WO2021079122A1 - Engineered regulatory t cell - Google Patents

Engineered regulatory t cell Download PDF

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Publication number
WO2021079122A1
WO2021079122A1 PCT/GB2020/052659 GB2020052659W WO2021079122A1 WO 2021079122 A1 WO2021079122 A1 WO 2021079122A1 GB 2020052659 W GB2020052659 W GB 2020052659W WO 2021079122 A1 WO2021079122 A1 WO 2021079122A1
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WO
WIPO (PCT)
Prior art keywords
tcr
cell
seq
chain
foxp3
Prior art date
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Ceased
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PCT/GB2020/052659
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English (en)
French (fr)
Inventor
Hans Stauss
Sharyn THOMAS
Olivier PREHAM
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UCL Business Ltd
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UCL Business 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
Priority claimed from GB201915347A external-priority patent/GB201915347D0/en
Priority claimed from GB201915354A external-priority patent/GB201915354D0/en
Priority claimed from GB201915341A external-priority patent/GB201915341D0/en
Priority claimed from GB201915366A external-priority patent/GB201915366D0/en
Priority claimed from GB201915344A external-priority patent/GB201915344D0/en
Priority claimed from GB201915348A external-priority patent/GB201915348D0/en
Priority claimed from GB201915351A external-priority patent/GB201915351D0/en
Priority claimed from GB201915360A external-priority patent/GB201915360D0/en
Priority claimed from GB201915357A external-priority patent/GB201915357D0/en
Priority claimed from GB201915362A external-priority patent/GB201915362D0/en
Priority to CA3154606A priority Critical patent/CA3154606A1/en
Priority to JP2022523913A priority patent/JP2022553540A/ja
Priority to US17/771,466 priority patent/US20220364057A1/en
Priority to CN202080076993.4A priority patent/CN114641564B/zh
Application filed by UCL Business Ltd filed Critical UCL Business Ltd
Priority to EP20800254.3A priority patent/EP4048294A1/en
Priority to AU2020370033A priority patent/AU2020370033A1/en
Publication of WO2021079122A1 publication Critical patent/WO2021079122A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/7051—T-cell receptor (TcR)-CD3 complex
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K40/20—Cellular immunotherapy characterised by the effect or the function of the cells
    • A61K40/22—Immunosuppressive or immunotolerising
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • C07K14/4702—Regulators; Modulating activity
    • 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
    • C07K14/4713—Autoimmune diseases, e.g. Insulin-dependent diabetes mellitus, multiple sclerosis, rheumathoid arthritis, systemic lupus erythematosus; Autoantigens
    • 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
    • C12N15/86—Viral vectors
    • 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
    • C12N5/0637—Immunosuppressive T lymphocytes, e.g. regulatory T cells or Treg
    • 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
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/10041—Use of virus, viral particle or viral elements as a vector
    • C12N2740/10043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

  • the a chain of the TCR may comprise three CDRs having the following amino acid sequences: CDR1a - TSINN (SEQ ID NO: 3)
  • a method for treating or preventing a disease in a subject in need of same which comprises the step of administering an engineered Treg or pharmaceutical composition according to the invention to the subject.
  • the repertoire of TOR variable regions is generated by combinatorial joining of variable (V), joining (J) and diversity (D) genes; and by N region diversification (nucleotides inserted by the enzyme deoxynucleotidyl-transferase).
  • V variable
  • J joining
  • D diversity
  • N region diversification nucleotides inserted by the enzyme deoxynucleotidyl-transferase
  • the TCR is codon optimised for expression in a mouse.
  • the delimitations of the FR and CDR regions are defined within the IMGT numbering system.
  • the FR1 region comprises positions 1-26 (25-26 amino acids, depending on the V-GENE group or subgroup) with 1st-CYS at position 23.
  • the FR2 region comprises positions 39-55 (16-17 amino acids) with a conserved TRP at position 41.
  • the FR3 region comprises positions 66-104 (36-39 amino acids, depending on the VGENE group or subgroup) with a conserved hydrophobic amino acid at position 89 and the 2nd-CYS at position 104.
  • Residue 1 of the IGMT numbering system is the first residue in FR1.
  • Residue 104 of the IGMT numbering system is the last residue in FR3.
  • An aliphatic, polar uncharged amino may be a cysteine, serine, threonine, methionine, asparagine or glutamine residue.
  • the nucleotide sequence encoding the TCR a chain variable regions may comprise SEQ ID NO: 14 or a sequence having at least 80% sequence identity to SEQ ID NO: 14.
  • the nucleotide sequence may have at least 85%, 90%, 95%, or 99% identity to SEQ ID NO: 14.
  • the polynucleotide may comprise a nucleic acid sequence encoding an a chain and a nucleic acid sequence a b chain linked by an internal self-cleaving sequence.
  • the alignment process itself is typically not based on an all-or-nothing pair comparison. Instead, a scaled similarity score matrix is generally used that assigns scores to each pairwise comparison based on chemical similarity or evolutionary distance.
  • a scaled similarity score matrix is generally used that assigns scores to each pairwise comparison based on chemical similarity or evolutionary distance.
  • An example of such a matrix commonly used is the BLOSUM62 matrix - the default matrix for the BLAST suite of programs.
  • GCG Wisconsin programs generally use either the public default values or a custom symbol comparison table if supplied (see user manual for further details). It is preferred to use the public default values for the GCG package, or in the case of other software, the default matrix, such as BLOSUM62.
  • the variant maintains the function of the parent sequence.
  • the host cell may be any cell which can be used to express and produce a TCR.
  • stem cell means an undifferentiated cell which is capable of indefinitely giving rise to more stem cells of the same type, and from which other, specialised cells may arise by differentiation.
  • Stem cells are multipotent. Stem cells may be for example, embryonic stem cells or adult stem cells.
  • the term “regulatory T cell” or Treg means a T cell which expresses the markers CD4, CD25 and FOXP3 (CD4 + CD25 + FOXP3 + ). Tregs may also be identified using the cell surface markers CD4 and CD25 in the absence of or in combination with low-level expression of the surface protein CD127 (CD4 + CD25 + CD127 ⁇ ). Tregs may also express on the cell surface, high levels of CTLA-4 (cytotoxic T-lymphocyte associated molecule-4) or GITR (glucocorticoid-induced TNF receptor). Unlike conventional T cells, regulatory T cells do not produce IL-2 and are therefore anergic at baseline. Treg cells include thymus-derived, natural Treg (nTreg) cells and peripherally generated, induced Treg (iTreg) cells.
  • a Treg is a CD4 + CD25 + CD127 ⁇ T cell.
  • the present invention provides a method for treating and/or preventing a disease which comprises the step of administering an engineered Treg of the present invention to a subject.
  • the invention provides a method for producing an engineered Treg, which method comprises introducing into a cell in vitro or ex vivo a polynucleotide encoding a TCR as defined herein and a polynucleotide encoding a FOXP3 protein.
  • the cell may be a natural Treg as defined herein.
  • the polynucleotide encoding a TCR as defined herein and the polynucleotide encoding a FOXP3 protein are provided as separate polynucleotides.
  • the separate polypeptides are introduced separately, sequentially or simultaneously into the cell.
  • the Ob-1A12 TCR was cloned into the retroviral pMP71 vector using the alpha chain - P2A - beta chain - T2A - truncated murine CD19 (tmCD19) configuration ( Figure 1A).
  • Figure 5 B shows splenocytes from mice that received Treg transduced with TCR or TCR+FOXP3 stained with Thy1.1 to identify transferred cells (top panel) and FOXP3 and TCR (bottom panel).
  • Figure 5, C shows cumulative data showing fold change in transduction efficiency (left panel) and fold change in absolute number of transduced cells (right panel) relative to day of injection for Treg transduced with TCR or TCR+FOXP3.
  • Figure 5, D shows a representative expression of FOXP3 within transduced cells 7 weeks after transfer. Graphs show cumulative of percentage FOXP3+ cells within the transduced population at week 7 (left) and the fold change in FOXP3+ cells relative to the day of injection.
  • Example 2B - Treg expressing exogenous FOXP3 retain Treg functionality after 7 weeks in vivo whilst Tregs not expressing exogenous FOXP3 acquire the ability to produce effector cytokines

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Zoology (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Biotechnology (AREA)
  • Wood Science & Technology (AREA)
  • Molecular Biology (AREA)
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  • Cell Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Toxicology (AREA)
  • Hematology (AREA)
  • General Engineering & Computer Science (AREA)
  • Microbiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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PCT/GB2020/052659 2019-10-23 2020-10-22 Engineered regulatory t cell Ceased WO2021079122A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
JP2022523913A JP2022553540A (ja) 2019-10-23 2020-10-22 操作された制御性ｔ細胞
AU2020370033A AU2020370033A1 (en) 2019-10-23 2020-10-22 Engineered regulatory T cell
EP20800254.3A EP4048294A1 (en) 2019-10-23 2020-10-22 Engineered regulatory t cell
CN202080076993.4A CN114641564B (zh) 2019-10-23 2020-10-22 工程化的调节性t细胞
CA3154606A CA3154606A1 (en) 2019-10-23 2020-10-22 Engineered regulatory t cell
US17/771,466 US20220364057A1 (en) 2019-10-23 2020-10-22 Engineered regulatory t cell

Applications Claiming Priority (20)

Application Number Priority Date Filing Date Title
GB201915348A GB201915348D0 (en) 2019-10-23 2019-10-23 Engineered regulatory t cell
GB201915357A GB201915357D0 (en) 2019-10-23 2019-10-23 Engineered regulatory t cell
GB201915360A GB201915360D0 (en) 2019-10-23 2019-10-23 Engineered regulatory t cell
GB201915362A GB201915362D0 (en) 2019-10-23 2019-10-23 Engineered regulatory t cell
GB1915362.6 2019-10-23
GB1915341.0 2019-10-23
GB201915354A GB201915354D0 (en) 2019-10-23 2019-10-23 Engineered regulatory t cell
GB1915348.5 2019-10-23
GB201915351A GB201915351D0 (en) 2019-10-23 2019-10-23 Engineered regulatory t cell
GB201915344A GB201915344D0 (en) 2019-10-23 2019-10-23 Engineered regulatory T cell
GB1915347.7 2019-10-23
GB1915366.7 2019-10-23
GB201915347A GB201915347D0 (en) 2019-10-23 2019-10-23 Engineered regulatory t cell
GB1915351.9 2019-10-23
GB1915354.3 2019-10-23
GB1915360.0 2019-10-23
GB201915366A GB201915366D0 (en) 2019-10-23 2019-10-23 Engineered regulatory t cell
GB1915357.6 2019-10-23
GB1915344.4 2019-10-23
GB201915341A GB201915341D0 (en) 2019-10-23 2019-10-23 Engineered regulatory T cell

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PCT/GB2020/052659 Ceased WO2021079122A1 (en) 2019-10-23 2020-10-22 Engineered regulatory t cell

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US (1) US20220364057A1 (https=)
EP (1) EP4048294A1 (https=)
JP (1) JP2022553540A (https=)
CN (1) CN114641564B (https=)
AU (1) AU2020370033A1 (https=)
CA (1) CA3154606A1 (https=)
WO (1) WO2021079122A1 (https=)

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WO2023050063A1 (zh) * 2021-09-28 2023-04-06 溧阳瑅赛生物医药有限公司 一种识别hla-a*02:01/e629-38的tcr及其应用
WO2024039576A3 (en) * 2022-08-19 2024-03-28 Memorial Sloan-Kettering Cancer Center T cell receptors targeting ras mutations and uses thereof
WO2024036290A3 (en) * 2022-08-12 2024-05-16 Abata Therapeutics, Inc. Cell therapies for multiple sclerosis

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023050063A1 (zh) * 2021-09-28 2023-04-06 溧阳瑅赛生物医药有限公司 一种识别hla-a*02:01/e629-38的tcr及其应用
WO2024036290A3 (en) * 2022-08-12 2024-05-16 Abata Therapeutics, Inc. Cell therapies for multiple sclerosis
WO2024039576A3 (en) * 2022-08-19 2024-03-28 Memorial Sloan-Kettering Cancer Center T cell receptors targeting ras mutations and uses thereof

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CN114641564B (zh) 2024-07-19
US20220364057A1 (en) 2022-11-17
CA3154606A1 (en) 2021-04-29
EP4048294A1 (en) 2022-08-31
CN114641564A (zh) 2022-06-17
JP2022553540A (ja) 2022-12-23
AU2020370033A1 (en) 2022-06-02

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