WO2017201635A1 - Expression cellulaire de hyaluronidase et utilisation de cette dernière dans la thérapie cellulaire contre des tumeurs solides - Google Patents

Expression cellulaire de hyaluronidase et utilisation de cette dernière dans la thérapie cellulaire contre des tumeurs solides Download PDF

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WO2017201635A1
WO2017201635A1 PCT/CN2016/000275 CN2016000275W WO2017201635A1 WO 2017201635 A1 WO2017201635 A1 WO 2017201635A1 CN 2016000275 W CN2016000275 W CN 2016000275W WO 2017201635 A1 WO2017201635 A1 WO 2017201635A1
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hyaluronidase
cells
sequence
gene
car
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Chinese (zh)
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蔡胜和
赵昕
刘瑾
蔡林志
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    • 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
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy

Definitions

  • the present invention discloses a cell expression of hyaluronidase and a method of use thereof in the treatment of solid tumor cells.
  • Cell therapy is the treatment of disease with cells. Compared with organic small molecule drugs and biomacromolecular drugs, cells as a drug have significant curative effects and a wide range of indications. Cell therapy is increasingly becoming an important means of treating and curing diseases in humans.
  • Cellular therapy can be used to treat many diseases, such as diabetes, infectious diseases, neurodegenerative diseases, and a wide variety of cancers.
  • Cells that can act as drugs mainly include different types of immune cells and stem cells. These cells, through amplification, activation, and genetic modification in various ways, have become important weapons for treating and curing diseases.
  • T lymphocytes T
  • natural killers Natural killers
  • NK-T cells Natural killers
  • T (4) dendritic cells (DC)
  • CIK cytokine-induced killers
  • CTL Cytotoxic lymphocytes
  • TIL Tumor infiltrating lymphocytes
  • CAR Chimeric Antigen Receptor
  • CAR-T T cell receptors
  • TCR-T T cell receptors
  • TCR-T T cell receptors
  • CAR-T cell therapy is used in combination with other therapeutic drugs, for example, in combination with chemotherapeutic drugs, in combination with cancer therapeutic antibody drugs such as immunological checkpoint antibodies (Clin Cancer Res. 2013 Oct15; 19(20): 5636-46. Doi:10.1158/1078-0432.CCR-13-0458).
  • CAR-T design Optimize the CAR-T design.
  • different CAR-Ts are designed to recognize more specific antigen targets of different malignant solid tumors (including advanced or metastatic malignant solid tumors); on the other hand, design a CAR-T to recognize two or Specific antigenic targets for multiple malignant solid tumors (including advanced or metastatic malignant solid tumors) (Nat Rev Clin Oncol. 2016 Mar 22.doi:10.1038/nrclinonc.2016.36); and, in the CAR-T design Regulatory elements, regulation of CAR-T activity, strength and weakness with other drugs or other methods (Science.2015 Oct 16; 350 (6258): aab4077.doi: 10.1126/science.aab4077).
  • CAR-T cells express IL-12 or other cytokines while expressing CAR to further enhance CAR-T anti-tumor activity, so-called "Trucks" (T cells redirected for universal cytokine-mediated killing) (Expert 0pin Biol Ther .2015;15(8):1145-54.doi:10.1517/14712598.2015.1046430); or co-expressing catalase to protect T cells from reactive oxygen species damage to T cell structure and function (J Immunol.2016Jan 15;196(2):759-66.doi:10.4049/jimmunol.1401710); alternatively, co-expressing heparanase to enhance T cell entry into the tumor stroma and enhance T cell infiltration (Nat Med) .2015 May; 21(5): 524-9.doi: 10.1038/nm.3833; PCT/US2014/020936).
  • CAR-T treats malignant solid tumors (There are still significant obstacles including advanced or metastatic malignant solid tumors (J Immunol Res. 2016; 2016: 3850839. doi: 10.1155/2017/3850839; Mol Ther Oncolytics. 2016 Apr 13; 3: 16006. doi: 10.1038/mto. 2016.6).
  • CAR-T The main obstacle to the treatment of malignant solid tumors (including advanced or metastatic malignant solid tumors) by CAR-T is that CAR-T is difficult to enter into malignant solid tumors (including advanced or metastatic malignant solid tumors), and anti-tumor of CAR-T The function cannot be fully utilized.
  • the present invention expresses the hyaluronidase on the surface of CAR-T or other cells, promotes the entry of cells such as CAR-T into malignant solid tumors (including advanced or metastatic malignant solid tumors), and enhances the malignancy of cells such as CAR-T. Efficacy in the treatment of solid tumors, including advanced or metastatic malignant solid tumors.
  • Hyaluronidases (EC 3.2.1.35) are a family of enzymes that are capable of decomposing hyaluronic acid. Human hyaluronidase is encoded by six genes in which expression of hyaluronidase activity includes HYAL1 (NP_149349), HYAL2 (NP_003764), and PH-20/SPAM1 (NP_001167515). Hyaluronidase catalyzes the hydrolysis of hyaluronic acid. Hyaluronic acid is a component of the extracellular matrix (ECM). Hyaluronidase reduces the viscosity of hyaluronic acid by hydrolyzing hyaluronic acid and enhances tissue permeability. Hyaluronidase, in combination with other drugs, promotes drug diffusion and delivery (Chem Rev. 2006 Mar; 106(3): 818-839).
  • Hyaluronidase has been approved by the FDA as a drug.
  • the human hyaluronidase PH-20 drug from the genetic recombination source is sold under the trade name Hylenex.
  • HyQvia a sub-cutaneous immunoglobulin (SCIG) using recombinant human hyaluronidase Hylenex.
  • SCIG sub-cutaneous immunoglobulin
  • HyQvia contains hyaluronidase Hylenex to allow subcutaneous injection of large volumes of SCIG.
  • Roche has combined its cancer therapeutic antibody drug Herceptin with Halozyme's recombinant human hyaluronidase Hylenex as a subcutaneous injection. This dosage form has been approved by the European Union on September 2, 2013 and is in Phase III clinical trials in the United States.
  • the Herceptin subcutaneous injection form containing hyaluronidase takes only 3-5 minutes, while the standard intravenous injection takes 30-90 minutes.
  • the present invention expresses the hyaluronidase on the surface of CAR-T or other cells, promotes the entry of cells such as CAR-T into malignant solid tumors (including advanced or metastatic malignant solid tumors), and enhances the malignancy of cells such as CAR-T. Efficacy in the treatment of solid tumors, including advanced or metastatic malignant solid tumors.
  • hyaluronidase can be expressed as a secreted protein
  • CAR-T cells or other cells express hyaluronidase
  • hyaluronidase is secreted outside the cell
  • free hyaluronidase acts outside the cell.
  • hyaluronidase can be expressed as a transmembrane fusion protein.
  • hyaluronidase In the natural state, hyaluronidase is expressed in the form of a secreted protein rather than a transmembrane protein.
  • the hyaluronidase protein coding sequence is included as an extracellular domain sequence, with a signal peptide sequence, a hinge sequence, a transmembrane sequence, and a cytoplasmic domain. Sequence fusion to form a fusion gene [see Figure (1)].
  • This fusion protein gene is transferred to CAR-T or other immune cells and can express hyaluronidase protein on the cell surface [see Figure (2)] for malignant solid tumors (including advanced or metastatic malignant solid tumors). Cell therapy.
  • the hyaluronidase coding sequence in the secretory hyaluronidase or hyaluronidase transmembrane fusion protein gene sequence can be derived from human HYAL1 (NP_149349), HYAL2 (NP_003764) and PH-20/.
  • SPAM1 NP_001167515
  • the hyaluronidase coding sequence in the secretory hyaluronidase or hyaluronidase transmembrane fusion protein gene sequence may be all protein coding sequences or may contain hyaluronidase-encoding activity. Partial sequence.
  • the signal peptide sequence, the hinge region sequence, the transmembrane region sequence and the intracellular region sequence in the hyaluronidase transmembrane fusion protein gene sequence can be derived from any fusion protein.
  • the secretory hyaluronidase or hyaluronidase transmembrane fusion protein gene can be expressed not only on the surface of CAR-T cells but also on the surface of other immune cells, including but not limited to T cells.
  • a CAR-T cell or other immune cell expressing a secretory hyaluronidase or a hyaluronidase transmembrane fusion protein gene maintains a specific anti-tumor function determined by CAR-T while passing through it.
  • the hyaluronidase expressed by the cell breaks down hyaluronic acid in the tissues of malignant solid tumors (including advanced or metastatic malignant solid tumors), and enhances the entry of immune cells such as CAR-T into malignant solid tumors (including advanced or metastatic malignant solid tumors).
  • CAR-T Enhance the entry and infiltration of immune cells such as CAR-T in malignant solid tumors (including advanced or metastatic malignant solid tumors), and enhance the treatment of malignant solid tumors (including advanced or metastatic malignant solid tumors) by immunological cells such as CAR-T.
  • hyaluronidase activity is limited to specific local malignant solid tumors (including late or metastatic malignant solid tumors) that are specifically defined by other genetic elements of CAR-T cells (eg, CAR).
  • the transmembrane hyaluronidase activity is more concentrated in the specific tumor region determined by CAR-T than the free-type diffusing hyaluronidase, and has a stronger decomposition of hyaluronic acid and a decrease in hyalurance.
  • the viscosity of the acid and the enhancement of the permeability of the ECM tissue are more conducive to the penetration of CAR-T cells into solid tumors and infiltration in solid tumors, thereby enhancing the efficacy of CAR-T cells in the treatment of solid tumors.
  • the secretory hyaluronidase or hyaluronidase transmembrane fusion protein gene can be used as an expression unit alone or in combination with other expression elements to form an expression unit; the secretory hyaluronidase Alternatively, the hyaluronidase transmembrane fusion protein gene can be expressed on the cell surface alone or in combination with other gene expression elements on the cell surface.
  • the CAR-T and other immune cells expressing a secretory hyaluronidase or hyaluronidase transmembrane fusion protein gene are used for the treatment of malignant solid tumors (including advanced or metastatic malignant solid tumors), Including but not limited to originating from human and animal brain, central nervous system, kidney, liver, gallbladder, head and neck, mouth, thyroid, skin, mucous membrane, gland, blood vessels, bone tissue, lymph nodes, lung, esophagus, stomach, breast Primary or secondary cancer, sarcoma or carcinosarcoma of the pancreas, eyes, nasopharynx, uterus, ovary, endometrium, cervix, prostate, bladder, colon or rectum.
  • malignant solid tumors including advanced or metastatic malignant solid tumors
  • malignant solid tumors including advanced or metastatic malignant solid tumors
  • malignant solid tumors including advanced or metastatic malignant solid tumors
  • malignant solid tumors including advanced
  • Figure (1) Schematic diagram of hyaluronidase expression elements
  • the free hyaluronidase gene expression element consists of a signal peptide sequence (SP) and a hyaluronidase coding sequence (HYAL).
  • the transmembrane fusion protein type hyaluronidase gene expression element consists of a signal peptide sequence (SP), an extracellular domain hyaluronidase coding sequence (HYAL), and a hinge sequence (HIN). , transmembrane sequence (TM), cytoplasmic domain sequence (CYTO) composition. Both expression elements contain a promoter sequence (PRO) and 5' and 3' expression control sequences.
  • FIG. 2 Schematic diagram of CAR-T cells co-expressing hyaluronidase transmembrane fusion protein
  • the CAR expressed in T cells consists of CD3XX signal sequence (CD3 ⁇ ), costimulatory signal 1 sequence (co-stim 1), costimulatory signal 2 sequence (co-stim 2), transmembrane sequence (TM), hinge region sequence ( HIN)
  • CD3XX signal sequence CD3 ⁇
  • costimulatory signal 1 sequence co-stim 1
  • costimulatory signal 2 sequence co-stim 2
  • transmembrane sequence TM
  • hinge region sequence HIN
  • scFv single-chain variable region
  • the hyaluronidase transmembrane fusion protein co-expressed by this CAR-T cell is composed of a cytoplasmic domian, a transmembrane sequence (TM), a hinge region (HIN) sequence, and a hyaluronidase sequence. .
  • CAR-T cells co-expressing the hyaluronidase transmembrane fusion protein, degrading hyaluronic acid in the extracellular matrix (ECM) by hyaluronidase on the cell surface, reducing the viscosity of hyaluronic acid and enhancing ECM Tissue permeability, which facilitates the penetration of CAR-T cells into solid tumors And infiltration in solid tumors, thereby enhancing the efficacy of CAR-T cells in the treatment of solid tumors.
  • ECM extracellular matrix
  • hyaluronidase activity is limited to the specific tumor area identified by CAR-T, thereby avoiding the damage of hyaluronidase to healthy tissues.
  • Synthetic hyaluronidase transmembrane fusion protein gene DNA molecule is synthesized by a synthetic method: human hyaluronidase PH-20 coding sequence (NM_001174044.1) including 5'-end signal peptide sequence, human IgG4 hinge sequence, CD8 The transmembrane sequence, the CD28 intracellular sequence, the 4-1BB intracellular sequence, the CD3zeta domain (NM_000734.3) intracellular sequence, and the appropriate restriction endonuclease sites are added to the 5' and 3' ends of the DNA molecule.
  • the synthetic hyaluronidase transmembrane fusion gene was cloned into a lentivirus vector and transfected into a 293FT cell together with a packaging plasmid to prepare a hyaluronidase transmembrane fusion virus.
  • CAR-T cell culture After 3 days of CAR-T cell culture, hyaluronidase transmembrane fusion virus was added to CAR-T cells, and after 6 days of culture, hyaluronidase-positive expression was screened by hyaluronidase antibody immobilized on magnetic beads.
  • CAR-T cells continue to culture CAR-T cells to the required amount, collect hyaluronidase-positive CAR-T cells, and apply to cell therapy of solid tumors (including advanced or metastatic malignant solid tumors).

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  • Proteomics, Peptides & Aminoacids (AREA)
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Abstract

L'invention concerne une protéine de fusion libre ou transmembranaire qui est exprimée par des cellules CAR-T ou d'autres cellules. Tout en maintenant l'activité antitumorale des cellules CAR-T ou des autres cellules, la hyaluronidase exprimée par ces cellules peut dégrader l'acide hyaluronique dans la matrice extracellulaire (MEC), diminuer la viscosité de l'acide hyaluronique, augmenter la perméabilité tissulaire de la MEC, et faciliter la pénétration des cellules CAR-T ou des autres cellules dans les tumeurs solides ainsi que l'infiltration de ces dernières dans les tumeurs solides, permettant ainsi d'améliorer l'efficacité des cellules CAR-T ou des autres cellules dans le traitement des tumeurs solides.
PCT/CN2016/000275 2016-05-23 2016-05-23 Expression cellulaire de hyaluronidase et utilisation de cette dernière dans la thérapie cellulaire contre des tumeurs solides Ceased WO2017201635A1 (fr)

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Cited By (6)

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CN109913422A (zh) * 2017-12-13 2019-06-21 苏州康聚生物科技有限公司 一种包含肿瘤抗原识别受体的免疫细胞及其应用
WO2022229412A1 (fr) * 2021-04-30 2022-11-03 Cellectis S.A. Nouveaux car anti-muc1 et cellules immunitaires modifiées par un gène pour une immunothérapie anticancéreuse de tumeurs solides
WO2023168305A1 (fr) * 2022-03-01 2023-09-07 Exuma Biotech Corp. Particules virales comprenant de l'hyaluronidase liée à une membrane
US12258574B2 (en) 2016-03-19 2025-03-25 Exuma Biotech Corp. Methods and compositions for transducing lymphocytes and regulating the activity thereof
US12325728B2 (en) 2016-03-19 2025-06-10 Exuma Biotech Corp. Methods and compositions for genetically modifying lymphocytes to express polypeptides comprising the intracellular domain of CD79A and CD79B
US12590321B2 (en) 2016-03-19 2026-03-31 Exuma Biotech Corp. Methods and compositions for genetically modifying and expanding lymphocytes and regulating the activity thereof

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12258574B2 (en) 2016-03-19 2025-03-25 Exuma Biotech Corp. Methods and compositions for transducing lymphocytes and regulating the activity thereof
US12325728B2 (en) 2016-03-19 2025-06-10 Exuma Biotech Corp. Methods and compositions for genetically modifying lymphocytes to express polypeptides comprising the intracellular domain of CD79A and CD79B
US12590321B2 (en) 2016-03-19 2026-03-31 Exuma Biotech Corp. Methods and compositions for genetically modifying and expanding lymphocytes and regulating the activity thereof
CN109913422A (zh) * 2017-12-13 2019-06-21 苏州康聚生物科技有限公司 一种包含肿瘤抗原识别受体的免疫细胞及其应用
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WO2022229412A1 (fr) * 2021-04-30 2022-11-03 Cellectis S.A. Nouveaux car anti-muc1 et cellules immunitaires modifiées par un gène pour une immunothérapie anticancéreuse de tumeurs solides
WO2023168305A1 (fr) * 2022-03-01 2023-09-07 Exuma Biotech Corp. Particules virales comprenant de l'hyaluronidase liée à une membrane

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