[go: up one dir, main page]

WO2025181329A1 - Récepteurs de lymphocytes t humains et leurs utilisations - Google Patents

Récepteurs de lymphocytes t humains et leurs utilisations

Info

Publication number
WO2025181329A1
WO2025181329A1 PCT/EP2025/055503 EP2025055503W WO2025181329A1 WO 2025181329 A1 WO2025181329 A1 WO 2025181329A1 EP 2025055503 W EP2025055503 W EP 2025055503W WO 2025181329 A1 WO2025181329 A1 WO 2025181329A1
Authority
WO
WIPO (PCT)
Prior art keywords
seq
amino acid
acid sequence
variable domain
chain variable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/055503
Other languages
English (en)
Inventor
Emily Tang
Kan XING WU
Dan MACLEOD
Katja Fink
Melissa WIRAWAN
Andreas WILM
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Immunoscape Pte Ltd
Original Assignee
Immunoscape Pte Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Immunoscape Pte Ltd filed Critical Immunoscape Pte Ltd
Publication of WO2025181329A1 publication Critical patent/WO2025181329A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A61K40/11—T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/30—Cellular immunotherapy characterised by the recombinant expression of specific molecules in the cells of the immune system
    • A61K40/32—T-cell receptors [TCR]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/42—Cancer antigens
    • A61K40/4267—Cancer testis antigens, e.g. SSX, BAGE, GAGE or SAGE
    • A61K40/4268—MAGE
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4748—Tumour specific antigens; Tumour rejection antigen precursors [TRAP], e.g. MAGE
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterized by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the cancer treated
    • A61K2239/55—Lung
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the cancer treated
    • A61K2239/57—Skin; melanoma
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/15011—Lentivirus, not HIV, e.g. FIV, SIV
    • C12N2740/15041—Use of virus, viral particle or viral elements as a vector
    • C12N2740/15043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

  • the present invention relates to TCR sequences, and their use in TCR-based immunotherapies and in the treatment of MAGE-A10-expressing neoplasms and cancers.
  • Immunotherapy has revolutionized cancer treatment. Starting with early observations that a patient’s own T cells can kill tumor cells (Rosenberg & Restifo, 2015), ongoing research has led to the development of immune checkpoint inhibitors, adoptive transfer of ex vivo expanded tumor infiltrating T cells, CAR-T cell therapy and TCR-T therapy.
  • the binding domain of Chimeric antigen receptors are based on antibody fragments that bind to unprocessed antigens, such as tumor antigens on the surface of tumor cells. Upon binding to a certain threshold number of target antigens displayed on the target cell, the CAR-ex pressing T cell can become activated and can kill the tumor cell.
  • TCR T cell receptor
  • T cells can be genetically modified to equip them with a TCR specifically targeting a peptide that is processed from a tumor antigen and presented on the surface of a patient’s tumor in the context of a Human Leukocyte Antigen (HLA) molecule.
  • HLA Human Leukocyte Antigen
  • the TCRs can be used in other immunotherapeutic modalities, such as bi-specific molecules.
  • An example for this modality is the marketed drug KIMMTRAK® that comprises a TCR specific for a gp100-derived peptide when presented in the context of HLA-A*02:01 , linked to a T cell engaging anti-CD3 binding domain.
  • TCR-based therapies are based on the binding of TCRs to peptides presented in the context of MHC molecules (also referred to herein as ‘HLA molecules’).
  • MHC molecules also referred to herein as ‘HLA molecules’.
  • the target antigens of the TCR must be expressed in tumor cells, and the patient must express the HLA allele to which the TCR is restricted.
  • antigens are broken down into peptides by the proteasome or immunoproteasome, leading to the presentation of these peptides on MHC molecules.
  • CD8+ T cells via their TCR, bind to peptides presented on a given allele of MHC class I molecules.
  • T cells The specific binding of T cells to peptides presented by a given MHC class I molecule is called HLA restriction of the T cell response (Murphy & Weaver (2017) Janeway’s Immunobiology 9).
  • tumor antigens There are different types of tumor antigens that can be targeted for TCR-based therapy. Ideally, the antigen should be expressed exclusively or predominantly on the tumor compared to normal healthy tissue.
  • a key success factor for TCR-based therapies is the selection of the tumor antigen, such that as many patients as possible can benefit from a given therapy. Tumor antigens that are expressed in several tumor types and in a large proportion of patients (so-called shared tumor antigens) are therefore of high priority.
  • CTAs cancer testis antigens
  • MAGE antigens are a well described class of cancer testis antigens, with expression in a variety of tumors, and in a varying but large percentage of patients with these tumors (Weon & Potts, 2015).
  • MAGE (melanoma-associated antigen) proteins all contain a MAGE homology domain and MAGE genes are highly conserved in eukaryotes. Some MAGEs are ubiquitously expressed in tissues, whereas other MAGEs are only expressed in germ cells, with aberrant expression in tumours. MAGE proteins regulate diverse cellular and developmental pathways, implicating them in many diseases including cancer. Since the discovery of MAGEs, a major research focus has been developing MAGE-targeted immunotherapies.
  • MAGE-A10 (melanoma-associated antigen 10) is encoded by MAGEA 10 in humans and is a highly immunogenic member of the MAGE-A family whose members are known to influence cellular signalling pathways through their E3 ubiquitin ligase-binding MAGE homology domain.
  • MAGE-A10 is only expressed in the testis, reviewed e.g. Schultz-Thater et al., (2011).
  • erroneous expression of MAGE-A10 is associated with cancers, such as lung, skin and urothelial tumours.
  • the present invention relates to T cell receptors (TCRs) that are capable of binding to MAGE-A10, e.g. antigenic peptides derived from MAGE-A10.
  • TCRs T cell receptors
  • TCR T cell receptor
  • a T cell receptor comprising a TCRa chain variable domain comprising a CDR3a having at least 95% sequence identity to an amino acid sequence of SEQ ID NO:7, 13, 19, 25, 31 , 117 or 123; in combination with a TCRp chain variable domain comprising a CDR3p having at least 95% sequence identity to an amino acid sequence of SEQ ID NO:10, 16, 22, 28, 34, 120 or 126.
  • the TCR comprises: (a)(i) a TCRa chain variable domain comprising a CDR3a having the amino acid sequence of SEQ ID NO:7, and/or (ii) a TCRp chain variable domain comprising a CDR3p having the amino acid sequence of SEQ ID NQ:10; (b) (i) a TCRa chain variable domain comprising a CDR3a having the amino acid sequence of SEQ ID NO:13, and/or (ii) a TCRp chain variable domain comprising a CDR3p having the amino acid sequence of SEQ ID NO:16; (c) (i) a TCRa chain variable domain comprising a CDR3a having the amino acid sequence of SEQ ID NO:19, and/or (ii) a TCRp chain variable domain comprising a CDR3p having the amino acid sequence of SEQ ID NO:22; (d) (i) a TCRa chain variable domain comprising a CDR3a having the amino acid sequence of SEQ ID NO:7,
  • the TCR comprises: (a)(i) a TCRa chain variable domain incorporating the following CDRs: CDR1a having the amino acid sequence of SEQ ID NO:5, CDR2a having the amino acid sequence of SEQ ID NO:6, CDR3a having the amino acid sequence of SEQ ID NOT, and/or (ii) a TCRp chain variable domain incorporating the following CDRs: CDR1 p having the amino acid sequence of SEQ ID NO:8, CDR2p having the amino acid sequence of SEQ ID NO:9, CDR3p having the amino acid sequence of SEQ ID NQ:10; (b)(i) a TCRa chain variable domain incorporating the following CDRs: CDR1a having the amino acid sequence of SEQ ID NO:11 , CDR2a having the amino acid sequence of SEQ ID NO:12, CDR3a having the amino acid sequence of SEQ ID NO:13, and/or (ii) a TCRp chain variable domain incorporating the following CDRs: CDR1p
  • the TCR comprises a TCRa chain variable domain comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:35, 37, 39, 41 , 43, 127 or 129.
  • the TCR comprises a TCRp chain variable domain comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:36, 38, 40, 42, 44, 128 or 130.
  • the TCR is capable of binding to GLYDGMEHL (SEQ ID NO:1), SLLKFLAKV (SEQ ID NO:2), NYEDHFPLL (SEQ ID NO:3) or NYEDHFPLLF (SEQ ID NO:4) when presented by an MHC class I molecule.
  • the TCR is capable of binding to GLYDGMEHL (SEQ ID NQ:1)-HLA-A*02 complex, SLLKFLAKV (SEQ ID NQ:2)-HLA-A*02 complex, NYEDHFPLL (SEQ ID NO:3)-HLA-A*24 complex or NYEDHFPLLF (SEQ ID NO:4)-HLA-A*24 complex.
  • the TCR is capable of binding to GLYDGMEHL (SEQ ID NQ:1)-HLA-A*02:01 complex, SLLKFLAKV (SEQ ID NQ:2)-HLA-A*02:01 complex, NYEDHFPLL (SEQ ID NQ:3)-HLA-A*24:02 complex or NYEDHFPLLF (SEQ ID NQ:4)-HLA-A*24:02 complex.
  • the TCR is capable of binding to XIX2LKFX3X4KX5 (SEQ ID NO:156) or X1X2X3X4FX5X6KX7 (SEQ ID NO: 157) when presented by an MHC class I molecule. In some embodiments, the TCR is capable of binding to XIX2LKFXSX4KX5 (SEQ ID NO:156)-HLA-A*02 complex, or X1X2X3X4FX5X6KX7 (SEQ ID NO:157)-HLA-A*02 complex,
  • the TCR is capable of binding to XIX2LKFX3X4KX5 (SEQ ID N0:156)-HLA-A*02:01 complex, or X1X2X3X4FX5X6KX7 (SEQ ID NQ:157)-HLA-A*02:01 complex,
  • TCR T cell receptor
  • GLYDGMEHL SEQ ID NO:1
  • SLLKFLAKV SEQ ID NO:2
  • NYEDHFPLL SEQ ID NO:3
  • NYEDHFPLLF SEQ ID NO:4
  • the TCR is capable of binding to GLYDGMEHL (SEQ ID NQ:1)-HLA-A*02 complex, SLLKFLAKV (SEQ ID NQ:2)-HLA-A*02 complex, NYEDHFPLL (SEQ ID NQ:3)-HLA-A*02 complex or NYEDHFPLLF (SEQ ID NQ:4)-HLA-A*02 complex.
  • the TCR is capable of binding to GLYDGMEHL (SEQ ID NQ:1)-HLA-A*02:01 complex, SLLKFLAKV (SEQ ID NQ:2)-HLA-A*02:01 complex, NYEDHFPLL (SEQ ID NQ:3)-HLA-A*02:01 complex or NYEDHFPLLF (SEQ ID NQ:4)-HLA-A*02:01 complex.
  • TCR T cell receptor
  • the TCR is capable of binding to X1X2LKFX3X4KX5 (SEQ ID NO:156) or X1X2X3X4FX5X6KX7 (SEQ ID NO:157) when presented by an MHC class I molecule.
  • the TCR is capable of binding to XIX2LKFX3X4KX5 (SEQ ID NQ:156)-HLA-A*02 complex, or X1X2X3X4FX5X6KX7 (SEQ ID NQ:157)-HLA-A*02 complex,
  • the TCR is capable of binding to XIX2LKFX3X4KX5 (SEQ ID NQ:156)-HLA-A*02:01 complex, or X1X2X3X4FX5X6KX7 (SEQ ID NO:157)-HLA-A*02:01 complex
  • the TCR comprises a TCRa chain variable domain comprising a CDR3a having at least 95% sequence identity to an amino acid sequence of SEQ ID NO: 7, 13, 19, 25, 31 , 1 17 or 123; in combination with a TCRp chain variable domain comprising a CDR3p having at least 95% sequence identity to an amino acid sequence of SEQ ID NO:10, 16, 22, 28, 34, 120 or 126, respectively.
  • the TCR comprises: (a)(i) a TCRa chain variable domain comprising a CDR3a having the amino acid sequence of SEQ ID NO:7, and/or (ii) a TCRp chain variable domain comprising a CDR3p having the amino acid sequence of SEQ ID NO:10; (b)(i) a TCRa chain variable domain comprising a CDR3a having the amino acid sequence of SEQ ID NO:13, and/or (ii) a TCRp chain variable domain comprising a CDR3p having the amino acid sequence of SEQ ID NO:16; (c)(i) a TCRa chain variable domain comprising a CDR3a having the amino acid sequence of SEQ ID NO:19, and/or (ii) a TCRp chain variable domain comprising a CDR3p having the amino acid sequence of SEQ ID NO:22; (d)(i) a TCRa chain variable domain comprising a CDR3a having the amino acid sequence of SEQ ID NO:
  • the TCR comprises: (a)(i) a TCRa chain variable domain incorporating the following CDRs: CDR1a having the amino acid sequence of SEQ ID NO:5,CDR2a having the amino acid sequence of SEQ ID NO:6, CDR3a having the amino acid sequence of SEQ ID NO:7, and (ii) a TCRp chain variable domain incorporating the following CDRs: CDR1 having the amino acid sequence of SEQ ID NO:8, CDR2p having the amino acid sequence of SEQ ID NO:9, CDR3p having the amino acid sequence of SEQ ID NQ:10; (b)(i) a TCRa chain variable domain incorporating the following CDRs: CDR1a having the amino acid sequence of SEQ ID NO:11 , CDR2a having the amino acid sequence of SEQ ID NO:12, CDR3a having the amino acid sequence of SEQ ID NO:13, and (ii) a TCRp chain variable domain incorporating the following CDRs: CDR1p having the amino acid
  • the TCR comprises a TCRp chain variable domain comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:36, 38, 40, 42,44, 128 or 130.
  • the TCR comprises a TCRa chain variable domain encoded by a nucleotide sequence having at least 80% sequence identity to SEQ ID NO:45, 47, 49, 51 , 53, 55, 57, 59, 61 , 63,
  • the TCR comprises a TCRp chain variable domain encoded by a nucleotide sequence having at least 80% sequence identity to SEQ ID NO:46, 48, 50, 52, 54, 56, 58, 60, 62, 64,
  • the TCR comprises a TCRa chain variable domain encoded by a nucleotide sequence having at least 80% sequence identity to SEQ ID NO:45, 47, 49, 51 ,53, 55, 57, 59, 61 , 63, 131 ,
  • TCRp chain variable domain encoded by a nucleotide sequence having at least 80% sequence identity to SEQ ID NO:46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 132, 134, 136 or 138.
  • the TCR comprises: (a)(i) a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:45 in combination with (ii) a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:46; (b)(i) a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:47 in combination with (ii) a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:48; (c)(i) a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:49 in combination with (ii) a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NQ:50; (d)(i) a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:51 in combination with (ii) a TCRp chain variable domain
  • the TCR comprises a TCRa chain constant domain comprising an amino acid sequence having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:65 or 68.
  • the TCR comprises a TCRp chain constant domain comprising an amino acid sequence having at least 80% sequence identity to an amino acid sequence selected from SEQ ID NO:66, 67 or 69.
  • a multispecific antigen-binding molecule comprising a TCR or an antigen-binding fragment of a TCR according to the invention.
  • the multispecific antigen-binding molecule further comprises an antigen-binding moiety capable of binding to a molecule expressed by an immune cell, optionally wherein the molecule expressed by an immune cell is CD3.
  • nucleic acid comprising a nucleotide sequence encoding all or part of a TCR according to the invention.
  • nucleic acid comprising a nucleotide sequence having at least 80% sequence identity to: (i) SEQ ID NO:45, 46, 55 and/or 56; (ii) SEQ ID NO:47, 48, 57 and/or 58; (iii) SEQ ID NO:49, 50, 59 and/or 60; (iv) SEQ ID NO:51 , 52, 61 and/or 62; (v) SEQ ID NO:53, 54, 63 and/or 64; (vi) SEQ ID NO:131 , 132, 135 and/or 136; or (vii) SEQ ID NO: 133, 134, 137 and/or 138.
  • nucleic acid comprising a nucleotide sequence having at least 80% sequence identity to: (i) SEQ ID NO:55 and/or 56; (ii) SEQ ID NO:57 and/or 58; (iii) SEQ ID NO:59 and/or 60; (iv) SEQ ID NO:61 and/or 62; (v) SEQ ID NO:63 and/or 64; (vi) SEQ ID NO:135 and/or 136; or (vii) SEQ ID NO:137 and/or 138.
  • nucleic acid comprising a nucleotide sequence encoding all or part of a multispecific antigen-binding molecule according to the invention.
  • the vector further comprises a nucleotide sequence of SEQ ID NO:71 . In some embodiments, the vector comprises the nucleotide sequence of SEQ ID NOTO.
  • a host cell comprising and/or expressing: a TCR according to the invention, a multispecific antigen-binding molecule according to the invention, a nucleic acid according to the invention, and/or a vector according to the invention.
  • the host cell is an immune cell.
  • the host cell is a T lymphocyte.
  • composition comprising a TCR according to the invention, a multispecific antigenbinding molecule according to the invention, a nucleic acid according to the invention, a vector according to the invention, or a host cell according to the invention.
  • the composition further comprises a pharmaceutical carrier or excipient.
  • TCR a TCR according to the invention
  • a multispecific antigen-binding molecule according to the invention
  • a nucleic acid according to the invention a vector according to the invention, a host cell according to the invention, or a composition according to the invention, for use as a medicament.
  • a composition according to the invention for use as a medicament.
  • TCR a TCR according to the invention, a multispecific antigen-binding molecule according to the invention, a nucleic acid according to the invention, a vector according to the invention, a host cell according to the invention, or a composition according to the invention, for use in a method of treating a disease or condition associated with expression of MAGE-A10.
  • TCR a TCR according to the invention
  • a multispecific antigen-binding molecule according to the invention
  • a nucleic acid according to the invention a vector according to the invention, a host cell according to the invention, or a composition according to the invention, in the manufacture of a medicament for the treatment of disease or condition associated with expression of MAGE-A10.
  • the disease or condition is cancer or a neoplasm.
  • the disease or condition is selected from: a MAGE-A10-associated cancer, a cancer comprising cells comprising/presenting a peptide of a MAGE-A10 antigen, a cancer comprising cells comprising/presenting a peptide of SEQ ID NO:1 , 2, 3, 4, 156 or 157, a cancer comprising cells comprising/presenting a peptide of MAGE-A10 and a major histocompatibility complex (MHC) molecule comprising an MHC class I molecule encoded by a HLA-A*02:01 allele, a cancer comprising cells comprising/presenting a peptide of MAGE-A10 and a major histocompatibility complex (MHC) molecule comprising an MHC class I molecule encoded by a HLA-A*24:02 allele, a cancer comprising cells comprising/presenting a peptide of SEQ ID NO:1 , 2, 156 or 157 and a major histocompatibility complex (MHC) molecule comprising
  • the disease or condition is selected from: a solid cancer, a hematological cancer, gastric cancer (e.g. gastric carcinoma, gastric adenocarcinoma, gastrointestinal cancer, gastrointestinal adenocarcinoma), liver cancer (hepatocellular carcinoma, cholangiocarcinoma), head and neck cancer (e.g. head and neck squamous cell carcinoma), oral cavity cancer (e.g. oropharyngeal cancer (e.g. oropharyngeal carcinoma), oral cancer, oral squamous cell carcinoma (OSCC), laryngeal cancer, nasopharyngeal carcinoma, oesophageal cancer), colorectal cancer (e.g.
  • gastric cancer e.g. gastric carcinoma, gastric adenocarcinoma, gastrointestinal cancer, gastrointestinal adenocarcinoma
  • liver cancer hepatocellular carcinoma, cholangiocarcinoma
  • head and neck cancer e.g. head and neck squamous
  • lung cancer e.g. NSCLC, small cell lung cancer, lung adenocarcinoma, squamous lung cell carcinoma), bladder cancer, urothelial carcinoma, urogenital cancer, skin cancer (e.g. melanoma, advanced melanoma), renal cell cancer (e.g. renal cell carcinoma), ovarian cancer (e.g. ovarian carcinoma), mesothelioma, breast cancer (e.g. TNBC), brain cancer (e.g.
  • glioblastoma glioblastoma
  • prostate cancer pancreatic cancer
  • a myeloid hematologic malignancy a lymphoblastic hematologic malignancy
  • myelodysplastic syndrome MDS
  • acute myeloid leukemia AML
  • chronic myeloid leukemia CML
  • acute lymphoblastic leukemia ALL
  • lymphoma non-Hodgkin’s lymphoma (NHL), thymoma and multiple myeloma (MM).
  • NHL non-Hodgkin’s lymphoma
  • MM multiple myeloma
  • the treatment further comprises administering one or more immune modulating agents to the subject, optionally wherein the one or more immune modulating agents are selected from the group consisting of: immune cell-depleting agents, cytokines, TLR agonists, RIG-I like receptor (RLR) agonists, immune checkpoint inhibitors, chemotherapeutic agents, antibodies, radiotherapy, and a combination thereof.
  • the one or more immune modulating agents are selected from the group consisting of: immune cell-depleting agents, cytokines, TLR agonists, RIG-I like receptor (RLR) agonists, immune checkpoint inhibitors, chemotherapeutic agents, antibodies, radiotherapy, and a combination thereof.
  • the treatment comprises: (a) modifying a cell to express or comprise the TCR or a nucleic acid or vector encoding the TCR, and/or (b) administering a/the cell modified to express or comprise a TCR or nucleic acid or vector encoding the TCR to a subject.
  • the treatment comprises administering at least one TCR, multispecific antigenbinding molecule, nucleic acid, vector, cell and/or composition according to the invention to a subject, in combination with at least one non-identical TCR, multispecific antigen-binding molecule, nucleic acid, vector, cell and/or composition.
  • the subject comprises a cell that expresses MAGE-A10, and/or that expresses a MAGE-A10 peptide of SEQ ID NO: 1 , 2, 3 or 4.
  • the invention includes the combination of the aspects and preferred features described except where such a combination is clearly impermissible or expressly avoided.
  • the present invention relates to TCR sequences for use in TCR-based immunotherapies against cells expressing MAGE-A10.
  • T cells are the most actively studied cell type in the growing field of adoptive cellular therapeutics. T cells interact specifically with the target of their T cell receptor (TCR), enabling highly specific responses with minimal side effects. These potentially highly effective and specific responses can be engineered towards novel antigens and targets by inserting a new receptor with the desired specificity into a T cell.
  • TCR T cell receptor
  • development of entirely new types of receptors is time consuming, expensive, and fails to take advantage of the fact that, through development of the endogenous T cell repertoire, the body naturally produces TCRs that bind almost any possible antigenic target.
  • the ability to obtain human T cells and replace their endogenous TCR with a TCR having a desired antigen specificity could be transformative in the development and application of adoptive T cell therapies.
  • the present invention provides human T cell receptors (TCRs) that are capable of binding to MAGE-A10 antigenic peptides which are associated with diseases such as cancer. Also provided is the use of the TCRs of the invention in fusion constructs, nucleic acids encoding the TCRs of the invention, vectors comprising said nucleic acids, and host cells comprising or expressing TCRs of the invention. The present invention also provides TCRs of the invention for use as a medicament and/or in treating a disease or condition associated with expression of MAGE-A10, such as cancer.
  • Effector cells transduced with the presently claimed TCRs show dose-dependent T cell activation and dose-dependent cytotoxic activity.
  • Primary T cells transduced with TCRs of the present invention demonstrate cell killing activity against MAGE-A10-expressing cell lines, such lung cell line EKVX and melanoma cell lines SK-MEL-2 and A375. Accordingly, the T cell transduced with TCRs of the present invention exhibit cell killing activity towards cancer cell lines displaying the MAGE-A10 antigen of interest on the corresponding HLA molecule.
  • the Melanoma Antigen Gene (MAGE) protein family is a large, highly conserved group of proteins that share a common MAGE homology domain.
  • the MAGEA gene locus on chromosome Xq28 comprises 12 genes encoding subtypes A1-A12.
  • MAGE proteins are restricted to reproductive tissues, e.g. testis, placenta, embryonic tissue, with limited expression in normal tissues.
  • MAGE proteins are aberrantly expressed in a wide variety of cancers, see e.g. Weon and Potts, Curr Opin Cell Biol. 2015 Dec; 37: 1-8, which is hereby incorporated by reference in its entirety.
  • MAGEs are associated with poor clinical prognosis and can function as drivers of tumorigenesis. They are also associated with resistance to chemotherapy, metastasis and cancer cells that have increased potential for survival.
  • Type I MAGEs are considered cancer-testis antigens (CTAs) and in humans include the MAGE- A, -B, and -C subfamily members which are clustered on the X-chromosome.
  • Type II MAGEs (MAGE-D, - E, -F, -G, -H, -L subfamilies and Necdin) are expressed throughout many tissues in the body and are not restricted to the X chromosome. Both type I and type II MAGEs contain a MAGE homology domain (MHD) that is approximately 170 amino acids, which on average is 46% conserved amongst all human MAGEs.
  • MHD MAGE homology domain
  • MAGE-A10 is a member of the MAGE-A family, whose members are known to influence cellular signaling pathways through their E3 ubiquitin ligase-binding MAGE homology domain. MAGE-A10 has been found to be significantly expressed in distinct subgroups of multiple major tumour types with high unmet medical need, for example in lung, skin, urothelial and ovarian malignancies.
  • MAGE-A10 refers to MAGE-A10 from any species and includes MAGE-A10 isoforms, fragments, variants or homologues from any species.
  • the MAGE-A10 is MAGE-A10 from a mammal (e.g.
  • Isoforms, fragments, variants or homologues of MAGE-A10 may optionally be characterised as having at least 70% (e.g. one of >70%, >75%, >80%, >85%, >86%, >87%, >88%, >89%, >90%, >91%, >92%, >93%, >94%, >95%, >96%, >97%, >98%, >99% or 100%) sequence identity to the amino acid sequence of an immature or mature MAGE-A10 isoform from a given species, e.g. human.
  • Human MAGE-A10 is shown in SEQ ID NO:72.
  • the MAGE-A10 comprises, or consists of, an amino acid sequence having at least 70%, preferably one of 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity to SEQ ID NO:72.
  • the present disclosure provides antigen-binding molecules and fragments, chains, polypeptides and complexes thereof, e.g. T cell receptors.
  • T cell receptor refers to a heteromeric cell-surface receptor capable of specifically interacting with a target antigen.
  • a ‘TCR’ or an antigen-binding fragment thereof may also be referred to as an ‘antigen-binding molecule’.
  • TCR includes but is not limited to naturally occurring and non-naturally occurring TCRs; full-length TCRs and antigen binding portions thereof, chimeric TCRs; TCR fusion constructs; and synthetic TCRs. In humans, TCRs are expressed on the surface of T cells, and they are responsible for T cell recognition and targeting of antigen presenting cells.
  • Antigen presenting cells display fragments of foreign or self proteins (antigens) complexed with the major histocompatibility complex (MHC; also referred to herein as complexed with a HLA molecule, e.g., a HLA class I or class II molecule).
  • MHC major histocompatibility complex
  • a TCR recognizes and binds to the antigemHLA complex and recruits CD3 (expressed by T cells), activating the TCR. The activated TCR initiates downstream signaling and an immune response, including the destruction of the APC.
  • a TCR can comprise two chains, an alpha chain and a beta chain (or less commonly a gamma chain and a delta chain), interconnected by disulfide bonds to form a heterodimeric receptor.
  • Each chain comprises a variable domain (e.g. alpha chain variable domain and beta chain variable domain) and a constant region (e.g. alpha chain constant region and beta chain constant region).
  • the variable domain is located distal to the cell membrane, and the variable domain interacts with an antigen.
  • a variable domain may also be referred to herein as a ‘variable region’.
  • the constant region is located proximal to the cell membrane, acts to anchor the protein in the cell membrane, and associates with invariant subunits of the CD3 signaling apparatus.
  • a TCR can further comprise a transmembrane region and a short cytoplasmic tail.
  • the term ‘constant region’ encompasses the transmembrane region and the cytoplasmic tail, when present, as well as the traditional ‘constant region.’
  • variable domains can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDRs complementarity determining regions
  • FR framework regions
  • Each alpha chain variable domain and beta chain variable domain comprises three CDRs and four FRs: FR1 , CDR1 , FR2, CDR2, FR3, CDR3, FR4.
  • Each variable domain contains a binding domain that interacts with an antigen. This may be called an antigen-binding domain or antigen-binding fragment of a TCR. Together, the 6 CDRs form the majority of the antigen binding site of the TCR, thus conferring onto each TCR its specificity (Schroeder and Cavacini, J Allergy Clin Immunol 125(202):S41-S52 (2010); Bhati et al., Protein Science 23:260-272 (2014), which are hereby incorporated by reference in their entirety).
  • the CDRs interact with a complex between an antigenic peptide bound to a protein encoded by the major histocompatibility complex (pepMHC) (Davis and Bjorkman (1988) Nature, 334, 395-402; Davis et al. (1998) Annu Rev Immunol, 16, 523-544; Murphy (2012), xix, 868 p., which are hereby incorporated by reference in their entirety).
  • pepMHC major histocompatibility complex
  • CDR3 is believed to be the primary antigen binding region, interacting with the peptide in the HLA complex groove during TCR binding.
  • CDR1 and CDR2 are believed to primarily recognize the HLA complex.
  • CDR3 used herein describes the CDR3 region optionally including the fixed C’-terminal amino acid C (cysteine) and N’-terminal amino acid F (phenylalanine) or W (Tryptophan), or the respective nucleotide sequences coding for these amino acids.
  • CDR3 including C’-terminal C and N’-terminal F/W, or the respective codons, is also termed ‘Junction’ in the field.
  • novel antigen-binding molecules e.g. TCRs, TCR polypeptides, and fragments/chains thereof, comprising one or more of: the TCRa and TCRp CDR sequences listed in Table A, the FR sequences listed in Table B, the TCRa and TCRp variable domain amino acid sequences listed in Table C, and/or the TCRa and TCRp variable domain nucleotide sequences listed in Table D.
  • TCR also includes an antigen-binding fragment or an antigen-binding portion of any TCR disclosed herein, and includes a monovalent and a divalent fragment or portion, and a single chain TCR or TCR fragment.
  • An ‘antigen binding molecule,’ ‘portion of a TCR,’ or ‘TCR fragment’ may refer to a portion of an TCR less than the whole.
  • An ‘antigen binding molecule’, ‘portion of a TCR’ or ‘TCR fragment’ can include the antigenic complementarity determining regions (CDRs).
  • TCR is not limited to naturally occurring TCRs bound to the surface of a T cell.
  • TCR further refers to a TCR described herein that is expressed on the surface of a cell other than a T cell (e.g., a cell that naturally expresses or that is modified to express CD3, as described herein), or a TCR described herein that is free from a cell membrane (e.g., an isolated TCR or a soluble TCR).
  • an antigen-binding molecule e.g. TCR or TCR chain/polypeptide, described herein is provided in isolated or purified form, e.g. substantially purified form.
  • articles according to the present disclosure may be isolated/purified from naturally-occurring biological material.
  • an antigen-binding molecule described herein e.g. TCR or TCR chain/polypeptide
  • an antigen-binding molecule described herein, e.g. TCR or TCR chain/polypeptide, is soluble.
  • an antigen-binding molecule described herein, e.g. TCR or TCR chain/polypeptide, (or a nucleotide sequence encoding the antigen-binding molecule) is comprised within and/or expressed by a cell, e.g. a cell as described herein.
  • the TCR chain sequences are listed together with the leader sequence preceding FR1 . The leader sequence regulates gene expression of the protein but is not present in the mature TCR protein.
  • Example leader sequences for TCRa and TCRp chains are provided in SEQ ID NO:70.
  • the present invention provides an antigen-binding molecule, e.g. a TCR or fragment/chain thereof, that binds to a MAGE-A10-derived antigenic peptide, such as when presented by a major histocompatibility complex (MHC) molecule.
  • an antigen-binding molecule e.g. a TCR or fragment/chain thereof, that binds to a MAGE-A10-derived antigenic peptide, such as when presented by a major histocompatibility complex (MHC) molecule.
  • MHC major histocompatibility complex
  • the antigen-binding molecule comprises a TCRa chain, or a fragment thereof.
  • the TCRa chain comprises a TCRa variable domain.
  • the TCRa chain e.g. TCRa chain variable domain, comprises a CDR3a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO: 7, 13, 19, 25, 31 , 117 or 123.
  • the CDR3a has an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:19, and wherein the amino acid at position 4 of CDR3a is T.
  • the CDR3a has an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:117, and wherein the amino acid at position 4 of CDR3a is W.
  • the CDR3a has an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:123, and wherein the amino acid at position 3 of CDR3a is G, and/or the amino acid at position 4 of CDR3a is Y.
  • the antigen-binding molecule comprises a TCRp chain, or a fragment thereof.
  • the TCRp chain comprises a TCRp variable domain.
  • the TCRp chain e.g. TCRp chain variable domain, comprises a CDR3p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NQ:10, 16, 22, 28, 34, 120 or 126.
  • the TCRp chain e.g. TCRp chain variable domain, comprises a CDR3p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:22, and wherein the amino acid at position 5 of CDR3p is S.
  • the TCRp chain e.g.
  • TCRp chain variable domain comprises a CDR3p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:16, and wherein the amino acid at position 8 of CDR3p is S.
  • the TCRp chain e.g.
  • TCRp chain variable domain comprises a CDR3p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:126, and wherein the amino acid at position 5 of CDR3p is V.
  • the antigen-binding molecule comprises a TCRa chain having a TCRa variable domain comprising a CDR3a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO: 7, 13, 19, 25,31 , 117 or 123; in combination with a TCRp chain having a TCRp chain variable domain comprising a CDR3p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:
  • the antigen-binding molecule comprises a TCRa chain having a TCRa variable domain comprising a CDR3a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:7; in combination with a TCRp chain having a TCRp chain variable domain comprising a CDR3p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NQ:10.
  • the antigen-binding molecule comprises a TCRa chain having a TCRa variable domain comprising a CDR3a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:13; in combination with a TCRp chain having a TCRp chain variable domain comprising a CDR3p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:16, optionally wherein
  • the antigen-binding molecule comprises a TCRa chain having a TCRa variable domain comprising a CDR3a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:19, optionally wherein the amino acid at position 4 of CDR3a is T; in combination with a TCRp chain having a TCRp chain variable domain comprising a CDR3p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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
  • the antigen-binding molecule comprises a TCRa chain having a TCRa variable domain comprising a CDR3a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:25; in combination with a TCRp chain having a TCRp chain variable domain comprising a CDR3p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:28.
  • the antigen-binding molecule comprises a TCRa chain having a TCRa variable domain comprising a CDR3a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:31 ; in combination with a TCRp chain having a TCRp chain variable domain comprising a CDR3p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:34.
  • the antigen-binding molecule comprises a TCRa chain having a TCRa variable domain comprising a CDR3a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:117, optionally wherein the amino acid at position 4 of CDR3a is W; in combination with a TCRp chain having a TCRp chain variable domain comprising a CDR3p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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
  • the antigen-binding molecule comprises a TCRa chain having a TCRa variable domain comprising a CDR3a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:123, optionally wherein the amino acid at position 3 of CDR3a is G and/or wherein the amino acid at position 4 of CDR3a is Y; in combination with a TCRp chain having a TCRp chain variable domain comprising a CDR3p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%,
  • the antigen-binding molecule comprises a TCRa chain having a TCRa variable domain comprising a CDR3a having the amino acid sequence of SEQ ID NOT, 13, 19, 25, 31 , 117 or 123; in combination with a TCRp chain having a TCRp chain variable domain comprising a CDR3p having the amino acid sequence of SEQ ID NO:10, 16, 22, 28,34, 120 or 126.
  • the antigen-binding molecule comprises a TCRa chain having a TCRa variable domain comprising a CDR3a having the amino acid sequence of SEQ ID NO: 7; in combination with a TCRp chain having a TCRp chain variable domain comprising a CDR3p having the amino acid sequence of SEQ ID NO:10.
  • the antigen-binding molecule comprises a TCRa chain having a TCRa variable domain comprising a CDR3a having the amino acid sequence of SEQ ID NO:13; in combination with a TCRp chain having a TCRp chain variable domain comprising a CDR3p having the amino acid sequence of SEQ ID NO:16.
  • the antigen-binding molecule comprises a TCRa chain having a TCRa variable domain comprising a CDR3a having the amino acid sequence of SEQ ID NO:19; in combination with a TCRp chain having a TCRp chain variable domain comprising a CDR3p having the amino acid sequence of SEQ ID NO: 22.
  • the antigen-binding molecule comprises a TCRa chain having a TCRa variable domain comprising a CDR3a having the amino acid sequence of SEQ ID NO:25; in combination with a TCRp chain having a TCRp chain variable domain comprising a CDR3p having the amino acid sequence of SEQ ID NO: 28.
  • the antigen-binding molecule comprises a TCRa chain having a TCRa variable domain comprising a CDR3a having the amino acid sequence of SEQ ID NO:31 ; in combination with a TCRp chain having a TCRp chain variable domain comprising a CDR3p having the amino acid sequence of SEQ ID NO:34.
  • the antigen-binding molecule comprises a TCRa chain having a TCRa variable domain comprising a CDR3a having the amino acid sequence of SEQ ID NO:117; in combination with a TCRp chain having a TCRp chain variable domain comprising a CDR3p having the amino acid sequence of SEQ ID NQ:120.
  • the antigen-binding molecule comprises a TCRa chain having a TCRa variable domain comprising a CDR3a having the amino acid sequence of SEQ ID NO:123; in combination with a TCRp chain having a TCRp chain variable domain comprising a CDR3p having the amino acid sequence of SEQ ID NO:126.
  • the antigen-binding molecule comprises a TCRa chain e.g. TCRa variable domain, comprising CDR1a, CDR2a and/or CDR3a according to the same row of column A of Table A.
  • the antigen-binding molecule comprises a TCRp chain e.g. TCRp variable domain, comprising CDR1 p, CDR2p and/or CDR3p according to the same row of column B of Table A.
  • the sequences of columns A and B are selected from the same row of Table A.
  • the antigen-binding molecule comprises a TCRa chain having a TCRa variable domain comprising: a CDR1a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:5, 11 , 17, 23,29, 115 or 121 ; a CDR2a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:6, 12, 18, 24, 30, 116 or
  • the antigen-binding molecule comprises a TCRa chain having a TCRa variable domain comprising: a CDR1a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:5; a CDR2a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:6; and/or a CDR3a having an amino acid sequence sharing
  • the antigen-binding molecule comprises a TCRa chain having a TCRa variable domain comprising: a CDR1 a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:11 ; a CDR2a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:12; and/or a CDR3a
  • the antigen-binding molecule comprises a TCRa chain having a TCRa variable domain comprising: a CDR1 a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:17; a CDR2a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:18; and/or a CDR3a having
  • the antigen-binding molecule comprises a TCRa chain having a TCRa variable domain comprising: a CDR1 a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:23; a CDR2a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:24; and/or a CDR3a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least
  • the antigen-binding molecule comprises a TCRa chain having a TCRa variable domain comprising: a CDR1 a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:29; a CDR2a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NQ:30; and/or a CDR3a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at
  • the antigen-binding molecule comprises a TCRa chain having a TCRa variable domain comprising: a CDR1 a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:115; a CDR2a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:116; and/or a CDR3a having
  • the antigen-binding molecule comprises a TCRa chain having a TCRa variable domain comprising: a CDR1 a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:121 ; a CDR2a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:122; and/or a CDR3a
  • the antigen-binding molecule comprises a TCRp chain having a TCRp variable domain comprising: a CDR1 having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:8, 14, 20, 26, 32, 118 or 124; a CDR2p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:9, 15, 21 , 27, 33,
  • the antigen-binding molecule comprises a TCRp chain having a TCRp variable domain comprising: a CDR1 p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:8; a CDR2p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:9; and/or a CDR3p having
  • the antigen-binding molecule comprises a TCRp chain having a TCRp variable domain comprising: a CDR1 p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:14; a CDR2p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:15; and/or a CDR3p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least
  • the antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRp chain having a TCRp variable domain comprising: a CDR1 p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NQ:20; a CDR2p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO: 21 ; and/or a CDR3
  • the antigen-binding molecule comprises a TCRp chain having a TCRp variable domain comprising: a CDR1 p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:26; a CDR2p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:27; and/or a CDR3p having
  • the antigen-binding molecule comprises a TCRp chain having a TCRp variable domain comprising: a CDR1 p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:32; a CDR2p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:33; and/or a CDR3p having
  • the antigen-binding molecule comprises a TCRp chain having a TCRp variable domain comprising: a CDR1 p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:118; a CDR2p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:119; and/or a CDR3p having
  • the antigen-binding molecule comprises a TCRp chain having a TCRp variable domain comprising: a CDR1 p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:124; a CDR2p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:125; and/or a CDR3p having
  • the antigen-binding molecule e.g. TCR or fragment thereof, comprises:
  • a TCRa chain variable domain incorporating the following CDRs: a CDR1 a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:5, 11 , 17, 23,29, 115 or 121 ; a CDR2a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:6, 12, 18, 24, 30, 116 or 122; a CDR3a having an amino acid sequence sharing at least about 70%,
  • a TCRp chain variable domain incorporating the following CDRs: a CDR1 p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:8, 14, 20, 26,32, 118 or 124; a CDR2p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:9, 15, 21 , 27, 33, 119 or 125; and/or a CDR3p having an amino acid sequence sharing
  • the antigen-binding molecule e.g. TCR or fragment thereof, comprises:
  • a TCRa chain variable domain incorporating the following CDRs: a CDR1 a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:5; a CDR2a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:6; a CDR3a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 91
  • a TCRp chain variable domain incorporating the following CDRs: a CDR1 p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:8; a CDR2p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:9; and/or a CDR3p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%,
  • the antigen-binding molecule e.g. TCR or fragment thereof, comprises:
  • a TCRa chain variable domain incorporating the following CDRs: a CDR1 a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:11 ; a CDR2a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:12; a CDR3a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 99% or
  • a TCRp chain variable domain incorporating the following CDRs: a CDR1 p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:14; a CDR2p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:15; and/or a CDR3p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%,
  • the antigen-binding molecule e.g. TCR or fragment thereof, comprises:
  • a TCRa chain variable domain incorporating the following CDRs: a CDR1 a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:17; a CDR2a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:18; a CDR3a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, at least
  • a TCRp chain variable domain incorporating the following CDRs: a CDR1 p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO: 20; a CDR2p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:21 ; and/or a CDR3p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%
  • the antigen-binding molecule e.g. TCR or fragment thereof, comprises:
  • a TCRa chain variable domain incorporating the following CDRs: a CDR1 a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO: 23; a CDR2a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:24; a CDR3a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 91
  • a TCRp chain variable domain incorporating the following CDRs: a CDR1 p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:26; a CDR2p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:27; and/or a CDR3p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%,
  • the antigen-binding molecule e.g. TCR or fragment thereof, comprises:
  • a TCRa chain variable domain incorporating the following CDRs: a CDR1 a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:29; a CDR2a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NQ:30; a CDR3a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 99% or
  • a TCRp chain variable domain incorporating the following CDRs: a CDR1 having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:32; a CDR2p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:33; and/or a CDR3p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, at least
  • the antigen-binding molecule e.g. TCR or fragment thereof, comprises:
  • a TCRa chain variable domain incorporating the following CDRs: a CDR1 a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:115; a CDR2a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:116; a CDR3a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 91
  • a TCRp chain variable domain incorporating the following CDRs: a CDR1 p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:118; a CDR2p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:119; and/or a CDR3p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%,
  • a TCRa chain variable domain incorporating the following CDRs: a CDR1a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:121 ; a CDR2a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:122; a CDR3a having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 91%, at least 9 least 9
  • a TCRp chain variable domain incorporating the following CDRs: a CDR1 p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:124; a CDR2p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:125; and/or a CDR3p having an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 91%, at least
  • the antigen-binding molecule e.g. TCR or fragment thereof, comprises:
  • CDR1a having the amino acid sequence of SEQ ID NO:5, 11 , 17, 23,29, 115 or 121 ;
  • CDR2a having the amino acid sequence of SEQ ID NO:6, 12, 18, 24,30, 116 or 122;
  • CDR3a having the amino acid sequence of SEQ ID NO:7, 13, 19, 25, 31 , 117 or 123; or a variant thereof in which 1 or 2 or 3 amino acids in CDR1a, and/or in which 1 or 2 or 3 amino acids in CDR2a, and/or in which 1 or 2 or 3 amino acids in CDR3a are substituted with another amino acid; and/or
  • CDR1 p having the amino acid sequence of SEQ ID NO:8, 14, 20, 26, 32, 118 or 124;
  • CDR2p having the amino acid sequence of SEQ ID NO:9, 15, 21 , 27, 33, 119 or 125;
  • CDR3p having the amino acid sequence of SEQ ID NQ:10, 16, 22, 28, 34, 120 or 126; or a variant thereof in which 1 or 2 or 3 amino acids in CDR1 p, and/or in which 1 or 2 or 3 amino acids in CDR2p, and/or in which 1 or 2 or 3 amino acids in CDR3p are substituted with another amino acid.
  • the antigen-binding molecule e.g. TCR or fragment thereof, comprises:
  • CDR3a having the amino acid sequence of SEQ ID NO: 7, or a variant thereof in which 1 or 2 or 3 amino acids in CDR1a, and/or in which 1 or 2 or 3 amino acids in CDR2a, and/or in which 1 or 2 or 3 amino acids in CDR3a are substituted with another amino acid; and/or
  • CDR3p having the amino acid sequence of SEQ ID NO: 10, or a variant thereof in which 1 or 2 or 3 amino acids in CDR1 p, and/or in which 1 or 2 or 3 amino acids in CDR2p, and/or in which 1 or 2 or 3 amino acids in CDR3p are substituted with another amino acid.
  • the antigen-binding molecule e.g. TCR or fragment thereof, comprises:
  • CDR3a having the amino acid sequence of SEQ ID NO:13, or a variant thereof in which 1 or 2 or 3 amino acids in CDR1a, and/or in which 1 or 2 or 3 amino acids in CDR2a, and/or in which 1 or 2 or 3 amino acids in CDR3a are substituted with another amino acid; and/or
  • the antigen-binding molecule e.g. TCR or fragment thereof, comprises:
  • CDR1a having the amino acid sequence of SEQ ID NO:17
  • CDR2a having the amino acid sequence of SEQ ID NO:18
  • CDR3a having the amino acid sequence of SEQ ID NO:19, or a variant thereof in which 1 or 2 or 3 amino acids in CDR1a, and/or in which 1 or 2 or 3 amino acids in CDR2a, and/or in which 1 or 2 or 3 amino acids in CDR3a are substituted with another amino acid.
  • the amino acid at position 4 of CDR3a is T; and/or
  • CDR1 p having the amino acid sequence of SEQ ID NQ:20
  • CDR2p having the amino acid sequence of SEQ ID NO:21
  • CDR3p having the amino acid sequence of SEQ ID NO:22, or a variant thereof in which 1 or 2 or 3 amino acids in CDR1 p, and/or in which 1 or 2 or 3 amino acids in CDR2p, and/or in which 1 or 2 or 3 amino acids in CDR3p are substituted with another amino acid.
  • the amino acid at position 5 of CDR3p is S.
  • the antigen-binding molecule e.g. TCR or fragment thereof, comprises:
  • CDR3a having the amino acid sequence of SEQ ID NO:25, or a variant thereof in which 1 or 2 or 3 amino acids in CDR1a, and/or in which 1 or 2 or 3 amino acids in CDR2a, and/or in which 1 or 2 or 3 amino acids in CDR3a are substituted with another amino acid; and/or
  • CDR1 p having the amino acid sequence of SEQ ID NO:26
  • CDR2p having the amino acid sequence of SEQ ID NO:27
  • CDR3p having the amino acid sequence of SEQ ID NO:28, or a variant thereof in which 1 or 2 or 3 amino acids in CDR1 p, and/or in which 1 or 2 or 3 amino acids in CDR2p, and/or in which 1 or 2 or 3 amino acids in CDR3p are substituted with another amino acid.
  • the antigen-binding molecule e.g. TCR or fragment thereof, comprises:
  • CDR1a having the amino acid sequence of SEQ ID NO:29
  • CDR2a having the amino acid sequence of SEQ ID NQ:30
  • CDR3a having the amino acid sequence of SEQ ID NO:31
  • 1 or 2 or 3 amino acids in CDR1a and/or in which 1 or 2 or 3 amino acids in CDR2a, and/or in which 1 or 2 or 3 amino acids in CDR3a are substituted with another amino acid;
  • CDR3p having the amino acid sequence of SEQ ID NO:34, or a variant thereof in which 1 or 2 or 3 amino acids in CDR1 p, and/or in which 1 or 2 or 3 amino acids in CDR2p, and/or in which 1 or 2 or 3 amino acids in CDR3p are substituted with another amino acid.
  • the antigen-binding molecule e.g. TCR or fragment thereof, comprises:
  • CDR1a having the amino acid sequence of SEQ ID NO:115
  • CDR2a having the amino acid sequence of SEQ ID NO:116
  • CDR3a having the amino acid sequence of SEQ ID NO:117, or a variant thereof in which 1 or 2 or 3 amino acids in CDR1a, and/or in which 1 or 2 or 3 amino acids in CDR2a, and/or in which 1 or 2 or 3 amino acids in CDR3a are substituted with another amino acid.
  • the amino acid at position 4 of CDR3a is W; and/or
  • CDR3p having the amino acid sequence of SEQ ID NQ:120, or a variant thereof in which 1 or 2 or 3 amino acids in CDR1 p, and/or in which 1 or 2 or 3 amino acids in CDR2p, and/or in which 1 or 2 or 3 amino acids in CDR3p are substituted with another amino acid.
  • the antigen-binding molecule e.g. TCR or fragment thereof, comprises:
  • CDR1a having the amino acid sequence of SEQ ID NO:121
  • CDR2a having the amino acid sequence of SEQ ID NO:122
  • CDR3a having the amino acid sequence of SEQ ID NO:123, or a variant thereof in which 1 or 2 or 3 amino acids in CDR1a, and/or in which 1 or 2 or 3 amino acids in CDR2a, and/or in which 1 or 2 or 3 amino acids in CDR3a are substituted with another amino acid.
  • the amino acid at position 3 of CDR3a is G and/or the amino acid at position 4 of CDR3a is Y; and/or
  • CDR3p having the amino acid sequence of SEQ ID NO:126, or a variant thereof in which 1 or 2 or 3 amino acids in CDR1 p, and/or in which 1 or 2 or 3 amino acids in CDR2p, and/or in which 1 or 2 or 3 amino acids in CDR3p are substituted with another amino acid.
  • the amino acid at position 5 of CDR3p is V.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises a TCRa chain variable domain comprising FR1 , FR2, FR3 and FR4 according to the same row of column A of Table B.
  • an antigen-binding molecule, e.g. TCR or fragment thereof, according to the present disclosure comprises a TCRp chain variable domain comprising FR1 , FR2, FR3 and FR4 according to the same row of column B of Table B.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises a TCRa chain variable domain comprising FR1 , FR2, FR3 and FR4 according to the same row of column A of Table B, and a TCRp chain variable domain comprising FR1 , FR2, FR3 and FR4 according to the same row of column B of Table B.
  • the sequences of columns A and B are selected from the same row of Table B.
  • FR1 , FR2, FR3 and FR4 from a numbered row in Table B can be combined with CDR1 , CDR2 and CDR3 from the same numbered row in Table A.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises:
  • a TCRa chain variable domain comprising SEQ ID NOs:73, 74, 75 and/or 76, or one or more sequences having at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with one or more of SEQ ID NOs:73, 74, 75 and/or 76; and/or
  • a TCRp chain variable domain comprising SEQ ID NOs:77, 78, 79 and/or 80, or one or more sequences having at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with one or more of SEQ ID NOs:77, 78, 79 and/or 80.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises:
  • a TCRa chain variable domain comprising SEQ ID NOs:81 , 82, 83 and/or 84, or one or more sequences having at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with one or more of SEQ ID NOs:81 , 82, 83 and/or 84; and/or
  • a TCRp chain variable domain comprising SEQ ID NOs:85, 86, 87 and/or 88, or one or more sequences having at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with one or more of SEQ ID NOs:85, 86, 87 and/or 88.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises: (i) a TCRa chain variable domain comprising SEQ ID NOs:89, 90, 91 and/or 92, or one or more sequences having at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with one or more of SEQ ID NOs:89, 90, 91 and/or 92; and/or
  • a TCRp chain variable domain comprising SEQ ID NOs:93, 94, 95 and/or 96, or one or more sequences having at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with one or more of SEQ ID NOs:93, 94, 95 and/or 96.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises:
  • a TCRa chain variable domain comprising SEQ ID NOs:97, 98, 99 and/or 100, or one or more sequences having at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with one or more of SEQ ID NOs:97, 98, 99 and/or 100; and/or
  • a TCRp chain variable domain comprising SEQ ID NQs:101 , 102, 103 and/or 104, or one or more sequences having at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with one or more of SEQ ID NQs:101 , 102, 103 and/or 104.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises:
  • a TCRa chain variable domain comprising SEQ ID NQs:105, 106, 107 and/or 108, or one or more sequences having at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with one or more of SEQ ID NQs:105, 106, 107 and/or 108; and/or
  • a TCRp chain variable domain comprising SEQ ID NQs:109, 110, 111 and/or 112, or one or more sequences having at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with one or more of SEQ ID NQs:109, 110, 111 and/or 112.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises: (i) a TCRa chain variable domain comprising SEQ ID NOs:139, 140, 141 and/or 142, or one or more sequences having at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with one or more of SEQ ID NOs:139, 140, 141 and/or 142; and/or
  • a TCRp chain variable domain comprising SEQ ID NOs:143, 144, 145 and/or 146, or one or more sequences having at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with one or more of SEQ ID NOs:143, 144, 145 and/or 146.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises:
  • a TCRa chain variable domain comprising SEQ ID NOs:147, 148, 149 and/or 150, or one or more sequences having at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with one or more of SEQ ID NOs:147, 148, 149 and/or 150; and/or
  • a TCRp chain variable domain comprising SEQ ID NOs:151 , 152, 153 and/or 154, or one or more sequences having at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with one or more of SEQ ID NOs:151 , 152, 153 and/or 154.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises a TCRa chain variable domain comprising the CDRs according to the same row of column A of Table A and the FRs according to the same row of column A of Table B.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises a TCRp chain variable domain comprising the CDRs according to the same row of column B of Table A and the FRs according to the same row of column B of Table B.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises a TCRa chain variable domain having an amino acid sequence as shown in column A of Table C.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises a TCRp chain variable domain having an amino acid sequence as shown in column B of Table C.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises a TCRa chain variable domain having an amino acid sequence as shown in column A of Table C and a TCRp chain variable domain having an amino acid sequence as shown in column B of Table C, wherein the TCRa chain variable domain sequence and TCRp chain variable domain sequence are selected from the same row of Table C.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises a TCRa chain variable domain having an amino acid sequence as shown in SEQ ID NO:35, or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:35.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises a TCRp chain variable domain having an amino acid sequence as shown in SEQ ID NO:36, or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:36.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises:
  • a TCRa chain variable domain having an amino acid sequence as shown in SEQ ID NO:35, or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:35; and
  • a TCRp chain variable domain having an amino acid sequence as shown in SEQ ID NO:36, or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:36.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises a TCRa chain variable domain having an amino acid sequence as shown in SEQ ID NO:37, or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:37.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises a TCRp chain variable domain having an amino acid sequence as shown in SEQ ID NO:38, or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:38.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises:
  • a TCRa chain variable domain having an amino acid sequence as shown in SEQ ID NO:37, or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:37; and
  • a TCRp chain variable domain having an amino acid sequence as shown in SEQ ID NO:37, or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:38.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises a TCRa chain variable domain having an amino acid sequence as shown in SEQ ID NO:39, or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:39.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises a TCRp chain variable domain having an amino acid sequence as shown in SEQ ID NQ:40, or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NQ:40.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises:
  • a TCRa chain variable domain having an amino acid sequence as shown in SEQ ID NO:39, or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:39; and
  • a TCRp chain variable domain having an amino acid sequence as shown in SEQ ID NQ:40, or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NQ:40.
  • an antigen-binding molecule e.g.
  • TCR or fragment thereof comprises a TCRa chain variable domain having an amino acid sequence as shown in SEQ ID NO:41 , or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:41 .
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises a TCRp chain variable domain having an amino acid sequence as shown in SEQ ID NO:42, or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:42.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises:
  • a TCRa chain variable domain having an amino acid sequence as shown in SEQ ID NO:41 , or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:41 ; and
  • TCRp chain variable domain having an amino acid sequence as shown in SEQ ID NO:42, or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:42.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises a TCRa chain variable domain having an amino acid sequence as shown in SEQ ID NO:43, or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:43.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises a TCRp chain variable domain having an amino acid sequence as shown in SEQ ID NO:44, or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:44.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises: (vii) a TCRa chain variable domain having an amino acid sequence as shown in SEQ ID NO:43, or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:43; and
  • a TCRp chain variable domain having an amino acid sequence as shown in SEQ ID NO:44, or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:44.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises a TCRa chain variable domain having an amino acid sequence as shown in SEQ ID NO:127, or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:127.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises a TCRp chain variable domain having an amino acid sequence as shown in SEQ ID NO:128, or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:128.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises:
  • a TCRa chain variable domain having an amino acid sequence as shown in SEQ ID NO:127, or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:127; and
  • a TCRp chain variable domain having an amino acid sequence as shown in SEQ ID NO:128, or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:128.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises a TCRa chain variable domain having an amino acid sequence as shown in SEQ ID NO:129, or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:129.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises a TCRp chain variable domain having an amino acid sequence as shown in SEQ ID NO:130, or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NQ:130.
  • an antigen-binding molecule e.g. TCR or fragment thereof, according to the present disclosure comprises:
  • a TCRa chain variable domain having an amino acid sequence as shown in SEQ ID NO:129, or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NO:129; and
  • a TCRp chain variable domain having an amino acid sequence as shown in SEQ ID NQ:130, or an amino acid sequence sharing at least about 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with the amino acid sequence of SEQ ID NQ:130.
  • an antigen-binding molecule according to the present disclosure comprises the CDRs, FRs and/or the alpha and/or beta chain variable domains of a TCR described herein, or CDRs, FRs and/or alpha and/or beta chain variable domains which are derived from those of a TCR described herein.
  • a TCR is selected from TCR_A0385, TCR_A0390, TCR_A0398, TCR_A409,TCR_A0425, TCR_A0435 and TCR_A0436.
  • the TCRs according to the present disclosure may be synthetic/artificial TCRs comprising TCRa and TCRp human variable regions and mouse constant regions, for example to improve the expression of the TCR, and in order to use the mouse constant region for the tracking of transfected human T cells with an anti-mouse antibody.
  • human/mouse hybrid TCRs comprising mouse TCRa and TCRb constant region amino acid sequences of SEQ ID NOs: 113 and 114, respectively.
  • TCRs e.g. synthetic or artificial TCRs, comprising TCRa and TCRp human variable regions and human constant regions.
  • the human TCRa constant region is shown in SEQ ID NO:65.
  • the human TCRp constant region is shown in SEQ ID NO:66 or 67.
  • any TCRa chain described herein may comprise a constant region comprising a mutated version of the human TCRa constant region as in SEQ ID NO:68.
  • any TCRp chain described herein may comprise a constant region comprising a mutated version of the human TCRp constant region as in SEQ ID NO:69.
  • any TCR described herein may comprise a human TCR constant region comprising a mutated version of the human TCRa constant region as in SEQ ID NO:68 and a mutated version of human TCRp constant region as in SEQ ID NO:69.
  • the mutation comprises the introduction of a Cys in both the alpha and beta chains of the TCR to create a stabilizing disulfide bridge between the two chains.
  • TCR chains were modified by mutagenesis of residue 48 in the Ca region from Thr to Cys and residue 57 of the Cp region from Ser to Cys. The method has been described previously in Kuball et al, Blood. 2007 Mar 15; 109(6): 2331-2338., which is hereby incorporated by reference in its entirety.
  • the mutation promotes stable expression and pairing of the transduced TCR in human T cells in which the endogenous TCR is not knocked out.
  • an antigen-binding molecule according to the present disclosure comprises a TCRa chain comprising a TCRa constant region having at least 80%, 85%, 90%, or 95% sequence identity to an amino acid sequence selected from: SEQ ID NO: 68, 65 and 113; and a TCRp chain comprising a TCRp constant region having at least 80%, 85%, 90%, or 95% sequence identity to an amino acid sequence selected from: SEQ ID NO: 69, 66, 67 and 114.
  • an antigen-binding molecule according to the present disclosure comprises a TCRa chain comprising a TCRa constant region having at least 80%, 85%, 90%, or 95% sequence identity to SEQ ID NO:68, and a TCRp chain comprising a TCRp constant region having at least 80%, 85%, 90%, or 95% sequence identity to SEQ ID NO:69.
  • an antigen-binding molecule according to the present disclosure comprises a TCRa chain comprising a TCRa constant region having at least 80%, 85%, 90%, or 95% sequence identity to SEQ ID NO:65, and a TCRp chain comprising a TCRp constant region having at least 80%, 85%, 90%, or 95% sequence identity to SEQ ID NO: 66 or 67.
  • any antigen-binding molecule e.g. TCR or fragment thereof, described herein may be capable of recognising and/or binding to a peptide or antigen derived from MAGE-A10 protein, i.e. a MAGE-A10-derived peptide or antigen, such as when presented by a major histocompatibility complex (MHC) molecule.
  • MAGE-A10 comprises or consists of the amino acid sequence of SEQ ID NO:72.
  • an ‘antigen’ refers to any molecule, e.g., a peptide, that provokes an immune response or is capable of being bound by a TCR.
  • An ‘epitope,’ as used herein, refers to a portion of a polypeptide that provokes an immune response or is capable of being bound by a TCR.
  • the immune response may involve either antibody production, or the activation of specific immunologically competent cells, or both.
  • any macromolecule, including virtually all proteins or peptides can serve as an antigen.
  • An antigen and/or an epitope can be endogenously expressed, i.e. expressed by genomic DNA, or can be recombinantly expressed.
  • An antigen and/or epitope can be of exogenous origin.
  • An antigen and/or epitope can possess modifications to the amino acids comprising the antigen and/or epitope if of polypeptide origin (e.g. phosphorylation, glycosylation, cysteinylation, deamidation, and/or other post-translational modifications to the amino acids within the antigen and/or epitope).
  • An antigen and/or an epitope can be specific to a certain tissue, such as a cancer cell, or it can be broadly expressed.
  • fragments of larger molecules can act as antigens.
  • antigens are tumor antigens.
  • An epitope can be present in a longer polypeptide (e.g., in a protein), or an epitope can be present as a fragment of a longer polypeptide.
  • an epitope is complexed with a major histocompatibility complex (MHC; also referred to herein as a HLA molecule, e.g., a HLA class I or class II molecule).
  • MHC major histocompatibility complex
  • TCRs bind, via their CDR loops, to peptides presented by molecules of the major histocompatibility complex (MHC).
  • MHC major histocompatibility complex
  • This TCR-MHC interaction is crucially important in cell mediated immunity, with the specificity in the cellular immune response being attributable to MHC polymorphism, an extensive TCR repertoire, and a variable peptide cargo.
  • the conventional T-cell response is mediated by TCR recognition of short peptide fragments bound to MHC class I or MHC class II molecules.
  • MHC- I present peptides derives from endogenous protein that are recognized by cytotoxic T-cells
  • MHC-II present exogenously-derived peptides to T helper cells (see e.g. Bhati et al., Protein Science, 23:260-272 (2014), which is hereby incorporated by reference in its entirety).
  • HLA refers to the human leukocyte antigen.
  • MHCs are encoded by the human leukocyte antigen (HLA) locus on chromosome 6.
  • HLA-A, HLA-B and HLA-C human leukocyte antigen locus
  • HLA-E, HLA-F and HLA-G three major HLA gene loci
  • HLA-E, HLA-F and HLA-G three minor loci
  • This locus is highly polymorphic, spans over 5 mega bases and covers over 200 genes.
  • Individual subjects normally express 6 different classical MHC-I and 6 MHC-II molecules that can differ from each other by a single amino acid, or by more than 30 amino acids.
  • MHC proteins are expressed on the surface of cells and are involved in activation of the immune response.
  • HLA class I genes encode MHC class I molecules, which are expressed on the surface of cells in complex with peptide fragments (antigens) of self or non-self proteins.
  • T cells expressing TCR and CD3 recognize the antigemMHC class I complex and initiate an immune response to target and destroy antigen presenting cells displaying non-self proteins.
  • an ‘HLA class I molecule’ or ‘MHC class I molecule’ refers to a protein product of a wildtype or variant HLA class I gene encoding an MHC class I molecule. Accordingly, ‘HLA class I molecule’ and ‘MHC class I molecule’ are used interchangeably herein.
  • MHC class I a-chains are polymorphic, and different a-chains are capable of binding and presenting different peptides. Genes encoding MHC class I a polypeptides are highly variable, with the result that cells from different subjects often express different MHC class I molecules.
  • the MHC Class I molecule comprises two protein chains: the alpha chain (a-chain) and the p2- microglobulin (p 2m) chain.
  • Human p 2m is encoded by the B2M gene.
  • the amino acid sequence of p 2m is set forth in SEQ ID NO:155.
  • the alpha chain of the MHC Class I molecule is encoded by the HLA gene complex.
  • the HLA complex is located within the 6p21 .3 region on the short arm of human chromosome 6 and contains more than 220 genes of diverse function.
  • HLA genes are highly variant, with over 36,000 HLA alleles and related alleles, including over 25,000 HLA Class I alleles, known in the art, encoding thousands of HLA proteins, including over 14,000 HLA Class I proteins (see, e.g., hla.alleles.org).
  • HLA-A HLA-A
  • HLA-B HLA-B
  • HLA-C HLA-C
  • HLA-E, HLA-F, and HLA-G encode proteins that associate with p 2m chain to form the MHC Class I molecule.
  • antigen-presenting cell designates cells having the capability to present processed antigenic moiety fragments via MHC class I or MHC class II molecules. Most cell types including cancer cells can express MHC class I molecules and present fragments via MHC class I molecules, while MHC class II molecules are expressed on professional antigen presenting cells.
  • Professional antigen-presenting cells may be a B-cell, a monocyte, or a dendritic cell.
  • the antigen presenting cells may be synthetic, or be isolated from peripheral blood mononuclear cells (PBMCs).
  • Artificial APCs are a type of cell line that expresses a HLA molecule of interest for testing of TCR binding.
  • the HLA protein can be endogenously expressed, or the artificial APCs can be engineered to express the HLA molecule of interest.
  • Artificial APCs expressing the HLA allele of interest can be loaded with peptides such that the binding of a TCR to a peptide:HLA class I complex can be tested.
  • Antigen-derived for example ‘MAGE-A10-derived’, refers to an immunogenic peptide/epitope being a portion of the antigen/polypeptide from which it has been processed.
  • an antigen is processed in the cell by the proteasome or immunoproteasome and the resulting antigen-derived peptides are presented on the MHC class I or MHC class II complex.
  • An antigen-binding molecule as described herein e.g. a TCR or fragment thereof, may be capable of recognising and/or binding to a MAGE-A10-derived peptide.
  • the MAGE-A10-derived peptide is SEQ ID NO:1. This peptide is located at positions 254-262 of SEQ ID NO:72 and may also be described as MAGE-AIO254-262.
  • the MAGE-A10-derived peptide is SEQ ID NO:2. This peptide is located at positions 310-318 of SEQ ID NO:72 and may also be described as MAGE-AIO31O-318.
  • the MAGE-A10-derived peptide is SEQ ID NO:3. This peptide is located at positions 167-175 of SEQ ID NO:72 and may also be described as MAGE-A 167-175.
  • the MAGE-A10-derived peptide is SEQ ID NO:4. This peptide is located at positions 167-176 of SEQ ID NO:72 and may also be described as MAGE-AIO167-176.
  • a peptide that is presented by an MHC class I molecule comprising an MHC class I a chain polypeptide encoded by a given HLA allele or a HLA allele within a given genus of HLA alleles may be referred to simply as being presented ‘through’ or ‘on’ the relevant allele.
  • a TCR that binds to a MAGE-A10-derived antigenic peptide presented by an MHC class I molecule comprising a polypeptide encoded by a HLA-A*02 allele may be described as a TCR that binds to a MAGE-A10-derived antigenic peptide presented through/on a HLA-A*02 allele.
  • a TCR that binds to a MAGE-A10-derived antigenic peptide presented by an MHC class I molecule comprising a polypeptide encoded by a HLA-A*24 allele may be described as a TCR that binds to a MAGE-A10-derived antigenic peptide presented through/on a HLA-A*24 allele.
  • an antigen-binding molecule as described herein, e.g. a TCR or fragment thereof is capable of recognizing/binding to a MAGE-A10 peptide, e.g. when presented by a major histocompatibility complex (MHC) molecule comprising a polypeptide (e.g. a MHC class I a chain polypeptide) encoded by HLA-A*02 (also known as HLA-A2, HLA-A02, and HLA-A*2). That is, when presented on HLA-A*02.
  • MHC major histocompatibility complex
  • an antigen-binding molecule as described herein e.g. a TCR or fragment thereof, is capable of recognizing/binding to a MAGE-A10 peptide, e.g. when presented by a major histocompatibility complex (MHC) molecule comprising a polypeptide (e.g. a MHC class I a chain polypeptide) encoded by a HLA-A*02:01 allele. That is, when presented on HLA-A*02:01 .
  • MHC major histocompatibility complex
  • the antigen-binding molecule is capable of recognizing/binding, e.g. specifically binds, to a MAGE-A10-derived antigenic peptide presented through another HLA-A*02 allele, including but not restricted to: HLA-A*02:02, HLA-A*02:03, HLA-A*02:04, HLA-A*02:05, HLA-A*02:06, HLA- A*02:07, HLA-A*02:11, HLA-A*02:12, HLA-A*02:19, HLA-A*02:24, HLA-A*02:264, or HLA-A*02:52.
  • an antigen-binding molecule as described herein e.g. a TCR or fragment thereof, is capable of recognizing/binding to a MAGE-A10 peptide, e.g. when presented by a major histocompatibility complex (MHC) molecule comprising a polypeptide (e.g. a MHC class I a chain polypeptide) encoded by HLA-A*24. That is, when presented on HLA-A*24.
  • MHC major histocompatibility complex
  • an antigen-binding molecule as described herein e.g. a TCR or fragment thereof, is capable of recognizing/binding to a MAGE-A10 peptide, e.g. when presented by a major histocompatibility complex (MHC) molecule comprising a polypeptide (e.g. a MHC class I a chain polypeptide) encoded by a HLA-A*24:02 allele. That is, when presented on HLA-A*24:02.
  • MHC major histocompatibility complex
  • the antigen-binding molecule is capable of recognizing/binding, e.g. specifically binds, to a MAGE-A10-derived antigenic peptide presented through another HLA-A*24 allele, including but not restricted to: HLA-A*24:03, sister serotype HLA-A*23 (e.g. HLA-A*23:01) or broader serotype group HLA-A9.
  • an antigen-binding molecule as described herein e.g. a TCR or fragment thereof, is capable of recognizing/binding to SEQ ID NO:1 or 2 , e.g. when presented by a major histocompatibility complex (MHC) molecule comprising a polypeptide (e.g. a MHC class I a chain polypeptide) encoded by HLA-A*02 (also known as HLA-A2, HLA-A02, and HLA-A*2). That is, when presented on HLA-A*02.
  • MHC major histocompatibility complex
  • an antigen-binding molecule as described herein e.g. a TCR or fragment thereof, is capable of recognizing/binding to SEQ ID NO:1 or 2 , e.g. when presented by a major histocompatibility complex (MHC) molecule comprising a polypeptide (e.g. a MHC class I a chain polypeptide) encoded by a HLA-A*02:01 allele. That is, when presented on HLA-A*02:01.
  • MHC major histocompatibility complex
  • an antigen-binding molecule as described herein e.g. a TCR or fragment thereof, is capable of recognizing/binding to SEQ ID NO:3 or 4, e.g. when presented by a major histocompatibility complex (MHC) molecule comprising a polypeptide (e.g. a MHC class I a chain polypeptide) encoded by HLA-A*24. That is, when presented on HLA-A*24.
  • MHC major histocompatibility complex
  • an antigen-binding molecule as described herein, e.g. a TCR or fragment thereof is capable of recognizing/binding to SEQ ID NO:3 or 4, e.g.
  • MHC major histocompatibility complex
  • an antigen-binding molecule as described herein e.g. a TCR or fragment thereof, is capable of recognizing/binding to a GLYDGMEHL (SEQ ID NO:1)-HLA-A*02 complex.
  • the antigenbinding molecule may be TCR A0385, comprising any combination of relevant CDR, FR and/or variable domain sequences as described above and in Tables A-D.
  • TCR A0385 comprises at least one, some or all of the sequences presented in Row 1 of Table A, Row 1 of Table B, Row 1 of Table C and/or is encoded by one or more sequences in Rows 1 and 2 of Table D.
  • an antigen-binding molecule as described herein e.g. a TCR or fragment thereof, is capable of recognizing/binding to a GLYDGMEHL (SEQ ID NQ:1)-HLA-A*02:01 complex.
  • the antigenbinding molecule may be TCR A0385, comprising any combination of relevant CDR, FR and/or variable domain sequences as described above and in Tables A-D.
  • TCR A0385 comprises at least one, some or all of the sequences presented in Row 1 of Table A, Row 1 of Table B, Row 1 of Table C and/or is encoded by one or more sequences in Rows 1 and 2 of Table D.
  • an antigen-binding molecule as described herein e.g. a TCR or fragment thereof, is capable of recognizing/binding to a SLLKFLAKV (SEQ ID NQ:2)-HLA-A*02 complex.
  • the antigenbinding molecule may be TCR A0390, comprising any combination of relevant CDR, FR and/or variable domain sequences as described above and in Tables A-D.
  • the antigen-binding molecule may be TCR A0398, comprising any combination of relevant CDR, FR and/or variable domain sequences as described above and in Tables A-D.
  • the antigen-binding molecule may be TCR A0409, comprising any combination of relevant CDR, FR and/or variable domain sequences as described above and in Tables A-D.
  • the antigen-binding molecule may be TCR A0435, comprising any combination of relevant CDR, FR and/or variable domain sequences as described above and in Tables A-D.
  • the antigen-binding molecule may be TCR A0436, comprising any combination of relevant CDR, FR and/or variable domain sequences as described above and in Tables A-D.
  • TCR A0390 comprises at least one, some or all of the sequences presented in Row 2 of Table A, Row 2 of Table B, Row 2 of Table C and/or is encoded by one or more sequences in Rows 3 and 4 of Table D.
  • TCR A0398 comprises at least one, some or all of the sequences presented in Row 3 of Table A, Row 3 of Table B, Row 3 of Table C and/or is encoded by one or more sequences in Rows 5 and 6 of Table D.
  • TCR A0409 comprises at least one, some or all of the sequences presented in Row 4 of Table A, Row 4 of Table B, Row 4 of Table C and/or is encoded by one or more sequences in Rows 7 and 8 of Table D.
  • TCR A0435 comprises at least one, some or all of the sequences presented in Row 6 of Table A, Row 6 of Table B, Row 6 of Table C and/or is encoded by one or more sequences in Rows 11 and 12 of Table D.
  • TCR A0436 comprises at least one, some or all of the sequences presented in Row 7 of Table A, Row 7 of Table B, Row 7 of Table C and/or is encoded by one or more sequences in Rows 13 and 14 of Table D.
  • an antigen-binding molecule as described herein e.g. a TCR or fragment thereof, is capable of recognizing/binding to a SLLKFLAKV (SEQ ID N0:2)-HLA-A*02:01 complex.
  • the antigenbinding molecule may be TCR A0390, comprising any combination of relevant CDR, FR and/or variable domain sequences as described above and in Tables A-D.
  • the antigen-binding molecule may be TCR A0398, comprising any combination of CDR, FR and/or variable domain sequences as described above and in Tables A-D.
  • the antigen-binding molecule may be TCR A0409, comprising any combination of CDR, FR and/or variable domain sequences as described above and in Tables A-D.
  • the antigen-binding molecule may be TCR A0435, comprising any combination of CDR, FR and/or variable domain sequences as described above and in Tables A-D.
  • the antigen-binding molecule may be TCR A0436, comprising any combination of CDR, FR and/or variable domain sequences as described above and in Tables A-D.
  • TCR A0390 comprises at least one, some or all of the sequences presented in Row 2 of Table A, Row 2 of Table B, Row 2 of Table C and/or is encoded by one or more sequences in Rows 3 and 4 of Table D.
  • TCR A0398 comprises at least one, some or all of the sequences presented in Row 3 of Table A, Row 3 of Table B, Row 3 of Table C and/or is encoded by one or more sequences in Rows 5 and 6 of Table D.
  • TCR A0409 comprises at least one, some or all of the sequences presented in Row 4 of Table A, Row 4 of Table B, Row 4 of Table C and/or is encoded by one or more sequences in Rows 7 and 8 of Table D.
  • TCR A0435 comprises at least one, some or all of the sequences presented in Row 6 of Table A, Row 6 of Table B, Row 6 of Table C and/or is encoded by one or more sequences in Rows 11 and 12 of Table D.
  • TCR A0436 comprises at least one, some or all of the sequences presented in Row 7 of Table A, Row 7 of Table B, Row 7 of Table C and/or is encoded by one or more sequences in Rows 13 and 14 of Table D.
  • an antigen-binding molecule as described herein e.g. a TCR or fragment thereof, is capable of recognizing/binding to a NYEDHFPLL (SEQ ID NO:3)-HLA-A*24 complex.
  • the antigenbinding molecule may be TCR A0425, comprising any combination of relevant CDR, FR and/or variable domain sequences as described above and in Tables A-D.
  • TCR A0425 comprises at least one, some or all of the sequences presented in Row 5 of Table A, Row 5 of Table B, Row 5 of Table C and/or is encoded by one or more sequences in Row 9 (and optionally Row 10) of Table D.
  • an antigen-binding molecule as described herein e.g. a TCR or fragment thereof, is capable of recognizing/binding to a NYEDHFPLL (SEQ ID NO:3)-HLA-A*24:02 complex.
  • the antigenbinding molecule may be TCR A0425, comprising any combination of relevant CDR, FR and/or variable domain sequences as described above and in Tables A-D.
  • TCR A0425 comprises at least one, some or all of the sequences presented in Row 5 of Table A, Row 5 of Table B, Row 5 of Table C and/or is encoded by one or more sequences in Row 9 (and optionally Row 10) of Table D.
  • an antigen-binding molecule as described herein e.g. a TCR or fragment thereof, is capable of recognizing/binding to a NYEDHFPLLF (SEQ ID NO:4)-HLA-A*24 complex.
  • the antigenbinding molecule may be TCR A0425, comprising any combination of relevant CDR, FR and/or variable domain sequences as described above and in Tables A-D.
  • TCR A0425 comprises at least one, some or all of the sequences presented in Row 5 of Table A, Row 5 of Table B, Row 5 of Table C and/or is encoded by one or more sequences in Row 9 (and optionally Row 10) of Table D.
  • an antigen-binding molecule as described herein e.g. a TCR or fragment thereof, is capable of recognizing/binding to a NYEDHFPLLF (SEQ ID NQ:4)-HLA-A*24:02 complex.
  • the antigenbinding molecule may be TCR A0425, comprising any combination of relevant CDR, FR and/or variable domain sequences as described above and in Tables A-D.
  • TCR A0425 comprises at least one, some or all of the sequences presented in Row 5 of Table A, Row 5 of Table B, Row 5 of Table C and/or is encoded by one or more sequences in Row 9 (and optionally Row 10) of Table D.
  • an antigen-binding molecule as described herein e.g. a TCR or fragment thereof, is capable of recognizing/binding to a peptide:MHC complex comprising an MHC class I a chain polypeptide encoded by a HLA-A*02 allele (e.g. HLA-A*02:01), and a peptide comprising or consisting of GLYDGMEHL (SEQ ID NO:1).
  • the antigen-binding molecule may be TCR A0385, comprising any combination of relevant CDR, FR and/or variable domain sequences as described above and in Tables A- D (e.g. in row 1 in Tables A, B, and/or C, and encoded by one or more sequences in rows 1 and 2 of Table D).
  • an antigen-binding molecule as described herein e.g. a TCR or fragment thereof, is capable of recognizing/binding to a peptide:MHC complex comprising an MHC class I a chain polypeptide encoded by a HLA-A*02 allele (e.g. HLA-A*02:01), and a peptide comprising or consisting of SLLKFLAKV (SEQ ID NO:2).
  • the antigen-binding molecule may be TCR A0390, comprising any combination of relevant CDR, FR and/or variable domain sequences as described above and in Tables A- D (e.g.
  • the antigen-binding molecule may be TCR A0398, comprising any combination of relevant CDR, FR and/or variable domain sequences as described above and in Tables A-D (e.g. in row 3 in Tables A, B, and/or C, and encoded by one or more sequences in rows 5 and 6 of Table D).
  • the antigenbinding molecule may be TCR A0409, comprising any combination of relevant CDR, FR and/or variable domain sequences as described above and in Tables A-D (e.g.
  • the antigen-binding molecule may be TCR A0435, comprising any combination of relevant CDR, FR and/or variable domain sequences as described above and in Tables A-D (e.g. in row 6 in Tables A, B, and/or C, and encoded by one or more sequences in rows 11 and 12 of Table D).
  • the antigen-binding molecule may be TCR A0436, comprising any combination of relevant CDR, FR and/or variable domain sequences as described above and in Tables A-D (e.g. in row 7 in Tables A, B, and/or C, and encoded by one or more sequences in rows 13 and 14 of Table D).
  • an antigen-binding molecule as described herein e.g. a TCR or fragment thereof, is capable of recognizing/binding to a peptide:MHC complex comprising an MHC class I a chain polypeptide encoded by a HLA-A*24 allele (e.g. HLA-A*24:02), and a peptide comprising or consisting of NYEDHFPLL (SEQ ID NO:3) or NYEDHFPLLF (SEQ ID NO:4).
  • the antigen-binding molecule may be TCR A0425, comprising any combination of relevant CDR, FR and/or variable domain sequences as described above and in Tables A-D (e.g. in row 5 in Tables A, B, and/or C, and encoded by one or more sequences in rows 9 (and optionally 10) of Table D).
  • the TCRs/antigen-binding molecules described herein may be comprised within multispecific molecules. That is, the present invention provides a multispecific antigen-binding molecule comprising an antigenbinding molecule e.g. TCR described herein.
  • a multispecific antigen-binding molecule may be e.g. bispecific, trispecific, etc.
  • a TCR/antigen-binding molecule described herein as part of a fusion construct, wherein said fusion construct comprises a TCR/antigen-binding molecule described herein and an antigen-binding molecule that is capable of binding to a molecule expressed (e.g. specifically expressed) by immune cells, e.g. T cells, including but not limited to CD3.
  • a multispecific antigen-binding molecule according to the present disclosure comprises an antigen-binding molecule e.g. TCR described herein and at least one further antigenbinding molecule that is capable of binding to a molecule expressed by an immune cell.
  • the two or more antigen-binding molecules may be expressed/presented as a fusion construct or fusion protein.
  • a multispecific antigen-binding molecule comprises an antigen-binding molecule e.g. TCR described herein and at least one further antigenbinding molecule that is capable of binding to a molecule expressed by a T cell.
  • the molecule expressed by an immune cell/a T cell may be CD3.
  • the molecule expressed by an immune cell/a T cell may be CD4 or CD8. That is, the TCRs/antigen-binding molecules described herein may be used in bispecific T cell engagers (BiTEs) or T cell Engaging Receptors (TCER®).
  • BiTEs bispecific T cell engagers
  • TCER® T cell Engaging Receptors
  • Such multispecific molecules can target immune cells, e.g. via a CD3-binding arm, to diseased cells that are recognised via the TCR moiety.
  • the TCR/antigen-binding molecule described herein and/or the at least one further antigen-binding molecule that is capable of binding to a molecule expressed by an immune cell are single-chain molecules, e.g. in scFv form.
  • the at least two antigen binding molecules may be connected via a linker.
  • an article described herein may possess one or more of the following properties: recognizes and/or binds (e.g. specifically binds) to MAGE-A10; recognizes and/or binds (e.g. specifically binds) to a MAGE-A10 peptide (e.g. antigenic peptide); recognizes and/or binds (e.g. specifically binds) to GLYDGMEHL (SEQ ID NO:1); recognizes and/or binds (e.g.
  • SLLKFLAKV SEQ ID NO:2
  • NYEDHFPLL SEQ ID NO:3
  • NYEDHFPLLF SEQ ID NO:4
  • X1X2LKFX3X4KX5 SEQ ID NO:156
  • X1X2X3X4FX5X6KX7 SEQ ID NO:157
  • recognizes and/or binds e.g.
  • MHC major histocompatibility complex
  • a MAGE-A10 peptide e.g. antigenic peptide
  • MHC major histocompatibility complex
  • a polypeptide e.g. a MHC class I a chain polypeptide
  • HLA-A*02 e.g. encoded by HLA-A*02:01
  • HLA-A*02 e.g. encoded by HLA-A*02:01
  • recognizes and/or binds e.g. specifically binds
  • SLLKFLAKV SEQ ID NO:2
  • MHC major histocompatibility complex
  • HLA-A*02 e.g. encoded by HLA-A*02:01
  • recognizes and/or binds e.g. specifically binds
  • HLA-A*02 e.g. encoded by HLA-A*02:01
  • MHC major histocompatibility complex
  • MHC major histocompatibility complex
  • a polypeptide e.g. a MHC class I a chain polypeptide
  • HLA-A*24 e.g. encoded by HLA-A*24:02
  • recognizes and/or binds e.g. specifically binds) to NYEDHFPLLF (SEQ ID NO:4) when presented by a major histocompatibility complex (MHC) molecule comprising an MHC class I a chain polypeptide, e.g. encoded by HLA-A*24, e.g.
  • HLA-A*24:02 recognizes and/or binds (e.g. specifically binds) to X1X2LKFX3X4KX5 (SEQ ID NO:156) when presented by a major histocompatibility complex (MHC) molecule comprising a polypeptide (e.g. a MHC class I a chain polypeptide), e.g. encoded by HLA-A*02, e.g. encoded by HLA-A*02:01 ; recognizes and/or binds (e.g.
  • MHC major histocompatibility complex
  • MHC major histocompatibility complex
  • a polypeptide e.g. a MHC class I a chain polypeptide
  • HLA-A*02 e.g. encoded by HLA-A*02:01
  • recognizes and/or binds e.g. specifically binds
  • HAGE-A10 e.g. specifically binds
  • recognizes and/or binds e.g. specifically binds to a cell expressing a MAGE-A10 peptide
  • recognizes and/or binds e.g. specifically binds
  • MHC major histocompatibility complex
  • A*02:01 recognizes and/or binds (e.g. specifically binds) to a cell presenting SLLKFLAKV (SEQ ID NO:2), e.g. when presented by a major histocompatibility complex (MHC) molecule comprising a polypeptide (e.g. a MHC class I a chain polypeptide), e.g. encoded by HLA-A*02, e.g. encoded by HLA-A*02:01 ; recognizes and/or binds (e.g. specifically binds) to a cell presenting NYEDHFPLL (SEQ ID NO:3), e.g.
  • MHC major histocompatibility complex
  • MHC major histocompatibility complex
  • a major histocompatibility complex (MHC) molecule comprising a polypeptide (e.g. a MHC class I a chain polypeptide), e.g. encoded by HLA-A*24, e.g. encoded by HLA-A*24:02; recognizes and/or binds (e.g. specifically binds) to a cell presenting NYEDHFPLLF (SEQ ID NO:4), e.g. when presented by a major histocompatibility complex (MHC) molecule comprising a polypeptide (e.g. a MHC class I a chain polypeptide), e.g. encoded by HLA-A*24, e.g.
  • MHC major histocompatibility complex
  • HLA- A*24:02 recognizes and/or binds (e.g. specifically binds) to a cell presenting X1X2LKFX3X4KX5 (SEQ ID NO:156), e.g. when presented by a major histocompatibility complex (MHC) molecule comprising a polypeptide (e.g. a MHC class I a chain polypeptide), e.g. encoded by HLA-A*02, e.g. encoded by HLA- A*02:01 ; recognizes and/or binds (e.g.
  • MHC major histocompatibility complex
  • a cell presenting X1X2X3X4FX5X6KX7 SEQ ID NO:157
  • a major histocompatibility complex (MHC) molecule comprising a polypeptide (e.g. a MHC class I a chain polypeptide), e.g. encoded by HLA-A*02, e.g. encoded by HLA- A*02:01 ; activates a host cell, e.g. T cell, in which the article is comprised/expressed; promotes cell killing activity of a cell in which the article is comprised/expressed; has an ‘anti-cancer’ effect when comprised/expressed in a host cell, e.g.
  • MHC major histocompatibility complex
  • T cell has an ‘anti-tumour effect when comprised/expressed in a host cell, e.g. T cell; confers cytotoxic activity when comprised/expressed in a host cell, e.g. T cell; promotes IFNy secretion from a host cell, e.g. T cell (e.g. a CD8+ T cell and/or a CD4+ T cell), in which it is comprised/expressed; and/or promotes TNFa secretion from a host cell, e.g. T cell (e.g. a CD8+ T cell and/or a CD4+ T cell), in which it is comprised/expressed.
  • T cell e.g. a CD8+ T cell and/or a CD4+ T cell
  • a given antigen-binding molecule may display more than one of the properties recited in the preceding paragraph.
  • a given antigen-binding molecule may be evaluated for the properties recited in the preceding paragraph using suitable assays.
  • the assays may be e.g. in vitro assays, optionally cell-based assays or cell-free assays.
  • the assays may be e.g. in vivo assays, i.e. performed in non-human animals.
  • the assays may be e.g. ex vivo assays, i.e. performed using cells/tissue/an organ obtained from a subject.
  • assays are cell-based assays, they may comprise treating cells with a given host cell comprising/expressing the antigen-binding molecule/TCR in order to determine whether the host cells/antigen-binding molecule/TCR displays one or more of the recited properties.
  • Assays may employ species labelled with detectable entities in order to facilitate their detection.
  • Assays may comprise evaluating the recited properties following treatment of cells separately with a range of quantities/concentrations of a given host cells/antigen-binding molecule/TCR (e.g. a dilution series). It will be appreciated that the cells preferably express the target antigen for the antigen-binding molecule/TCR (i.e. a MAGE-A10 peptide, such as those described herein).
  • an ‘anti-tumor effect’ as used herein refers to a biological effect that can present as a decrease in tumor volume, a decrease in the number of tumor cells, a decrease in tumor cell proliferation, a decrease in the number of metastases, an increase in overall or progression-free survival, an increase in life expectancy, or amelioration of various physiological symptoms associated with the tumor.
  • An anti-tumor effect can also refer to the prevention of the occurrence of a tumor, e.g., a vaccine.
  • T cell receptor specifically binds, is meant a T cell receptor which recognizes a specific antigen complexed with an MHC molecule, but does not substantially recognize or bind other antigemMHC complexes in a sample.
  • the functionality of TCRs can be assessed by quantification of cytokine secretion in the cell culture media (e.g. IFNy, TNFa). In some embodiments, the functionality of TCRs can be assessed by quantification of intracellular cytokine expression (e.g. IFNy, TNFa).
  • IFNy Interferon gamma
  • IFNy secreted by T cells into the culture medium during the cytotoxicity assay can be quantified by ELISA methodology.
  • TCRs can be assessed using primary human T cells transduced with said TCRs.
  • PBMCs Peripheral blood mononuclear cells from healthy donors can be used as a source of primary T cells for the preparation of effector cells, e.g. as described herein. Transduction efficiency can be verified by flow cytometry, e.g. using an anti-mouse TCR antibody to verify that at least 50% of T cells express the transduced TCR.
  • TCRs can be assessed by quantification of cytotoxicity using a flow cytometry assay, e.g. as described herein.
  • TCR-expressing T cells can be used as effector cells and can be mixed with cells expressing the target peptide (target cells).
  • TCRs can also be assessed by quantification of cytotoxicity, e.g. using xCelligence impedance readout as described herein.
  • Any antigen-binding molecule e.g. TCR, multispecific antigen-binding molecule or fragment thereof, according to the present disclosure may be encoded by any nucleotide sequence that encodes for the required amino acid sequence(s), taking into account codon degeneracy.
  • nucleic acids and pluralities of nucleic acids, encoding the TCRs, antigen-binding molecules, polypeptides and polypeptide complexes according to the present disclosure.
  • the nucleic acid(s) comprise or consist of DNA and/or RNA.
  • the nucleic acid is a polynucleotide, e.g. a polydeoxyribonucleotide or a polyribonucleotide.
  • the present disclosure also provides vectors, plasmids, and pluralities of vectors and/or plasmids containing nucleic acids, and pluralities of nucleic acids, encoding the TCRs, antigen-binding molecules, polypeptides and polypeptide complexes according to the present disclosure.
  • Nucleic acids, nucleotide sequences, plasmids and vectors according to the present disclosure may be provided in purified or isolated form, i.e. from other nucleic acids, plasmids, vectors or naturally-occurring biological material.
  • the TCR of the present disclosure comprises a polypeptide or polypeptides encoded by a nucleic acid/nucleotide sequence described herein. In some embodiments, the TCR of the present disclosure comprises an alpha chain of a TCR encoded by a nucleotide sequence in Table D herein, and a beta chain of a TCR encoded by a nucleotide sequence in Table D herein.
  • the TCR comprises a polypeptide or polypeptides encoded by: (i) a nucleotide sequence comprising a sequence as indicated in column A of Table D, and (ii) a nucleic acid sequence comprising a sequence as indicated in column B of Table D, wherein the sequences of columns A and B are selected from the same row of Table D.
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:45, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:45.
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:55, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:55.
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:47, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:47.
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:57, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:57.
  • an antigen-binding molecule e.g.
  • TCR or fragment thereof comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:49, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:49.
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:59, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:59.
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:51 , or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:51 .
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:61 , or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:61 .
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:53, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:53.
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:63, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:63.
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:131 , or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:131.
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:135, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:135.
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:133, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:133.
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:137, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:137.
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:46, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:46.
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:56, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:56.
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:48, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:48.
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:58, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:58.
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NQ:50, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NQ:50.
  • an antigen-binding molecule e.g.
  • TCR or fragment thereof comprises a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:60, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID 1X10:60.
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:52, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:52.
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:62, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:62.
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:54, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:54.
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:64, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:64.
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:132, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:132.
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:136, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:136.
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:134, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:134.
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:138, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:138.
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:45, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:45; in combination with a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:46, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:55, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:55; in combination with a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:56, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%,
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:45, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:45; in combination with a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:56, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:55, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:55; in combination with a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:46, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 9
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:47, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:47; in combination with a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:48, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:57, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:57; in combination with a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:58, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%,
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:47, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:47; in combination with a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:58, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:57, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:57; in combination with a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:48, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 9
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:49, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:49; in combination with a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NQ:50, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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%
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:59, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:59; in combination with a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NQ:60, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:49, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:49; in combination with a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NQ:60, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 9
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:59, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:59; in combination with a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NQ:50, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:51 , or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:51 ; in combination with a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:52, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:61 , or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:61 ; in combination with a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:62, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 9
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:51 , or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:51 ; in combination with a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:62, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:61 , or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:61 ; in combination with a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:52, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:63, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:63; in combination with a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:64, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%,
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:53, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:53; in combination with a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:64, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:63, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:63; in combination with a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:54, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 9
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:131 , or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:131 ; in combination with a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:132, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:135, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:135; in combination with a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:136, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:131 , or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:131 ; in combination with a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:136, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:135, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:135; in combination with a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:132, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:133, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:133; in combination with a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:134, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:137, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:137; in combination with a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:138, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%,
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:133, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:133; in combination with a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:138, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%
  • an antigen-binding molecule e.g. TCR or fragment thereof, comprises a TCRa chain variable domain encoded by a nucleotide sequence of SEQ ID NO:137, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:137; in combination with a TCRp chain variable domain encoded by a nucleotide sequence of SEQ ID NO:134, or a nucleotide sequence sharing at least 70%, preferably one of at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 9
  • nucleotide sequences described herein may be replaced by a codon degenerate nucleotide sequence thereof encoding the amino acid sequence encoded by the reference sequence.
  • nucleic acid refers to a polymer comprising multiple nucleotide monomers (e.g., ribonucleotide monomers or deoxyribonucleotide monomers).
  • Nucleic acid includes, for example, genomic DNA, cDNA, RNA, and DNA-RNA hybrid molecules. Nucleic acid molecules can be naturally occurring, recombinant, or synthetic. In addition, nucleic acid molecules can be single- stranded, doublestranded or triple- stranded. In some embodiments, nucleic acid molecules can be modified. In the case of a double-stranded polymer, ‘nucleic acid’ can refer to either or both strands of the molecule.
  • nucleotide sequence in reference to a nucleic acid, refers to a contiguous series of nucleotides that are joined by covalent linkages, such as phosphorus linkages (e.g., phosphodiester, alkyl and aryl- phosphonate, phosphorothioate, phosphotriester bonds), and/or non-phosphorus linkages (e.g., peptide and/or sulfamate bonds).
  • the nucleotide sequence encoding, e.g., a targetbinding molecule linked to a localizing domain is a heterologous sequence (e.g., a gene that is of a different species or cell type origin).
  • nucleotide and ‘nucleotide monomer’ refer to naturally occurring ribonucleotide or deoxyribonucleotide monomers, as well as non-naturally occurring derivatives and analogs thereof. Accordingly, nucleotides can include, for example, nucleotides comprising naturally occurring bases (e.g., adenosine, thymidine, guanosine, cytidine, uridine, inosine, deoxyadenosine, deoxythymidine, deoxyguanosine, or deoxycytidine) and nucleotides comprising modified bases known in the art.
  • naturally occurring bases e.g., adenosine, thymidine, guanosine, cytidine
  • uridine inosine
  • inosine deoxyadenosine
  • deoxythymidine deoxyguanosine
  • deoxycytidine or deoxycytidine
  • nucleotide sequence where a nucleotide sequence is disclosed herein, the reverse complement thereof is also expressly contemplated. Moreover, in each instance wherein a nucleotide sequence is disclosed herein, codon degenerate nucleotide sequences thereof encoding the same amino acid sequence are also expressly contemplated.
  • a ‘codon degenerate nucleotide sequence’ of a reference nucleotide sequence refers to a nucleotide sequence having a non-identical nucleotide sequence to the nucleotide sequence of the reference nucleotide sequence, but encoding the same amino acid sequence as the amino acid sequence encoded by the reference nucleotide sequence, as a consequence of degeneracy of the genetic code.
  • Encoding refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as a gene, a cDNA, or an mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (/.e., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom.
  • a gene encodes a protein if transcription and translation of mRNA corresponding to that gene produces the protein in a cell or other biological system.
  • Both the coding strand, the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings, and the noncoding strand, used as the template for transcription of a gene or cDNA, can be referred to as encoding the protein or other product of that gene or cDNA.
  • nucleotide sequence encoding an amino acid sequence includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence.
  • the phrase nucleotide sequence that encodes a protein or an RNA may also include introns to the extent that the nucleotide sequence encoding the protein may in some version contain an intron(s).
  • a nucleotide sequence according to the present disclosure encoding one or more antigen binding molecules or polypeptides of the TCR is codon optimized, e.g. for expression in a chosen cell, such as a mammalian cell.
  • the mammalian cell may be an immune cell, such as a T cell, e.g. a human T cell.
  • Codon optimization is a common method used to increase the expression of recombinant proteins, especially in the field of biotherapeutics. Its basis lies in the use of synonymous codon mutations in messenger RNA (mRNA) coding regions. Codon optimization is known to maximize protein expression by overcoming expression limitations associated with codon usage. This routine method has been reported to increase protein expression by up to >1000-fold. This method is often applied in order to fine-tune the expression of one of two light chain genes of a bispecific antibody (Mauro, BioDrugs 32;69-81 (2016)).
  • codon usage is possible since the 20 amino acids are encoded by 61 codons. Except for methionine and tryptophane, which are encoded by a single codon each, all other amino acids are specified by two to six redundant codons. Synonymous codon usage is not random, as it varies between different organisms, between different tissues of the same organism, and even between different parts of the same gene (Mauro, BioDrugs 32;69-81 (2016)).
  • nucleotide sequence encoding of SEQ ID NO:55 or a nucleotide sequence sharing at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:55, which encodes a TCRa chain variable domain and which is a codon-optimised sequence derived from SEQ ID NO:45. That is, SEQ ID NO:45 is codon-optimised to produce SEQ ID NO:55.
  • nucleotide sequence encoding of SEQ ID NO:56 or a nucleotide sequence sharing at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:56, which encodes a TCRp chain variable domain and which is a codon-optimised sequence derived from SEQ ID NO:46. That is, SEQ ID NO:46 is codon-optimised to produce SEQ ID NO:56.
  • nucleotide sequence encoding of SEQ ID NO:57 or a nucleotide sequence sharing at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:57, which encodes a TCRa chain variable domain and which is a codon-optimised sequence derived from SEQ ID NO:47. That is, SEQ ID NO:47 is codon-optimised to produce SEQ ID NO:57.
  • nucleotide sequence encoding of SEQ ID NO:58 or a nucleotide sequence sharing at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:58, which encodes a TCRp chain variable domain and which is a codon-optimised sequence derived from SEQ ID NO:48. That is, SEQ ID NO:48 is codon-optimised to produce SEQ ID NO:58.
  • nucleotide sequence encoding of SEQ ID NO:59 or a nucleotide sequence sharing at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:59, which encodes a TCRa chain variable domain and which is a codon-optimised sequence derived from SEQ ID NO:49. That is, SEQ ID NO:49 is codon-optimised to produce SEQ ID NO:59.
  • nucleotide sequence encoding of SEQ ID 1X10:60 or a nucleotide sequence sharing at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:60, which encodes a TCRp chain variable domain and which is a codon-optimised sequence derived from SEQ ID NO:50. That is, SEQ ID NO:50 is codon-optimised to produce SEQ ID NO:60.
  • nucleotide sequence encoding of SEQ ID NO:61 or a nucleotide sequence sharing at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:61 , which encodes a TCRa chain variable domain and which is a codon-optimised sequence derived from SEQ ID NO:51 . That is, SEQ ID NO:51 is codon-optimised to produce SEQ ID NO:61 .
  • nucleotide sequence encoding of SEQ ID NO:62 or a nucleotide sequence sharing at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:62, which encodes a TCRp chain variable domain and which is a codon-optimised sequence derived from SEQ ID NO:52. That is, SEQ ID NO:52 is codon-optimised to produce SEQ ID NO:62.
  • nucleotide sequence encoding of SEQ ID NO:63 or a nucleotide sequence sharing at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:63, which encodes a TCRa chain variable domain and which is a codon-optimised sequence derived from SEQ ID NO:53. That is, SEQ ID NO:53 is codon-optimised to produce SEQ ID NO:63.
  • nucleotide sequence encoding of SEQ ID NO:64 or a nucleotide sequence sharing at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:64, which encodes a TCRp chain variable domain and which is a codon-optimised sequence derived from SEQ ID NO:54. That is, SEQ ID NO:54 is codon-optimised to produce SEQ ID NO:64.
  • nucleotide sequence encoding of SEQ ID NO:136 or a nucleotide sequence sharing at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:136, which encodes a TCRp chain variable domain and which is a codon-optimised sequence derived from SEQ ID NO:132. That is, SEQ ID NO:132 is codon-optimised to produce SEQ ID NO:136.
  • nucleotide sequence encoding of SEQ ID NO:137 or a nucleotide sequence sharing at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:137, which encodes a TCRa chain variable domain and which is a codon-optimised sequence derived from SEQ ID NO:133. That is, SEQ ID NO:133 is codon-optimised to produce SEQ ID NO:137.
  • nucleotide sequence encoding of SEQ ID NO:138 or a nucleotide sequence sharing at least 80%, at least 85%, at least 90%, 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 with SEQ ID NO:138, which encodes a TCRp chain variable domain and which is a codon-optimised sequence derived from SEQ ID NO:134. That is, SEQ ID NO:134 is codon-optimised to produce SEQ ID NO:138.
  • any TCR described herein may be expressed as a hybrid TCR construct comprising a human TCRa variable region amino acid sequence and a human TCRp variable region amino acid sequence, along with a mouse TCR constant region comprising alpha constant region of SEQ ID NO:113 and beta constant region of SEQ ID NO:114.
  • any TCR described herein may be expressed as a TCR construct comprising a human TCRa variable region amino acid sequence and a human TCRp variable region amino acid sequence, along with a human TCR constant region comprising TCRa constant region of SEQ ID NO:65 and a TCRp constant region of SEQ ID NO:66 or 67.
  • any TCR described herein may be expressed as a TCR construct comprising a human TCRa variable region amino acid sequence and a human TCRp variable region amino acid sequence, along with a human TCR constant region comprising a mutated version of the human TCRa constant region of SEQ ID NO:68 and a mutated version of human TCRp constant region of SEQ ID NO:69.
  • the mutation comprises the introduction of a Cys in both the alpha and beta chains of the TCR to create a stabilizing disulfide bridge between the two chains.
  • TCR chains were modified by mutagenesis of residue 48 in the Ca region from Thr to Cys and residue 57 of the Cp region from Ser to Cys. The method has been described previously in Kuball et al, Blood. 2007 Mar 15; 109(6): 2331-2338., which is hereby incorporated by reference in its entirety.
  • the mutation promotes stable expression and pairing of the transduced TCR in human T cells in which the endogenous TCR is not knocked out.
  • a TCR, antigen-binding molecule or polypeptide according to the present disclosure may be produced within a cell by translation of RNA encoding the relevant polypeptide(s).
  • a TCR, antigen-binding molecule or polypeptide according to the present disclosure may be produced within a cell by transcription from nucleic acid(s) encoding the relevant polypeptide(s), and subsequent translation of the transcribed RNA.
  • Constituent polypeptides of a TCR or antigen-binding molecule according to the present disclosure may be encoded by different nucleic acids of the plurality of nucleic acids, or by different vectors of the plurality of vectors.
  • a nucleotide sequence encoding an antigen-binding molecule according to the present disclosure is comprised/contained within a vector or plasmid. That is, the present disclosure provides a vector or plasmid comprising a nucleotide sequence encoding an antigen-binding molecule according to the present disclosure, e.g. a TCR or fragment thereof.
  • a ‘vector’ may be a nucleic acid molecule used as a vehicle to transfer exogenous nucleic acid into a cell.
  • the present disclosure also provides a vector, or plurality of vectors, comprising the nucleic acid or plurality of nucleic acids according to the present disclosure.
  • the vector may facilitate delivery of the nucleic acid(s) encoding a polypeptide according to the present disclosure to a cell.
  • the vector may be an expression vector comprising elements required for expressing a polypeptide according to the present disclosure.
  • the vector may comprise elements facilitating integration of the nucleic acid(s) into the genomic DNA of cell into which the vector is introduced.
  • a vector may be a vector for expression of the nucleic acid in a cell (i.e. an expression vector).
  • Vectors may include a promoter sequence operably linked to a nucleotide sequence encoding a TCR/antigen- binding molecule/polypeptide according to the present disclosure.
  • a vector may also include a termination codon (i.e. 3’ in the nucleotide sequence of the vector to the nucleotide sequence encoding the polypeptide(s)) and expression enhancers. Any suitable vectors, promoters, enhancers and termination codons known in the art may be used to express a peptide or polypeptide from a vector according to the present disclosure.
  • operably linked may include the situation where nucleic acid encoding a polypeptide according to the present disclosure and regulatory nucleotide sequence(s) (e.g. a promoter and/or enhancers) are covalently linked in such a way as to place the expression of the nucleic acid encoding a polypeptide under the influence or control of the regulatory nucleotide sequence(s) (thereby forming an expression cassette).
  • regulatory nucleotide sequence e.g. a promoter and/or enhancers
  • a regulatory sequence is operably linked to the selected nucleotide sequence if the regulatory sequence is capable of effecting transcription of the nucleotide sequence.
  • the resulting transcript(s) may then be translated into the desired polypeptide(s).
  • ‘Expression vector’ refers to a vector comprising a recombinant polynucleotide comprising expression control sequences operatively linked to a nucleotide sequence to be expressed.
  • An expression vector comprises sufficient cis-acting elements for expression; other elements for expression can be supplied by the host cell or in an in vitro expression system.
  • Expression vectors include all those known in the art, such as cosmids, plasmids (e.g., naked or contained in liposomes) and viruses (e.g., Sendai viruses, lentiviruses, retroviruses, adenoviruses, and adeno-associated viruses) that incorporate the recombinant polynucleotide.
  • the expression vector backbone may be the sequence of SEQ ID NO:71 .
  • Vectors contemplated in connection with the present disclosure include DNA vectors, RNA vectors, plasmids (e.g. conjugative plasmids (e.g. F plasmids), non-conjugative plasmids, R plasmids, col plasmids, episomes), viral vectors (e.g. retroviral vectors, e.g. gammaretroviral vectors (e.g. murine Leukemia virus (MLV)-derived vectors, e.g.
  • plasmids e.g. conjugative plasmids (e.g. F plasmids), non-conjugative plasmids, R plasmids, col plasmids, episomes
  • viral vectors e.g. retroviral vectors, e.g. gammaretroviral vectors (e.g. murine Leukemia virus (MLV)-derived vectors, e.g.
  • a vector according to the present disclosure is a lentiviral vector.
  • a vector is selected based on tropism for a cell type/tissue/organ to which it is desired to deliver the nucleic acid. In some embodiments, a vector is selected based on tropism for a cell type in which it is desired to express the TCR/antigen-binding moleculeZpolypeptide(s). For example, it may be desired to deliver the nucleic acid/express the TCR/antigen-binding molecule/polypeptide(s) in an immune cell, e.g. a T cell. In some embodiments, the nucleic acid is a vector suitable for delivering the nucleic acid encoding the antigen-binding-molecule/TCR as a gene therapy.
  • the vector is an adeno-associated virus (AAV) vector.
  • Adeno-associated virus vectors and their use to vector gene therapy is reviewed e.g. in Wang et al., Nat. Rev. Drug Discov. (2019) 18: 358-378 and Li and Samulski, Nat. Rev. Genet. (2020) 12: 255-272, both of which are hereby incorporated by reference in their entirety.
  • a vector may be an adeno-associated virus vector described in Wang et al., Nat. Rev. Drug Discov. (2019) 18: 358-378.
  • a vector may be an adeno-associated virus vector described in Li and Samulski, Nat. Rev. Genet. (2020) 12: 255-272.
  • a vector may be an adeno-associated viral vector of one of the following serotypes: AAV1 , AAV2, AAV2i8, AAV5, AAV6, AAV8, AAV9, AAV9.45, AAV10 or AAVrh74.
  • a vector may be a lentiviral vector.
  • a ‘lentivirus’ as used herein refers to a genus of the Retroviridae family. Lentiviruses are unique among the retroviruses in being able to infect nondividing cells; they can deliver a significant amount of genetic information into the DNA of the host cell, so they are one of the most efficient methods of a gene delivery vector. HIV, SIV, and FIV are all examples of lentiviruses. Vectors derived from lentiviruses offer the means to achieve significant levels of gene transfer in vivo. For example, pALD lentiviral vectors can be obtained from Aldevron/Oxgene.
  • the vector may be a eukaryotic vector, i.e. a vector comprising the elements necessary for expression of protein from the vector in a eukaryotic cell.
  • the vector may be a mammalian vector, e.g. comprising a cytomegalovirus (CMV) or SV40 promoter to drive protein expression.
  • CMV cytomegalovirus
  • a vector comprises modification to increase binding to and/or transduction of a cell-type of interest (j.e. as compared to the level of binding/transduction by the unmodified vector).
  • modification is to a capsid protein.
  • a vector comprises a capsid protein comprising a cell-targeting peptide.
  • the cell-targeting peptide is a cell-targeting peptide described in Buning and Srivastava, Molecular Therapy: Methods & Clinical Development (2019) 12: 248-265, which is hereby incorporated by reference in its entirety.
  • a vector comprises a capsid protein comprising substitution to one or more tyrosine residues, e.g. one or more surface-exposed tyrosine residues. In some embodiments, one or more tyrosine residues of the capsid protein are substituted with phenylalanine. In some embodiments a vector comprises a capsid protein in which one or more tyrosine residues are substituted with another amino acid as described in lida et al., Biomed Res Int. (2013) 2013: 974819, which is hereby incorporated by reference in its entirety.
  • a vector may be an adeno-associated virus vector described in Buning and Srivastava, supra. In some embodiments, a vector may be an adeno-associated virus vector described in lida et al., supra.
  • SEQ ID NO:70 herein provides an exemplary expression vector for the delivery and/or expression of TCR A0385. In some embodiments, a vector is based on SEQ ID NO:70 or SEQ ID NO:71 herein. In some embodiments, any nucleic acid(s)/nucleotide sequence(s) encoding a TCR can be inserted into the backbone of SEQ ID NO:71.
  • the nucleic acid/vector comprises one or more sequences for controlling expression of the nucleic acid. Accordingly, in some embodiments the nucleic acid/vector comprises a control element for inducible expression of the nucleic acid.
  • a sequence for controlling expression of the nucleic acid may provide for expression of the nucleic acid by cells of a particular type or tissue.
  • expression may be under the control of a cell type- or tissue-specific promoter.
  • promoter as used herein is defined as a DNA sequence recognized by the synthetic machinery of the cell, or introduced synthetic machinery, required to initiate the specific transcription of a polynucleotide sequence.
  • Promoters for cell type- or tissue-specific expression of a nucleic acid in accordance with the present invention can be selected in accordance with the disease to be treated/prevented.
  • the promoter may drive expression in an immune cell.
  • the promoter may be a tissue-specific promoter, e.g. which, when operably linked with a polynucleotide encodes or specified by a gene, causes the gene product to be produced in a cell substantially only if the cell is a cell of the tissue type corresponding to the promoter.
  • Expression may be under the control of a constitutive promoter, e.g. a nucleotide sequence which, when operably linked with a polynucleotide which encodes or specifies a gene product, causes the gene product to be produced in a cell under most or all physiological conditions of the cell.
  • a constitutive promoter e.g. a nucleotide sequence which, when operably linked with a polynucleotide which encodes or specifies a gene product, causes the gene product to be produced in a cell under most or all physiological conditions of the cell.
  • a sequence for controlling expression of the nucleic acid may provide for expression of the nucleic acid in response to e.g. a given agent/signal.
  • expression may be under the control of inducible promoter.
  • the agent may provide for inducible expression of the nucleic acid in vivo by administration of the agent to a subject having been administered with a modified cell according to the disclosure, or ex vivo/in vitro by administration of the agent to cells in culture ex vivo or in vitro.
  • a nucleic acid or vector according to the present disclosure may employ a conditional expression system for controlling expression of the nucleic acid encoding the antigen-binding- molecule/TCR by cells comprising the nucleic acid/vector.
  • conditional expression may also be referred to herein as ‘inducible expression’, and refers to expression contingent on certain conditions, e.g. the presence of a particular agent.
  • Conditional expression systems are well known in the art and are reviewed e.g. in Ryding et al. Journal of Endocrinology (2001) 171 , 1-14, which is hereby incorporated by reference in its entirety.
  • the present disclosure provides a cell, or pluralities/populations of cells, comprising/expressing antigenbinding molecules, e.g. T cell receptors (TCRs).
  • TCRs T cell receptors
  • the cell/cells may express or comprise an antigenbinding molecule, e.g. TCR or fragment/chain thereof, according to the present disclosure.
  • the cell/cells may comprise or express nucleic acid encoding an antigen-binding molecule, e.g. TCR or fragment/chain thereof, according to the present disclosure.
  • Such cells may be called TCR-expressing cells.
  • a TCR-expressing cell comprises the TCR it expresses.
  • a cell expressing nucleic acid encoding a TCR also expresses and comprises the TCR encoded by the nucleic acid.
  • aspects and embodiments of the present disclosure relate to host cells, and in particular immune cells. It will be appreciated that where cells are referred to herein in the singular (/.e. ‘a/the cell’), pluralities/populations of such cells are also contemplated.
  • the cells are primary cells. That is, in some embodiments, the cells are/were isolated directly from living tissue/a living subject.
  • the cells may be from any animal or human.
  • the cells may be mammalian, more preferably human.
  • the cells may be from a human patient.
  • the host cell is an immune cell.
  • An ‘immune cell’ may be a cell of hematopoietic origin, e.g. a neutrophil, eosinophil, basophil, dendritic cell, lymphocyte, or monocyte.
  • a lymphocyte may be e.g. a T cell, B cell, NK cell, NKT cell or innate lymphoid cell (ILC), or a precursor thereof.
  • the host cell/immune cell may express e.g. CD3 polypeptides (e.g. CD3y CD3e CD3 or CD35), TCR polypeptides (TCRa or TCRp), CD27, CD28, CD4 or CD8.
  • the host cell/immune cell is a T cell, e.g. a CD3+ T cell.
  • the T cell is a CD3+, CD4+ T cell.
  • the T cell is a CD3+, CD8+ T cell.
  • the T cell is a T helper cell (TH cell).
  • the T cell is a cytotoxic T cell (e.g. a cytotoxic T lymphocyte (CTL)).
  • CTL cytotoxic T lymphocyte
  • An antigen-specific T cell may display certain functional properties of a T cell in response to the antigen/antigenic peptide for which the T cell is specific, or in response a cell comprising/expressing the antigen/antigenic peptide.
  • the properties are functional properties associated with effector T cells, e.g. cytotoxic T lymphocytes (CTLs).
  • CTLs cytotoxic T lymphocytes
  • an antigen-specific T cell may display one or more of the following properties: cytotoxicity to a cell comprising/expressing the antigen/peptide thereof for which the T cell is specific; proliferation, IFNy expression, CD107a expression, IL-2 expression, TNFa expression, perforin expression, granzyme expression, granulysin expression, and/or FAS ligand (FASL) expression in response to stimulation with the antigen/peptide thereof for which the T cell is specific, or in response to exposure to a cell comprising/expressing the antigen/peptide thereof for which the T cell is specific.
  • FSL FAS ligand
  • Antigen-specific T cells express/comprise an antigen-binding molecule/TCR/fragment thereof that is capable of recognising a peptide of the antigen for which the T cell is specific when presented by the appropriate MHC molecule.
  • the antigen-specific immune cell is a T cell, e.g. a CD3+ T cell.
  • the T cell is a CD3+, CD4+ T cell.
  • the T cell is a CD3+, CD8+ T cell.
  • the T cell is a T helper cell (TH cell)).
  • the T cell is a cytotoxic T cell (e.g. a cytotoxic T lymphocyte (CTL)).
  • CTL cytotoxic T lymphocyte
  • an antigen-specific immune cell e.g. an antigen-specific T cell
  • MAGE-A10-specific immune cells expresses/comprises a receptor (preferably a T cell receptor) capable of recognising a peptide of an antigen of MAGE-A10 (e.g. when presented by an MHC molecule).
  • the MAGE-A10-specific immune cell expresses/comprises a TCR specific for a peptide of a MAGE-A10 antigen presented by MHC class I.
  • the MAGE-A10-specific immune cell expresses/comprises a TCR specific for GLYDGMEHL (SEQ ID NO:1) presented by MHC class I. In some embodiments, the MAGE-A10-specific immune cell expresses/comprises a TCR specific for SLLKFLAKV (SEQ ID NO:2) presented by MHC class I. In some embodiments, the MAGE-A10-specific immune cell expresses/comprises a TCR specific for NYEDHFPLL (SEQ ID NO:3) presented by MHC class I. In some embodiments, the MAGE-A10-specific immune cell expresses/comprises a TCR specific for NYEDHFPLLF (SEQ ID NO:4) presented by MHC class I.
  • the MAGE-A10- specific immune cell expresses/comprises a TCR specific for X1X2LKFX3X4KX5 (SEQ ID NO:156) presented by MHC class I. In some embodiments, the MAGE-A10-specific immune cell expresses/comprises a TCR specific for X1X2X3X4FX5X6KX7 (SEQ ID NO:157) presented by MHC class I.
  • Host cells e.g. immune cells or T cells according to the present disclosure, may be described as ‘engineered cells’ or ‘genetically engineered cells’.
  • an ‘engineered cell’ refers to a cell, e.g. immune cell/T cell, that has been genetically modified as compared to a naturally-occurring cell.
  • the term ‘genetically engineered’ or ‘engineered’ refers to a method of modifying the genome of a cell, including, but not limited to, deleting a coding or non-coding region or a portion thereof or inserting a coding region or a portion thereof.
  • the cell that is modified is a lymphocyte, e.g., a T cell or a modified cell that expresses CD3, which can either be obtained from a patient or a donor.
  • the cell can be modified (e.g. as described herein) to express an exogenous construct, such as, e.g., an antigen-binding molecule/TCR disclosed herein, which can be incorporated into the cell's genome.
  • the cell is modified to express CD3.
  • the engineered cells have an anti-cancer and/or anti-tumor effect.
  • any host/immune/T cell provided herein may be provided in a ‘purified’, ‘substantially purified’ or ‘isolated’ form.
  • a ‘substantially purified’ cell is a cell that is essentially free of other cell types.
  • a substantially purified cell also refers to a cell which has been separated from other cell types with which it is normally associated in its naturally occurring state.
  • a population of substantially purified cells refers to a homogenous population of cells. In other instances, this term refers simply to cells that have been separated from the cells with which they are naturally associated in their natural state, or have been separated/isolated/purified from naturally-occurring biological material.
  • the cells are cultured in vitro. In other embodiments, the cells are not cultured in vitro.
  • Cells described herein may comprise a combination of TCRs, e.g. one or more TCRs according to the present disclosure, and optionally one or more further TCRs.
  • the TCRs may be introduced into the cells via the same or different vectors.
  • a plurality/population of cells described herein may comprise two or more TCRs, including TCR(s) from the present disclosure.
  • cells within the plurality/population of cells may each comprise two or more TCRs.
  • different cells within the plurality/population of cells may each comprise at least one TCR, where the TCRs are identical or non-identical. Different TCRs may be individually transduced into different host cells.
  • An immune cell comprising an antigen-binding molecule/TCR or a nucleic acid encoding an antigenbinding molecule/TCR according to the present disclosure may be characterised by reference to functional properties of the cells.
  • an immune cell comprising an antigen-binding molecule/TCR or a nucleic acid encoding an antigen-binding molecule/TCR according to the present disclosure displays one or more of the following properties:
  • cytotoxic/effector factors e.g. IFNy, granzyme, perforin, granulysin, CD107a, TNFa, FASL
  • cytotoxic/effector factors e.g. IFNy, granzyme, perforin, granulysin, CD107a, TNFa, FASL
  • proliferation/population expansion, and/or growth factor e.g. IL-2, GM-CSF
  • growth factor e.g. IL-2, GM-CSF
  • anti-cancer activity e.g. cytotoxicity to cancer cells, tumor growth inhibition, reduction of metastasis, etc.
  • cancer comprising cells presenting the MHC:peptide complex for which the TCR is specific.
  • Cell proliferation/population expansion can be investigated by analysing cell division or the number of cells over a period of time.
  • Cell division can be analysed, for example, by in vitro analysis of incorporation of 3 H-thymidine or by CFSE dilution assay, e.g. as described in Fulcher and Wong, Immunol Cell Biol (1999) 77(6): 559-564, hereby incorporated by reference in its entirety.
  • Proliferating cells can also be identified by analysis of incorporation of 5-ethynyl-2'-deoxyuridine (Edll) by an appropriate assay, as described e.g. in Buck et al., Biotechniques. 2008 Jun; 44(7):927-9, and Sali and Mitchison, PNAS USA 2008 Feb 19; 105(7): 2415-2420, both hereby incorporated by reference in their entirety.
  • Edll 5-ethynyl-2'-deoxyuridine
  • ‘expression’ may be gene expression or protein expression.
  • Gene expression encompasses transcription of DNA to RNA, and can be measured by various means known to those skilled in the art, for example by measuring levels of mRNA by quantitative real-time PCR (qRT-PCR), or by reporter-based methods.
  • protein expression can be measured by various methods well known in the art, e.g. by antibody-based methods, for example by western blot, immunohistochemistry, immunocytochemistry, flow cytometry, ELISA, ELISPOT, or reporter-based methods.
  • Cytotoxicity and cell killing can be investigated, for example, using any of the methods reviewed in Zaritskaya et al., Expert Rev Vaccines (2011), 9(6):601-616, hereby incorporated by reference in its entirety.
  • in vitro assays of cytotoxicity/cell killing assays include release assays such as the 51 Cr release assay, the lactate dehydrogenase (LDH) release assay, the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyl tetrazolium bromide (MTT) release assay, and the calcein-acetoxy methyl (calcein-AM) release assay. These assays measure cell killing based on the detection of factors released from lysed cells.
  • LDH lactate dehydrogenase
  • MTT 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyl tetrazolium bromide
  • calcein-AM calcein-acetoxy methyl
  • Cell killing by a given cell type can be analysed e.g. by co-culturing the test cells with the given cell type, and measuring the number/proportion of cells viable/dead test cells after a suitable period of time.
  • suitable assays include the xCELLigence real-time cytolytic in vitro potency assay described in Cerignoli etal., PLoS One. (2016) 13(3): e0193498 (hereby incorporated by reference in its entirety).
  • Cells may be evaluated for anti-cancer activity by analysis in an appropriate in vitro assays or in vivo models of the relevant cancer.
  • Methods for producing cells comprising/expressing an antigen-binding molecule/TCR of interest are well known to the skilled person, and generally comprise introducing nucleic acid(s)/vector(s) encoding constituent polypeptide(s) of the antigen-binding molecule/TCR into the cells.
  • Such methods may comprise nucleic acid transfer for permanent (/.e. stable) or transient expression of the transferred nucleic acid.
  • the transfer may involve methods of transfection, transformation or transduction.
  • the term ‘transfected’ or ‘transformed’ or ‘transduced’ as used herein refers to a process by which exogenous nucleic acid is transferred or introduced into the host cell.
  • a ‘transfected’ or ‘transformed’ or ‘transduced’ cell is one which has been transfected, transformed or transduced with exogenous nucleic acid.
  • the cell includes the primary subject cell and its progeny.
  • nucleic acid(s) encoding the polypeptide(s) of the TCR may be integrated into or form part of the genomic DNA of the cell.
  • nucleic acid(s) encoding the polypeptide(s) may be maintained extrachromosomally.
  • Any suitable genetic engineering platform may be used, and include gammaretroviral vectors, lentiviral vectors, adenovirus vectors, DNA transfection, transposon-based gene delivery and RNA transfection, for example as described in Maus et al., Annu Rev Immunol (2014) 32:189-225, hereby incorporated by reference in its entirety. Methods also include those described e.g. in Wang and Riviere Mol Ther Oncolytics. (2016) 3:16015, which is hereby incorporated by reference in its entirety. Suitable methods for introducing nucleic acid(s)/vector(s) into cells include transduction, transfection and electroporation.
  • Suitable culture conditions i.e. cell culture media, additives, stimulations, temperature, gaseous atmosphere
  • cell numbers i.e. cell numbers, culture periods and methods for introducing nucleic acid(s)/vector(s) encoding polypeptide(s) of interest into cells, etc.
  • GMP good manufacturing practice
  • cultures of cells according to the present disclosure may be maintained at 37°C in a humidified atmosphere containing 5% CO2.
  • the cells of cell cultures can be established and/or maintained at any suitable density, as can readily be determined by the skilled person.
  • Cultures can be performed in any vessel suitable for the volume of the culture, e.g. in wells of a cell culture plate, cell culture flasks, a bioreactor, etc.
  • cells are cultured in a bioreactor, e.g. a bioreactor described in Somerville and Dudley, Oncoimmunology (2012) 1 (8): 1435-1437, which is hereby incorporated by reference in its entirety.
  • Introducing nucleic acid(s) into a cell may comprise transduction, e.g. lentiviral transduction.
  • Transduction of immune cells with viral vectors is described e.g. in Simmons and Alberola-lla, Methods Mol Biol. (2016) 1323:99-108, which is hereby incorporated by reference in its entirety.
  • Hexadimethrine bromide is a cationic polymer which is commonly used to improve transduction, through neutralising charge repulsion between virions and sialic acid residues expressed on the cell surface.
  • Other agents commonly used to enhance transduction include e.g. the poloxamer-based agents such as LentiBOOST (Sirion Biotech), Retronectin (Takara), Vectofusin (Miltenyi Biotech) and also SureENTRY (Qiagen) and ViraDuctin (Cell Biolabs).
  • the methods comprise centrifuging the cells into which it is desired to introduce nucleic acid encoding polypeptide(s) of the TCR in the presence of cell culture medium comprising viral vector comprising the nucleic acid (referred to in the art as ‘spinfection’).
  • the methods generally comprise introducing a nucleic acid encoding polypeptide(s) of the TCR into a cell, and culturing the cell under conditions suitable for expression of the polypeptide(s) by the cell.
  • the methods comprise culturing immune cells into which nucleic acid encoding the polypeptide(s) has been introduced, in order to expand their number.
  • the methods comprise analysing the cells to confirm successful introduction of the nucleic acid into the cells. In some embodiments, the methods comprise analysing the cells to confirm expression of the polypeptide(s) by the cells (e.g. via evaluation of a detectable entity).
  • the methods further comprise separating/isolating/purifying/enriching cells expressing the TCR e.g. from other cells (e.g. cells which do not express the TCR).
  • Methods for purifying/isolating immune cells from heterogeneous populations of cells are well known in the art, and may employ e.g. FACS- or MACS-based methods for sorting populations of cells based on the expression of the TCR/constituent polypeptide(s) thereof.
  • the methods comprise separating/isolating/purifying/enriching cells of a particular type, e.g. CD8+ T cells or CTLs expressing the TCR of interest.
  • Methods for producing cells according to the present disclosure may comprise modifying the cells to reduce the expression of a CD3-TCR complex polypeptide.
  • the methods comprise modifying nucleic acid (e.g. endogenous nucleic acid) encoding the CD3-TCR complex polypeptide.
  • Modification of a given target nucleic acid can be achieved in a variety of ways known to the skilled person, including modification of the target nucleic acid by homologous recombination, and target nucleic acid editing using site-specific nucleases (SSNs).
  • SSNs site-specific nucleases
  • Suitable methods may employ targeting by homologous recombination, which is reviewed, for example, in
  • Enzymes capable of creating site-specific double strand breaks can be engineered to introduce DSBs to target nucleotide sequence(s) of interest.
  • DSBs may be repaired by either error-prone non-homologous end-joining (NHEJ), in which the two ends of the break are rejoined, often with insertion or deletion of nucleotides.
  • NHEJ error-prone non-homologous end-joining
  • DSBs may be repaired by homology-directed repair (HDR), a high-fidelity mechanism in which a DNA template with ends homologous to the break site is supplied and introduced at the site of the DSB.
  • HDR homology-directed repair
  • SSNs capable of being engineered to generate target nucleotide sequence-specific DSBs include zinc- finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced palindromic repeats/CRISPR-associated-9 (CRISPR/Cas9) systems.
  • ZFN systems are reviewed e.g. in Umov et al., Nat Rev Genet. (2010) 11 (9):636-46, which is hereby incorporated by reference in its entirety.
  • ZFNs comprise a programmable Zinc Finger DNA-binding domain and a DNA- cleaving domain (e.g. a Fokl endonuclease domain).
  • the DNA-binding domain may be identified by screening a Zinc Finger array capable of binding to the target nucleotide sequence.
  • TALEN systems are reviewed e.g. in Mahfouz et al., Plant Biotechnol J. (2014) 12(8): 1006-14, which is hereby incorporated by reference in its entirety.
  • TALENs comprise a programmable DNA-binding TALE domain and a DNA- cleaving domain (e.g. a Fokl endonuclease domain).
  • TALEs comprise repeat domains consisting of repeats of 33-39 amino acids, which are identical except for two residues at positions 12 and 13 of each repeat which are repeat variable di-residues (RVDs).
  • sgRNA single-guide RNA
  • the sgRNA can be engineered to target endonuclease activity to nucleotide sequences of interest.
  • modifying nucleic acid e.g. endogenous nucleic acid
  • modifying nucleic acid encoding the CD3-TCR complex polypeptide in accordance with the present disclosure employs a site-specific nuclease (SSN) system targeting nucleic acid encoding the CD3-TCR complex polypeptide.
  • SSN site-specific nuclease
  • the SSN system may be a ZFN system, a TALEN system, CRISPR/Cas9 system, a CRISPR/Cpf1 system, a CRISPR/C2c1 system, a CRISPR/C2c2 system or a CRISPR/C2c3 system.
  • a method for producing a cell according to the present disclosure comprises introducing nucleic acid(s) encoding CRISPR/Cas9 system(s) targeting TRAC, TRBC1 and/or TRBC2 (e.g. TRAC and TRBC1) into a cell.
  • the nucleic acid(s) encode a CRISPR RNA (crRNA) targeting TRAC, TRBC1 and/or TRBC2 (e.g. TRAC and TRBC1 ; e.g. an exon of TRAC, TRBC1 and/or TRBC2 (e.g. TRAC and TRBC1)) and a trans-activating crRNA (tracrRNA) for processing the crRNA to its mature form.
  • crRNA CRISPR RNA
  • tracrRNA trans-activating crRNA
  • compositions comprising the TCRs, antigen-binding molecules, polypeptides, nucleic acids, vectors and cells described herein.
  • polypeptides, polypeptide complexes, nucleic acids, expression vectors and cells described herein may be formulated as pharmaceutical compositions or medicaments for clinical use, and may comprise a pharmaceutically-acceptable carrier, diluent, excipient or adjuvant.
  • the present disclosure provides a pharmaceutical composition or medicament comprising a cell according to the present disclosure.
  • the present disclosure also provides a pharmaceutical composition/medicament comprising a polypeptide, polypeptide complex, nucleic acid/plurality, expression vector/plurality or cell/plurality described herein.
  • a pharmaceutical composition/medicament according to the present disclosure comprises a nucleic acid/plurality, expression vector/plurality or cell described herein.
  • compositions/medicaments of the present disclosure may comprise one or more pharmaceutically-acceptable carriers (e.g. liposomes, micelles, microspheres, nanoparticles), diluents/excipients (e.g. starch, cellulose, a cellulose derivative, a polyol, dextrose, maltodextrin, magnesium stearate), adjuvants, fillers, buffers, preservatives (e.g. vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methyl paraben, propyl paraben), anti-oxidants (e.g.
  • pharmaceutically-acceptable carriers e.g. liposomes, micelles, microspheres, nanoparticles
  • diluents/excipients e.g. starch, cellulose, a cellulose derivative, a polyol, dextrose, maltodextrin, magnesium
  • Each carrier, diluent, excipient, adjuvant, filler, buffer, preservative, anti-oxidant, lubricant, binder, stabiliser, solubiliser, surfactant, masking agent, colouring agent, flavouring agent or sweetening agent of a composition according to the present disclosure must also be ‘acceptable’ in the sense of being compatible with the other ingredients of the formulation.
  • compositions and medicaments of the present disclosure may be formulated for topical, parenteral, systemic, intracavitary, intravenous, intra-arterial, intramuscular, intrathecal, intraocular, intraconjunctival, intratumoral, subcutaneous, intradermal, intrathecal, oral or transdermal routes of administration.
  • a pharmaceutical composition/medicament may be formulated for administration by injection or infusion, or administration by ingestion.
  • Suitable formulations may comprise the cell provided in a sterile or isotonic medium.
  • Medicaments and pharmaceutical compositions may be formulated in fluid, including gel, form.
  • Fluid formulations may be formulated for administration by injection or infusion (e.g. via catheter) to a selected region of the human or animal body.
  • a further aspect of the present disclosure relates to a method of formulating or producing a medicament or pharmaceutical composition for use in the treatment of a disease/condition (e.g. a disease/condition described herein), the method comprising formulating a pharmaceutical composition or medicament by mixing a cell described herein with a pharmaceutically-acceptable carrier, adjuvant, excipient or diluent.
  • a disease/condition e.g. a disease/condition described herein
  • the method comprising formulating a pharmaceutical composition or medicament by mixing a cell described herein with a pharmaceutically-acceptable carrier, adjuvant, excipient or diluent.
  • compositions according to the present disclosure may optionally be provided in isolated or purified form.
  • articles according to the present disclosure may be isolated/purified from naturally-occurring biological material.
  • TCRs antigen-binding molecules, polypeptides, nucleic acids, vectors, cells and compositions described herein find use in therapeutic and prophylactic methods.
  • the present disclosure provides a TCR, antigen-binding molecule, polypeptide, nucleic acid (or plurality thereof), vector (or plurality thereof), cell (or plurality thereof), or composition described herein for use in a method of medical treatment or prophylaxis. Also provided is a TCR, antigen-binding molecule, polypeptide, nucleic acid (or plurality thereof), vector (or plurality thereof), cell (or plurality thereof), or composition described herein for use as a medicament. Also provided is a TCR, antigen-binding molecule, polypeptide, nucleic acid (or plurality thereof), vector (or plurality thereof), cell (or plurality thereof), or composition described herein for use in a method of treating or preventing a disease or condition described herein.
  • TCR TCR
  • antigen-binding molecule polypeptide, nucleic acid (or plurality thereof), vector (or plurality thereof), cell (or plurality thereof), or composition described herein in the manufacture of a medicament for treating or preventing a disease or condition described herein.
  • a method of treating or preventing a disease or condition described herein comprising administering to a subject a therapeutically or prophylactically effective amount of a TCR, antigen-binding molecule, polypeptide, nucleic acid (or plurality thereof), vector (or plurality thereof), cell (or plurality thereof), or composition described herein.
  • the methods (of treatment) may be effective to reduce the development or progression of a disease/condition, alleviation of the symptoms of a disease/condition or reduction in the pathology of a disease/condition.
  • the methods may be effective to prevent progression of the disease/condition, e.g. to prevent worsening of, or to slow the rate of development of, the disease/condition.
  • the methods may lead to an improvement in the disease/condition, e.g. a reduction in the symptoms of the disease/condition or reduction in some other correlate of the severity/activity of the disease/condition.
  • the methods may prevent development of the disease/condition to a later stage (e.g. a chronic stage or metastasis).
  • treatment or prevention of a disease/condition may comprise one or more of the following: reducing the number and/or activity of cells presenting the MHC:peptide complex for which the TCR is specific; cell killing of/cytotoxicity to cells presenting the MHC:peptide complex for which the TCR is specific; and anti-cancer activity (e.g. cytotoxicity to cancer cells, tumor growth inhibition, reduction of metastasis, etc.) against cancer comprising cells presenting the MHC:peptide complex for which the TCR is specific.
  • anti-cancer activity e.g. cytotoxicity to cancer cells, tumor growth inhibition, reduction of metastasis, etc.
  • articles of the present disclosure find use in the treatment/prevention of diseases/conditions that would derive therapeutic or prophylactic benefit from a reduction in the number or activity of cells expressing MAGE-A10-derived antigenic peptides, e.g. cells of a MAGE-A10- associated cancer.
  • the disease/condition may be associated with expression of MAGE-A10.
  • the disease/condition may be described as a MAGE-A10-associated disease or condition.
  • the disease/condition may be a disease/condition in which a cell comprising a MAGE-A10 antigen or a cell comprising a peptide of a MAGE-A10 antigen (e.g. a peptide of a MAGE-A10 antigen described herein, e.g. SEQ ID NO:1 , 2, 3 or 4) is pathologically implicated.
  • diseases/conditions include those in which a cell comprising a MAGE-A10 antigen or a cell comprising a peptide of a MAGE- A10 antigen (e.g. a peptide of a MAGE-A10 antigen described herein, e.g.
  • SEQ ID NO:1 , 2, 3 or 4 is positively-associated with the onset, development or progression of the disease/condition, and/or severity of one or more symptoms of the disease/condition, or in which such a cell is a risk factor for the onset, development or progression of the disease/condition.
  • the disease/condition to be treated/prevented in accordance with the present disclosure is a disease/condition characterized by the presence of a cell comprising a MAGE-A10 antigen or a cell comprising a peptide of a MAGE-A10 antigen (e.g. SEQ ID NO:1 , 2, 3 or 4).
  • the disease/condition is characterized by an increased number/proportion/activity of such cells as compared to the number/proportion/activity of such cells observed in the absence of the disease/condition (e.g. in a healthy subject, or in equivalent non-diseased tissue).
  • the disease to be treated/prevented in accordance with the present disclosure is a cancer.
  • Cancer may refer to any unwanted cell proliferation (or any disease manifesting itself by unwanted cell proliferation), neoplasm or tumor.
  • the cancer may be benign or malignant and may be primary or secondary (metastatic).
  • a ‘cancer’ or ‘cancer tissue’ can include a neoplasm or tumor.
  • a neoplasm or tumor may be any abnormal growth or proliferation of cells and may be located in any tissue.
  • the cancer is a cancer in which MAGE-A10 is pathologically implicated.
  • the cancer may be a MAGE-A10-associated cancer.
  • the cancer may be of tissues/cells derived from e.g. the adrenal gland, adrenal medulla, anus, appendix, bladder, blood, bone, bone marrow, brain, breast, cecum, central nervous system (including or excluding the brain) cerebellum, cervix, colon, duodenum, endometrium, epithelial cells (e.g.
  • kidney oesophagus
  • glial cells heart, ileum, jejunum, kidney, lacrimal glad, larynx, liver, lung, lymph, lymph node, lymphoblast, maxilla, mediastinum, mesentery, myometrium, nasopharynx, omentum, oral cavity, ovary, pancreas, parotid gland, peripheral nervous system, peritoneum, pleura, prostate, salivary gland, sigmoid colon, skin, small intestine, soft tissues, spleen, stomach, testis, thymus, thyroid gland, tongue, tonsil, trachea, uterus, vulva, and/or white blood cells.
  • Tumors may be nervous or non-nervous system tumors.
  • Nervous system tumors may originate either in the central or peripheral nervous system, e.g. glioma, medulloblastoma, meningioma, neurofibroma, ependymoma, Schwannoma, neurofibrosarcoma, astrocytoma and oligodendroglioma.
  • Non-nervous system cancers/tumors may originate in any other non-nervous tissue, examples include melanoma, mesothelioma, lymphoma, myeloma, leukemia, Non-Hodgkin’s lymphoma (NHL), Hodgkin’s lymphoma, chronic myelogenous leukemia (CML), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), cutaneous T cell lymphoma (CTCL), chronic lymphocytic leukemia (CLL), hepatoma, epidermoid carcinoma, prostate carcinoma, breast cancer, lung cancer, colon cancer, ovarian cancer, pancreatic cancer, thymic carcinoma, non-small cell lung carcinoma (NSCLC), hematologic cancer and sarcoma.
  • NSCLC non-small cell lung carcinoma
  • the cancer is selected from the group consisting of: a solid cancer, a hematological cancer, gastric cancer (e.g. gastric carcinoma, gastric adenocarcinoma, gastrointestinal cancer, gastrointestinal adenocarcinoma), liver cancer (hepatocellular carcinoma, cholangiocarcinoma), head and neck cancer (e.g. head and neck squamous cell carcinoma (HNSCC)), oral cavity cancer (e.g. oropharyngeal cancer (e.g. oropharyngeal carcinoma), oral cancer, oral squamous cell carcinoma (OSCC), laryngeal cancer, nasopharyngeal carcinoma, oesophageal cancer), colorectal cancer (e.g.
  • gastric cancer e.g. gastric carcinoma, gastric adenocarcinoma, gastrointestinal cancer, gastrointestinal adenocarcinoma
  • liver cancer hepatocellular carcinoma, cholangiocarcinoma
  • head and neck cancer e.g.
  • lung cancer e.g. NSCLC, small cell lung cancer, lung adenocarcinoma, squamous lung cell carcinoma), bladder cancer, urothelial carcinoma (UC), urogenital cancer, skin cancer (e.g. melanoma, advanced melanoma), renal cell cancer (e.g. renal cell carcinoma), ovarian cancer (e.g. ovarian carcinoma), mesothelioma, breast cancer (e.g. TNBC), brain cancer (e.g.
  • glioblastoma glioblastoma
  • prostate cancer pancreatic cancer
  • a myeloid hematologic malignancy a lymphoblastic hematologic malignancy
  • myelodysplastic syndrome MDS
  • acute myeloid leukemia AML
  • chronic myeloid leukemia CML
  • acute lymphoblastic leukemia ALL
  • lymphoma non-Hodgkin’s lymphoma (NHL), thymoma or multiple myeloma (MM).
  • NHL non-Hodgkin’s lymphoma
  • MM multiple myeloma
  • MAGE-A10 a cell comprising a MAGE-A10 antigen or a cell comprising a peptide of a MAGE-A10 antigen may be pathologically implicated in any of the cancers described herein.
  • Any of the cancers herein may comprise a cell comprising/expressing a MAGE-A10 antigen or a cell comprising/expressing a peptide of a MAGE-A10 antigen (e.g. a peptide of a MAGE-A10 antigen described herein, e.g. SEQ ID NO:1 , 2, 3 or 4).
  • Any of the cancers herein may express MAGE-A10.
  • Any of the cancers herein may comprise a cell that expresses MAGE-A10.
  • any of the cancers described herein may comprise a cell comprising/expressing a MAGE-A10 antigen or a cell comprising/expressing a peptide of a MAGE-A10 antigen (e.g. a peptide of a MAGE-A10 antigen described herein, e.g. SEQ ID NO:1 or 2), and a major histocompatibility complex (MHC) molecule comprising a polypeptide (e.g. an MHC class I a chain polypeptide) encoded by a HLA-A*02:01 allele.
  • MHC major histocompatibility complex
  • any of the cancers described herein may comprise a cell comprising/expressing a MAGE-A10 antigen or a cell comprising/expressing a peptide of a MAGE-A10 antigen (e.g. a peptide of a MAGE-A10 antigen described herein, e.g. SEQ ID NO:3 or 4), and a major histocompatibility complex (MHC) molecule comprising a polypeptide (e.g. an MHC class I a chain polypeptide) encoded by a HLA-A*24:02 allele.
  • MHC major histocompatibility complex
  • the peptide may be presented on the MHC molecule on the surface of the cell.
  • the cancer may be relapsed/refractory.
  • the cancer may be resistant to chemotherapy and/or radiotherapy.
  • Methods of the present invention can be used to reduce the tumor size of a tumor.
  • the cancer can be responsive to chemotherapy or radiation therapy or the cancer can be refractory.
  • a ‘refractory cancer’ refers to a cancer that is not amenable to surgical intervention, and the cancer is either initially unresponsive to chemotherapy or radiation therapy or the cancer becomes unresponsive over time.
  • Administration of the antigen-binding molecules, TCRs, polypeptides, nucleic acids, vectors, cells and compositions of the present disclosure is preferably in a ‘therapeutically-effective’ or ‘prophylactically- effective’ amount, this being sufficient to show therapeutic or prophylactic benefit to the subject.
  • the actual amount administered, and rate and time-course of administration will depend on the nature and severity of the disease/condition and the particular article administered. Prescription of treatment, e.g. decisions on dosage etc., is within the responsibility of general practitioners and other medical doctors, and typically takes account of the disease/disorder to be treated, the condition of the individual subject, the site of delivery, the method of administration and other factors known to practitioners.
  • a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays. Examples of the techniques and protocols mentioned above can be found in Remington’s ‘The Science and Practice of Pharmacy’ (Ed. A. Adejare), 23rd Edition (2020), Academic Press. ‘Administration’ refers to the physical introduction of an agent/article to a subject, using any of the various methods and delivery systems known to those skilled in the art.
  • Administration of the articles of the present disclosure may be e.g. parenteral, systemic, topical, intracavitary, intravascular, intravenous, intra-arterial, intramuscular, intrathecal, intraocular, intraconjunctival, intratumoral, subcutaneous, intradermal, oral or transdermal. Administration may be by injection, infusion or ingestion.
  • articles of the present disclosure may be administered to a tissue/organ of interest (e.g. a tissue/organ affected by the disease/condition (e.g. a tissue/organ in which symptoms of the disease/condition manifest)).
  • a tissue/organ of interest e.g. a tissue/organ affected by the disease/condition (e.g. a tissue/organ in which symptoms of the disease/condition manifest)
  • articles of the present disclosure may be administered to the blood (/.e. intravenous/intra-arterial administration) by injection or infusion (e.g. via cannula), or may be administered subcutaneously or orally.
  • Exemplary routes of administration for the articles disclosed herein include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, for example by injection or infusion.
  • parenteral administration means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, as well as in vivo electroporation.
  • composition of the invention includes, e.g., subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), or intrasternal injection, or infusion techniques.
  • the formulation is administered via a non-parenteral route, e.g., orally.
  • Other non- parenteral routes include a topical, epidermal or mucosal route of administration, for example, intranasally, vaginally, rectally, sublingually or topically.
  • Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
  • therapeutic or prophylactic intervention according to the present disclosure may further comprise administering another agent for the treatment/prevention of the relevant disease/condition.
  • TCRs antigen-binding molecules, polypeptides, nucleic acids, vectors, cells and compositions described herein may be alone or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated.
  • the TCRs, antigen-binding molecules, polypeptides, nucleic acids, vectors, cells and compositions described herein may be administered in combination with another TCR, antigenbinding molecule, polypeptide, nucleic acid, vector, cell or composition.
  • a subject is administered with a plurality of (e.g. 2, 3, 4, or more) non-identical TCRs, antigen-binding molecules, polypeptides, nucleic acids, vectors, cells and compositions, where for example at least one of the plurality is an article described herein.
  • a subject is administered with nucleic acidZvector(s) encoding a plurality of non-identical TCRs/antigen-binding molecules/polypeptides. In some embodiments, a subject is administered with cells comprising/expressing a plurality of non-identical TCRs/antigen-binding molecules/polypeptides, or cells comprising nucleic acid/vector(s) encoding a plurality of non-identical TCRs/antigen-binding molecules/polypeptides.
  • a treatment or therapy described herein comprises administering at least one TCR, multispecific antigen-binding molecule, nucleic acid, vector, cell and/or composition according to the present disclosure in combination with at least one non-identical TCR, multispecific antigen-binding molecule, nucleic acid, vector, cell and/or composition.
  • the at least one non-identical TCR, multispecific antigen-binding molecule, nucleic acid, vector, cell and/or composition may be one described herein.
  • a plurality of e.g.
  • non-identical TCRs 2, 3, 4, or more non-identical TCRs, antigen-binding molecules, polypeptides, nucleic acids, vectors, cells and compositions comprises 1 , 2, 3, 4, 5, 6, or 7 non-identical TCRs, antigen-binding molecules, polypeptides, nucleic acids, vectors, cells or compositions described herein, optionally in combination with other TCRs, antigen-binding molecules, polypeptides, nucleic acids, vectors, cells or compositions that are not described herein.
  • Simultaneous administration refers to administration with another therapeutic agent together, for example as a pharmaceutical composition containing both agents (combined preparation), or immediately after each other and optionally via the same route of administration (e.g. to the same tissue, artery, vein or other blood vessel).
  • Sequential administration refers to administration of one agent followed after a given time interval by separate administration of another agent. It is not required that the two agents are administered by the same route, although this is the case in some embodiments.
  • the time interval may be any time interval.
  • compositions of the present disclosure may be provided.
  • One or more, or each, of the doses may be accompanied by simultaneous or sequential administration of another therapeutic agent.
  • Multiple doses may be separated by a predetermined time interval, which may be selected to be one of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 days, or 1 , 2, 3, 4, 5, or 6 months.
  • doses may be given once every 7, 14, 21 or 28 days (plus or minus 3, 2, or 1 days).
  • TCR TCR
  • antigen-binding molecule nucleic acid
  • vector cell or composition described herein and another prophylactic/therapeutic agent may be administered simultaneously or sequentially.
  • the methods comprise additional therapeutic or prophylactic intervention, e.g. for the treatment/prevention of a cancer.
  • the therapeutic or prophylactic intervention is selected from chemotherapy, immunotherapy, radiotherapy, surgery, vaccination and/or hormone therapy.
  • the therapeutic or prophylactic intervention comprises leukapheresis.
  • the therapeutic or prophylactic intervention comprises a stem cell transplant.
  • Simultaneous administration refers to administration of the TCR, antigen-binding molecule, nucleic acid, vector cell or composition and therapeutic agent together, for example as a pharmaceutical composition containing both agents (combined preparation), or immediately after each other and optionally via the same route of administration, e.g. to the same artery, vein or other blood vessel.
  • Sequential administration refers to administration of one of the TCR, antigen-binding molecule, nucleic acid, vector cell or composition or therapeutic agent followed after a given time interval by separate administration of the other agent. It is not required that the two agents are administered by the same route, although this is the case in some embodiments.
  • the time interval may be any time interval.
  • treatment of cancer further comprises chemotherapy and/or radiotherapy.
  • Chemotherapy and radiotherapy respectively refer to treatment of a cancer with a drug or with ionising radiation (e.g. radiotherapy using X-rays or y-rays).
  • the drug may be a chemical entity, e.g. small molecule pharmaceutical, antibiotic, DNA intercalator, protein inhibitor (e.g. kinase inhibitor), or a biological agent, e.g. antibody, antibody fragment, aptamer, nucleic acid (e.g. DNA, RNA), peptide, polypeptide, or protein.
  • the drug may be formulated as a pharmaceutical composition or medicament.
  • the formulation may comprise one or more drugs (e.g. one or more active agents) together with one or more pharmaceutically acceptable diluents, excipients or carriers.
  • Chemotherapy may involve administration of more than one drug.
  • a drug may be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the condition to be treated.
  • the chemotherapy may be administered by one or more routes of administration, e.g. parenteral, intravenous injection, oral, subcutaneous, intradermal or intratumoral.
  • routes of administration e.g. parenteral, intravenous injection, oral, subcutaneous, intradermal or intratumoral.
  • the chemotherapy may be administered according to a treatment regime.
  • the treatment regime may be a pre-determined timetable, plan, scheme or schedule of chemotherapy administration which may be prepared by a physician or medical practitioner and may be tailored to suit the patient requiring treatment.
  • the treatment regime may indicate one or more of: the type of chemotherapy to administer to the patient; the dose of each drug or radiation; the time interval between administrations; the length of each treatment; the number and nature of any treatment holidays, if any etc.
  • a single treatment regime may be provided which indicates how each drug is to be administered.
  • Chemotherapeutic drugs may be selected from: Abemaciclib, Abiraterone Acetate, Abitrexate (Methotrexate), Abraxane (Paclitaxel Albumin-stabilized Nanoparticle Formulation), ABVD, ABVE, ABVE- PC, AC, Acalabrutinib, AC-T, Adcetris (Brentuximab Vedotin), ADE, Ado-Trastuzumab Emtansine, Adriamycin (Doxorubicin Hydrochloride), Afatinib Dimaleate, Afinitor (Everolimus), Akynzeo (Netupitant and Palonosetron Hydrochloride), Aldara (Imiquimod), Aldesleukin, Alecensa (Alectinib), Alectinib, Alemtuzumab, Alimta (Pemetrexed Disodium), Aliqopa (Copanlisib Hydrochloride), Alkeran for
  • the treatment may comprise administration of Melphalan Hydrochloride, Melphalan, and/or Cyclophosphamide.
  • the treatment may comprise administration of a corticosteroid, e.g. dexamethasone and/or prednisone.
  • a corticosteroid e.g. dexamethasone and/or prednisone.
  • the TCRs, antigen-binding molecules, nucleic acids, vectors, cells and compositions described herein are used in T-cell-based adoptive cell transfer (ACT), immunotherapy or cellular immunotherapy.
  • ACT T-cell-based adoptive cell transfer
  • immunotherapy immunotherapy or cellular immunotherapy.
  • the engineered TCRs described herein are exogenously expressed on T-cells through genetic engineering methods including, but not limited to, lentiviral transduction, or messenger ribonucleic acid (mRNA) transfection, of nucleic acids encoding for the TCR sequences described herein.
  • the TCRs used for ACT comprise a TCR sequence fused with a T-cell binding domain, including but not limited to a single-chain fragment binding to CD3.
  • the TCRs are used in T-cell based ACT in combination with one or more therapeutic agents, e.g., immune modulating agents, including but not limited to cytokines, TLR agonists, RIG-I like receptor (RLR) agonists.
  • Adoptive cell transfer is an immunotherapy involving administration of immune cells with direct anticancer activity to a subject in need thereof.
  • Adoptive cell transfer generally refers to a process by which cells (e.g. immune cells) are obtained from a subject, typically by drawing a blood sample from which the cells are isolated. The cells are then typically modified and/or expanded, and then administered either to the same subject (in the case of adoptive transfer of autologous/autogeneic cells) or to a different subject (in the case of adoptive transfer of allogeneic cells). The treatment is typically aimed at providing a population of cells with certain desired characteristics to a subject, or increasing the frequency of such cells with such characteristics in that subject. Adoptive transfer may be performed with the aim of introducing a cell or population of cells into a subject, and/or increasing the frequency of a cell or population of cells in a subject.
  • an autologous T cell therapy comprises administering to a subject a T cell that was isolated from the same subject.
  • allogeneic refers to any material derived from one individual which is then introduced to another individual of the same species.
  • an allogeneic T cell transplantation comprises administering to a subject a T cell that was obtained from a donor other than the subject.
  • immunotherapy refers to the treatment of a subject afflicted with, or at risk of contracting or suffering a recurrence of, a disease by a method comprising inducing, enhancing, suppressing or otherwise modifying an immune response.
  • immunotherapy include, but are not limited to, T cell therapies, antibody therapy, fusion protein therapy.
  • T cell therapy can include adoptive T cell therapy, tumor-infiltrating lymphocyte (TIL) immunotherapy, autologous cell therapy, engineered autologous cell therapy (eACT), and allogeneic T cell transplantation (see, e.g., June, C.
  • an ‘immune response’ refers to the action of a cell of the immune system (for example, T lymphocytes, B lymphocytes, natural killer (NK) cells, macrophages, eosinophils, mast cells, dendritic cells and neutrophils) and soluble macromolecules produced by any of these cells or the liver (including antibodies, cytokines, and complement) that results in selective targeting, binding to, damage to, destruction of, and/or elimination from a vertebrate's body of invading pathogens, cells or tissues infected with pathogens, cancerous or other abnormal cells, or, in cases of autoimmunity or pathological inflammation, normal human cells or tissues.
  • a cell of the immune system for example, T lymphocytes, B lymphocytes, natural killer (NK) cells, macrophages, eosinophils, mast cells, dendritic cells and neutrophils
  • soluble macromolecules produced by any of these cells or the liver including antibodies, cytokines, and complement
  • T cells used in immunotherapy described herein can come from any source known in the art.
  • T cells can be differentiated in vitro from a hematopoietic stem cell population, or T cells can be obtained from a subject.
  • T cells can be obtained from, e.g., peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors.
  • the T cells can be derived from one or more T cell lines available in the art.
  • T cells can also be obtained from a unit of blood collected from a subject using any number of techniques known to the skilled artisan, such as FICOLL.TM. separation and/or apheresis. Additional methods of isolating T cells for a T cell therapy are disclosed in U.S. Patent Publication No.
  • An immunotherapy can also comprise administering a modified cell to a subject, wherein the modified cell expresses CD3 and a TCR disclosed herein.
  • An immunotherapy can comprise administering a nucleic acid to a subject, e.g. using a vector or another type of targeting method, such that a cell is modified in vivo to express the nucleic acid.
  • the nucleic acid can encode a TCR.
  • the modified cell is not a T cell.
  • ACT antitumor T-cells
  • the antitumor T-cells can be grown in vitro in large numbers, then selected for high-avidity recognition of the desired tumor antigen, as well as effector functions.
  • in vitro activation circumvents the presence of inhibitory factors found in vivo.
  • ACT allows for manipulation of the host before cell transfer to provide a favorable microenvironment supporting antitumor activity (Rosenberg and Restifo, Science 348(6230) :62-68 (2015)).
  • TCR-expressing T-cells are used for T-cell-based adoptive cell transfer (ACT) as a therapeutic treatment in a subject suffering from cancer, including an EBV-associated cancer.
  • ACT is used in combination with immune modulating agents, selected from the group of; immune cell-depleting agents, cytokines, TLR agonist, RIG-I like receptor (RLR) agonists, immune checkpoint inhibitors, chemotherapeutic agents, antibodies, radiotherapy and a combination thereof.
  • immune modulating agents selected from the group of; immune cell-depleting agents, cytokines, TLR agonist, RIG-I like receptor (RLR) agonists, immune checkpoint inhibitors, chemotherapeutic agents, antibodies, radiotherapy and a combination thereof.
  • the present disclosure provides methods comprising administering antigen-specific immune cells comprising/expressing a TCR/antigen-binding molecule according to the present disclosure, or antigenspecific immune cells comprising/expressing nucleic acid/a vector encoding a TCR/antigen-binding molecule according to the present disclosure, to a subject.
  • the methods comprise generating antigen-specific immune cells, or generating/expanding a population of antigen-specific immune cells. In some embodiments, the methods comprise modifying an immune cell to co mprise/ex press a TCR/antigen-binding molecule according to the present disclosure. In some embodiments, the methods comprise modifying an immune cell to comprise/express nucleic acid/a vector encoding a TCR/antigen-binding molecule according to the present disclosure.
  • the methods comprise administering to a subject antigen-specific immune cells modified to express/comprise a TCR/antigen-binding molecule according to the present disclosure (or modified to express/comprise a nucleic acid/vector encoding such a TCR/antigen-binding molecule).
  • the methods comprise:
  • the methods comprise:
  • the subject from which the immune cells (e.g. PBMCs) are isolated is the same subject to which cells are administered (/.e., adoptive transfer may be of autologous/autogeneic cells). In some embodiments, the subject from which the immune cells (e.g. PBMCs) are isolated is a different subject to the subject to which cells are administered (/.e., adoptive transfer may be of allogeneic cells).
  • the methods may comprise one or more of: obtaining a blood sample from a subject; isolating immune cells (e.g. PBMCs) from a blood sample which has been obtained from a subject; culturing the immune cells in in vitro or ex vivo cell culture; modifying an immune cell to express or comprise a TCR/antigen-binding molecule according to the present disclosure, or to express or comprise nucleic acid/a vector encoding a TCR/antigen- binding molecule according to the present disclosure (e.g.
  • the cells by mixing the cells with a pharmaceutically acceptable adjuvant, diluent, or carrier; administering immune cells expressing/comprising a TCR/antigen-binding molecule according to the present disclosure, or expressing/comprising a nucleic acid/a vector encoding a TCR/antigen- binding molecule according to the present disclosure, or a pharmaceutical composition comprising such cells, to a subject.
  • a pharmaceutically acceptable adjuvant, diluent, or carrier administering immune cells expressing/comprising a TCR/antigen-binding molecule according to the present disclosure, or expressing/comprising a nucleic acid/a vector encoding a TCR/antigen- binding molecule according to the present disclosure, or a pharmaceutical composition comprising such cells, to a subject.
  • the methods may additionally comprise treating the cells or subject to induce/enhance expression of the TCR/antigen-binding molecule, and/or to induce/enhance proliferation or survival of immune cells comprising/expressing the TCR/antigen-binding molecule.
  • a subject is administered lymphodepleting chemotherapy prior to administration of immune cells expressing/comprising a TCR/antigen-binding molecule described herein (or expressing/comprising nucleic acid/a vector encoding such a TCR/antigen-binding molecule).
  • methods of treating/preventing a disease/condition in accordance with the present disclosure comprise: (i) administering a lymphodepleting chemotherapy to a subject, and (ii) subsequently administering an immune cell expressing/comprising a TCR/antigen-binding molecule described herein, or expressing/comprising nucleic acid/a vector encoding a TCR/antigen-binding molecule described herein.
  • lymphocytes e.g. T cells, B cells, NK cells, NKT cells or innate lymphoid cell (ILCs), or precursors thereof
  • a ‘lymphodepleting chemotherapeutic agent’ refers to a chemotherapeutic agent which results in depletion of lymphocytes.
  • Lymphodepleting chemotherapy and its use in methods of treatment by adoptive cell transfer are described e.g. in Klebanoff et al., Trends Immunol. (2005) 26(2):111-7 and Muranski et al., Nat Clin Pract Oncol. (2006) (12):668-81 , both of which are hereby incorporated by reference in their entirety.
  • the aim of lymphodepleting chemotherapy is to deplete the recipient subject’s endogenous lymphocyte population.
  • lymphodepleting chemotherapy is typically administered prior to adoptive cell transfer, to condition the recipient subject to receive the adoptively transferred cells.
  • Lymphodepleting chemotherapy is thought to promote the persistence and activity of adoptively transferred cells by creating a permissive environment, e.g. through elimination of cells expressing immunosuppressive cytokines, and creating the ‘lymphoid space’ required for expansion and activity of adoptively transferred lymphoid cells.
  • Chemotherapeutic agents commonly used in lymphodepleting chemotherapy include e.g. fludarabine, cyclophosphamide, bedamustine and pentostatin.
  • therapeutic or prophylactic intervention for the treatment/prevention of a disease/condition in accordance with the present disclosure comprises administration of a nucleic acid/vector, or of a composition comprising a nucleic acid/vector according to the present disclosure.
  • administration of such an article results in modification of a cell or cells (e.g. in vivo) to comprise/express a nucleic acid/vector, and/or to comprise/express TCR/antigen-binding molecule/polypeptide(s) according to the present disclosure. That is, in some embodiments the nucleic acid/vector/composition is employed as a gene therapy.
  • the methods comprise intravascular (e.g. intravenous or intra-arterial), intramuscular or subcutaneous administration and wherein the relevant article is formulated in a targeted agent delivery system (e.g. as described herein).
  • Suitable targeted delivery systems include, for example, nanoparticles, liposomes, micelles, beads, polymers, metal particles, dendrimers, antibodies, aptamers, nanotubes or micro-sized silica rods.
  • Such systems may comprise a magnetic element to direct the agent to the desired organ or tissue.
  • Suitable nanocarriers and delivery systems will be apparent to one skilled in the art.
  • the present disclosure further provides the use of an antigen-binding molecule/TCR/TCR fragment or chain/nucleic acid/vector/cell/composition according to the present disclosure to: recog nize/bi nd to a cell expressing MAGE-A10 (e.g. a MAGE-A10 peptide, e.g. SEQ ID NO: 1 , 2, 3 or 4, e.g. when presented by an appropriate MHC class I molecule); activate a host cell, e.g. T cell, in which the article is comprised/expressed; confer cytotoxic activity; kill cancer and/or tumour cells; kill cells expressing MAGE-A10; and/or kill cancer cells expressing MAGE-A10.
  • MAGE-A10 e.g. a MAGE-A10 peptide, e.g. SEQ ID NO: 1 , 2, 3 or 4, e.g. when presented by an appropriate MHC class I molecule
  • activate a host cell e.g. T cell, in which the
  • the present disclosure further provides methods for recognizing/binding to a cell expressing MAGE-A10 (e.g. a MAGE-A10 peptide, e.g. SEQ ID NO:1 , 2, 3, 4, 156 or 157 e.g. when presented by an appropriate MHC class I molecule); activating a host cell, e.g. T cell, in which the article is comprised/expressed; conferring cytotoxic activity; killing cancer and/or tumour cells; killing cells expressing MAGE-A10; and/or killing cancer cells expressing MAGE-A10, using an antigen-binding molecule/TCR/TCR fragment or chain/nucleic acid/vector/cell/composition according to the present disclosure.
  • Such uses/methods may be in vitro, or may be in vivo in a subject.
  • the present disclosure provides methods for recognizing/binding to a cell expressing MAGE- A10 (e.g. a MAGE-A10 peptide, e.g. SEQ ID NO:1 , 2, 3, 4, 156 or 157 e.g. when presented by an appropriate MHC class I molecule); activating a host cell, e.g. T cell, in which the article is comprised/expressed; conferring cytotoxic activity; killing cancer and/or tumour cells; killing cells expressing MAGE-A10; and/or killing cancer cells expressing MAGE-A10, comprising administering to a subject an antigen-binding molecule/TCR/TCR fragment or chain/nucleic acid/vector/cell/composition according to the present disclosure.
  • MAGE- A10 e.g. a MAGE-A10 peptide, e.g. SEQ ID NO:1 , 2, 3, 4, 156 or 157 e.g. when presented by an appropriate MHC class I molecule
  • activating a host cell
  • a ‘subject’ as used herein includes any human who is afflicted with a disease/condition (e.g., a cancer) as described herein.
  • a disease/condition e.g., a cancer
  • the terms ‘subject’ and ‘patient’ are used interchangeably herein.
  • the subject in accordance with aspects of the present disclosure may be any animal or human.
  • the subject is preferably mammalian, more preferably human.
  • the subject may be a non-human mammal, but is more preferably human.
  • the subject may be male or female.
  • the subject may be a patient.
  • a subject may have been diagnosed with a disease or condition described herein requiring treatment (e.g. a cancer), may be suspected of having such a disease/condition, or may be at risk of developing/contracting such a disease/condition.
  • the subject is preferably a human subject.
  • the subject to be treated according to a therapeutic or prophylactic method of the present disclosure is a subject having, or at risk of developing, a disease/condition described herein.
  • a subject may be selected for treatment according to the methods based on characterisation for certain markers of such a disease/condition.
  • a subject may comprise cells comprising/expressing MAGE-A10.
  • a subject may comprise cells comprising/expressing a peptide described herein, e.g. SEQ ID NO:1 , 2, 3, 4, 156 or 157.
  • a subject may comprise cells presenting a peptide :MHC complex described herein.
  • a subject comprises an HLA allele as described herein. In some embodiments, a subject comprises an HLA-A*02 allele. In some embodiments, a subject comprises HLA-A*02:01. In some embodiments, a subject comprises HLA-A*02:02, HLA-A*02:03, HLA-A*02:04, HLA-A*02:05, HLA- A*02:06, HLA-A*02:07, HLA-A*02:11 , HLA-A*02:12, HLA-A*02:19, HLA-A*02:24, HLA-A*02:264, or HLA- A*02:52.
  • a subject comprises an HLA-A*24 allele. In some embodiments, a subject comprises HLA-A*24:02. In some embodiments, a subject comprises HLA-A*24:03, HLA-A*23, HLA- A*23:01 , or HLA-A9.
  • a subject to be administered immune cells in accordance with the present disclosure may be autogeneic/autologous with respect to the subject from which immune cells administered to the subject are derived.
  • a subject to be administered immune cells in accordance with the present disclosure may be genetically identical to the subject from which immune cells administered to the subject are derived.
  • a subject to be administered immune cells in accordance with the present disclosure may be the same subject as the subject from which immune cells administered to the subject are derived.
  • a subject to be treated/prevented in accordance with the present disclosure may be HLA-matched with respect to the subject from which immune cells administered to the subject are derived.
  • a subject to which cells are administered may comprise MHC/HLA genes encoding MHC/HLA molecules which are identical to the MHC/HLA molecules encoded by the MHC/HLA genes of the subject from which immune cells administered to the subject are derived.
  • the subject is a >4/8 (/.e. 4/8, 5/8, 6/8, 7/8 or 8/8) match across HLA-A, -B, -C, and -DRB1 .
  • the subject is a >5/10 (/.e. 5/10, 6/10, 7/10, 8/10, 9/10 or 10/10) match across HLA-A, -B, -C, -DRB1 and -DQB1.
  • the subject is a >6/12 (/.e. 6/12, 7/12 8/12, 9/12, 10/12, 11/12 or 12/12) match across HLA-A, -B, -C, -DRB1 , -DQB1 and -DPB1.
  • the subject is an 8/8 match across HLA-A, -B, -C, and -DRB1 . In some embodiments, the subject is a 10/10 match across HLA-A, -B, -C, -DRB1 and -DQB1. In some embodiments, the subject is a 12/12 match across HLA-A, -B, -C, -DRB1 , -DQB1 and -DPB1.
  • kits of parts relate to kits for producing a cell (e.g. an antigen-specific cell) according to the present disclosure.
  • kits for performing the methods according to the present disclosure relate to kits for performing the methods according to the present disclosure.
  • the kit may have at least one container having a predetermined quantity of a TCR, antigen-binding molecule, polypeptide, nucleic acid, vector, cell or composition described herein.
  • the kit may provide the relevant articles together with instructions (e.g. a protocol) as to how to employ them in accordance with a method described herein.
  • a kit of parts comprises materials for producing a polypeptide according to the present disclosure.
  • a kit of parts comprises materials for producing a TCR/antigen-binding molecule according to the present disclosure.
  • a kit of parts comprises materials for producing a cell according to the present disclosure.
  • a kit of parts comprises materials for producing a composition according to the present disclosure.
  • the kit may comprise materials for producing a TCR, antigen-binding molecule, polypeptide, nucleic acid, vector, cell or composition described herein.
  • the kit of parts may comprise materials for formulating a TCR, antigen-binding molecule, polypeptide, nucleic acid, vector, cell or composition described herein to a pharmaceutical composition/medicament, e.g. in a composition further comprising a pharmaceutically-acceptable carrier, diluent, excipient or adjuvant.
  • Kits according to the present disclosure may include instructions for use, e.g. in the form of an instruction booklet or leaflet.
  • the instructions may include a protocol for performing any one or more of the methods described herein.
  • sequence identity refers to the percent of nucleotides/amino acid residues in a subject sequence that are identical to nucleotides/amino acid residues in a reference sequence, after aligning the sequences and, if necessary, introducing gaps, to achieve the maximum percent sequence identity between the sequences. Pairwise and multiple sequence alignment for the purposes of determining percent sequence identity between two or more amino acid or nucleic acid sequences can be achieved in various ways known to a person of skill in the art, for instance, using publicly available computer software such as ClustalOmega (Soding, J. 2005, Bioinformatics 21 , 951-960), T-coffee (Notredame et al. 2000, J. Mol. Biol.
  • FIGS 1A to 1C Functional validation of MAGE-A10-specific TCRs.
  • A Binding of Jurkat reporter TCR-knockout cells transduced with TCR A0385 (JR A0385) to a range of concentrations of MAGE-A10 peptide GLYDGMEHL (SEQ ID NO:1) (0.000005 - 5 pM, 10-fold dilutions).
  • B Binding of Jurkat cells transduced (lentiviral) with TCR A0390 (A0390) and TCR A0398 (A0398) to a range of concentrations of MAGE-A10 peptide SLLKFLAKV (SEQ ID NO:2) (0.000005 - 5 pM, 10-fold dilutions).
  • FIG. 3 Cytotoxic activity of primary T cells transduced with TCR A0409.
  • Primary human T cells transfected with TCR A0409 (specific for MAGE-A10 peptide SLLKFLAKV (SEQ ID NO:2)) were used as effector (E) cells.
  • the cell viability index represents the ratio of peptide pulsed versus un-pulsed Raji-A*02 target (T) cells.
  • Three E:T ratios, 1 :1 , 2:1 and 6:1 were tested in duplicate.
  • An un-pulsed control condition was used for normalization (not tested in duplicate).
  • the graph shows mean and range of the two measurements per condition except for the no-peptide control which is a single measurement.
  • Nontransduced (NT) cells were used as a control.
  • Figures 4A-4F Cytotoxic activity of primary cells transduced with TCR A0385 against target cells expressing MAGE-A10.
  • the following target cell lines expressing MAGE-A10 were tested from two different donors (A and B): 4A-4B: EKVX cells, optionally transduced with HLA-A*02:01 ; 4C-4D: SK-MEL- 2 cells, optionally transduced with HLA-A*02:01 (3C-3D); 4E-4F: A375 cells that endogenously express HLA-A*02:01 .
  • Effector cells expressing TCR A0385 were added to target cells at Effector to Target (E:T) ratios indicated in the Figures. IFNy production was used to measure T cell activation.
  • Non-transduced (NT) cells were used as a control.
  • Figures 5A-5F Cytotoxic activity of primary cells transduced with TCR A0390 and A0398 using target cells expressing MAGE-A10.
  • the following target cell lines expressing MAGE-A10 were tested: 5A, 5D: EKVX cells, optionally transduced with HLA-A*02:01 ; 5B, 5E: SK-MEL-2 cells, optionally transduced with HLA-A*02:01 ; and 5C, 5F: A375 cells that endogenously express HLA-A*02:01.
  • Effector cells from donor A expressing TCR A0390 (5A-5C) and TCR A0398 (5D-5F) were added to target cells at Effector to Target (E:T) ratios indicated in the Figures. IFNy production was used to measure T cell activation.
  • Non-transduced (NT) cells were used as a control.
  • FIG. 6 Continuous killing activity measurement over 140 hours with primary cells transduced with TCR A0390 and A0398.
  • xCelligence technology was used to measure killing activity of TCR A0390-transduced or TCR A0398-transduced primary T cells against cell lines which express MAGE-A10 peptides.
  • Cytotoxicity against melanoma cell line SK-MEL2, optionally transduced with HLA-A*02:01 was measured at an Effector to Target (E:T) ratio of 3:1 .
  • Non-transduced (NT) cells were used as a control.
  • FIGS. 7A-7G Alanine scan and safety assessment for potential binding of TCRs to endogenous proteins.
  • (7A-7B) Alanine scan of TCR A0409 (A) and A0436 (B) for target peptide, SLLKFLAKV (SEQ ID NO:2).
  • Raji cells expressing HLA-A*02:01 were pulsed with EC90 levels of SLLKFLAKV (SEQ ID NO:2) carrying single alanine-substitutions at indicated positions.
  • Primary T cells transduced with indicated TCRs were introduced at a 1 :1 ratio and T cell activation was measured through levels of IFNy secretion.
  • TCR-T line was evaluated for T cell activation through levels of IFNy secretion. Means and standard deviations from duplicate measurements were shown with values adjusted against non-transduced T cell controls. In (G) black bars represent HC11 NT, grey bars represent HC11 A0436.
  • FIGS. 8A to 8C Cytotoxic activity of primary T cells transduced with MAGE-A10 specific TCRs.
  • E:T ratio of 1 :1 with means and standard deviations shown from duplicate measurements.
  • FIGS 9A and 9B Cytotoxic activity of primary CD8+ and CD4+ T cells transduced with MAGE- A10 specific TCRs.
  • (9A) Flow cytometric events of primary T cells expressing the transduced TCRs were gated to reveal CD8+ and CD4+ T cell sub populations along with their levels of cytotoxic activities as demonstrated by their staining intensity for intracellular IFNy (y-axis).
  • the CD8- (CD4+) T cell populations transduced with A0409 did not show signs of activation upon target peptide stimulation while those of A0436 demonstrated clear signs of cytotoxic activation.
  • FIGS 10A and 10B In vivo tumor regression by primary T cells expressing TCR A0409 in a murine model.
  • 10B Individual tumor volume measurements of mice in each group are shown in for Group 1 , for Group 2 and for Group 3.
  • EXAMPLE 1 Functional validation of MAGE-A10-specific T cell receptors (TCRs)
  • TCR sequence recovery In vitro expanded T cells were stained with HLA multimers and surface antibodies to sort specific T cells into individual wells for single cell PCR (scPCR). A Melody flow cytometer (Becton Dickinson BD) was used for the sorting. Sorted cells were immediately frozen and stored at -80 °C until further use. Reverse transcription (RT) reaction was performed, followed by a nested PCR protocol to amplify the variable TCR regions of the TCR alpha (TCRa) and TCR beta (TCRp) chains using primers binding in the V gene. The protocol was described previously in Albert C. Shaw (ed.), Immunosenescence: Methods and Protocols, Methods in Molecular Biology, vol. 1343, which is hereby incorporated herein by reference in its entirety. TCR sequences were obtained by Sanger sequencing of PCR products.
  • Lentiviral vectors were produced for each TCR by transfection of the transgene plasmid along with packaging plasmids encoding the additional lentiviral components into HEK293 cells.
  • TCR sequences were codon optimised with an algorithm provided by Genscript (GenSmart Codon Optimisation). The optimisation was done for expression in human cells or human T cells. See, for example, W02020024917A1 which is incorporated herein by reference in its entirety.
  • An exemplary expression vector sequence for codon-optimised, constant region-stabilised TCR A0385 is shown in SEQ ID NO:70. Lentiviral vectors collected from the transfected HEK293 cells were then used to transduce each TCR into T cells. Transduction efficiency and expression of the introduced TCR were confirmed by flow cytometry.
  • the TCR was transfected into Jurkat cells using mRNA technology.
  • mRNA was produced via IVT reaction (HiScribe® T7 mRNA Kit with CleanCap® Reagent AG, New England Biolabs) with template from restriction enzyme linearised plasmids containing T7 promoter followed by TCR alpha and TCR beta variable and constant regions.
  • mRNA was transfected into Jurkat TCRap-knockout, CD8+ reporter T cells using a NeonTM Electroporation System. Expression of the TCR was validated and quantified by staining with anti-TCRap antibody followed by flow cytometry.
  • Activation of successfully transfected Jurkat cells was tested in a dose response experiment, using a range of peptides presented on antigen-presenting cells (APCs), for example Raji cells stably transfected with A*01 :01 , A*03:01 , A*02:01 , A*24:02 or B*07:02.
  • APCs antigen-presenting cells
  • HLA-A*02:01 -expressing Raji antigen presenting cells were seeded into 96 well plates at 50,000 cells per well.
  • 50,000 Jurkat reporter cells that were transduced or non-transduced with the TCR to be tested were added to the antigen presenting cells.
  • Transduction efficiency was quantified by flow cytometry to verify that at least 10% of Jurkat reporter cells express the transduced TCR.
  • MAGE-A10 peptide dilutions were prepared to the desired range of concentrations (10-fold dilution from 0.000005 uM to 5 uM) for dose-response testing .
  • Peptides were added to the plate containing the antigen presenting cells and Jurkat cells. Plates were incubated at 37 °C in a cell culture incubator for 3h50min with a final 10min of incubation at room temperature (4h incubation in total). To reveal the luciferase signal, Bio-Glo-NLTM reagent was added to all wells, reacted for 5 min and luminescence read on a SpectraMax i3x (Molecular Devices) plate reader.
  • Jurkat cells transduced with TCR A0385 showed dose-dependent T cell activation after being contacted with HLA-A*02:01 -expressing antigen presenting Raji cells in the presence of MAGE-A10 GLYDGMEHL peptide (SEQ ID NO:1) as demonstrated in Figure 1A.
  • MAGE-A10 GLYDGMEHL peptide SEQ ID NO:1
  • Jurkat cells transduced with TCR A0390 and A0398 showed dose-dependent dependent T cell activation after being contacted with HLA-A*02:01 -expressing antigen presenting cells in the presence of MAGE- A10 SLLKFLAKV peptide (SEQ ID NO:2) as demonstrated in Figure 1B.
  • MAGE- A10 SLLKFLAKV peptide SEQ ID NO:2
  • non-transduced Jurkat cells did not demonstrate dose-dependent T cell activation.
  • TCR A0409 and A0436 were compared in the same assay. Both TCRs tested (A0409) and (A0436) demonstrated dose-dependent T cell activation after being contacted with HLA-A*02:01 -expressing antigen presenting cells in the presence of MAGE-A10 SLLKFLAKV peptide (SEQ ID NO:2) as demonstrated in Figure 1C.
  • EXAMPLE 2 Cytotoxic activity of TCR A0385- or TCR A0409-transduced T cells against MAGE- A10
  • PBMCs Peripheral blood mononuclear cells
  • donor A and donor B peripheral blood mononuclear cells
  • CD4+ and CD8+ T cells were positively enriched from PBMC using either A) CD4 and CD8 microbeads, and LS columns and magnets from Miltenyi or B) CliniMACS® CD4 and CD8 GMP MicroBeads, CliniMACS tubing set on the Miltenyi CliniMACS automated cell processing system.
  • Cells were resuspended in AIM V medium with 10% heat-inactivated human AB serum and 10ng/ml IL-15.
  • T cell activation cells were incubated with TransActTM beads (Miltenyi). On the same or the next day, lentiviruses containing nucleic acids encoding the TCRs of interest were added to the activated T cells and incubated for three days. Non-transduced cells were used as negative controls. Transduction efficiency was quantified by flow cytometry prior to performing cell based functional assays.
  • Raji cells stably expressing HLA-A*02:01 were used as target cells (T) and were labelled with a low or a high concentration of cell-trace violet (CTV) to differentiate between pulsed and unpulsed cells.
  • CTVhigh cells were pulsed with MAGE-A10 peptides, whereas CTVIow cells were left un-pulsed.
  • 25,000 CTVhigh and CTVIow cells were incubated for 4h with primary cells transfected with the TCR of interest using mRNA technology.
  • Enriched primary human CD8 T cells were expanded for 10 days using activation beads and cytokines IL- 2, IL-15 and IL-7. TCRs of interest were then transduced using mRNA technology. These effector cells were used in the cytotoxicity assay 18 hours after TCR transfection. Quantification of cytokine secretion. IFNy secreted by T cells transduced with TCR A0385, TCR A0390, TCR A0398 or TCR A0409 (or non-transduced (NT) control) into the culture medium during the cytotoxicity assay was quantified by ELISA methodology. The OptEIA IFNy Kit from Becton Dickinson (BD) was used. Absorbance was measured with the SpectraMax i3x (Molecular Devices) plate reader and cytokine concentration calculated based on standard curve using SoftMax Pro 7.1.2 software.
  • Cancer cell lines endogenously expressing MAGE- A10 antigens were used as target cells: lung cancer cell lines EKVX (WT or stably transfected with HLA- A*02:01); melanoma cell line SK-MEL-2 (WT or stably transfected with HLA-A*02:01); and HLA-A*02:01 positive melanoma cell line A375 which endogenously expresses MAGE-A10 and HLA-A*02:01 .
  • Non-TCR transduced (NT) T cells were used as a negative control.
  • Target cell lines were seeded in xCelligence 96 well E-plates at 10,000-25,000 cells per well, depending on the cell line used. Effector cells were added the next day at the Effector:Target (E:T) ratio of 3:1 , preparing each condition in duplicate. Impedance readings were recorded for up to 140 hours. The % of cytolysis per condition and time point was calculated using standard protocols and XCelligence Immunotherapy software.
  • T cells transduced with TCR A0385 or A0409 showed dose-dependent secretion of IFNy with increasing concentrations of respective MAGE-A10 peptides GLYDGMEHL (SEQ ID NO: 1) or SLLKFLAKV (SEQ ID NO:2) (0.00005 - 50 pM, 10-fold dilution) as exemplified in Figure 2.
  • EC50 values for TCR A0385 and TCR A0409 were 0.01366 and 9.501 e-005 respectively.
  • non-transduced cells (NT) did not show dose-dependent secretion of IFNy with increasing concentrations of MAGE-A10 peptides.
  • Direct cell killing was measured using flow cytometry.
  • Primary human T cells were transfected with TCR A0409 using mRNA technology and used as effector cells (E) which were contacted with Raji HLA- A*02:01 -expressing antigen presenting cells (target cells; T).
  • the cell viability index demonstrated in Figure 3 represents the ratio of peptide-pulsed versus peptide-un- pulsed HLA-A*02:01 -expressing antigen presenting cells in increasing Effector to Target ratios. As shown in Figure 3, a higher E:T ratio resulted in more efficient killing. HLA-A*02:01 -expressing cells showed decreased cell viability index at increasing E:T concentrations as a result of increased cell killing of peptide-pulsed target cells (which display the MAGE-A10 SLLKFLAKV peptide (SEQ ID NO:2) on HLA- A*02:01) at increasing concentrations of TCR A0409-transduced T cells. Cell viability index remained higher when antigen presenting cells were contacted with non-transduced (NT) T cells.
  • NT non-transduced
  • Figures 4A and 4B show the cell killing activity of TCR A0385-transduced primary T cells from two donors (donor A and donor B) against lung cell line EKVX at E:T ratios of 1 :1 , 3:1 and 9:1 .
  • Figures 4C and 4D show the cell killing activity of TCR A0385-transduced primary T cells from two donors (donor A and donor B) for melanoma cell line SK-MEL-2 at E:T ratios of 1 :1 , 3:1 and 9:1 .
  • Figures 4E and 4F show the cell killing activity of TCR A0385-transduced primary T cells from two donors (donor A and donor B) for melanoma cell line A375 at E:T ratios of 1 :1 , 3:1 and 9:1 .
  • Figure 5A shows the cell killing activity of TCR A0390-transduced primary T cells against lung cell line EKVX at E:T ratios of 1 :1 , 3:1 and 9:1 .
  • Figure 5B shows the cell killing activity of TCR A0390-transduced primary T cells against melanoma cell line SK-MEL-2 at E:T ratios of 1 :1 , 3:1 and 9:1 .
  • Figure 5C shows the cell killing activity of TCR A0390-transduced primary T cells against melanoma cell line A375 at E:T ratios of 1 :1 , 3:1 and 9:1 .
  • Figure 5D shows the cell killing activity of TCR A0398-transduced primary T cells against lung cell line EKVX at E:T ratios of 1 :1 , 3:1 and 9:1.
  • Figure 5E shows the cell killing activity of TCR A0398-transduced primary T cells against melanoma cell line SK-MEL-2 at E:T ratios of 1 :1 , 3:1 and 9:1 .
  • Figure 5F shows the cell killing activity of TCR A0398-transduced primary T cells against melanoma cell line A375 at E:T ratios of 1 :1 , 3:1 and 9:1 .
  • SK-MEL-2 cells do not endogenously express HLA-A*02:01.
  • A0390-transduced primary T cells from donor A exhibit cell killing activity against SK-MEL-2 cells at a comparable level to non-transduced (NT) cells.
  • A0390-transduced primary T cells show increased cell killing activity of SK-MEL-2 cells that were transduced with HLA-A*02:01 (SK-MEL2HLAA02).
  • A0398-transduced primary T cells from donor A exhibit marginally higher cell killing activity against SK-MEL-2 cells to non-transduced (NT) cells.
  • A0390-transduced primary T cells exhibit higher cell killing activity against SK-MEL-2 cells transduced with HLA-A*02:01 (SK-MEL2HLAA02). These results demonstrate the cell killing activity of primary cells transduced with TCR A0390 or TCR A0398.
  • EXAMPLE 3 the constant reqion of TCR constructs
  • TCR Any TCR described herein may be expressed as a TCR construct comprising a human TCRa variable region amino acid sequence (SEQ ID NOs:35, 37, 39, 41 ,43, 127 or 129) and a human TCRp variable region amino acid sequence (SEQ ID NOs:36, 38, 40, 42, 44, 128 or 130), along with a human TCR constant region comprising a TCRa constant region (SEQ ID NO:65) and a TCRp constant region (SEQ ID NO:66 or 67).
  • a human TCRa variable region amino acid sequence SEQ ID NOs:35, 37, 39, 41 ,43, 127 or 129
  • SEQ ID NOs:36, 38, 40, 42, 44, 128 or 130 a human TCR constant region comprising a TCRa constant region (SEQ ID NO:65) and a TCRp constant region (SEQ ID NO:66 or 67).
  • Any TCR described herein may be expressed as a TCR construct comprising a human TCRa variable region amino acid sequence (SEQ ID NO:35, 37, 39, 41 ,43, 127 or 129) and a human TCRp variable region amino acid sequence (SEQ ID NO:36, 38, 40, 42,44, 128 or 130), along with a human TCR constant region comprising a mutated version of the human TCRa constant region of SEQ ID NO:68 and a mutated version of the human TCRp constant region of SEQ ID NO:69.
  • the mutation comprises the introduction of a Cys in both the alpha and beta chains of the TCR to create a stabilizing disulfide bridge between the two chains.
  • TCR chains were modified by mutagenesis of residue 48 in the Ca region from Thr (T) to Cys (C) and residue 57 of the Cp region from Ser (S) to Cys (C).
  • the method has been described previously in Kuball et al., 2007 which is hereby incorporated by reference in its entirety.
  • the mutation promotes stable expression and pairing of the transduced TCR in human T cells in which the endogenous TCR is not knocked out.
  • EXAMPLE 4 Alanine scan and safetv assessment to test potential binding of TCRs to ous proteins
  • Figure 7A and 7B demonstrate the alanine-substitutions in the target peptide, SLLKFLAKV (SEQ ID NO:2), tolerated by TCRs A0409 and A0436 respectively.
  • Functional recognition of target peptide was defined by the above-background (NT) detection of IFNy release by primary T cells transduced with each TCR. Recognition motif for each TCR was then defined with ‘x’ indicating tolerated positional mutations. From the results here, we defined target peptide motifs of xxLKFxxKx for A0409 and xxxxFxxKx for A0436.I Endogenous peptides matching these motifs were found from ScanProsite (Expasy, Swiss Institute of Bioinformatics).
  • TCRs A0385, A0409 and A0436 all demonstrate safe and specific targeting profiles with no TCR-dependent IFNy release detected in all LCL lines tested; Figures 7E, 7F and 7G.
  • T cells transduced with TCR A0409 were co-incubated with the following target cell lines: EKVX (non-small cell lung cancer, NSCLC) overexpressing HLA A*02:01 , SK- MEL-2 (melanoma) overexpressing HLA A*02:01 , A375 (melanoma) and UACC-62 (melanoma).
  • EKVX non-small cell lung cancer
  • NSCLC non-small cell lung cancer
  • SK- MEL-2 melanoma
  • UACC-62 melanoma
  • T cells transduced with TCR A0436 were co-incubated with the following target cell lines: NSCLC lines: EKVX, NCI-H1299 and NCI-H1573, all optionally transduced with HLA A*02:01 ; Melanoma lines: SK-MEL-2 and A375 (melanoma), all optionally transduced with HLA A*02:01 . IFNy secreted into the culture medium was then quantified by ELISA as described above. Non-transduced T cells were used as negative controls. T cells were also transduced with external TCR benchmarks capable of binding to MAGE-A10, A0433 and A0434.
  • TCR benchmark A0433 is as encoded by SEQ ID NO:20 and SEQ ID NO:21 as described in WQ2021/005108A1 .
  • TCR benchmark A0434 comprises a variable region encoded by a codon-optimised nucleic acid sequence derived from SEQ ID NQ:20 and SEQ ID NO:21 as described in WQ2021/005108A1 , and paired with human constant regions. Effector cells were added at an Effector:Target (E:T) ratio of 0.3:1 , 1 :1 or 3:1.
  • E:T Effector:Target
  • Cytotoxicity with xCelligence impedance readout Cancer cell lines endogenously expressing MAGE- A10 antigens were used as target cells. Primary CD4+ and CD8+ T cells transduced with TCR A0385, A0409, A0436 or external benchmark A0433 were used as effector cells. Non-TCR transduced (NT) T cells were used as a negative control. Target cell lines were seeded in xCelligence 96 well E-plates at 10,000-25,000 cells per well, depending on the cell line used. Effector cells were added the next day at the Effector:Target (E:T) ratio of 0.3:1 or 1 :1. The percentage of cytolysis per condition and time point was calculated using standard protocols and XCelligence Immunotherapy software. 5.2 Results
  • Figure 8A demonstrates cytotoxic activity of T cells transduced with TCR A0409, through their secretion of IFNy after co-incubation with tumor cells that express endogenous levels of MAGE-A10.
  • Figure 8B demonstrates cytotoxic activity of T cells transduced with TCR A0409 or TCR A0436 through their secretion of IFNy after co-incubation with tumor cells that express endogenous levels of MAGE-A10.
  • Both A0409 and A0436 outperformed both external benchmark TCRs, A0433 and A0434 at each of the tested E:T ratios for the EKVX, NCI-H1573 and A375 cell lines, and at the lower E:T ratios for the NCI-H1299 and SKMEL2 cell lines.
  • TCR A0385, A0409, A0436 or an external benchmark TCR A0433 was measured using xCELLigence technology where demonstrable cytolysis could be measured over a 150h period at ET ratios of 0.3:1 and 1 :1 against cancer cell lines, SK-MEL-2 + HLA A*02:01 , NCI- H1299 + HLA A*02:01 , and EKVX + HLA A*02:01 in Figure 8C. Results showed that TCRs A0409 and A0436 outperformed the benchmark TCR across all cell lines and that TCR A0385 outperformed the benchmark TCR against the EKVX cell line. These results demonstrate the higher efficacy of A0409, A0436 and A0385 over the benchmark TCR.
  • EXAMPLE 6 Cytotoxic activities of CD4+ and CD8+ T cells transduced with TCR A0409 or TCR A0436 upon peptide stimulation
  • T cells transduced with TCR A0409 or A0436 were stimulated with target peptide, SLLKFLAKV (SEQ ID NO:2) at a final concentration of 1 pM for 4-6 hours before cells were fixed for intracellular staining of IFNy and TNFa, along with antibodies against surface markers of CD8, CD4 and CD3.
  • target peptide SEQ ID NO:2
  • Figure 9A and 9B demonstrate the differential cytotoxic activities driven by the stimulation of TCRs A0409 and A0436 in primary CD8+ and CD4+ T cells.
  • Flow cytometric analysis of CD8+ and CD4+ T cells in primary T cells transduced with either MAGE-A10 specific TCRs revealed that cytotoxic activities in T cells transduced with the TCR A0409 were CD8 co-receptor dependent with almost no expression of IFNy or TNFa in CD4+ T cells. Cytotoxic activities upon target peptide stimulation were only observed in transduced CD8+ T cells.
  • TCR A0436 was able to induce cytotoxic activities in CD4+ T cells in a co-receptor independent manner, with upregulation in both IFNy and TNFa upon target peptide stimulation. This suggests that TCR A0436 transduced CD4+ T cells can participate directly in tumorkilling activities alongside CD8+ cytotoxic T cells.
  • EXAMPLE 7 In vivo tumor regression by TCR A0409-transduced T cells in a cell-line derived xenograft murine model
  • a subcutaneous tumor model was established in NSG (NOD scid gamma) mice for the evaluation of in vivo efficacy of T cells transduced with the MAGE-A10 specific TCR A0409.
  • 10 million SK-MEL-2 + HLA A*02:01 cells were implanted subcutaneously into each NSG mouse for tumor development.
  • 4 mice were randomly assigned to each of the 3 different treatment groups: Vehicle, Non-transduced (NT) or A0409.
  • T cells were then introduced intravenously at a single dose of 15X10 A 8 cells per mouse when applicable. Body weight and tumor volume were measured at least twice a week throughout the study.
  • Figure 10A demonstrates the in vivo efficacy of TCR A0409 wherein the group treated with T cells transduced with A0409 had signs of tumor regression starting at Day 20 post-treatment and nearcomplete tumor clearance by Day 40. In contrast, both Vehicle and NT treated groups had consistent tumor growth throughout the study period.
  • Figure 10B shows the tumor volume measurements of individual mice in Vehicle, NT and A0409 treatment groups respectively.
  • MAGE-A10 is a nuclear protein frequently expressed in high percentages of tumor cells in lung, skin and urothelial malignancies. Int J Cancer. 2011 Sep 1 ;129(5):1137-48.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Toxicology (AREA)
  • Zoology (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Cell Biology (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente divulgation concerne des récepteurs de lymphocytes T (TCR) qui se lient à des peptides antigéniques de MAGE-A10 présentés par des molécules HLA-A. La divulgation concerne également des acides nucléiques codant pour ces TCR, des vecteurs comprenant ces acides nucléiques, des cellules comprenant ces TCR, des acides nucléiques et des vecteurs, ainsi que des compositions contenant ces TCR, acides nucléiques, vecteurs et cellules. La divulgation concerne en outre des méthodes de traitement de maladies/affections utilisant ces TCR, acides nucléiques, vecteurs, cellules et compositions, et leurs utilisations médicales.
PCT/EP2025/055503 2024-03-01 2025-02-28 Récepteurs de lymphocytes t humains et leurs utilisations Pending WO2025181329A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202463560297P 2024-03-01 2024-03-01
US63/560,297 2024-03-01

Publications (1)

Publication Number Publication Date
WO2025181329A1 true WO2025181329A1 (fr) 2025-09-04

Family

ID=94924853

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2025/055503 Pending WO2025181329A1 (fr) 2024-03-01 2025-02-28 Récepteurs de lymphocytes t humains et leurs utilisations

Country Status (1)

Country Link
WO (1) WO2025181329A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130287748A1 (en) 2010-12-09 2013-10-31 The Trustees Of The University Of Pennsylvania Use of Chimeric Antigen Receptor-Modified T-Cells to Treat Cancer
WO2018177966A1 (fr) 2017-03-27 2018-10-04 F. Hoffmann-La Roche Ag Récepteurs de liaison à l'antigène améliorés
WO2020024917A1 (fr) 2018-07-30 2020-02-06 Nanjingjinsirui Science & Technology Biology Corp. Optimisation de codon
WO2020227091A1 (fr) * 2019-05-03 2020-11-12 Gigamune, Inc. Cellules modifiées exprimant des récepteurs des lymphocytes t antitumoraux et leurs méthodes d'utilisation
WO2021005108A1 (fr) 2019-07-09 2021-01-14 Medigene Immunotherapies Gmbh Récepteurs de lymphocytes t spécifiques de magea10 et leur utilisation
WO2023218399A1 (fr) * 2022-05-11 2023-11-16 Fundação D. Anna De Sommer Champalimaud E Dr. Carlos Montez Champalimaud - Centro De Investigação Da Fundação Champalimaud Procédé de préparation et de multiplication d'une population de cellules immunitaires pour la thérapie anticancéreuse, test d'activité biologique pour la reconnaissance des tumeurs, préparation de vaccins biologiques et cible épitope pour les anticorps
TWI826891B (zh) * 2016-03-16 2023-12-21 德商英麥提克生物技術股份有限公司 轉染 t 細胞和 t 細胞受體用於癌症免疫治療

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130287748A1 (en) 2010-12-09 2013-10-31 The Trustees Of The University Of Pennsylvania Use of Chimeric Antigen Receptor-Modified T-Cells to Treat Cancer
TWI826891B (zh) * 2016-03-16 2023-12-21 德商英麥提克生物技術股份有限公司 轉染 t 細胞和 t 細胞受體用於癌症免疫治療
WO2018177966A1 (fr) 2017-03-27 2018-10-04 F. Hoffmann-La Roche Ag Récepteurs de liaison à l'antigène améliorés
WO2020024917A1 (fr) 2018-07-30 2020-02-06 Nanjingjinsirui Science & Technology Biology Corp. Optimisation de codon
WO2020227091A1 (fr) * 2019-05-03 2020-11-12 Gigamune, Inc. Cellules modifiées exprimant des récepteurs des lymphocytes t antitumoraux et leurs méthodes d'utilisation
WO2021005108A1 (fr) 2019-07-09 2021-01-14 Medigene Immunotherapies Gmbh Récepteurs de lymphocytes t spécifiques de magea10 et leur utilisation
WO2023218399A1 (fr) * 2022-05-11 2023-11-16 Fundação D. Anna De Sommer Champalimaud E Dr. Carlos Montez Champalimaud - Centro De Investigação Da Fundação Champalimaud Procédé de préparation et de multiplication d'une population de cellules immunitaires pour la thérapie anticancéreuse, test d'activité biologique pour la reconnaissance des tumeurs, préparation de vaccins biologiques et cible épitope pour les anticorps

Non-Patent Citations (56)

* Cited by examiner, † Cited by third party
Title
"Immunology 9th edition", 1 January 2021, ELSEVIER, ISBN: 978-0-7020-7844-6, article MALE DAVID ET AL: "T-cell receptors and Major Histocompatibility Complex Molecules", XP093219815 *
"Methods in Molecular Biology", vol. 1343, article "Immunosenescence: Methods and Protocols"
"Remington's `The Science and Practice of Pharmacy", 2020, ACADEMIC PRESS
ALTSCHUL ET AL., J. MOL. BIOL., vol. 215, 1990, pages 403
BAULU ESTELLE ET AL: "TCR-engineered T cell therapy in solid tumors: State of the art and perspectives", SCIENCE ADVANCES, vol. 9, no. 7, 17 February 2023 (2023-02-17), XP093068209, DOI: 10.1126/sciadv.adf3700 *
BAULU, EGARDET, C.CHUVIN, N.DEPIL, S: "TCR-engineered T cell therapy in solid tumors: State of the art and perspectives", SCIENCE ADVANCES, vol. 9, no. 7, 2023, XP093068209, Retrieved from the Internet <URL:https://doi.org/10.1126/SCIADV.ADF3700> DOI: 10.1126/sciadv.adf3700
BHAT ET AL., CELL DEATH DIS., vol. 8, no. 6, 1 June 2017 (2017-06-01), pages 2836
BHATI ET AL., PROTEIN SCIENCE, vol. 23, 2014, pages 260 - 272
BISHOP ET AL., FRONT IMMUNOL., 13 April 2021 (2021-04-13)
BUCK ET AL., BIOTECHNIQUES, vol. 44, no. 7, June 2008 (2008-06-01), pages 927 - 9
BÜNINGSRIVASTAVA, MOLECULAR THERAPY: METHODS & CLINICAL DEVELOPMENT, vol. 12, 2019, pages 248 - 265
CERIGNOLI ET AL., PLOS ONE., vol. 13, no. 3, 2018, pages 0193498
DAI ET AL., J NAT CANCER INST, vol. 108, no. 7, 2016, pages 439
DAVIS ET AL., ANNU REV IMMUNOL, vol. 16, 1998, pages 523 - 544
DAVIS ET AL., CANCER J., vol. 21, no. 6, 2015, pages 486 - 491
DAVISBJORKMAN, NATURE, vol. 334, 1988, pages 395 - 402
EIDMAHFOUZ, EXP MOL MED., vol. 48, no. 10, October 2016 (2016-10-01), pages 265
ELKE SCHULTZ-THATER ET AL: "MAGE-A10 is a nuclear protein frequently expressed in high percentages of tumor cells in lung, skin and urothelial malignancies", INTERNATIONAL JOURNAL OF CANCER, JOHN WILEY & SONS, INC, US, vol. 129, no. 5, 12 January 2011 (2011-01-12), pages 1137 - 1148, XP071286204, ISSN: 0020-7136, DOI: 10.1002/IJC.25777 *
FULCHERWONG, IMMUNOL CELL BIOL, vol. 77, no. 6, 1999, pages 559 - 564
KALOSJUNE, IMMUNITY, vol. 39, no. 1, 2013, pages 49 - 60
KATOHSTANDLEY, MOLECULAR BIOLOGY AND EVOLUTION, vol. 30, no. 4, 2013, pages 772 - 780
KLEBANOFF ET AL., TRENDS IMMUNOL., vol. 26, no. 2, 2005, pages 111 - 7
KUBALL ET AL., BLOOD, vol. 109, no. 6, 15 March 2007 (2007-03-15), pages 2331 - 2338
KUBALL ET AL., BLOOD., vol. 109, no. 6, 15 March 2007 (2007-03-15), pages 2331 - 2338
KUBALL, J., DOSSETT, M. L., WOLFL, M., HO, W. Y., VOSS, R. H., FOWLER, C., & GREENBERG, P. D.: "Facilitating matched pairing and expression of TCR chains introduced into human T cells", BLOOD, vol. 109, no. 6, pages 2331 - 2338, XP086509877, Retrieved from the Internet <URL:https://doi.org/10.1182/BLOOD-2006-05-023069> DOI: 10.1182/blood-2006-05-023069
LASSMANNSONNHAMMER, BMC BIOINFORMATICS, vol. 6, no. 298, 2005
LIDA ET AL., BIOMED RES INT., 2013, pages 974819
LISAMULSKI, NAT. REV. GENET., vol. 12, 2020, pages 255 - 272
LIU, B.HU, X.FENG, K. ET AL.: "Temporal single-cell tracing reveals clonal revival and expansion of precursor exhausted T cells during anti-PD-1 therapy in lung cancer", NAT CANCER, vol. 3, 2022, pages 108 - 121
MAHFOUZ ET AL., PLANT BIOTECHNOL J., vol. 12, no. 8, 2014, pages 1006 - 14
MANFREDI FRANCESCO ET AL: "TCR Redirected T Cells for Cancer Treatment: Achievements, Hurdles, and Goals", FRONTIERS IN IMMUNOLOGY, vol. 11, 3 September 2020 (2020-09-03), pages 1689, XP055856596, DOI: 10.3389/fimmu.2020.01689 *
MAURO, BIODRUGS, vol. 32, 2018, pages 69 - 81
MAUS ET AL., ANNU REV IMMUNOL, vol. 32, 2014, pages 189 - 225
MOSCOUBOGDANOVE, SCIENCE, vol. 326, no. 5959, 2009, pages 1501
MURANSKI ET AL., NAT CLIN PRACT ONCOL., vol. 12, 2006, pages 668 - 81
MURPHY, K.WEAVER, C., JANEWAY'S IMMUNOBIOLOGY, vol. 9
NAKADE ET AL., BIOENGINEERED, vol. 8, no. 3, 2017, pages 265 - 273
NOTREDAME ET AL., J. MOL. BIOL., vol. 302, 2000, pages 205 - 217
ROSENBERG, S. A., & RESTIFO, N. P.: "Adoptive cell transfer as personalized immunotherapy for human cancer", SCIENCE, vol. 348, no. 6230, 2015, pages 62 - 68, XP055256712, Retrieved from the Internet <URL:https://doi.org/10.1126/SCIENCE.AAA4967> DOI: 10.1126/science.aaa4967
RYDING ET AL., JOURNAL OF ENDOCRINOLOGY, vol. 171, 2001, pages 1 - 14
SALIMITCHISON, PNAS, vol. 105, no. 7, 19 February 2008 (2008-02-19), pages 2415 - 2420
SAMBROOK, J.RUSSEL, D.W.: "Cancer Chemotherapy and Biotherapy: Principles and Practice", 2001, LIPPINCOTT WILLIAMS & WILKINS
SCHROEDERCAVACINI, J ALLERGY CLIN IMMUNOL, vol. 125, no. 202, 2010, pages S41 - S52
SCHULTZ-THATER ET AL.: "MAGE-A10 is a nuclear protein frequently expressed in high percentages of tumor cells in lung, skin and urothelial malignancies.", INTJ CANCER., vol. 129, no. 5, 1 September 2011 (2011-09-01), pages 1137 - 48, XP071286204, DOI: 10.1002/ijc.25777
SIMISTER PHILIP C ET AL: "Structural insights into engineering a T-cell receptor targeting MAGE-A10 with higher affinity and specificity for cancer immunotherapy", JOURNAL FOR IMMUNOTHERAPY OF CANCER, vol. 10, no. 7, 17 May 2022 (2022-05-17), GB, pages e004600, XP093268798, ISSN: 2051-1426, Retrieved from the Internet <URL:https://jitc.bmj.com/content/jitc/10/7/e004600.full.pdf> DOI: 10.1136/jitc-2022-004600 *
SIMMONSALBEROLA-ILA, METHODS MOL BIOL., vol. 1323, 2016, pages 99 - 108
SÖDING, J., BIOINFORMATICS, vol. 21, 2005, pages 951 - 960
SOMERVILLEDUDLEY, ONCOIMMUNOLOGY, vol. 1, no. 8, 2012, pages 1435 - 1437
UMOV ET AL., NAT REV GENET., vol. 11, no. 9, 2010, pages 636 - 46
VASQUEZ ET AL., PNAS, vol. 98, no. 15, 2001, pages 8403 - 8410
VONDERHEIDE ET AL.: "Immun. Research", vol. 27, 2003, pages: 1 - 15
WANG ET AL., NAT. REV. DRUG DISCOV., vol. 18, 2019, pages 358 - 378
WANG, DRUG DISCOV., vol. 18, 2019, pages 358 - 378
WEON, J. L.POTTS, P. R.: "The MAGE protein family and cancer", CURRENT OPINION IN CELL BIOLOGY, vol. 37, 2015, XP029343219, DOI: 10.1016/j.ceb.2015.08.002
WEONPOTTS, CURR OPIN CELL BIOL., vol. 37, December 2015 (2015-12-01), pages 1 - 8
ZARITSKAYA ET AL., EXPERT REV VACCINES, vol. 9, no. 6, 2011, pages 601 - 616

Similar Documents

Publication Publication Date Title
US20190247432A1 (en) Genetically Modified Immune Cells Targeting NY-ESO-1 and Methods of Use Thereof
JP2021090444A (ja) 改変キメラ抗原受容体（ｃａｒ）ｔ細胞のヒト応用
US20230220097A1 (en) Treatment and prevention of cancer using virus-specific immune cells expressing chimeric antigen receptors
US20180128833A1 (en) Methods of treating with tumor membrane vesicle-based immunotherapy and predicting therapeutic response thereto
US20240376429A1 (en) Virus-specific immune cells expressing chimeric antigen receptors
WO2021207274A2 (fr) Cellules immunitaires humaines modifiées génomiquement pour exprimer des récepteurs orthogonaux
US11766455B2 (en) Subject-specific tumor inhibiting cells and the use thereof
US20250025559A1 (en) Irf-4 engineered t cells and uses thereof in treating cancer
WO2025181329A1 (fr) Récepteurs de lymphocytes t humains et leurs utilisations
WO2024081858A1 (fr) Récepteurs de lymphocytes t spécifiques à un néo-antigène kras/tp53
WO2025146286A1 (fr) Récepteurs de lymphocytes t humains et leurs utilisations
US20250262242A1 (en) Human t cell receptors specific for antigenic peptides derived from mitogen-activated protein kinase 8 interacting protein 2 (mapk8ip2), epstein-barr virus or human endogenous retrovirus, and uses thereof
US20230338423A1 (en) Targetable immune checkpoint for immunotherapy
US20240269177A1 (en) Subject-Specific Tumor Inhibiting Cells and the Use Thereof
US20250312465A1 (en) Stroma penetrating therapeutic t-cell engager for cancer immunotherapy
US20250213687A1 (en) Therapeutic t cell product
US20240299546A1 (en) High potency t cell receptors for immunotherapy
WO2025034996A1 (fr) Lymphocytes t modifiés comportant des récepteurs de cellules nk et leurs utilisations
CN121127257A (zh) 携带kras结合蛋白并敲除内源性tcr的宿主细胞及其使用方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25710339

Country of ref document: EP

Kind code of ref document: A1