.e. wherein the variant TCR Va domain retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 153) when part of a binding protein described herein). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 35. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 35, or substitution, deletion or insertion of non-critical amino acids in non-critical regions of the protein.

[0253] Non-functional variants are amino acid sequence variants of SEQ ID NO: 35 that do not bind to the peptide shown in SEQ ID NO: 153. Non-functional variants will typically contain a nonconservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 35 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0254] In one example, the encoded TCR Va domain may have an amino acid sequence having at least 75%, at least 80%, at least 85% or at least 90% (or at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) sequence identity to the amino acid sequence of SEQ ID NO: 35, whilst retaining the ability to (specifically) bind to the peptide shown in SEQ ID NO: 153. In other words, a functional TCR Va domain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 35 is also encompassed. As stated previously, the amino acid substitution may be a conservative amino acid substitution. The variability in sequence compared to SEQ ID NO: 35 may all be in regions of the TCR Va domain that do not form CDRs (i.e. the variant may have the CDRs of SEQ I D NO: 31 , SEQ I D NO: 29 and / or SEQ I D NO: 30, and still have 25% (or less) sequence variability compared to SEQ ID NO: 35). In other words, the sequence of the CDRs of SEQ ID NO: 35 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above. Suitably, percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 35).

[0255] As an example, the encoded TCR Va domain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 35, wherein the TCR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 31. In this example, the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 29 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 30.

[0256] As another example, the encoded TCR Va domain may comprise an amino acid sequence with 0 to 10 (or 0 to 5) amino acid substitutions, insertions or deletions compared to SEQ ID NO:35, wherein the TCR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 31. In this example, the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 29 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 30. In examples where the TCR Va domain has the amino acid sequence of SEQ ID NO: 35, the TOR Va domain may be encoded by the nucleic acid sequence of SEQ ID NO: 36, or a genetically degenerate sequence thereof (i.e. other nucleic acid sequences that encode the same protein as a result of the degeneracy of the genetic code).

[0257] For the avoidance of doubt, the nucleic acid sequence encoding the TCR Va domain may also encode a TCR a chain constant domain. Examples of suitable constant domains are generally discussed above.

[0258] An example of a specific TCR a chain amino acid sequence that includes a TCR Va domain described herein with an appropriate constant domain is shown in SEQ ID NO: 39. Appropriate functional variants of SEQ ID NO: 39 are also encompassed (e.g. variants having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 39, wherein the variant TCR a chain amino acid sequence retains its ability to (specifically) bind to the peptide shown in SEQ ID NO: 153 when part of a binding protein described herein). In other words, a functional TCR a chain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 39 is also encompassed. As stated previously, the amino acid substitution may be a conservative amino acid substitution. The variability in sequence compared to SEQ ID NO: 39 may all be in regions of the TCR a chain that do not form CDRs (i.e. the variant may have the CDRs of SEQ ID NO: 31 , SEQ ID NO: 29 and / or SEQ ID NO: 30, and still have 25% (or less) sequence variability compared to SEQ ID NO: 39). In other words, the sequence of the CDRs of SEQ ID NO: 39 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above. Suitably, percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 39).

[0259] As an example, the encoded TCR a chain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 39, wherein the TCR a chain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 31 . In this example, the TCR a chain CDR1 may have an amino acid sequence of SEQ ID NO: 29 and the TCR a chain CDR2 may have an amino acid sequence of SEQ ID NO: 30.

[0260] In examples where the TCR a chain has the amino acid sequence of SEQ ID NO: 39, the TCR a chain may be encoded by the nucleic acid sequence of SEQ ID NO: 40, or a genetically degenerate sequence thereof (i.e. other nucleic acid sequences that encode the same protein as a result of the degeneracy of the genetic code). It is noted that SEQ ID NQ:40 is the nucleic acid sequence for TCR a chain of clone AJV_1.32. In one example, the nucleic acid composition provided herein comprises a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO:31 , or a functional fragment thereof.

[0261] In another example, the CDR3 of the Va domain of a nucleic acid composition provided herein comprises or consists of the amino acid sequence of SEQ ID NO: 31.

[0262] In another example, the Va domain of a nucleic acid composition provided herein comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 35.

[0263] As provided elsewhere herein, the inventors also identified TCR clone EWO_4.1G7 which also interacts with GPRWPPRMTH (SEQ ID NO:73) in the context of HLA-B*07:02. The sequences provided herein that correspond to TCR clone EWO_4.1G7 are SEQ ID NO:s 43 to 56.

[0264] An example of an appropriate TCR Va domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to GPRWPPRMTH (SEQ ID NO:73) is shown in SEQ ID NO: 45. As would be clear to a person of skill in the art, variants of the amino acid sequence shown in SEQ ID NO: 45 may also be functional (i.e. retain their ability to confer (specific) binding to the peptide GPRWPPRMTH (SEQ ID NO:73)) when the CDR3 is part of TCR Va domain). Such functional variants are therefore encompassed herein.

[0265] For example, appropriate (functional) Va domain CDR3 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 45, i.e. they may have at least 80%, at least 90%, or 100% sequence identity to SEQ ID NO: 45. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 45). In other words, appropriate (functional) Va domain CDR3 amino acid sequences may vary from the sequence shown in SEQ ID NO: 45 by one or several (e.g. two etc) amino acids.

[0266] As stated above, functional variants of SEQ ID NO: 45 retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO: 73 when the CDR3 is part of TCR Va domain.

[0267] Functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 45. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one, two or more amino acids of SEQ ID NO: 45, or substitution, deletion or insertion of non-critical amino acids in non- critical regions of the CDR3.

[0268] Non-functional variants are amino acid sequence variants of SEQ ID NO: 45 that do not bind to the peptide shown in SEQ ID NO: 73. Non-functional variants will typically contain a nonconservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 45 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0269] In one example, the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 45. In examples where the TOR Va domain CDR3 has the amino acid sequence of SEQ ID NO: 45, the CDR3 may be encoded by any appropriate nucleic acid sequence.

[0270] The encoded TOR Va domain may comprise, in addition to the specified CDR3, a CDR1 comprising an amino acid sequence of SEQ ID NO: 43, or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 73). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 43. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 43, or substitution, deletion or insertion of non-critical amino acids in non- critical regions of the protein.

[0271] Non-functional variants are amino acid sequence variants of SEQ ID NO: 43 that do not bind to the peptide shown in SEQ ID NO: 73. Non-functional variants will typically contain a nonconservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 43 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0272] For example, appropriate functional Va domain CDR1 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 43, i.e. it may have at least 80%, at least 83%, or 100% sequence identity to SEQ ID NO: 43. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 43). In other words, appropriate functional Va domain CDR1 amino acid sequences may vary from the sequence shown in SEQ ID NO: 43 by one or several amino acids. As stated previously, the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO: 43. As stated above, functional variants of SEQ ID NO: 43 retain the ability to (specifically) bind to the peptide shown in SEQ ID NO: 73 when the CDR1 is part of TCR Va domain.

[0273] In one example, the CDR1 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 43. In examples where the TCR Va domain CDR1 has the amino acid sequence of SEQ ID NO: 43, the CDR1 may be encoded by any appropriate nucleic acid sequence.

[0274] The encoded TCR Va domain may also comprise, in addition to the specified CDR3 (and optionally the specified CDR1 above), a CDR2 comprising an amino acid sequence of SEQ ID NO: 44, or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HLA-B*07:02). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 44. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 44, or substitution, deletion or insertion of non-critical amino acids in non-critical regions of the protein.

[0275] Non-functional variants are amino acid sequence variants of SEQ ID NO: 44 that do not specifically bind to HLA-B*07:02. Non-functional variants will typically contain a non-conservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 44 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0276] For example, appropriate functional Va domain CDR2 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 44, i.e. it may have at least 80%, at least 83%, or 100% sequence identity to SEQ ID NO: 44. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 44). In other words, appropriate (functional) Va domain CDR2 amino acid sequences may vary from the sequence shown in SEQ ID NO: 44 by one or several amino acids. As stated previously, the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO: 44). As stated above, a functional variant of SEQ ID NO: 44 retains the ability to specifically bind to HLA-B*07:02.

[0277] In one example, the CDR2 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 44. In examples where the TCR Va domain CDR2 has the amino acid sequence of SEQ ID NO: 44, the CDR2 may be encoded by any appropriate nucleic acid sequence.

[0278] The encoded TCR Va domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NO:45, SEQ ID NO: 43 and SEQ ID NO: 44, or functional variants thereof), with appropriate intervening sequences between the CDRs.

[0279] The encoded TCR Va domain may comprise an amino acid sequence of SEQ ID NO: 49, or a functional variant thereof (i.e. wherein the variant TCR Va domain retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 73 when part of a binding protein described herein). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 49. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 49, or substitution, deletion or insertion of non-critical amino acids in non-critical regions of the protein. Non-functional variants are amino acid sequence variants of SEQ ID NO: 49 that do not bind to the peptide shown in SEQ ID NO:73. Non-functional variants will typically contain a nonconservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 49 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0280] In one example, the encoded TCR Va domain may have an amino acid sequence having at least 75%, at least 80%, at least 85% or at least 90% (or at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) sequence identity to the amino acid sequence of SEQ ID NO: 49, whilst retaining the ability to (specifically) bind to the peptide shown in SEQ ID NO: 73. In other words, a functional TCR Va domain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 49 is also encompassed. As stated previously, the amino acid substitution may be a conservative amino acid substitution. The variability in sequence compared to SEQ ID NO: 49 may all be in regions of the TCR Va domain that do not form CDRs (i.e. the variant may have the CDRs of SEQ ID NO: 45, SEQ ID NO: 43 and / or SEQ ID NO: 44, and still have 25% (or less) sequence variability compared to SEQ ID NO:49). In other words, the sequence of the CDRs of SEQ ID NO: 49 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above. Suitably, percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 49).

[0281] As an example, the encoded TCR Va domain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 49, wherein the TCR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 45. In this example, the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 43 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 44.

[0282] As another example, the encoded TCR Va domain may comprise an amino acid sequence with 0 to 10 (or 0 to 5) amino acid substitutions, insertions or deletions compared to SEQ ID NO:49, wherein the TCR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 45. In this example, the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 43 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 44.

[0283] In examples where the TCR Va domain has the amino acid sequence of SEQ ID NO: 49, the TCR Va domain may be encoded by the nucleic acid sequence of SEQ ID NO: 50, or a genetically degenerate sequence thereof (i.e. other nucleic acid sequences that encode the same protein as a result of the degeneracy of the genetic code). For the avoidance of doubt, the nucleic acid sequence encoding the TCR Va domain may also encode a TCR a chain constant domain. Examples of suitable constant domains are generally discussed above.

[0284] An example of a specific TCR a chain amino acid sequence that includes a TCR Va domain described herein with an appropriate constant domain is shown in SEQ ID NO: 53. Appropriate functional variants of SEQ ID NO:53 are also encompassed (e.g. variants having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 53, wherein the variant TCR a chain amino acid sequence retains its ability to (specifically) bind to the peptide shown in SEQ ID NO: 73 when part of a binding protein described herein). In other words, a functional TCR a chain with one or several amino acid substitutions compared to the sequence of SEQ ID NO:53 is also encompassed. As stated previously, the amino acid substitution may be a conservative amino acid substitution. The variability in sequence compared to SEQ ID NO:53 may all be in regions of the TCR a chain that do not form CDRs (i.e. the variant may have the CDRs of SEQ ID NO: 45, SEQ ID NO: 43 and / or SEQ ID NO: 44, and still have 25% (or less) sequence variability compared to SEQ ID NO: 53). In other words, the sequence of the CDRs of SEQ ID NO: 53 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above. Suitably, percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 53).

[0285] As an example, the encoded TCR a chain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 53, wherein the TCR a chain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 45. In this example, the TCR a chain CDR1 may have an amino acid sequence of SEQ ID NO:43 and the TCR a chain CDR2 may have an amino acid sequence of SEQ ID NO: 44.

[0286] In examples where the TCR a chain has the amino acid sequence of SEQ ID NO:53, the TCR a chain may be encoded by the nucleic acid sequence of SEQ ID NO:54, or a genetically degenerate sequence thereof (i.e. other nucleic acid sequences that encode the same protein as a result of the degeneracy of the genetic code). It is noted that SEQ ID NO:54 is the nucleic acid sequence for TCR a chain of clone EWO_4.1G7.

[0287] In one example, the nucleic acid composition provided herein comprises a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO:45, or a functional fragment thereof.

[0288] In another example, the CDR3 of the Va domain of a nucleic acid composition provided herein comprises or consists of the amino acid sequence of SEQ ID NO: 45. In another example, the Va domain of a nucleic acid composition provided herein comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 49.

[0289] (iv) Va domains that interact with GQAGFFPSPF (SEQ ID NO:74)

[0290] As discussed above, an isolated nucleic acid composition that encodes a haematopoietic- restricted MiHA-specific binding protein having a TOR a chain variable (Va) domain and a TOR p chain variable (VP) domain is provided, the composition comprising: (a) a nucleic acid sequence that encodes a TOR Va domain comprising a CDR3 amino acid sequence; and (b) a nucleic acid sequence that encodes a TOR Vp domain comprising a CDR3 amino acid sequence; wherein the CDR3 amino acid sequences of (a) and (b) together bind (e.g. specifically bind) to an MiHA that comprises the amino acid sequence GQAGFFPSPF (SEQ ID NO:74).

[0291] As provided elsewhere herein, the inventors identified TCR clone HJS_1-55 which interacts with GQAGFFPSPF (SEQ ID NO:74) in the context of HLA-B*15:01. The sequences provided herein that correspond to TCR clone HJS_1-55 are SEQ ID NO:s 57 to 70.

[0292] An example of an appropriate TCR Va domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to GQAGFFPSPF (SEQ ID NO:74) is shown in SEQ ID NO: 59. As would be clear to a person of skill in the art, variants of the amino acid sequence shown in SEQ ID NO: 59 may also be functional (i.e. retain their ability to confer (specific) binding to the peptide GQAGFFPSPF (SEQ ID NO:74)) when the CDR3 is part of TCR Va domain). Such functional variants are therefore encompassed herein.

[0293] For example, appropriate (functional) Va domain CDR3 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 59, i.e. they may have at least 80%, at least 93%, or 100% sequence identity to SEQ ID NO: 59. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 59). In other words, appropriate (functional) Va domain CDR3 amino acid sequences may vary from the sequence shown in SEQ ID NO: 59 by one or several (e.g. two etc) amino acids.

[0294] As stated above, functional variants of SEQ ID NO: 59 retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO: 74 when the CDR3 is part of TCR Va domain.

[0295] Functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 59. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one, two or more amino acids of SEQ ID NO: 59, or substitution, deletion or insertion of non-critical amino acids in non- critical regions of the CDR3. Non-functional variants are amino acid sequence variants of SEQ ID NO: 59 that do not bind to the peptide shown in SEQ ID NO: 74. Non-functional variants will typically contain a nonconservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 59 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0296] In one example, the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 59. In examples where the TCR Va domain CDR3 has the amino acid sequence of SEQ ID NO: 59, the CDR3 may be encoded by any appropriate nucleic acid sequence.

[0297] The encoded TCR Va domain may comprise, in addition to the specified CDR3, a CDR1 comprising an amino acid sequence of SEQ ID NO: 57, or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 74). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 57. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 57, or substitution, deletion or insertion of non-critical amino acids in non- critical regions of the protein.

[0298] Non-functional variants are amino acid sequence variants of SEQ ID NO: 57 that do not bind to the peptide shown in SEQ ID NO: 74. Non-functional variants will typically contain a nonconservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 57 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0299] For example, appropriate functional Va domain CDR1 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 57, i.e. it may have at least 80%, at least 83%, or 100% sequence identity to SEQ ID NO: 57. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 57). In other words, appropriate functional Va domain CDR1 amino acid sequences may vary from the sequence shown in SEQ ID NO: 57 by one or several amino acids. As stated previously, the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO: 57. As stated above, functional variants of SEQ ID NO: 57 retain the ability to (specifically) bind to the peptide shown in SEQ ID NO: 74 when the CDR1 is part of TCR Va domain).

[0300] In one example, the CDR1 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 57. In examples where the TCR Va domain CDR1 has the amino acid sequence of SEQ ID NO: 57, the CDR1 may be encoded by any appropriate nucleic acid sequence. The encoded TCR Va domain may also comprise, in addition to the specified CDR3 (and optionally the specified CDR1 above), a CDR2 comprising an amino acid sequence of SEQ ID NO: 58, or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HLA-B*15:01). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 58. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 58, or substitution, deletion or insertion of non-critical amino acids in non-critical regions of the protein.

[0301] Non-functional variants are amino acid sequence variants of SEQ ID NO: 58 that do not specifically bind to HLA-B*15:01. Non-functional variants will typically contain a non-conservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 58 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0302] For example, appropriate functional Va domain CDR2 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 58, i.e. it may have at least 80%, at least 87%, or 100% sequence identity to SEQ ID NO: 58. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 58). In other words, appropriate (functional) Va domain CDR2 amino acid sequences may vary from the sequence shown in SEQ ID NO: 58 by one or several amino acids. As stated previously, the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO: 58). As stated above, a functional variant of SEQ ID NO: 58 retains the ability to specifically bind to HLA-B*15:01.

[0303] In one example, the CDR2 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 58. In examples where the TCR Va domain CDR2 has the amino acid sequence of SEQ ID NO: 58, the CDR2 may be encoded by any appropriate nucleic acid sequence.

[0304] The encoded TCR Va domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NO:59, SEQ ID NO: 57 and SEQ ID NO: 58, or functional variants thereof), with appropriate intervening sequences between the CDRs.

[0305] The encoded TCR Va domain may comprise an amino acid sequence of SEQ ID NO: 63, or a functional variant thereof (i.e. wherein the variant TCR Va domain retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 74) when part of a binding protein described herein). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 63. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 63, or substitution, deletion or insertion of non-critical amino acids in non-critical regions of the protein.

[0306] Non-functional variants are amino acid sequence variants of SEQ ID NO: 63 that do not bind to the peptide shown in SEQ ID NO: 74. Non-functional variants will typically contain a nonconservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 63 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0307] In one example, the encoded TCR Va domain may have an amino acid sequence having at least 75%, at least 80%, at least 85% or at least 90% (or at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) sequence identity to the amino acid sequence of SEQ ID NO: 63, whilst retaining the ability to (specifically) bind to the peptide shown in SEQ ID NO: 74. In other words, a functional TCR Va domain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 63 is also encompassed. As stated previously, the amino acid substitution may be a conservative amino acid substitution. The variability in sequence compared to SEQ ID NO: 63 may all be in regions of the TCR Va domain that do not form CDRs (i.e. the variant may have the CDRs of SEQ ID NO: 59, SEQ ID NO: 57 and / or SEQ ID NO: 58, and still have 25% (or less) sequence variability compared to SEQ ID NO:63). In other words, the sequence of the CDRs of SEQ ID NO: 63 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above. Suitably, percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 63).

[0308] As an example, the encoded TCR Va domain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 63, wherein the TCR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 59. In this example, the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 57 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 58.

[0309] As another example, the encoded TCR Va domain may comprise an amino acid sequence with 0 to 10 (or 0 to 5) amino acid substitutions, insertions or deletions compared to SEQ ID NO:63, wherein the TCR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 59. In this example, the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 57 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 58.

[0310] In examples where the TCR Va domain has the amino acid sequence of SEQ ID NO: 63, the TCR Va domain may be encoded by the nucleic acid sequence of SEQ ID NO: 64, or a genetically degenerate sequence thereof (i.e. other nucleic acid sequences that encode the same protein as a result of the degeneracy of the genetic code).

[0311] For the avoidance of doubt, the nucleic acid sequence encoding the TCR Va domain may also encode a TCR a chain constant domain. Examples of suitable constant domains are generally discussed above.

[0312] An example of a specific TCR a chain amino acid sequence that includes a TCR Va domain described herein with an appropriate constant domain is shown in SEQ ID NO: 67. Appropriate functional variants of SEQ ID NO:67 are also encompassed (e.g. variants having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 67, wherein the variant TCR a chain amino acid sequence retains its ability to (specifically) bind to the peptide shown in SEQ ID NO: 74 when part of a binding protein described herein). In other words, a functional TCR a chain with one or several amino acid substitutions compared to the sequence of SEQ ID NO:67 is also encompassed. As stated previously, the amino acid substitution may be a conservative amino acid substitution. The variability in sequence compared to SEQ ID NO:67 may all be in regions of the TCR a chain that do not form CDRs (i.e. the variant may have the CDRs of SEQ ID NO: 59, SEQ ID NO: 57 and / or SEQ ID NO: 58, and still have 25% (or less) sequence variability compared to SEQ ID NO: 67). In other words, the sequence of the CDRs of SEQ ID NO: 67 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above. Suitably, percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 67).

[0313] As an example, the encoded TCR a chain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 67, wherein the TCR a chain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 59. In this example, the TCR a chain CDR1 may have an amino acid sequence of SEQ ID NO:57 and the TCR a chain CDR2 may have an amino acid sequence of SEQ ID NO: 58.

[0314] In examples where the TCR a chain has the amino acid sequence of SEQ ID NO: 67, the TCR a chain may be encoded by the nucleic acid sequence of SEQ ID NO: 68, or a genetically degenerate sequence thereof (i.e. other nucleic acid sequences that encode the same protein as a result of the degeneracy of the genetic code). It is noted that SEQ ID NO:68 is the nucleic acid sequence for TCR a chain of clone HJS_1-55.

[0315] In one example, the nucleic acid composition provided herein comprises a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO:59, or a functional fragment thereof. In another example, the CDR3 of the Va domain of a nucleic acid composition provided herein comprises or consists of the amino acid sequence of SEQ ID NO: 59.

[0316] In another example, the Va domain of a nucleic acid composition provided herein comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 63.

[0317] Components of the TOR 8 chain variable (VB) domain

[0318] The isolated nucleic acid composition described herein encodes a haematopoietic-restricted MiHA-specific binding protein. As discussed herein, the inventors identified several TCRs that specifically bind to a haematopoietic-restricted MiHA selected from VSMNPYQEL (SEQ ID NO:71), GPRPSPTRSV (SEQ ID NO: 72), GPRWPPRMTH (SEQ ID NO: 73), GPRWPPRMT (SEQ ID NO: 153) and GQAGFFPSPF (SEQ ID NO: 74). The sequences for the Va domains are discussed above, with the corresponding sequences for the V|3 domains discussed below.

[0319] (i) VB domains that interact with VSMNPYQEL (SEQ ID NO: 71)

[0320] As provided elsewhere herein, the inventors identified TCR clone VDL_3.1 F9 which interacts with VSMNPYQEL (SEQ ID NO: 71) in the context of HLA-C*03:03 and / or HLA-C*03:04. The sequences provided herein that correspond to TCR clone VDL_3.1 F9 are SEQ ID NO:s 1 to 14.

[0321] Accordingly, an example of an appropriate TCR VB domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to VSMNPYQEL (SEQ ID NO: 71) is shown in SEQ ID NO:6. As would be clear to a person of skill in the art, variants of the amino acid sequence shown in SEQ ID NO:6 may also be functional (i.e. retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO: 71 when the CDR3 is part of TCR VB domain). Such functional variants are therefore encompassed herein.

[0322] For example, appropriate (functional) VB domain CDR3 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 6, i.e. they may have at least 80%, at least 93%, or 100% sequence identity to SEQ ID NO: 6. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 6). In other words, appropriate (functional) VB domain CDR3 amino acid sequences may vary from the sequence shown in SEQ ID NO: 6 by one or several (e.g. two) amino acids. As stated above, functional variants of SEQ ID NO: 6 retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO: 71 when the CDR3 is part of TCR VB domain.

[0323] Functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 6. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 6, or substitution, deletion or insertion of non-critical amino acids in non- critical regions of the CDR3.

[0324] Non-functional variants are amino acid sequence variants of SEQ ID NO: 6 that do not bind to the peptide shown in SEQ ID NO: 71 . Non-functional variants will typically contain a non-conservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 6 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0325] In one example, the CDR3 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 6. In examples where the TCR Vp domain CDR3 has the amino acid sequence of SEQ ID NO:6, the CDR3 may be encoded by any appropriate nucleic acid sequence.

[0326] The encoded TCR Vp domain may comprise, in addition to the specified CDR3, a CDR1 comprising an amino acid sequence of SEQ ID NO: 4, or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 71). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 4. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 4, or substitution, deletion or insertion of non-critical amino acids in non- critical regions of the protein.

[0327] Non-functional variants are amino acid sequence variants of SEQ ID NO: 4 that do not bind to the peptide shown in SEQ ID NO: 71 . Non-functional variants will typically contain a non-conservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 4 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0328] For example, appropriate functional Vp domain CDR1 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 4, i.e. it may have at least 80%, or 100% sequence identity to SEQ ID NO: 4. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 4). In other words, appropriate (functional) Vp domain CDR1 amino acid sequences may vary from the sequence shown in SEQ ID NO:4 by one or several amino acids. As stated previously, the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO:4). As stated above, functional variants of SEQ ID NO: 4 retain the ability to (specifically) bind to the peptide shown in SEQ ID NO: 71 when the CDR1 is part of TCR Vp domain). In one example, the CDR1 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 4. In examples where the TOR Vp domain CDR1 has the amino acid sequence of SEQ ID NO:4, the CDR1 may be encoded by any appropriate nucleic acid sequence.

[0329] The encoded TOR Vp domain may also comprise, in addition to the specified CDR3 (and optionally the specified CDR1 above), a CDR2 having an amino acid sequence of SEQ ID NO: 5, or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HLA-C*03:03 and / or HLA-C*03:04). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 5. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 5, or substitution, deletion or insertion of non-critical amino acids in non-critical regions of the protein.

[0330] Non-functional variants are amino acid sequence variants of SEQ ID NO: 5 that do not specifically bind to HLA-C*03:03 and / or HLA-C*03:04. Non-functional variants will typically contain a nonconservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 5 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0331] For example, appropriate functional Vp domain CDR2 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 5, i.e. it may have at least 80%, at least 83%, or 100% sequence identity to SEQ ID NO: 5. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 5). In other words, appropriate (functional) Vp domain CDR2 amino acid sequences may vary from the sequence shown in SEQ ID NO: 5 by one or several amino acids. As stated previously, the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO: 5). As stated above, a functional variant of SEQ ID NO: 5 retains the ability to specifically bind to HLA-C*03:03 and / or HI_A-C*03:04.

[0332] In one example, the CDR2 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 5. In examples where the TCR Vp domain CDR2 has the amino acid sequence of SEQ ID NO:5, the CDR2 may be encoded by any appropriate nucleic acid sequence.

[0333] The encoded TCR Vp domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NO:6, SEQ ID NO: 4 and SEQ ID NO: 5, or functional variants thereof), with appropriate intervening sequences between the CDRs.

[0334] The encoded TCR Vp domain may have an amino acid sequence of SEQ ID NO: 9, or a functional variant thereof (i.e. wherein the variant TCR Vp domain retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 71 when part of a binding protein described herein). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 9. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 9, or substitution, deletion or insertion of non-critical amino acids in non- critical regions of the protein.

[0335] Non-functional variants are amino acid sequence variants of SEQ ID NO: 9 that do not bind to the peptide shown in SEQ ID NO: 71 . Non-functional variants will typically contain a non-conservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO:9 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0336] In one example, the encoded TCR p domain may have an amino acid sequence having at least 75%, at least 80%, at least 85% or at least 90% (or at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) sequence identity to the amino acid sequence of SEQ ID NO: 9, whilst retaining the ability to (specifically) bind to the peptide shown in SEQ ID NO: 71. In other words, a functional TCR V domain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 9 is also encompassed. As stated previously, the amino acid substitution may be a conservative amino acid substitution. The variability in sequence compared to SEQ ID NO:9 may all be in regions of the TCR Vp domain that do not form CDRs (i.e. the variant may have the CDRs of SEQ ID NO: 6, SEQ ID NO: 4 and / or SEQ ID NO: 5, and still have 25% (or less) sequence variability compared to SEQ ID NO: 9). In other words, the sequence of the CDRs of SEQ ID NO: 9 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above. Suitably, percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 9).

[0337] As an example, the encoded TCR Vp domain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 9, wherein the TCR Vp domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 6. In this example, the TCR Vp domain CDR1 may have an amino acid sequence of SEQ ID NO:4 and the TCR Vp domain CDR2 may have an amino acid sequence of SEQ ID NO: 5.

[0338] In examples where the TCR Vp domain has the amino acid sequence of SEQ ID NO:9, the TCR VP domain may be encoded by the nucleic acid sequence of SEQ ID NO: 10, or a genetically degenerate sequence thereof (i.e. other nucleic acid sequences that encode the same protein as a result of the degeneracy of the genetic code). For the avoidance of doubt, the nucleic acid sequence encoding the TCR Vp domain may also encode a TCR chain constant domain. Examples of suitable constant domains are generally discussed above.

[0339] An example of a specific TCR p chain amino acid sequence that includes a TCR Vp domain described herein and an appropriate constant domain is shown in SEQ ID NO: 13. Appropriate functional variants of SEQ ID NO: 13 are also encompassed (e.g. variants having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 13, wherein the variant TCR p chain amino acid sequence retains its ability to (specifically) bind to the peptide shown in SEQ ID NO: 71 when part of a binding protein described herein). In other words, a functional TCR p chain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 13 is also encompassed. As stated previously, the amino acid substitution may be a conservative amino acid substitution. The variability in sequence compared to SEQ ID NO: 13 may all be in regions of the TCR p chain that do not form CDRs (i.e. the variant may have the CDRs of SEQ ID NO: 6, SEQ ID NO: 4 and / or SEQ ID NO: 5, and still have 25% (or less) sequence variability compared to SEQ ID NO: 13. In other words, the sequence of the CDRs of SEQ ID NO: 13 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above. Suitably, percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 13).

[0340] As an example, the encoded TCR p chain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 13, wherein the TCR p chain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 6. In this example, the TCR p chain CDR1 may have an amino acid sequence of SEQ ID NO: 4 and the TCR p chain CDR2 may have an amino acid sequence of SEQ ID NO: 5.

[0341] In examples where the TCR p chain has the amino acid sequence of SEQ ID NO: 13, the TCR p chain may be encoded by the nucleic acid sequence of SEQ ID NO: 14, or a genetically degenerate sequence thereof (i.e. other nucleic acid sequences that encode the same protein as a result of the degeneracy of the genetic code). It is noted that SEQ ID NO: 14 is the nucleic acid sequence for TCR p chain of clone VDL_3.1 F9.

[0342] In an example, the nucleic acid composition provided herein comprises a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO:6, or a functional fragment thereof.

[0343] In another example, the CDR3 of the Vp domain of a nucleic acid composition provided herein comprises or consists of the amino acid sequence of SEQ ID NO:6. In a further example, the Vp domain of a nucleic acid composition provided herein comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 9.

[0344] The TOR Vp domain sequences derived from TOR clone VDL_3.1 F9 discussed above are particularly compatible with the TOR Va domain sequences derived from TOR clone VDL_3.1 F9 discussed elsewhere herein.

[0345] Accordingly, in one example, a nucleic acid composition described herein encodes a haematopoietic-restricted MiHA-specific binding protein having TOR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO:3, or a functional fragment thereof; and a nucleic acid sequence that encodes a TCR p domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO:6, or a functional fragment thereof.

[0346] In a particular example, a nucleic acid composition described herein encodes a haematopoietic- restricted MiHA-specific binding protein having a TCR Va domain with a CDR3 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 3; and a TCR Vp domain with a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO:6. In addition, the haematopoietic-restricted MiHA may comprise or consist of the sequence shown in SEQ ID NO: 71. Furthermore, the TCR Va domain may be part of a TCR a chain having a constant domain and the TCR Vp domain may be part of a TCR p chain having a constant domain.

[0347] In this particular example, the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 7; and the Vp domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 9. In one example, the Va domain comprises the amino acid sequence of SEQ ID NO: 7 and the Vp domain comprises the amino acid sequence of SEQ ID NO: 9. In such cases, the Va domain may be encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 8; and the Vp domain may be encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 10.

[0348] In this particular example, the TCR Va domain may include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO:1 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO:2. Furthermore, the TCR Vp domain may include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO:4 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 5. For the avoidance of doubt, this particular example encompasses components of TCR clone VDL_3.1 F9 exemplified herein. The different components of TCR clone VDL_3.1 F9 and their respective SEQ ID Nos are summarised in Table 6 below.

[0349] As stated in more detail elsewhere herein, the nucleic acid composition described herein encodes both a TCR Va domain and a TCR Vp domain, which form the binding protein that is capable of specifically binding to a haematopoietic-restricted MiHA. In examples where the TCR Va domain and the TCR p domain are encoded by the same nucleic acid sequence, the TCR Va domain and TCR Vp domain may be joined together via a linker, e.g. a linker that enables expression of two proteins or polypeptides from the same vector. By way of example, a linker comprising a porcine teschovirus-1 2A (P2A) sequence may be used, such as 2A sequences from foot-and- mouth disease virus (F2A), equine rhinitis A virus (E2A) or Thosea asigna virus (T2A) as published by A.L. Szymczak et al., Nature Biotechnology 22, 589 - 594 (2004) or 2A-like sequences. 2A and 2A-like sequences are linkers that are cleavable once the nucleic acid molecule has been transcribed and translated. Another example of a linker is an internal ribosomal entry sites (IRES) which enables translation of two proteins or polypeptides from the same transcript. Any other appropriate linker may also be used. As a further example, the nucleic acid sequence encoding the TCR Va domain and nucleic acid sequence encoding the TCR Vp domain may be cloned into a vector with dual internal promoters (see e.g. S Jones et al., Human Gene Ther 2009). The identification of appropriate linkers and vectors that enable expression of both the TCR Va domain and the TCR Vp domain is well within the routine capabilities of a person of skill in the art.

[0350] Additional appropriate polypeptide domains may also be encoded by the nucleic acid sequences that encode the TCR Va domain and / or the TCR Vp domain. By way of example only, the nucleic acid sequence may comprise a membrane targeting sequence that provides for transport of the encoded polypeptide to the cell surface membrane of the modified cell. Other appropriate additional domains are well known and are described, for example, in WO2016 / 071758.

[0351] In one example, the nucleic acid composition described herein may encode a soluble TCR. For example, the nucleic acid composition may encode the variable domain of the TCR alpha and beta chains respectively together with an immune-modulator molecule such as a CD3 agonist (e.g. an anti-CD3 scFv). The CD3 antigen is present on mature human T cells, thymocytes and a subset of natural killer cells. It is associated with the TCR and is involved in signal transduction of the TCR. Antibodies specific for the human CD3 antigen are well known. One such antibody is the murine monoclonal antibody OKT3, which is the first monoclonal antibody approved by the FDA. Other antibodies specific for CD3 have also been reported (see e.g. W02004 / 106380; U.S. Patent Application Publication No. 2004 / 0202657; U.S. Pat. No. 6,750,325). Immune mobilising mTCR Against Cancer (ImmTAC; Immunocore Limited, Milton Partk, Abington, Oxon, United Kingdom) are bifunctional proteins that combine affinity monoclonal T cell receptor (mTCR) targeting with a therapeutic mechanism of action (i.e. , an anti-CD3 scFv). In another example, a soluble TCR of the invention may be combined with a radioisotope or a toxic drug. Appropriate radioisotopes and / or toxic drugs are well known in the art and are readily identifiable by a person of ordinary skill in the art.

[0352] In one example, the nucleic acid composition may encode a chimeric single chain TCR wherein the TCR alpha chain variable domain is linked to the TCR beta chain variable domain and a constant domain which is e.g. fused to the CD3 zeta signalling domain. In this example, the linker is non-cleavable. In an alternative embodiment, the nucleic acid composition may encode a chimeric two chain TCR in which the TCR alpha chain variable domain and the TCR beta chain variable domain are each linked to a CD3 zeta signalling domain or other transmembrane and intracellular domains. Methods for preparing such single chain TCRs and two chain TCRs are well known in the art; see for example RA Willemsen et al, Gene Therapy 2000.

[0353] (ii) VP domains that interact with GPRPSPTRSV (SEQ ID NO:72)

[0354] As provided elsewhere herein, the inventors have also identified TCR clone VDL_T1 which interacts with GPRPSPTRSV (SEQ ID NO:72) in the context of HI_A-B*07:02. The sequences provided herein that correspond to TCR clone VDL_T1 are SEQ ID NO:s 15 to 28.

[0355] An example of an appropriate TCR Vp domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to GPRPSPTRSV (SEQ ID NO:72) is shown in SEQ ID NQ:20. As would be clear to a person of skill in the art, variants of the amino acid sequence shown in SEQ ID NQ:20 may also be functional (i.e. retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO: 72) when the CDR3 is part of TCR Vp domain). Such functional variants are therefore encompassed herein.

[0356] For example, appropriate (functional) Vp domain CDR3 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 20, i.e. they may have at least 80%, at least 91%, or 100% sequence identity to SEQ ID NO: 20. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 20). In other words, appropriate (functional) Vp domain CDR3 amino acid sequences may vary from the sequence shown in SEQ ID NO: 20 by one or several (e.g. two) amino acids. As stated above, functional variants of SEQ ID NO: 20 retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO: 72) when the CDR3 is part of TCR Vp domain.

[0357] Functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 20. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 20, or substitution, deletion or insertion of non-critical amino acids in non- critical regions of the CDR3. Non-functional variants are amino acid sequence variants of SEQ ID NO: 20 that do not bind to the peptide shown in SEQ ID NO: 72. Non-functional variants will typically contain a nonconservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 20 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0358] In one example, the CDR3 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 20. In examples where the TCR Vp domain CDR3 has the amino acid sequence of SEQ ID NQ:20, the CDR3 may be encoded by any appropriate nucleic acid sequence.

[0359] The encoded TCR Vp domain may comprise, in addition to the specified CDR3, a CDR1 comprising an amino acid sequence of SEQ ID NO: 18, or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 72). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 18. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 18, or substitution, deletion or insertion of non-critical amino acids in non- critical regions of the protein.

[0360] Non-functional variants are amino acid sequence variants of SEQ ID NO: 18 that do not bind to the peptide shown in SEQ ID NO: 72. Non-functional variants will typically contain a nonconservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 18 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0361] For example, appropriate functional Vp domain CDR1 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 18, i.e. it may have at least 80%, or 100% sequence identity to SEQ ID NO: 18. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 18). In other words, appropriate (functional) Vp domain CDR1 amino acid sequences may vary from the sequence shown in SEQ ID NO: 18 by one or several amino acids. As stated previously, the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO: 18). As stated above, functional variants of SEQ ID NO: 18 retain the ability to (specifically) bind to the peptide shown in SEQ ID NO: 72 when the CDR1 is part of TCR Vp domain).

[0362] In one example, the CDR1 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 18. In examples where the TCR Vp domain CDR1 has the amino acid sequence of SEQ ID NO: 18, the CDR1 may be encoded by any appropriate nucleic acid sequence. The encoded TCR Vp domain may also comprise, in addition to the specified CDR3 (and optionally the specified CDR1 above), a CDR2 having an amino acid sequence of SEQ ID NO: 19, or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HLA-B*07:02). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 19. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 19, or substitution, deletion or insertion of non-critical amino acids in non-critical regions of the protein.

[0363] Non-functional variants are amino acid sequence variants of SEQ ID NO: 19 that do not specifically bind to HLA-B*07:02. Non-functional variants will typically contain a non-conservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ I D NO: 19 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0364] For example, appropriate functional Vp domain CDR2 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 19, i.e. it may have at least 80%, at least 83%, or 100% sequence identity to SEQ ID NO: 19. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 19). In other words, appropriate (functional) Vp domain CDR2 amino acid sequences may vary from the sequence shown in SEQ ID NO: 19 by one or several amino acids. As stated previously, the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO: 19). As stated above, a functional variant of SEQ ID NO: 19 retains the ability to specifically bind to HLA-B*07:02.

[0365] In one example, the CDR2 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 19. In examples where the TCR Vp domain CDR2 has the amino acid sequence of SEQ ID NO: 19, the CDR2 may be encoded by any appropriate nucleic acid sequence.

[0366] The encoded TCR Vp domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NQ:20, SEQ ID NO: 18 and SEQ ID NO: 19, or functional variants thereof), with appropriate intervening sequences between the CDRs.

[0367] The encoded TCR Vp domain may have an amino acid sequence of SEQ ID NO: 23, or a functional variant thereof (i.e. wherein the variant TCR Vp domain retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 72 when part of a binding protein described herein). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 23. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 23, or substitution, deletion or insertion of non-critical amino acids in non-critical regions of the protein.

[0368] Non-functional variants are amino acid sequence variants of SEQ ID NO: 23 that do not bind to the peptide shown in SEQ ID NO: 72. Non-functional variants will typically contain a nonconservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO:23 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art

[0369] In one example, the encoded TCR p domain may have an amino acid sequence having at least 75%, at least 80%, at least 85% or at least 90% (or at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) sequence identity to the amino acid sequence of SEQ ID NO: 23, whilst retaining the ability to (specifically) bind to the peptide shown in SEQ ID NO: 72. In other words, a functional TCR Vp domain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 23 is also encompassed. As stated previously, the amino acid substitution may be a conservative amino acid substitution. The variability in sequence compared to SEQ ID NO:23 may all be in regions of the TCR Vp domain that do not form CDRs (i.e. the variant may have the CDRs of SEQ ID NO: 20, SEQ ID NO: 18 and / or SEQ ID NO: 19, and still have 25% (or less) sequence variability compared to SEQ ID NO: 23). In other words, the sequence of the CDRs of SEQ ID NO: 23 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above. Suitably, percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 23).

[0370] As an example, the encoded TCR Vp domain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 23, wherein the TCR Vp domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 20. In this example, the TCR Vp domain CDR1 may have an amino acid sequence of SEQ ID NO:18 and the TCR Vp domain CDR2 may have an amino acid sequence of SEQ ID NO: 19.

[0371] In examples where the TCR Vp domain has the amino acid sequence of SEQ ID NO:23, the TCR VP domain may be encoded by the nucleic acid sequence of SEQ ID NO:24, or a genetically degenerate sequence thereof (i.e. other nucleic acid sequences that encode the same protein as a result of the degeneracy of the genetic code).

[0372] For the avoidance of doubt, the nucleic acid sequence encoding the TCR p domain may also encode a TCR p chain constant domain. Examples of suitable constant domains are generally discussed above. An example of a specific TCR p chain amino acid sequence that includes a TCR Vp domain described herein and an appropriate constant domain is shown in SEQ ID NO: 27. Appropriate functional variants of SEQ ID NO: 27 are also encompassed (e.g. variants having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 27, wherein the variant TCR p chain amino acid sequence retains its ability to (specifically) bind to the peptide shown in SEQ ID NO: 72 when part of a binding protein described herein). In other words, a functional TCR p chain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 27 is also encompassed. As stated previously, the amino acid substitution may be a conservative amino acid substitution. The variability in sequence compared to SEQ ID NO:27 may all be in regions of the TCR p chain that do not form CDRs (i.e. the variant may have the CDRs of SEQ ID NO: 20, SEQ ID NO: 18 and / or SEQ ID NO: 19, and still have 25% (or less) sequence variability compared to SEQ ID NO:27. In other words, the sequence of the CDRs of SEQ ID NO: 27 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above. Suitably, percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 27).

[0373] As an example, the encoded TCR p chain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 27, wherein the TCR p chain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 20. In this example, the TCR p chain CDR1 may have an amino acid sequence of SEQ ID NO: 18 and the TCR p chain CDR2 may have an amino acid sequence of SEQ ID NO: 19.

[0374] In examples where the TCR p chain has the amino acid sequence of SEQ ID NO:27, the TCR p chain may be encoded by the nucleic acid sequence of SEQ ID NO:28, or a genetically degenerate sequence thereof (i.e. other nucleic acid sequences that encode the same protein as a result of the degeneracy of the genetic code). It is noted that SEQ ID NO:28 is the nucleic acid sequence for TCR p chain of clone VDL_T 1.

[0375] In an example, the nucleic acid composition provided herein comprises a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NQ:20, or a functional fragment thereof.

[0376] In another example, the CDR3 of the Vp domain of a nucleic acid composition provided herein comprises or consists of the amino acid sequence of SEQ ID NQ:20.

[0377] In a further example, the Vp domain of a nucleic acid composition provided herein comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 23. The TCR Vp domain sequences derived from TCR clone VDL_T1 discussed above are particularly compatible with the TCR Va domain sequences derived from TCR clone VDL_T1 discussed elsewhere herein.

[0378] Accordingly, in one example, a nucleic acid composition described herein encodes a haematopoietic-restricted MiHA-specific binding protein having TCR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 17, or a functional fragment thereof; and a nucleic acid sequence that encodes a TCR p domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO:20, or a functional fragment thereof.

[0379] In a particular example, a nucleic acid composition described herein encodes a haematopoietic- restricted MiHA-specific binding protein having a TCR Va domain with a CDR3 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 17; and a TCR Vp domain with a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NQ:20. In addition, the haematopoietic-restricted MiHA-specific may comprise or consist of the sequence shown in SEQ ID NO: 72. Furthermore, the TCR Va domain may be part of a TCR a chain having a constant domain and the TCR Vp domain may be part of a TCR p chain having a constant domain.

[0380] In this particular example, the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 21 ; and the Vp domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 23. In one example, the Va domain comprises the amino acid sequence of SEQ ID NO: 21 and the Vp domain comprises the amino acid sequence of SEQ ID NO: 23. In such cases, the Va domain may be encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 22; and the Vp domain may be encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 24.

[0381] In this particular example, the TCR Va domain may include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 15 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO:16. Furthermore, the TCR Vp domain may include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 18 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 19.

[0382] For the avoidance of doubt, this particular example encompasses components of TCR clone VDL_T 1 exemplified herein. The different components of TCR clone VDL_T 1 and their respective SEQ ID Nos are summarised in Table 7 below. As stated in more detail elsewhere herein, the nucleic acid composition described herein encodes both a TCR Va domain and a TCR Vp domain, which form the binding protein that is capable of specifically binding to a haematopoietic-restricted MiHA as described herein. In examples where the TCR Va domain and the TCR p domain are encoded by the same nucleic acid sequence, the TCR Va domain and TCR Vp domain may be joined together via a linker. Suitable linkers are discussed generally elsewhere herein. Additional appropriate polypeptide domains that may also be encoded by the nucleic acid sequences that encode the TCR Va domain and / or the TCR Vp domain are also discussed generally elsewhere herein.

[0383] In one example, the nucleic acid composition described herein may encode a soluble TCR or a chimeric single chain TCR wherein the TCR alpha chain variable domain is linked to the TCR beta chain variable domain and a constant domain which is e.g. fused to the CD3 zeta signalling domain. These are discussed generally in more detail elsewhere herein.

[0384] (iii) VP domains that interact with GPRWPPRMTH (SEQ ID NO: 73) and / or GPRWPPRMT (SEQ ID NO: 153)

[0385] As provided elsewhere herein, the inventors identified TCR clone AJV_1.32 which interacts with GPRWPPRMT (SEQ ID NO: 153) in the context of HI_A-B*07:02. The sequences provided herein that correspond to TCR clone AJV_1 .32 are SEQ ID NO:s 29 to 42.

[0386] An example of an appropriate TCR Vp domain CDR3 amino acid sequence that confers binding (e.g specific binding) to GPRWPPRMT (SEQ ID NO: 153) is shown in SEQ ID NO:34. As would be clear to a person of skill in the art, variants of the amino acid sequence shown in SEQ ID NO:34 may also be functional (i.e. retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO: 153 when the CDR3 is part of TCR Vp domain). Such functional variants are therefore encompassed herein.

[0387] For example, appropriate (functional) Vp domain CDR3 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 34, i.e. they may have at least 80%, at least 93%, or 100% sequence identity to SEQ ID NO: 34. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 34). In other words, appropriate (functional) Vp domain CDR3 amino acid sequences may vary from the sequence shown in SEQ ID NO: 34 by one or several (e.g. two) amino acids. As stated above, functional variants of SEQ ID NO: 34 retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO: 153 when the CDR3 is part of TCR Vp domain.

[0388] Functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 34. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 34, or substitution, deletion or insertion of non-critical amino acids in non- critical regions of the CDR3.

[0389] Non-functional variants are amino acid sequence variants of SEQ ID NO: 34 that do not bind to the peptide shown in SEQ ID NO: 153. Non-functional variants will typically contain a nonconservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 34 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0390] In one example, the CDR3 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 34. In examples where the TCR Vp domain CDR3 has the amino acid sequence of SEQ ID NO:34, the CDR3 may be encoded by any appropriate nucleic acid sequence.

[0391] The encoded TCR Vp domain may comprise, in addition to the specified CDR3, a CDR1 comprising an amino acid sequence of SEQ ID NO: 32, or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 153). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 32. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 32, or substitution, deletion or insertion of non-critical amino acids in non- critical regions of the protein.

[0392] Non-functional variants are amino acid sequence variants of SEQ ID NO: 32 that do not bind to the peptide shown in SEQ ID NO: 153. Non-functional variants will typically contain a nonconservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 32 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0393] For example, appropriate functional Vp domain CDR1 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 32, i.e. it may have at least 80%, or 100% sequence identity to SEQ ID NO: 32. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 32). In other words, appropriate (functional) Vp domain CDR1 amino acid sequences may vary from the sequence shown in SEQ ID NO:32 by one or several amino acids. As stated previously, the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO:32). As stated above, functional variants of SEQ ID NO: 32 retain the ability to (specifically) bind to the peptide shown in SEQ ID NO: 153 when the CDR1 is part of TCR Vp domain). In one example, the CDR1 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 32. In examples where the TOR Vp domain CDR1 has the amino acid sequence of SEQ ID NO:32, the CDR1 may be encoded by any appropriate nucleic acid sequence.

[0394] The encoded TOR Vp domain may also comprise, in addition to the specified CDR3 (and optionally the specified CDR1 above), a CDR2 having an amino acid sequence of SEQ ID NO: 33, or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HLA-B*07:02). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 33. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 33, or substitution, deletion or insertion of non-critical amino acids in non-critical regions of the protein.

[0395] Non-functional variants are amino acid sequence variants of SEQ ID NO: 33 that do not specifically bind to HLA-B*07:02. Non-functional variants will typically contain a non-conservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 33 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0396] For example, appropriate functional Vp domain CDR2 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 33, i.e. it may have at least 80%, at least 83%, or 100% sequence identity to SEQ ID NO: 33. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 33). In other words, appropriate (functional) Vp domain CDR2 amino acid sequences may vary from the sequence shown in SEQ ID NO: 33 by one or several amino acids. As stated previously, the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO: 33). As stated above, a functional variant of SEQ ID NO: 33 retains the ability to specifically bind to HLA-B*07:02.

[0397] In one example, the CDR2 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 33. In examples where the TCR Vp domain CDR2 has the amino acid sequence of SEQ ID NO:33, the CDR2 may be encoded by any appropriate nucleic acid sequence.

[0398] The encoded TCR Vp domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NO:34, SEQ ID NO: 32 and SEQ ID NO: 33, or functional variants thereof), with appropriate intervening sequences between the CDRs.

[0399] The encoded TCR Vp domain may have an amino acid sequence of SEQ ID NO: 37, or a functional variant thereof (i.e. wherein the variant TCR Vp domain retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 153 when part of a binding protein described herein). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 37. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 37, or substitution, deletion or insertion of non-critical amino acids in non-critical regions of the protein.

[0400] Non-functional variants are amino acid sequence variants of SEQ ID NO: 37 that do not bind to the peptide shown in SEQ ID NO: 153. Non-functional variants will typically contain a nonconservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO:37 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0401] In one example, the encoded TCR p domain may have an amino acid sequence having at least 75%, at least 80%, at least 85% or at least 90% (or at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) sequence identity to the amino acid sequence of SEQ ID NO: 37, whilst retaining the ability to (specifically) bind to the peptide shown in SEQ ID NO: 153. In other words, a functional TCR V domain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 37 is also encompassed. As stated previously, the amino acid substitution may be a conservative amino acid substitution. The variability in sequence compared to SEQ ID NO:37 may all be in regions of the TCR Vp domain that do not form CDRs (i.e. the variant may have the CDRs of SEQ ID NO: 34, SEQ ID NO: 32 and / or SEQ ID NO: 33, and still have 25% (or less) sequence variability compared to SEQ ID NO: 37). In other words, the sequence of the CDRs of SEQ ID NO: 37 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above. Suitably, percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 37).

[0402] As an example, the encoded TCR Vp domain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 37, wherein the TCR Vp domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 34. In this example, the TCR Vp domain CDR1 may have an amino acid sequence of SEQ ID NO:32 and the TCR Vp domain CDR2 may have an amino acid sequence of SEQ ID NO: 33.

[0403] In examples where the TCR Vp domain has the amino acid sequence of SEQ ID NO:37, the TCR VP domain may be encoded by the nucleic acid sequence of SEQ ID NO:38, or a genetically degenerate sequence thereof (i.e. other nucleic acid sequences that encode the same protein as a result of the degeneracy of the genetic code). For the avoidance of doubt, the nucleic acid sequence encoding the TCR Vp domain may also encode a TCR chain constant domain. Examples of suitable constant domains are generally discussed above.

[0404] An example of a specific TCR p chain amino acid sequence that includes a TCR Vp domain described herein and an appropriate constant domain is shown in SEQ ID NO: 41. Appropriate functional variants of SEQ ID NO: 41 are also encompassed (e.g. variants having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 41 , wherein the variant TCR p chain amino acid sequence retains its ability to (specifically) bind to the peptide shown in SEQ ID NO: 153 when part of a binding protein described herein). In other words, a functional TCR p chain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 41 is also encompassed. As stated previously, the amino acid substitution may be a conservative amino acid substitution. The variability in sequence compared to SEQ ID NO:41 may all be in regions of the TCR p chain that do not form CDRs (i.e. the variant may have the CDRs of SEQ ID NO: 34, SEQ ID NO: 32 and / or SEQ ID NO: 33, and still have 25% (or less) sequence variability compared to SEQ ID NO:41. In other words, the sequence of the CDRs of SEQ ID NO: 41 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above. Suitably, percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 41).

[0405] As an example, the encoded TCR p chain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 41 , wherein the TCR p chain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 34. In this example, the TCR p chain CDR1 may have an amino acid sequence of SEQ ID NO: 32 and the TCR p chain CDR2 may have an amino acid sequence of SEQ ID NO: 33.

[0406] In examples where the TCR p chain has the amino acid sequence of SEQ ID NO:41 , the TCR p chain may be encoded by the nucleic acid sequence of SEQ ID NO: 42, or a genetically degenerate sequence thereof (i.e. other nucleic acid sequences that encode the same protein as a result of the degeneracy of the genetic code). It is noted that SEQ ID NO:42 is the nucleic acid sequence for TCR p chain of clone AJV_1.32.

[0407] In an example, the nucleic acid composition provided herein comprises a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO:34, or a functional fragment thereof.

[0408] In another example, the CDR3 of the Vp domain of a nucleic acid composition provided herein comprises or consists of the amino acid sequence of SEQ ID NO:34. In a further example, the Vp domain of a nucleic acid composition provided herein comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 37.

[0409] The TOR Vp domain sequences derived from TOR clone AJV_1.32 discussed above are particularly compatible with the TOR Va domain sequences derived from TOR clone AJV_1.32 discussed elsewhere herein.

[0410] Accordingly, in one example, a nucleic acid composition described herein encodes a haematopoietic-restricted MiHA-specific binding protein having TOR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO:31 , or a functional fragment thereof; and a nucleic acid sequence that encodes a TCR p domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO:34, or a functional fragment thereof.

[0411] In a particular example, a nucleic acid composition described herein encodes a haematopoietic- restricted MiHA-specific binding protein having a TCR Va domain with a CDR3 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 31 ; and a TCR Vp domain with a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO:34. In addition, the haematopoietic-restricted MiHA may comprise or consist of the sequence shown in SEQ ID NO: 153. Furthermore, the TCR Va domain may be part of a TCR a chain having a constant domain and the TCR Vp domain may be part of a TCR p chain having a constant domain.

[0412] In this particular example, the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 35; and the Vp domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 37. In one example, the Va domain comprises the amino acid sequence of SEQ ID NO: 35 and the Vp domain comprises the amino acid sequence of SEQ ID NO: 37. In such cases, the Va domain may be encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 36; and the Vp domain may be encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 38.

[0413] In this particular example, the TCR Va domain may include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 29 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NQ:30. Furthermore, the TCR Vp domain may include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO:32 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 33. For the avoidance of doubt, this particular example encompasses components of TCR clone AJV_1.32 exemplified herein. The different components of TCR clone AJV_1.32 and their respective SEQ ID Nos are summarised in Table 8 below.

[0414] As stated in more detail elsewhere herein, the nucleic acid composition described herein encodes both a TCR Va domain and a TCR Vp domain, which form the binding protein that is capable of specifically binding to a haematopoietic-restricted MiHA. In examples where the TCR Va domain and the TCR p domain are encoded by the same nucleic acid sequence, the TCR Va domain and TCR Vp domain may be joined together via a linker. Suitable linkers are discussed generally elsewhere herein. Additional appropriate polypeptide domains that may also be encoded by the nucleic acid sequences that encode the TCR Va domain and / or the TCR Vp domain are also discussed generally elsewhere herein.

[0415] In one example, the nucleic acid composition described herein may encode a soluble TCR or a chimeric single chain TCR wherein the TCR alpha chain variable domain is linked to the TCR beta chain variable domain and a constant domain which is e.g. fused to the CD3 zeta signalling domain. These are discussed generally in more detail elsewhere herein.

[0416] As discussed above, an isolated nucleic acid composition that encodes a haematopoietic- restricted MiHA-specific binding protein having a TCR a chain variable (Va) domain and a TCR p chain variable (Vp) domain is provided, the composition comprising: (a) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence; and (b) a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence; wherein the CDR3 amino acid sequences of (a) and (b) together bind (e.g. specifically bind) to an MiHA that comprises the amino acid sequence GPRWPPRMTH (SEQ ID NO:73).

[0417] As provided elsewhere herein, the inventors also identified TCR clone EWO_4.1G7 which also interacts with GPRWPPRMTH (SEQ ID NO: 73) in the context of HI_A-B*07:02. The sequences provided herein that correspond to TCR clone EWO_4.1G7 are SEQ ID NO:s 43 to 56.

[0418] An example of an appropriate TCR Vp domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to GPRWPPRMTH (SEQ ID NO: 73) is shown in SEQ ID NO:48. As would be clear to a person of skill in the art, variants of the amino acid sequence shown in SEQ ID NO:48 may also be functional (i.e. retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO: 73 when the CDR3 is part of TCR Vp domain). Such functional variants are therefore encompassed herein.

[0419] For example, appropriate (functional) Vp domain CDR3 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 48, i.e. they may have at least 80%, at least 93%, or 100% sequence identity to SEQ ID NO: 48. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 48). In other words, appropriate (functional) Vp domain CDR3 amino acid sequences may vary from the sequence shown in SEQ ID NO: 48 by one or several (e.g. two) amino acids. As stated above, functional variants of SEQ ID NO: 48 retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO: 73 when the CDR3 is part of TCR Vp domain.

[0420] Functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 48. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 48, or substitution, deletion or insertion of non-critical amino acids in non- critical regions of the CDR3.

[0421] Non-functional variants are amino acid sequence variants of SEQ ID NO: 48 that do not bind to the peptide shown in SEQ ID NO: 73. Non-functional variants will typically contain a nonconservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 48 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0422] In one example, the CDR3 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 48. In examples where the TCR Vp domain CDR3 has the amino acid sequence of SEQ ID NO:48, the CDR3 may be encoded by Any appropriate nucleic acid sequence.

[0423] The encoded TCR Vp domain may comprise, in addition to the specified CDR3, a CDR1 comprising an amino acid sequence of SEQ ID NO: 46, or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 73). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 46. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 46, or substitution, deletion or insertion of non-critical amino acids in non- critical regions of the protein.

[0424] Non-functional variants are amino acid sequence variants of SEQ ID NO: 46 that do not bind to the peptide shown in SEQ ID NO: 73. Non-functional variants will typically contain a nonconservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 46 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0425] For example, appropriate functional Vp domain CDR1 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 46, i.e. it may have at least 80%, or 100% sequence identity to SEQ ID NO: 46. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 46). In other words, appropriate (functional) Vp domain CDR1 amino acid sequences may vary from the sequence shown in SEQ ID NO:46 by one or several amino acids. As stated previously, the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO:46). As stated above, functional variants of SEQ ID NO: 46 retain the ability to (specifically) bind to the peptide shown in SEQ ID NO: 73 when the CDR1 is part of TCR Vp domain.

[0426] In one example, the CDR1 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 46. In examples where the TCR Vp domain CDR1 has the amino acid sequence of SEQ ID NO:46, the CDR1 may be encoded by any appropriate nucleic acid sequence.

[0427] The encoded TCR Vp domain may also comprise, in addition to the specified CDR3 (and optionally the specified CDR1 above), a CDR2 having an amino acid sequence of SEQ ID NO: 47, or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HLA-B*07:02). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 47. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 47, or substitution, deletion or insertion of non-critical amino acids in non-critical regions of the protein.

[0428] Non-functional variants are amino acid sequence variants of SEQ ID NO: 47 that do not specifically bind to HLA-B*07:02. Non-functional variants will typically contain a non-conservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 47 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0429] For example, appropriate functional Vp domain CDR2 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 47, i.e. it may have at least 80%, at least 83%, or 100% sequence identity to SEQ ID NO: 47. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 47). In other words, appropriate (functional) Vp domain CDR2 amino acid sequences may vary from the sequence shown in SEQ ID NO: 47 by one or several amino acids. As stated previously, the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO: 47). As stated above, a functional variant of SEQ ID NO: 47 retains the ability to specifically bind to HLA-B*07:02.

[0430] In one example, the CDR2 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 47. In examples where the TCR Vp domain CDR2 has the amino acid sequence of SEQ ID NO:47, the CDR2 may be encoded by any appropriate nucleic acid sequence. The encoded TCR Vp domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NO:48, SEQ ID NO: 46 and SEQ ID NO: 47, or functional variants thereof), with appropriate intervening sequences between the CDRs.

[0431] The encoded TCR Vp domain may have an amino acid sequence of SEQ ID NO: 51 , or a functional variant thereof (i.e. wherein the variant TCR Vp domain retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 73 when part of a binding protein described herein). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 51. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 51 , or substitution, deletion or insertion of non-critical amino acids in non-critical regions of the protein.

[0432] Non-functional variants are amino acid sequence variants of SEQ ID NO: 51 that do not bind to the peptide shown in SEQ ID NO: 73. Non-functional variants will typically contain a nonconservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO:51 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0433] In one example, the encoded TCR Vp domain may have an amino acid sequence having at least 75%, at least 80%, at least 85% or at least 90% (or at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) sequence identity to the amino acid sequence of SEQ ID NO: 51 , whilst retaining the ability to (specifically) bind to the peptide shown in SEQ ID NO: 73. In other words, a functional TCR Vp domain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 51 is also encompassed. As stated previously, the amino acid substitution may be a conservative amino acid substitution. The variability in sequence compared to SEQ ID NO:51 may all be in regions of the TCR Vp domain that do not form CDRs (i.e. the variant may have the CDRs of SEQ ID NO: 48, SEQ ID NO: 46 and / or SEQ ID NO: 47, and still have 25% (or less) sequence variability compared to SEQ ID NO: 51). In other words, the sequence of the CDRs of SEQ ID NO: 51 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above. Suitably, percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 51).

[0434] As an example, the encoded TCR Vp domain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 51 , wherein the TCR Vp domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 48. In this example, the TCR Vp domain CDR1 may have an amino acid sequence of SEQ ID NO:46 and the TCR p domain CDR2 may have an amino acid sequence of SEQ ID NO: 47.

[0435] In examples where the TCR Vp domain has the amino acid sequence of SEQ ID NO:51 , the TCR VP domain may be encoded by the nucleic acid sequence of SEQ ID NO:52, or a genetically degenerate sequence thereof (i.e. other nucleic acid sequences that encode the same protein as a result of the degeneracy of the genetic code).

[0436] For the avoidance of doubt, the nucleic acid sequence encoding the TCR p domain may also encode a TCR p chain constant domain. Examples of suitable constant domains are generally discussed above.

[0437] An example of a specific TCR p chain amino acid sequence that includes a TCR p domain described herein and an appropriate constant domain is shown in SEQ ID NO: 55. Appropriate functional variants of SEQ ID NO: 55 are also encompassed (e.g. variants having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 55, wherein the variant TCR p chain amino acid sequence retains its ability to (specifically) bind to the peptide shown in SEQ ID NO: 73 when part of a binding protein described herein). In other words, a functional TCR p chain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 55 is also encompassed. As stated previously, the amino acid substitution may be a conservative amino acid substitution. The variability in sequence compared to SEQ ID NO:55 may all be in regions of the TCR p chain that do not form CDRs (i.e. the variant may have the CDRs of SEQ ID NO: 48, SEQ ID NO: 46 and / or SEQ ID NO: 47, and still have 25% (or less) sequence variability compared to SEQ ID NO:55. In other words, the sequence of the CDRs of SEQ ID NO: 55 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above. Suitably, percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 55).

[0438] As an example, the encoded TCR p chain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 55, wherein the TCR p chain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 48. In this example, the TCR p chain CDR1 may have an amino acid sequence of SEQ ID NO: 46 and the TCR p chain CDR2 may have an amino acid sequence of SEQ ID NO: 47.

[0439] In examples where the TCR p chain has the amino acid sequence of SEQ ID NO:55, the TCR p chain may be encoded by the nucleic acid sequence of SEQ ID NO:56, or a genetically degenerate sequence thereof (i.e. other nucleic acid sequences that encode the same protein as a result of the degeneracy of the genetic code). It is noted that SEQ ID NO:56 is the nucleic acid sequence for TCR p chain of clone EWO_4.1G7. In an example, the nucleic acid composition provided herein comprises a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO:48, or a functional fragment thereof.

[0440] In another example, the CDR3 of the Vp domain of a nucleic acid composition provided herein comprises or consists of the amino acid sequence of SEQ ID NO:48.

[0441] In a further example, the Vp domain of a nucleic acid composition provided herein comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 51.

[0442] The TCR Vp domain sequences derived from TCR clone EWO_4.1G7 discussed above are particularly compatible with the TCR Va domain sequences derived from TCR clone EWO_4.1G7 discussed elsewhere herein.

[0443] Accordingly, in one example, a nucleic acid composition described herein encodes a haematopoietic-restricted MiHA-specific binding protein having TCR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO:45, or a functional fragment thereof; and a nucleic acid sequence that encodes a TCR p domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO:48, or a functional fragment thereof.

[0444] In a particular example, a nucleic acid composition described herein encodes a haematopoietic- restricted MiHA-specific binding protein having a TCR Va domain with a CDR3 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 45; and a TCR Vp domain with a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO:48. In addition, the haematopoietic-restricted MiHA may comprise or consist of the sequence shown in SEQ ID NO: 73. Furthermore, the TCR Va domain may be part of a TCR a chain having a constant domain and the TCR Vp domain may be part of a TCR p chain having a constant domain.

[0445] In this particular example, the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 49; and the Vp domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 51. In one example, the Va domain comprises the amino acid sequence of SEQ ID NO: 49 and the Vp domain comprises the amino acid sequence of SEQ ID NO: 51 . In such cases, the Va domain may be encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 50; and the Vp domain may be encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 52.

[0446] In this particular example, the TCR Va domain may include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 43 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO:44. Furthermore, the TCR Vp domain may include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO:46 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 47.

[0447] For the avoidance of doubt, this particular example encompasses components of TCR clone EWO_4.1G7 exemplified herein. The different components of TCR clone EWO_4.1G7 and their respective SEQ ID Nos are summarised in Table 9 below.

[0448] As stated in more detail elsewhere herein, the nucleic acid composition described herein encodes both a TCR Va domain and a TCR Vp domain, which form the binding protein that is capable of specifically binding to a haematopoietic-restricted MiHA as described herein. In examples where the TCR Va domain and the TCR p domain are encoded by the same nucleic acid sequence, the TCR Va domain and TCR Vp domain may be joined together via a linker. Suitable linkers are discussed generally elsewhere herein. Additional appropriate polypeptide domains that may also be encoded by the nucleic acid sequences that encode the TCR Va domain and / or the TCR Vp domain are also discussed generally elsewhere herein.

[0449] In one example, the nucleic acid composition described herein may encode a soluble TCR or a chimeric single chain TCR wherein the TCR alpha chain variable domain is linked to the TCR beta chain variable domain and a constant domain which is e.g. fused to the CD3 zeta signalling domain. These are discussed generally in more detail elsewhere herein.

[0450] (iv) VP domains that interact with GQAGFFPSPF (SEQ ID NO:74)

[0451] As provided elsewhere herein, the inventors identified TCR clone HJS_1-55 which interacts with GQAGFFPSPF (SEQ ID NO:74) in the context of HLA-B*15:01. The sequences provided herein that correspond to TCR clone HJS_1-55 are SEQ ID NO:s 57 to 70.

[0452] An example of an appropriate TCR Vp domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to GQAGFFPSPF (SEQ ID NO:74) is shown in SEQ ID NO:62. As would be clear to a person of skill in the art, variants of the amino acid sequence shown in SEQ ID NO:62 may also be functional (i.e. retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO: 74 when the CDR3 is part of TCR Vp domain). Such functional variants are therefore encompassed herein.

[0453] For example, appropriate (functional) Vp domain CDR3 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 62, i.e. they may have at least 80%, at least 93%, or 100% sequence identity to SEQ ID NO: 62. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 62). In other words, appropriate (functional) Vp domain CDR3 amino acid sequences may vary from the sequence shown in SEQ ID NO: 62 by one or several (e.g. two) amino acids. As stated above, functional variants of SEQ ID NO: 62 retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO: 74 when the CDR3 is part of TOR Vp domain.

[0454] Functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 62. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 62, or substitution, deletion or insertion of non-critical amino acids in non- critical regions of the CDR3.

[0455] Non-functional variants are amino acid sequence variants of SEQ ID NO: 62 that do not bind to the peptide shown in SEQ ID NO: 74. Non-functional variants will typically contain a nonconservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 62 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0456] In one example, the CDR3 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 62. In examples where the TCR Vp domain CDR3 has the amino acid sequence of SEQ ID NO:62, the CDR3 may be encoded by any appropriate nucleic acid sequence.

[0457] The encoded TCR Vp domain may comprise, in addition to the specified CDR3, a CDR1 comprising an amino acid sequence of SEQ ID NO: 60, or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 74). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 60. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 60, or substitution, deletion or insertion of non-critical amino acids in non- critical regions of the protein.

[0458] Non-functional variants are amino acid sequence variants of SEQ ID NO: 60 that do not bind to the peptide shown in SEQ ID NO: 74. Non-functional variants will typically contain a nonconservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 60 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0459] For example, appropriate functional Vp domain CDR1 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 60, i.e. it may have at least 80%, or 100% sequence identity to SEQ ID NO: 60. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 60). In other words, appropriate (functional) Vp domain CDR1 amino acid sequences may vary from the sequence shown in SEQ ID NO:60 by one or several amino acids. As stated previously, the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO:60). As stated above, functional variants of SEQ ID NO: 60 retain the ability to (specifically) bind to the peptide shown in SEQ ID NO: 74 when the CDR1 is part of TOR Vp domain).

[0460] In one example, the CDR1 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 60. In examples where the TCR Vpa domain CDR1 has the amino acid sequence of SEQ ID NQ:60, the CDR1 may be encoded by any appropriate nucleic acid sequence.

[0461] The encoded TCR Vp domain may also comprise, in addition to the specified CDR3 (and optionally the specified CDR1 above), a CDR2 having an amino acid sequence of SEQ ID NO: 61 , or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HLA-B*15:01). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 61. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 61 , or substitution, deletion or insertion of non-critical amino acids in non-critical regions of the protein.

[0462] Non-functional variants are amino acid sequence variants of SEQ ID NO: 61 that do not specifically bind to HLA-B*15:01. Non-functional variants will typically contain a non-conservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO: 61 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0463] For example, appropriate functional Vp domain CDR2 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 61 , i.e. it may have at least 80%, at least 83%, or 100% sequence identity to SEQ ID NO: 61. Suitably, percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 61). In other words, appropriate (functional) Vp domain CDR2 amino acid sequences may vary from the sequence shown in SEQ ID NO: 61 by one or several amino acids. As stated previously, the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO: 61). As stated above, a functional variant of SEQ ID NO: 61 retains the ability to specifically bind to HLA-B*15:01.

[0464] In one example, the CDR2 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 61 . In examples where the TCR Vp domain CDR2 has the amino acid sequence of SEQ ID NO:61 , the CDR2 may be encoded by any appropriate nucleic acid sequence. The encoded TCR Vp domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NO:62, SEQ ID NO: 60 and SEQ ID NO: 61 , or functional variants thereof), with appropriate intervening sequences between the CDRs.

[0465] The encoded TCR Vp domain may have an amino acid sequence of SEQ ID NO: 65, or a functional variant thereof (i.e. wherein the variant TCR Vp domain retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 74 when part of a binding protein described herein). Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 65. The term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 65, or substitution, deletion or insertion of non-critical amino acids in non-critical regions of the protein.

[0466] Non-functional variants are amino acid sequence variants of SEQ ID NO: 65 that do not bind to the peptide shown in SEQ ID NO: 74. Non-functional variants will typically contain a nonconservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ ID NO:65 or a substitution, insertion or deletion in critical amino acids or critical regions. Methods for identifying functional and non-functional variants are well known to a person of ordinary skill in the art.

[0467] In one example, the encoded TCR Vp domain may have an amino acid sequence having at least 75%, at least 80%, at least 85% or at least 90% (or at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) sequence identity to the amino acid sequence of SEQ ID NO: 65, whilst retaining the ability to (specifically) bind to the peptide shown in SEQ ID NO: 74. In other words, a functional TCR Vp domain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 65 is also encompassed. As stated previously, the amino acid substitution may be a conservative amino acid substitution. The variability in sequence compared to SEQ ID NO:65 may all be in regions of the TCR Vp domain that do not form CDRs (i.e. the variant may have the CDRs of SEQ ID NO: 62, SEQ ID NO: 60 and / or SEQ ID NO: 61 , and still have 25% (or less) sequence variability compared to SEQ ID NO: 65). In other words, the sequence of the CDRs of SEQ ID NO: 65 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above. Suitably, percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 65).

[0468] As an example, the encoded TCR Vp domain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 65, wherein the TCR Vp domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 62. In this example, the TCR Vp domain CDR1 may have an amino acid sequence of SEQ ID NO:60 and the TCR p domain CDR2 may have an amino acid sequence of SEQ ID NO: 61.

[0469] In examples where the TCR Vp domain has the amino acid sequence of SEQ ID NO:65, the TCR VP domain may be encoded by the nucleic acid sequence of SEQ ID NO: 66, or a genetically degenerate sequence thereof (i.e. other nucleic acid sequences that encode the same protein as a result of the degeneracy of the genetic code).

[0470] For the avoidance of doubt, the nucleic acid sequence encoding the TCR p domain may also encode a TCR p chain constant domain. Examples of suitable constant domains are generally discussed above.

[0471] An example of a specific TCR p chain amino acid sequence that includes a TCR p domain described herein and an appropriate constant domain is shown in SEQ ID NO: 69. Appropriate functional variants of SEQ ID NO: 69 are also encompassed (e.g. variants having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 69, wherein the variant TCR p chain amino acid sequence retains its ability to (specifically) bind to the peptide shown in SEQ ID NO: 74 when part of a binding protein described herein). In other words, a functional TCR p chain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 69 is also encompassed. As stated previously, the amino acid substitution may be a conservative amino acid substitution. The variability in sequence compared to SEQ ID NO:69 may all be in regions of the TCR p chain that do not form CDRs (i.e. the variant may have the CDRs of SEQ ID NO: 62, SEQ ID NO: 60 and / or SEQ ID NO: 61 , and still have 25% (or less) sequence variability compared to SEQ ID NO:69. In other words, the sequence of the CDRs of SEQ ID NO: 69 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above. Suitably, percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 69).

[0472] As an example, the encoded TCR p chain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 69, wherein the TCR p chain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 62. In this example, the TCR p chain CDR1 may have an amino acid sequence of SEQ ID NO: 60 and the TCR p chain CDR2 may have an amino acid sequence of SEQ ID NO: 61.

[0473] In examples where the TCR p chain has the amino acid sequence of SEQ ID NO:69, the TCR p chain may be encoded by the nucleic acid sequence of SEQ ID NQ:70, or a genetically degenerate sequence thereof (i.e. other nucleic acid sequences that encode the same protein as a result of the degeneracy of the genetic code). It is noted that SEQ ID NQ:70 is the nucleic acid sequence for TCR p chain of clone HJS_1-55. In an example, the nucleic acid composition provided herein comprises a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO:62, or a functional fragment thereof.

[0474] In another example, the CDR3 of the Vp domain of a nucleic acid composition provided herein comprises or consists of the amino acid sequence of SEQ ID NO:62.

[0475] In a further example, the Vp domain of a nucleic acid composition provided herein comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 65.

[0476] The TCR Vp domain sequences derived from TCR clone HJS_1-55 discussed above are particularly compatible with the TCR Va domain sequences derived from TCR clone HJS_1-55 discussed elsewhere herein.

[0477] Accordingly, in one example, a nucleic acid composition described herein encodes a haematopoietic-restricted MiHA-specific binding protein having TCR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO:59, or a functional fragment thereof; and a nucleic acid sequence that encodes a TCR p domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO:62, or a functional fragment thereof.

[0478] In a particular example, a nucleic acid composition described herein encodes a haematopoietic- restricted MiHA-specific binding protein having a TCR Va domain with a CDR3 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 59; and a TCR Vp domain with a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO:62. In addition, the haematopoietic-restricted MiHA may comprise or consist of the sequence shown in SEQ ID NO: 74. Furthermore, the TCR Va domain may be part of a TCR a chain having a constant domain and the TCR Vp domain may be part of a TCR p chain having a constant domain.

[0479] In this particular example, the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 63; and the Vp domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 65. In one example, the Va domain comprises the amino acid sequence of SEQ ID NO: 63 and the Vp domain comprises the amino acid sequence of SEQ ID NO: 65. In such cases, the Va domain may be encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 64; and the Vp domain may be encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 66.

[0480] In this particular example, the TCR Va domain may include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO:57 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO:58. Furthermore, the TCR Vp domain may include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO:60 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 61 .

[0481] For the avoidance of doubt, this particular example encompasses components of TCR clone HJS_1-55 exemplified herein. The different components of TCR clone HJS_1-55 and their respective SEQ ID Nos are summarised in Table 10 below.

[0482] Additional TCR components

[0483] TCR components that interact with GPRPSPTRSV (SEQ ID NO:72)

[0484] As provided elsewhere herein, the inventors have identified TCR clone VDL_T3 which interacts with GPRPSPTRSV (SEQ ID NO:72) in the context of HI_A-B*07:02. The nucleic acid and polypeptide sequences provided herein that correspond to TCR clone VDL_T3 are SEQ ID NO:s 97 to 110. See also table 11.

[0485] As discussed above, an isolated nucleic acid composition that encodes a haematopoietic- restricted MiHA-specific binding protein having a TCR a chain variable (Va) domain and a TCR p chain variable (V ) domain is provided, the composition comprising: (a) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence; and (b) a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence; wherein the CDR3 amino acid sequences of (a) and (b) together bind (e.g. specifically bind) to an MiHA that comprises the amino acid sequence GPRPSPTRSV (SEQ ID NO:72).

[0486] An example of an appropriate TCR Va domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to GPRPSPTRSV (SEQ ID NO:72) is shown in SEQ ID NO: 99. In one example, the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 99, or is a functional variant thereof ((i.e. where the variant retains its ability to confer (specific) binding to the peptide GPRPSPTRSV (SEQ ID NO:72)) when the CDR3 is part of TCR Va domain). In examples where the TCR Va domain CDR3 has the amino acid sequence of SEQ ID NO: 99, the CDR3 may be encoded by any appropriate nucleic acid sequence (see for example table 11).

[0487] The encoded TCR Va domain may comprise, in addition to the specified CDR3, a CDR1 comprising or consisting of an amino acid sequence of SEQ ID NO: 97, or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO:72). In examples where the TCR Va domain CDR1 has the amino acid sequence of SEQ ID NO: 97, the CDR1 may be encoded by any appropriate nucleic acid sequence (see for example table 11). The encoded TCR Va domain may also comprise, in addition to the specified CDR3 (and optionally the specified CDR1 above), a CDR2 comprising or consisting of an amino acid sequence of SEQ ID NO:98, or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to HLA-B*07:02). In examples where the TCR Va domain CDR2 has the amino acid sequence of SEQ ID NO:98, the CDR2 may be encoded by any appropriate nucleic acid sequence (see for example table 11).

[0488] The encoded TCR Va domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NO:99, SEQ ID NO:97 and SEQ ID NO: 98, or functional variants thereof), with appropriate intervening sequences between the CDRs.

[0489] The encoded TCR Va domain may comprise an amino acid sequence of SEQ ID NO: 103, or a functional variant thereof (i.e. wherein the variant TCR Va domain retains the ability to (specifically) bind to the peptide shown in SEQ ID NO:72 when part of a binding protein described herein). In examples where the TCR Va domain has the amino acid sequence of SEQ ID NO: 103, the TCR Va domain may be encoded by any appropriate nucleic acid sequence (see for example table 11).

[0490] As an example, the encoded TCR Va domain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 103, wherein the TCR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 99. In this example, the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 97 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 98.

[0491] As another example, the encoded TCR Va domain may comprise an amino acid sequence with 0 to 10 (or 0 to 5) amino acid substitutions, insertions or deletions compared to SEQ ID NO: 103, wherein the TCR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 99. In this example, the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 97 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 98.

[0492] For the avoidance of doubt, the nucleic acid sequence encoding the TCR Va domain may also encode a TCR a chain constant domain. Examples of suitable constant domains are generally discussed elsewhere herein. See also table 11.

[0493] An example of an appropriate TCR Vp domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to GPRPSPTRSV (SEQ ID NO:72) is shown in SEQ ID NO: 102. In one example, the CDR3 of the V domain comprises or consists of the amino acid sequence of SEQ ID NO: 102, or is a functional variant thereof ((i.e. where the variant retains its ability to confer (specific) binding to the peptide GPRPSPTRSV (SEQ ID NO:72)) when the CDR3 is part of TCR Vp domain). In examples where the TCR Vp domain CDR3 has the amino acid sequence of SEQ ID NO: 102, the CDR3 may be encoded by any appropriate nucleic acid sequence (see for example table 11).

[0494] The encoded TOR p domain may comprise, in addition to the specified CDR3, a CDR1 comprising an amino acid sequence of SEQ ID NO: 100, or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 72). In examples where the TOR Vp domain CDR1 has the amino acid sequence of SEQ ID NO: 100, the CDR1 may be encoded by any appropriate nucleic acid sequence (see for example table 11).

[0495] The encoded TOR Vp domain may also comprise, in addition to the specified CDR3 (and optionally the specified CDR1 above), a CDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 101 , or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HLA-B*07:02). In examples where the TOR Vp domain CDR2 has the amino acid sequence of SEQ ID NO: 101 , the CDR2 may be encoded by any appropriate nucleic acid sequence (see for example table 11).

[0496] The encoded TOR Vp domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NO: 102, SEQ ID NO: 100 and SEQ ID NO: 101 , or functional variants thereof), with appropriate intervening sequences between the CDRs.

[0497] The encoded TOR Vp domain may have an amino acid sequence of SEQ ID NO: 105, or a functional variant thereof (i.e. wherein the variant TOR Vp domain retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 72 when part of a binding protein described herein). In examples where the TOR Vp domain has the amino acid sequence of SEQ ID NQ:105, the TOR Vp domain may be encoded by any appropriate nucleic acid sequence (see for example table 11).

[0498] As an example, the encoded TOR p domain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 105, wherein the TOR p domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 102. In this example, the TOR p domain CDR1 may have an amino acid sequence of SEQ ID NQ:100 and the TOR p domain CDR2 may have an amino acid sequence of SEQ ID NO: 101.

[0499] As another example, the encoded TOR p domain may comprise an amino acid sequence with 0 to 10 (or 0 to 5) amino acid substitutions, insertions or deletions compared to SEQ ID NO: 105, wherein the TOR p domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 102. In this example, the TOR p domain CDR1 may have an amino acid sequence of SEQ ID NO: 100 and the TOR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 101. For the avoidance of doubt, the nucleic acid sequence encoding the TCR Vp domain may also encode a TCR chain constant domain. Examples of suitable constant domains are generally discussed elsewhere herein. See also table 11.

[0500] In a particular example, a nucleic acid composition described herein encodes a haematopoietic- restricted MiHA-specific binding protein having a TCR Va domain with a CDR3 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 99; and a TCR Vp domain with a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 102. Optionally, the TCR Va domain may also include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO:97 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO:98. Furthermore, the TCR p domain may include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 100 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 101.

[0501] Optionally, the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 103; and the Vp domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NQ:105. In one example, the Va domain comprises the amino acid sequence of SEQ ID NO: 103 and the Vp domain comprises the amino acid sequence of SEQ ID NO: 105.

[0502] Functional variants may have at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to the (reference) sequence shown in table 11. In other words, appropriate functional variants may vary from the sequence shown in table 11 by one or several (e.g. two etc) amino acids. Functional variants will typically contain only conservative substitutions of one, two or more amino acids of the reference sequence, or substitution, deletion or insertion of non-critical amino acids in non-critical regions of the reference sequence shown in table 11 .

[0503] TCR components that interact with GPRWPPRMTH (SEQ ID NO: 73) and / or GPRWPPRMT (SEQ ID NO: 153)

[0504] As provided elsewhere herein, the inventors have identified TCR clone EW0_18-22-23 which interacts with GPRWPPRMTH (SEQ ID NO: 73) in the context of HLA-B*07:02; and also interacts with GPRWPPRMT (SEQ ID NO: 153) in the context of HI_A-B*07:02. The nucleic acid and polypeptide sequences provided herein that correspond to TCR clone EW0_18-22-23 are SEQ ID NO:s 111 to 124. See also table 12.

[0505] As discussed above, an isolated nucleic acid composition that encodes a haematopoietic- restricted MiHA-specific binding protein having a TCR a chain variable (Va) domain and a TCR p chain variable (V ) domain is provided, the composition comprising: (a) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence; and (b) a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence; wherein the CDR3 amino acid sequences of (a) and (b) together bind (e.g. specifically bind) to an MiHA that comprises the amino acid sequence GPRWPPRMTH (SEQ ID NO: 73) and / or GPRWPPRMT (SEQ ID NO: 153).

[0506] An example of an appropriate TCR Va domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to GPRWPPRMTH (SEQ ID NO: 73) and / or GPRWPPRMT (SEQ ID NO: 153) is shown in SEQ ID NO: 113. In one example, the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 113, or is a functional variant thereof ((i.e. where the variant retains its ability to confer (specific) binding to the peptide GPRWPPRMTH (SEQ ID NO: 73) and / or GPRWPPRMT (SEQ ID NO: 153)) when the CDR3 is part of TCR Va domain). In examples where the TCR Va domain CDR3 has the amino acid sequence of SEQ ID NO: 113, the CDR3 may be encoded by any appropriate nucleic acid sequence (see for example table 12).

[0507] The encoded TCR Va domain may comprise, in addition to the specified CDR3, a CDR1 comprising or consisting of an amino acid sequence of SEQ ID NO: 111 , or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO:73 and / or SEQ ID NO: 153). In examples where the TCR Va domain CDR1 has the amino acid sequence of SEQ ID NO: 111 , the CDR1 may be encoded by any appropriate nucleic acid sequence (see for example table 12).

[0508] The encoded TCR Va domain may also comprise, in addition to the specified CDR3 (and optionally the specified CDR1 above), a CDR2 comprising or consisting of an amino acid sequence of SEQ ID NO:112, or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HLA-B*07:02). In examples where the TCR Va domain CDR2 has the amino acid sequence of SEQ ID NO:112, the CDR2 may be encoded by any appropriate nucleic acid sequence (see for example table 12).

[0509] The encoded TCR Va domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NO: 113, SEQ ID NO:111 and SEQ ID NO: 112, or functional variants thereof), with appropriate intervening sequences between the CDRs.

[0510] The encoded TCR Va domain may comprise an amino acid sequence of SEQ ID NO: 117, or a functional variant thereof (i.e. wherein the variant TCR Va domain retains the ability to (specifically) bind to the peptide shown in SEQ ID NO:73 and / or SEQ ID NO: 153 when part of a binding protein described herein). In examples where the TCR Va domain has the amino acid sequence of SEQ ID NO: 117, the TCR Va domain may be encoded by any appropriate nucleic acid sequence (see for example table 12). As an example, the encoded TCR Va domain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 117, wherein the TCR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 113. In this example, the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 111 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 112.

[0511] As another example, the encoded TCR Va domain may comprise an amino acid sequence with 0 to 10 (or 0 to 5) amino acid substitutions, insertions or deletions compared to SEQ ID NO: 117, wherein the TCR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 113. In this example, the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 111 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 112.

[0512] For the avoidance of doubt, the nucleic acid sequence encoding the TCR Va domain may also encode a TCR a chain constant domain. Examples of suitable constant domains are generally discussed elsewhere herein. See also table 12.

[0513] An example of an appropriate TCR Vp domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to GPRWPPRMTH (SEQ ID NO: 73) and / or GPRWPPRMT (SEQ ID NO: 153) is shown in SEQ ID NO: 116. In one example, the CDR3 of the V domain comprises or consists of the amino acid sequence of SEQ ID NO: 116, or is a functional variant thereof ((i.e. where the variant retains its ability to confer (specific) binding to the peptide GPRWPPRMTH (SEQ ID NO: 73) and / or GPRWPPRMT (SEQ ID NO: 153)) when the CDR3 is part of TCR Vp domain). In examples where the TCR Vp domain CDR3 has the amino acid sequence of SEQ ID NO: 116, the CDR3 may be encoded by any appropriate nucleic acid sequence (see for example table 12).

[0514] The encoded TCR Vp domain may comprise, in addition to the specified CDR3, a CDR1 comprising an amino acid sequence of SEQ ID NO: 114, or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 73 and / or SEQ ID NO:153). In examples where the TCR Vp domain CDR1 has the amino acid sequence of SEQ ID NO: 114, the CDR1 may be encoded by any appropriate nucleic acid sequence (see for example table 12).

[0515] The encoded TCR Vp domain may also comprise, in addition to the specified CDR3 (and optionally the specified CDR1 above), a CDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 115, or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HLA-B*07:02). In examples where the TCR Vp domain CDR2 has the amino acid sequence of SEQ ID NO:115, the CDR2 may be encoded by any appropriate nucleic acid sequence (see for example table 12). The encoded TCR Vp domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NO:116, SEQ ID NO: 114 and SEQ ID NO: 115, or functional variants thereof), with appropriate intervening sequences between the CDRs.

[0516] The encoded TCR Vp domain may have an amino acid sequence of SEQ ID NO: 119, or a functional variant thereof (i.e. wherein the variant TCR Vp domain retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 73 and / or SEQ ID NO: 153 when part of a binding protein described herein). In examples where the TCR Vp domain has the amino acid sequence of SEQ ID NO: 119, the TCR Vp domain may be encoded by any appropriate nucleic acid sequence (see for example table 12).

[0517] As an example, the encoded TCR Vp domain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 119, wherein the TCR Vp domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 116. In this example, the TCR Vp domain CDR1 may have an amino acid sequence of SEQ ID NO:114 and the TCR Vp domain CDR2 may have an amino acid sequence of SEQ ID NO: 115.

[0518] As another example, the encoded TCR Vp domain may comprise an amino acid sequence with 0 to 10 (or 0 to 5) amino acid substitutions, insertions or deletions compared to SEQ ID NO: 119, wherein the TCR Vp domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 116. In this example, the TCR Vp domain CDR1 may have an amino acid sequence of SEQ ID NO: 114 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 115.

[0519] For the avoidance of doubt, the nucleic acid sequence encoding the TCR Vp domain may also encode a TCR p chain constant domain. Examples of suitable constant domains are generally discussed elsewhere herein. See also table 12.

[0520] In a particular example, a nucleic acid composition described herein encodes a haematopoietic- restricted MiHA-specific binding protein having a TCR Va domain with a CDR3 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 113; and a TCR p domain with a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 116. Optionally, the TCR Va domain may also include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO:111 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO:112. Furthermore, the TCR Vp domain may include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO:114 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 115.

[0521] Optionally, the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 117; and the Vp domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO:119. In one example, the Va domain comprises the amino acid sequence of SEQ ID NO: 117 and the Vp domain comprises the amino acid sequence of SEQ ID NO: 119.

[0522] Functional variants may have at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to the (reference) sequence shown in table 12. In other words, appropriate functional variants may vary from the sequence shown in table 12 by one or several (e.g. two etc) amino acids. Functional variants will typically contain only conservative substitutions of one, two or more amino acids of the reference sequence, or substitution, deletion or insertion of non-critical amino acids in non-critical regions of the reference sequence shown in table 12.

[0523] TCR components that interact with GQAGFFPSPF (SEQ ID NO: 74)

[0524] As provided elsewhere herein, the inventors have identified TCR clone HJS_BLK_01 which interacts with GQAGFFPSPF (SEQ ID NO: 74) in the context of HLA-B*15:01. The nucleic acid and polypeptide sequences provided herein that correspond to TCR clone HJS_BLK_01 are SEQ ID NO:s 125 to 138. See also table 13.

[0525] As discussed above, an isolated nucleic acid composition that encodes a haematopoietic- restricted MiHA-specific binding protein having a TCR a chain variable (Va) domain and a TCR chain variable (VP) domain is provided, the composition comprising: (a) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence; and (b) a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence; wherein the CDR3 amino acid sequences of (a) and (b) together bind (e.g. specifically bind) to an MiHA that comprises the amino acid sequence GQAGFFPSPF (SEQ ID NO: 74).

[0526] An example of an appropriate TCR Va domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to GQAGFFPSPF (SEQ ID NO: 74) is shown in SEQ ID NO: 127. In one example, the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 127, or is a functional variant thereof ((i.e. where the variant retains its ability to confer (specific) binding to the peptide GQAGFFPSPF (SEQ ID NO: 74)) when the CDR3 is part of TCR Va domain). In examples where the TCR Va domain CDR3 has the amino acid sequence of SEQ ID NO: 127, the CDR3 may be encoded by any appropriate nucleic acid sequence (see for example table 13).

[0527] The encoded TCR Va domain may comprise, in addition to the specified CDR3, a CDR1 comprising or consisting of an amino acid sequence of SEQ ID NO: 125, or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO:74). In examples where the TCR Va domain CDR1 has the amino acid sequence of SEQ ID NO: 125, the CDR1 may be encoded by any appropriate nucleic acid sequence (see for example table 13).

[0528] The encoded TOR Va domain may also comprise, in addition to the specified CDR3 (and optionally the specified CDR1 above), a CDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 126, or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HLA-B*15:01). In examples where the TOR Va domain CDR2 has the amino acid sequence of SEQ ID NO: 126, the CDR2 may be encoded by any appropriate nucleic acid sequence (see for example table 13).

[0529] The encoded TCR Va domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NO:127, SEQ ID NO:125 and SEQ ID NO: 126, or functional variants thereof), with appropriate intervening sequences between the CDRs.

[0530] The encoded TCR Va domain may comprise an amino acid sequence of SEQ ID NO: 131 , or a functional variant thereof (i.e. wherein the variant TCR Va domain retains the ability to (specifically) bind to the peptide shown in SEQ ID NO:74 when part of a binding protein described herein). In examples where the TCR Va domain has the amino acid sequence of SEQ ID NO: 131 , the TCR Va domain may be encoded by any appropriate nucleic acid sequence (see for example table 13).

[0531] As an example, the encoded TCR Va domain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 131, wherein the TCR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 127. In this example, the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 125 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 126.

[0532] As another example, the encoded TCR Va domain may comprise an amino acid sequence with 0 to 10 (or 0 to 5) amino acid substitutions, insertions or deletions compared to SEQ ID NO: 131, wherein the TCR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 127. In this example, the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 125 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 126.

[0533] For the avoidance of doubt, the nucleic acid sequence encoding the TCR Va domain may also encode a TCR a chain constant domain. Examples of suitable constant domains are generally discussed elsewhere herein. See also table 13.

[0534] An example of an appropriate TCR Vp domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to GQAGFFPSPF (SEQ ID NO: 74) is shown in SEQ ID NO: 130. In one example, the CDR3 of the V domain comprises or consists of the amino acid sequence of SEQ ID NO: 130, or is a functional variant thereof ((i.e. where the variant retains its ability to confer (specific) binding to the peptide GQAGFFPSPF (SEQ ID NO: 74)) when the CDR3 is part of TOR VP domain). In examples where the TOR Vp domain CDR3 has the amino acid sequence of SEQ ID NO: 130, the CDR3 may be encoded by any appropriate nucleic acid sequence (see for example table 13).

[0535] The encoded TOR Vp domain may comprise, in addition to the specified CDR3, a CDR1 comprising an amino acid sequence of SEQ ID NO: 128, or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 74). In examples where the TCR Vp domain CDR1 has the amino acid sequence of SEQ ID NO: 128, the CDR1 may be encoded by any appropriate nucleic acid sequence (see for example table 13).

[0536] The encoded TCR Vp domain may also comprise, in addition to the specified CDR3 (and optionally the specified CDR1 above), a CDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 129, or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HLA-B*15:01). In examples where the TCR Vp domain CDR2 has the amino acid sequence of SEQ ID NO: 129, the CDR2 may be encoded by any appropriate nucleic acid sequence (see for example table 13).

[0537] The encoded TCR Vp domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NQ:130, SEQ ID NO: 128 and SEQ ID NO: 129, or functional variants thereof), with appropriate intervening sequences between the CDRs.

[0538] The encoded TCR Vp domain may have an amino acid sequence of SEQ ID NO: 133, or a functional variant thereof (i.e. wherein the variant TCR Vp domain retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 74 when part of a binding protein described herein). In examples where the TCR Vp domain has the amino acid sequence of SEQ ID NO:133, the TCR Vp domain may be encoded by any appropriate nucleic acid sequence (see for example table 13).

[0539] As an example, the encoded TCR p domain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 133, wherein the TCR p domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 130. In this example, the TCR p domain CDR1 may have an amino acid sequence of SEQ ID NO:128 and the TCR p domain CDR2 may have an amino acid sequence of SEQ ID NO: 129.

[0540] As another example, the encoded TCR p domain may comprise an amino acid sequence with 0 to 10 (or 0 to 5) amino acid substitutions, insertions or deletions compared to SEQ ID NO: 133, wherein the TCR p domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 130. In this example, the TCR Vp domain CDR1 may have an amino acid sequence of SEQ ID NO: 128 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 129.

[0541] For the avoidance of doubt, the nucleic acid sequence encoding the TCR Vp domain may also encode a TCR p chain constant domain. Examples of suitable constant domains are generally discussed elsewhere herein. See also table 13.

[0542] In a particular example, a nucleic acid composition described herein encodes a haematopoietic- restricted MiHA-specific binding protein having a TCR Va domain with a CDR3 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 127; and a TCR p domain with a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 130. Optionally, the TCR Va domain may also include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO:125 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 126. Furthermore, the TCR Vp domain may include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 128 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 129.

[0543] Optionally, the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 131 ; and the Vp domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO:133. In one example, the Va domain comprises the amino acid sequence of SEQ ID NO: 131 and the Vp domain comprises the amino acid sequence of SEQ ID NO: 133.

[0544] Functional variants may have at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to the (reference) sequence shown in table 13. In other words, appropriate functional variants may vary from the sequence shown in table 13 by one or several (e.g. two etc) amino acids. Functional variants will typically contain only conservative substitutions of one, two or more amino acids of the reference sequence, or substitution, deletion or insertion of non-critical amino acids in non-critical regions of the reference sequence shown in table 13.

[0545] TCR components that interact with GPRWPPRMTH (SEQ ID NO: 73)

[0546] As provided elsewhere herein, the inventors have identified TCR clone MBF_1-31 which interacts with GPRWPPRMTH (SEQ ID NO: 73) in the context of HI_A-B*07:02. The nucleic acid and polypeptide sequences provided herein that correspond to TCR clone MBF_1-31 are SEQ ID NO:s 139 to 152. See also table 14.

[0547] As discussed above, an isolated nucleic acid composition that encodes a haematopoietic- restricted MiHA-specific binding protein having a TCR a chain variable (Va) domain and a TCR p chain variable (Vp) domain is provided, the composition comprising: (a) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence; and (b) a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence; wherein the CDR3 amino acid sequences of (a) and (b) together bind (e.g. specifically bind) to an MiHA that comprises the amino acid sequence GPRWPPRMTH (SEQ ID NO: 73).

[0548] An example of an appropriate TCR Va domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to GPRWPPRMTH (SEQ ID NO: 73) is shown in SEQ ID NO: 141. In one example, the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 141 , or is a functional variant thereof ((i.e. where the variant retains its ability to confer (specific) binding to the peptide GPRWPPRMTH (SEQ ID NO: 73)) when the CDR3 is part of TCR Va domain). In examples where the TCR Va domain CDR3 has the amino acid sequence of SEQ ID NO: 141 , the CDR3 may be encoded by any appropriate nucleic acid sequence (see for example table 14).

[0549] The encoded TCR Va domain may comprise, in addition to the specified CDR3, a CDR1 comprising or consisting of an amino acid sequence of SEQ ID NO: 139, or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO:73). In examples where the TCR Va domain CDR1 has the amino acid sequence of SEQ ID NO: 139, the CDR1 may be encoded by any appropriate nucleic acid sequence (see for example table 14).

[0550] The encoded TCR Va domain may also comprise, in addition to the specified CDR3 (and optionally the specified CDR1 above), a CDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 140, or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HLA-B*07:02). In examples where the TCR Va domain CDR2 has the amino acid sequence of SEQ ID NO: 140, the CDR2 may be encoded by any appropriate nucleic acid sequence (see for example table 14).

[0551] The encoded TCR Va domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NO:139, SEQ ID NQ:140 and SEQ ID NO: 141 , or functional variants thereof), with appropriate intervening sequences between the CDRs.

[0552] The encoded TCR Va domain may comprise an amino acid sequence of SEQ ID NO: 145, or a functional variant thereof (i.e. wherein the variant TCR Va domain retains the ability to (specifically) bind to the peptide shown in SEQ ID NO:73 when part of a binding protein described herein). In examples where the TCR Va domain has the amino acid sequence of SEQ ID NO: 145, the TCR Va domain may be encoded by any appropriate nucleic acid sequence (see for example table 14).

[0553] As an example, the encoded TCR Va domain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 145, wherein the TOR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 141. In this example, the TOR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 139 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 140.

[0554] As another example, the encoded TCR Va domain may comprise an amino acid sequence with 0 to 10 (or 0 to 5) amino acid substitutions, insertions or deletions compared to SEQ ID NO: 145, wherein the TCR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO:

[0555] 141. In this example, the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 139 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 140.

[0556] For the avoidance of doubt, the nucleic acid sequence encoding the TCR Va domain may also encode a TCR a chain constant domain. Examples of suitable constant domains are generally discussed elsewhere herein. See also table 14.

[0557] An example of an appropriate TCR Vp domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to GPRWPPRMTH (SEQ ID NO: 73) is shown in SEQ ID NO: 144. In one example, the CDR3 of the V domain comprises or consists of the amino acid sequence of SEQ ID NO: 144, or is a functional variant thereof ((i.e. where the variant retains its ability to confer (specific) binding to the peptide GPRWPPRMTH (SEQ ID NO: 73)) when the CDR3 is part of TCR Vp domain). In examples where the TCR Vp domain CDR3 has the amino acid sequence of SEQ ID NO: 144, the CDR3 may be encoded by any appropriate nucleic acid sequence (see for example table 14).

[0558] The encoded TCR Vp domain may comprise, in addition to the specified CDR3, a CDR1 comprising an amino acid sequence of SEQ ID NO: 142, or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 73). In examples where the TCR Vp domain CDR1 has the amino acid sequence of SEQ ID NO:

[0559] 142, the CDR1 may be encoded by any appropriate nucleic acid sequence (see for example table 14).

[0560] The encoded TCR Vp domain may also comprise, in addition to the specified CDR3 (and optionally the specified CDR1 above), a CDR2 comprising or consisting of an amino acid sequence of SEQ ID NO: 143, or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HLA-B*07:02). In examples where the TCR Vp domain CDR2 has the amino acid sequence of SEQ ID NO: 143, the CDR2 may be encoded by any appropriate nucleic acid sequence (see for example table 14).

[0561] The encoded TCR Vp domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NO:142, SEQ ID NO: 143 and SEQ ID NO: 144, or functional variants thereof), with appropriate intervening sequences between the CDRs. The encoded TCR Vp domain may have an amino acid sequence of SEQ ID NO: 147, or a functional variant thereof (i.e. wherein the variant TCR Vp domain retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 73 when part of a binding protein described herein). In examples where the TCR Vp domain has the amino acid sequence of SEQ ID NO:147, the TCR Vp domain may be encoded by any appropriate nucleic acid sequence (see for example table 14).

[0562] As an example, the encoded TCR p domain may comprise an amino acid sequence having at least 75% (e.g. at least 75%, at least 80%, at least 85%, at least 90%, at least 95% etc) sequence identity to the amino acid sequence of SEQ ID NO: 147, wherein the TCR p domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 144. In this example, the TCR p domain CDR1 may have an amino acid sequence of SEQ ID NO:142 and the TCR p domain CDR2 may have an amino acid sequence of SEQ ID NO: 143.

[0563] As another example, the encoded TCR p domain may comprise an amino acid sequence with 0 to 10 (or 0 to 5) amino acid substitutions, insertions or deletions compared to SEQ ID NO: 147, wherein the TCR p domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 144. In this example, the TCR p domain CDR1 may have an amino acid sequence of SEQ ID NO: 142 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 143.

[0564] For the avoidance of doubt, the nucleic acid sequence encoding the TCR p domain may also encode a TCR p chain constant domain. Examples of suitable constant domains are generally discussed elsewhere herein. See also table 14.

[0565] In a particular example, a nucleic acid composition described herein encodes a haematopoietic- restricted MiHA-specific binding protein having a TCR Va domain with a CDR3 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 141 ; and a TCR Vp domain with a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO:144. Optionally, the TCR Va domain may also include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO:139 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 140. Furthermore, the TCR Vp domain may include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 142 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 143.

[0566] Optionally, the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 145; and the Vp domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO:147. In one example, the Va domain comprises the amino acid sequence of SEQ ID NO: 145 and the Vp domain comprises the amino acid sequence of SEQ ID NO: 147. Functional variants may have at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99% or 100% sequence identity to the (reference) sequence shown in table 14. In other words, appropriate functional variants may vary from the sequence shown in table 14 by one or several (e.g. two etc) amino acids. Functional variants will typically contain only conservative substitutions of one, two or more amino acids of the reference sequence, or substitution, deletion or insertion of non-critical amino acids in non-critical regions of the reference sequence shown in table 14.

[0567] As stated in more detail elsewhere herein, the nucleic acid composition described herein encodes both a TCR Va domain and a TCR Vp domain, which form the binding protein that is capable of specifically binding to a haematopoietic-restricted MiHA. In examples where the TCR Va domain and the TCR p domain are encoded by the same nucleic acid sequence, the TCR Va domain and TCR Vp domain may be joined together via a linker. Suitable linkers are discussed generally elsewhere herein. Additional appropriate polypeptide domains that may also be encoded by the nucleic acid sequences that encode the TCR Va domain and / or the TCR Vp domain are also discussed generally elsewhere herein.

[0568] In one example, the nucleic acid composition described herein may encode a soluble TCR or a chimeric single chain TCR wherein the TCR alpha chain variable domain is linked to the TCR beta chain variable domain and a constant domain which is e.g. fused to the CD3 zeta signalling domain. These are discussed generally in more detail elsewhere herein.

[0569] In one example, an isolated nucleic acid composition is provided that encodes a T cell receptor (TCR) having a TCR a chain variable (Va) domain and a TCR p chain variable (Vp) domain, wherein the TCR binds to a peptide: HI_A complex selected from the group consisting of: a VSMNPYQEL:HLA-C*03:03 complex; a VSMNPYQEL:HLA-C*03:04 complex; a GPRPSPTRSV:HLA-B*07:02 complex; a GPRWPPRMTH:HLA- B*07:02 complex; a GPRWPPRMT:HLA- B*07:02 complex; and a GQAGFFPSPF:B*15:01 complex.

[0570] In one example, an isolated nucleic acid composition is provided that encodes a T cell receptor (TCR), wherein the TCR comprises:

[0571] (i) TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 3, and a TCR Vp domain comprising a CDR3 amino acid sequence of SEQ ID NO: 6; or

[0572] (ii) a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 17; and a TCR Vp domain comprising a CDR3 amino acid sequence of SEQ ID NO: 20; or

[0573] (iii) a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 45; and a TCR Vp domain comprising a CDR3 amino acid sequence of SEQ ID NO: 48; or

[0574] (iv) a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 31 ; and a TCR Vp domain comprising a CDR3 amino acid sequence of SEQ ID NO: 34; or (v) a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 59; and a TOR VP domain comprising a CDR3 of SEQ ID NO: 62; or

[0575] (vi) a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 99; and a TCR Vp domain comprising a CDR3 amino acid sequence of SEQ ID NO: 102; or

[0576] (vii) a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 113; and a TCR Vp domain comprising a CDR3 amino acid sequence of SEQ ID NO: 116; or

[0577] (viii) a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 127; and a TCR Vp domain comprising a CDR3 of SEQ ID NO: 130; or

[0578] (ix) a Va domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 7; and (ii) a Vp domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 9; or

[0579] (x) a Va domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 21 ; and (ii) a Vp domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 23; or

[0580] (xi) a Va domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 49; and (ii) a Vp domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 51 ; or

[0581] (xii) a Va domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 35; and (ii) a Vp domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 37; or

[0582] (xiii) a Va domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 63; and (ii) a Vp domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 65; or

[0583] (xiv) a Va domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 103; and (ii) a Vp domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 105; or

[0584] (xv) a Va domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 117; and (ii) a Vp domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 119; or

[0585] (xvi) a Va domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 131 ; and (ii) a Vp domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 133; or

[0586] (xvii) a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 141 ; and a TCR Vp domain comprising a CDR3 of SEQ ID NO: 144; or

[0587] (xviii) a Va domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 145; and (ii) a Vp domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 147. Optionally, the composition may comprise:

[0588] (i) a nucleic acid sequence that encodes a TOR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 3, and a nucleic acid sequence that encodes a TOR Vp domain comprising a CDR3...

Claims

Claims1. An isolated nucleic acid composition that encodes a haematopoietic-restricted minor histocompatibility antigen (MiHA)-specific binding protein, the binding protein having a TCR a chain variable (Va) domain and a TCR p chain variable (VP) domain, the composition comprising:(a) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence; and(b) a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence; wherein the CDR3 amino acid sequences of (a) and (b) together bind to an MiHA that comprises an amino acid sequence selected from the group consisting of: VSMNPYQEL (SEQ ID NO:71), GPRPSPTRSV (SEQ ID NO: 72), GPRWPPRMTH (SEQ ID NO: 73), GPRWPPRMT (SEQ ID NO: 153) and GQAGFFPSPF (SEQ ID NO: 74).

2. The nucleic acid composition of claim 1 , wherein the encoded binding protein is capable of binding to a peptide:HLA complex selected from the group consisting of: a VSMNPYQELHLA- C*03:03 complex; a VSMNPYQEL:HLA-C*03:04 complex; a GPRPSPTRSV:HLA-B*07:02 complex; a GPRWPPRMTH:HLA- B*07:02 complex; a GPRWPPRMT:HLA- B*07:02 complex; and a GQAGFFPSPF:B*15:01 complex.

3. The nucleic acid composition of any one of the preceding claims wherein the composition comprises:(i) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 3, or a functional fragment thereof; and a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 6, or a functional fragment thereof, and the encoded binding protein is capable of binding to a VSMNPYQEL:HI_A-C*03:03 complex or a VSMNPYQEL:HI_A-C*03:04 complex; or(ii) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 17, or a functional fragment thereof; and a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 20, or a functional fragment thereof, and the encoded binding protein is capable of binding to a GPRPSPTRSV:HLA-B*07:02 complex; or(iii) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 45, or a functional fragment thereof; and a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 48, or a functional fragmentthereof, and the encoded binding protein is capable of binding to a GPRWPPRMTH:HI_A-B*07:02 complex; or(iv) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 31 , or a functional fragment thereof; and a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 34, or a functional fragment thereof, and the encoded binding protein is capable of binding to a GPRWPPRMT:HLA-B*07:02 complex; or(v) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 59, or a functional fragment thereof; and a nucleic acid sequence that encodes a TCR p domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 62, or a functional fragment thereof, and the encoded binding protein is capable of binding to a GQAGFFPSPF:B*15:01 complex; or(vi) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 99, or a functional fragment thereof; and a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 102, or a functional fragment thereof, and the encoded binding protein is capable of binding to a GPRPSPTRSV:HLA-B*07:02 complex; or(vii) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 113, or a functional fragment thereof; and a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 116, or a functional fragment thereof, and the encoded binding protein is capable of binding to a GPRWPPRMTH:HI_A-B*07:02 complex and / or a GPRWPPRMT:HI_A-B*07:02 complex; or(viii) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 127, or a functional fragment thereof; and a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 130, or a functional fragment thereof, and the encoded binding protein is capable of binding to a GQAGFFPSPF:B*15:01 complex; or(ix) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 141 , or a functional fragment thereof; and a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence having at least 80% sequence identity to SEQ ID NO: 144, or a functional fragment thereof, and the encoded binding protein is capable of binding to a GPRWPPRMTH:HI_A-B*07:02 complex.

4. The nucleic acid composition of any preceding claim, wherein:(i) the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 3, and the CDR3 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 6, and the encoded binding protein is capable of binding to a VSMNPYQEL:HLA-C*03:03 complex or a VSMNPYQEL:HLA-C*03:04 complex; or(ii) the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 17, and the CDR3 of the p domain comprises or consists of the amino acid sequence of SEQ ID NO: 20, and the encoded binding protein is capable of binding to a GPRPSPTRSV:HI_A- B*07:02 complex; or(iii) the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 45, and the CDR3 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 48, and the encoded binding protein is capable of binding to a GPRWPPRMTH:HLA- B*07:02 complex; or(iv) the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 31 , and the CDR3 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 34, and the encoded binding protein is capable of binding to a GPRWPPRMT:HLA- B*07:02 complex; or(v) the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ I D NO: 59, and the CDR3 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 62, and the encoded binding protein is capable of binding to a GQAGFFPSPF:B*15:01 complex; or(vi) the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 99, and the CDR3 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 102, and the encoded binding protein is capable of binding to a GPRPSPTRSV:HI_A- B*07:02 complex; or(vii) the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 113, and the CDR3 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 116, and the encoded binding protein is capable of binding to a GPRWPPRMTH:HLA-B*07:02 complex and / or a GPRWPPRMT:HLA-B*07:02 complex; or(viii) the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 127, and the CDR3 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 130, and the encoded binding protein is capable of binding to a GQAGFFPSPF:B*15:01 complex; or(ix) the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 141 , and the CDR3 of the Vp domain comprises or consists of the amino acid sequence of SEQID NO: 144, and the encoded binding protein is capable of binding to a GPRWPPRMTH:HLA- B*07:02 complex.

5. The nucleic acid composition of any preceding claim, wherein:(i) the Va domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 7; and (ii) the Vp domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 9, and the encoded binding protein is capable of binding to a VSMNPYQEL:HLA-C*03:03 complex or a VSMNPYQEL:HLA-C*03:04 complex; or(ii) the Va domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 21 ; and (ii) the p domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 23, and the encoded binding protein is capable of binding to a GPRPSPTRSV:HLA-B*07:02 complex; or(iii) the Va domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 49; and (ii) the Vp domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 51 , and the encoded binding protein is capable of binding to a GPRWPPRMTH:HI_A-B*07:02 complex; or(iv) the Va domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 35; and (ii) the Vp domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 37, and the encoded binding protein is capable of binding to a GPRWPPRMT:HLA-B*07:02 complex; or(v) the Va domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 63; and (ii) the Vp domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 65, and the encoded binding protein is capable of binding to a GQAGFFPSPF:B*15:01 complex; or(vi) the Va domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 103; and (ii) the Vp domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 105, and the encoded binding protein is capable of binding to a GPRPSPTRSV:HLA-B*07:02 complex; or(vii) the Va domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 117; and (ii) the Vp domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 119, and the encoded binding protein is capable of binding to a GPRWPPRMTH:HLA-B*07:02 complex and / or a GPRWPPRMT:HI_A-B*07:02 complex; or(viii) the Va domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 131 ; and (ii) the Vp domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 133, and the encoded binding protein is capable of binding to a GQAGFFPSPF:B*15:01 complex; or(ix) the Va domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 145; and (ii) the p domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 147, and the encoded binding protein is capable of binding to a GPRWPPRMTH:HLA-B*07:02 complex.

6. The nucleic acid composition of any preceding claim, wherein the nucleic acid sequence is codon optimised for expression in a host cell, optionally wherein the host cell is a human cell.

7. The nucleic acid composition of any preceding claim, further comprising a TCR a chain constant domain and / or a TCR p chain constant domain.

8. The nucleic acid composition of any preceding claim, wherein the encoded binding protein comprises a TCR, an antigen binding fragment of a TCR, a chimeric antigen receptor (CAR), or an ImmTAC.

9. The nucleic acid composition of claim 8, wherein the antigen binding fragment of a TCR is a single chain TCR (scTCR) or a chimeric TCR dimer in which the antigen binding fragment of the TCR is linked to an alternative transmembrane and intracellular signalling domain.

10. A vector system comprising a nucleic acid composition according to any one of claims 1 to 9.

11. The vector system of claim 10, wherein the vector is a plasmid, a viral vector, or a cosmid, optionally wherein the vector is selected from the group consisting of a retrovirus, lentivirus, adeno-associated virus, adenovirus, vaccinia virus, canary poxvirus, herpes virus, minicircle vector and synthetic DNA or RNA.

12. A modified cell comprising a nucleic acid composition according to any of claims 1 to 9, or a vector system according to claim 10 or 11 .

13. The modified cell of claim 12, wherein the modified cell is selected from the group consisting of a CD8 T cell, a CD4 T cell, an NK cell, an NKT cell, a gamma-delta T cell, ahematopoietic stem cell, an inducible pluripotent stem cell, a progenitor cell, a T cell line and a NK-92 cell line.

14. The modified cell of claim 12 or 13, wherein the modified cell is a human cell.

15. An isolated peptide comprising or consisting of an amino acid sequence selected from the group consisting of: VSMNPYQEL (SEQ ID NO:71), GPRPSPTRSV (SEQ ID NO: 72), GPRWPPRMTH (SEQ ID NO: 73), and GPRWPPRMT (SEQ ID NO: 153).

16. The peptide of claim 15, wherein the peptide has no more than 30 amino acids, no more than 25 amino acids or no more than 20 amino acids.

17. An isolated nucleic acid sequence encoding the peptide of any one of claims 15 or 16.

18. A vector system comprising the nucleic acid sequence of claim 17.

19. A binding agent that binds to a peptide: H LA complex, wherein the complex is selected from the group consisting of: a VSMNPYQEL:HLA-C*03:03 complex; a VSMNPYQEL:HLA- C*03:04 complex; a GPRPSPTRSV:HLA-B*07:02 complex; a GPRWPPRMTH:HLA- B*07:02 complex; a GPRWPPRMT:HLA-B*07:02 complex; and a GQAGFFPSPF:B*15:01 complex.

20. The binding agent of claim 19, wherein the binding agent is an antibody, an antibody fragment or a T cell receptor.

21. A pharmaceutical composition comprising a nucleic acid composition according to any of claims 1 to 9, a vector system according to claim 10, 11 or 18, a modified cell according to any of claims 12 to 14, an isolated peptide of any of claims 15 or 16, a nucleic acid sequence according to claim 17, or a binding agent of any of claims 19 or 20, and a pharmaceutically acceptable excipient, adjuvant, diluent and / or carrier.

22. A pharmaceutical composition according to claim 21 for use in therapy.

23. A method for treating or preventing a relapse of a haematological malignancy after allogeneic stem cell transplantation (allo-SCT) in a human subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to claim 21.

24. A pharmaceutical composition according to claim 21 for use in treating or preventing a relapse of a haematological malignancy after allogeneic stem cell transplantation (allo-SCT) in a human subject.

25. Use of a pharmaceutical composition according to claim 21 in the manufacture of a medicament for treating or preventing a relapse of a haematological malignancy after allogeneic stem cell transplantation (allo-SCT) in a human subject.

26. The method, pharmaceutical composition for use, or use according to any of claims 23 to 25, wherein the haematological malignancy comprises a leukemia, a lymphoma, a myelodysplastic disorder, or a myeloma.

27. The method, pharmaceutical composition for use, or use according to claim 26, wherein:(i) the haematological malignancy comprises a leukemia, wherein the leukemia is selected from the group consisting of acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL) (such as B-ALL or T-ALL), mixed phenotype acute leukemia (MPAL), acute undifferentiated leukemia (AUL), chronic myeloid leukemia (CML), B cell prolymphocytic leukemia, hairy cell leukemia, or chronic lymphocytic leukemia (CLL); or(ii) the haematological malignancy comprises a lymphoma, wherein the lymphoma is selected from the group consisting of Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL), a central nervous system lymphoma, small lymphocytic lymphoma (SLL), CD37+ dendritic cell lymphoma, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, B-cell lymphoma, extra- nodal marginal zone B-cell lymphoma of mucosa-associated (MALT) lymphoid tissue, nodal marginal zone B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, precursor B-lymphoblastic lymphoma, immunoblastic large cell lymphoma, intravascular large B- cell lymphoma, primary effusion lymphoma, or Burkitt's lymphoma; or(iii) the hematological malignancy comprises a multiple myeloma; or(iv) the hematological malignancy comprises a myelodysplastic disorder, wherein the myelodysplastic disorder is selected from refractory cytopenia with unilineage dysplasia (refractory anemia, refractory neutropenia, and refractory thrombocytopenia), refractory anemia with ring sideroblasts (RARS), refractory anemia with ring sideroblasts - thrombocytosis (RARS- t), refractory cytopenia with multilineage dysplasia (RCMD), refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS), refractory anemia with excess blasts (RAEB), myelodysplasia unclassifiable, or refractory cytopenia of childhood.

28. The method, pharmaceutical composition for use, or use according to any of 23 to 27, wherein the subject has previously received lymphodepleting chemotherapy.

29. The method, pharmaceutical composition for use, or use according to claim 28, wherein the lymphodepleting chemotherapy comprises cyclophosphamide, fludarabine, anti-thymocyte globulin, or a combination thereof.

30. The method, pharmaceutical composition for use, or use according to any of claims 23 to 29, wherein one or more of the modified cells within the composition of claim 21 are allogeneic to the subject.

31. The pharmaceutical composition for use, or use according to any one of claims 23 to 30, wherein:(a) when the subject has haematopoietic cells comprising VSMNPYQEL:HLA-C*03:03 complexes, the composition comprises (i) a peptide comprising the amino acid sequence of VSMNPYQEL, and / or a nucleic acid sequence, vector or cell encoding said peptide, and / or (ii) a nucleic acid composition, vector or modified cell encoding a binding protein that binds said complex, optionally wherein the subject has a haematological malignancy that is selected from the group consisting of: AML, ALL (such as T-ALL or B-ALL), HL, NHL, CLL, MPN (such as CML), B-cell lymphoma, MDS and multiple myeloma; or(b) when the subject has haematopoietic cells comprising VSMNPYQEL:HLA-C*03:04 complexes, the composition comprises (i) a peptide comprising the amino acid sequence of VSMNPYQEL, and / or a nucleic acid sequence, vector or cell encoding said peptide, and / or (ii) a nucleic acid composition, vector or modified cell encoding a binding protein that binds said complex, optionally wherein the subject has a haematological malignancy that is selected from the group consisting of: AML, ALL (such as T-ALL or B-ALL), HL, NHL, CLL, MPN (such as CML), MDS, B-cell lymphoma, and multiple myeloma; or(c) when the subject has haematopoietic cells comprising GPRPSPTRSV:HLA-B*07:02 complexes, the composition comprises (i) a peptide comprising the amino acid sequence of GPRPSPTRSV, and / or a nucleic acid sequence, vector or cell encoding said peptide, and / or (ii) a nucleic acid composition, vector or modified cell encoding a binding protein that binds said complex, optionally wherein the subject has a haematological malignancy further optionally wherein the haematological malignancy is selected from the group consisting of AML, MDS, MPN (such as CML), and multiple myeloma; or(d) when the subject has haematopoietic cells comprising GPRWPPRMTH:HLA-B*07:02 complexes, the composition comprises (i) a peptide comprising the amino acid sequence of GPRWPPRMTH, and / or a nucleic acid sequence, vector or cell encoding said peptide, and / or (ii) a nucleic acid composition, vector or modified cell encoding a binding protein that binds said complex, optionally wherein the subject has a haematological malignancy that is selected fromthe group consisting of: AML, ALL, HL, NHL, CLL, MPN (such as CML), MDS and multiple myeloma; or(e) when the subject has haematopoietic cells comprising GQAGFFPSPF:B*15:01 complexes, the composition comprises (i) a nucleic acid composition, vector or modified cell encoding a binding protein that binds said complex, optionally wherein the subject has a haematological malignancy selected from the group consisting of: AML, ALL (such as B-ALL or T-ALL), HL, NHL, CLL, MPN (such as CLM), MDS and multiple myeloma; or(f) when the subject has haematopoietic cells comprising GPRWPPRMT:HLA-B*07:02 complexes, the composition comprises (i) a peptide comprising the amino acid sequence of GPRWPPRMT, and / or a nucleic acid sequence, vector or cell encoding said peptide, and / or (ii) a nucleic acid composition, vector or modified cell encoding a binding protein that binds said complex, optionally wherein the subject has a haematological malignancy that is selected from the group consisting of: AML, ALL, HL, NHL, CLL, MPN (such as CML), MDS and multiple myeloma.

32. A method of generating a binding protein that is capable of binding to a peptide containing a MiHA and does not bind to a peptide that does not contain the MiHA, comprising contacting a nucleic acid composition according to any of claims 1 to 9 with a cell under conditions in which the nucleic acid composition is incorporated and expressed by the cell.

33. The method of claim 32, wherein the method is ex vivo.

34. An isolated nucleic acid composition that encodes a T cell receptor (TOR), wherein the TCR comprises:(i) TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 3, and a TCR Vp domain comprising a CDR3 amino acid sequence of SEQ ID NO: 6; or(ii) a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 17; and a TCR p domain comprising a CDR3 amino acid sequence of SEQ ID NO: 20; or(iii) a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 45; and a TCR Vp domain comprising a CDR3 amino acid sequence of SEQ ID NO: 48; or(iv) a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 31 ; and a TCR Vp domain comprising a CDR3 amino acid sequence of SEQ ID NO: 34; or(v) a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 59; and a TCR Vp domain comprising a CDR3 of SEQ ID NO: 62; or(vi) a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 99; and a TCR Vp domain comprising a CDR3 amino acid sequence of SEQ ID NO: 102; or(vii) a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 113; and a TCR Vp domain comprising a CDR3 amino acid sequence of SEQ ID NO: 116; or(viii) a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 127; and a TOR VP domain comprising a CDR3 of SEQ ID NO: 130; or(ix) a Va domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 7; and (ii) a Vp domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 9; or(x) a Va domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 21 ; and (ii) a Vp domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 23; or(xi) a Va domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 49; and (ii) a Vp domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 51 ; or(xii) a Va domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 35; and (ii) a Vp domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 37; or(xiii) a Va domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 63; and (ii) a Vp domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 65; or(xiv) a Va domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 103; and (ii) a Vp domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 105; or(xv) a Va domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 117; and (ii) a Vp domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 119; or(xvi) a Va domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 131 ; and (ii) a Vp domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 133; or(xvii) a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 141 ; and a TCR Vp domain comprising a CDR3 of SEQ ID NO: 144; or(xviii) a Va domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 145; and (ii) a Vp domain having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 147.

35. An isolated nucleic acid composition according to claim 34 for use in therapy.

Images