WO2021193928A1 - 腫瘍細胞を死滅させるための医薬 - Google Patents

腫瘍細胞を死滅させるための医薬 Download PDF

Info

Publication number
WO2021193928A1
WO2021193928A1 PCT/JP2021/012922 JP2021012922W WO2021193928A1 WO 2021193928 A1 WO2021193928 A1 WO 2021193928A1 JP 2021012922 W JP2021012922 W JP 2021012922W WO 2021193928 A1 WO2021193928 A1 WO 2021193928A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
tumor cells
sodium
verteporfin
tumor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2021/012922
Other languages
English (en)
French (fr)
Japanese (ja)
Inventor
奈緒子 戸田
須藤　幸夫
浜窪　隆雄
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Photoq3 Inc
Original Assignee
Photoq3 Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Photoq3 Inc filed Critical Photoq3 Inc
Priority to EP21776170.9A priority Critical patent/EP4129333A4/en
Priority to JP2022510744A priority patent/JP7329288B2/ja
Priority to US17/913,578 priority patent/US20230135752A1/en
Priority to CN202180024823.6A priority patent/CN115335082A/zh
Publication of WO2021193928A1 publication Critical patent/WO2021193928A1/ja
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A61K31/787—Polymers containing nitrogen containing heterocyclic rings having nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/409—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
    • 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
    • A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • 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
    • A61K38/168—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from plants
    • 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
    • A61K38/45—Transferases (2)
    • 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
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0028—Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
    • 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
    • A61K47/51—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
    • A61K47/62—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 a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • 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
    • A61K47/51—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
    • 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
    • A61K47/51—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
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A61K47/6817—Toxins
    • A61K47/6819—Plant toxins
    • A61K47/6825—Ribosomal inhibitory proteins, i.e. RIP-I or RIP-II, e.g. Pap, gelonin or dianthin
    • 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
    • A61K47/51—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
    • 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
    • A61K47/51—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
    • A61K47/6851—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 determinant of a tumour cell
    • A61K47/6855—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 determinant of a tumour cell the tumour determinant being from breast cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C07K16/2863—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • 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
    • C07K16/32—Immunoglobulins [IG], 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
    • C12Y—ENZYMES
    • C12Y302/00—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
    • C12Y302/02—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2) hydrolysing N-glycosyl compounds (3.2.2)
    • C12Y302/02022—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2) hydrolysing N-glycosyl compounds (3.2.2) rRNA N-glycosylase (3.2.2.22)

Definitions

  • the present invention relates to a drug for killing a tumor cell, which comprises a conjugate of a substance that binds to a target substance on the surface of the tumor cell and a cytotoxic substance, and talaporfin sodium, porphimer sodium or verteporfin.
  • small molecule anticancer drugs cancer chemotherapy
  • cancer chemotherapy due to its strong cancer specificity, antibody drugs can reduce the strong side effects of small molecule anticancer drugs and are becoming widely used, but they are still effective for solid tumors.
  • ADCs antibody drug conjugates
  • ADCs antibody drug conjugates
  • immunotherapeutic antibodies which are new antibody drugs, have strong efficacy against a wide range of cancer types by a new mechanism, but there are not always many patients who are effective, and in some cases death may occur. It has been found to show severe side effects.
  • PDT PhotoDynamic Therapy
  • PDT is a method of treating the affected area by irradiating the affected area with light of a wavelength that activates the photosensitizing pigment collected at the tumor site, and it has shown a certain effect in lung cancer etc. I can't say.
  • An object to be solved by the present invention is to provide a drug for killing tumor cells with few side effects.
  • PDT is a method of destroying tumor cells by accumulating a sensitizing dye in tumor tissue and irradiating it with light.
  • Known sensitizers used in PDT include highly water-soluble and highly tumor-accumulating sensitizers such as Talaporfin Sodium, Porfimer Sodium, and Verteporfin. All of them have already been used for the treatment of lung cancer and the like.
  • PDT is a less invasive treatment method, it has the disadvantage that its efficacy is not always satisfactory.
  • PCI Photochemical Internalization
  • TPCS2a sulfonized tetraphenylchlorin
  • AlPcS2a aluminum phthalocyanine
  • amphipathic sulfonized tetraphenylchlorin (TPCS2a) and aluminum phthalocyanine (AlPcS2a) are (1) concerned about neurotoxicity, and (2) accumulate in cell membranes other than endosome membranes and cause cytotoxicity. There are concerns about drawbacks such as (3) low tumor accumulation and non-specific side effects.
  • the highly water-soluble talaporfin sodium, porfimmer sodium or verteporfin has the unpredictable effect of increasing the permeability of endosome membranes at low concentrations. I found that. Furthermore, they have found that the combination of a substance that binds to a target substance on the surface of tumor cells and a cytotoxic substance and a combination of talaporfin sodium, porphimer sodium or verteporfin can significantly enhance cytotoxicity and tumor specificity. , The present invention has been completed.
  • ⁇ 1> A combination of a substance that binds to a target substance on the surface of a tumor cell and a cytotoxic substance; and talaporfin sodium, porphimer sodium or verteporfin; Drugs for killing tumor cells, including.
  • ⁇ 2> The medicament according to ⁇ 1>, wherein the substance that binds to the target substance on the surface of the tumor cell is an antibody, an antibody fragment, a ligand, or a peptide.
  • cytotoxicity is saporin, gelonin, or Pseudomonas aeruginosa exotoxin.
  • Tumor cells have Epidermal Growth Factor Receptor (EGFR, ERBB1, ERBB2, ERBB3, ERBB4), Mesothelin, Ephrin type-A receptor 2 (EphA2), Glypican3 (GPC3), Cadherin17 (CDH17), or Roundabout on the cell surface.
  • EGFR Epidermal Growth Factor Receptor
  • EphA2 Ephrin type-A receptor 2
  • Glypican3 Glypican3
  • CDH17 Cadherin17
  • the medicament according to any one of ⁇ 1> to ⁇ 3>, which is a cell expressing homolog 1 (Robo1).
  • Tumor cells are head and neck cancer, lung cancer, liver cancer, colon cancer, skin cancer, esophageal cancer, gastric cancer, cervical cervical cancer, endometrial cancer, mesenteric tumor, brain tumor, malignant melanoma , Breast cancer, bile duct cancer, pancreatic cancer, ovarian cancer, renal cancer, bladder cancer, prostate cancer or malignant lymphoma, or osteosarcoma, ⁇ 1> to ⁇ 4> The medicine described in any one.
  • ⁇ 6> (1) Step of contacting the conjugate with tumor cells; (2) Steps of contacting talaporfin sodium, porphimer sodium or verteporfin with the tumor cells; and (3) Talaporfin sodium, porfimer sodium or verteporfin at a wavelength effective to activate the tumor cells. Step of killing the cells by irradiation: The medicament according to any one of ⁇ 1> to ⁇ 5>, which kills tumor cells by means of.
  • ⁇ 7> (1) Step of contacting talaporfin sodium, porphimer sodium or verteporfin with tumor cells; (2) The step of contacting the conjugate with the tumor cell; and (3) Irradiating the tumor cell with a wavelength effective for activating talaporfin sodium, porphimer sodium or verteporfin.
  • the process of killing The medicament according to any one of ⁇ 1> to ⁇ 5>, which kills tumor cells by means of. ⁇ 8> (1)
  • the step of killing the tumor cells by irradiating the tumor cells with a wavelength effective for The medicament according to any one of ⁇ 1> to ⁇ 5>, which kills tumor cells by means of.
  • a step of contacting a tumor cell with a substance that binds to a target substance on the surface of the tumor cell and a conjugate of a cytotoxic substance (2) Steps of contacting talaporfin sodium, porphimer sodium or verteporfin with the tumor cells; and (3) Talaporfin sodium, porfimer sodium or verteporfin at a wavelength effective to activate the tumor cells.
  • Step of killing the cells by irradiation Methods of killing tumor cells, including.
  • ⁇ B> A step of contacting a substance that binds to a target substance on the surface of a tumor cell with a cytotoxic substance and talaporfin sodium, porphimer sodium or verteporfin with the tumor cell. (2) Then, the step of killing the tumor cells by irradiating the tumor cells with a wavelength effective for activating talaporfin sodium, porphimer sodium or verteporfin: Methods of killing tumor cells, including.
  • FIG. 1 shows cell viability in the A431 cytotoxic assay.
  • FIG. 2 shows cell viability in the A549 cytotoxic assay.
  • FIG. 3 shows cell viability in the MKK7 cytotoxic assay.
  • FIG. 4 shows cell viability in the MDA-MB-453 cytotoxicity assay.
  • FIG. 5 shows cell viability in the A431 / PEP-T cytotoxic assay.
  • FIG. 6 shows cell viability in the A431 / Verteporfin cytotoxic assay.
  • the present inventors have found for the first time that the water-soluble sensitizing dyes taraporphyrin, porphymer sodium or verteporfin improve the permeability of endosomes by light irradiation.
  • the conjugate of the substance that binds to the target substance on the surface of the tumor cell and the cytotoxic substance is encapsulated in the endosome after binding to the tumor. Irradiation of separately (or simultaneously) added talaporfin sodium, porphimer sodium or verteporfin with light to release the immunotoxin (or its degradation products) in the endosome into the cytoplasm. We believe that tumor cells can be killed.
  • Talaporfin sodium, porphimer sodium and verteporfin are water-soluble and have side effects on localization to membranes such as amphipathic sulfonized tetraphenylchlorin (TPCS2a) and aluminum phthalocyanine (AlPcS2a). It has the advantage of less concern. Furthermore, since the absorption wavelength is 664 nm, which does not overlap with the absorption wavelength of hemoglobin, the depth of light reach is deep.
  • the methods for killing tumor cells include (1) a combination of a substance that binds to a target substance on the surface of the tumor cell and a cytotoxic substance, (2) and talaporfin sodium, porphimer sodium or verteporfin. In the presence, (3) a form of irradiating light having a wavelength that activates talaporfin sodium, porphimer sodium, or verteporfin can be mentioned.
  • a substance that binds to the target substance on the surface of the tumor cell and a conjugate of cytotoxicity are administered, and then (2) talaporfin sodium, porphimer sodium or verteporfin is administered, and then (3).
  • talaporfin sodium, porphimer sodium or verteporfin As another form, (1) after administration of talaporfin sodium, porphimer sodium or verteporfin, (2) administration of a substance that binds to a target substance on the surface of tumor cells and a conjugate of cytotoxicity, and then (3). ) It can also be achieved by irradiating light with a wavelength that activates talaporfin sodium, porphimer sodium or verteporfin.
  • a substance that binds to a target substance on the surface of the tumor cell and a conjugate of a cytotoxic substance and (2) talaporfin sodium, porphimer sodium or verteporfin are simultaneously administered, and then (3).
  • ⁇ Photosensitizer> sodium taraporphyrin, sodium porphymer or verteporfin is used as a sensitizer.
  • Talaporfin sodium is a sensitizing dye used in PDT, also known as rezaphyrin, NPe6, monoasparatylchlorin e6.
  • Porfimer Sodium can be used as a sensitizing dye.
  • Porphymer sodium is a PDT dye, also called photophyllin.
  • Verteporfin can be used as a sensitizing dye. Verteporfin is a PDT dye, also known as Visudyne.
  • Substances that bind to target substances on the surface of tumor cells include, but are not limited to, an antibody, an antibody fragment, a ligand, or a peptide.
  • the target substance on the surface of a tumor cell for example, Epidermal Growth Factor Receptor (EGFR, ERBB1, ERBB2, ERBB3, ERBB4), Mesothelin, Ephrin type
  • EGFR Epidermal Growth Factor Receptor
  • ERBB1, ERBB2, ERBB3, ERBB4 Mesothelin
  • Ephrin type Ephrin type
  • EGFR Epidermal Growth Factor Receptor
  • GPC3 Glypican3
  • Cadhelin17 CDH17
  • Cadherin3 CDH3
  • Robo1 Roundabout homolog1
  • the type of antibody used in the present invention is not particularly limited, and is artificially used for the purpose of reducing heterologous antigenicity to humans, mouse antibody, human antibody, rat antibody, rabbit antibody, sheep antibody, camel antibody, triantibody, etc.
  • Any of the recombinantly modified antibody for example, a chimeric antibody, a humanized antibody, or the like may be used.
  • the recombinant antibody can be produced using a known method.
  • a chimeric antibody is an antibody consisting of a heavy chain of a mouse antibody, a variable region of a light chain, and a heavy chain of a human antibody, a constant region of a light chain, and a DNA encoding the variable region of a mouse antibody.
  • Humanized antibodies are obtained by transplanting the complementarity determining regions (CDRs) of non-human mammals, for example, mouse antibodies into the complementarity determining regions of human antibodies, and their general gene recombination methods are also known. .. Specifically, several oligos prepared so as to have an overlapping portion at the end of a DNA sequence designed to link the CDR of a mouse antibody and the framework region (FR) of a human antibody. It is synthesized from nucleotides by the PCR method. It is obtained by ligating the obtained DNA to the DNA encoding the human antibody constant region, then incorporating it into an expression vector, introducing it into a host and producing it (EP 239400, WO96 / 02576, etc.). ).
  • a method for obtaining human antibodies is known.
  • a human lymphocyte is sensitized in vitro with a desired antigen or a cell expressing the desired antigen, and the sensitized lymphocyte is fused with a human myeloma cell such as U266 to have a desired human antibody having an antigen-binding activity.
  • a desired human antibody can be obtained by immunizing a transgenic animal having the entire repertoire of human antibody genes with a desired antigen (WO93 / 12227, WO92 / 03918, WO94 / 02602, WO94 / 25585, See WO96 / 34096, WO96 / 33735).
  • a technique for obtaining a human antibody by panning using a human antibody library is also known.
  • a phage that binds to an antigen can be selected by expressing the variable region of a human antibody as a single-chain antibody (scFv) on the surface of the phage by the phage display method.
  • scFv single-chain antibody
  • the DNA sequence encoding the variable region of the human antibody that binds to the antigen can be determined.
  • an appropriate expression vector can be prepared for the sequence to obtain a human antibody.
  • Antibodies that bind to tumor cells are preferably humanized or human antibodies, but are not limited thereto.
  • these antibodies are low-molecular-weight antibodies such as antibody fragments or antibody modifications, as long as they do not lose the property of recognizing the entire length or part of the protein encoded by the antigen gene on the surface of tumor cells.
  • An antibody fragment is a portion of an antibody that retains its ability to bind to ROBO1. Specific examples of the antibody fragment include Fab, Fab', F (ab') 2, Fv, Diabody, and a single chain antibody fragment (scFv).
  • a gene encoding these antibody fragments may be constructed, introduced into an expression vector, and then expressed in an appropriate host cell.
  • an antibody bound to various molecules such as polyethylene glycol (PEG) can also be used.
  • the DNA encoding the monoclonal antibody is easily isolated and sequenced by conventional methods (eg, using an oligonucleotide probe capable of specifically binding to the genes encoding the heavy and light chains of the monoclonal antibody). can. Hybridoma cells are a preferred starting material for such DNA. Once isolated, the DNA was inserted into the expression vector and E. coli. Monoclonal antibodies can be produced from recombinant host cells, such as colli cells, COS cells, CHO cells, or myeloma cells that do not produce immunoglobulin unless transformed.
  • Ligand can be used as a substance that binds to the target substance on the surface of the tumor cell.
  • a receptor such as Epidermal Growth Factor Receptor (EGFR, ERBB1, ERBB2, ERBB3, ERBB4), Mesothelin, Ephrin type-A receptor 2 (EphA2)
  • EGFR Epidermal Growth Factor Receptor
  • EphA2 Ephrin type-A receptor 2
  • Peptides can also be used as substances that bind to target substances on the surface of tumor cells. Peptides that bind to target substances on the surface of tumor cells can be designed and manufactured by those skilled in the art.
  • the cytotoxic substance is preferably a protein having cytotoxicity, but is not limited to this, and may be a compound having a synthetic / natural anticancer activity such as bleomycin, or a compound used in ADC.
  • Preferred embodiments of cytotoxic proteins include saporins, geronins, ciguatoxins, ricin A chains, glycated chain ricin A chains, ribosome inactivating proteins, alphasalcin, aspergillin, restrictocin, ribonuclease, etc. Examples thereof include epodophilotoxin, diphtheriatoxin, ciguatoxin and its variants, and gene recombinants.
  • a combination of a substance that binds to a target substance on the surface of a tumor cell and a cytotoxic substance The substance that binds to the target substance on the surface of the tumor cell and the cytotoxic must be directly or indirectly bound.
  • an antibody or fragment thereof is used as a substance that binds to a target substance on the surface of a tumor cell
  • the method of directly chemically binding this to a cytotoxic substance is used in a known ADC (Antibody Drug Conjugate). You can use the binding method that is used. It is also possible to use a bifunctional cross-linking agent when the cytotoxicity is a protein.
  • immunotoxin can be produced by genetically modifying a toxin and an antibody or a fragment thereof to form a protein.
  • a method of indirectly binding an antibody or a fragment thereof with a cytotoxic agent using a second binding pair.
  • avidin-biotin, antibody-hapten and the like can be used as an example of the second binding pair.
  • a peptide or ligand that binds to a target substance on the surface of a tumor cell and a conjugate of the toxin can be used.
  • the administration method when the medicament of the present invention is administered to a subject having a tumor is not particularly limited.
  • the conjugate of the substance that binds to the target substance on the surface of the tumor cell and the cytotoxic substance should be administered, for example, by intravenous administration, arterial administration, intramuscular administration, subcutaneous administration, intradermal administration, intraperitoneal administration, or oral administration. Can be done.
  • Talaporfin sodium, porphimer sodium or verteporfin can be administered, for example, by intravenous administration, arterial administration, intramuscular administration, subcutaneous administration, intradermal administration, intraperitoneal administration, or oral administration.
  • intravenous administration arterial administration
  • intramuscular administration subcutaneous administration
  • intradermal administration intraperitoneal administration
  • oral administration oral administration
  • the dose of the binding between the substance that binds to the target substance on the surface of the tumor cell and the cytotoxic substance is not particularly limited, but is, for example, 1 ⁇ g / kg body weight to 100 mg / body weight kg, preferably 10 ⁇ g / kg body weight to 10 mg / kg body weight. It can be administered.
  • the dose of talaporfin sodium, porphimer sodium or verteporfin is not particularly limited, but can be administered, for example, at 1 ⁇ g / kg body weight to 100 mg / kg body weight, preferably 10 ⁇ g / kg body weight to 10 mg / kg body weight.
  • the number of administrations is not particularly limited, and can be administered once or more and multiple times (1 to 20 times, preferably 1 to 10 times), for example, every 2 to 4 weeks, or every 1 to 2 months. be able to. Further, the number of times of light irradiation is not particularly limited, and the light irradiation can be performed once or more times.
  • the tumors to which the medicament of the present invention is administered are Epidermal Growth Factor Receptor (EGFR, ERBB1, ERBB2, ERBB3, ERBB4), Mesothelin, Ephrin type-A receptor 2 (EphA2), Glypican3 (GPC3), Cadhelin17 (CDH17). , Cadhelin3 (CDH3), or Roundabout homolog 1 (Robo1), etc. on the surface of the tumor.
  • EGFR Epidermal Growth Factor Receptor
  • EphA2 Ephrin type-A receptor 2
  • Glypican3 Glypican3
  • CDH17 Cadhelin17
  • Cadhelin3 CDH3
  • Roundabout homolog 1 Robot1
  • head and neck cancer lung cancer, liver cancer, colon cancer, skin cancer, esophageal cancer, gastric cancer, cervical cancer, endometrial cancer, mesenteric tumor, brain tumor, malignant melanoma, breast cancer, Cancers such as bile duct cancer, pancreatic cancer, ovarian cancer, renal cancer, bladder cancer, prostate cancer or malignant lymphoma, and osteosarcoma can be mentioned.
  • the present invention can also be used for the treatment of non-human animals such as dogs, cats and horses, in addition to the treatment of human diseases.
  • Example 1 ⁇ Obtaining materials> As an EGFR-expressing strain, A431 (human epidermal cell cancer-derived cell line) was obtained from KAC Co., Ltd. (Kyoto, Japan). Cetuximab was obtained from Selleck Biotech Co., Ltd. (Tokyo, Japan) as an anti-EGFR antibody. As a photosensitizer, Talaporfin sodium was purchased from Medchemexpress (New Jersey) and used. I purchased an LED lamp (54W) with a peak wavelength of 650nm from King Do Way (18PCS E27, Amazon.co.jp).
  • ⁇ Cell culture> A431 was cultured under conditions of 37 ° C. and 5% CO2 concentration using a medium containing 10% fetal bovine serum added to a high glucose-containing medium of Dulbecco's modified Eagle's medium (DMEM).
  • DMEM Dulbecco's modified Eagle's medium
  • Cetuximab dissolved in PBS (-) and EZ-LINK sulfo-NHS-LC-biotinylated reagent (Thermo Fisher Scientific, Massachusetts) dissolved in ultrapure water are mixed so as to have a molar ratio of 1:40. After reaction, it was purified using PD SpinTrap G-25 (GE Healthcare Life Sciences, England). The obtained biotinylated Cetuximab and streptavidin-saporin (Biotin-Z Internalization Kit [KIT-27-Z], Advanced Targeting Systems, California) were mixed in equal amounts and reacted at room temperature for 30 minutes to add saporin-added Cetuximab (Cetuximab). IT-Cetuximab) was obtained.
  • Condition 1 Add only IT-Cetuximab at a concentration of 0.006-4 nM
  • Condition 2 Add IT-Cetuximab at a concentration of 0.006-4 nM and Talaporfin sodium at a concentration of 30 ⁇ M
  • Condition 3 Add IT-Cetuximab at a concentration of 0.006-4 nM And after adding 30 ⁇ M Talaporfin sodium, light irradiation (650 nm, 37.6 mJ / cm 2 )
  • IT-Cetuximab and Talaporfin sodium were added according to each condition, and after 16 hours, the cells were washed once with PBS (-), and a new drug-free medium was added. After another 4 hours, the cell group under condition 3 was irradiated with light at 650 nm so as to be 37.6 mJ / cm 2. After culturing for 72 hours, add 10 ⁇ l of CCK-8 kit solution (Cell Counting Kit-8, Dojin Chemical Laboratory, Japan) to each well, react for 1 to 2 hours, and then absorb each 450 nm. It was measured. Using the obtained results, the cell viability was calculated according to the following formula (Fig. 1).
  • Cell viability (%) (ac) / (bc) x 100
  • a is the absorbance of each sample
  • b is the absorbance of the negative control sample without IT
  • c is the absorbance of the medium alone.
  • the EC50 value was fitted to a sigmoid curve using ImageJ, an open source analysis software, and the IT-Cetuximab concentration showing a 50% survival rate was determined (Table 1).
  • IT-Cetuximab showed concentration-dependent cytotoxic activity, and its 50% effective concentration (EC50) was 0.36 nM.
  • EC50 50% effective concentration
  • Example 2 ⁇ Obtaining materials> As an EGFR-expressing strain, A549 (human lung cancer cells) was obtained from KAC Co., Ltd. (Kyoto, Japan). The anti-EGFR antibody Cetuximab, the photosensitizer Talaporfin sodium, and the LED lamp with a peak wavelength at 650 nm were the same as those used in Example 1.
  • ⁇ Cell culture> A549 was cultured under conditions of 37 ° C. and 5% CO2 concentration using a medium containing 10% fetal bovine serum added to a high glucose-containing medium of Dulbecco's modified Eagle's medium (DMEM).
  • DMEM Dulbecco's modified Eagle's medium
  • Condition 1 Add only IT-Cetuximab at a concentration of 0.006-4 nM
  • Condition 2 Add IT-Cetuximab at a concentration of 0.006-4 nM and Talaporfin sodium at a concentration of 30 ⁇ M
  • Condition 3 Add IT-Cetuximab at a concentration of 0.006-4 nM And after adding 30 ⁇ M Talaporfin sodium, light irradiation (650 nm, 37.6 mJ / cm 2 )
  • IT-Cetuximab and Talaporfin sodium were added according to each condition, and after 16 hours, the cells were washed once with PBS (-), and a new drug-free medium was added. After another 4 hours, the cell group under condition 3 was irradiated with light at 650 nm so as to be 37.6 mJ / cm 2.
  • IT-Cetuximab showed concentration-dependent cytotoxic activity, and its 50% effective concentration (EC50) was 0.70 nM.
  • EC50 50% effective concentration
  • IT-Cetuximab and Rezaphyrin were added at the same time under Condition 2
  • the EC50 was 1.4 nM, which was almost the same as the result of Condition 1, and the effect of Rezaphyrin addition was almost the same. I could't see it.
  • condition 3 in which IT-Cetuximab and rezaphyrin were added and further irradiated with light, the cytotoxic activity was remarkably increased, and its EC50 was 6.9 pM.
  • Example 3 Cylindrical assay using HER2-expressing strain (MKN7, MDA-MB-453), Talaporfin sodium, IT-Trastuzumab ⁇ cell culture>
  • MKN7 human gastric cancer-derived cells
  • MDA-MB-453 human breast cancer cells
  • MKN7 was cultured in RPMI1640 medium supplemented with 10% fetal bovine serum under the conditions of 37 ° C. and a CO 2 concentration of 5%
  • MDA-MB-453 was cultured in L-15 medium supplemented with 10% fetal bovine serum under the conditions of 37 ° C. and 0% CO 2 concentration.
  • trastuzumab (IT-Trastuzumab) to which saporin was added was obtained by the same method as the immunotoxin preparation method of Example 1.
  • MKN7 and MDA-MB-453 were seeded in 96-well plates at 1 ⁇ 10 4 per well, cultured overnight, and then immunotoxin and a photosensitizer were added and light-irradiated under the following three conditions. The degree of cell damage under each condition was compared.
  • Condition 1 Add only IT-Trastuzumab at a concentration of 0.032-20 nM
  • Condition 2 Add IT-Trastuzumab at a concentration of 0.032-20 nM and Talaporfin sodium at a concentration of 20 ⁇ M
  • Condition 3 IT-Trastuzumab at a concentration of 0.032-20 nM And after adding 20 ⁇ M Talaporfin sodium, light irradiation (650 nm, 37.6 J / cm 2 )
  • IT-Trastuzumab and Talaporfin sodium were added according to each condition, and after 16 hours, the cells were washed once with PBS (-), and a new drug-free medium was added. After another 4 hours, the cell group under condition 3 was irradiated with light at 650 nm so as to be 37.6 J / cm 2. After culturing for 72 hours, 10 ⁇ l of CCK-8 kit solution was added to each well, and the reaction was carried out for 1 to 2 hours, and then the absorption at 450 nm of each was measured. From the absorbance obtained in the same manner as in Example 1, the cell viability (FIGS. 3 and 4) and the IT-Trastuzumab concentration showing a 50% viability were calculated.
  • Example 4 Cell damage assay using EGFR expression strain (A431), Talaporfin sodium, peptide toxin (PEP-T) ⁇ cell culture>
  • A431 was cultured in Dulbecco's modified Eagle's medium (DMEM) high glucose-containing medium supplemented with 10% fetal bovine serum under the conditions of 37 ° C and 5% CO 2 concentration.
  • DMEM Dulbecco's modified Eagle's medium
  • Peptide molecules are known as substances that bind to EGFR.
  • peptide GE11 sequence: YHWYGYTPQNVI
  • 6-mer peptide D4 sequence: LARLLT
  • a peptide sequence: YHWYGYTPENVI
  • a biotin-modified C-terminal of this peptide was purchased from Cosmo Bio Co., Ltd. and used in the experiment.
  • the purchased biotin peptide and streptavidin-saporin were mixed in equivalent amounts and reacted at room temperature for 30 minutes to obtain a peptide (PET-T) to which saporin was added.
  • PEP-T and Talaporfin sodium were added according to each condition, and after 16 hours, the cells were washed once with PBS (-), and a new drug-free medium was added. After another 4 hours, the cell group under condition 3 was irradiated with light at 650 nm so as to be 37.6 J / cm 2.
  • Example 6 Cellular injury assay using EGFR expression strain (A431), Verteporfin, IT-Cetuximab ⁇ Obtaining materials> The photosensitizer Verteporfin was obtained from Cayman Chemical (USA). The EGFR-expressing strain A431, the anti-EGFR antibody Cetuximab, and the LED lamp having a peak wavelength at 650 nm were the same as those used in Example 1.
  • ⁇ Cell culture> A431 was cultured under conditions of 37 ° C. and 5% CO2 concentration using a medium containing 10% fetal bovine serum added to a high glucose-containing medium of Dulbecco's modified Eagle's medium (DMEM).
  • DMEM Dulbecco's modified Eagle's medium
  • Condition 1 Add only IT-Cetuximab at a concentration of 0.006-4 nM
  • Condition 2 Add IT-Cetuximab at a concentration of 0.006-4 nM and Verteporfin at 0.7 ⁇ M
  • Condition 3 Add IT-Cetuximab at a concentration of 0.006-4 nM and After adding 0.7 ⁇ M Verteporfin, light irradiation (650 nm, 2.82 J / cm 2 )
  • IT-Cetuximab was added according to each condition, and Verteporfin was added 20 hours later. After another 2 hours, the cells were washed once with PBS (-), and a new drug-free medium was added. The cell group under condition 3 was irradiated with light at 650 nm at 2.82 J / cm 2. After culturing for 72 hours, 10 ⁇ l of CCK-8 kit solution was added to each well, and the reaction was carried out for 1 to 2 hours, and then the absorption at 450 nm of each was measured. From the absorbance obtained in the same manner as in Example 1, the cell viability (FIG. 6) and the IT-Cetuximab concentration showing a 50% viability were calculated.
  • IT-Cetuximab showed concentration-dependent cytotoxic activity.
  • concentration-dependent damaging activity against IT-Cetuximab was observed, and its EC50 was 0.3 nM.
  • the addition of Verteporfin tended to increase the cytotoxic activity.
  • condition 3 in which IT-Cetuximab and Verteporfin were further added and further irradiated with light, the cytotoxic activity was further increased, and the EC50 was 0.05 nM.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Molecular Biology (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Cell Biology (AREA)
  • Botany (AREA)
  • Biophysics (AREA)
  • Toxicology (AREA)
  • Zoology (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • General Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Wood Science & Technology (AREA)
  • Biomedical Technology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicinal Preparation (AREA)
PCT/JP2021/012922 2020-03-27 2021-03-26 腫瘍細胞を死滅させるための医薬 Ceased WO2021193928A1 (ja)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP21776170.9A EP4129333A4 (en) 2020-03-27 2021-03-26 PHARMACEUTICAL MEDICINAL PRODUCT FOR THE DESTROYING OF TUMOR CELLS
JP2022510744A JP7329288B2 (ja) 2020-03-27 2021-03-26 腫瘍細胞を死滅させるための医薬
US17/913,578 US20230135752A1 (en) 2020-03-27 2021-03-26 Medicament for killing tumor cells
CN202180024823.6A CN115335082A (zh) 2020-03-27 2021-03-26 用于杀死肿瘤细胞的医药品

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2020057561 2020-03-27
JP2020-057561 2020-03-27

Publications (1)

Publication Number Publication Date
WO2021193928A1 true WO2021193928A1 (ja) 2021-09-30

Family

ID=77891937

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2021/012922 Ceased WO2021193928A1 (ja) 2020-03-27 2021-03-26 腫瘍細胞を死滅させるための医薬

Country Status (5)

Country Link
US (1) US20230135752A1 (https=)
EP (1) EP4129333A4 (https=)
JP (1) JP7329288B2 (https=)
CN (1) CN115335082A (https=)
WO (1) WO2021193928A1 (https=)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230149555A1 (en) * 2020-04-06 2023-05-18 PhotoQ3 Inc. Medicament for killing tumor cells

Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0239400A2 (en) 1986-03-27 1987-09-30 Medical Research Council Recombinant antibodies and methods for their production
WO1992001047A1 (en) 1990-07-10 1992-01-23 Cambridge Antibody Technology Limited Methods for producing members of specific binding pairs
WO1992003918A1 (en) 1990-08-29 1992-03-19 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
WO1992020791A1 (en) 1990-07-10 1992-11-26 Cambridge Antibody Technology Limited Methods for producing members of specific binding pairs
WO1993006213A1 (en) 1991-09-23 1993-04-01 Medical Research Council Production of chimeric antibodies - a combinatorial approach
WO1993011236A1 (en) 1991-12-02 1993-06-10 Medical Research Council Production of anti-self antibodies from antibody segment repertoires and displayed on phage
WO1993012227A1 (en) 1991-12-17 1993-06-24 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
WO1993019172A1 (en) 1992-03-24 1993-09-30 Cambridge Antibody Technology Limited Methods for producing members of specific binding pairs
WO1994002602A1 (en) 1992-07-24 1994-02-03 Cell Genesys, Inc. Generation of xenogeneic antibodies
WO1994025585A1 (en) 1993-04-26 1994-11-10 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
WO1995001438A1 (en) 1993-06-30 1995-01-12 Medical Research Council Sbp members with a chemical moiety covalently bound within the binding site; production and selection thereof
WO1995015388A1 (en) 1993-12-03 1995-06-08 Medical Research Council Recombinant binding proteins and peptides
WO1996002576A1 (en) 1994-07-13 1996-02-01 Chugai Seiyaku Kabushiki Kaisha Reconstituted human antibody against human interleukin-8
WO1996033735A1 (en) 1995-04-27 1996-10-31 Abgenix, Inc. Human antibodies derived from immunized xenomice
WO1996034096A1 (en) 1995-04-28 1996-10-31 Abgenix, Inc. Human antibodies derived from immunized xenomice
CN110229323A (zh) * 2019-05-31 2019-09-13 苏州大学 还原敏感可逆交联的具有不对称膜结构的聚合物囊泡及其在制备治疗肝癌药物中的应用

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7498298B2 (en) * 2003-11-06 2009-03-03 Seattle Genetics, Inc. Monomethylvaline compounds capable of conjugation to ligands
US20070196269A1 (en) * 2003-12-19 2007-08-23 Karl-Hermann Schlingensiepen Pharmaceutical composition
WO2006132670A2 (en) * 2004-11-12 2006-12-14 Seattle Genetics, Inc. Auristatins having an aminobenzoic acid unit at the n terminus
WO2006084078A2 (en) * 2005-02-02 2006-08-10 Raven Biotechnologies, Inc. Jam-3 and antibodies that bind thereto
DOP2006000277A (es) * 2005-12-12 2007-08-31 Bayer Pharmaceuticals Corp Anticuerpos anti mn y métodos para su utilización
DE102005062440B4 (de) * 2005-12-27 2011-02-24 Lts Lohmann Therapie-Systeme Ag Proteinbasiertes Trägersystem zur Resistenzüberwindung von Tumorzellen
JP5514482B2 (ja) * 2009-07-15 2014-06-04 株式会社荏原製作所 給水装置及び給水システム
WO2018156725A1 (en) * 2017-02-24 2018-08-30 Thomas Jefferson University Methods and compositions for inhibiting tumor growth and enhancing immune responses to tumors
WO2018195302A1 (en) * 2017-04-19 2018-10-25 Bluefin Biomedicine, Inc. Anti-vtcn1 antibodies and antibody drug conjugates
US20230149555A1 (en) * 2020-04-06 2023-05-18 PhotoQ3 Inc. Medicament for killing tumor cells
EP4174071A4 (en) * 2020-06-24 2024-09-11 The University of Tokyo PHOTOSENSITIZING DYE
US20240316203A1 (en) * 2021-09-24 2024-09-26 PhotoQ3 Inc. Medicament for killing tumor cells
CN117999098A (zh) * 2021-09-24 2024-05-07 光爱科技公司 用于杀死肿瘤细胞的医药品

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0239400A2 (en) 1986-03-27 1987-09-30 Medical Research Council Recombinant antibodies and methods for their production
WO1992001047A1 (en) 1990-07-10 1992-01-23 Cambridge Antibody Technology Limited Methods for producing members of specific binding pairs
WO1992020791A1 (en) 1990-07-10 1992-11-26 Cambridge Antibody Technology Limited Methods for producing members of specific binding pairs
WO1992003918A1 (en) 1990-08-29 1992-03-19 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
WO1993006213A1 (en) 1991-09-23 1993-04-01 Medical Research Council Production of chimeric antibodies - a combinatorial approach
WO1993011236A1 (en) 1991-12-02 1993-06-10 Medical Research Council Production of anti-self antibodies from antibody segment repertoires and displayed on phage
WO1993012227A1 (en) 1991-12-17 1993-06-24 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
WO1993019172A1 (en) 1992-03-24 1993-09-30 Cambridge Antibody Technology Limited Methods for producing members of specific binding pairs
WO1994002602A1 (en) 1992-07-24 1994-02-03 Cell Genesys, Inc. Generation of xenogeneic antibodies
WO1994025585A1 (en) 1993-04-26 1994-11-10 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
WO1995001438A1 (en) 1993-06-30 1995-01-12 Medical Research Council Sbp members with a chemical moiety covalently bound within the binding site; production and selection thereof
WO1995015388A1 (en) 1993-12-03 1995-06-08 Medical Research Council Recombinant binding proteins and peptides
WO1996002576A1 (en) 1994-07-13 1996-02-01 Chugai Seiyaku Kabushiki Kaisha Reconstituted human antibody against human interleukin-8
WO1996033735A1 (en) 1995-04-27 1996-10-31 Abgenix, Inc. Human antibodies derived from immunized xenomice
WO1996034096A1 (en) 1995-04-28 1996-10-31 Abgenix, Inc. Human antibodies derived from immunized xenomice
CN110229323A (zh) * 2019-05-31 2019-09-13 苏州大学 还原敏感可逆交联的具有不对称膜结构的聚合物囊泡及其在制备治疗肝癌药物中的应用

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BASKARAN RENGARAJAN, LEE JUNGHAN, YANG SU-GEUN: "Clinical development of photodynamic agents and therapeutic applications", BIOMATER RES, vol. 22, no. 25, 2018, pages 1 - 8, XP055861893, ISSN: 1226-4601 *
GILABERT-ORIOL, R. ET AL.: "Modified Trastuzumab and Cetuximab Mediate Efficient Toxin Delivery While Retaining Antibody-Dependent Cell -Mediated Cytotoxicity in Target Cells", MOL PHARM, vol. 10, 2013, pages 4347 - 57, XP055677139, ISSN: 1543-8384, DOI: 10.1021/mp400444q *
LI, Z. ET AL.: "Identification and characterization of a novel peptide ligand of epidermal growth factor receptor for targeted delivery of therapeutics", FASEB J, vol. 19, 2005, pages 1978 - 1985, XP002394913, DOI: 10.1096/fj.05-4058com
See also references of EP4129333A4
SONG, S. ET AL.: "Novel peptide ligand directs liposomes toward EGF-R high-expressing cancer cells in vitro and in vivo", FASEB J, vol. 23, 2009, pages 1396 - 1404, XP055225879, DOI: 10.1096/fj.08-117002

Also Published As

Publication number Publication date
JP7329288B2 (ja) 2023-08-18
CN115335082A (zh) 2022-11-11
JPWO2021193928A1 (https=) 2021-09-30
EP4129333A1 (en) 2023-02-08
US20230135752A1 (en) 2023-05-04
EP4129333A4 (en) 2024-06-12

Similar Documents

Publication Publication Date Title
US12312417B2 (en) Binding proteins 1
JP7473474B2 (ja) 抗体－薬物コンジュゲート投与による転移性脳腫瘍の治療
US10792370B2 (en) Antibody-drug conjugate
Siegall Targeted toxins as anticancer agents
JP2023524678A (ja) 抗ｃ－Ｍｅｔ抗体薬物複合体及びその応用
US12600734B2 (en) Photosensitizing dye
JP7329288B2 (ja) 腫瘍細胞を死滅させるための医薬
US20250000998A1 (en) Medicament for killing tumor cells
JP7769386B2 (ja) 腫瘍細胞を死滅させるための医薬
TW202207993A (zh) 位點特異性her2抗體-藥物共軛物之治療
WO2023048233A1 (ja) 腫瘍細胞を死滅させるための医薬
HK40081045A (en) Pharmaceutical drug for destroying tumor cells
HK40085994A (en) Pharmaceutical drug for destroying tumor cells
HK40084443A (en) Medicine for killing tumor cells
HK40110461A (zh) 用於杀死肿瘤细胞的医药品
HK40085768A (en) Medicine for killing tumor cells
WO2026060187A1 (en) Multispecific antibody-drug conjugates (adc) targeting cdh17-expressing tumors and method of making and using thereof
HK40027464A (en) Antibody-drug conjugate

Legal Events

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

Ref document number: 21776170

Country of ref document: EP

Kind code of ref document: A1

DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
ENP Entry into the national phase

Ref document number: 2022510744

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2021776170

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2021776170

Country of ref document: EP

Effective date: 20221027

NENP Non-entry into the national phase

Ref country code: DE