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NZ747982B2 - T cell receptors - Google Patents
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NZ747982B2 - T cell receptors - Google Patents

T cell receptors Download PDF

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Publication number
NZ747982B2
NZ747982B2 NZ747982A NZ74798217A NZ747982B2 NZ 747982 B2 NZ747982 B2 NZ 747982B2 NZ 747982 A NZ747982 A NZ 747982A NZ 74798217 A NZ74798217 A NZ 74798217A NZ 747982 B2 NZ747982 B2 NZ 747982B2
Authority
NZ
New Zealand
Prior art keywords
amino acid
tcr
sequence
seq
acid residues
Prior art date
Application number
NZ747982A
Other versions
NZ747982A (en
Inventor
Eleanor Bagg
William Lawrance
Nicholas Tribble
Original Assignee
Adaptimmune Limited
Filing date
Publication date
Application filed by Adaptimmune Limited filed Critical Adaptimmune Limited
Priority claimed from PCT/EP2017/058576 external-priority patent/WO2017174822A1/en
Publication of NZ747982A publication Critical patent/NZ747982A/en
Publication of NZ747982B2 publication Critical patent/NZ747982B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1774—Immunoglobulin superfamily (e.g. CD2, CD4, CD8, ICAM molecules, B7 molecules, Fc-receptors, MHC-molecules)
    • 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
    • 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
    • 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
    • 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
    • C07K14/70539—MHC-molecules, e.g. HLA-molecules
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2833—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against MHC-molecules, e.g. HLA-molecules
    • 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
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/62—DNA sequences coding for fusion proteins
    • 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
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • 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
    • C12N2510/00—Genetically modified cells
    • 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
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0636—T lymphocytes

Abstract

The present invention relates to T cell receptors (TCRs) which bind the HLA-A*0201 restricted peptide GVYDGEEHSV (SEQ ID NO: 1) derived from the MAGE-B2 protein. The TCRs of the invention demonstrate excellent specificity profiles for this MAGE epitope. Also provided are nucleic acids encoding the TCRs, cells engineered to present the TCRs, cells harbouring expression vectors encoding the TCRs and pharmaceutical compositions comprising the TCRs, nucleic acids or cells of the invention.

Claims (19)

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:
1. A T cell receptor (TCR) that comprises a TCR alpha chain variable domain and a TCR beta chain variable domain, wherein: 5 Alpha CDR1 is VSPFSN; Alpha CDR2 is LTIMTF or LTRMTF; Alpha CDR3 is CVVSGGTDSWGKLQF; Beta CDR1 is KGHDR or KGRDR; Beta CDR2 is SFDVK; and 10 Beta CDR3 is CATSGQGAYREQFF, CATSGQGAYKEQFF or CATSGQGAYNEQFF.
2. A TCR according to claim 1, wherein the TCR has the property of binding to GVYDGEEHSV (SEQ ID No: 1) in complex with HLA-A*0201 with a dissociation constant of from 0.05 µM to 20.0 µM when measured with surface plasmon resonance at 25ºC and at a pH between 7.1 and 7.5 using a soluble form of the TCR, and has at least a ten-fold selectivity of binding to 15 SEQ ID No:1 in complex with HLA-A*0201 over binding to GVYDGREHTV (SEQ ID No 2) in complex with HLA-A*0201, and wherein the TCR variable domains form contacts with at least residues V2, Y3 and D4 of GVYDGEEHSV (SEQ ID No: 1).
3. A TCR according to claim 1 or 2, which is an alpha-beta heterodimer, having an alpha chain TRAV10 + TRAC constant domain sequence and a beta chain TRBV24-1 + TRBC-2 constant 20 domain sequence.
4. A TCR as claimed in claim 1 or 2, which is in single chain format of the type Va-L-Vß, Vß-
5. L-Va, Va-Ca-L-Vß, or Va-L-Vß-Cß, wherein Va and Vß are TCR a and ß variable regions respectively, Ca and Cß are TCR a and ß constant regions respectively, and L is a linker sequence. 25 5. A TCR as claimed in any one of the preceding claims, which is covalently associated with a detectable label, a therapeutic agent or a PK modifying moiety.
6. A TCR as claimed in any one of the preceding claims, wherein the TCR alpha chain variable domain comprises an amino acid sequence that has at least 80% identity to the sequence of amino acid residues 1-105 of SEQ ID No: 3 and wherein Alpha CDR2 is LTRMTF, 30 and/or the TCR beta chain variable domain comprises an amino acid sequence that has at least 80% identity to the sequence of amino acid residues 1-123 of SEQ ID No: 4 and wherein Beta CDR1 is KGRDR, and/or Beta CDR3 is CATSGQGAYREQFF.
7. A TCR as claimed in any one of the preceding claims, wherein the TCR alpha chain variable domain is comprised in a sequence in which: (i) amino acid residues 1-27 thereof has (a) at least 90% identity to the sequence of amino acid residues 1-27 of SEQ ID No: 3 or (b) one, two or three amino acid insertions, deletions or substitutions relative to the sequence of (a); (ii) amino acid residues 28-33 is VSPFSN; 5 (iii) amino acid residues 34-47 thereof has (a) at least 90% identity to the sequence of amino acid residues 34-47 of SEQ ID NO: 3 or (b) one, two or three amino acid insertions, deletions or substitutions relative to the sequence of (a); (iv) amino acid residues 48-53 is LTIMTF or LTRMTF; (v) amino acid residues 54-90 thereof has (a) at least 90% identity to the sequence of amino 10 acid residues 54-90 of SEQ ID No: 3 or (b) one, two or three amino acid insertions, deletions or substitutions relative to the sequence of (a); and (vi) amino acid residues 91-105 is CVVSGGTDSWGKLQF.
8. A TCR as claimed in any one of the preceding claims, wherein the TCR alpha chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 3 or 7. 15 9. A TCR according to any one of the preceding claims, wherein the TCR beta chain variable domain in comprised in a sequence in which: (i) amino acid residues 1-45 thereof has (a) at least 90% identity to the sequence of amino acid residues 1-45 of SEQ ID No: 4 or (b) one, two or three amino acid insertions, deletions or substitutions relative to the sequence of (a); 20 (ii) amino acid residues 46-50 is KGHDR or KGRDR (iii) amino acid residues 51-67 thereof has (a) at least 90% identity to the sequence of amino acid residues 51-67 of SEQ ID NO: 4 or (b) one, two or three amino acid insertions, deletions or substitutions relative to the sequence of (a); (iv) amino acid residues 68-72 is SFDVK; 25 (v) amino acid residues 73-109 thereof has (a) at least 90% identity to the sequence of amino acid residues 73-109 of SEQ ID NO: 4 or (b) one, two or three amino acid insertions, deletions or substitutions relative to the sequence of (a); and (vi) amino acid residues 110-123 is CATSGQGAYNEQFF or CATSGQGAYREQFF or
9. CATSGQGAYKEQFF. 30 10. A TCR according to any one of the preceding claims, wherein the TCR beta chain variable domain is comprised in the amino acid sequence of any one of SEQ ID NOs: 4, 8, 9 or
10.
11. A TCR according to any one of the preceding claims, wherein: the TCR alpha chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 3, and the TCR beta chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 4; or the TCR alpha chain variable domain is comprised in the amino acid sequence of SEQ ID 5 NO: 7, and the TCR beta chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 4; or the TCR alpha chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 3, and the TCR beta chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 8; or 10 the TCR alpha chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 3, and the TCR beta chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 9; or the TCR alpha chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 7, and the TCR beta chain variable domain is comprised in the amino acid sequence of SEQ 15 ID NO: 9; or the TCR alpha chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 3, and the TCR beta chain variable domain is comprised in the amino acid sequence of SEQ ID NO: 10.
12. Nucleic acid encoding a TCR as claimed in any one of the preceding claims. 20
13. An isolated cell, presenting a TCR as claimed in any one of claims 1 to 11.
14. The isolated cell according to claim 13, wherein the cell is a T-cell.
15. An isolated cell presenting a TCR encoded by a nucleic acid, wherein the nucleic acid encodes a TCR that comprises: (A) a TCR alpha chain variable domain in which: 25 (i) amino acid residues 1-27 thereof has (a) at least 90% identity to the sequence of amino acid residues 1-27 of SEQ ID No: 3 or (b) one, two or three amino acid insertions, deletions or substitutions relative to the sequence of (a); (ii) amino acid residues 28-33 is VSPFSN; (iii) amino acid residues 34-47 thereof has (a) at least 90% identity to the sequence of 30 amino acid residues 34-47 of SEQ ID NO: 3 or (b) one, two or three amino acid insertions, deletions or substitutions relative to the sequence of (a); (iv) amino acid residues 48-53 is LTIMTF or LTRMTF; (v) amino acid residues 54-90 thereof has (a) at least 90% identity to the sequence of amino acid residues 54-90 of SEQ ID No: 3 or (b) one, two or three amino acid insertions, 35 deletions or substitutions relative to the sequence of (a); and (vi) amino acid residues 91-105 is CVVSGGTDSWGKLQF; and (B) a TCR beta chain variable domain in which: (i) amino acid residues 1-45 thereof has (a) at least 90% identity to the amino acid sequence of residues 1-45 of SEQ ID No: 4 or (b) one, two or three amino acid insertions, 5 deletions or substitutions relative to the sequence of (a); (ii) amino acid residues 46-50 is KGHDR or KGRDR; (iii) amino acid residues 51-67 thereof has (a) at least 90% identity to the sequence of amino acid residues 51-67 of SEQ ID NO: 4 or (b) one, two or three amino acid insertions, deletions or substitutions relative to the sequence of (a); 10 (iv) amino acid residues 68-72 is SFDVK; (v) amino acid residues 73-109 thereof has (a) at least 90% identity to the sequence of amino acid residues 73-109 of SEQ ID NO: 4 or (b) one, two or three amino acid insertions, deletions or substitutions relative to the sequence of (a); and (vi) amino acid residues 110-123 is CATSGQGAYREQFF, CATSGQGAYKEQFF or 15 CATSGQGAYNEQFF.
16. An isolated cell harbouring (a) a TCR expression vector which comprises nucleic acid as claimed in claim 12 in a single open reading frame, or two distinct open reading frames encoding the alpha chain and the beta chain respectively; or 20 (b) a first expression vector which comprises nucleic acid encoding the alpha chain of a TCR as claimed in any of claims 1 to 11, and a second expression vector which comprises nucleic acid encoding the beta chain of a TCR as claimed in any of claims 1 to 11.
17. A pharmaceutical composition comprising a TCR as claimed in any one of claims 1 to 11, nucleic acid of claim 12 or a cell as claimed in any one of claims 13 to 16, together with one or 25 more pharmaceutically acceptable carriers or excipients.
18. The TCR of any one of claims 1 to 11, nucleic acid of claim 12 or cell of any one of claims 13 to 16 for use in medicine.
19. Use of the TCR of any one of claims 1 to 11, the nucleic acid of claim 12, or the cell of any one of claims 13 to 16, in the manufacture of a medicament for the treatment of cancer.
NZ747982A 2017-04-10 T cell receptors NZ747982B2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB201606172 2016-04-08
PCT/EP2017/058576 WO2017174822A1 (en) 2016-04-08 2017-04-10 T cell receptors

Publications (2)

Publication Number Publication Date
NZ747982A NZ747982A (en) 2024-12-20
NZ747982B2 true NZ747982B2 (en) 2025-03-21

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