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WO2025159638A1 - Antigènes d'histocompatibilité mineure à restriction hématopoïétique et leurs utilisations - Google Patents

Antigènes d'histocompatibilité mineure à restriction hématopoïétique et leurs utilisations

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Publication number
WO2025159638A1
WO2025159638A1 PCT/NL2025/050036 NL2025050036W WO2025159638A1 WO 2025159638 A1 WO2025159638 A1 WO 2025159638A1 NL 2025050036 W NL2025050036 W NL 2025050036W WO 2025159638 A1 WO2025159638 A1 WO 2025159638A1
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seq
acid sequence
amino acid
domain
tcr
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English (en)
Inventor
Marieke Griffioen
J.H. Frederik Falkenburg
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Leids Universitair Medisch Centrum LUMC
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Leids Universitair Medisch Centrum LUMC
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Publication of WO2025159638A1 publication Critical patent/WO2025159638A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/7051—T-cell receptor (TcR)-CD3 complex
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Novel nucleic acid compositions 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.
  • alloSCT allogeneic stem cell transplantation
  • 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.
  • 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).
  • AML acute myeloid leukemia
  • MDS myelodysplastic syndrome
  • NHL multiple myeloma
  • NHL non-Hodgkin’s lymphoma
  • CLL chronic lymphocytic leukemia
  • ALL acute lymphoblastic leukemia
  • 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).
  • GvHD Graft-versus-Host Disease
  • GvL Graft-versus-Leukemia effect
  • HLA Human Leukocyte Antigens
  • HLA molecules present small protein fragments, so-called peptides, to the immune system.
  • 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.
  • 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.
  • 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.
  • DLI delayed pre-emptive donor lymphocyte infusion
  • 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.
  • 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.
  • 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: 116) 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • RVRGTTLHLLL SEQ ID NO: 113; also referred to as “LB-LTA-1 R” herein
  • LPRPDSPYSRL SEQ ID NO: 114; also referred to as “LB-DOK2-1 L” herein
  • GLLSLTFVL SEQ ID NO: 115, also referred to as “LB- SLAMF1-1 F” herein
  • ITFYTGVLK SEQ ID NO: 131 , also referred to as “LB-F13A1-1L” herein
  • RPRGLRLPQL SEQ ID NO: 133, also referred to as “LB-TXNDC11-1 P” herein
  • KPQQKGLRLL SEQ ID NO: 135, also referred to as “LB-APOBEC3H-1 K” herein
  • RIFASRLYY SEQ ID NO: 137
  • the new haematopoietic restricted minor histocompatibility antigens provided herein are presented by common HLA class I alleles and encoded by genes with strong expression in AML and potentially also in other types of haematological malignancy.
  • these new antigens and TCRs for these antigens can be used to treat patients with AML 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.
  • the above mentioned peptides 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.
  • 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).
  • TILs tumour-infiltrating lymphocytes
  • the inventors have identified several TCRs that bind to a specific haematopoietic-restricted minor histocompatibility antigen presented in HLA-B*07:02, HLA-A*03:01 or HLA-A*02:01. Specifically, the inventors identified the following haematopoietic-restricted MiHA-specific TCR clones:
  • TCR clone HHS_2.004 which interacts with RVRGTTLHLLL (SEQ ID NO: 113) in the context of HLA-B*07:02;
  • TCR clone FHA_1 H8 which interacts with LPRPDSPYSRL (SEQ ID NO: 114) in the context of HLA-B*07:02;
  • TCR clone PML_H.4G10 which interacts with LPRPDSPYSRL (SEQ ID NO: 114) in the context of HLA-B*07:02;
  • T cell clone EBJ_1.195 which interacts with ITFYTGVLK (SEQ ID NO: 131) in the context of HLA-A*03:01;
  • T cell clone USF_3.41 which interacts with RIFASRLYY (SEQ ID NO: 137) in the context of HLA-A*03:01. 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 TCRs of the T cell clones referred to in (i) to (xii) above have been sequenced.
  • the TCR components of clones (i) to (xii) 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.
  • cells expressing the haematopoietic-restricted minor histocompatibility antigenspecific binding proteins described herein can be used as an effective immunotherapy in the treatment of haematological malignancies, as described in more detail below.
  • 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:
  • an MiHA that comprises an amino acid sequence selected from the group consisting of: RVRGTTLHLLL (SEQ ID NO: 113), LPRPDSPYSRL (SEQ ID NO: 114), GLLSLTFVL (SEQ ID NO: 115), ITF
  • 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 RVRGTTLHLLL:HI_A-B*07:02 complex; a LPRPDSPYSRL:HLA-B*07:02 complex; a RPRGLRLPQL: HLA-B*07:02 complex; a KPQQKGLRLL:HLA-B*07:02 complex; a GLLSLTFVL:HLA-A*02:01 complex; a ITFYTGVLK:HLA-A*03:01 complex and a RIFASRLYY:HLA-A*03:01 complex.
  • a peptide:HI_A complex selected from the group consisting of: a RVRGTTLHLLL:HI_A-B*07:02 complex; a LPRPDSPYSRL:HLA-B*07:02 complex; a RPRGLRLPQL: HLA-B*07:02 complex;
  • composition may comprise:
  • 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 LPRPDSPYSRL: HLA-B*07:02 complex; or
  • 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: 73, 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: 76, or a functional fragment thereof, and the encoded binding protein is capable of binding (e.g. specifically binding) to a LPRPDSPYSRL: HLA-B*07:02 complex; or
  • 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: 87, 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: 90, or a functional fragment thereof, and the encoded binding protein is capable of binding (e.g.
  • 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 p 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 ITFYTGVLK:HLA-A*03:01 complex; or
  • (x) 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: 155, 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: 158, or a functional fragment thereof, and the encoded binding protein is capable of binding (e.g. specifically binding) to a RPRGLRLPQL:HLA-B*07:02 complex; or
  • xi 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: 169, 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: 172, or a functional fragment thereof, and the encoded binding protein is capable of binding (e.g. specifically binding) to a KPQQKGLRLL:HLA-B*07:02 complex; or
  • xii 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: 183, 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: 186, or a functional fragment thereof, and the encoded binding protein is capable of binding (e.g. specifically binding) to a RIFASRLYY: HLA-A*03:01 complex.
  • the CDR3 of the Va domain may comprise or consist of the amino acid sequence of SEQ ID NO: 3
  • the CDR3 of the Vp domain may comprise or consist of the amino acid sequence of SEQ ID NO: 6
  • the encoded binding protein may be capable of binding (e.g. specifically binding) to a RVRGTTLHLLL:HLA-B*07:02 complex; or
  • 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 Vp 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 RVRGTTLHLLL:HLA-B*07:02 complex; or
  • the CDR3 of the Va domain may comprise or consist of the amino acid sequence of SEQ ID NO: 31
  • the CDR3 of the Vp domain may comprise or consist of the amino acid sequence of SEQ ID NO: 34
  • the encoded binding protein may be capable of binding (e.g. specifically binding) to a RVRGTTLHLLL:HLA-B*07:02 complex; or
  • the CDR3 of the Va domain may comprise or consist of the amino acid sequence of SEQ ID NO: 45
  • the CDR3 of the p domain may comprise or consist of the amino acid sequence of SEQ ID NO: 48
  • the encoded binding protein may be capable of binding (e.g. specifically binding) to a LPRPDSPYSRL: HLA-B*07:02 complex; or
  • the CDR3 of the Va domain may comprise or consist of the amino acid sequence of SEQ ID NO: 59
  • the CDR3 of the Vp domain may comprise or consist of the amino acid sequence of SEQ ID NO: 62
  • the encoded binding protein may be capable of binding (e.g. specifically binding) to a LPRPDSPYSRL: HLA-B*07:02 complex; or
  • the CDR3 of the Va domain may comprise or consist of the amino acid sequence of SEQ ID NO: 73
  • the CDR3 of the Vp domain may comprise or consist of the amino acid sequence of SEQ ID NO: 76
  • the encoded binding protein may be capable of binding (e.g. specifically binding) to a LPRPDSPYSRL: HLA-B*07:02 complex; or
  • the CDR3 of the Va domain may comprise or consist of the amino acid sequence of SEQ ID NO: 87
  • the CDR3 of the Vp domain may comprise or consist of the amino acid sequence of SEQ ID NO: 90
  • the encoded binding protein may be capable of binding (e.g. specifically binding) to a GLLSLTFVL:HLA-A*02:01 complex; or
  • the CDR3 of the Va domain may comprise or consist of the amino acid sequence of SEQ ID NO: 101
  • the CDR3 of the Vp domain may comprise or consist of the amino acid sequence of SEQ ID NO: 104
  • the encoded binding protein may be capable of binding (e.g. specifically binding) to a GLLSLTFVL:HLA-A*02:01 complex; or
  • the CDR3 of the Va domain may comprise or consist of the amino acid sequence of SEQ ID NO: 141
  • the CDR3 of the Vp domain may comprise or consist of the amino acid sequence of SEQ ID NO: 144
  • the encoded binding protein may be capable of binding (e.g. specifically binding) to a ITFYTGVLK:HLA-A*03:01 complex; or
  • the CDR3 of the Va domain may comprise or consist of the amino acid sequence of SEQ ID NO: 155
  • the CDR3 of the Vp domain may comprise or consist of the amino acid sequence of SEQ ID NO: 158
  • the encoded binding protein may be capable of binding (e.g. specifically binding) to a RPRGLRLPQL:HLA-B*07:02 complex; or
  • the CDR3 of the Va domain may comprise or consist of the amino acid sequence of SEQ ID NO: 169, and the CDR3 of the Vp domain may comprise or consist of the amino acid sequence of SEQ ID NO: 172, and the encoded binding protein may be capable of binding (e.g. specifically binding) to a KPQQKGLRLL:HLA-B*07:02 complex; or (xii) the CDR3 of the Va domain may comprise or consist of the amino acid sequence of SEQ ID NO: 183, and the CDR3 of the Vp domain may comprise or consist of the amino acid sequence of SEQ ID NO: 186, and the encoded binding protein may be capable of binding (e.g. specifically binding) to a RIFASRLYY: HLA-A*03:01 complex.
  • 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 RVRGTTLHLLL:HLA-B*07:02 complex; or
  • 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 RVRGTTLHLLL:HLA-B*07:02 complex; or
  • 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 RVRGTTLHLLL:HLA-B*07:02 complex; or
  • 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 LPRPDSPYSRL: HLA-B*07:02 complex; or
  • 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 LPRPDSPYSRL: HLA-B*07:02 complex; or
  • the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 77; 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: 79, and the encoded binding protein may be capable of binding (e.g. specifically binding) to a LPRPDSPYSRL: HLA-B*07:02 complex; or
  • the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 91 ; 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: 93, and the encoded binding protein may be capable of binding (e.g. specifically binding) to a GLLSLTFVL:HLA-A*02:01 complex; or
  • the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 105; 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: 107, and the encoded binding protein may be capable of binding (e.g. specifically binding) to a GLLSLTFVL:HLA-A*02:01 complex; or
  • 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 p 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 ITFYTGVLK:HLA-A*03:01 complex; or
  • the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 159; 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: 161 , and the encoded binding protein may be capable of binding (e.g. specifically binding) to a RPRGLRLPQL:HLA-B*07:02 complex; or
  • the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 173 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: 175, and the encoded binding protein may be capable of binding (e.g. specifically binding) to a KPQQKGLRLL:HLA-B*07:02 complex; or
  • the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 187; 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: 189, and the encoded binding protein may be capable of binding (e.g. specifically binding) to a RIFASRLYY: HLA-A*03:01 complex.
  • the nucleic acid sequence may be codon optimised for expression in a host cell, optionally wherein the host cell is a human cell.
  • composition may further comprise a TCR a chain constant domain and/or a TCR p chain constant domain.
  • the encoded binding protein may comprise a TCR, an antigen binding fragment of a TCR, a chimeric antigen receptor (CAR), or an ImmTAC.
  • 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.
  • the invention also provides a vector system comprising a nucleic acid composition according to the invention.
  • 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.
  • the invention also provides a modified cell comprising a nucleic acid composition according to the invention, or a vector system according to the invention.
  • the modified cell may be selected from the group consisting of a CD8 T cell, a CD4 T cell, an NK cell, an NK-T 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.
  • the modified cell may be a human cell.
  • the invention also provides an isolated peptide comprising or consisting of an amino acid sequence selected from the group consisting of: RVRGTTLHLLL (SEQ ID NO: 113), LPRPDSPYSRL (SEQ ID NO: 114), GLLSLTFVL (SEQ ID NO: 115), ITFYTGVLK (SEQ ID NO: 131), RPRGLRLPQL (SEQ ID NO: 133), KPQQKGLRLL (SEQ ID NO: 135), and RIFASRLYY (SEQ ID NO: 137).
  • the peptide may have no more than 30 amino acids, no more than 25 amino acids or no more than 20 amino acids.
  • the invention also provides an isolated nucleic acid sequence encoding the peptide of the invention.
  • the invention also provides a vector system comprising the nucleic acid sequence of the invention.
  • the invention also 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 RVRGTTLHLLL: HLA- B*07:02 complex; a LPRPDSPYSRL:HLA-B*07:02 complex; a RPRGLRLPQL: HLA-B*07:02 complex; a KPQQKGLRLL: HLA-B*07:02 complex; a GLLSLTFVL:HLA-A*02:01 complex; a ITFYTGVLK:HLA-A*03:01 complex and a RIFASRLYY:HLA-A*03:01 complex.
  • 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 RVRGTTLHLLL: HLA- B*07:02 complex; a LPRPDSPYSRL
  • the binding agent may be an antibody, an antibody fragment or a T cell receptor.
  • the invention also provides a pharmaceutical composition
  • 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 of the invention, a nucleic acid sequence according to the invention, or a binding agent of the invention, and a pharmaceutically acceptable excipient, adjuvant, diluent and/or carrier.
  • the invention also provides a pharmaceutical composition according to the invention for use in therapy.
  • the invention also 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.
  • allo-SCT allogeneic stem cell transplantation
  • the invention also 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.
  • allo-SCT allogeneic stem cell transplantation
  • the invention also 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.
  • allo-SCT allogeneic stem cell transplantation
  • the haematological malignancy comprises a leukemia, a lymphoma, a myelodysplastic disorder, or a myeloma.
  • the haematological malignancy may comprise a leukemia, wherein the leukemia is selected from the group consisting of acute myeloid leukemia (AML), acute lymphocytic leukemia (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
  • the haematological malignancy may comprise 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,
  • the hematological malignancy may comprise a multiple myeloma
  • the hematological malignancy may comprise 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.
  • the myelodysplastic disorder is selected from refractory cytopenia with unilineage dysplasia (refractory anemia, refractory neutr
  • the subject may have previously received lymphodepleting chemotherapy.
  • the lymphodepleting chemotherapy may comprise cyclophosphamide, fludarabine, antithymocyte globulin, or a combination thereof.
  • one or more of the modified cells within the composition of the invention may be allogeneic to the subject.
  • the composition may comprise (i) a peptide comprising the amino acid sequence of RVRGTTLHLLL, 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.
  • haematological malignancy that is selected from the group consisting of: AML, ALL, HL, NHL, CLL, B-cell lymphoma, MPN (such as CML), MDS and multiple myeloma; or
  • the composition may comprise (i) a peptide comprising the amino acid sequence of LPRPDSPYSRL, 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
  • the composition may comprise (i) a peptide comprising the amino acid sequence of GLLSLTFVL, 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.
  • haematological malignancy that is selected from the group consisting of: AML, ALL, HL, NHL, CLL, B-cell lymphoma, MPN (such as CML), MDS and multiple myeloma
  • the composition may comprise (i) a peptide comprising the amino acid sequence of RPRGLRLPQL, 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
  • the composition may comprise (i) a peptide comprising the amino acid sequence of KPQQKGLRLL , 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
  • the composition may comprise (i) a peptide comprising the amino acid sequence of ITFYTGVLK, 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
  • the composition may comprise (i) a peptide comprising the amino acid sequence of RIFASRLYY, 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.
  • the invention also 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.
  • the method may be ex vivo.
  • the invention also provides an isolated nucleic acid composition that encodes a T cell receptor (TCR), wherein the TCR comprises:
  • 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;
  • 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;
  • 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;
  • TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 73; and a TCR Vp domain comprising a CDR3 of SEQ ID NO: 76; or
  • TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 87; and a TCR Vp domain comprising a CDR3 of SEQ ID NO: 90; or
  • TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 101 ; and a TCR Vp domain comprising a CDR3 of SEQ ID NO: 104; or
  • TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 141
  • TCR Vp domain comprising a CDR3 amino acid sequence of SEQ ID NO: 144
  • the invention also provides an isolated nucleic acid composition according to the invention for use in therapy.
  • 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.
  • FIG. 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.
  • FIG. 2 shows that often the same MiHAs are targeted by T cells.
  • 174 T cell clones for 108 different MiHAs were isolated from 39 patients.
  • 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).
  • FIG. 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.
  • 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).
  • FIG. 5 shows pMHC tetramer staining of TCRs for hematopoietic-restricted MiHAs.
  • 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.
  • MP71-flex human TCRa and variable regions are cloned in-frame with murine TCRa and p constant regions.
  • CD8 cells were stimulated with anti-CD3/CD28 and IL-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.
  • 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).
  • 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.
  • TCRs for LB-SLAMF1-1 F expressed by T cell clones GRZ_003 and ORZ_2.231 from patient 9701 have been transferred to CD8 T cells from donor 10433.
  • 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.
  • FIG. 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.
  • 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).
  • Figure 7 shows T-cell reactivity against skin fibroblasts.
  • TCR-T cells for hematopoietic- restricted MiHAs black bars
  • TCR-T cells for CMVpp65 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.
  • 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.
  • FIG. 8 shows TCR-T cells for three new haematopoietic restricted minor histocompatibility antigens.
  • 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.
  • 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.
  • FIG. 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.
  • CD8 cells were isolated by magnetic activated cell sorting (MACS) using anti-CD8 microbeads, stimulated with anti-CD3/CD28 and IL-2.
  • MCS magnetic activated cell sorting
  • TCR-T cells 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).
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • FIG 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.
  • FIG 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
  • control TCR-T cells gray bars
  • EBV-B cells EBV-B cells from a MiHA-positive patient (pEBV) and its corresponding MiHA-negative stem cell donor (dEBV).
  • 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.
  • FIG. 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 lymphocy
  • 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.
  • 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.
  • FIG. 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
  • control TCR-T cells for CMVpp65 white bars
  • 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.
  • AML 7503, AML 2250, AML 9559 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.
  • 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:
  • an MiHA that comprises an amino acid sequence selected from the group consisting of: RVRGTTLHLLL (SEQ ID NO: 113), LPRPDSPYSRL (SEQ ID NO: 114), GLLSLTFVL (SEQ ID NO: 115), ITF
  • 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.
  • 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).
  • 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.
  • TCR T cell receptor
  • 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: 113 to 115, 131 , 133, 135 and 137) and does not bind to a peptide that does not contain a haematopoietic-restricted MiHA (e.g.
  • haematopoietic-restricted MiHA comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 113 to 115, 131 , 133, 135 and 137).
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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).
  • 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).
  • 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 chain (including the constant domain), optionally wherein the sequence encoding the functional TCR a chain is separated from the sequence encoding the functional TCR 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.
  • 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: 113, SEQ ID NO: 114, SEQ ID NO: 115, SEQ ID NO: 131 , SEQ ID NO: 133, SEQ ID NO: 135 and SEQ ID NO: 137).
  • 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.
  • 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).
  • 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.
  • 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.
  • a TCR constant domain is modified to enhance pairing of desired TCR chains.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • CAR Chimeric antigen receptor
  • 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))
  • intracellular signalling domains optionally containing co-stimulatory domain(s)
  • 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.
  • 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.
  • T cell receptor 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.
  • MHC major histocompatibility complex
  • 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.
  • the encoded binding protein is capable of specifically binding to a haematopoietic-restricted MiHA:specific HI_A complex.
  • 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.
  • RVRGTTLHLLL (SEQ ID NO: 113) in the context of HLA- B*07:02; LPRPDSPYSRL (SEQ ID NO: 114) in the context of HLA-B*07:02; GLLSLTFVL (SEQ ID NO: 115) in the context of HLA-A*02:01; ITFYTGVLK (SEQ ID NO: 131) in the context of HLA- A*03:01 , RPRGLRLPQL (SEQ ID NO: 133) in the context of HLA-B*07:02, KPQQKGLRLL (SEQ ID NO: 135) in the context of HLA-B*07:02, or RIFASRLYY (SEQ ID NO: 137) in the context of HLA-A*03:01.
  • HI_A-A*02:01 is a globally common human leukocyte antigen subtype within the HI_A-A group. Peptides that are presented by HLA-A*02:01 to TCRs are described as being “HLA-A*02:01 restricted”.
  • HI_A-A*03:01 is also a common human leukocyte antigen subtype within the HLA-A group. Peptides that are presented by HLA-A*03:01 to TCRs are described as being “HLA-A*03:01 restricted”.
  • HI_A-B*07:02 is also a common human leukocyte antigen subtype within the HLA-B group. Peptides that are presented by HLA-B*07:02 to TCRs are described as being “HLA-B*07:02 restricted”. HLA-A*02:01 can be referred to herein as HLA-A2. Similarly, HI_A-A*03:01 can be referred to herein as HLA-A3 and HLA-B*07:02 is also referred to herein as HLA-B7.
  • HI_A-B haematopoietic-restricted MiHA derived peptides presented on haematopoietic cells in HI_A-B*07:02 (HLA-B7), HI_A-A*03:01 (HI_A-A3) or HLA-A*02:01 (HI_A-A2).
  • the inventors identified the haematopoietic-restricted MiHA derived peptides RVRGTTLHLLL (SEQ ID NO: 113), LPRPDSPYSRL (SEQ ID NO: 114), GLLSLTFVL (SEQ ID NO: 115), ITFYTGVLK (SEQ ID NO: 131), RPRGLRLPQL (SEQ ID NO: 133), KPQQKGLRLL (SEQ ID NO: 135), and RIFASRLYY (SEQ ID NO: 137).
  • 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: RVRGTTLHLLL (SEQ ID NO: 113), LPRPDSPYSRL (SEQ ID NO: 114), GLLSLTFVL (SEQ ID NO: 115), ITFYTGVLK (SEQ ID NO: 131), RPRGLRLPQL (SEQ ID NO: 133), KPQQKGLRLL (SEQ ID NO: 135), and RIFASRLYY (SEQ ID NO: 137).
  • the antigen may be an antigenic fragment (i.e.
  • RVRGTTLHLLL SEQ ID NO: 113
  • LPRPDSPYSRL SEQ ID NO: 114
  • GLLSLTFVL SEQ ID NO: 115
  • ITFYTGVLK SEQ ID NO: 131
  • RPRGLRLPQL SEQ ID NO: 133
  • KPQQKGLRLL SEQ ID NO: 135
  • RIFASRLYY SEQ ID NO: 137
  • it may consist of an amino acid sequence selected from the group consisting of: RVRGTTLHLLL (SEQ ID NO: 113), LPRPDSPYSRL (SEQ ID NO: 114), GLLSLTFVL (SEQ ID NO: 115), ITFYTGVLK (SEQ ID NO: 131), RPRGLRLPQL (SEQ ID NO: 133), KPQQKGLRLL (SEQ ID NO: 135), and RIFASRLYY (SEQ ID NO: 137), or it may comprise
  • RVRGTTLHLLL SEQ ID NO: 113
  • LPRPDSPYSRL SEQ ID NO: 114
  • GLLSLTFVL SEQ ID NO: 115
  • ITFYTGVLK SEQ ID NO: 131
  • RPRGLRLPQL SEQ ID NO: 133
  • KPQQKGLRLL SEQ ID NO: 135
  • RIFASRLYY SEQ ID NO: 137
  • the haematopoietic-restricted MiHA comprises an amino acid sequence selected from the group consisting of: RVRGTTLHLLL (SEQ ID NO: 113), LPRPDSPYSRL (SEQ ID NO: 114), GLLSLTFVL (SEQ ID NO: 115), ITFYTGVLK (SEQ ID NO: 131), RPRGLRLPQL (SEQ ID NO: 133), KPQQKGLRLL (SEQ ID NO: 135), and RIFASRLYY (SEQ ID NO: 137).
  • the haematopoietic-restricted MiHA comprises the amino acid sequence RVRGTTLHLLL (SEQ ID NO: 113). In another example, the haematopoietic-restricted MiHA comprises the amino acid sequence LPRPDSPYSRL (SEQ ID NO: 114). In a further example, the haematopoietic-restricted MiHA comprises the amino acid sequence GLLSLTFVL (SEQ ID NO: 115). In a further example, the haematopoietic-restricted MiHA comprises the amino acid sequence ITFYTGVLK (SEQ ID NO: 131).
  • the haematopoietic-restricted MiHA comprises the amino acid sequence RPRGLRLPQL (SEQ ID NO: 133). In a further example, the haematopoietic-restricted MiHA comprises the amino acid sequence KPQQKGLRLL (SEQ ID NO: 135). In a further example, the haematopoietic-restricted MiHA comprises the amino acid sequence RIFASRLYY (SEQ ID NO: 137).
  • the encoded binding protein is capable of specifically binding to a peptide:HLA complex selected from the group consisting of: a RVRGTTLHLLL: HLA-B*07:02 complex; a LPRPDSPYSRL:HLA-B*07:02 complex; a RPRGLRLPQL: HLA-B*07:02 complex; a KPQQKGLRLL: HLA-B*07:02 complex; a GLLSLTFVL:HLA-A*02:01 complex; a ITFYTGVLK:HLA-A*03:01 complex and a RIFASRLYY:HLA-A*03:01 complex.
  • a peptide:HLA complex selected from the group consisting of: a RVRGTTLHLLL: HLA-B*07:02 complex; a LPRPDSPYSRL:HLA-B*07:02 complex; a RPRGLRLPQL: HLA-B*07:02 complex; a KPQQKGLRLL: HLA
  • the encoded binding protein is capable of specifically binding to a RVRGTTLHLLL: HLA-B*07:02 complex. In another example, the encoded binding protein is capable of specifically binding to a LPRPDSPYSRL:HLA-B*07:02 complex. In another example, the encoded binding protein is capable of specifically binding to a GLLSLTFVL:HLA-A*02:01 complex. In another example, the encoded binding protein is capable of specifically binding to a RPRGLRLPQL: HLA-B*07:02 complex. In another example, the encoded binding protein is capable of specifically binding to a KPQQKGLRLL: HLA-B*07:02 complex.
  • the encoded binding protein is capable of specifically binding to a ITFYTGVLK:HLA-A*03:01 complex. In another example, the encoded binding protein is capable of specifically binding to a RIFASRLYY:HLA-A*03:01 complex.
  • the haematopoietic-restricted MiHA derived peptide of the peptide:HLA complex comprises an antigenic fragment of an amino acid sequence selected from the group consisting of: SEQ ID NO: 113 to 115, 131 , 133, 135 and 137.
  • 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 I D NO: 113 to 115, 131 , 133, 135 and 137.
  • 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 HLA (e.g. in the context of HLA-B*07:02, HLA-A*03:01 and/or HLA-A*02:01 , as appropriate), the T cell is activated through signal transduction.
  • 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.
  • An isolated nucleic acid composition that encodes a haematopoietic-restricted MiHA antigenspecific binding protein having a TCR a chain variable (Va) domain and a TCR P chain variable (VP) domain.
  • the nucleic acid composition described herein may comprise a TCR a chain constant domain and/or a TCR p chain constant domain.
  • the variable domain of each chain has three hypervariable regions (also called complementarity determining regions (CDRs)).
  • 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.
  • 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.
  • CDR3 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.
  • 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.
  • 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.
  • the isolated nucleic acid composition described herein encodes a haematopoietic-restricted MiHA-specific binding protein.
  • the inventors have identified and sequenced several TCRs that bind (e.g. specifically bind) to a haematopoietic-restricted MiHA selected from: RVRGTTLHLLL (SEQ ID NO: 113), LPRPDSPYSRL (SEQ ID NO: 114), GLLSLTFVL (SEQ ID NO: 115), ITFYTGVLK (SEQ ID NO: 131), RPRGLRLPQL (SEQ ID NO: 133), KPQQKGLRLL (SEQ ID NO: 135) and RIFASRLYY (SEQ ID NO: 137).
  • TCR clone HHS_2.004 which interacts with RVRGTTLHLLL (SEQ ID NO: 113) in the context of HLA-B*07:02.
  • sequences provided herein that correspond to TCR clone HHS_2.004 are SEQ ID NO:s 1 to 14.
  • 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
  • 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 RVRGTTLHLLL (SEQ ID NO: 113).
  • TCR Va domain CDR3 amino acid sequence that confers binding e.g. specific binding
  • RVRGTTLHLLL SEQ ID NO: 113
  • 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 RVRGTTLHLLL (SEQ ID NO: 113)) when the CDR3 is part of TCR Va domain). Such functional variants are therefore encompassed herein.
  • 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 92%, or 100% sequence identity to SEQ ID NO: 3.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO:3).
  • 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.
  • SEQ ID NO:3 retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO:113 when the CDR3 is part of TCR Va domain.
  • 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.
  • 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: 113. 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: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.
  • the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 3.
  • the TOR Va domain CDR3 has the amino acid sequence of SEQ ID NO:3, the CDR3 may be encoded by any appropriate nucleic acid sequence.
  • the encoded TOR 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:113).
  • 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.
  • 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: 113. 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: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.
  • 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%, at least 85%, or 100% sequence identity to SEQ ID NO: 1.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO:1).
  • 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.
  • 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.
  • functional variants of SEQ ID NO: 1 retain the ability to (specifically) bind to the peptide shown in SEQ ID NO:113 when the CDR1 is part of TCR Va domain.
  • the CDR1 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO:1.
  • 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:2, 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: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.
  • Non-functional variants are amino acid sequence variants of SEQ ID NO: 2 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: 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.
  • 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 87%, or 100% sequence identity to SEQ ID NO: 2.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO:2).
  • 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.
  • 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.
  • a functional variant of SEQ ID NO: 2 retains the ability to specifically bind to HLA-B*07:02.
  • the CDR2 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 2.
  • the CDR2 may be encoded by any appropriate nucleic acid sequence.
  • 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.
  • 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:113 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.
  • 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: 113. 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: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.
  • 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: 113.
  • a functional TCR Va domain with one or several amino acid substitutions compared to the sequence of SEQ ID NO:7 is also encompassed.
  • 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).
  • 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.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 7).
  • 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: 7, wherein the TCR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 3.
  • the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 1
  • the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 2.
  • 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.
  • the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 1
  • the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 2.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • naked (synthetic) DNA/RNA can also be used to introduce the TCR.
  • 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.
  • single stranded or double stranded DNA or RNA can be inserted by homologous directed repair into the TCR locus (see Roth eta/ 2018 Nature vol 559; page 405).
  • non - homologous end joining is possible.
  • SEQ ID NO: 11 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:113 when part of a binding protein described herein).
  • a functional TCR a chain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 11 is also encompassed.
  • 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).
  • 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.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 11).
  • 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.
  • 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.
  • 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 HHS_2.004.
  • 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.
  • 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.
  • 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.
  • TCR clone HHS_2.043 which also interacts with RVRGTTLHLLL (SEQ ID NO: 113) in the context of HLA-B*07:02.
  • the sequences provided herein that correspond to TCR clone HHS_2.043 are SEQ ID NO:s 15 to 28.
  • an example of an appropriate TCR Va domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to RVRGTTLHLLL (SEQ ID NO: 113) is shown in SEQ ID NO: 17.
  • 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 RVRGTTLHLLL (SEQ ID NO: 113)) when the CDR3 is part of TCR Va domain). Such functional variants are therefore encompassed herein.
  • 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 90%, or 100% sequence identity to SEQ ID NO: 17.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO:17).
  • 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.
  • SEQ I D NO: 17 retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO:113 when the CDR3 is part of TCR Va domain.
  • 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: 113. 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.
  • the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 17.
  • the CDR3 may be encoded by any appropriate nucleic acid sequence.
  • 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: 113.
  • 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.
  • 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: 113. 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.
  • 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 83%, or 100% sequence identity to SEQ ID NO: 15.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO:15).
  • 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.
  • 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.
  • the CDR1 of the Va domain comprises or consists of 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.
  • 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.
  • 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%, at least 83%, or 100% sequence identity to SEQ ID NO: 16.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO:16).
  • 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.
  • 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).
  • a functional variant of SEQ ID NO: 16 retains the ability to specifically bind to HLA-B*07:02.
  • the CDR2 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 16.
  • the CDR2 may be encoded by any appropriate nucleic acid sequence.
  • 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.
  • 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:113 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.
  • 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: 113. 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.
  • 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: 113.
  • a functional TCR Va domain with one or several amino acid substitutions compared to the sequence of SEQ ID NO:21 is also encompassed.
  • 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).
  • 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.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 21).
  • 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.
  • the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 15
  • the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 16.
  • 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.
  • 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.
  • 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).
  • 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.
  • SEQ ID NO: 25 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:113 when part of a binding protein described herein).
  • a functional TCR a chain with one or several amino acid substitutions compared to the sequence of SEQ ID NO:25 is also encompassed.
  • 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).
  • 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.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 25).
  • 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.
  • 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.
  • 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).
  • SEQ ID NO:26 is the nucleic acid sequence for TCR a chain of clone HHS_2.043.
  • 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.
  • 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.
  • 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.
  • TCR clone HHS_2.269 which interacts with RVRGTTLHLLL (SEQ ID NO: 113) in the context of HLA-B*07:02.
  • the sequences provided herein that correspond to TCR clone HHS_2.269 are SEQ ID NO:s 29 to 42.
  • SEQ ID NO:31 An example of an appropriate TCR Va domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to RVRGTTLHLLL (SEQ ID NO: 113) is shown in SEQ ID NO:31.
  • 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 RVRGTTLHLLL (SEQ ID NO: 113)) when the CDR3 is part of TCR Va domain). Such functional variants are therefore encompassed herein.
  • 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 91%, or 100% sequence identity to SEQ ID NO: 31.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO:31).
  • 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.
  • SEQ ID NO: 31 retain their ability to confer (specific) binding to the peptide shown in SEQ I D NO: 113) when the CDR3 is part of TCR Va domain.
  • 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.
  • 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: 113. 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.
  • the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 31.
  • the CDR3 may be encoded by any appropriate nucleic acid sequence.
  • the encoded TOR 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: 113).
  • 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.
  • 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: 113. 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.
  • 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.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 29).
  • 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.
  • 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.
  • functional variants of SEQ ID NO: 29 retain the ability to (specifically) bind to the peptide shown in SEQ ID NO: 113 when the CDR1 is part of TCR Va domain).
  • the CDR1 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 29.
  • 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: 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.
  • 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.
  • 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.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NQ:30).
  • 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.
  • 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).
  • a functional variant of SEQ ID NO: 30 retains the ability to specifically bind to HLA-B*07:02.
  • the CDR2 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 30.
  • the CDR2 may be encoded by any appropriate nucleic acid sequence.
  • 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.
  • 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: 113) 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.
  • 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: 113. 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.
  • 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: 113.
  • a functional TCR Va domain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 35 is also encompassed.
  • 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 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: 35).
  • 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.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 35).
  • 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.
  • 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.
  • 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.
  • 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.
  • the TCR 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).
  • 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.
  • SEQ ID NO: 39 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: 113 when part of a binding protein described herein).
  • a functional TCR a chain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 39 is also encompassed.
  • 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).
  • 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.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 39).
  • 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.
  • 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.
  • 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 HHS_2.269.
  • 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.
  • 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.
  • 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.
  • 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
  • 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 LPRPDSPYSRL (SEQ ID NO: 114).
  • TCR clone FHA_1 H8 which also interacts with LPRPDSPYSRL (SEQ ID NO: 114) in the context of HLA-B*07:02.
  • the sequences provided herein that correspond to TCR clone FHA_1 H8 are SEQ ID NO:s 43 to 56.
  • SEQ ID NO: 45 An example of an appropriate TCR Va domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to LPRPDSPYSRL (SEQ ID NO: 114) is shown in SEQ ID NO: 45.
  • 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 LPRPDSPYSRL (SEQ ID NO: 114)) when the CDR3 is part of TCR Va domain). Such functional variants are therefore encompassed herein.
  • 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 91%, or 100% sequence identity to SEQ ID NO: 45.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 45).
  • 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.
  • SEQ ID NO: 45 retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO: 114 when the CDR3 is part of TCR Va domain.
  • 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.
  • 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: 114.
  • 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.
  • the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 45.
  • the CDR3 may be encoded by any appropriate nucleic acid sequence.
  • the encoded TCR 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: 114).
  • 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.
  • 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: 114. 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.
  • 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.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 43).
  • 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.
  • 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.
  • functional variants of SEQ ID NO: 43 retain the ability to (specifically) bind to the peptide shown in SEQ ID NO: 114 when the CDR1 is part of TCR Va domain.
  • the CDR1 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 43.
  • 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: 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.
  • 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.
  • 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 85%, or 100% sequence identity to SEQ ID NO: 44.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 44).
  • 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.
  • 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).
  • a functional variant of SEQ ID NO: 44 retains the ability to specifically bind to HLA-B*07:02.
  • the CDR2 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 44.
  • the CDR2 may be encoded by any appropriate nucleic acid sequence.
  • 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.
  • 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: 114 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:114. 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.
  • 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: 114.
  • a functional TCR Va domain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 49 is also encompassed.
  • 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).
  • 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.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 49).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • SEQ ID NO: 53 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: 114 when part of a binding protein described herein).
  • a functional TCR a chain with one or several amino acid substitutions compared to the sequence of SEQ ID NO:53 is also encompassed.
  • 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).
  • 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.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 53).
  • 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.
  • 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.
  • 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 FHA_1 H8.
  • 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.
  • 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.
  • 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.
  • TOR clone MHU_1.052 which interacts with LPRPDSPYSRL (SEQ ID NO: 114) in the context of HLA-B*07:02.
  • the sequences provided herein that correspond to TCR clone MHU_1.052 are SEQ ID NO:s 57 to 70.
  • TCR Va domain CDR3 amino acid sequence that confers binding e.g. specific binding
  • LPRPDSPYSRL SEQ ID NO: 114
  • 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 LPRPDSPYSRL (SEQ ID NO: 114)) when the CDR3 is part of TCR Va domain). Such functional variants are therefore encompassed herein.
  • 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 92%, or 100% sequence identity to SEQ ID NO: 59.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 59).
  • 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.
  • SEQ ID NO: 59 retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO: 114 when the CDR3 is part of TCR Va domain.
  • 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: 114. 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.
  • the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 59.
  • the CDR3 may be encoded by any appropriate nucleic acid sequence.
  • the encoded TOR 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: 114).
  • 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.
  • 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: 114. 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.
  • 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%, or 100% sequence identity to SEQ ID NO: 57.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 57).
  • 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.
  • 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.
  • functional variants of SEQ ID NO: 57 retain the ability to (specifically) bind to the peptide shown in SEQ ID NO: 114 when the CDR1 is part of TCR Va domain).
  • the CDR1 of the Va domain comprises or consists of 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 HI_A-B*07:02).
  • 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.
  • Non-functional variants are amino acid sequence variants of SEQ ID NO: 58 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: 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.
  • 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 85%, or 100% sequence identity to SEQ ID NO: 58.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 58).
  • 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.
  • 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).
  • a functional variant of SEQ ID NO: 58 retains the ability to specifically bind to HLA-B*07:02.
  • the CDR2 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 58.
  • the CDR2 may be encoded by any appropriate nucleic acid sequence.
  • 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.
  • 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: 114) 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.
  • 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: 114. 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.
  • 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: 114.
  • a functional TCR Va domain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 63 is also encompassed.
  • 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).
  • 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.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 63).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • the nucleic acid sequence encoding the TCR Va domain may also encode a TCR a chain constant domain.
  • suitable constant domains are generally discussed above.
  • 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.
  • the variant TCR a chain amino acid sequence retains its ability to (specifically) bind to the peptide shown in SEQ ID NO: 114 when part of a binding protein described herein).
  • a functional TCR a chain with one or several amino acid substitutions compared to the sequence of SEQ ID NO:67 is also encompassed.
  • 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).
  • 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.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 67).
  • 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.
  • 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.
  • 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 MHU_1.052.
  • 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.
  • 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.
  • 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.
  • the inventors also identified TCR clone PML_H.4G10 which also interacts with LPRPDSPYSRL (SEQ ID NO: 114) in the context of HLA-B07:02.
  • the sequences provided herein that correspond to TCR clone PML_H.4G10 are SEQ ID NO:s 71 to 84.
  • SEQ ID NO: 73 An example of an appropriate TCR Va domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to LPRPDSPYSRL (SEQ ID NO: 114) is shown in SEQ ID NO: 73.
  • variants of the amino acid sequence shown in SEQ ID NO: 73 may also be functional (i.e. retain their ability to confer (specific) binding to the peptide LPRPDSPYSRL (SEQ ID NO: 114) when the CDR3 is part of TCR Va domain). Such functional variants are therefore encompassed herein.
  • appropriate (functional) Va domain CDR3 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 73, i.e. they may have at least 80%, at least 90%, or 100% sequence identity to SEQ ID NO: 73.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 73).
  • appropriate (functional) Va domain CDR3 amino acid sequences may vary from the sequence shown in SEQ ID NO: 73 by one or several (e.g. two etc) amino acids.
  • SEQ ID NO: 73 retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO: 114) when the CDR3 is part of TCR Va domain.
  • Functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 73.
  • 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: 73, 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: 73 that do not bind to the peptide shown in SEQ ID NO: 114. 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: 73 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.
  • the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 73.
  • the CDR3 may be encoded by any appropriate nucleic acid sequence.
  • the encoded TCR Va domain may comprise, in addition to the specified CDR3, a CDR1 comprising an amino acid sequence of SEQ ID NO: 71 , or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 114).
  • Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 71.
  • 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: 71 , 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: 71 that do not bind to the peptide shown in SEQ ID NO: 114. 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: 71 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.
  • appropriate functional Va domain CDR1 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 71 , i.e. it may have at least 80%, at least 83%, or 100% sequence identity to SEQ ID NO: 71.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 71).
  • appropriate functional Va domain CDR1 amino acid sequences may vary from the sequence shown in SEQ ID NO: 71 by one or several amino acids.
  • the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO: 71.
  • functional variants of SEQ ID NO: 71 retain the ability to (specifically) bind to the peptide shown in SEQ ID NO: 114 when the CDR1 is part of TCR Va domain.
  • the CDR1 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 71.
  • 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: 72, or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HI_A-B*07:02).
  • Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 72.
  • 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: 72, 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: 72 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: 72 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.
  • appropriate functional Va domain CDR2 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 72, i.e. it may have at least 80%, at least 83%, or 100% sequence identity to SEQ ID NO: 72.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 72).
  • appropriate (functional) Va domain CDR2 amino acid sequences may vary from the sequence shown in SEQ ID NO: 72 by one or several amino acids.
  • the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO: 72).
  • a functional variant of SEQ ID NO: 72 retains the ability to specifically bind to HLA-B*07:02.
  • the CDR2 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 72.
  • the CDR2 may be encoded by any appropriate nucleic acid sequence.
  • the encoded TCR Va domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NO:73, SEQ ID NO: 71 and SEQ ID NO: 72, or functional variants thereof), with appropriate intervening sequences between the CDRs.
  • the encoded TCR Va domain may comprise an amino acid sequence of SEQ ID NO: 77, 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: 114 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: 77.
  • 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: 77, 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: 77 that do not bind to the peptide shown in SEQ ID NO: 114. 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: 77 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.
  • 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: 77, whilst retaining the ability to (specifically) bind to the peptide shown in SEQ ID NO: 114.
  • a functional TOR Va domain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 77 is also encompassed.
  • the amino acid substitution may be a conservative amino acid substitution.
  • the variability in sequence compared to SEQ ID NO: 77 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: 73, SEQ ID NO: 71 and/or SEQ ID NO: 72, and still have 25% (or less) sequence variability compared to SEQ ID NO:77).
  • the sequence of the CDRs of SEQ ID NO: 77 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 77).
  • 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: 77, wherein the TCR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 73.
  • the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 71 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 72.
  • 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: 77, wherein the TCR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 73.
  • the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 71 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 72.
  • the TCR Va domain may be encoded by the nucleic acid sequence of SEQ ID NO: 78, 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).
  • 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.
  • SEQ ID NO: 81 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: 81.
  • Appropriate functional variants of SEQ ID NO:81 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: 81 , wherein the variant TCR a chain amino acid sequence retains its ability to (specifically) bind to the peptide shown in SEQ ID NO: 114 when part of a binding protein described herein).
  • a functional TCR a chain with one or several amino acid substitutions compared to the sequence of SEQ ID NO:81 is also encompassed.
  • the amino acid substitution may be a conservative amino acid substitution.
  • the variability in sequence compared to SEQ ID NO:81 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: 73, SEQ ID NO: 71 and/or SEQ ID NO: 72, and still have 25% (or less) sequence variability compared to SEQ ID NO: 81).
  • sequence of the CDRs of SEQ ID NO: 81 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 81).
  • 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: 81 , wherein the TCR a chain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 73.
  • the TCR a chain CDR1 may have an amino acid sequence of SEQ ID NO:71 and the TCR a chain CDR2 may have an amino acid sequence of SEQ ID NO: 72.
  • the TCR a chain may be encoded by the nucleic acid sequence of SEQ ID NO: 82, 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:82 is the nucleic acid sequence for TCR a chain of clone PML_H.4G10.
  • 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:73, or a functional fragment thereof.
  • 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: 73.
  • 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: 77.
  • 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
  • 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 GLLSLTFVL (SEQ ID NO: 115).
  • TCR clone ORZ_2.321 which interacts with GLLSLTFVL (SEQ ID NO: 115) in the context of HLA-A*02:01.
  • the sequences provided herein that correspond to TCR clone ORZ_2.321 are SEQ ID NO:s 85 to 98.
  • TCR Va domain CDR3 amino acid sequence that confers binding e.g. specific binding
  • GLLSLTFVL SEQ ID NO: 115
  • variants of the amino acid sequence shown in SEQ ID NO:87 may also be functional (i.e. retain their ability to confer (specific) binding to the peptide GLLSLTFVL (SEQ ID NO: 115) when the CDR3 is part of TCR Va domain). Such functional variants are therefore encompassed herein.
  • appropriate (functional) Va domain CDR3 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 87, i.e. they may have at least 80%, at least 93%, or 100% sequence identity to SEQ ID NO: 87.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 87).
  • appropriate (functional) Va domain CDR3 amino acid sequences may vary from the sequence shown in SEQ ID NO: 87 by one or several (e.g. two etc) amino acids.
  • SEQ ID NO: 87 retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO:115 when the CDR3 is part of TCR Va domain.
  • Functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 87.
  • 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: 87, 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: 87 that do not bind to the peptide shown in SEQ ID NO: 115. 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: 87 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.
  • the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 87.
  • the CDR3 may be encoded by any appropriate nucleic acid sequence.
  • the encoded TCR Va domain may comprise, in addition to the specified CDR3, a CDR1 comprising an amino acid sequence of SEQ ID NO: 85, or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 115).
  • Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 85.
  • 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: 85, 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: 85 that do not bind to the peptide shown in SEQ ID NO: 115. 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: 85 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.
  • appropriate functional Va domain CDR1 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 85, i.e. it may have at least 80%, at least 83%, or 100% sequence identity to SEQ ID NO: 85.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 85).
  • appropriate functional Va domain CDR1 amino acid sequences may vary from the sequence shown in SEQ ID NO: 85 by one or several amino acids.
  • the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO: 85.
  • functional variants of SEQ ID NO: 85 retain the ability to (specifically) bind to the peptide shown in SEQ ID NO:115 when the CDR1 is part of TCR Va domain.
  • the CDR1 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 85.
  • 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: 86, or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HI_A-A*02:01).
  • Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 86.
  • 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: 86, 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: 86 that do not specifically bind to HLA-A*02:01. 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: 86 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.
  • appropriate functional Va domain CDR2 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 86, i.e. it may have at least 80%, at least 83%, or 100% sequence identity to SEQ ID NO: 86.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 86).
  • appropriate (functional) Va domain CDR2 amino acid sequences may vary from the sequence shown in SEQ ID NO: 86 by one or several amino acids.
  • the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO: 86).
  • a functional variant of SEQ ID NO: 86 retains the ability to specifically bind to HLA-A*02:01.
  • the CDR2 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 86.
  • the CDR2 may be encoded by any appropriate nucleic acid sequence.
  • the encoded TCR Va domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NO:87, SEQ ID NO: 85 and SEQ ID NO: 86, or functional variants thereof), with appropriate intervening sequences between the CDRs.
  • the encoded TCR Va domain may comprise an amino acid sequence of SEQ ID NO: 91 , 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: 115 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: 91.
  • 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: 91 , 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: 91 that do not bind to the peptide shown in SEQ ID NO: 115. 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: 91 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.
  • 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: 91 , whilst retaining the ability to (specifically) bind to the peptide shown in SEQ ID NO: 115.
  • a functional TOR Va domain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 91 is also encompassed.
  • the amino acid substitution may be a conservative amino acid substitution.
  • the variability in sequence compared to SEQ ID NO: 91 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: 87, SEQ I D NO: 85 and/or SEQ I D NO: 86, and still have 25% (or less) sequence variability compared to SEQ ID NO:91).
  • the sequence of the CDRs of SEQ ID NO: 91 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 91).
  • 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: 91 , wherein the TCR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 87.
  • the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 85 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 86.
  • 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: 91, wherein the TCR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 87.
  • the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 85 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 86.
  • the TCR Va domain may be encoded by the nucleic acid sequence of SEQ ID NO: 92, 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).
  • 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.
  • SEQ ID NO: 95 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: 95.
  • Appropriate functional variants of SEQ ID NO: 95 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: 95, wherein the variant TCR a chain amino acid sequence retains its ability to (specifically) bind to the peptide shown in SEQ ID NO:115 when part of a binding protein described herein).
  • a functional TCR a chain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 95 is also encompassed.
  • the amino acid substitution may be a conservative amino acid substitution.
  • the variability in sequence compared to SEQ ID NO: 95 may all be in regions of the TOR a chain that do not form CDRs (i.e. the variant may have the CDRs of SEQ ID NO: 87, SEQ ID NO: 85 and/or SEQ ID NO: 86, and still have 25% (or less) sequence variability compared to SEQ ID NO: 95).
  • sequence of the CDRs of SEQ ID NO: 95 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 95).
  • 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: 95, wherein the TCR a chain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 87.
  • the TCR a chain CDR1 may have an amino acid sequence of SEQ ID NO:85 and the TCR a chain CDR2 may have an amino acid sequence of SEQ ID NO: 86.
  • the TCR a chain may be encoded by the nucleic acid sequence of SEQ ID NO:96, 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:96 is the nucleic acid sequence for TCR a chain of clone ORZ_2.321.
  • 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:87, or a functional fragment thereof.
  • 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: 87.
  • 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: 91.
  • TCR clone QRZ_003 which interacts with GLLSLTFVL (SEQ ID NO: 115) in the context of HI_A-A*02:01.
  • the sequences provided herein that correspond to TCR clone QRZ_003 are SEQ ID NO:s 99 to 112.
  • SEQ ID NO: 101 Another example of an appropriate TCR Va domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to GLLSLTFVL (SEQ ID NO: 115) is shown in SEQ ID NO: 101.
  • variants of the amino acid sequence shown in SEQ ID NO: 101 may also be functional (i.e. retain their ability to confer (specific) binding to the peptide GLLSLTFVL (SEQ ID NO: 115) when the CDR3 is part of TOR Va domain). Such functional variants are therefore encompassed herein.
  • appropriate (functional) Va domain CDR3 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 101 , i.e. they may have at least 80%, at least 90%, or 100% sequence identity to SEQ ID NO: 101.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 101).
  • appropriate (functional) Va domain CDR3 amino acid sequences may vary from the sequence shown in SEQ ID NO: 101 by one or several (e.g. two etc) amino acids.
  • SEQ ID NO: 101 retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO:115 when the CDR3 is part of TCR Va domain.
  • Functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 101.
  • 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: 101 , 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: 101 that do not bind to the peptide shown in SEQ ID NO: 115. 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: 101 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.
  • the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 101.
  • the CDR3 may be encoded by any appropriate nucleic acid sequence.
  • the encoded TCR Va domain may comprise, in addition to the specified CDR3, a CDR1 comprising an amino acid sequence of SEQ ID NO:99, or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 115).
  • Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 99.
  • 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: 99, 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: 99 that do not bind to the peptide shown in SEQ ID NO: 115. 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: 99 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.
  • appropriate functional Va domain CDR1 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 99, i.e. it may have at least 80%, at least 83%, or 100% sequence identity to SEQ ID NO: 99.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO:99).
  • appropriate functional Va domain CDR1 amino acid sequences may vary from the sequence shown in SEQ ID NO: 99 by one or several amino acids.
  • the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO: 99.
  • functional variants of SEQ ID NO: 99 retain the ability to (specifically) bind to the peptide shown in SEQ ID NO:115 when the CDR1 is part of TCR Va domain.
  • the CDR1 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 99.
  • 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: 100, or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HI_A-A*02:01).
  • Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 100.
  • the term “variant” also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ I D NO: 100, 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: 100 that do not specifically bind to HLA-A*02:01. 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: 100 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.
  • appropriate functional Va domain CDR2 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 100, i.e. it may have at least 80%, at least 85%, or 100% sequence identity to SEQ ID NO: 100.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 100).
  • appropriate (functional) Va domain CDR2 amino acid sequences may vary from the sequence shown in SEQ ID NO: 100 by one or several amino acids.
  • the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO: 100).
  • a functional variant of SEQ ID NO: 100 retains the ability to specifically bind to HLA-A*02:01.
  • the CDR2 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 100.
  • the CDR2 may be encoded by any appropriate nucleic acid sequence.
  • the encoded TOR Va domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NO: 101 , SEQ ID NO: 99 and SEQ ID NO: 100, or functional variants thereof), with appropriate intervening sequences between the CDRs.
  • the encoded TOR Va domain may comprise an amino acid sequence of SEQ ID NO: 105, or a functional variant thereof (i.e. wherein the variant TOR Va domain retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 115 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: 105.
  • 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 NQ:105, 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: 105 that do not bind to the peptide shown in SEQ ID NO: 115. 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: 105 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.
  • 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: 105, whilst retaining the ability to (specifically) bind to the peptide shown in SEQ ID NO:115.
  • a functional TCR Va domain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 105 is also encompassed.
  • the amino acid substitution may be a conservative amino acid substitution.
  • the variability in sequence compared to SEQ ID NO: 105 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: 101 , SEQ ID NO: 99 and/or SEQ ID NO: 100, and still have 25% (or less) sequence variability compared to SEQ ID NQ:105).
  • the sequence of the CDRs of SEQ ID NO: 105 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 105).
  • 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: 105, wherein the TOR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 101.
  • the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 99 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 100.
  • 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: 105, wherein the TCR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 101.
  • the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 99 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 100.
  • the TCR Va domain may be encoded by the nucleic acid sequence of SEQ ID NO: 106, 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).
  • 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.
  • SEQ ID NO: 109 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: 109.
  • Appropriate functional variants of SEQ ID NO: 109 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: 109, wherein the variant TCR a chain amino acid sequence retains its ability to (specifically) bind to the peptide shown in SEQ ID NO:115 when part of a binding protein described herein).
  • a functional TCR a chain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 109 is also encompassed.
  • the amino acid substitution may be a conservative amino acid substitution.
  • the variability in sequence compared to SEQ ID NO: 109 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: 101 , SEQ ID NO: 99 and/or SEQ ID NO: 100, and still have 25% (or less) sequence variability compared to SEQ ID NO: 109).
  • the sequence of the CDRs of SEQ ID NO: 109 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 109).
  • 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: 109, wherein the TCR a chain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 101.
  • the TCR a chain CDR1 may have an amino acid sequence of SEQ ID NO:99 and the TCR a chain CDR2 may have an amino acid sequence of SEQ ID NO: 100.
  • the TCR a chain may be encoded by the nucleic acid sequence of SEQ ID NO: 110, 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:110 is the nucleic acid sequence for TCR a chain of clone QRZ_003.
  • 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: 101 , or a functional fragment thereof.
  • 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: 101.
  • 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: 105.
  • the isolated nucleic acid composition described herein encodes a haematopoietic-restricted MiHA-specific binding protein.
  • the inventors identified several TCRs that bind (e.g. specifically bind) to a haematopoietic-restricted MiHA selected from RVRGTTLHLLL (SEQ ID NO: 113), LPRPDSPYSRL (SEQ ID NO: 114) and GLLSLTFVL (SEQ ID NO: 115).
  • the sequences for the Va domains are discussed above, with the corresponding sequences for the Vp domains discussed below.
  • TCR clone HHS_2.004 which interacts with RVRGTTLHLLL (SEQ ID NO: 113) in the context of HLA-B*07:02.
  • the sequences provided herein that correspond to TCR clone HHS_2.004 are SEQ ID NO:s 1 to 14.
  • SEQ ID NO:6 an example of an appropriate TCR VB domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to RVRGTTLHLLL (SEQ ID NO: 113) is shown in SEQ ID NO:6.
  • 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: 113 when the CDR3 is part of TOR Vp domain). Such functional variants are therefore encompassed herein.
  • appropriate (functional) Vp 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 92%, or 100% sequence identity to SEQ ID NO: 6.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 6).
  • appropriate (functional) Vp 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.
  • SEQ ID NO: 6 retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO: 113 when the CDR3 is part of TCR Vp domain.
  • 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.
  • 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: 113. 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: 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.
  • the CDR3 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 6.
  • the CDR3 may be encoded by any appropriate nucleic acid sequence.
  • 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: 113).
  • 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.
  • 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: 113. 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: 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.
  • 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.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 4).
  • 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.
  • 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).
  • functional variants of SEQ ID NO: 4 retain the ability to (specifically) bind to the peptide shown in SEQ ID NO: 113 when the CDR1 is part of TCR Vp domain).
  • the CDR1 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 4.
  • 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: 5, or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HI_A-B*07:02).
  • 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.
  • Non-functional variants are amino acid sequence variants of SEQ ID NO: 5 that do not specifically bind to HI_A-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: 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.
  • 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.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 5).
  • 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.
  • 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).
  • a functional variant of SEQ ID NO: 5 retains the ability to specifically bind to HLA-B*07:02.
  • the CDR2 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 5.
  • the CDR2 may be encoded by any appropriate nucleic acid sequence.
  • the encoded TOR 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.
  • the encoded TOR Vp domain may have an amino acid sequence of SEQ ID NO: 9, 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: 113 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.
  • 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: 113. 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: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.
  • 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: 9, whilst retaining the ability to (specifically) bind to the peptide shown in SEQ ID NO: 113.
  • a functional TCR Vp domain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 9 is also encompassed.
  • 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).
  • 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.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 9).
  • 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: 9, wherein the TCR Vp domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 6.
  • 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.
  • 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).
  • 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.
  • SEQ ID NO: 13 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: 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: 113 when part of a binding protein described herein).
  • a functional TCR p chain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 13 is also encompassed.
  • 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.
  • 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.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 13).
  • 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.
  • 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.
  • the TOR 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 HHS_2.004.
  • 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.
  • 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.
  • 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.
  • TCR Vp domain sequences derived from TCR clone HHS_2.004 discussed above are particularly compatible with the TCR Va domain sequences derived from TCR clone HHS_2.004 discussed elsewhere herein.
  • 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: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.
  • 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.
  • the haematopoietic-restricted MiHA may comprise or consist of the sequence shown in SEQ ID NO: 113.
  • 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.
  • 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.
  • 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.
  • 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.
  • the TOR 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.
  • 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.
  • this particular example encompasses components of TCR clone HHS_2.004 exemplified herein.
  • the different components of TCR clone HHS_2.004 and their respective SEQ ID Nos are summarised in Table 6 below.
  • 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.
  • the TCR Va domain and the 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.
  • 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.
  • IRS internal ribosomal entry sites
  • any other appropriate linker may also be used.
  • 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).
  • 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.
  • nucleic acid sequences that encode the TCR Va domain and/or the TCR Vp domain may also be encoded by the nucleic acid sequences that encode the TCR Va domain and/or the TCR Vp domain.
  • 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 WQ2016/071758.
  • the nucleic acid composition described herein may encode a soluble TCR.
  • 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).
  • 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.
  • Immune mobilising mTCR Against Cancer are bifunctional proteins that combine affinity monoclonal T cell receptor (mTCR) targeting with a therapeutic mechanism of action (i.e. , an anti-CD3 scFv).
  • mTCR monoclonal T cell receptor
  • 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.
  • 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.
  • the linker is non-cleavable.
  • 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.
  • TCR clone HHS_2.043 which interacts with RVRGTTLHLLL (SEQ ID NO: 113) in the context of HLA-B*07:02.
  • the sequences provided herein that correspond to TCR clone HHS_2.043 are SEQ ID NO:s 15 to 28.
  • SEQ ID NQ:20 An example of an appropriate TCR p domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to RVRGTTLHLLL (SEQ ID NO: 113) is shown in SEQ ID NQ:20.
  • 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: 113) when the CDR3 is part of TCR p domain). Such functional variants are therefore encompassed herein.
  • appropriate (functional) p 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 92%, or 100% sequence identity to SEQ ID NO: 20.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 20).
  • appropriate (functional) p 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.
  • functional variants of SEQ ID NO: 20 retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO: 113) when the CDR3 is part of TOR Vp domain.
  • 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: 113. 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.
  • the CDR3 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 20.
  • the CDR3 may be encoded by any appropriate nucleic acid sequence.
  • 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: 113).
  • 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.
  • 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: 113. 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.
  • 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.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 18).
  • 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.
  • 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).
  • functional variants of SEQ ID NO: 18 retain the ability to (specifically) bind to the peptide shown in SEQ ID NO: 113 when the CDR1 is part of TOR Vp domain).
  • the CDR1 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 18.
  • the CDR1 may be encoded by any appropriate nucleic acid sequence.
  • 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: 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.
  • 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.
  • 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.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 19).
  • 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.
  • 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).
  • a functional variant of SEQ ID NO: 19 retains the ability to specifically bind to HLA-B*07:02.
  • the CDR2 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 19.
  • 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:20, SEQ ID NO: 18 and SEQ ID NO: 19, 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: 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: 113 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.
  • 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: 113. 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.
  • 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: 23, whilst retaining the ability to (specifically) bind to the peptide shown in SEQ ID NO: 113.
  • a functional TCR Vp domain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 23 is also encompassed.
  • 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).
  • 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.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 23).
  • 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.
  • the TCR Vp domain CDR1 may have an amino acid sequence of SEQ ID NO:18 and the TCR p domain CDR2 may have an amino acid sequence of SEQ ID NO: 19.
  • 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).
  • 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.
  • SEQ ID NO: 27 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: 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: 113 when part of a binding protein described herein).
  • a functional TCR p chain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 27 is also encompassed.
  • 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.
  • 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.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 27).
  • 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.
  • 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.
  • 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).
  • SEQ ID NO:28 is the nucleic acid sequence for TCR p chain of clone HHS_2.043.
  • 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:20, or a functional fragment thereof.
  • 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:20.
  • 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.
  • TCR Vp domain sequences derived from TCR clone HHS_2.043 discussed above are particularly compatible with the TCR Va domain sequences derived from TCR clone HHS_2.043 discussed elsewhere herein.
  • 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 NQ:20, or a functional fragment thereof.
  • 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.
  • the haematopoietic-restricted MiHA-specific may comprise or consist of the sequence shown in SEQ ID NO: 113.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • TCR clone HHS_2.043 exemplified herein.
  • the different components of TCR clone HHS_2.043 and their respective SEQ ID Nos are summarised in Table 7 below.
  • 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.
  • the TCR Va domain and the TCR p 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.
  • 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.
  • TCR clone HHS_2.269 which interacts with RVRGTTLHLLL (SEQ ID NO: 113) in the context of HLA-B*07:02.
  • the sequences provided herein that correspond to TCR clone HHS_2.269 are SEQ ID NO:s 29 to 42.
  • SEQ ID NO:34 An example of an appropriate TCR Vp domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to RVRGTTLHLLL (SEQ ID NO: 113) is shown in SEQ ID NO:34.
  • 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: 113 when the CDR3 is part of TCR Vp domain). Such functional variants are therefore encompassed herein.
  • 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.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 34).
  • 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.
  • functional variants of SEQ ID NO: 34 retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO: 113 when the CDR3 is part of TOR Vp domain.
  • 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.
  • 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: 113. 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.
  • the CDR3 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 34.
  • the CDR3 may be encoded by any appropriate nucleic acid sequence.
  • 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: 113).
  • 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.
  • 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: 113. 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.
  • 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.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 32).
  • 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.
  • 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).
  • functional variants of SEQ ID NO: 32 retain the ability to (specifically) bind to the peptide shown in SEQ ID NO: 113 when the CDR1 is part of TOR Vp domain).
  • the CDR1 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 32.
  • 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: 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.
  • 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.
  • 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.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 33).
  • 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.
  • 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).
  • a functional variant of SEQ ID NO: 33 retains the ability to specifically bind to HLA-B*07:02.
  • the CDR2 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 33.
  • 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:34, SEQ ID NO: 32 and SEQ ID NO: 33, 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: 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: 113 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.
  • 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: 113. 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.
  • 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: 37, whilst retaining the ability to (specifically) bind to the peptide shown in SEQ ID NO: 113.
  • a functional TCR Vp domain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 37 is also encompassed.
  • 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).
  • 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.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 37).
  • 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.
  • the TCR Vp domain CDR1 may have an amino acid sequence of SEQ ID NO:32 and the TCR p domain CDR2 may have an amino acid sequence of SEQ ID NO: 33.
  • 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).
  • 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.
  • SEQ ID NO: 41 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: 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: 113 when part of a binding protein described herein).
  • a functional TCR p chain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 41 is also encompassed.
  • 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.
  • 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.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 41).
  • 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.
  • 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.
  • 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).
  • SEQ ID NO:42 is the nucleic acid sequence for TCR p chain of clone HHS_2.269.
  • 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.
  • 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.
  • 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.
  • TCR Vp domain sequences derived from TCR clone HHS_2.269 discussed above are particularly compatible with the TCR Va domain sequences derived from TCR clone HHS_2.269 discussed elsewhere herein.
  • 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: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.
  • 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.
  • the haematopoietic-restricted MiHA may comprise or consist of the sequence shown in SEQ ID NO: 113.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • TCR clone HHS_2.269 exemplified herein.
  • the different components of TCR clone HHS_2.269 and their respective SEQ ID Nos are summarised in Table 8 below.
  • 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.
  • the TCR Va domain and the TCR p 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.
  • 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.
  • 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
  • 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 LPRPDSPYSRL (SEQ ID NO: 114).
  • TCR clone FHA_1 H8 which interacts with LPRPDSPYSRL (SEQ ID NO: 114) in the context of HLA-B*07:02.
  • the sequences provided herein that correspond to TCR clone FHA_1 H8 are SEQ ID NO:s 43 to 56.
  • TCR Vp domain CDR3 amino acid sequence that confers binding e.g. specific binding
  • LPRPDSPYSRL SEQ ID NO: 114
  • 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: 114 when the CDR3 is part of TCR Vp domain). Such functional variants are therefore encompassed herein.
  • appropriate (functional) Vp domain CDR3 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 48, i.e.
  • SEQ ID NO: 48 may have at least 80%, at least 91%, or 100% sequence identity to SEQ ID NO: 48.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 48).
  • 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.
  • functional variants of SEQ ID NO: 48 retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO: 114 when the CDR3 is part of TCR Vp domain.
  • 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.
  • 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: 114. 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.
  • the CDR3 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 48.
  • the CDR3 may be encoded by Any appropriate nucleic acid sequence.
  • 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: 114).
  • 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.
  • 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: 114.
  • 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.
  • 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.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 46).
  • 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.
  • 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).
  • functional variants of SEQ ID NO: 46 retain the ability to (specifically) bind to the peptide shown in SEQ ID NO: 114 when the CDR1 is part of TCR Vp domain.
  • the CDR1 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 46.
  • 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: 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.
  • 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.
  • 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.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 47).
  • 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.
  • 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).
  • the CDR2 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 47.
  • the CDR2 may be encoded by any appropriate nucleic acid sequence.
  • the encoded TOR 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.
  • 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: 114 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.
  • 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: 114. 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.
  • 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: 114.
  • a functional TCR Vp domain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 51 is also encompassed.
  • 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).
  • 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.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 51).
  • 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 TOR p domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 48.
  • the TOR Vp domain CDR1 may have an amino acid sequence of SEQ ID NO:46 and the TCR Vp domain CDR2 may have an amino acid sequence of SEQ ID NO: 47.
  • 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).
  • 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.
  • SEQ ID NO: 55 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: 114 when part of a binding protein described herein).
  • a functional TCR p chain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 55 is also encompassed.
  • 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.
  • 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.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 55).
  • 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.
  • 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.
  • 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 FHA_1 H8.
  • 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.
  • 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.
  • 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.
  • TCR Vp domain sequences derived from TCR clone FHA_1 H8 discussed above are particularly compatible with the TCR Va domain sequences derived from TCR clone FHA_1 H8 discussed elsewhere herein.
  • 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.
  • 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.
  • the haematopoietic-restricted MiHA may comprise or consist of the sequence shown in SEQ ID NO: 114.
  • 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.
  • 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.
  • 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 .
  • 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.
  • 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.
  • 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.
  • TCR clone FHA_1 H8 exemplified herein.
  • the different components of TCR clone FHA_1 H8 and their respective SEQ ID Nos are summarised in Table 9 below.
  • the nucleic acid composition described herein encodes both a TCR Va domain and a TCR p domain, which form the binding protein that is capable of specifically binding to a haematopoietic-restricted MiHA as described herein.
  • the TCR Va domain and the 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.
  • 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.
  • TCR clone MHU_1.052 which interacts with LPRPDSPYSRL (SEQ ID NO: 114) in the context of HI_A-B*07:02.
  • the sequences provided herein that correspond to TCR clone MHU_1.052 are SEQ ID NO:s 57 to 70.
  • SEQ ID NO:62 An example of an appropriate TCR Vp domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to LPRPDSPYSRL (SEQ ID NO: 114) is shown in SEQ ID NO:62.
  • 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: 114 when the CDR3 is part of TCR Vp domain). Such functional variants are therefore encompassed herein.
  • 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 94%, or 100% sequence identity to SEQ ID NO: 62.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 62).
  • 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.
  • functional variants of SEQ ID NO: 62 retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO: 114 when the CDR3 is part of TCR Vp domain.
  • 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.
  • 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: 114. 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.
  • the CDR3 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 62.
  • the CDR3 may be encoded by any appropriate nucleic acid sequence.
  • 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: 114).
  • 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.
  • 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: 114. 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.
  • 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.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 60).
  • 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.
  • 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).
  • functional variants of SEQ ID NO: 60 retain the ability to (specifically) bind to the peptide shown in SEQ ID NO: 114 when the CDR1 is part of TCR Vp domain).
  • the CDR1 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 60.
  • 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: 61 , 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: 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.
  • Non-functional variants are amino acid sequence variants of SEQ ID NO: 61 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: 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.
  • 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.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 61).
  • 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.
  • 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).
  • a functional variant of SEQ ID NO: 61 retains the ability to specifically bind to HLA-B*07:02.
  • the CDR2 of the Vp domain comprises or consists of 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.
  • 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: 114 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.
  • 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: 114. 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.
  • 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: 114.
  • a functional TCR Vp domain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 65 is also encompassed.
  • 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).
  • 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.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 65).
  • 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.
  • 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.
  • 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).
  • 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.
  • SEQ ID NO: 69 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: 114 when part of a binding protein described herein).
  • a functional TCR p chain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 69 is also encompassed.
  • 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.
  • 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.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 69).
  • 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.
  • 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.
  • 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).
  • SEQ ID NQ:70 is the nucleic acid sequence for TCR p chain of clone MHU_1.052.
  • 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.
  • 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.
  • 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.
  • TCR Vp domain sequences derived from TCR clone MHU_1.052 discussed above are particularly compatible with the TCR Va domain sequences derived from TCR clone MHU_1.052 discussed elsewhere herein.
  • 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.
  • 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.
  • the haematopoietic-restricted MiHA may comprise or consist of the sequence shown in SEQ ID NO: 114.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 .
  • TCR clone MHU_1.052 exemplified herein.
  • the different components of TCR clone MHU_1.052 and their respective SEQ ID Nos are summarised in Table 10 below.
  • 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.
  • the TCR Va domain and the TCR p 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.
  • 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.
  • TCR clone PML_H.4G10 which interacts with LPRPDSPYSRL (SEQ ID NO: 114) in the context of HLA-B*07:02.
  • the sequences provided herein that correspond to TCR clone PML_H.4G10 are SEQ ID NO:s 71 to 84.
  • SEQ ID NO:76 An example of an appropriate TCR Vp domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to LPRPDSPYSRL (SEQ ID NO: 114) is shown in SEQ ID NO:76.
  • variants of the amino acid sequence shown in SEQ ID NO:76 may also be functional (i.e. retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO: 114 when the CDR3 is part of TCR Vp domain). Such functional variants are therefore encompassed herein.
  • appropriate (functional) Vp domain CDR3 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 76, i.e. they may have at least 80%, at least 91%, or 100% sequence identity to SEQ ID NO: 76.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 76).
  • appropriate (functional) Vp domain CDR3 amino acid sequences may vary from the sequence shown in SEQ ID NO: 76 by one or several (e.g. two) amino acids.
  • functional variants of SEQ ID NO: 76 retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO: 114 when the CDR3 is part of TCR Vp domain.
  • Functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 76.
  • 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: 76, 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: 76 that do not bind to the peptide shown in SEQ ID NO: 114. 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: 76 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.
  • the CDR3 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 76.
  • the CDR3 may be encoded by any appropriate nucleic acid sequence.
  • the encoded TCR Vp domain may comprise, in addition to the specified CDR3, a CDR1 comprising an amino acid sequence of SEQ ID NO: 74, or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 114).
  • Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 74.
  • 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: 74, 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: 74 that do not bind to the peptide shown in SEQ ID NO: 114. 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: 74 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.
  • appropriate functional Vp domain CDR1 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 74, i.e. it may have at least 80%, or 100% sequence identity to SEQ ID NO: 74.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 74).
  • appropriate (functional) Vp domain CDR1 amino acid sequences may vary from the sequence shown in SEQ ID NO:74 by one or several amino acids.
  • the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO:74).
  • functional variants of SEQ ID NO: 74 retain the ability to (specifically) bind to the peptide shown in SEQ ID NO: 114 when the CDR1 is part of TOR Vp domain).
  • the CDR1 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 74.
  • 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: 75, 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: 75.
  • 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: 75, 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: 75 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: 75 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.
  • appropriate functional Vp domain CDR2 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 75, i.e. it may have at least 80%, at least 83%, or 100% sequence identity to SEQ ID NO: 75.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 75).
  • appropriate (functional) Vp domain CDR2 amino acid sequences may vary from the sequence shown in SEQ ID NO: 75 by one or several amino acids.
  • the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO: 75).
  • a functional variant of SEQ ID NO: 75 retains the ability to specifically bind to HLA-B*07:02.
  • the CDR2 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 75.
  • 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:76, SEQ ID NO: 74 and SEQ ID NO: 75, or functional variants thereof), with appropriate intervening sequences between the CDRs.
  • the encoded TCR p domain may have an amino acid sequence of SEQ ID NO: 79, 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: 114 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: 79.
  • variant also encompasses homologues and fragments. Functional variants will typically contain only conservative substitutions of one or more amino acids of SEQ ID NO: 79, 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: 79 that do not bind to the peptide shown in SEQ ID NO: 114. 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:79 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.
  • 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: 79, whilst retaining the ability to (specifically) bind to the peptide shown in SEQ ID NO: 114.
  • a functional TCR Vp domain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 79 is also encompassed.
  • the amino acid substitution may be a conservative amino acid substitution.
  • the variability in sequence compared to SEQ ID NO:79 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: 76, SEQ ID NO: 74 and/or SEQ ID NO: 75, and still have 25% (or less) sequence variability compared to SEQ ID NO: 79).
  • the sequence of the CDRs of SEQ ID NO: 79 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 79).
  • 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: 79, wherein the TCR Vp domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 76.
  • the TCR Vp domain CDR1 may have an amino acid sequence of SEQ ID NO:74 and the TCR Vp domain CDR2 may have an amino acid sequence of SEQ ID NO: 75.
  • the TCR VP domain may be encoded by the nucleic acid sequence of SEQ ID NQ:80, 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).
  • 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.
  • SEQ ID NO: 83 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: 83.
  • Appropriate functional variants of SEQ ID NO: 83 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: 83, wherein the variant TCR p chain amino acid sequence retains its ability to (specifically) bind to the peptide shown in SEQ ID NO: 114 when part of a binding protein described herein).
  • a functional TCR p chain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 83 is also encompassed.
  • the amino acid substitution may be a conservative amino acid substitution.
  • the variability in sequence compared to SEQ ID NO:83 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: 76, SEQ ID NO: 74 and/or SEQ ID NO: 75, and still have 25% (or less) sequence variability compared to SEQ ID NO:83.
  • sequence of the CDRs of SEQ ID NO: 83 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 83).
  • 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: 83, wherein the TCR p chain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 76.
  • the TCR p chain CDR1 may have an amino acid sequence of SEQ ID NO: 74 and the TCR p chain CDR2 may have an amino acid sequence of SEQ ID NO: 75.
  • the TCR p chain may be encoded by the nucleic acid sequence of SEQ ID NO: 84, 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: 84 is the nucleic acid sequence for TCR p chain of clone PML_H.4G10.
  • 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:76, or a functional fragment thereof.
  • 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:76.
  • 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: 79.
  • TCR Vp domain sequences derived from TCR clone PML_H.4G10 discussed above are particularly compatible with the TCR Va domain sequences derived from TCR clone PML_H.4G10 discussed elsewhere herein.
  • 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:73, 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:76, or a functional fragment thereof.
  • 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: 73; and a TCR Vp domain with a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO:76.
  • the haematopoietic-restricted MiHA may comprise or consist of the sequence shown in SEQ ID NO: 114.
  • 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.
  • the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 77; and the Vp domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 79.
  • the Va domain comprises the amino acid sequence of SEQ ID NO: 77 and the Vp domain comprises the amino acid sequence of SEQ ID NO: 79.
  • the Va domain may be encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 78; and the Vp domain may be encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 80.
  • the TCR Va domain may include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 71 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO:72.
  • the TCR Vp domain may include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO:74 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 75.
  • this particular example encompasses components of TCR clone PML_H.4G10 exemplified herein. The different components of TCR clone PML_H.4G10 and their respective SEQ ID Nos are summarised in Table 11 below.
  • 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.
  • the TCR Va domain and the TCR p 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.
  • 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.
  • 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
  • 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 GLLSLTFVL (SEQ ID NO: 115).
  • TCR clone ORZ_2.321 which interacts with GLLSLTFVL (SEQ ID NO: 115) in the context of HLA-A*02:01.
  • the sequences provided herein that correspond to TCR clone ORZ_2.321 are SEQ ID NO:s 85 to 98.
  • TCR Vp domain CDR3 amino acid sequence that confers binding e.g. specific binding
  • GLLSLTFVL GLLSLTFVL
  • SEQ ID NQ:90 An example of an appropriate TCR Vp domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to GLLSLTFVL (SEQ ID NO: 115) is shown in SEQ ID NQ:90.
  • variants of the amino acid sequence shown in SEQ ID NQ:90 may also be functional (i.e. retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO: 115 when the CDR3 is part of TCR Vp domain). Such functional variants are therefore encompassed herein.
  • appropriate (functional) Vp domain CDR3 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 90, i.e. they may have at least 80%, at least 93%, or 100% sequence identity to SEQ ID NO: 90.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 90).
  • appropriate (functional) Vp domain CDR3 amino acid sequences may vary from the sequence shown in SEQ ID NO: 90 by one or several (e.g. two) amino acids.
  • functional variants of SEQ ID NO: 90 retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO: 115 when the CDR3 is part of TCR Vp domain.
  • Functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 90.
  • 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: 90, 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: 90 that do not bind to the peptide shown in SEQ ID NO: 115. 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: 90 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.
  • the CDR3 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 90.
  • the CDR3 may be encoded by Any appropriate nucleic acid sequence.
  • the encoded TCR Vp domain may comprise, in addition to the specified CDR3, a CDR1 comprising an amino acid sequence of SEQ ID NO: 88, or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 115).
  • Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 88.
  • 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: 88, 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: 88 that do not bind to the peptide shown in SEQ ID NO: 115. 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: 88 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.
  • appropriate functional Vp domain CDR1 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 88, i.e. it may have at least 80%, or 100% sequence identity to SEQ ID NO: 88.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 88).
  • appropriate (functional) Vp domain CDR1 amino acid sequences may vary from the sequence shown in SEQ ID NO:88 by one or several amino acids.
  • the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO:88).
  • functional variants of SEQ ID NO: 88 retain the ability to (specifically) bind to the peptide shown in SEQ ID NO: 115 when the CDR1 is part of TCR Vp domain.
  • the CDR1 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 88.
  • 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: 89, or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HLA-A*02:01).
  • Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 89.
  • 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: 89, 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: 89 that do not specifically bind to HLA-A*02:01. 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: 89 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.
  • appropriate functional Vp domain CDR2 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 89, i.e. it may have at least 80%, at least 83%, or 100% sequence identity to SEQ ID NO: 89.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 89).
  • appropriate (functional) Vp domain CDR2 amino acid sequences may vary from the sequence shown in SEQ ID NO: 89 by one or several amino acids.
  • the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO: 89).
  • the CDR2 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 89.
  • the CDR2 may be encoded by any appropriate nucleic acid sequence.
  • the encoded TOR Vp domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NQ:90, SEQ ID NO: 88 and SEQ ID NO: 89, 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: 93, 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: 115 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: 93.
  • 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: 93, 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: 93 that do not bind to the peptide shown in SEQ ID NO: 115. 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:93 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.
  • 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: 93, whilst retaining the ability to (specifically) bind to the peptide shown in SEQ ID NO: 115.
  • a functional TCR Vp domain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 93 is also encompassed.
  • the amino acid substitution may be a conservative amino acid substitution.
  • the variability in sequence compared to SEQ ID NO:93 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: 90, SEQ ID NO: 88 and/or SEQ ID NO: 89, and still have 25% (or less) sequence variability compared to SEQ ID NO: 93).
  • the sequence of the CDRs of SEQ ID NO: 93 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 93).
  • 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: 93, wherein the TOR p domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 90.
  • the TOR Vp domain CDR1 may have an amino acid sequence of SEQ ID NO:88 and the TCR Vp domain CDR2 may have an amino acid sequence of SEQ ID NO: 89.
  • the TCR VP domain may be encoded by the nucleic acid sequence of SEQ ID NO:94, 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).
  • 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.
  • SEQ ID NO: 97 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: 97.
  • Appropriate functional variants of SEQ ID NO: 97 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: 97, wherein the variant TCR p chain amino acid sequence retains its ability to (specifically) bind to the peptide shown in SEQ ID NO: 115 when part of a binding protein described herein).
  • a functional TCR p chain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 97 is also encompassed.
  • the amino acid substitution may be a conservative amino acid substitution.
  • the variability in sequence compared to SEQ ID NO:97 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: 90, SEQ ID NO: 88 and/or SEQ ID NO: 89, and still have 25% (or less) sequence variability compared to SEQ ID NO:97.
  • sequence of the CDRs of SEQ ID NO: 97 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 97).
  • 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: 97, wherein the TCR p chain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 90.
  • the TCR p chain CDR1 may have an amino acid sequence of SEQ ID NO: 88 and the TCR p chain CDR2 may have an amino acid sequence of SEQ ID NO: 89.
  • the TCR p chain may be encoded by the nucleic acid sequence of SEQ ID NO:98, 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:98 is the nucleic acid sequence for TCR p chain of clone ORZ_2.321 .
  • 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:90, or a functional fragment thereof.
  • 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:90.
  • 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: 93.
  • TCR Vp domain sequences derived from TCR clone ORZ_2.321 discussed above are particularly compatible with the TCR Va domain sequences derived from TCR clone ORZ_2.321 discussed elsewhere herein.
  • 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:87, 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 NQ:90, or a functional fragment thereof.
  • 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: 87; and a TCR Vp domain with a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NQ:90.
  • the haematopoietic-restricted MiHA may comprise or consist of the sequence shown in SEQ ID NO: 115.
  • 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.
  • the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 91 ; and the Vp domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 93.
  • the Va domain comprises the amino acid sequence of SEQ ID NO: 91 and the Vp domain comprises the amino acid sequence of SEQ ID NO: 93.
  • the Va domain may be encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 92; and the Vp domain may be encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 94.
  • the TCR Va domain may include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 85 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO:86.
  • the TCR Vp domain may include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO:88 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 89.
  • this particular example encompasses components of TCR clone ORZ_2.321 exemplified herein.
  • the different components of TCR clone ORZ_2.321 and their respective SEQ ID Nos are summarised in Table 12 below.
  • the nucleic acid composition described herein encodes both a TCR Va domain and a TCR p domain, which form the binding protein that is capable of specifically binding to a haematopoietic-restricted MiHA as described herein.
  • the TCR Va domain and the 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.
  • 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.
  • TCR clone QRZ_003 which interacts with GLLSLTFVL (SEQ ID NO: 115) in the context of HLA-A*02:01.
  • sequences provided herein that correspond to TCR clone QRZ_003 are SEQ ID NO:s 99 to 112.
  • TCR Vp domain CDR3 amino acid sequence that confers binding e.g. specific binding
  • GLLSLTFVL GLLSLTFVL
  • SEQ ID NO: 115 GLLSLTFVL
  • variants of the amino acid sequence shown in SEQ ID NO: 104 may also be functional (i.e. retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO: 115 when the CDR3 is part of TCR Vp domain). Such functional variants are therefore encompassed herein.
  • appropriate (functional) Vp domain CDR3 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 104, i.e. they may have at least 80%, at least 92%, or 100% sequence identity to SEQ ID NO: 104.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 104).
  • appropriate (functional) Vp domain CDR3 amino acid sequences may vary from the sequence shown in SEQ ID NO: 104 by one or several (e.g. two) amino acids.
  • functional variants of SEQ ID NO: 104 retain their ability to confer (specific) binding to the peptide shown in SEQ ID NO: 115 when the CDR3 is part of TCR Vp domain.
  • Functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 104.
  • 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: 104, 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: 104 that do not bind to the peptide shown in SEQ ID NO: 115. 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: 104 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.
  • the CDR3 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 104.
  • the CDR3 may be encoded by any appropriate nucleic acid sequence.
  • the encoded TCR Vp domain may comprise, in addition to the specified CDR3, a CDR1 comprising an amino acid sequence of SEQ ID NO: 102, or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 115).
  • Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 102.
  • 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: 102, 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: 102 that do not bind to the peptide shown in SEQ ID NO: 115. 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: 102 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.
  • appropriate functional Vp domain CDR1 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 102, i.e. it may have at least 80%, or 100% sequence identity to SEQ ID NO: 102.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 102).
  • appropriate (functional) p domain CDR1 amino acid sequences may vary from the sequence shown in SEQ ID NO: 102 by one or several amino acids.
  • the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO:102).
  • functional variants of SEQ ID NO: 102 retain the ability to (specifically) bind to the peptide shown in SEQ ID NO: 115 when the CDR1 is part of TCR Vp domain).
  • the CDR1 of the p domain comprises or consists of the amino acid sequence of SEQ ID NO: 102.
  • the CDR1 may be encoded by any appropriate nucleic acid sequence.
  • the encoded TCR p 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: 103, or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HLA-A*02:01).
  • Such functional variants may be naturally occurring, synthetic, or synthetically improved functional variants of SEQ ID NO: 103.
  • 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: 103, 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: 103 that do not specifically bind to HLA-A*02:01. 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: 103 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.
  • appropriate functional p domain CDR2 amino acid sequences may have at least 80% sequence identity to SEQ ID NO: 103, i.e. it may have at least 80%, at least 83%, or 100% sequence identity to SEQ ID NO: 103.
  • percent identity is calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 103).
  • appropriate (functional) p domain CDR2 amino acid sequences may vary from the sequence shown in SEQ ID NO: 103 by one or several amino acids.
  • the variant may comprise an amino acid substitution such as a conservative amino acid substitution compared to the sequence shown in SEQ ID NO: 103).
  • a functional variant of SEQ ID NO: 103 retains the ability to specifically bind to HLA-A*02:01.
  • the CDR2 of the p domain comprises or consists of the amino acid sequence of SEQ ID NO: 103.
  • 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: 104, SEQ ID NO: 102 and SEQ ID NO: 103, 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: 107, 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: 115 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: 107.
  • 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: 107, 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: 107 that do not bind to the peptide shown in SEQ ID NO: 115. Non-functional variants will typically contain a nonconservative substitution, a deletion, or insertion or premature truncation of the amino acid sequence of SEQ I D NO: 107 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.
  • 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: 107, whilst retaining the ability to (specifically) bind to the peptide shown in SEQ ID NO: 115.
  • a functional TCR Vp domain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 107 is also encompassed.
  • the amino acid substitution may be a conservative amino acid substitution.
  • the variability in sequence compared to SEQ ID NO: 107 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: 104, SEQ ID NO: 102 and/or SEQ ID NO: 103, and still have 25% (or less) sequence variability compared to SEQ ID NO: 107).
  • the sequence of the CDRs of SEQ ID NO: 107 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 107).
  • 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: 107, wherein the TCR Vp domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 104.
  • the TCR Vp domain CDR1 may have an amino acid sequence of SEQ ID NO: 102 and the TOR p domain CDR2 may have an amino acid sequence of SEQ ID NO: 103.
  • the TCR Vp domain may be encoded by the nucleic acid sequence of SEQ ID NO: 108, 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).
  • 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.
  • SEQ ID NO: 111 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: 111.
  • Appropriate functional variants of SEQ ID NO: 111 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: 111 , wherein the variant TCR p chain amino acid sequence retains its ability to (specifically) bind to the peptide shown in SEQ ID NO: 115 when part of a binding protein described herein).
  • a functional TCR p chain with one or several amino acid substitutions compared to the sequence of SEQ ID NO: 111 is also encompassed.
  • the amino acid substitution may be a conservative amino acid substitution.
  • the variability in sequence compared to SEQ ID NO:111 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: 104, SEQ ID NO: 102 and/or SEQ ID NO: 103, and still have 25% (or less) sequence variability compared to SEQ ID NO: 111.
  • sequence of the CDRs of SEQ ID NO: 111 may be retained whilst the rest of the sequence is varied, as appropriate within the “at least 75% identity” parameters specified above.
  • percent identity can be calculated as the percentage of identity to the entire length of the reference sequence (e.g. SEQ ID NO: 111).
  • 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: 111 , wherein the TCR p chain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 104.
  • the TCR p chain CDR1 may have an amino acid sequence of SEQ ID NO: 102 and the TCR p chain CDR2 may have an amino acid sequence of SEQ ID NO: 103.
  • the TCR P chain may be encoded by the nucleic acid sequence of SEQ ID NO:112, 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).
  • SEQ ID NO:112 is the nucleic acid sequence for TCR p chain of clone QRZ_003.
  • 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: 104, or a functional fragment thereof.
  • 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: 104.
  • 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: 107.
  • TCR Vp domain sequences derived from TCR clone QRZ_003 discussed above are particularly compatible with the TCR Va domain sequences derived from TCR clone QRZ_003 discussed elsewhere herein.
  • 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: 101 , 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: 104, or a functional fragment thereof.
  • 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: 101 ; and a TCR Vp domain with a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 104.
  • the haematopoietic-restricted MiHA may comprise or consist of the sequence shown in SEQ ID NO: 115.
  • 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.
  • the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 105; and the Vp domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 107.
  • the Va domain comprises the amino acid sequence of SEQ ID NO: 105 and the Vp domain comprises the amino acid sequence of SEQ ID NO: 107.
  • the Va domain may be encoded by a nucleic acid sequence comprising the sequence of SEQ I D NO: 106; and the Vp domain may be encoded by a nucleic acid sequence comprising the sequence of SEQ ID NO: 108.
  • the TCR Va domain may include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO:99 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 100.
  • the TCR Vp domain may include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 102 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 103.
  • this particular example encompasses components of TCR clone QRZ_003 exemplified herein.
  • the different components of TCR clone QRZ_003 and their respective SEQ ID Nos are summarised in Table 13 below.
  • TCR clone EBJ_1.195 which interacts with ITFYTGVLK (SEQ ID NO: 131) in the context of HLA- A*03:01.
  • the nucleic acid and polypeptide sequences provided herein that correspond to TCR clone EBJ_1.195 are SEQ ID NO:s 139 to 152. See also table 14.
  • 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
  • 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 binding (e.g. specifically bind) to an MiHA that comprises the amino acid sequence ITFYTGVLK (SEQ ID NO: 131).
  • TCR Va domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to ITFYTGVLK (SEQ ID NO: 131) is shown in SEQ ID NO:141.
  • 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 ITFYTGVLK (SEQ ID NO: 131)) when the CDR3 is part of TCR Va domain).
  • the TCR Va domain CDR3 may be encoded by any appropriate nucleic acid sequence (see for example table 14).
  • 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:131).
  • the CDR1 may be encoded by any appropriate nucleic acid sequence (see for example table 14).
  • 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-A*03:01).
  • the CDR2 may be encoded by any appropriate nucleic acid sequence (see for example table 14).
  • the encoded TOR Va domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NO:141 , SEQ ID NO:139 and SEQ ID NO: 140, or functional variants thereof), with appropriate intervening sequences between the CDRs.
  • 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: 131 when part of a binding protein described herein).
  • the TCR Va domain may be encoded by any appropriate nucleic acid sequence (see for example table 14).
  • 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 TCR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 141.
  • 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.
  • 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: 141.
  • 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.
  • 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.
  • TCR Vp domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to ITFYTGVLK (SEQ ID NO: 131) is shown in SEQ ID NO:144.
  • 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 ITFYTGVLK (SEQ ID NO: 131)) when the CDR3 is part of TCR Vp domain).
  • the TCR Vp domain CDR3 may be encoded by any appropriate nucleic acid sequence (see for example table 14).
  • 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: 131).
  • the CDR1 may be encoded by any appropriate nucleic acid sequence (see for example table 14).
  • 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-A*03:01).
  • the TCR Vp domain CDR2 may be encoded by any appropriate nucleic acid sequence (see for example table 14).
  • the encoded TCR Vp domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NO: 144, SEQ ID NO: 142 and SEQ ID NO: 143, 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: 131 when part of a binding protein described herein).
  • the TCR Vp domain may be encoded by any appropriate nucleic acid sequence (see for example table 14).
  • 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: 147, wherein the TCR Vp domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 144.
  • the TCR Vp domain CDR1 may have an amino acid sequence of SEQ ID NO:142 and the TCR Vp domain CDR2 may have an amino acid sequence of SEQ ID NO: 143.
  • 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: 147, wherein the TCR Vp domain comprises a CDR3 having an amino acid sequence of SEQ ID NO:144.
  • the TCR Vp 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.
  • 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 14.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • TCR clone FHA_5E5 which interacts with RPRGLRLPQL (SEQ ID NO: 133) in the context of HLA-B*07:02.
  • the nucleic acid and polypeptide sequences provided herein that correspond to TCR clone FHA_5E5 are SEQ ID NO:s 153 to 166. See also table 15.
  • 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
  • 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 RPRGLRLPQL (SEQ ID NO: 133).
  • an appropriate TOR Va domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to RPRGLRLPQL (SEQ ID NO: 133) is shown in SEQ ID NO:155.
  • the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 155, or is a functional variant thereof ((i.e. where the variant retains its ability to confer (specific) binding to the peptide RPRGLRLPQL (SEQ ID NO: 133)) when the CDR3 is part of TCR Va domain).
  • the CDR3 may be encoded by any appropriate nucleic acid sequence (see for example table 15).
  • 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: 153, or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO:133).
  • the TCR Va domain CDR1 may be encoded by any appropriate nucleic acid sequence (see for example table 115).
  • 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: 154, or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HLA-B*07:02).
  • the TCR Va domain CDR2 has the amino acid sequence of SEQ ID NO: 154
  • the CDR2 may be encoded by any appropriate nucleic acid sequence (see for example table 15).
  • the encoded TCR Va domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NO: 155, SEQ ID NO: 153 and SEQ ID NO: 154, or functional variants thereof), with appropriate intervening sequences between the CDRs.
  • the encoded TCR Va domain may comprise an amino acid sequence of SEQ ID NO: 159, 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: 133 when part of a binding protein described herein).
  • the TCR Va domain may be encoded by any appropriate nucleic acid sequence (see for example table 15).
  • 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: 159, wherein the TCR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 155.
  • the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 153 and the TOR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 154.
  • the encoded TOR 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: 159, wherein the TCR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 155.
  • the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 153 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 154.
  • the nucleic acid sequence encoding the TCR Va domain may also encode a TCR a chain constant domain.
  • suitable constant domains are generally discussed elsewhere herein. See also table 15.
  • TCR Vp domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to RPRGLRLPQL is shown in SEQ ID NO:158.
  • the CDR3 of the V domain comprises or consists of the amino acid sequence of SEQ ID NO: 158, or is a functional variant thereof ((i.e. where the variant retains its ability to confer (specific) binding to the peptide RPRGLRLPQL (SEQ ID NO: 133)) when the CDR3 is part of TCR Vp domain).
  • the TCR Vp domain CDR3 may be encoded by any appropriate nucleic acid sequence (see for example table 15).
  • the encoded TCR Vp domain may comprise, in addition to the specified CDR3, a CDR1 comprising an amino acid sequence of SEQ ID NO: 156, or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 133).
  • the CDR1 may be encoded by any appropriate nucleic acid sequence (see for example table 15).
  • 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: 157, or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HLA-B*07:02).
  • the TCR Vp domain CDR2 may be encoded by any appropriate nucleic acid sequence (see for example table 15).
  • the encoded TCR Vp domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NO: 158, SEQ ID NO: 156 and SEQ ID NO: 157, 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: 161 , 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: 133 when part of a binding protein described herein).
  • the TOR Vp domain may be encoded by any appropriate nucleic acid sequence (see for example table 15).
  • the encoded TOR 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: 161, wherein the TCR Vp domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 158.
  • the TCR Vp domain CDR1 may have an amino acid sequence of SEQ ID NO:156 and the TCR Vp domain CDR2 may have an amino acid sequence of SEQ ID NO: 157.
  • 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: 161, wherein the TCR Vp domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 158.
  • the TCR Vp domain CDR1 may have an amino acid sequence of SEQ ID NO: 156 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 157.
  • the nucleic acid sequence encoding the TCR Vp domain may also encode a TCR p chain constant domain.
  • suitable constant domains are generally discussed elsewhere herein. See also table 15.
  • 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: 155; and a TCR p domain with a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 158.
  • the TCR Va domain may also include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 153 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 154.
  • the TCR Vp domain may include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 156 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 157.
  • the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 159; and the Vp domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 161.
  • the Va domain comprises the amino acid sequence of SEQ ID NO: 159 and the Vp domain comprises the amino acid sequence of SEQ ID NO: 161.
  • 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 15.
  • appropriate functional variants may vary from the sequence shown in table 15 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 15.
  • TCR clone PML_074 which interacts with KPQQKGLRLL (SEQ ID NO: 135) in the context of HLA-B*07:02.
  • the nucleic acid and polypeptide sequences provided herein that correspond to TCR clone PML_074 are SEQ ID NO:s 167 to 180. See also table 16.
  • 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
  • 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 (specifically bind) to an MiHA that comprises the amino acid sequence KPQQKGLRLL (SEQ ID NO: 135).
  • TCR Va domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to KPQQKGLRLL (SEQ ID NO: 135) is shown in SEQ ID NO:169.
  • the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 169, or is a functional variant thereof ((i.e. where the variant retains its ability to confer (specific) binding to the peptide KPQQKGLRLL (SEQ ID NO: 135)) when the CDR3 is part of TCR Va domain).
  • the TCR Va domain CDR3 may be encoded by any appropriate nucleic acid sequence (see for example table 16).
  • 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: 167, or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO:135).
  • the TCR Va domain CDR1 may be encoded by any appropriate nucleic acid sequence (see for example table 16).
  • 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: 168, or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HLA-B*07:02).
  • the TCR Va domain CDR2 has the amino acid sequence of SEQ ID NO: 168
  • the CDR2 may be encoded by any appropriate nucleic acid sequence (see for example table 16).
  • the encoded TOR Va domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NO:169, SEQ ID NO:167 and SEQ ID NO: 168, or functional variants thereof), with appropriate intervening sequences between the CDRs.
  • the encoded TCR Va domain may comprise an amino acid sequence of SEQ ID NO: 173, 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: 135 when part of a binding protein described herein).
  • the TCR Va domain may be encoded by any appropriate nucleic acid sequence (see for example table 16).
  • 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: 173, wherein the TCR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 169.
  • the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 167 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 168.
  • 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: 173, wherein the TCR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 169.
  • the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 167 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 168.
  • 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 16.
  • TCR Vp domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to KPQQKGLRLL (SEQ ID NO: 135) is shown in SEQ ID NO:172.
  • the CDR3 of the V domain comprises or consists of the amino acid sequence of SEQ ID NO: 172, or is a functional variant thereof ((i.e. where the variant retains its ability to confer (specific) binding to the peptide KPQQKGLRLL (SEQ ID NO: 135)) when the CDR3 is part of TCR Vp domain).
  • the TCR Vp domain CDR3 may be encoded by any appropriate nucleic acid sequence (see for example table 16).
  • the encoded TCR Vp domain may comprise, in addition to the specified CDR3, a CDR1 comprising an amino acid sequence of SEQ ID NO: 170, or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 135).
  • the CDR1 may be encoded by any appropriate nucleic acid sequence (see for example table 16).
  • 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: 171 , or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HLA-B*07:02).
  • the CDR2 may be encoded by any appropriate nucleic acid sequence (see for example table 16).
  • the encoded TCR Vp domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NO: 172, SEQ ID NO: 170 and SEQ ID NO: 171 , 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: 175, 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: 135 when part of a binding protein described herein).
  • the TCR Vp domain may be encoded by any appropriate nucleic acid sequence (see for example table 16).
  • 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: 175, wherein the TCR Vp domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 172.
  • the TCR Vp domain CDR1 may have an amino acid sequence of SEQ ID NQ:170 and the TCR Vp domain CDR2 may have an amino acid sequence of SEQ ID NO: 171.
  • 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: 175, wherein the TCR Vp domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 172.
  • the TCR Vp domain CDR1 may have an amino acid sequence of SEQ ID NO: 170 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 171.
  • the nucleic acid sequence encoding the TCR Vp domain may also encode a TCR p chain constant domain.
  • suitable constant domains are generally discussed elsewhere herein. See also table 16.
  • 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: 169; and a TOR Vp domain with a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 172.
  • the TOR Va domain may also include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO:167 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 168.
  • the TCR VP domain may include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 170 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 171.
  • the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 173; and the Vp domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 175.
  • the Va domain comprises the amino acid sequence of SEQ ID NO: 173 and the Vp domain comprises the amino acid sequence of SEQ ID NO: 175.
  • 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 16.
  • appropriate functional variants may vary from the sequence shown in table 16 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 16.
  • TCR clone USF_3.41 which interacts with RIFASRLYY (SEQ ID NO: 137) in the context of HLA-A*03:01.
  • the nucleic acid and polypeptide sequences provided herein that correspond to TCR clone USF_3.41 are SEQ ID NO:s 181 to 1194. See also table 17.
  • 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
  • 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 RIFASRLYY (SEQ ID NO: 137).
  • the CDR3 of the Va domain comprises or consists of the amino acid sequence of SEQ ID NO: 183, or is a functional variant thereof ((i.e. where the variant retains its ability to confer (specific) binding to the peptide RIFASRLYY (SEQ ID NO: 137)) when the CDR3 is part of TOR Va domain).
  • the CDR3 may be encoded by any appropriate nucleic acid sequence (see for example table 17).
  • the encoded TOR Va domain may comprise, in addition to the specified CDR3, a CDR1 comprising or consisting of an amino acid sequence of SEQ ID NO: 181 , or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO:137).
  • the CDR1 may be encoded by any appropriate nucleic acid sequence (see for example table 17).
  • 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: 182, or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HLA-A*03:01).
  • the CDR2 may be encoded by any appropriate nucleic acid sequence (see for example table 17).
  • the encoded TOR Va domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NO:13, SEQ ID NO:181 and SEQ ID NO: 182, or functional variants thereof), with appropriate intervening sequences between the CDRs.
  • the encoded TOR Va domain may comprise an amino acid sequence of SEQ ID NO: 187, or a functional variant thereof (i.e. wherein the variant TOR Va domain retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 137 when part of a binding protein described herein).
  • the TOR Va domain may be encoded by any appropriate nucleic acid sequence (see for example table 17).
  • 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: 187, wherein the TOR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 183.
  • the TOR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 181 and the TOR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 182.
  • the encoded TOR 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: 187, wherein the TOR Va domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 183.
  • the TCR Va domain CDR1 may have an amino acid sequence of SEQ ID NO: 181 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 182.
  • 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 17.
  • TCR Vp domain CDR3 amino acid sequence that confers binding (e.g. specific binding) to RIFASRLYY (SEQ ID NO: 137) is shown in SEQ ID NO:186.
  • the CDR3 of the Vp domain comprises or consists of the amino acid sequence of SEQ ID NO: 186, or is a functional variant thereof ((i.e. where the variant retains its ability to confer (specific) binding to the peptide RIFASRLYY (SEQ ID NO: 137)) when the CDR3 is part of TCR Vp domain).
  • the TCR Vp domain CDR3 may be encoded by any appropriate nucleic acid sequence (see for example table 17).
  • the encoded TCR Vp domain may comprise, in addition to the specified CDR3, a CDR1 comprising an amino acid sequence of SEQ ID NO: 184, or a functional variant thereof (i.e. wherein the variant retains the ability to (specifically) bind to the peptide shown in SEQ ID NO: 137).
  • the CDR1 may be encoded by any appropriate nucleic acid sequence (see for example table 17).
  • 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: 185, or a functional variant thereof (i.e. wherein the variant retains the ability to specifically bind to HLA-A*03:01).
  • the TCR Vp domain CDR2 may be encoded by any appropriate nucleic acid sequence (see for example table 17).
  • the encoded TCR Vp domain may therefore comprise the CDRs mentioned in detail above (by SEQ ID specifically i.e. SEQ ID NO: 186, SEQ ID NO: 184 and SEQ ID NO: 185, 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: 189, 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: 137 when part of a binding protein described herein).
  • the TCR Vp domain may be encoded by any appropriate nucleic acid sequence (see for example table 17).
  • the encoded TCR Vp domain may comprise an amino acid sequence having at least 75% (e.g.
  • the TCR Vp domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 186.
  • the TCR Vp domain CDR1 may have an amino acid sequence of SEQ ID NO:184 and the TCR Vp domain CDR2 may have an amino acid sequence of SEQ ID NO: 185.
  • 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: 189, wherein the TCR Vp domain comprises a CDR3 having an amino acid sequence of SEQ ID NO: 186.
  • the TCR Vp domain CDR1 may have an amino acid sequence of SEQ ID NO: 184 and the TCR Va domain CDR2 may have an amino acid sequence of SEQ ID NO: 185.
  • the nucleic acid sequence encoding the TCR Vp domain may also encode a TCR p chain constant domain.
  • suitable constant domains are generally discussed elsewhere herein. See also table 17.
  • 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: 183; and a TCR p domain with a CDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 186.
  • the TCR Va domain may also include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 181 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 182.
  • the TCR Vp domain may include a CDR1 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 184 and a CDR2 amino acid sequence comprising or consisting of the amino acid sequence of SEQ ID NO: 185.
  • the Va domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 183; and the Vp domain may comprise an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 186.
  • the Va domain comprises the amino acid sequence of SEQ ID NO: 183 and the Vp domain comprises the amino acid sequence of SEQ ID NO: 186.
  • 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 17.
  • appropriate functional variants may vary from the sequence shown in table 17 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 17.
  • 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.
  • the TCR Va domain and the TCR p 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.
  • 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.
  • an isolated nucleic acid composition 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 RVRGTTLHLLL: HLA-B*07:02 complex; a LPRPDSPYSRL:HLA-B*07:02 complex; a RPRGLRLPQL: HLA-B*07:02 complex; a KPQQKGLRLL: HLA-B*07:02 complex; a GLLSLTFVL:HLA-A*02:01 complex; a ITFYTGVLK:HLA-A*03:01 complex and a RIFASRLYY:HLA-A*03:01 complex.
  • TCR T cell receptor
  • Va chain variable
  • Vp TCR p chain variable
  • an isolated nucleic acid composition that encodes a T cell receptor (TCR), wherein the TCR comprises:
  • 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;
  • 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;
  • 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;
  • TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 73; and a TCR Vp domain comprising a CDR3 of SEQ ID NO: 76; or
  • TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 87; and a TCR Vp domain comprising a CDR3 of SEQ ID NO: 90; or
  • a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 101 ; and a TCR Vp domain comprising a CDR3 of SEQ ID NO: 104; or (ix) a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 141 , and a TOR Vp domain comprising a CDR3 amino acid sequence of SEQ ID NO: 144; or
  • composition may comprise:
  • (x) a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 155; and a nucleic acid sequence that encodes a TCR p domain comprising a CDR3 amino acid sequence of SEQ ID NO: 158, wherein the encoded TCR binds to a RPRGLRLPQL:HI_A-B*07:02 complex; or
  • xii a nucleic acid sequence that encodes a TCR Va domain comprising a CDR3 amino acid sequence of SEQ ID NO: 183; and a nucleic acid sequence that encodes a TCR Vp domain comprising a CDR3 amino acid sequence of SEQ ID NO: 186, wherein the encoded TCR binds to a RIFASRLYY: HLA-A*03:01 complex.
  • 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 TCR binds to a RVRGTTLHLLL:HI_A-B*07:02 complex; or
  • 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 Vp domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 23, and the encoded TCR binds to a RVRGTTLHLLL:HLA-B*07:02 complex; or
  • 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 TCR binds to a RVRGTTLHLLL:HLA-B*07:02 complex; or
  • 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 TCR binds to a LPRPDSPYSRL: HI_A-B*07:02 complex; or
  • 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 TOR binds to a LPRPDSPYSRL: HLA-B*07:02 complex;
  • the Va domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 73; and (ii) the Vp domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 76, and the encoded TCR binds to a LPRPDSPYSRL: HLA-B*07:02 complex; or
  • Va domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 87
  • p domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 90
  • the encoded TCR binds to a GLLSLTFVL:HLA-A*02:01 complex; or
  • the Va domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 101
  • the Vp domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 104 and the encoded TCR binds to a GLLSLTFVL:HLA-A*02:01 complex; or
  • 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 Vp domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 147, and the encoded TCR binds to a ITFYTGVLK:HLA-A*03:01 complex; or
  • the Va domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 159; and (ii) the Vp domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 161 , and the encoded TCR binds to a RPRGLRLPQL:HLA-B*07:02 complex; or
  • the Va domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 173 and (ii) the Vp domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 175, and the encoded TCR binds to a KPQQKGLRLL:HLA-B*07:02 complex; or
  • the Va domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 187; and (ii) the Vp domain comprises an amino acid sequence having at least 80% sequence identity to, comprising, or consisting of, SEQ ID NO: 189, and the encoded TCR binds to a RIFASRLYY: HLA-A*03:01 complex.
  • the isolated nucleic acid compositions may be for use in therapy.
  • Vector systems
  • a vector system which includes a nucleic acid composition described herein.
  • the vector system may have one or more vectors.
  • the binding protein components that are encoded by the nucleic acid composition may be encoded by one or more nucleic acid sequences in the nucleic acid composition.
  • the nucleic acid sequence may be present within a single vector (and thus the vector system described herein may comprise of one vector only).
  • the binding protein components are encoded by two or more nucleic acid sequences (wherein the plurality of nucleic acid sequences, together, encode all of the components of the binding protein) these two or more nucleic acid sequences may be present within one vector (e.g. in different open reading frames of the vector), or may be distributed over two or more vectors.
  • the vector system will comprise a plurality of distinct vectors (i.e. vectors with different nucleotide sequences).
  • a vector system comprising a nucleic acid composition described herein.
  • the vector may be a plasmid, a cosmid, or a viral vector, such as a retroviral vector or a lentiviral vector.
  • Adenovirus, adeno- associated virus, vaccinia virus, canary poxvirus, herpes virus, minicircle vectors and naked (synthetic) DNA/RNA may also be used (for details on minicircle vectors, see for example non- viral Sleeping Beauty transposition from minicircle vectors as published by R Monjezi et al., Leukemia 2017).
  • single stranded or double stranded DNA or RNA can be used to transfect lymphocytes with a TCR of interest (see Roth et al 2018 Nature vol 559; page 405).
  • 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.
  • the term “vector” refers to a nucleic acid sequence capable of transporting another nucleic acid sequence to which it has been operably linked.
  • the vector can be capable of autonomous replication or it can integrate into a host DNA.
  • the vector may include restriction enzyme sites for insertion of recombinant DNA and may include one or more selectable markers or suicide genes.
  • the vector can be a nucleic acid sequence in the form of a plasmid, a bacteriophage or a cosmid.
  • the vector is suitable for expression in a cell (i.e. the vector is an “expression vector”).
  • the vector is suitable for expression in a human T cell such as a CD8 + T cell or CD4 + T cell, or stem cell, iPS cell, or NK cell.
  • the vector is a viral vector, such as a retroviral vector, a lentiviral vector or an adeno-associated vector.
  • the vector is selected from the group consisting of an adenovirus, vaccinia virus, canary poxvirus, herpes virus, minicircle vector and synthetic DNA or synthetic RNA.
  • the (expression) vector is capable of propagation in a host cell and is stably transmitted to future generations.
  • the vector may comprise regulatory sequences.
  • Regulatory sequences refers to, DNA or RNA elements that are capable of controlling gene expression. Examples of expression control sequences include promoters, enhancers, silencers, TATA- boxes, internal ribosomal entry sites (IRES), attachment sites fortranscription factors, transcriptional terminators, polyadenylation sites etc.
  • the vector includes one or more regulatory sequences operatively linked to the nucleic acid sequence to be expressed. Regulatory sequences include those which direct constitutive expression, as well as tissue-specific regulatory and/or inducible sequences.
  • the vector comprises the nucleic acid sequence of interest operably linked to a promoter.
  • Promoter refers to the nucleotide sequences in DNA to which RNA polymerase binds to start transcription.
  • the promoter may be inducible or constitutively expressed. Alternatively, the promoter is under the control of a repressor or stimulatory protein.
  • the promoter may be one that is not naturally found in the host cell (e.g. it may be an exogenous promoter). The skilled person in the art is well aware of appropriate promoters for use in the expression of target proteins, wherein the selected promoter will depend on the host cell.
  • “Operably linked” refers to a single or a combination of the below-described control elements together with a coding sequence in a functional relationship with one another, for example, in a linked relationship so as to direct expression of the coding sequence.
  • the vector may comprise a transcriptional terminator.
  • Preferred transcriptional terminators are characterized by a run of T residues preceded by a GC rich dyad symmetrical region.
  • the vector may comprise a translational control element.
  • Translational control element refers to DNA or RNA elements that control the translation of mRNA.
  • Preferred translational control elements are ribosome binding sites.
  • the translational control element is from a homologous system as the promoter, for example a promoter and its associated ribozyme binding site. Preferred ribosome binding sites are known, and will depend on the chosen host cell.
  • the vector may comprise restriction enzyme recognition sites.
  • Restition enzyme recognition site refers to a motif on the DNA recognized by a restriction enzyme.
  • the vector may comprise a selectable marker.
  • Selectable marker refers to proteins that, when expressed in a host cell, confer a phenotype onto the cell which allows a selection of the cell expressing said selectable marker gene. Generally this may be a protein that confers a new beneficial property onto the host cell (e.g. antibiotic resistance) or a protein that is expressed on the cell surface and thus accessible for antibody binding. Appropriate selectable markers are well known in the art.
  • the vector may also comprise a suicide gene.
  • suicide gene encodes a protein that induces death of the modified cell upon treatment with specific drugs.
  • suicide can be induced in cells modified by the herpes simplex virus thymidine kinase gene upon treatment with specific nucleoside analogs including ganciclovir, cells modified by human CD20 upon treatment with anti-CD20 monoclonal antibody and cells modified with inducible Caspase9 (iCasp9) upon treatment with AP1903 (reviewed by BS Jones, LS Lamb, F Goldman, A Di Stasi; Improving the safety of cell therapy products by suicide gene transfer. Front Pharmacol. (2014) 5:254). Appropriate suicide genes are well known in the art.
  • the vector comprises those genetic elements which are necessary for expression of the binding proteins described herein by a host cell.
  • the elements required for transcription and translation in the host cell include a promoter, a coding region for the protein(s) of interest, and a transcriptional terminator.
  • the (expression) vector system described herein can be introduced into cells by conventional techniques such as transformation, transfection or transduction.
  • Transformation refer generally to techniques for introducing foreign (exogenous) nucleic acid sequences into a host cell, and therefore encompass methods such as electroporation, microinjection, gene gun delivery, transduction with retroviral, lentiviral or adeno- associated vectors, lipofection, superfection etc.
  • the specific method used typically depends on both the type of vector and the cell.
  • nucleic acid sequences and vectors into host cells such as human cells are well known in the art; see for example Sambrook et al (1989) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y; Ausubel et al (1987) Current Protocols in Molecular Biology, John Wiley and Sons, Inc., NY; Cohen et al (1972) Proc. Natl. Acad. Sci. USA 69, 2110; Luchansky et al (1988) Mol. Microbiol. 2, 637-646. Further conventional methods that are suitable for preparing expression vectors and introducing them into appropriate host cells are described in detail in WO2016/071758 for example. It is understood that in some examples, the host cell is contacted with the vector system (e.g. viral vector) in vitro, ex vivo, and in some examples, the host cell is contacted with the vector system (e.g. viral vector) in vivo.
  • the vector system e.g. viral vector
  • the term "host cell” includes any cell into which the nucleic acid composition or vector system described herein may be introduced. Once a nucleic acid molecule or vector system has been introduced into the cell, it may be referred to as a “modified cell” herein. Once the nucleic acid molecule or vector is introduced into the host cell, the resultant modified cell should be capable of expressing the encoded binding protein (and e.g. correctly localising the encoded binding protein for its intended function e.g. transporting the encoded binding protein to the cell surface).
  • the nucleic acid composition or vector system may be introduced into the cell using any conventional method known in the art.
  • the nucleic acid composition or vector system may be introduced using CRISPR technology. Insertion of the nucleic acid sequences at the endogenous TCR locus by engineering with CRISPR/Cas9 and homologous directed repair (HDR) or non-homologous end joining (NHEJ) is therefore encompassed. Other conventional methods such as transfection, transduction or transformation of the cell may also be used.
  • modified cell refers to a genetically altered (e.g. recombinant) cell.
  • the modified cell includes at least one exogenous nucleic acid sequence (i.e. a nucleic acid sequence that is not naturally found in the host cell).
  • the exogenous sequence comprises at least one of the T cell receptor component parts described herein for any of clones HHS_2.004, HHS_2.043, HHS_2.269, FHA_1 H8, MHU_1.052, PML_H.4G10, ORZ_2.321 , ORZ_003, EBJ_1.195, FHA_5E5, PML
  • modified cell refers to the particular subject cell and also to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein.
  • a modified cell comprises a nucleic acid composition or a vector system provided herein.
  • the host cell (and thus the modified cell) is typically a eukaryotic cell, and particularly a human cell (e.g. a T cell such as a CD8 + T cell or a CD4 + T cell, or a mixture thereof, or a haematopoietic stem cell, an iPSC, or gamma-delta T cell, or a pluripotent stem cell, or a NKT cell or NK cell).
  • the host cell (and thus the modified cell) may be an autologous or allogeneic cell (e.g.
  • Allogeneic cell refers to a cell derived from a different individual to the individual to which it is later administered. In other words, the host cell (and thus the modified cell) may be an isolated cell from a distinct individual compared to the subject to be treated. “Autologous cell” refers to a cell derived from the individual to which it is also later administered. In other words, the host cell (and thus the modified cell) may be an isolated cell from the subject that is to be treated.
  • the modified cell is a human cell.
  • the host cell may be any cell that is able to confer anti-tumor immunity after TCR gene transfer.
  • suitable cells include autologous or allogeneic CD8 T cells, CD4 T cells, Natural Killer (NK) cells, NKT cells, gamma-delta T cells, inducible pluripotent stem cells (iPSCs), haematopoietic stem cells or other progenitor cells and any other autologous or allogeneic cell or cell line (NK-92 for example or T cell lines) that is able to confer anti-tumor immunity after TCR gene transfer.
  • NK Natural Killer
  • iPSCs inducible pluripotent stem cells
  • NK-92 for example or T cell lines
  • 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, a haematopoietic stem cell, an inducible pluripotent stem cell, a progenitor cell, a T cell line and a NK-92 cell line.
  • the host cell (and thus the modified cell) is typically for administration to a HI_A-B*07:02, HLA-A*03:01 and/or HLA-A*02:01 positive human subject.
  • the host cell (and thus the modified cell) is typically HLA-B*07:02, HI_A-A*03:01 and/or HI_A-A*02:01 positive.
  • the host cell is modified to express a binding protein described herein, it is necessary that the host cell is negative for the haematopoietic- restricted peptide that is recognised by the binding protein.
  • the modified cell is negative for the haematopoietic-restricted peptide that is recognised by the binding protein that the modified cell encodes.
  • the host cell (and thus the modified cell) that is to be administered to the subject can either be autologous or allogeneic.
  • the modified cell is capable of expressing the binding protein encoded by the nucleic acid composition or vector system described herein (i.e. the TCR component parts) such that the modified cell provides an immunotherapy that specifically targets cells that express the haematopoietic-restricted MiHA(s) described herein (i.e.
  • the inventors identified the haematopoietic-restricted MiHA antigens RVRGTTLHLLL (SEQ ID NO: 113), LPRPDSPYSRL (SEQ ID NO: 114), GLLSLTFVL (SEQ ID NO: 115), ITFYTGVLK (SEQ ID NO: 131), RPRGLRLPQL (SEQ ID NO: 133), KPQQKGLRLL (SEQ ID NO: 135), and RIFASRLYY (SEQ ID NO: 137).
  • an isolated peptide comprising or consisting of an amino acid sequence selected from the group consisting of: RVRGTTLHLLL (SEQ ID NO: 113), LPRPDSPYSRL (SEQ ID NO: 114), GLLSLTFVL (SEQ ID NO: 115), ITFYTGVLK (SEQ ID NO: 131), RPRGLRLPQL (SEQ ID NO: 133), KPQQKGLRLL (SEQ ID NO: 135), and RIFASRLYY (SEQ ID NO: 137).
  • the invention specifically provides for an isolated peptide comprising or consisting of an amino acid sequence of RVRGTTLHLLL (SEQ ID NO: 113).
  • the invention specifically provides for an isolated peptide comprising or consisting of an amino acid sequence of LPRPDSPYSRL (SEQ ID NO: 114).
  • the invention specifically provides for an isolated peptide comprising or consisting of an amino acid sequence of GLLSLTFVL (SEQ ID NO: 115).
  • the invention specifically provides for an isolated peptide comprising or consisting of an amino acid sequence of ITFYTGVLK (SEQ ID NO: 131).
  • the invention specifically provides for an isolated peptide comprising or consisting of an amino acid sequence of RPRGLRLPQL (SEQ ID NO: 133).
  • the invention specifically provides for an isolated peptide comprising or consisting of an amino acid sequence of KPQQKGLRLL (SEQ ID NO: 135).
  • the invention specifically provides for an isolated peptide comprising or consisting of an amino acid sequence of RIFASRLYY (SEQ ID NO: 137).
  • an “isolated peptide” refers to a peptide that is not in its natural environment.
  • the peptide may therefore be of synthetic origin (or alternatively, of natural original, but isolated from its natural environment).
  • the isolated peptide may be relatively short (i.e. no more than 30 amino acids, no more than 25 amino acids, no more than 20 amino acids; e.g. no more than 19, 18, 17, 16, 15, 14, 13, 12, 11 , or 10 amino acids). In one example, the peptide may be no more than 30 amino acids long. In one example, the peptide may be no more than 25 amino acids long. In one example, the peptide may be no more than 20 amino acids long.
  • the peptide may consist of the amino acid sequence of SEQ ID NO: 113, SEQ ID NO: 114, SEQ ID NO:115, SEQ ID NO: 131 , SEQ ID NO: 133, SEQ ID NO: 135 or SEQ ID NO: 137 only.
  • the peptide may consist of the amino acid sequence of SEQ ID NO:113.
  • the peptide may consist of the amino acid sequence of SEQ ID NO:114.
  • the peptide may consist of the amino acid sequence of SEQ ID NO:115.
  • the peptide may consist of the amino acid sequence of SEQ ID NO:131.
  • the peptide may consist of the amino acid sequence of SEQ ID NO:133.
  • the peptide may consist of the amino acid sequence of SEQ ID NO:135.
  • the peptide may consist of the amino acid sequence of SEQ ID NO:137.
  • the peptide may comprise one or more amino acid sequence selected from the amino acid sequences of SEQ ID NO:113, SEQ ID NO: 114, SEQ ID NO: 115, SEQ ID NO: 131 , SEQ ID NO: 133, SEQ ID NO: 135 and/or SEQ ID NO: 137.
  • the isolated peptide may be administered to a human subject in order to treat or prevent a haematological malignancy.
  • the isolated peptide may be administered to the subject in order to induce or enhance their immune response.
  • the peptide may therefore be administered to the subject to induce T cell activation (e.g. in vivo T cell activation) in the subject, wherein the activated T cells are specific for the peptide (and thus will specifically target cells that present the peptide at the cell surface in the context of HLA).
  • the isolated peptide (or a nucleic acid encoding the same) may be administered as a peptide vaccine for treating or preventing a haematological malignancy.
  • the isolated peptide (or nucleic acid) may be administered to induce or enhance activation of T cells specific for cells that present the peptide at the cell surface in the context of HLA.
  • the isolated peptide may be administered to patients (or stem cell donors) to stimulate anti-tumor immunity after allogeneic stem cell transplantation, to treat or prevent relapse of blood cancer after allogeneic stem cell transplantation.
  • RVRGTTLHLLL SEQ ID NO: 113
  • LPRPDSPYSRL SEQ ID NO: 114
  • GLLSLTFVL SEQ ID NO: 115
  • ITFYTGVLK SEQ ID NO: 131
  • RPRGLRLPQL SEQ ID NO: 133
  • KPQQKGLRLL SEQ ID NO: 135
  • RIFASRLYY SEQ ID NO: 137
  • These peptides therefore represent bonafide immunogenic haematopoietic-specific antigens that may be further exploited in the development of personalized vaccines, which may be particularly useful as an adjunct to other therapies (e.g. alloSCT as described herein).
  • These immunogenic peptides can therefore be used as an immunotherapy in the form of peptide, RNA, DNA, dendritic cell based therapies, and adoptive TCR transgenic T cell-based therapies.
  • An isolated peptide as described herein may therefore be useful as an immunotherapy.
  • such isolated peptides may be used as an immunotherapy for subjects at risk of developing, or suspected of having a haematological malignancy.
  • Nucleic acid sequences and vectors encoding these peptides may also be useful for this purpose.
  • Nucleic acid sequences and vectors encoding such isolated peptides are therefore also provided herein.
  • a general discussion of vectors and nucleic acid sequences is provided elsewhere herein and applies equally to this aspect.
  • the particular peptide for administration may be chosen based on the HI_A status of the subject.
  • a peptide comprising the sequence of SEQ ID NO: 113, SEQ ID NO: 133, SEQ ID NO: 135 and/or SEQ ID NO: 114 may be particularly suitable for administration to a subject that is HI_A-B*07 positive (e.g. HI_A-B*07:02)
  • a peptide comprising the sequence of SEQ ID NO:115 may be particularly suitable for administration to a subject that is positive for HI_A-A*02:01.
  • a peptide comprising the sequence of SEQ ID NO:131 and/or SEQ ID NO: 137 may be particularly suitable for administration to a subject that is positive for HLA-A*03:01.
  • Isolated peptides of the invention may also be provided in compositions that comprise more than one of the peptides discussed above.
  • an isolated peptide may be provided (and/or administered) as a composition that comprises a mixture of (a) an isolated peptide comprising the amino acid sequence SEQ ID NO: 113; and (b) an isolated peptide comprising the amino acid sequence SEQ ID NO:114.
  • This composition may be particularly useful for administration to a subject that is positive for both of these haematopoietic-restricted MiHA(s).
  • an isolated peptide may be provided (and/or administered) as a composition that comprises a mixture of (a) an isolated peptide comprising the amino acid sequence SEQ ID NO: 113; and (b) an isolated peptide comprising the amino acid sequence SEQ ID NO: 115 (which would be particularly useful for subjects that are positive for both of these haematopoietic-restricted MiHA(s)).
  • an isolated peptide may be provided (and/or administered) as a composition that comprises a mixture of (a) an isolated peptide comprising the amino acid sequence SEQ ID NO: 114; and (b) an isolated peptide comprising the amino acid sequence SEQ ID NO: 115 (which would be particularly useful for subjects that are positive for both of these haematopoietic-restricted MiHA(s)).
  • an isolated peptide may be provided (and/or administered) as a composition that comprises a mixture of (a) an isolated peptide comprising the amino acid sequence SEQ ID NO: 113; (b) an isolated peptide comprising the amino acid sequence SEQ ID N0:114; and (c) an isolated peptide comprising the amino acid sequence SEQ ID NO:115 (which would be particularly useful for subjects that are positive for all of these haematopoietic-restricted MiHA(s)).
  • HI_A complexes can be targeted to stimulate anti-tumor immunity after allogeneic stem cell transplantation, and TCR gene therapy to produce large numbers of antigen-specific T cells that are infused in patients to treat or prevent relapse of blood cancer after allogeneic stem cell transplantation in patients in need thereof.
  • T cell receptors are an example of a suitable binding agent that binds (e.g. specifically binds) to a peptide:HI_A complex (for example a complex selected from the group consisting of: a RVRGTTLHLLL: HLA-B*07:02 complex; a LPRPDSPYSRL:HLA-B*07:02 complex; a RPRGLRLPQL: HLA-B*07:02 complex; a KPQQKGLRLL: HLA-B*07:02 complex; a GLLSLTFVL:HLA-A*02:01 complex; a ITFYTGVLK:HLA-A*03:01 complex and a RIFASRLYY:HLA-A*03:01 complex).
  • a peptide:HI_A complex for example a complex selected from the group consisting of: a RVRGTTLHLLL: HLA-B*07:02 complex; a LPRPDSPYSRL:HLA-B*07:02 complex; a
  • a person of skill in the art would also be aware of other suitable binding agents that bind (e.g. specifically) bind to a peptide:HLA complex (for example a complex selected from the group consisting of: a RVRGTTLHLLL: HLA-B*07:02 complex; a LPRPDSPYSRL:HLA-B*07:02 complex; a RPRGLRLPQL: HLA-B*07:02 complex; a KPQQKGLRLL: HLA-B*07:02 complex; a GLLSLTFVL:HLA-A*02:01 complex; a ITFYTGVLK:HLA-A*03:01 complex and a RIFASRLYY:HLA-A*03:01 complex).
  • a peptide:HLA complex for example a complex selected from the group consisting of: a RVRGTTLHLLL: HLA-B*07:02 complex; a LPRPDSPYSRL:HLA-B*07:02 complex; a
  • the binding agent may be an antibody.
  • the binding agent may be a TCR-like antibody.
  • TCR-like antibodies are known in the art, see for example He, Q., et al. J Hematol Oncol 12, 99 (2019); and Emily Han-Chung Hsiue et al., Science. 2021 Mar 5;371(6533):eabc8697.
  • TCR-like antibodies comprise a relatively new family of antibodies that can recognize peptide/MHC complexes on tumor cell surfaces. TCR-like antibodies can execute specific and significant anti-tumor immunity through several distinct molecular mechanisms.
  • TCR-like antibodies can trigger a broad range of pharmacological pathways e.g. it can trigger ADCC, CDC, antibody-dependent cellular phagocytosis (ADCP), or the direct induction of apoptosis.
  • ADCP antibody-dependent cellular phagocytosis
  • a Fc region is required.
  • TCR-like antibodies can also be produced as bispecific antibodies containing one Fab fragment binding to the MHC:peptide complex and another Fab fragment binding to T cells. These antibodies also trigger anti-tumor immunity by attracting T cells to the tumor and stimulate the T cells. If these antibodies contain a Fc region, they can also trigger ADCC, CDC, ADCP and/or apoptosis.
  • TCR-like antibodies can also be produced as bispecific diabodies. In this case, the Fc part is lacking. Diabodies therefore only stimulate anti- tumor immunity by attracting and stimulating T cells via the Fab fragment that binds to the T cells.
  • TCR-like antibodies can be converted to a chimeric antigen receptor (CAR) structure to mediate the specific recognition of tumor cells by T cells, such as CAR-T cells.
  • CAR-T cells chimeric antigen receptor
  • binding proteins that comprise an antigen binding fragment of a TCR, a chimeric antigen receptor (CAR), or an immTAC are also contemplated herein in the context of the invention.
  • a nucleic acid composition, vector system, modified cell, isolated peptide or isolated nucleic acid sequence described herein may be provided as part of a pharmaceutical composition.
  • such compositions may be administered to a human subject in need thereof (as described elsewhere herein).
  • a particularly suitable composition may be selected based on the HI_A subtype of the human subject, as described in detail elsewhere herein.
  • a pharmaceutical composition may comprise a nucleic acid composition, vector system, modified cell, isolated peptide or isolated nucleic acid sequence described herein along with a pharmaceutically acceptable excipient, adjuvant, diluent and/or carrier.
  • compositions may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, supplementary immune potentiating agents such as adjuvants and cytokines and optionally other therapeutic agents or compounds.
  • pharmaceutically acceptable refers to a material that is not biologically or otherwise undesirable, i.e., the material may be administered to an individual along with the selected nucleic acid composition, vector system, modified cell, isolated peptide or isolated nucleic acid sequence without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.
  • Excipients are natural or synthetic substances formulated alongside an active ingredient (e.g. a nucleic acid sequence, a nucleic acid composition, vector or vector system, modified cell, isolated peptide or isolated nucleic acid as provided herein), included for the purpose of bulking-up the formulation or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption or solubility.
  • Excipients can also be useful in the manufacturing process, to aid in the handling of the active substance concerned such as by facilitating powder flowability or non-stick properties, in addition to aiding in vitro stability such as prevention of denaturation over the expected shelf life.
  • Pharmaceutically acceptable excipients are well known in the art. A suitable excipient is therefore easily identifiable by one of ordinary skill in the art.
  • suitable pharmaceutically acceptable excipients include water, saline, aqueous dextrose, glycerol, and ethanol.
  • Adjuvants are pharmacological and/or immunological agents that modify the effect of other agents in a formulation.
  • Pharmaceutically acceptable adjuvants are well known in the art. A suitable adjuvant is therefore easily identifiable by one of ordinary skill in the art.
  • Diluents are diluting agents. Pharmaceutically acceptable diluents are well known in the art. A suitable diluent is therefore easily identifiable by one of ordinary skill in the art.
  • Carriers are non-toxic to recipients at the dosages and concentrations employed and are compatible with other ingredients of the formulation.
  • carrier denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application.
  • Pharmaceutically acceptable carriers are well known in the art. A suitable carrier is therefore easily identifiable by one of ordinary skill in the art.
  • the pharmaceutical composition comprises an isolated peptide described herein, an isolated nucleic acid sequence encoding the peptide or a vector system comprising said nucleic acid sequence, wherein the pharmaceutical composition is formulated as a vaccine (e.g. a composition that it used to stimulate the immune system and provide immunity against one or several diseases, where the composition acts as an antigen without inducing the disease).
  • a vaccine e.g. a composition that it used to stimulate the immune system and provide immunity against one or several diseases, where the composition acts as an antigen without inducing the disease.
  • the immunotherapies described herein can be used in treatment strategies in which peptides or nucleic acids encoding the antigens are used to vaccinate patients (or stem cell donors) to stimulate anti-tumor immunity. Such treatments are particularly useful after allogeneic stem cell transplantation and TCR gene therapy to produce large numbers of antigen-specific T cells that are infused in patients to treat or prevent relapse of blood cancer after allogeneic stem cell transplantation.
  • the treatments provided herein may also be useful in nontransplanted patients.
  • antigens that are encoded by genes that are highly expressed in specific hematopoietic cell types but not T cells may also be useful as targets for T cell receptors to treat non-transplanted patients (as well as transplanted patients). These include LB-F13A1-L, LB-TXNDC11-1 P and LB-LILRB4-1G.
  • TCRs may be introduced into autologous T cells of non-transplanted patients. Since the gene is not expressed in T cells, the TCR-T cells will not kill each other (fratricide).
  • compositions described herein may advantageously be administered to a HLA- B*07:02, HLA-A*03:01 and/or HI_A-A*02:01 positive human subject in need thereof (where certain compositions are more suitable for certain human subjects, based on their HLA status and MiHA status, as described in more detail elsewhere herein).
  • compositions described herein may alternatively or additionally be administered to a human stem cell donor to induce anti-tumour immunity before allo-SCT is performed on a human subject in need thereof.
  • the subject in need of treatment may advantageously be a HI_A-B*07:02, HI_A-A*03:01 and/or HI_A-A*02:01 positive human subject (where certain compositions are more suitable for certain human subjects, based on their HLA status and MiHA status, as described in more detail elsewhere herein).
  • compositions described herein may advantageously be used to treat or prevent a relapse of a haematological malignancy after allogeneic stem cell transplantation (allo-SCT) in a HLA-B*07:02, HLA-A*03:01 and/or HLA-A*02:01 positive human subject, wherein the subject is also positive for the relevant MiHA (such that they are positive for one or more peptide:HLA complex selected from the group consisting of: a RVRGTTLHLLL: HLA-B*07:02 complex; a LPRPDSPYSRL:HLA-B*07:02 complex; a RPRGLRLPQL: HLA-B*07:02 complex; a KPQQKGLRLL: HLA-B*07:02 complex; a GLLSLTFVL:HLA-A*02:01 complex; a ITFYTGVLK:HLA-A*03:01 complex and a RIFASRLYY:HLA-A*03:01 complex).
  • the method of treatment or prevention of a relapse of a haematological malignancy described herein results in an induced or enhanced immune response (e.g. a cell mediated response) in the subject (e.g. a targeted immune response to malignant cells that present one of the HLA-B*07:02, HLA-A*03:01 and/or HLA-A*02:01 restricted peptides (peptide:HLA complexes) described herein).
  • an induced or enhanced immune response e.g. a cell mediated response
  • induced or enhanced immune response refers to an increase in the immune response (e.g. a cell mediated immune response such as a T cell mediated immune response) of the subject during or after treatment compared to their immune response prior to treatment.
  • An “induced or enhanced” immune response therefore encompasses any measurable increase in the immune response that is directly or indirectly targeted to the haematological malignancy being treated (or prevented).
  • haematological malignancies that may be may be treated in accordance with the invention.
  • appropriate haematological malignancies include leukemia, lymphoma, myelodysplastic disorder, or myeloma.
  • the leukemia may be acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), mixed phenotype acute leukemia (MPAL), chronic myeloid leukemia (CML), B cell prolymphocytic leukemia, hairy cell leukemia, or chronic lymphocytic leukemia (CLL).
  • AML acute myeloid leukemia
  • ALL acute lymphocytic leukemia
  • MPAL mixed phenotype acute leukemia
  • CML chronic myeloid leukemia
  • B cell prolymphocytic leukemia hairy cell leukemia
  • CLL chronic lymphocytic leukemia

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Abstract

L'invention concerne de nouvelles compositions d'acides nucléiques, des systèmes de vecteurs, des cellules modifiées, des peptides isolés, des séquences d'acides nucléiques isolées et des compositions pharmaceutiques qui codent pour ou expriment des composants de récepteurs de lymphocytes T dirigés contre des antigènes d'histocompatibilité mineure à restriction hématopoïétique (MIHA). Ces nouveaux composants peuvent être utilisés dans le traitement d'un sujet ayant une malignité hématologique, en particulier après que le sujet a subi une transplantation de cellules souches allogéniques (alloSCT). L'invention concerne également des procédés associés pour traiter de tels sujets.
PCT/NL2025/050036 2024-01-22 2025-01-22 Antigènes d'histocompatibilité mineure à restriction hématopoïétique et leurs utilisations Pending WO2025159638A1 (fr)

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