WO2020242218A1 - Support d'administration de médicament précurseur du glutathion comprenant une glutathion-s-transférase et une protéine, possédant une capacité de liaison pour une cellule cible ou une protéine cible, et utilisation correspondante - Google Patents

Support d'administration de médicament précurseur du glutathion comprenant une glutathion-s-transférase et une protéine, possédant une capacité de liaison pour une cellule cible ou une protéine cible, et utilisation correspondante Download PDF

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WO2020242218A1
WO2020242218A1 PCT/KR2020/006906 KR2020006906W WO2020242218A1 WO 2020242218 A1 WO2020242218 A1 WO 2020242218A1 KR 2020006906 W KR2020006906 W KR 2020006906W WO 2020242218 A1 WO2020242218 A1 WO 2020242218A1
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glutathione
protein
transferase
receptor
target
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PCT/KR2020/006906
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English (en)
Korean (ko)
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김채규
유자형
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울산과학기술원
주식회사 퓨전바이오텍
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Publication of WO2020242218A1 publication Critical patent/WO2020242218A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
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    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
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    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • 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
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • 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
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y205/00—Transferases transferring alkyl or aryl groups, other than methyl groups (2.5)
    • C12Y205/01—Transferases transferring alkyl or aryl groups, other than methyl groups (2.5) transferring alkyl or aryl groups, other than methyl groups (2.5.1)
    • C12Y205/01018—Glutathione transferase (2.5.1.18)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2318/00—Antibody mimetics or scaffolds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • a glutathione precursor drug comprising a protein having glutathione-S-transferase and a target cell or target protein-binding ability as a delivery vehicle and a pharmaceutical composition.
  • anticancer drugs include chemical anticancer drugs, targeted anticancer drugs, and immune anticancer drugs.
  • Chemical anticancer agents are also called cytotoxic anticancer agents and chemical anticancer agents. Although other anticancer drugs are not without side effects, chemotherapy drugs, which are the first-generation anticancer drugs, are the main culprit of white blood cell reduction, hair loss, vomiting, middle age, and diarrhea, which are commonly known side effects of chemotherapy. Using chemical anticancer drugs does not destroy all normal cells. It mainly affects the hematopoietic stem cells, hair follicle cells, oral and intestinal mucosa through which food passes, and reproductive organs of the bone marrow. This is because Hwaak anticancer drugs are designed to find and attack the characteristics of cancer cells that proliferate in a short period of time.
  • CAR-T cell therapy refers to a method of inducing reprogrammed T cells to attack cancer cells by inserting artificially designed genes into T cells extracted from patients.
  • CAR-T therapy shows high therapeutic effect in patients with intractable cancer who do not work well with anticancer drugs, but the toxicity is very strong, and when cytokine release syndrome appears as a side effect, the patient dies in many cases, making it unstable. many.
  • the cost of a single administration reaches 150 million US standards, and the treatment effect is not great for solid cancer.
  • GST glutathione-S-transferase
  • a protein having a target cell or target protein binding ability A linker connecting the glutathione-S-transferase and a protein having the ability to bind to a target cell or a target protein; And it is to provide a drug delivery system containing the glutathione precursor drug combined with the glutathione-S-transferase.
  • GST glutathione-S-transferase
  • a protein having a target cell or target protein binding ability A linker connecting the glutathione-S-transferase and a protein having the ability to bind to a target cell or a target protein;
  • a pharmaceutical composition for preventing or treating cancer comprising a glutathione precursor drug combined with the glutathione-S-transferase.
  • GST glutathione-S-transferase
  • a protein having a target cell or target protein binding ability A linker connecting the glutathione-S-transferase and a protein having the ability to bind to a target cell or a target protein; And administering a composition containing the glutathione precursor drug conjugated to the glutathione-S-transferase to an individual in need thereof.
  • GST glutathione-S-transferase
  • a protein having a target cell or target protein binding ability A linker connecting the glutathione-S-transferase and a protein having the ability to bind to a target cell or a target protein;
  • GST glutathione-S-transferase
  • a linker connecting the glutathione-S-transferase and a protein having the ability to bind to a target cell or a target protein and it is to provide a method for preventing or treating cancer comprising administering a composition containing a glutathione precursor drug conjugated to the glutathione-S-transferase to an individual in need thereof.
  • GST glutathione-S-transferase
  • a protein having a target cell or target protein binding ability A linker connecting the glutathione-S-transferase and a protein having the ability to bind to a target cell or a target protein; And it provides a drug delivery system containing the glutathione precursor drug combined with the glutathione-S-transferase.
  • a protein having the ability to bind to a target cell or a target protein refers to a receptor or a target protein of a cell. It may mean a protein that is specifically recognized or specifically binds to a receptor or a target protein of a cell.
  • the protein that specifically binds to the receptor or target protein of the cell is any one selected from the group consisting of an antibody, an antigen-binding fragment, an affibody, a diabody, and an aptamer. Can be.
  • the term "affibody molecule” may refer to an antibody mimic capable of binding to a specific target protein (receptor).
  • the Affibody molecule is composed of 20 to 150 amino acid residues, and may be composed of 2 to 10 alpha helixes.
  • the affibody molecule may include an anti-ErbB affibody molecule (ab31889), a HER2-specific affibody molecule (ZHER2:342), an anti-EGFR affibody molecule (ZEGFR:2377), and the like.
  • the present invention is not limited thereto, and includes all affibody molecules capable of recognizing a specific receptor or target protein of a cell.
  • target receptors or target proteins examples include amyloid beta peptide, synuclein (e.g., alpha-synuclein), apolipoprotein (e.g., apolipoprotein A1), complement Complement factor (e.g., C5), carbonic anhydrase (e.g. CAIX), interleukin-2 receptor alpha chain (IL2RA; CD25), CD antigen on the cell surface (e.g.
  • the target cell or protein having the ability to bind to the target protein may specifically bind to receptor tyrosine kinases (RTKs). More specifically, the receptor tyrosine kinase is an epidermal growth factor receptor, insulin receptor, platelet-derived growth factor receptor, vascular endothelial growth factor receptor, fibroblast growth factor receptor, cholecystokinin (CCK) receptor, neurotrophic factor (NGF). ) Receptor, hepatocyte growth factor (HGF) receptor, ephrin (Eph) receptor, angiopoietin receptor, and related to receptor tyrosine kinase (RYK) receptor. .
  • RTKs receptor tyrosine kinases
  • the GST and the target cell or a protein having a target protein binding ability may be linked through a linker.
  • the linker may be a polypeptide consisting of 1 to 400, 1 to 200, or 2 to 200 arbitrary amino acids.
  • the peptide linker may include Gly, Asn and Ser residues, and neutral amino acids such as Thr and Ala may also be included.
  • Amino acid sequences suitable for peptide linkers are known in the art. It is also possible to adjust the copy number "n" by taking into account the optimization of the linker to achieve proper separation between functional moieties or to maintain the necessary inter-moiety interaction.
  • the linker may be a flexible linker including G, S, and/or T residues.
  • linkers include (GGGGS) n (SEQ ID NO: 2), (SGGGG) n (SEQ ID NO: 3), (SRSSG) n (SEQ ID NO: 4), (SGSSC) n (SEQ ID NO: 5), (GKSSGSGSESKS) n (SEQ ID NO: 6), (RPPPPC) n (SEQ ID NO: 7), (SSPPPPC) n (SEQ ID NO: 8), (GSTSGSGKSSEGKG) n (SEQ ID NO: 9), (GSTSGSGKSSEGSGSTKG) n (SEQ ID NO: 10), (GSTSGSGKPGSGEGSTKG) n (SEQ ID NO: 11), or (EGKSSGSGSESKEF) n (SEQ ID NO: 12), wherein n is an integer of 1 to 20, or 1 to 10.
  • Another aspect provides a polynucleotide encoding the fusion protein.
  • polynucleotide refers to a deoxyribonucleotide or a polymer of ribonucleotides present in a single-stranded or double-stranded form. It encompasses RNA genomic sequences, DNA (gDNA and cDNA) and RNA sequences transcribed therefrom, and unless specifically stated otherwise, includes natural polynucleotides as well as their analogs with modified sugar or base sites.
  • the polynucleotide is a single chain polynucleotide.
  • Another aspect provides a vector comprising the polynucleotide.
  • the term "vector” refers to a vector capable of expressing a protein of interest in a suitable host cell, and refers to a genetic construct comprising a regulatory element operably linked to express a gene insert.
  • a vector may include an expression control element such as a promoter, an operator, an initiation codon, a stop codon, a polyadenylation signal, and/or an enhancer, and the promoter of the vector may be constitutive or inducible.
  • the vector may be an expression vector capable of stably expressing the fusion protein in a host cell.
  • the expression vector may be a conventional one used in the art to express foreign proteins in plants, animals or microorganisms.
  • the recombinant vector can be constructed through various methods known in the art.
  • the vector may include a selectable marker for selecting a host cell containing the vector, and in the case of a replicable vector, may include an origin of replication.
  • the vector can be self-replicating or introduced into the host DNA, the vector selected from the group consisting of plasmid, lentivirus, adenovirus, adeno-associated virus, retrovirus, herpes simplex virus, and basinia virus. Can be.
  • the vector includes a promoter operable in animal cells, for example, mammalian cells.
  • Suitable promoters include promoters derived from mammalian virus and promoters derived from the genome of mammalian cells, such as CMV (Cytomegalovirus) promoter, U6 promoter and H1 promoter, MLV (Murine Leukemia Virus) LTR (Long terminal repeat) promoter, adenovirus early promoter, adenovirus late promoter, vaccinia virus 7.5K promoter, SV40 promoter, HSV tk promoter, RSV promoter, EF1 alpha promoter, metallotionine promoter, beta-actin promoter, Promoter of human IL-2 gene, promoter of human IFN gene, promoter of human IL-4 gene, promoter of human lymphotoxin gene, promoter of human GM-CSF gene, human phosphoglycerate kinase (PGK) promoter, mouse force Phoglycerate kina
  • the fusion protein described above may be operably linked to a promoter.
  • operably linked refers to a functional linkage between a nucleic acid expression control sequence (eg, a promoter, a signal sequence, or an array of transcriptional regulatory factor binding sites) and another nucleic acid sequence, thereby The regulatory sequence controls the transcription and/or translation of the other nucleic acid sequence.
  • Another aspect provides a host cell comprising the fusion protein, polynucleotide, or vector.
  • the cells are yeast, fungi, protozoa, plants, higher plants and insects, or cells of amphibians, or cells of mammals such as CHO, HeLa, HEK293, and COS-1.
  • yeast fungi, protozoa, plants, higher plants and insects, or cells of amphibians, or cells of mammals such as CHO, HeLa, HEK293, and COS-1.
  • the organism may be yeast, fungi, protozoa, plants, higher plants and insects, amphibians, or mammals.
  • the cells may be animal cells or plant cells.
  • the binding of the glutathione-S-transferase and the glutathione precursor drug may be caused by GSH (Glutathione).
  • the glutathione precursor drug may be any one or more selected from the group consisting of any one of the following Formulas 1 to 7 or a pharmaceutically acceptable salt thereof. Since the glutathione precursor drug contains glutathione, it may be combined with glutathione-S-transferase as described above.
  • GST glutathione-S-transferase
  • a protein having a target cell or target protein binding ability A linker connecting the glutathione-S-transferase and a protein having the ability to bind to a target cell or a target protein;
  • a pharmaceutical composition for preventing or treating cancer comprising a glutathione precursor drug combined with the glutathione-S-transferase.
  • GST glutathione-S-transferase
  • a protein having a target cell or target protein binding ability A linker connecting the glutathione-S-transferase and a protein having the ability to bind to a target cell or a target protein;
  • GST glutathione-S-transferase
  • GST glutathione-S-transferase
  • a protein having a target cell or target protein binding ability A linker connecting the glutathione-S-transferase and a protein having the ability to bind to a target cell or a target protein;
  • GST glutathione-S-transferase
  • a linker connecting the glutathione-S-transferase and a protein having the ability to bind to a target cell or a target protein and it provides a method for preventing or treating cancer comprising administering a composition containing the glutathione precursor drug conjugated to the glutathione-S-transferase to an individual in need thereof.
  • the glutathione precursor drug may be any one or more selected from the group consisting of any one of Formulas 1 to 7 or a pharmaceutically acceptable salt thereof.
  • GST glutathione-S-transferase
  • a protein having a target cell or target protein binding ability a protein having a target cell or target protein binding ability
  • a glutathione precursor drug bound to the glutathione-S-transferase are as described above.
  • subject preferably a mammal, more preferably a human.
  • Mammals include, but are not limited to, murines, monkeys, humans, farm animals, sports animals and pets. Tissues, cells and their progeny of biological entities obtained in vivo or cultured in vitro are also included.
  • therapeutic agent or “pharmaceutical composition” refers to a molecule or compound that imparts several beneficial effects upon administration to a subject.
  • the beneficial effect is to enable diagnostic decisions; Improvement of a disease, symptom, disorder or condition; Reducing or preventing the onset of a disease, symptom, disorder or condition; And the response of a disease, symptom, disorder or condition in general.
  • treatment or “treating” or “relaxing” or “improving” are used interchangeably. These terms refer to methods of obtaining beneficial or desired results, including but not limited to therapeutic benefits and/or prophylactic benefits.
  • a therapeutic benefit refers to any therapeutically significant improvement or effect thereon of one or more diseases, disorders or symptoms under treatment.
  • the composition may be administered to a subject at risk of developing a particular disease, condition, or symptom, or to a subject reporting one or more physiological symptoms of the disease, even if the disease, condition, or symptom is not yet present.
  • an effective amount refers to an amount of an agent sufficient to produce an advantageous or desired result.
  • the therapeutically effective amount may vary according to one or more of the subject and condition to be treated, the weight and age of the subject, the severity of the condition, the mode of administration, and the like, which can be easily determined by those skilled in the art. Further, the term applies to the capacity to provide an image for detection by any of the imaging methods described herein.
  • the specific dosage may vary depending on one or more of the particular agent selected, the dosage regimen that follows, whether it is administered in combination with other compounds, the timing of administration, the tissue being imaged, and the body delivery system carrying it.
  • the cancer may be lung cancer (eg, non-small cell lung cancer), pancreatic cancer, gastric cancer, liver cancer, colon cancer, brain cancer, breast cancer, thyroid cancer, bladder cancer, esophageal cancer, or uterine cancer.
  • the cancer may be any one or more selected from the group consisting of gastric cancer, breast cancer, lung cancer, liver cancer, esophageal cancer, and prostate cancer having resistance to anticancer drugs (eg, multi-drug resistance).
  • the pharmaceutical composition can be administered parenterally during clinical administration and can be used in the form of a general pharmaceutical formulation.
  • Parenteral administration may mean administration through a route other than oral administration such as rectal, intravenous, peritoneal, muscle, arterial, transdermal, nasal, inhalation, ocular and subcutaneous.
  • the pharmaceutical composition of the present invention may further contain one or more active ingredients exhibiting the same or similar functions.
  • the pharmaceutical composition When formulating the pharmaceutical composition, it is prepared by using a diluent or excipient such as a commonly used filler, extender, binder, wetting agent, disintegrant, and surfactant.
  • a diluent or excipient such as a commonly used filler, extender, binder, wetting agent, disintegrant, and surfactant.
  • Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories.
  • the non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used.
  • a base for the suppository Witepsol, Macrogol, Tween 61, cacao butter, liurinji, glycerogelatin, and the like may be used.
  • the pharmaceutical composition may be used by mixing with various carriers (Carriers) allowed as drugs such as physiological saline or organic solvents, and carbohydrates such as glucose, sucrose or dextran, ascorbic acid in order to increase stability or absorption.
  • Carriers allowed as drugs such as physiological saline or organic solvents, and carbohydrates such as glucose, sucrose or dextran, ascorbic acid in order to increase stability or absorption.
  • Antioxidants such as (Ascorbic acid) or glutathione, chelating agents, small molecule proteins or other stabilizers can be used as drugs.
  • the effective dose of the pharmaceutical composition is 0.01 to 100 mg/kg, preferably 0.1 to 10 mg/kg, and may be administered once to three times a day.
  • Another aspect provides a method for preparing a drug delivery system comprising the following steps i) to iii):
  • step i) linking a linker (eg, GSH) to the drug; ii) binding the GST fusion protein to the drug surface bonded to the linker in step i).
  • a linker eg, GSH
  • the delivery system of the glutathione precursor drug not only can the remaining time in the living body be sustained, but also the targeting ability to the target cells is improved and can be effectively delivered to the target cells, so it can be usefully used as a target therapeutic agent. There is an effect.
  • FIG. 1A is a result of confirming that the GST-Afb fusion protein does not decrease cell viability with respect to Afb target cells; And FIG. 1B is a result of confirming the cell targeting ability that the GST-Afb fusion protein exhibits against Afb target cells.
  • Figure 2 is a schematic diagram of the synthesis of entry 2, a type of glutathione precursor drug.
  • entry 3 is a schematic view of the synthesis of entry 3, which is a type of glutathione precursor drug.
  • Figure 4 is a schematic diagram of the synthesis of entry 5, a type of glutathione precursor drug.
  • Figure 5 is a schematic diagram of the synthesis of entry 7, a type of glutathione precursor drug.
  • FIG. 6 is a schematic diagram of the synthesis of entry 9, which is a type of glutathione precursor drug.
  • FIG. 7 is a schematic diagram of the synthesis of Entry 11, a type of glutathione precursor drug.
  • Figure 8 is a schematic diagram of the synthesis of entry 12, a type of glutathione precursor drug.
  • 9 is a graph showing binding affinity when entry 2 binds to a fusion protein.
  • 10 is a graph showing binding affinity when entry 3 binds to a fusion protein.
  • 11 is a graph showing binding affinity when Entry 5 binds to a fusion protein.
  • 12 is a table showing binding affinity values when entries 2,3,5,7,9,11 and 12 bind to a fusion protein.
  • 13 is a graph showing the cytotoxicity of the complex in which the fusion protein and Entry 2 are bound.
  • 15 is a graph showing the cytotoxicity of the complex in which the fusion protein and Entry 5 are bound.
  • 16 is a graph showing the cytotoxicity of the complex in which the fusion protein and Entry 7 are bound.
  • 17 is a graph showing the cytotoxicity of the complex in which the fusion protein and entry 9 are bound.
  • 19 is a graph showing the cytotoxicity of the complex in which the fusion protein and Entry 12 are bound.
  • FIG. 20 is a table showing IC50 values indicating cytotoxicity of complexes in which fusion proteins and entries 2,3,5,7,9,11 and 12 are bound.
  • Example 1 Expression of a fusion protein having glutathione-S-transferase and target cell or target protein binding ability
  • a fusion protein having a target function was prepared.
  • the fusion protein was expressed in a form in which affibody (Afb) capable of specifically binding to a receptor on the surface of cancer cells and GST were combined.
  • HER2 Afb specifically binding to HER2 and EGFR Afb specifically binding to EGFR were used as Afb.
  • a gene encoding an additional linker domain (SEQ ID NO: 1: GGGLVPRGSGGGCGGGGTGGGSGGG) was coupled to the end of the gene encoding each HER2 Afb or EGFR Afb, and then inserted into the pETduet plasmid.
  • a GST-encoding gene designed to connect a 6 ⁇ His tag to the N-terminus of GST was inserted into the pETduet plasmid, and a plasmid for overexpression of the fusion protein (GST-Afb) in which Afb and GST were linked by a linker was prepared.
  • GST-Afb the fusion protein
  • the constructed plasmid was inserted into the E. coli BL21 (DE3) strain and cultured, and then treated with IPTG and cultured at 30° C. for 16 hours to induce overexpression of GST-Afb.
  • the overexpression-induced E was inserted into the E. coli BL21 (DE3) strain and cultured, and then treated with IPTG and cultured at 30° C. for 16 hours to induce overexpression of GST-Afb.
  • coli cells were centrifuged at 4°C for 10 minutes at 5000 ⁇ g to obtain precipitated cells, and the cells were suspended in a phosphate buffer solution (50 mM sodium phosphate and 100 mM sodium chloride, pH 6.5). The cell suspension was treated with lysozyme and incubated for 20 minutes at room temperature, followed by disruption for 30 seconds and ultrasonic disruption for a total of 10 minutes at 1 minute intervals. After crushing, centrifugation was performed at 12000 ⁇ g at 4° C. for 1 hour to obtain a supernatant as a fraction containing GST-Afb.
  • phosphate buffer solution 50 mM sodium phosphate and 100 mM sodium chloride, pH 6.5
  • the supernatant was purified by immobilized metal affinity chromatography (1mL HisTrap FF column, GE HealthCare) using FPLC to separate GST-Afb.
  • the separated GST-Afb (GST-HER2 Afb and GST-EGFR Afb were dialyzed overnight in PBS (pH 7.4) and concentrated.)
  • the concentrated GST-HER2 Afb and GST-EGFR Afb were analyzed by SDS-PAGE and ESI-TOF. The purity and molecular weight of the separated protein were analyzed through electrospray ionization time-of-light mass spectrometry (MS) analysis.
  • MS electrospray ionization time-of-light mass spectrometry
  • SK-BR-3 cells a human breast cancer cell line
  • the prepared SK-BR-3 cells were cultured in DMEM medium (11995065, Invitrogen, S. Korea). 10% fetal bovine serum (FBS), 100 ⁇ g/ml streptomycin and 100 U/ml penicillin were added to the medium, and the medium was changed once daily during the culture period.
  • FBS fetal bovine serum
  • the culture environment was maintained in a 5% CO2 incubator at 37°C. When the cells proliferated to 85% saturation after cell inoculation, adherent cultured cells were separated and used in experiments.
  • SK-BR-3 cells were isolated, each cell was inoculated into a 96-well plate (Thermo Scientific Inc. Korea) at a concentration of 5x10 3 cells/well, and cultured in a 5% CO 2 incubator at 37° C. for 24 hours. Then, the GST-HER2 Afb obtained in Example ⁇ 1-1> was treated with the SK-BR-3 cells at a concentration of 0.3 ⁇ M to 10 ⁇ M, and further cultured for 24 hours. After completion of the culture, cell viability was confirmed using alamar blue dye (DAL 2015, Invitrogen, Korea).
  • the excitation wavelength for the fluorescent dye was set to 565 nm, and the monitoring emission was set to 590 nm, and fluorescence analysis was performed with a fluorescent plate reader (Tecan Infinite Series, Germany).
  • GST among GST-HER2 Afb was labeled with fluorescence-5-maleimide (F5M) to confirm the location of GST-HER2 Afb absorbed into cells (cell uptake).
  • F5M fluorescence-5-maleimide
  • normal epithelial cell line MCF-10A cells were used to perform the same method to confirm cell viability and intracellular absorption.
  • GST-HER2 Afb does not show toxicity to cells, but can be specifically absorbed by cancer cells.
  • GST-HER2 Afb was treated and cultured on SK-BR-3 cells and MCF-10A cells, it was confirmed that the degree of apoptosis was not exhibited regardless of the treatment concentration, so that cytotoxicity was not exhibited by GST-Afb (Fig. ), GST-HER2 Afb showed binding ability to bind only to SK-BR-3 cells, which is a breast cancer cell line, and it was confirmed that GST-Afb exhibited a specific targeting ability for cancer cells (FIG. 1B). Through this, it was confirmed that the GST-Afb fusion protein expressed for use as an outer layer of protein corona in the present invention does not exhibit toxicity to normal cells and can exhibit targeting ability against cancer cells.
  • the synthesis of the glutathione precursor drug of the present invention was prepared in the same scheme as in FIGS. 2 to 8.
  • the entries described below refer to the glutathione precursor drug.
  • 2-bromoethyl bis(2-chloroethyl)carbamate which is entry 1
  • is beet (2-chloroethyl) amine (Bis( 2-chloroethyl)amine) (20 mg, 0.1408 mmol) and sodium hydroxide (8.448 mg, 0.2112 mmol) were first mixed with 5 mL of methyl chloride, followed by 2-bromoethyl carbonochloridate (2-bromoethyl carbonochloridate) (26.39 mg, 0.1408 mmol) was added.
  • Entry 3 was cisplatin (10mg, 0.0333 mmol) mixed with GSH ((glutathione), 15mg, 0.05mmol) pH 7.4 PBS solution, reacted at room temperature for 24 hours, and separated through HPLC.
  • GSH (glutathione)
  • Figure 2 is a schematic diagram of the synthesis of entry 2, a type of glutathione precursor drug.
  • entry 3 is a schematic view of the synthesis of entry 3, which is a type of glutathione precursor drug.
  • Figure 4 is a schematic diagram of the synthesis of entry 5, a type of glutathione precursor drug.
  • Figure 5 is a schematic diagram of the synthesis of entry 7, a type of glutathione precursor drug.
  • 6 is a schematic view of the synthesis of entry 9, which is a type of glutathione precursor drug.
  • FIG. 7 is a schematic diagram of the synthesis of Entry 11, a type of glutathione precursor drug.
  • Figure 8 is a schematic diagram of the synthesis of entry 12, a type of glutathione precursor drug.
  • the binding between the glutathione precursor drug and the fusion protein was confirmed using an isothermal titration calorimetry (ITC) method.
  • ITC isothermal titration calorimetry
  • a control sample was filled with distilled water, and then a plastic syringe was connected to the injection port of the injection syringe using a tube.
  • the injection syringe was rinsed with distilled water and then rinsed with a buffer solution.
  • the injection syringe was completely emptied by aspirating air through the system.
  • the needle of the injection syringe was put into the glutathione-S-transferase solution to which the HER2 target affibody was attached, and the fusion protein was drawn into the syringe until the entire syringe was full.
  • the injection port of the syringe was immediately closed and the tube and the plastic syringe were separated.
  • the injection syringe was discharged two more times and filled to 300 uL again. Since the syringe was removed from the fusion protein solution and the volume could be removed from the syringe, the drop was removed by wiping the side with Kimwipe, taking care not to touch the syringe tip with Kimwipe. In addition, care was taken not to tap or bottle the syringe as it may cause loss of volume at the syringe tip.
  • the injection syringe was placed in a PBS buffer solution in which entries 2, 3, 5, 7, 9, 11 and 12 were dissolved, respectively.
  • the system is given time to equilibrate and wait 5 minutes for the heat signal to return to the baseline before the next injection occurs. Thereafter, the subsequent injection was maintained at 300 uL, and the experimental temperature was selected at 25°C. After setting the parameters as above, the experiment was started. The experiment was repeated 3 times to reduce the occurrence of errors.
  • the data were analyzed. Specifically, you can easily perform data fitting using macros in any data fitting program (usually provided by the manufacturer with the instrument). Select the data fitting model (single binding site, two/multiple binding sites, cooperative bonds, etc.) to be used to fit the data.
  • the data can be suitable for initial guessing of the fitting parameters, stoichiometry (n), enthalpy ( ⁇ H) and binding affinity (Ka) and ITC enthalpy values can be compared to the enthalpy of the van't Hoff plot. It may be helpful to use different concentrations of ligands or macromolecules because the absolute value of the heat signal must increase as the macromolecule concentration increases. If the buffers of the cells and syringes do not match, noise is likely to occur. Another possibility for noise arises in samples with impurities.
  • 9 is a graph showing binding affinity when entry 2 binds to a fusion protein.
  • 10 is a graph showing binding affinity when entry 3 binds to a fusion protein.
  • 11 is a graph showing binding affinity when Entry 5 binds to a fusion protein.
  • 12 is a table showing binding affinity values when entries 2,3,5,7,9,11 and 12 bind to a fusion protein.
  • Cytotoxicity was analyzed to observe the anticancer effect of the complex of glutathione precursor drug (entry) and fusion protein combined.
  • the cell viability of the complex in which Her2-oriented fusion protein and entries 2, 3, 5, 7, 9, 11, and 12 are respectively bound to SKBR3 cells, which are human breast cancer cells is 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT)
  • MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
  • 13 is a graph showing the cytotoxicity of the complex in which the fusion protein and Entry 2 are bound.
  • 15 is a graph showing the cytotoxicity of the complex in which the fusion protein and Entry 5 are bound.
  • 16 is a graph showing the cytotoxicity of the complex in which the fusion protein and Entry 7 are bound.
  • 17 is a graph showing the cytotoxicity of the complex in which the fusion protein and entry 9 are bound.
  • 19 is a graph showing the cytotoxicity of the complex in which the fusion protein and Entry 12 are bound.
  • FIG. 20 is a table showing IC50 values indicating cytotoxicity of complexes in which fusion proteins and entries 2,3,5,7,9,11 and 12 are bound.

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Abstract

La présente invention concerne un support d'administration de médicament précurseur du glutathion comprenant une glutathion-S-transférase et une protéine, possédant une capacité de liaison pour une cellule cible ou une protéine cible, et une utilisation correspondante comme composition pharmaceutique. Selon un aspect, un support d'administration de médicament précurseur du glutathion peut prolonger le temps de rétention in vivo et possède également une capacité de ciblage améliorée pour une cellule cible afin de pouvoir être efficacement administré à la cellule cible, pouvant ainsi être efficacement utilisé en tant qu'agent thérapeutique ciblé.
PCT/KR2020/006906 2019-05-28 2020-05-28 Support d'administration de médicament précurseur du glutathion comprenant une glutathion-s-transférase et une protéine, possédant une capacité de liaison pour une cellule cible ou une protéine cible, et utilisation correspondante WO2020242218A1 (fr)

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