WO2024054089A1 - Novel camptothecin derivatives and carrier-drug conjugate comprising same - Google Patents

Novel camptothecin derivatives and carrier-drug conjugate comprising same Download PDF

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WO2024054089A1
WO2024054089A1 PCT/KR2023/013502 KR2023013502W WO2024054089A1 WO 2024054089 A1 WO2024054089 A1 WO 2024054089A1 KR 2023013502 W KR2023013502 W KR 2023013502W WO 2024054089 A1 WO2024054089 A1 WO 2024054089A1
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cancer
receptor
carrier
interleukin
drug
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PCT/KR2023/013502
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French (fr)
Korean (ko)
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정두영
이진수
조현용
이병성
신승건
라오마티 강가드하
정진교
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주식회사 피노바이오
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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • 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
    • A61K47/68037—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a camptothecin [CPT] or derivatives
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings

Definitions

  • the present invention relates to a novel camptothecin derivative with excellent anticancer efficacy and safety, a carrier-drug conjugate containing the same, and its pharmaceutical use.
  • Inhibitors of type 1 topoisomerase I an isomerization enzyme involved in DNA replication and recombination, are drugs with an anticancer mechanism with proven efficacy and safety, and have been clinically used to treat colon cancer, lung cancer, breast cancer, and ovarian cancer. Excellent anticancer efficacy has been proven in various intractable solid cancers, such as:
  • Camptothecin (CPT) and its derivatives are known as representative type 1 topoisomerase inhibitors, but camptothecin has the problem of low water solubility and high toxicity.
  • camptothecin derivatives with low toxicity and high water solubility
  • drugs such as Irinotecan and Topotecan have been used to treat colon cancer, ovarian cancer, and lung cancer. It is licensed and commercially available.
  • SN-38 is a potent topoisomerase-I inhibitor with IC50 values in the nanomolar range in several cell lines, and is the active form of irinotecan, a prodrug used to treat colorectal cancer. It is also active in lung cancer, breast cancer, and brain cancer.
  • Trop-2-SN-38 Antibody-Drug Conjugate (ADC) is currently effective in many cancer types, including TNBC, bladder cancer, and stomach cancer, but the problem of SN-38 resistance still remains.
  • DXd Daiichi Sankyo used DXd, a derivative of exatecan, a cytotoxic drug that is about 10 times more active in cancer cells than SN-38, in the development of Enhertu.
  • DXd has good solubility, is relatively safe, and has a high killing effect on surrounding cells, making it advantageous for the treatment of heterogeneous tumors.
  • it has the disadvantage of having a short half-life that can reduce off-target effects.
  • camptothecin-based drugs developed to date are used as payloads in ADCs, they have lower cytotoxicity and still maintain safety compared to ADCs with existing ultra-toxic payloads such as MMAE or MMAF. Not only does it present a problem, but it also has the problem of reduced anti-cancer effectiveness due to the development of resistance due to overexpression of ABCG2 Drug Efflux Pump, etc.
  • camptothecin derivatives that not only exhibit higher cytotoxicity but are also superior in safety and have significantly reduced resistance that causes reduced anticancer effectiveness, particularly camptothecin derivatives suitable as payloads and carrier-drug conjugates containing the same.
  • the demand is urgent.
  • the purpose of the present invention is to provide a novel camptothecin derivative that has a strong type 1 topoisomerase inhibitor effect, exhibits high cytotoxicity, and has excellent safety.
  • Another object of the present invention is to provide a carrier-drug conjugate containing a camptothecin derivative according to the present invention, and a pharmaceutical composition containing a camptothecin derivative or a carrier-drug conjugate containing the same according to the present invention.
  • the purpose of the present invention is to provide a method of treating cancer using a camptothecin derivative or a carrier-drug conjugate containing the same according to the present invention.
  • a first aspect of the present invention provides a compound represented by any one of Formulas 1 to 8, an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.
  • a second aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer containing a compound represented by any one of Formulas 1 to 8, an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof. .
  • the present invention provides novel camptothecin derivatives having the structures of Formulas 1 to 8.
  • Camptothecin derivatives represented by Formulas 1 to 8 or isomers thereof according to the present invention are hydrophobic small molecules that can permeate cell membranes, so they are delivered to cancer tissues by the EPR effect (enhanced permeability and retention effect) and penetrate deep into cancer tissues. It can accumulate at high concentrations, penetrate the cell membrane, exert cytotoxicity inside the cell, kill the cell, and then be released and subsequently penetrate the cell membrane and move into the cell to act on surrounding cells.
  • camptothecin derivatives represented by the compounds of Formulas 1 to 8 or isomers thereof according to the present invention include not only the compounds of Formulas 1 to 8 or isomers thereof, but also pharmaceutically acceptable salts thereof, solvates thereof, and Includes prodrugs.
  • salts refer to salts commonly used in the pharmaceutical industry, such as salts of inorganic ions including sodium, potassium, calcium, magnesium, lithium, copper, manganese, zinc, iron, etc., and hydrochloric acid. , phosphoric acid, and sulfuric acid, as well as salts of organic acids such as ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, orotate acid, and acetylsalicylic acid.
  • amino acids such as lysine, arginine, and guanidine.
  • salts of organic ions such as tetramethyl ammonium, tetraethyl ammonium, tetrapropyl ammonium, tetrabutyl ammonium, benzyl trimethyl ammonium, and benzethonium that can be used in pharmaceutical reactions, purification, and separation processes, but are not limited to these.
  • Prodrug means something that is used in the relevant technical field.
  • an inactive compound is a drug that is converted to an active state through drug metabolism in the body.
  • a physiologically active substance or a therapeutically active organic compound is chemically modified and the parent compound is liberated or released under enzymatic or other conditions in vivo. refers to a compound designed to A prodrug is converted into the target compound in vivo after administration.
  • it is a useful drug it has unsuitable properties in terms of side effects, stability, solubility, absorption, and duration of action, and is chemically modified to enable clinical use.
  • Solidvate refers to a compound represented by any one of Formulas 1 to 8, or an isomer thereof and a pharmaceutically acceptable salt thereof, further comprising a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. it means.
  • the solvent is water
  • the solvate is a hydrate.
  • the present invention provides a carrier-drug conjugate comprising a compound represented by any one of Formulas 1 to 8 according to the present invention, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. provides.
  • Carrier refers to a substance that has the ability to selectively and specifically deliver the camptothecin derivative according to the present invention to the target site, for example, cancer cells, and includes antibodies, peptides, liposomes, etc. It may be a body, and/or an aptamer, but is not limited thereto, and is preferably an antibody.
  • Aptamer-Drug Conjugate is an aptamer introduced instead of an antibody in ADC.
  • Aptamers are single-stranded nucleic acids with a three-dimensional structure. Aptamers are usually discovered through the SELEX (Systematic Evolution of Ligands by Exponential enrichment) process. Selex is a technology that obtains functional nucleic acids that bind to target protein molecules in a compound library. Aptamers can bind to targets very strongly and selectively, so they are also called chemical antibodies. Aptamers are about 20 kDa in size and are known to have excellent cell penetration and low immunogenicity compared to antibodies.
  • aptamers can be chemically synthesized, precise design of the conjugation location and number of drugs is possible when manufacturing aptamer-drug conjugates.
  • the production cost is lower than that of ADC.
  • Aptamers are generally made of natural nucleic acids, so they are degraded by nucleic acid degrading enzymes in the body, making them less stable in vivo.
  • nucleic acid degrading enzymes in the body, making them less stable in vivo.
  • the limitations on the stability of modified aptamers can be overcome.
  • PDC Peptide-Drug Conjugate
  • ADC ADC in which peptides are introduced instead of antibodies.
  • Peptides are composed of amino acids and have a size ranging from 500 to 5000 Da (Dalton). This is a very small size compared to antibodies of 150 kDa (kilodaltons) or more. Therefore, peptide-based PDC has superior cell penetration ability compared to ADC, and the possibility of immunogenicity is very low. Additionally, peptides can be chemically synthesized. For this reason, PDC not only has a very low production cost, but also allows precise control of the conjugation position and ratio of peptide and drug.
  • peptides are easily degraded by proteolytic enzymes and therefore have a short biological half-life.
  • strategies using modified peptides such as cyclic peptides and introduction of non-natural amino acids are being proposed.
  • Repebody is a type of artificial antibody that does not have an antibody skeleton but has the function of recognizing antigens like an antibody. Lipibodies specific to target proteins can be discovered through phage display technology.
  • Phage display is a technology that expresses desired proteins on the surface of bacteriophage.
  • Lipibody is about 30kDa in size, which is 20% of an antibody drug. Therefore, it is known to have relatively low immunogenicity and improved cell penetration compared to antibodies.
  • lipibodies are expected to increase structural stability by controlling thermal and pH stability. Compared to antibodies, production costs are also assessed to be relatively low. Because of these advantages of lipibodies, interest in developing lipibody-drug conjugates (Repebody-DC) as a strategy to replace antibodies with lipibodies is also increasing.
  • Repebody-DC lipibody-drug conjugates
  • antigens include, but are not limited to, antigens selectively distributed on the surface of cancer, such as Her2, FolR, and PSMA, and antigens overexpressed in cancer cells, such as Trop2, which are distributed in small numbers in normal tissues.
  • Exemplary cancer cell target antigens include 5T4, ABL, ABCF1, ACVR1, ACVR1B, ACVR2, ACVR2B, ACVRL1, ADORA2A, AFP, Aggrecan, AGR2, AICDA, AIF1, AIGI, AKAP1, AKAP2, ALCAM, ALK, AMH, AMHR2, ANGPT1.
  • Non-limiting examples of antibodies in the present invention include Urelumab, Utomilumab, Bebtelovimab, Aducanumab, Bapinezumab, and Crenezumab. , Donanemab, Gantenerumab, Lecanemab, Solanezumab, Nesvacumab, Evinacumab, Enoblituzumab, Ombur Omburtamab, Belimumab, Ianalumab, Tabalumab, Bertilimumab, Mogamulizumab, Leronlimab, Cipilizumab ( Siplizumab), Foralumab, Muromonab-CD3, Otelixizumab, Teplizumab, Ibalizumab, Tregalizumab, Zanolimumab, Itolizumab, Efalizumab, Inebilizumab, Tafasitamab, Tositumomab, O
  • the carrier and the drug are conjugated through a linker.
  • the linker in the present invention should be stable in the bloodstream, preventing the drug from being separated from carriers such as antibodies, maintaining its structure until it reaches the target such as antigen, and minimizing damage to normal tissues.
  • the antibody-drug conjugate is stable when circulating throughout the body, it is cleaved in the target cells to appropriately release the cytotoxic drug and safely deliver the drug to the target, thereby ensuring that the antibody-drug conjugate has both efficacy and safety.
  • the carrier-drug conjugate according to the present invention may be characterized in that the carrier is conjugated to the drug, that is, the compound of Formula 1 to Formula 8 through a linker, but is not limited thereto.
  • the compounds of Formulas 1 to 8 can be linked to a linker at an appropriate site as long as their anticancer activity and other properties do not change. Accordingly, the present invention provides compounds of Formulas 1 to 8.
  • a drug-linker in which the compound of 8 and the linker are connected is provided.
  • the drug-linker according to the present invention may have the structure of Formula 1a to Formula 8a, but is not limited thereto.
  • L refers to a linker.
  • the linker may be in a form that is cleavable in a specific intracellular environment and/or condition, that is, a drug may be released from the antibody through cleavage of the linker in the intracellular environment.
  • the linker may be cleaved by a cleaving agent present in the intracellular environment, such as a lysosome or endosome, and may be a peptide that may be cleaved by an intracellular peptidase or protease enzyme, such as a lysosomal or endosomal protease. It may be a linker. Typically, peptide linkers are at least two amino acids long.
  • the cleavage agent may include cathepsin B, cathepsin D, and plasmin, and hydrolyzes the peptide to release the drug into the target cell.
  • the peptide linker can be cleaved by the thiol-dependent protease cathepsin-B, which is highly expressed in cancer tissues, for example, Gly-Gly-Phe-Gly (GGFG), Gly-Gly-Tyr-Gly (GGYG) , Phe-Leu or Gly-Phe-Leu-Gly linkers may be used, but are not limited thereto. Additionally, the peptide linker can be cleaved by, for example, an intracellular protease and may be a Val-Cit linker or a Phe-Lys linker.
  • the cleavable linker is pH sensitive and may be sensitive to hydrolysis at a specific pH value.
  • pH sensitive linkers indicate that they can be hydrolyzed under acidic conditions.
  • acid labile linkers that can be hydrolyzed in lysosomes such as hydrazone, semicarbazone, thiosemicarbazone, cis-aconitic amide, orthoester, acetal, It may be ketal, etc.
  • the linker may be cleaved under reducing conditions, for example, a disulfide linker may correspond to this.
  • SATA Nsuccinimidyl-S-acetylthioacetate
  • SPDP N-succinimidyl-3- (2-pyridyldithio)propionate
  • SPDB Nsuccinimidyl-3- (2-pyridyldithio)butyrate
  • SMPT N-succinimidyl-oxycarbonyl-alpha-methyl
  • a variety of disulfide bonds can be formed using -alpha-(2-pyridyl-dithio)toluene).
  • the linker may include a beta-glucuronide linker that is recognized and hydrolyzed by beta-glucuronidase, which exists in large numbers in lysosomes or is overexpressed in some tumor cells.
  • a beta-glucuronide linker disclosed in Korean Patent Publication No. 2015-0137015 for example, a beta-glucuronide linker containing a self-immolative group, may be used.
  • linker may be, for example, a non-cleavable linker, and the drug is released through an antibody hydrolysis step, producing, for example, an amino acid-linker-drug complex.
  • This type of linker can be a thioether group or maleimidocaproyl group and can maintain stability in the blood.
  • the linker according to the present invention is characterized by containing GGFG or GGYG, and in the case of the linker containing GGYG, the hydrogen atom of the hydroxyl group of the tyrosine (Y, Tyrosin) side chain is separated under specific conditions. May be substituted with a possible hydrophilic functional group.
  • the hydrophilic functional group is preferably a monovalent hydrophilic functional group, such as beta-glucuronide or PEG (PEG) having 3 to 100 ethylene glycol repeating units. Examples may include esters or carbonates having a polyethylene glycol (Polyethylene Glycol) group, but are not limited thereto.
  • the linker may have the structure of Formula 11 or Formula 12, but is not limited thereto.
  • n may be an integer of 3 to 10.
  • the drug and/or drug-linker which is the compound of Formula 1 to Formula 8, or the compound of Formula 1a to Formula 8a, is randomly selected through lysine in the antibody. It can be conjugated with or through the cysteine exposed when the disulfide bond chain is reduced.
  • a drug-linker may be bound through a genetically engineered tag, for example, lysine or cysteine present in a peptide or protein.
  • the present invention provides a method for preventing or treating cancer, including a compound represented by any one of Formulas 1 to 8 according to the present invention, an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a carrier-drug conjugate containing the same.
  • a pharmaceutical composition for use including a compound represented by any one of Formulas 1 to 8 according to the present invention, an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a carrier-drug conjugate containing the same.
  • a therapeutically effective amount of the compound represented by Formula 1 to Formula 8 or an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a carrier-drug conjugate containing the same is used.
  • a method for treating or preventing cancer comprising administering to a subject in need thereof.
  • the subject may be a mammal, including humans.
  • the cancer is caused by inhibition of topoisomerase I, and/or one or more cancer-related survival genes selected from the group consisting of survivin, Mcl-1, XIAP, and cIAP2. It includes all cancers that can be treated by inhibiting genes, and may be solid cancer or blood cancer. For example, pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, oral cavity cancer, mycosis fungoides, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma, ovary.
  • cancer-related survival genes selected from the group consisting of survivin, Mcl-1, XIAP, and cIAP2.
  • Epithelial cancer ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colon cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater cancer, bladder cancer, peritoneal cancer, Parathyroid cancer, adrenal cancer, sinonasal cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney cancer, heart cancer, duodenum Cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, ure
  • patient refers to animals, such as mammals.
  • the patient is a human.
  • the patient is a non-human animal, such as a dog, cat, domestic animal (e.g., horse, pig, or donkey), chimpanzee, or monkey.
  • therapeutically effective amount refers to a compound represented by any one of Formulas 1 to 8 that is effective in treating or preventing cancer, or an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or It indicates the amount of carrier-drug conjugate containing it.
  • therapeutically effective amount means an amount sufficient to treat the disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is determined by the type and severity of the individual, age, gender, type of disease, It can be determined based on factors including the activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, drugs used simultaneously, and other factors well known in the medical field.
  • the pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with commercially available therapeutic agents. And it can be administered single or multiple times. Considering all of the above factors, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, and the compound represented by any of Formulas 1 to 8 of the present invention, or an isomer thereof, or a pharmaceutically acceptable salt thereof , or a carrier-drug conjugate containing it exhibits a dose-dependent effect, so the administered dose can be easily determined by a person skilled in the art depending on various factors such as the patient's condition, age, gender, and complications. Since the active ingredient of the pharmaceutical composition of the present invention has excellent safety, it can be used at a dose exceeding the determined dosage.
  • the present invention provides a compound represented by any of Formulas 1 to 8, or an isomer thereof, for use in the production of a medicament for use in the treatment or prevention of cancer.
  • a pharmaceutically acceptable salt, a solvate thereof, or a carrier-drug conjugate comprising the same.
  • the compound represented by any one of Formulas 1 to 8, or an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a carrier-drug conjugate containing the same is used as a pharmaceutically acceptable auxiliary, diluent, or carrier. etc. can be mixed, and can be prepared as a composite preparation with other active agents to have a synergistic effect of the active ingredients.
  • the anticancer effect or therapeutic effect of an anticancer agent refers to the action of reducing the severity of cancer, reducing the size of a tumor, or delaying or slowing the progression of cancer that occurs while a patient is suffering from a specific cancer. It can be referred to.
  • the anticancer effect caused by an anticancer drug may be the Cell Viability (change in the degree of cytotoxicity or number of cells) of cancer cells after treating cancer cells with an anticancer drug in-vitro and/or in-vivo.
  • Cell Viability change in the degree of cytotoxicity or number of cells
  • cancer patients can directly confirm the anticancer effect of anticancer drugs, derive related data, and use it as a database.
  • animal model PK parameters and/or toxicity profiles can be considered in parallel.
  • the anticancer effect of an anticancer drug can be inferred from in-vitro data, such as the % maximum effect of the anticancer drug, such as IC 50 , IC 60 , IC 70 , IC 80 , and IC 90 , and the highest blood concentration of the drug. It can also be confirmed in non-clinical animal models and clinical cancer patients through in-vivo data such as concentration (Cmax) and/or area under the blood drug concentration-time curve (AUC).
  • Cmax concentration
  • AUC blood drug concentration-time curve
  • the reactivity of an anticancer drug refers to clinical sensitivity in terms of anticancer effect.
  • “Sensitivity” and “sensitive” when referring to treatment with anticancer agents are relative terms that refer to the degree of effectiveness of a compound in alleviating or reducing the progression of the tumor or disease being treated.
  • Effective patient anti-cancer effect/response refers to, e.g., 5%, 10%, 15%, 20% of patient response, as measured by any suitable means such as gene expression, cell counting, assay results, etc. , 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, or more.
  • the administered dose is the dose expected to have medicinal effect.
  • the medicinal effect may be an anti-cancer effect.
  • the reactivity (anti-cancer effect) of an anti-cancer drug is the degree of response, including the % maximum effect of the anti-cancer drug, such as IC 50 , IC 60 , IC 70 , IC 80 , and IC 90 , and the value of toxicity to normal cells (LC 50 ). It can be.
  • oral dosage forms can be formulated using various formulation techniques known in the art.
  • it may include a biodegradable (hydrolyzable) polymeric carrier used to adhere to the oral mucosa. It is manufactured to erode slowly over a predetermined period of time, where drug delivery is provided essentially holistically.
  • Drug delivery in oral dosage forms avoids the weaknesses encountered with oral drug administration, such as slow absorption, degradation of the active agent by fluids present in the gastrointestinal tract, and/or first-pass inactivation in the liver.
  • biodegradable (hydrolyzable) polymeric carriers virtually any such carrier can be used as long as the desired drug release profile is not impaired, and the carrier is compatible with any of the other ingredients present in the oral dosage unit.
  • polymeric carriers include hydrophilic (water-soluble and water-swellable) polymers that adhere to the wet surface of the oral mucosa.
  • Examples of polymeric carriers useful herein include acrylic acid polymers (eg, carbomers).
  • non-limiting examples of other ingredients that can be incorporated into oral dosage forms include disintegrants, diluents, binders, lubricants, flavoring agents, colorants, preservatives, etc. In some embodiments, it may be in the form of tablets, lozenges, or gels, formulated in a conventional manner for oral or sublingual administration.
  • administration of the compound is continued at the discretion of the physician if the patient's condition improves;
  • the dose of drug to be administered may be temporarily reduced or temporarily suspended for any length of time (i.e., a “dose washout”).
  • the length of the washout can vary between 2 days and 1 year, by way of example only: 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days. days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days.
  • the dose reduction during washout is 10%-100%, and by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55 %, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • the amount of a given agent that will correspond to such amount will vary depending on factors such as the particular compound, the severity of the disease, and the identity (e.g., body weight) of the subject in need of treatment, but will nevertheless vary, including, for example, the formulation to be administered, the administration Depending on the route, and the particular circumstances surrounding the subject to be treated, this can be routinely determined in a manner known in the art. In general, however, doses used for treatment of adult humans will typically range from 0.02-5000 mg/day, or about 1-1500 mg/day.
  • a single dosage herein may be given as a single dose or in divided doses administered simultaneously, for example, as 2, 3, 4 or more sub-doses.
  • the oral dosage form is in unit dosage form suitable for single administration of precise doses.
  • the formulation is divided into unit doses containing appropriate amounts of one or more compounds.
  • the unit dose is in the form of a packet containing discrete amounts of dosage form.
  • Non-limiting examples are packaged tablets or capsules, and powders in vials or in ampoules.
  • Aqueous suspension compositions can be packaged in single-dose, non-reclosable containers. Alternatively, multi-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition.
  • formulations for parenteral injection are provided in unit dosage form, including but not limited to ampoules, or in multi-dose containers, with an added preservative.
  • parenteral administration i.e., bolus, intravenous, and intratumoral injection
  • a pharmaceutically acceptable parenteral vehicle i.e., bolus, intravenous, and intratumoral injection
  • parenteral vehicle i.e., bolus, intravenous, and intratumoral injection
  • a pharmaceutically acceptable parenteral vehicle i.e., bolus, intravenous, and intratumoral injection
  • It is optionally mixed in the form of a lyophilized preparation or aqueous solution with pharmaceutically acceptable diluents, carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.).
  • camptothecin derivatives represented by Formulas 1 to 8 according to the present invention have more desirable properties than existing camptothecin derivatives in terms of efficacy, toxicity, selectivity, action time, administration, handling, stability and/or production potential, etc. It has the advantage of maximizing the efficacy of main drug target modulation through an additional mechanism of action that (i) simultaneously inhibits the Bcl family, such as the resistance protein Survivin, and/or (ii) inhibits the action of the efflux pump. .
  • the carrier-drug conjugate containing a camptothecin derivative represented by any one of Formulas 1 to 8 according to the present invention has the advantage of minimizing toxicity, providing high safety, and at the same time showing high therapeutic efficacy.
  • Figure 1 shows structural formulas of various camptothecin-based anticancer drugs (SN-38, Exatecan, Dxd, FL118).
  • Figure 2 is a diagram showing the results of in vitro cytotoxicity assay of the compound of Formula 2 in FaDu cell line.
  • the analysis conditions for the compounds according to the present invention are as follows.
  • the physicochemical properties, such as LogP, cLogP, and tPSA (topological polar surface area) values, of the compounds of Formulas 1 to 8 according to the present invention are shown in Table 1.
  • 3000 FaDu cell lines per well were seeded in a 96 well plate and incubated at constant temperature (37°C, 5% CO 2 ). After 24 hours, 100 ⁇ l of drugs at 9 concentrations (serial dilution of 1/5 from 1000 nM) were treated with the cells. At this time, 7MAD-MD-CPT (lactic acid), a compound of Formula 2, and a control group were treated, respectively.
  • Compounds of Formulas 1 to 8 according to the present invention are conjugated with Trastuzumab, Cetuximab, Nimotuzumab or Sacituzumab through the linker of Formula 11.
  • Antibody-drug conjugates containing the compounds according to the invention are prepared and their anticancer efficacy is tested.
  • the preparation of the antibody-drug conjugate is carried out as follows.
  • the drug-to-antibody ratio is about 8.
  • excess drug-linker was removed using a PD-10 desalting column, and the final antibody-drug conjugate was obtained.

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Abstract

The present invention relates to novel camptothecin derivatives having the structures of chemical formulas 1 to 8 and carrier-drug conjugates including same, wherein the derivatives possess more desirable properties compared to existing camptothecin derivatives in terms of efficacy, toxicity, selectivity, duration of action, administration, handling, stability, and/or manufacturability and enjoy the advantage of maximizing the efficacy of the main drug target modulation through (i) simultaneous inhibition of the Bcl family such as the resistance protein Survivin, etc. and/or (ii) the additional mechanism of inhibiting efflux pump activity. The novel camptothecin derivatives and carrier-drug conjugates according to the present invention have excellent anticancer efficacy and safety and thus can be applied to the treatment of various cancers.

Description

신규 캄토테신 유도체 및 이를 포함하는 운반체-약물 접합체Novel camptothecin derivatives and carrier-drug conjugates containing the same
본 발명은 우수한 항암 효능 및 안전성을 갖는 신규 캄토테신 유도체 및 이를 포함하는 운반체-약물 접합체, 그리고 이의 약학적 용도에 관한 것이다.The present invention relates to a novel camptothecin derivative with excellent anticancer efficacy and safety, a carrier-drug conjugate containing the same, and its pharmaceutical use.
DNA의 복제 및 재조합 등에 관여하는 이성질화 효소인 제1형 토포이소머라아제(Topoisomerase I)의 저해제는 효능/안전성이 검증된 항암기전을 가지는 약물로서, 임상에서 대장암, 폐암, 유방암, 난소암 등 다양한 난치성 고형암에서 뛰어난 항암 효능이 검증되었다. Inhibitors of type 1 topoisomerase I, an isomerization enzyme involved in DNA replication and recombination, are drugs with an anticancer mechanism with proven efficacy and safety, and have been clinically used to treat colon cancer, lung cancer, breast cancer, and ovarian cancer. Excellent anticancer efficacy has been proven in various intractable solid cancers, such as:
대표적인 제1형 토포이소머라제 저해제로 캄토테신(camptothecin, CPT) 및 그 유도체가 알려져 있는데, 캄토테신은 낮은 수 용해도를 가지며, 높은 독성을 가지고 있는 문제가 있었다. Camptothecin (CPT) and its derivatives are known as representative type 1 topoisomerase inhibitors, but camptothecin has the problem of low water solubility and high toxicity.
이러한 문제점을 해결하기 위해 낮은 독성과 높은 수용해도를 가지는 캄토테신 유도체들에 대한 연구가 이루어졌으며, 이리노테칸(Irinotecan)과 토포테칸(Topotecan) 등의 약물이 대장암, 난소암 및 폐암 등의 치료 용도로 허가 받아 시판 중에 있다. To solve these problems, research has been conducted on camptothecin derivatives with low toxicity and high water solubility, and drugs such as Irinotecan and Topotecan have been used to treat colon cancer, ovarian cancer, and lung cancer. It is licensed and commercially available.
현재까지도 다양한 캄토테신 유도체들이 개발되고 있는데, SN-38은 여러 세포주에서 나노몰 범위의 IC50 값을 갖는 강력한 토포이소머라제-I 억제제로, 결장직장암 치료에 사용되는 전구약물인 이리노테칸의 활성 형태이며 폐암, 유방암 및 뇌암에서도 활성을 나타낸다. Trop-2-SN-38 항체-약물 접합체(ADC : Antibody-Drug Conjugate)의 경우 현재 TNBC, 방광암, 위암 등 다수의 암종에서 효과를 나타내지만, 여전히 SN-38의 내성 문제는 남아 있다To this day, various camptothecin derivatives are being developed. SN-38 is a potent topoisomerase-I inhibitor with IC50 values in the nanomolar range in several cell lines, and is the active form of irinotecan, a prodrug used to treat colorectal cancer. It is also active in lung cancer, breast cancer, and brain cancer. Trop-2-SN-38 Antibody-Drug Conjugate (ADC) is currently effective in many cancer types, including TNBC, bladder cancer, and stomach cancer, but the problem of SN-38 resistance still remains.
또한, 다이이치 산쿄(Daiichi Sankyo)는 엔허투(Enhertu)의 개발에 SN-38보다 암세포에서 10배 정도 활성이 높은 세포독성약물인 엑사데칸(exatecan)의 유도체인 DXd를 사용하였다. DXd는 용해성이 좋고 비교적 안전하며 주변세포살상효과가 높아서 비균질 종양의 치료에 이점이 있지만, 오프타겟 효과를 줄일 수 있는 반감기는 짧다는 단점이 있다. In addition, Daiichi Sankyo used DXd, a derivative of exatecan, a cytotoxic drug that is about 10 times more active in cancer cells than SN-38, in the development of Enhertu. DXd has good solubility, is relatively safe, and has a high killing effect on surrounding cells, making it advantageous for the treatment of heterogeneous tumors. However, it has the disadvantage of having a short half-life that can reduce off-target effects.
현재까지 개발된 캄토테신계 약물을 ADC에 페이로드(payload)로 이용할 경우, MMAE나 MMAF와 같은 기존의 초독성(ultra-toxic) 페이로드를 갖는 ADC에 비해 낮은 세포 독성을 가지고 있으면서 안전성에서도 여전히 문제를 나타낼 뿐 아니라, ABCG2 Drug Efflux Pump 등의 과발현에 의한 저항성 발생에 따른 항암 효과 저하라는 문제를 가지고 있다.When camptothecin-based drugs developed to date are used as payloads in ADCs, they have lower cytotoxicity and still maintain safety compared to ADCs with existing ultra-toxic payloads such as MMAE or MMAF. Not only does it present a problem, but it also has the problem of reduced anti-cancer effectiveness due to the development of resistance due to overexpression of ABCG2 Drug Efflux Pump, etc.
따라서, 보다 높은 세포 독성을 나타내면서도 안전성이 우수할 뿐 아니라, 항암 효과 저하를 초래하는 저항성이 현저하게 감소된 캄토테신 유도체, 특히 페이로드로서 적합한 캄토테신 유도체 및 이를 포함하는 운반체-약물 접합체에 대한 수요는 절실한 상황이다. Therefore, camptothecin derivatives that not only exhibit higher cytotoxicity but are also superior in safety and have significantly reduced resistance that causes reduced anticancer effectiveness, particularly camptothecin derivatives suitable as payloads and carrier-drug conjugates containing the same. The demand is urgent.
이러한 기술적 배경 하에서, 본 발명은 강력한 제1형 토포이소머라제 억제제 효과를 가져 높은 세포 독성을 나타내면서 안전성이 매우 우수한 신규 캄토테신 유도체를 제공하는 것을 목적으로 한다. Under this technical background, the purpose of the present invention is to provide a novel camptothecin derivative that has a strong type 1 topoisomerase inhibitor effect, exhibits high cytotoxicity, and has excellent safety.
또한 본 발명은 본 발명에 따른 캄토테신 유도체를 포함하는 운반체-약물 접합체와, 본 발명에 따른 캄토테신 유도체 또는 이를 포함하는 운반체-약물 접합체를 포함하는 약제학적 조성물을 제공하는 것을 목적으로 한다. Another object of the present invention is to provide a carrier-drug conjugate containing a camptothecin derivative according to the present invention, and a pharmaceutical composition containing a camptothecin derivative or a carrier-drug conjugate containing the same according to the present invention.
나아가, 본 발명은 본 발명에 따른 캄토테신 유도체 또는 이를 포함하는 운반체-약물 접합체를 이용하여 암을 치료하는 방법을 제공하는 것을 목적으로 한다. Furthermore, the purpose of the present invention is to provide a method of treating cancer using a camptothecin derivative or a carrier-drug conjugate containing the same according to the present invention.
상기 과제를 해결하기 위해, 본 발명의 제1 양태는 화학식 1 내지 화학식 8 중 어느 하나로 표시되는 화합물, 이의 이성질체, 이의 약제학적 허용염, 이의 용매화물, 또는 이의 전구약물(prodrug)을 제공한다.In order to solve the above problem, a first aspect of the present invention provides a compound represented by any one of Formulas 1 to 8, an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.
본 발명의 제2 양태는 화학식 1 내지 화학식 8 중 어느 하나로 표시되는 화합물 또는 이의 이성질체 또는 이의 약제학적 허용염, 이의 용매화물, 또는 이의 전구약물을 함유하는 암 예방 또는 치료용 약제학적 조성물을 제공한다.A second aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer containing a compound represented by any one of Formulas 1 to 8, an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof. .
본 발명에 따른 화학식 1 내지 화학식 8 중 어느 하나의 화합물에 C1-3 알킬, 히드록시, 할로겐, 아민기 등의 간단한 작용기를 부가하거나 혹은 이미 존재하는 히드록시, 에틸, 옥소 작용기를 다른 작용기로 치환하거나 제거하더라도, 본 발명의 운반체-약물 접합체와 동등한 효능을 나타내는 한 본 발명의 균등범위에 포함됨은 자명하다.Adding simple functional groups such as C1-3 alkyl, hydroxy, halogen, and amine groups to any one of the compounds of Formulas 1 to 8 according to the present invention, or substituting existing hydroxy, ethyl, and oxo functional groups with other functional groups. Even if it is removed or removed, it is obvious that it is included in the scope of equivalents of the present invention as long as it exhibits the same efficacy as the carrier-drug conjugate of the present invention.
이하, 본 발명은 보다 구체적으로 설명한다. Hereinafter, the present invention will be described in more detail.
본 발명은 화학식 1 내지 화학식 8의 구조를 갖는 신규 캄토테신 유도체를 제공한다.The present invention provides novel camptothecin derivatives having the structures of Formulas 1 to 8.
Figure PCTKR2023013502-appb-img-000001
Figure PCTKR2023013502-appb-img-000001
본 발명에 따른 화학식 1 내지 화학식 8 또는 이의 이성질체로 표시되는 캄토테신 유도체는 세포막을 투과할 수 있는 소수성 저분자이므로, EPR 효과(enhanced permeability and retention effect)에 의해 암조직으로 전달되어 암조직 심부까지 침투하면서 높은 농도로 축적 가능하고, 세포막을 관통해 세포 내부에서 세포독성을 발휘하여 세포 사멸시킨 후 방출되어 연속적으로 주변 세포에도 세포막을 관통해 세포내로 이동하여 작용할 수 있다. Camptothecin derivatives represented by Formulas 1 to 8 or isomers thereof according to the present invention are hydrophobic small molecules that can permeate cell membranes, so they are delivered to cancer tissues by the EPR effect (enhanced permeability and retention effect) and penetrate deep into cancer tissues. It can accumulate at high concentrations, penetrate the cell membrane, exert cytotoxicity inside the cell, kill the cell, and then be released and subsequently penetrate the cell membrane and move into the cell to act on surrounding cells.
본 명세서에서, 본 발명에 따른 화학식 1 내지 화학식 8의 화합물 또는 이의 이성질체로 표시되는 캄토테신 유도체는 상기 화학식 1 내지 화학식 8의 화합물 또는 이의 이성질체 뿐만 아니라, 이의 약제학적 허용염, 이의 용매화물, 이의 전구약물(prodrug)을 포함한다. In the present specification, camptothecin derivatives represented by the compounds of Formulas 1 to 8 or isomers thereof according to the present invention include not only the compounds of Formulas 1 to 8 or isomers thereof, but also pharmaceutically acceptable salts thereof, solvates thereof, and Includes prodrugs.
본 명세서에서, 약제학적 허용염은 제약업계에서 통상적으로 사용되는 염을 의미하며, 예를 들어 나트륨, 칼륨, 칼슘, 마그네슘, 리튬, 구리, 망간, 아연, 철 등을 비롯한 무기이온의 염과 염산, 인산, 황산과 같은 무기산의 염이 있으며, 그 외에 아스코르브산, 시트르산, 타르타르산, 락트산, 말레산, 말론산, 푸마르산, 글리콜산, 숙신산, 프로피온산, 아세트산, 오로테이트산, 아세틸살리실산과 같은 유기산의 염 등과 라이신, 아르기닌, 구아니딘 등의 아미노산 염이 있다. 또한 약학적인 반응, 정제 및 분리과정에서 사용될 수 있는 테트라메틸 암모늄, 테트라에틸 암모늄, 테트라프로필 암모늄, 테트라부틸 암모늄, 벤질 트리메틸 암모늄, 벤제토늄 등의 유기이온의 염이 있지만 이에 한정되는 것은 아니다.In this specification, pharmaceutically acceptable salts refer to salts commonly used in the pharmaceutical industry, such as salts of inorganic ions including sodium, potassium, calcium, magnesium, lithium, copper, manganese, zinc, iron, etc., and hydrochloric acid. , phosphoric acid, and sulfuric acid, as well as salts of organic acids such as ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, orotate acid, and acetylsalicylic acid. There are salts of amino acids such as lysine, arginine, and guanidine. Additionally, there are salts of organic ions such as tetramethyl ammonium, tetraethyl ammonium, tetrapropyl ammonium, tetrabutyl ammonium, benzyl trimethyl ammonium, and benzethonium that can be used in pharmaceutical reactions, purification, and separation processes, but are not limited to these.
“전구약물(prodrug)”이란, 해당 기술 분야로 이용되고 있는 의미를 가지고 있다. 예컨대, 비활성 화합물로, 체내에서 약물 대사에 의해 활성 상태로 변환되는 약물이다. 예를 들면, 생리 활성 물질(physiologically active substance) 또는 치료적 활성 유기 화합물(therapeutically active organic compound)을 화학적으로 수식하고, 생체 내에서 효소적 또는 그 외의 조건하에서 모 화합물(parent compound)을 유리 혹은 방출하도록 설계된 화합물을 의미한다. 전구약물은 투여 후에 생체 내에서 목적으로 하는 화합물로 변화된다. 유용한 약물임에도 불구하고 부작용, 안정성, 용해성, 흡수성, 작용시간 등에서 적합하지 않은 성질을 가지고 있는 것에 화학적 수식을 가해서 임상사용 가능하게 한다.“Prodrug” means something that is used in the relevant technical field. For example, an inactive compound is a drug that is converted to an active state through drug metabolism in the body. For example, a physiologically active substance or a therapeutically active organic compound is chemically modified and the parent compound is liberated or released under enzymatic or other conditions in vivo. refers to a compound designed to A prodrug is converted into the target compound in vivo after administration. Although it is a useful drug, it has unsuitable properties in terms of side effects, stability, solubility, absorption, and duration of action, and is chemically modified to enable clinical use.
"용매화물"은, 비공유 분자간 힘에 의해 결합된 화학양론적 또는 비화학양론적 양의 용매를 추가로 포함하는 화학식 1 내지 화학식 8 중 어느 하나로 표시되는 화합물 또는 이의 이성질체 및 이의 약제학적 허용염을 의미한다. 용매가 물인 경우, 용매화물은 수화물이다.“Solvate” refers to a compound represented by any one of Formulas 1 to 8, or an isomer thereof and a pharmaceutically acceptable salt thereof, further comprising a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. it means. When the solvent is water, the solvate is a hydrate.
일 양태에서, 본 발명은 상기 본 발명에 따른 화학식 1 내지 화학식 8 중 어느 하나로 표시되는 화합물, 이의 이성질체, 이의 약제학적 허용염, 또는 이의 용매화물을 포함하는 운반체-약물 접합체(Carrier-Drug Conjugate)를 제공한다. In one aspect, the present invention provides a carrier-drug conjugate comprising a compound represented by any one of Formulas 1 to 8 according to the present invention, an isomer thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. provides.
본 발명에 있어, “운반체(Carrier)”는 본 발명에 따른 캄토테신 유도체를 목적하는 부위, 예를 들어 암세포에 선택적이고 특이적으로 전달할 수 있는 능력을 가지는 물질을 의미하며, 항체, 펩타이드, 리피바디, 및/또는 압타머일 수 있지만, 이에 한정되는 것은 아니며, 바람직하게는 항체이다. In the present invention, “Carrier” refers to a substance that has the ability to selectively and specifically deliver the camptothecin derivative according to the present invention to the target site, for example, cancer cells, and includes antibodies, peptides, liposomes, etc. It may be a body, and/or an aptamer, but is not limited thereto, and is preferably an antibody.
압타머-약물 접합체(Aptamer-Drug Conjugate, ApDC)는 ADC의 항체 대신 압타머를 도입한 것이다. 압타머는 3차원 입체구조를 갖는 단일 가닥 핵산이다. 압타머는 통상적으로 셀렉스(SELEX : Systematic Evolution of Ligands by Exponential enrichment) 과정을 통해 발굴된다. 셀렉스는 화합물 라이브러리에 표적하는 단백질 분자를 넣어 이와 결합하는 기능성 핵산을 얻는 기술이다. 압타머는 표적에 매우 강력하고 선택적으로 결합할 수 있어 화학적 항체(chemical antibody)라고도 불린다. 압타머는 20 kDa 정도의 크기이며, 항체에 비해 우수한 세포 침투성과 낮은 면역원성을 가진 것으로 알려져 있다.Aptamer-Drug Conjugate (ApDC) is an aptamer introduced instead of an antibody in ADC. Aptamers are single-stranded nucleic acids with a three-dimensional structure. Aptamers are usually discovered through the SELEX (Systematic Evolution of Ligands by Exponential enrichment) process. Selex is a technology that obtains functional nucleic acids that bind to target protein molecules in a compound library. Aptamers can bind to targets very strongly and selectively, so they are also called chemical antibodies. Aptamers are about 20 kDa in size and are known to have excellent cell penetration and low immunogenicity compared to antibodies.
압타머는 화학적 합성이 가능하므로 압타머-약물 접합체의 제조 시 결합 약물의 접합 위치 및 개수에 대한 정밀한 설계가 가능하다. ADC에 비해 생산비용이 낮다. 압타머는 일반적으로 천연 핵산으로 이루어져 있어서 체내 핵산분해효소로 분해돼 생체 내 안정성이 떨어진다. 하지만 압타머의 화학적 변형이 용이하다는 점을 이용해 변형된 압타머의 안정성에 대한 한계를 극복할 수 있다.Since aptamers can be chemically synthesized, precise design of the conjugation location and number of drugs is possible when manufacturing aptamer-drug conjugates. The production cost is lower than that of ADC. Aptamers are generally made of natural nucleic acids, so they are degraded by nucleic acid degrading enzymes in the body, making them less stable in vivo. However, by taking advantage of the ease of chemical modification of aptamers, the limitations on the stability of modified aptamers can be overcome.
펩타이드-약물 접합체(Peptide-Drug Conjugate, PDC)는 ADC에서 항체 대신 펩타이드를 도입한 형태다. 펩타이드는 아미노산으로 구성되며, 500~5000Da(달톤) 범위의 크기를 가진다. 이는 150kDa(킬로달톤)이상인 항체와 비교해 매우 작은 크기다. 따라서 펩타이드 기반인 PDC는 ADC에 비해 우수한 세포 침투 능력을 가지며, 면역원성이 발생할 가능성이 매우 낮다. 또한 펩타이드는 화학적 합성이 가능하다. 이 때문에 PDC는 생산비용이 매우 낮을 뿐 아니라 펩타이드와 약물의 접합 위치와 비율을 정밀하게 조절할 수 있다. 일반적으로 펩타이드는 단백질분해효소에 쉽게 분해되므로 짧은 생물학적 반감기를 갖는다. 이러한 펩타이드 기반 약물접합체의 한계를 극복하기 위해 고리형 펩타이드, 비천연아미노산 도입 등 변형된 펩타이드를 활용하는 전략이 제시되고 있다.Peptide-Drug Conjugate (PDC) is a form of ADC in which peptides are introduced instead of antibodies. Peptides are composed of amino acids and have a size ranging from 500 to 5000 Da (Dalton). This is a very small size compared to antibodies of 150 kDa (kilodaltons) or more. Therefore, peptide-based PDC has superior cell penetration ability compared to ADC, and the possibility of immunogenicity is very low. Additionally, peptides can be chemically synthesized. For this reason, PDC not only has a very low production cost, but also allows precise control of the conjugation position and ratio of peptide and drug. In general, peptides are easily degraded by proteolytic enzymes and therefore have a short biological half-life. To overcome these limitations of peptide-based drug conjugates, strategies using modified peptides such as cyclic peptides and introduction of non-natural amino acids are being proposed.
리피바디(Repebody)는 항체 골격을 갖고 있지는 않지만 항체와 같이 항원을 인식하는 기능을 갖는 일종의 인공항체다. 표적 단백질에 특이적인 리피바디는 파지디스플레이(phage display) 기술을 통해 발굴할 수 있다.Repebody is a type of artificial antibody that does not have an antibody skeleton but has the function of recognizing antigens like an antibody. Lipibodies specific to target proteins can be discovered through phage display technology.
파지디스플레이는 박테리오파지의 표면에 원하는 단백질을 발현시키는 기술이다. 리피바디는 항체의약 20% 수준인 30kDa 정도의 크기다. 따라서 항체에 비해 상대적으로 낮은 면역원성과 향상된 세포침투성을 갖는다고 알려져 있다. 또한, 리피바디는 열적 및 pH 안정성을 조절할 수 있어 구조적 안정성을 높일 수 있을 것으로 기대된다. 항체에 비해 생산 비용 또한 비교적 낮은 것으로 평가된다. 이러한 리피바디의 장점 때문에 항체를 리피바디로 대체하는 전략으로서 리피바디-약물 접합체(Repebody-DC) 개발에 대한 관심도 높아지고 있다.Phage display is a technology that expresses desired proteins on the surface of bacteriophage. Lipibody is about 30kDa in size, which is 20% of an antibody drug. Therefore, it is known to have relatively low immunogenicity and improved cell penetration compared to antibodies. In addition, lipibodies are expected to increase structural stability by controlling thermal and pH stability. Compared to antibodies, production costs are also assessed to be relatively low. Because of these advantages of lipibodies, interest in developing lipibody-drug conjugates (Repebody-DC) as a strategy to replace antibodies with lipibodies is also increasing.
본 발명에서의 운반체가 결합하는 타겟, 예를 들어 항원은 비제한적으로 Her2, FolR, PSMA 등 암 표면에 선택적으로 분포하는 항원 및 Trop2 등 정상 조직에도 소수 분포하는 암세포 과발현 항원들이 예시될 수 있다. Targets to which the carrier binds in the present invention, for example, antigens, include, but are not limited to, antigens selectively distributed on the surface of cancer, such as Her2, FolR, and PSMA, and antigens overexpressed in cancer cells, such as Trop2, which are distributed in small numbers in normal tissues.
예시적인 암 세포 표적 항원은 5T4, ABL, ABCF1, ACVR1, ACVR1B, ACVR2, ACVR2B, ACVRL1, ADORA2A, AFP, Aggrecan, AGR2, AICDA, AIF1, AIGI, AKAP1, AKAP2, ALCAM, ALK, AMH, AMHR2, ANGPT1, ANGPT2, ANGPTL3, ANGPTL4, ANPEP, APC, APOCl, AR, 아로마타제 (aromatase), ASPH, ATX, AX1, AXL, AZGP1 (zinc-a-glycoprotein), B4GALNT1, B7, B7.1, B7.2, B7-H1, B7-H3, B7-H4, B7-H6, BAD, BAFF, BAG1, BAI1, BCR, BCL2, BCL6, BCMA, BDNF, BLNK, BLR1 (MDR15), BIyS, BMP1, BMP2, BMP3B (GDFIO), BMP4, BMP6, BMP8, BMP10, BMPR1A, BMPR1B, BMPR2, BPAG1 (플렉틴), BRCA1, C19orflO (IL27w), C3, C4A, C5, C5R1, CA6, CA9, CANT1, CAPRIN-1, CASP1, CASP4, CAV1, CCBP2 (D6/JAB61), CCL1 (1-309), CCLI1 (에오탁신), CCL13 (MCP-4), CCL15 (MIP-Id), CCL16 (HCC-4), CCL17 (TARC), CCL18 (PARC), CCL19 (MIP-3b), CCL2 (MCP-1), MCAF, CCL20 (MIP-3a), CCL21 (MEP-2), SLC, exodus-2, CCL22(MDC/STC-I), CCL23 (MPIF-I), CCL24 (MPIF-2/에오탁신-2), CCL25 (TECK), CCL26(에오탁신-3), CCL27 (CTACK/ILC), CCL28, CCL3 (MIP-Ia), CCL4 (MIPIb), CCL5(RANTES), CCL7 (MCP-3), CCL8 (mcp-2), CCNA1, CCNA2, CCND1, CCNE1, CCNE2, CCR1 (CKR1/HM145), CCR2 (mcp-IRB/RA), CCR3 (CKR3/CMKBR3), CCR4, CCR5(CMKBR5/ChemR13), CCR6 (CMKBR6/CKR-L3/STRL22/DRY6), CCR7 (CKR7/EBI1), CCR8 또는 CDw198 (CMKBR8/TERI/CKR-L1), CCR9 (GPR-9-6), CCRL1 (VSHK1), CCRL2 (L-CCR), CD13, CD164, CD19, CDH6, CDIC, CD2, CD20, CD21, CD200, CD22, CD23, CD24, CD27, CD28, CD29, CD3, CD33, CD35, CD37, CD38, CD3E, CD3G, CD3Z, CD4, CD40, CD40L, CD44, CD45RB, CD47, CD52, CD56, CD69, CD70, CD72, CD74, CD79A, CD79B, CD8, CD80, CD81, CD83, CD86, CD97, CD99, CD117, CD125, CD137, CD147, CD179b, CD223, CD279, CD152, CD274, CDH1 (E-카드헤린), CDH1O, CDH12, CDH13, CDH18, CDH19, CDH2O, CDH3, CDH5, CDH7, CDH8, CDH9, CDH17, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK9, CDKN1A (p21Wap1/Cip1), CDKN1B (p27Kip1), CDKN1C, CDKN2A (p16INK4a), CDKN2B, CDKN2C, CDKN3, CEA, CEACAM5, CEACAM6, CEBPB, CERI, CFC1B, CHGA, CHGB, 키티나제 (Chitinase), CHST1O, CIK, CKLFSF2, CKLFSF3, CKLFSF4, CKLFSF5, CKLFSF6, CKLFSF7, CKLFSF8, CLDN3, CLDN6, CLDN7 (클라우딘-7), CLDN18, CLEC5A, CLEC6A, CLEC11A, CLEC14A, CLN3, CLU (클러스테린), CMKLR1, CMKOR1 (RDC1), CNR1, C-MET, COL18A1, COLIA1, COL4A3, COL6A1, CR2, Cripto, CRP, CSF1 (M-CSF), CSF2 (GM-CSF), CSF3 (GCSF), CTAG1B (NY-ESO-1), CTLA4, CTL8, CTNNB1 (b-카테닌), CTSB (카텝신 B), CX3CL1 (SCYD1), CX3CR1 (V28), CXCL1 (GRO1), CXCL1O (IP-IO), CXCLI1 (1-TAC/IP-9), CXCL12 (SDF1), CXCL13, CXCL14, CXCL16, CXCL2 (GRO2), CXCL3 (GRO3), CXCL5 (ENA-78/LIX), CXCL6 (GCP-2), CXCL9 (MIG), CXCR3 (GPR9/CKR-L2), CXCR4, CXCR6 (TYMSTR/STRL33/Bonzo), CYB5, CYC1, CYSLTR1, DAB2IP, DES, DKFZp451J0118, DLK1, DNCL1, DPP4, E2F1, Engel, Edge, Fennel, EFNA3, EFNB2, EGF, EGFR, ELAC2, ENG, Enola, ENO2, ENO3, EpCAM, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA9, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB5, EPHB6, EPHRIN-A1, EPHRIN-A2, EPHRINA3, EPHRIN-A4, EPHRIN-A5, EPHRIN-A6, EPHRIN-B1, EPHRIN-B2, EPHRIN-B3, EPHB4, EPG, ERBB2 (HER-2), ERBB3, ERBB4, EREG, ERK8, 에스 트로겐 수용체, Earl, ESR2, F3 (TF), FADD, FAP, 파르네실트란스퍼라제, FasL, FASNf, FCER1A, FCER2, FCGR3A, FGF, FGF1 (aFGF), FGF10, FGF1 1, FGF12, FGF12B, FGF13, FGF14, FGF16, FGF17, FGF18, FGF19, FGF2 (bFGF), FGF20, FGF21, FGF22, FGF23, FGF3 (int-2), FGF4 (HST), FGF5, FGF6 (HST-2), FGF7 (KGF), FGF8, FGF9, FGFR1, FGFR2, FGFR3, FGFR4, FIGF (VEGFD), FIL1(EPSILON), FBL1 (ZETA), FLJ12584, FLJ25530, FLRT1 (피브로넥틴), FLT1, FLT-3, FOLR1, FOS, FOSL1(FRA-1), FR-알파, FY (DARC), GABRP (GABAa), GAGEB1, GAGEC1, GALNAC4S-6ST, GATA3, GD2, GD3, GDF5, GFI1, GFRA1, GGT1, GM-CSF, GNAS1, GNRH1, GPC1, GPC3, GPNB, GPR2 (CCR10), GPR31, GPR44, GPR81 (FKSG80), GRCC1O (C1O), GRP, GSN (Gelsolin), GSTP1, GUCY2C, HAVCR1, HAVCR2, HDAC, HDAC4, HDAC5, HDAC7A, HDAC9, Hedgehog, HER3, HGF, HIF1A, HIP1, 히스타민 및 히스타민 수용체, HLA-A, HLA-DR, HLA-DRA, HLA-E, HM74, HMOXI, HSP90, HUMCYT2A, ICEBERG, ICOSL, ID2, IFN-a, IFNA1, IFNA2, IFNA4, IFNA5, EFNA6, BFNA7, IFNB1, IFN감마, IFNW1, IGBP1, IGF1, IGFIR, IGF2, IGFBP2, IGFBP3, IGFBP6, DL-1, ILIO, ILIORA, ILIORB, IL-1, IL1R1 (CD121a), IL1R2(CD121b), IL-IRA, IL-2, IL2RA (CD25), IL2RB(CD122), IL2RG(CD132), IL-4, IL-4R(CD123), IL-5, IL5RA(CD125), IL3RB(CD131), IL-6, IL6RA, (CD126), IR6RB(CD130), IL-7, IL7RA(CD127), IL-8, CXCR1 (IL8RA), CXCR2, (IL8RB/CD128), IL-9, IL9R(CD129), IL-10, IL10RA(CD210), IL10RB(CDW210B), IL-11, IL11RA, IL-12, IL-12A, IL-12B, IL-12RB1, IL-12RB2, IL-13, IL13RA1, IL13RA2, IL14, IL15, IL15RA, IL16, IL17, IL17A, IL17B, IL17C, IL17R, IL18, IL18BP, IL18R1, IL18RAP, IL19, ILIA, ILIB, ILIF10, ILIF5, IL1F6, ILIF7, IL1F8, DL1F9, ILIHYI, ILIR1, IL1R2, ILIRAP, ILIRAPLI, ILIRAPL2, ILIRL1, IL1RL2, ILIRN, IL2, IL20, IL20RA, IL21R, IL22, IL22R, IL22RA2, IL23, DL24, IL25, IL26, IL27, IL28A, IL28B, IL29, IL2RA, IL2RB, IL2RG, IL3, IL30, IL3RA, IL4, 1L4, IL6ST (당단백질 130), ILK, INHA, INHBA, INSL3, INSL4, IRAK1, IRAK2, ITGA1, ITGA2, ITGA3, ITGA6 (α6 인테그린), ITGAV, ITGB3, ITGB4 (β4 인테그린), JAG1, JAK1, JAK3, JTB, JUN, K6HF, KAI1, KDR, KIT, KITLG, KLF5 (GC Box BP), KLF6, KLK10, KLK12, KLK13, KLK14, KLK15, KLK3, KLK4, KLK5, KLK6, KLK9, KRT1, KRT19 (케라틴 19), KRT2A, KRTHB6 (헤어 (hair)-특이적 타입 II 케라틴), L1CAM, LAG3, LAMA5, LAMP1, LEP (렙틴), Lewis Y 항원 ("LeY"), LILRB1, Lingo-p75, Lingo-Troy, LGALS3BP, LRRC15, LPS, LTA (TNF-b), LTB, LTB4R (GPR16), LTB4R2, LTBR, LY75, LYPD3, MACMARCKS, MAG 또는 OMgp, MAGEA3, MAGEA6, MAP2K7 (c-Jun), MCP-1, MDK, MIB1, midkine, MIF, MISRII, MJP-2, MLSN, MK, MKI67 (Ki-67), MMP2, MMP9, MS4A1, MSMB, MT3 (메탈로티오넥틴-UI), mTOR, MTSS1, MUC1 (mucin), MUC16, MYC, MYD88, NCK2, NCR3LG1, 뉴로칸 (neurocan), NFKBI, NFKB2, NGFB (NGF), NGFR, NgR-Lingo, NgRNogo66, (Nogo), NgR-p75, NgR-Troy, NMEI (NM23A), NOTCH, NOTCH1, NOTCH3, NOX5, NPPB, NROB1, NROB2, NRID1, NR1D2, NR1H2, NR1H3, NR1H4, NR112, NR113, NR2C1, NR2C2, NR2E1, NR2E3, NR2F1, NR2F2, NR2F6, NR3C1, NR3C2, NR4A1, NR4A2, NR4A3, NR5A1, NR5A2, NR6A1, NRP1, NRP2, NT5E, NTN4, NY-ESO1, ODZI, OPRDI, P2RX7, PAP, PART1, PATE, PAWR, P-카드헤린, PCA3, PCD1, PD-L1, PCDGF, PCNA, PDGFA, PDGFB, PDGFRA, PDGFRB, PECAMI, L1-CAM, peg-아스파라기나제, PF4 (CXCL4), PGF, PGR, 포스파칸 (phosphacan), PIAS2, PI3 키나제, PIK3CG, PLAU (uPA), PLG, PLXDCI, PKC, PKC-베타, PPBP (CXCL7), PPID, PR1, PRAME, PRKCQ, PRKD1, PRL, PROC, PROK2, PSAP, PSCA, PSMA, PTAFR, PTEN, PTHR2, PTGS2 (COX-2), PTN, PVRIG, RAC2 (P21Rac2), RANK, RANK 리간드, RARB, RGS1, RGS13, RGS3, RNFI1O (ZNF144), Ron, ROBO2, ROR1, RXR, S100A2, SCGB 1D2 (리포필린 B), SCGB2A1 (맘마글로빈 2), SCGB2A2 (맘마글 로빈 1), SCYE1 (내피 단핵구-활성화 사이토카인), SDF2, SERPENA1, SERPINA3, SERPINB5 (마스핀), SERPINEI (PAI-I), SERPINFI, SHIP-1, SHIP-2, SHB1, SHB2, SHBG, SfcAZ, SLAMF7, SLC2A2, SLC33A1, SLC43A1, SLC44A4, SLC34A2, SLIT2, SPP1, SPRR1B (Spr1), ST6GAL1, ST8SIA1, STAB1, STATE, STEAP, STEAP2, TB4R2, TBX21, TCP1O, TDGF1, TEK, TGFA, TGFB1, TGFB1I1, TGFB2, TGFB3, TGFBI, TGFBR1, TGFBR2, TGFBR3, THIL, THBS1 (트롬보스폰딘-1), THBS2, THBS4, THPO, TIE (Tie-1), TIMP3, 조직 인자 (tissue factor), TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TNF, TNF-a, TNFAIP2 (B94), TNFAIP3, TNFRSFI1A, TNFRSF1A, TNFRSF1B, TNFRSF21, TNFRSF5, TNFRSF6 (Fas), TNFRSF7, TNFRSF8, TNFRSF9, TNFSF1O (TRAIL), TNFRSF10A, TNFRSF10B, TNFRSF12A, TNFRSF17, TNFSF1 1 (TRANCE), TNFSF12 (APO3L), TNFSF13 (April), TNFSF13B, TNFSF14 (HVEM-L), TNFRSF14 (HVEM), TNFSF15 (VEGI), TNFSF18, TNFSF4 (OX40 리간드), TNFSF5 (CD40 리간드), TNFSF6 (FasL), TNFSF7 (CD27 리간드), TNFSF8 (CD30 리간드), TNFSF9 (4-1BB 리간드), TOLLIP, Toll-유사 수용체, TOP2A (토포이소머라제 Iia), TP53, TPM1, TPM2, TRADD, TRAF1, TRAF2, TRAF3, TRAF4, TRAF5, TRAF6, TRKA, TREM1, TREM2, TROP2, TRPC6, TSLP, TWEAK, 티로시나제 (Tyrosinase), uPAR, VEGF, VEGFB, VEGFC, 베르시칸 (versican), VHL C5, VLA-4, WT1, Wnt-1, XCL1 (림포탁틴), XCL2 (SCM-Ib), XCRI (GPR5/CCXCR1), YY1, ZFPM2, CLEC4C (BDCA-2, DLEC, CD303, CDH6, CLECSF7), CLEC4D (MCL, CLECSF8), CLEC4E (Mincle), CLEC6A (덱틴-2), CLEC5A (MDL-1, CLECSF5), CLEC1B (CLEC-2), CLEC9A (DNGR-1), CLEC7A (덱틴-1), CLEC11A, PDGFRa, SLAMF7, GP6 (GPVI), LILRA1 (CD85I), LILRA2 (CD85H, ILT1), LILRA4 (CD85G, ILT7), LILRA5 (CD85F, ILT11), LILRA6 (CD85b, ILT8), LILRB1, NCR1 (CD335, LY94, NKp46), NCR3 (CD335, LY94, NKp46), NCR3 (CD337, NKp30), OSCAR, TARM1, CD30, CD300C, CD300E, CD300LB (CD300B), CD300LD (CD300D), KIR2DL4 (CD158D), KIR2DS, KLRC2 (CD159C, NKG2C), KLRK1 (CD314, NKG2D), NCR2 (CD336, NKp44), PILRB, SIGLEC1 (CD169, SN), SIGLEC5, SIGLEC6, SIGLEC7, SIGLEC8, SIGLEC9, SIGLEC10, SIGLEC11, SIGLEC12, SIGLEC14, SIGLEC15 (CD33L3), SIGLEC16, SIRPA, SIRPB1 (CD172B), TREM1 (CD354), TREM2, KLRF1 (NKp80), 17-1A, SLAM7, MSLN, CTAG1B/NY-ESO-1, MAGEA3/A6, ATP5I (Q06185), OAT (P29758), AIFM1 (Q9Z0X1), AOFA (Q64133), MTDC (P18155), CMC1 (Q8BH59), PREP (Q8K411), YMEL1 (O88967), LPPRC (Q6PB66), LONM (Q8CGK3), ACON (Q99KI0), ODO1 (Q60597), IDHP (P54071), ALDH2 (P47738), ATPB (P56480), AATM (P05202), TMM93 (Q9CQW0), ERGI3 (Q9CQE7), RTN4 (Q99P72), CL041 (Q8BQR4), ERLN2 (Q8BFZ9), TERA (Q01853), DAD1 (P61804), CALX (P35564), CALU (O35887), VAPA (Q9WV55), MOGS (Q80UM7), GANAB (Q8BHN3), ERO1A (Q8R180), UGGG1 (Q6P5E4), P4HA1 (Q60715), HYEP (Q9D379), CALR (P14211), AT2A2 (O55143), PDIA4 (P08003), PDIA1 (P09103), PDIA3 (P27773), PDIA6 (Q922R8), CLH (Q68FD5), PPIB (P24369), TCPG (P80318), MOT4 (P57787), NICA (P57716), BASI (P18572), VAPA (Q9WV55), ENV2 (P11370), VAT1 (Q62465), 4F2 (P10852), ENOA (P17182), ILK (O55222), GPNMB (Q99P91), ENV1 (P10404), ERO1A (Q8R180), CLH (Q68FD5), DSG1A (Q61495), AT1A1 (Q8VDN2), HYOU1 (Q9JKR6), TRAP1 (Q9CQN1), GRP75 (P38647), ENPL (P08113), CH60 (P63038), 또는 CH10 (Q64433)일 수 있으나, 이에 제한되지 않는다. 또한, 표적 항원은 정상세포 대비 암세포에 10배 이상 많이 분포하는 항원일 수 있다.Exemplary cancer cell target antigens include 5T4, ABL, ABCF1, ACVR1, ACVR1B, ACVR2, ACVR2B, ACVRL1, ADORA2A, AFP, Aggrecan, AGR2, AICDA, AIF1, AIGI, AKAP1, AKAP2, ALCAM, ALK, AMH, AMHR2, ANGPT1. , ANGPT2, ANGPTL3, ANGPTL4, ANPEP, APC, APOCl, AR, aromatase, ASPH, ATX, AX1, AXL, AZGP1 (zinc-a-glycoprotein), B4GALNT1, B7, B7.1, B7.2, B7-H1, B7-H3, B7-H4, B7-H6, BAD, BAFF, BAG1, BAI1, BCR, BCL2, BCL6, BCMA, BDNF, BLNK, BLR1 (MDR15), BIyS, BMP1, BMP2, BMP3B (GDFIO ), BMP4, BMP6, BMP8, BMP10, BMPR1A, BMPR1B, BMPR2, BPAG1 (plectin), BRCA1, C19orflO (IL27w), C3, C4A, C5, C5R1, CA6, CA9, CANT1, CAPRIN-1, CASP1, CASP4 , CAV1, CCBP2 (D6/JAB61), CCL1 (1-309), CCLI1 (eotaxin), CCL13 (MCP-4), CCL15 (MIP-Id), CCL16 (HCC-4), CCL17 (TARC), CCL18 (PARC), CCL19 (MIP-3b), CCL2 (MCP-1), MCAF, CCL20 (MIP-3a), CCL21 (MEP-2), SLC, exodus-2, CCL22(MDC/STC-I), CCL23 (MPIF-I), CCL24 (MPIF-2/Eotaxin-2), CCL25 (TECK), CCL26 (Eotaxin-3), CCL27 (CTACK/ILC), CCL28, CCL3 (MIP-Ia), CCL4 (MIPIb) ), CCL5 (RANTES), CCL7 (MCP-3), CCL8 (mcp-2), CCNA1, CCNA2, CCND1, CCNE1, CCNE2, CCR1 (CKR1/HM145), CCR2 (mcp-IRB/RA), CCR3 (CKR3) /CMKBR3), CCR4, CCR5 (CMKBR5/ChemR13), CCR6 (CMKBR6/CKR-L3/STRL22/DRY6), CCR7 (CKR7/EBI1), CCR8 or CDw198 (CMKBR8/TERI/CKR-L1), CCR9 (GPR- 9-6), CCRL1 (VSHK1), CCRL2 (L-CCR), CD13, CD164, CD19, CDH6, CDIC, CD2, CD20, CD21, CD200, CD22, CD23, CD24, CD27, CD28, CD29, CD3, CD33 , CD35, CD37, CD38, CD3E, CD3G, CD3Z, CD4, CD40, CD40L, CD44, CD45RB, CD47, CD52, CD56, CD69, CD70, CD72, CD74, CD79A, CD79B, CD8, CD80, CD81, CD83, CD86 , CD97, CD99, CD117, CD125, CD137, CD147, CD179b, CD223, CD279, CD152, CD274, CDH1 (E-cadherin), CDH1O, CDH12, CDH13, CDH18, CDH19, CDH2O, CDH3, CDH5, CDH7, CDH8 , CDH9, CDH17, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK9, CDKN1A (p21Wap1/Cip1), CDKN1B (p27Kip1), CDKN1C, CDKN2A (p16INK4a), CDKN2B, CDKN2C, CDKN3, CEA, CEACAM5, CEACAM6, CEBPB, CERI, CFC1B, CHGA, CHGB, Chitinase, CHST1O, CIK, CKLFSF2, CKLFSF3, CKLFSF4, CKLFSF5, CKLFSF6, CKLFSF7, CKLFSF8, CLDN3, CLDN6, CLDN7 (claudin-7), CLDN18, CLEC5A, CLEC6A , CLEC11A, CLEC14A, CLN3, CLU (clusterin), CMKLR1, CMKOR1 (RDC1), CNR1, C-MET, COL18A1, COLIA1, COL4A3, COL6A1, CR2, Cripto, CRP, CSF1 (M-CSF), CSF2 ( GM-CSF), CSF3 (GCSF), CTAG1B (NY-ESO-1), CTLA4, CTL8, CTNNB1 (b-catenin), CTSB (cathepsin B), CX3CL1 (SCYD1), CX3CR1 (V28), CXCL1 (GRO1) ), CXCL1O (IP-IO), CXCLI1 (1-TAC/IP-9), CXCL12 (SDF1), CXCL13, CXCL14, CXCL16, CXCL2 (GRO2), CXCL3 (GRO3), CXCL5 (ENA-78/LIX), CXCL6 (GCP-2), CXCL9 (MIG), CXCR3 (GPR9/CKR-L2), CXCR4, CXCR6 (TYMSTR/STRL33/Bonzo), CYB5, CYC1, CYSLTR1, DAB2IP, DES, DKFZp451J0118, DLK1, DNCL1, DPP4, E2F1, Engel, Edge, Fennel, EFNA3, EFNB2, EGF, EGFR, ELAC2, ENG, Enola, ENO2, ENO3, EpCAM, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA9, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB5, EPHB6, EPHRIN-A1, EPHRIN-A2, EPHRINA3, EPHRIN-A4, EPHRIN-A5, EPHRIN-A6, EPHRIN-B1, EPHRIN-B2, EPHRIN-B3, EPHB4, EPG, ERBB2 ( HER-2), ERBB3, ERBB4, EREG, ERK8, estrogen receptor, Earl, ESR2, F3 (TF), FADD, FAP, farnesyltransferase, FasL, FASNf, FCER1A, FCER2, FCGR3A, FGF, FGF1 ( aFGF), FGF10, FGF1 1, FGF12, FGF12B, FGF13, FGF14, FGF16, FGF17, FGF18, FGF19, FGF2 (bFGF), FGF20, FGF21, FGF22, FGF23, FGF3 (int-2), FGF4 (HST), FGF5 , FGF6 (HST-2), FGF7 (KGF), FGF8, FGF9, FGFR1, FGFR2, FGFR3, FGFR4, FIGF (VEGFD), FIL1 (EPSILON), FBL1 (ZETA), FLJ12584, FLJ25530, FLRT1 (fibronectin), FLT1 , FLT-3, FOLR1, FOS, FOSL1(FRA-1), FR-alpha, FY (DARC), GABRP (GABAa), GAGEB1, GAGEC1, GALNAC4S-6ST, GATA3, GD2, GD3, GDF5, GFI1, GFRA1, GGT1, GM-CSF, GNAS1, GNRH1, GPC1, GPC3, GPNB, GPR2 (CCR10), GPR31, GPR44, GPR81 (FKSG80), GRCC1O (C1O), GRP, GSN (Gelsolin), GSTP1, GUCY2C, HAVCR1, HAVCR2, HDAC, HDAC4, HDAC5, HDAC7A, HDAC9, Hedgehog, HER3, HGF, HIF1A, HIP1, histamine and histamine receptor, HLA-A, HLA-DR, HLA-DRA, HLA-E, HM74, HMOXI, HSP90, HUMCYT2A, ICEBERG , ICOSL, ID2,IFN-a,IFNA1,IFNA2,IFNA4,IFNA5,EFNA6,BFNA7,IFNB1,IFNgamma,IFNW1,IGBP1,IGF1,IGFIR,IGF2,IGFBP2,IGFBP3,IGFBP6,DL-1,ILIO,ILIORA, ILIORB, IL-1, IL1R1 (CD121a), IL1R2 (CD121b), IL-IRA, IL-2, IL2RA (CD25), IL2RB (CD122), IL2RG (CD132), IL-4, IL-4R (CD123), IL-5, IL5RA (CD125), IL3RB (CD131), IL-6, IL6RA, (CD126), IR6RB (CD130), IL-7, IL7RA (CD127), IL-8, CXCR1 (IL8RA), CXCR2, ( IL8RB/CD128), IL-9, IL9R (CD129), IL-10, IL10RA (CD210), IL10RB (CDW210B), IL-11, IL11RA, IL-12, IL-12A, IL-12B, IL-12RB1, IL-12RB2, IL-13, IL13RA1, IL13RA2, IL14, IL15, IL15RA, IL16, IL17, IL17A, IL17B, IL17C, IL17R, IL18, IL18BP, IL18R1, IL18RAP, IL19, ILIA, ILIB, ILIF10, ILIF5, IL1F6, ILIF7, IL1F8, DL1F9, ILIHYI, ILIR1, IL1R2, ILIRAP, ILIRAPLI, ILIRAPL2, ILIRL1, IL1RL2, ILIRN, IL2, IL20, IL20RA, IL21R, IL22, IL22R, IL22RA2, IL23, DL24, IL25, IL26, IL27, IL28A, IL28B, IL29, IL2RA, IL2RB, IL2RG, IL3, IL30, IL3RA, IL4, 1L4, IL6ST (glycoprotein 130), ILK, INHA, INHBA, INSL3, INSL4, IRAK1, IRAK2, ITGA1, ITGA2, ITGA3, ITGA6 (α6 integrins), ITGAV, ITGB3, ITGB4 (β4 integrin), JAG1, JAK1, JAK3, JTB, JUN, K6HF, KAI1, KDR, KIT, KITLG, KLF5 (GC Box BP), KLF6, KLK10, KLK12, KLK13, KLK14, KLK15, KLK3, KLK4, KLK5, KLK6, KLK9, KRT1, KRT19 (keratin 19), KRT2A, KRTHB6 (hair-specific type II keratin), L1CAM, LAG3, LAMA5, LAMP1, LEP (leptin), Lewis Y antigen (“LeY”), LILRB1, Lingo-p75, Lingo-Troy, LGALS3BP, LRRC15, LPS, LTA (TNF-b), LTB, LTB4R (GPR16), LTB4R2, LTBR, LY75, LYPD3, MACMARCKS, MAG or OMgp, MAGEA3, MAGEA6, MAP2K7 (c-Jun), MCP-1, MDK, MIB1, midkine, MIF, MISRII, MJP-2, MLSN, MK, MKI67 (Ki-67), MMP2, MMP9, MS4A1, MSMB, MT3 (metallothionectin-UI), mTOR, MTSS1, MUC1 (mucin), MUC16, MYC, MYD88, NCK2, NCR3LG1, neurocan, NFKBI, NFKB2, NGFB (NGF), NGFR, NgR-Lingo, NgRNogo66, (Nogo), NgR-p75, NgR-Troy, NMEI (NM23A), NOTCH, NOTCH1, NOTCH3, NOX5, NPPB, NROB1, NROB2, NRID1, NR1D2, NR1H2, NR1H3, NR1H4, NR112, NR113, NR2C1, NR2C2 , NR2E1, NR2E3, NR2F1, NR2F2, NR2F6, NR3C1, NR3C2, NR4A1, NR4A2, NR4A3, NR5A1, NR5A2, NR6A1, NRP1, NRP2, NT5E, NTN4, NY-ESO1, ODZI, OPRDI, P2RX7, PAP, PART1, PATE , PAWR, P-cadherin, PCA3, PCD1, PD-L1, PCDGF, PCNA, PDGFA, PDGFB, PDGFRA, PDGFRB, PECAMI, L1-CAM, peg-asparaginase, PF4 (CXCL4), PGF, PGR, phosphatase phosphacan, PIAS2, PI3 kinase, PIK3CG, PLAU (uPA), PLG, PLXDCI, PKC, PKC-beta, PPBP (CXCL7), PPID, PR1, PRAME, PRKCQ, PRKD1, PRL, PROC, PROK2, PSAP, PSCA, PSMA, PTAFR, PTEN, PTHR2, PTGS2 (COX-2), PTN, PVRIG, RAC2 (P21Rac2), RANK, RANK Ligand, RARB, RGS1, RGS13, RGS3, RNFI1O (ZNF144), Ron, ROBO2, ROR1, RXR, S100A2, SCGB 1D2 (lipophilin B), SCGB2A1 (mammaglobin 2), SCGB2A2 (mammaglobin 1), SCYE1 (endothelial monocyte-activating cytokine), SDF2, SERPENA1, SERPINA3, SERPINB5 (maspin), SERPINEI (PAI-I), SERPINFI, SHIP-1, SHIP-2, SHB1, SHB2, SHBG, SfcAZ, SLAMF7, SLC2A2, SLC33A1, SLC43A1, SLC44A4, SLC34A2, SLIT2, SPP1, SPRR1B (Spr1), ST6GAL1, ST8SIA1, STAB1 , STATE, STEAP, STEAP2, TB4R2, TBX21, TCP1O, TDGF1, TEK, TGFA, TGFB1, TGFB1I1, TGFB2, TGFB3, TGFBI, TGFBR1, TGFBR2, TGFBR3, THIL, THBS1 (thrombospondin-1), THBS2, THBS4, THPO, TIE (Tie-1), TIMP3, tissue factor, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TNF, TNF-a, TNFAIP2 (B94) , TNFAIP3, TNFRSFI1A, TNFRSF1A, TNFRSF1B, TNFRSF21, TNFRSF5, TNFRSF6 (Fas), TNFRSF7, TNFRSF8, TNFRSF9, TNFSF1O (TRAIL), TNFRSF10A, TNFRSF10B, TNFRSF12A, TNFRSF17, TNFSF1 1 (TRANCE), TNFSF12 (APO3L), TNFSF13 ( April), TNFSF13B, TNFSF14 (HVEM-L), TNFRSF14 (HVEM), TNFSF15 (VEGI), TNFSF18, TNFSF4 (OX40 ligand), TNFSF5 (CD40 ligand), TNFSF6 (FasL), TNFSF7 (CD27 ligand), TNFSF8 (CD30) Ligand), TNFSF9 (4-1BB Ligand), TOLLIP, Toll-like receptor, TOP2A (topoisomerase Iia), TP53, TPM1, TPM2, TRADD, TRAF1, TRAF2, TRAF3, TRAF4, TRAF5, TRAF6, TRKA, TREM1 , TREM2, TROP2, TRPC6, TSLP, TWEAK, Tyrosinase, uPAR, VEGF, VEGFB, VEGFC, versican, VHL C5, VLA-4, WT1, Wnt-1, XCL1 (lymphotactin), XCL2 (SCM-Ib), ), CLEC5A (MDL-1, CLECSF5), CLEC1B (CLEC-2), CLEC9A (DNGR-1), CLEC7A (Dectin-1), CLEC11A, PDGFRa, SLAMF7, GP6 (GPVI), LILRA1 (CD85I), LILRA2 ( CD85H, ILT1), LILRA4 (CD85G, ILT7), LILRA5 (CD85F, ILT11), LILRA6 (CD85b, ILT8), LILRB1, NCR1 (CD335, LY94, NKp46), NCR3 (CD335, LY94, NKp46), NCR3 (CD337, NKp30), OSCAR, TARM1, CD30, CD300C, CD300E, CD300LB (CD300B), CD300LD (CD300D), KIR2DL4 (CD158D), KIR2DS, KLRC2 (CD159C, NKG2C), KLRK1 (CD314, NKG2D), NCR2 (CD336, NKp44) ) , PILRB, SIGLEC1 (CD169, SN), SIGLEC5, SIGLEC6, SIGLEC7, SIGLEC8, SIGLEC9, SIGLEC10, SIGLEC11, SIGLEC12, SIGLEC14, SIGLEC15 (CD33L3), SIGLEC16, SIRPA, SIRPB1 (CD172B), TREM1 (CD354), TREM2, KLRF1 (NKp80), 17-1A, SLAM7, MSLN, CTAG1B/NY-ESO-1, MAGEA3/A6, ATP5I (Q06185), OAT (P29758), AIFM1 (Q9Z0X1), AOFA (Q64133), MTDC (P18155), CMC1 (Q8BH59), PREP (Q8K411), YMEL1 (O88967), LPPRC (Q6PB66), LONM (Q8CGK3), ACON (Q99KI0), ODO1 (Q60597), IDHP (P54071), ALDH2 (P47738), ATPB (P56480), AATM (P05202), TMM93 (Q9CQW0), ERGI3 (Q9CQE7), RTN4 (Q99P72), CL041 (Q8BQR4), ERLN2 (Q8BFZ9), TERA (Q01853), DAD1 (P61804), CALX (P35564), CALU (O35887), VAPA (Q9WV55), MOGS (Q80UM7), GANAB (Q8BHN3), ERO1A (Q8R180), UGGG1 (Q6P5E4), P4HA1 (Q60715), HYEP (Q9D379), CALR (P14211), AT2A2 (O55143), PDIA4 (P08003), PDIA1 (P09103), PDIA3 (P27773), PDIA6 (Q922R8), CLH (Q68FD5), PPIB (P24369), TCPG (P80318), MOT4 (P57787), NICA (P57716), BASI (P18572), VAPA (Q9WV55), ENV2 (P11370), VAT1 (Q62465), 4F2 (P10852), ENOA (P17182), ILK (O55222), GPNMB (Q99P91), ENV1 (P10404), ERO1A (Q8R180), CLH (Q68FD5), DSG1A (Q61495), AT1A1 (Q8VDN2), HYOU1 (Q9JKR6), TRAP1 (Q9CQN1), GRP75 (P38647), ENPL (P08113), CH60 (P63038), or CH10 (Q64433). Additionally, the target antigen may be an antigen that is more than 10 times more distributed in cancer cells than in normal cells.
본 발명에서 항체의 비제한적인 예로는 우렐루맙 (Urelumab), 우토밀루맙 (Utomilumab), 벱텔로비맙 (Bebtelovimab), 아두카누맙 (Aducanumab), 바피네주맙 (Bapinezumab), 크레네주맙 (Crenezumab), 도나네맙 (Donanemab), 간테네루맙 (Gantenerumab), 레카네맙 (Lecanemab), 솔라네주맙 (Solanezumab), 네스바쿠맙 (Nesvacumab), 에비나쿠맙 (Evinacumab), 에놉리투주맙 (Enoblituzumab), 옴부르타맙 (Omburtamab), 벨리무맙 (Belimumab), 이아나루맙 (Ianalumab), 타발루맙 (Tabalumab), 베르틸리무맙 (Bertilimumab), 모가물리주맙 (Mogamulizumab), 레론리맙 (Leronlimab), 시필리주맙 (Siplizumab), 포랄루맙 (Foralumab), 무로모납-CD3(Muromonab-CD3), 오텔릭시주맙 (Otelixizumab), 테플리주맙 (Teplizumab), 이발리주맙 (Ibalizumab), 트레갈리주맙 (Tregalizumab), 자노리무맙 (Zanolimumab), 이톨리주맙 (Itolizumab), 에팔리주맙 (Efalizumab), 이네빌리주맙 (Inebilizumab), 타파시타맙 (Tafasitamab), 토시투모맙 (Tositumomab), 오크렐리주맙(Ocrelizumab), 오파투무맙 (Ofatumumab), 리툭시맙 (Rituximab), 우블리툭시맙 (Ublituximab), 벨투주맙(Veltuzumab), 에프라투주맙 (Epratuzumab), 바실릭시맙 (Basiliximab), 다클리주맙 (Daclizumab), 바르릴루맙 (Varlilumab), 룰리주맙 (Lulizumab), 이라투무맙 (Iratumumab), 린투주맙 (Lintuzumab), 다라투무맙 (Daratumumab), 펠자르타맙 (Felzartamab), 이사툭시맙 (Isatuximab), 메자키타맙(Mezagitamab), 블레셀루맙 (Bleselumab), 다쎄투주맙 (Dacetuzumab), 이스칼리맙 (Iscalimab), 루카투무맙 (Lucatumumab), 미타잘리맙 (Mitazalimab), 소티갈리맙 (Sotigalimab), 다피롤리주맙 (Dapirolizumab), 아파미스타맙 (Apamistamab), 리구팔리맙 (Ligufalimab), 마그롤리맙 (Magrolimab), 알렘투주맙 (Alemtuzumab), 크리잔리주맙 (Crizanlizumab), 인클라쿠맙 (Inclacumab), 쿠사투주맙 (Cusatuzumab), 올레클루맙 (Oleclumab), 밀라투주맙 (Milatuzumab), 갈릭시맙 (Galiximab), 카로툭시맙 (Carotuximab), 아데카투무맙 (Adecatumumab), 엡티네주맙 (Eptinezumab), 에레누맙 (Erenumab), 프레마네주맙 (Fremanezumab), 갈카네주맙 (Galcanezumab), 졸베툭시맙 (Zolbetuximab), 오나르투주맙 (Onartuzumab), 에쿨리주맙 (Eculizumab), 포젤리맙 (Pozelimab), 라불리주맙 (Ravulizumab), 라크노투주맙 (Lacnotuzumab), 악사틸리맙(Axatilimab), 카비랄리주맙 (Cabiralizumab), 에막투주맙 (Emactuzumab), 이필리무맙 (Ipilimumab), 쿠아본리맙 (Quavonlimab), 트레멜리무맙 (Tremelimumab), 잘리프레리맙 (Zalifrelimab), 세툭시맙(Cetuximab), 데파툭시주맙 (Depatuxizumab), 푸툭시맙 (Futuximab), 임가투주맙 (Imgatuzumab), 마투주맙(Matuzumab), 모도특시맙 (Modotuximab), 네씨투무맙 (Necitumumab), 니모투주맙 (Nimotuzumab), 파니투무맙(Panitumumab), 토무조툭시맙 (Tomuzotuximab), 잘루투무맙 (Zalutumumab), 바토클리맙(Batoclimab), 니포칼리맙 (Nipocalimab), 로자놀릭시주맙 (Rozanolixizumab), 부로수맙 (Burosumab), 팔레투주맙 (Farletuzumab), 디누툭시맙 (Dinutuximab), 낙시타맙(Naxitamab), 라기필리맙 (Ragifilimab), 김실루맙 (Gimsilumab), 렌질루맙 (Lenzilumab), 마브릴리무맙 (Mavrilimumab), 나밀루맙 (Namilumab), 오틸리맙 (Otilimab), 플론마를리맙 (Plonmarlimab), 코드리투주맙 (Codrituzumab), 마르게툭시맙 (Margetuximab), 페르투주맙 (Pertuzumab), 트라스투주맙 (Trastuzumab), 다토포타맙(Datopotamab), 파트리투맙 (Patritumab), 세리반투맙 (Seribantumab), 둘리고투주맙 (Duligotuzumab), 피클라투주맙 (Ficlatuzumab), 릴로투무맙 (Rilotumumab), 알롬필리맙 (Alomfilimab), 아니프롤루맙 (Anifrolumab), 에마팔루맙 (Emapalumab), 리겔리주맙 (Ligelizumab), 오말리주맙 (Omalizumab), 씩수투무맙(Cixutumumab), 달로투주맙 (Dalotuzumab), 피키투무맙 (Figitumumab), 가니투맙 (Ganitumab), 테프로투무맙(Teprotumumab), 베르메키맙 (Bermekimab), 카나기누맙 (Canakinumab), 게보키주맙 (Gevokizumab), 브리아키누맙 (Briakinumab), 우스테키누맙 (Ustekinumab), 안루킨주맙 (Anrukinzumab), 쎈다키맙 (Cendakimab), 레브리키주맙 (Lebrikizumab), 트랄로키누맙 (Tralokinumab), 브로달루맙 (Brodalumab), 비메키주맙 (Bimekizumab), 익세키주맙 (Ixekizumab), 세쿠기누맙 (Secukinumab), 브라지쿠맙 (Brazikumab), 구셀쿠맙 (Guselkumab), 미리키주맙 (Mirikizumab), 리산키주맙 (Risankizumab), 틸드라키주맙 (Tildrakizumab), 네몰리주맙(Nemolizumab), 임시돌리맙 (Imsidolimab), 스페솔리맙 (Spesolimab), 파스콜리주맙 (Pascolizumab), 두필루맙 (Dupilumab), 데페모키맙 (Depemokimab), 메폴리주맙 (Mepolizumab), 레슬리주맙 (Reslizumab), 벤랄리주맙 (Benralizumab), 클라자키주맙 (Clazakizumab), 올로키주맙 (Olokizumab), 실툭시맙 (Siltuximab), 시루쿠맙 (Sirukumab), 질티베키맙 (Ziltivekimab), 레빌리맙 (Levilimab), 사릴루맙 (Sarilumab), 사트랄리주맙(Satralizumab), 토씰리주맙 (Tocilizumab), 아비투주맙 (Abituzumab), 파베젤리맙 (Favezelimab), 피안리맙 (Fianlimab), 이에라밀리맙 (Ieramilimab), 렐라틀리맙 (Relatlimab), 심투주맙 (Simtuzumab), 아바고보맙 (Abagovomab), 오레고보맙 (Oregovomab), 타네주맙 (Tanezumab), 이븍솔리맙 (Ivuxolimab), 로카틴리맙 (Rocatinlimab), 타볼리맙(Tavolimab), 델라조를리맙 (Telazorlimab), 본레롤리주맙 (Vonlerolizumab), 알리로쿠맙 (Alirocumab), 보코씨주맙 (Bococizumab), 에브로누씨맙 (Ebronucimab), 에볼로쿠맙 (Evolocumab), 프로보씨맙 (Frovocimab), 온게리씨맙 (Ongericimab), 타폴레씨맙 (Tafolecimab), 도스타를리맙 (Dostarlimab), 발스틸리맙 (Balstilimab), 캄렐리주맙 (Camrelizumab), 쎄미플리맙 (Cemiplimab), 겝타놀리맙 (Geptanolimab), 니볼루맙 (Nivolumab), 펨브롤리주맙 (Pembrolizumab), 펜풀리맙 (Penpulimab), 피딜리주맙 (Pidilizumab), 프롤골리맙(Prolgolimab), 레티판리맙 (Retifanlimab), 사산리맙 (Sasanlimab), 세르플루리맙 (Serplulimab), 신틸리맙(Sintilimab), 스파르탈리주맙 (Spartalizumab), 티슬렐리주맙 (Tislelizumab), 토리팔리맙 (Toripalimab), 에자벤리맙 (Ezabenlimab), 짐베렐리맙 (Zimberelimab), 아테졸리주맙 (Atezolizumab), 아벨루맙 (Avelumab), 코시벨리맙 (Cosibelimab), 수게말리맙 (Sugemalimab), 두르발루맙 (Durvalumab), 엔바폴리맙(Envafolimab), 수브라톡수맙 (Suvratoxumab), 데노수맙 (Denosumab), 질로베르타맙 (Zilovertamab), 엘로투주맙 (Elotuzumab), 돔바날리맙 (Domvanalimab), 에티길리맙(Etigilimab), 오씨페를리맙 (Ociperlimab), 티라골루맙 (Tiragolumab), 비보스톨리맙 (Vibostolimab), 수르제비씰리맙 (Surzebiclimab), 코볼리맙 (Cobolimab), 사바톨리맙 (Sabatolimab), 콘씨주맙(Concizumab), 마르스타씨맙 (Marstacimab), 아달리무맙 (Adalimumab), 골리무맙 (Golimumab), 인플릭시맙(Infliximab), 쎄르톨리주맙(Certolizumab), 코나투무맙 (Conatumumab), 티가투주맙(Tigatuzumab), 테제펠루맙 (Tezepelumab), 가티포투주맙 (Gatipotuzumab), 카비랄리주맙 (Cabiralizumab), 베바씨주맙 (Bevacizumab), 브롤루씨주맙 (Brolucizumab), 라니비주맙 (Ranibizumab), 올린바씨맙(Olinvacimab), 이크루쿠맙 (Icrucumab), 라무씨루맙 (Ramucirumab), 카프라씨주맙 (Caplacizumab), 아부릴루맙 (Abrilumab), 에트롤리주맙 (Etrolizumab), 베돌리주맙 (Vedolizumab), 인테투무맙 (Intetumumab), 나탈리주맙 (Natalizumab), 오브린다타맙 (Obrindatamab), 엘라나타맙 (Elranatamab), 린보셀타맙(Linvoseltamab), 테클리스타맙 (Teclistamab), 엡코리타맙 (Epcoritamab), 글로피타맙 (Glofitamab), 모수네투주맙 (Mosunetuzumab), 오드로넥스타맙 (Odronextamab), 플로테투주맙 (Flotetuzumab), 비베코타맙(Vibecotamab), 카투막소맙 (Catumaxomab), 씨비사타맙 (Cibisatamab), 탈쿠에타맙 (Talquetamab), 우바마타맙 (Ubamatamab), 엠피자타맙 (Emfizatamab), 블리나투모맙 (Blinatumomab), 아미반타맙 (Amivantamab), 에미씨주맙 (Emicizumab), 제노쿠투주맙 (Zenocutuzumab), 자니다타맙 (Zanidatamab), 티불리주맙 (Tibulizumab), 나프투모맙 (Naptumomab), 벨란타맙 (Belantamab), 피베키맙(Pivekimab), 프랄루자타맙 (Praluzatamab), 콜툭시맙 (Coltuximab), 데닌투주맙 (Denintuzumab), 론카스툭시맙 (Loncastuximab), 이브리투모맙(Ibritumomab), 이노투주맙 (Inotuzumab), 에프라투주맙 (Epratuzumab), 목세투모맙 (Moxetumomab), 브렌툭시맙 (Brentuximab), 겜투주맙 (Gemtuzumab), 바다스툭시맙 (Vadastuximab), 로보투주맙 (Lorvotuzumab), 폴라투주맙 (Polatuzumab), 투사마타맙 (Tusamitamab), 텔리소투주맙 (Telisotuzumab), 로발피투주맙 (Rovalpituzumab), 데파툭시주맙 (Depatuxizumab), 파를레투주맙 (Farletuzumab), 미르베툭시맙 (Mirvetuximab), 디시타맙 (Disitamab), 아네투맙 (Anetumab), 엔포르투맙 (Enfortumab), 사씨투주맙 고비테칸 (Sacituzumab), 보바릴리주맙(Vobarilizumab), 카도닐리맙 (Cadonilimab), 부달리맙 (Vudalimab), 테보텔리맙 (Tebotelimab), 이보네스씨맙 (Ivonescimab),에르폰릴리맙 (Erfonrilimab), 오조랄리주맙 (Ozoralizumab), 파리시맙 (Faricimab), 바누씨주맙(Vanucizumab) 또는 나비씩시주맙 (Navicixizumab) 등일 수 있으나, 이에 제한되지 않는다.Non-limiting examples of antibodies in the present invention include Urelumab, Utomilumab, Bebtelovimab, Aducanumab, Bapinezumab, and Crenezumab. , Donanemab, Gantenerumab, Lecanemab, Solanezumab, Nesvacumab, Evinacumab, Enoblituzumab, Ombur Omburtamab, Belimumab, Ianalumab, Tabalumab, Bertilimumab, Mogamulizumab, Leronlimab, Cipilizumab ( Siplizumab), Foralumab, Muromonab-CD3, Otelixizumab, Teplizumab, Ibalizumab, Tregalizumab, Zanolimumab, Itolizumab, Efalizumab, Inebilizumab, Tafasitamab, Tositumomab, Ocrelizumab, Ofatumumab, Rituximab, Ublituximab, Veltuzumab, Epratuzumab, Basiliximab, Daclizumab, Varlilumab, Lulizumab, Iratumumab, Lintuzumab, Daratumumab, Felzartamab, Isatuximab, Mezakita Mezagitamab, Bleselumab, Dacetuzumab, Iscalimab, Lucatumumab, Mitazalimab, Sotigalimab, Dapirolizumab (Dapirolizumab), Apamistamab, Ligufalimab, Magrolimab, Alemtuzumab, Crizanlizumab, Inclacumab, Cusatuzumab ( Cusatuzumab, Oleclumab, Milatuzumab, Galiximab, Carotuximab, Adecatumumab, Eptinezumab, Erenumab ), Fremanezumab, Galcanezumab, Zolbetuximab, Onartuzumab, Eculizumab, Pozelimab, Rabulizumab ( Ravulizumab, Lacnotuzumab, Axatilimab, Cabiralizumab, Emactuzumab, Ipilimumab, Quavonlimab, Tremelimumab ), Zalifrelimab, Cetuximab, Depatuxizumab, Futuximab, Imgatuzumab, Matuzumab, Modotuximab ), Necitumumab, Nimotuzumab, Panitumumab, Tomuzotuximab, Zalutumumab, Batoclimab, Nipocalimab ( Nipocalimab, Rozanolixizumab, Burosumab, Farletuzumab, Dinutuximab, Naxitamab, Ragifilimab, Gimsilumab , Lenzilumab, Mavrilimumab, Namilumab, Otilimab, Plonmarlimab, Codrituzumab, Margetuximab, Per Pertuzumab, Trastuzumab, Datopotamab, Patritumab, Seribantumab, Duligotuzumab, Ficlatuzumab, Rillotu Rilotumumab, Alomfilimab, Anifrolumab, Emapalumab, Ligelizumab, Omalizumab, Cixutumumab, Dalotuzumab ( Dalotuzumab, Figitumumab, Ganitumab, Teprotumumab, Bermekimab, Canakinumab, Gevokizumab, Briakinumab ), Ustekinumab, Anrukinzumab, Cendakimab, Lebrikizumab, Tralokinumab, Brodalumab, Bimekizumab ), Ixekizumab, Secukinumab, Brazikumab, Guselkumab, Mirikizumab, Risankizumab, Tildrakizumab, Nemolizumab, Imsidolimab, Spesolimab, Pascolizumab, Dupilumab, Depemokimab, Mepolizumab, Reslizumab (Reslizumab), Benralizumab, Clazakizumab, Olokizumab, Siltuximab, Sirukumab, Ziltivekimab, Levilimab ), Sarilumab, Satralizumab, Tocilizumab, Abituzumab, Favezelimab, Fianlimab, Ieramilimab , Relatlimab, Simtuzumab, Abagovomab, Oregovomab, Tanezumab, Ivuxolimab, Rocatinlimab, Tavolimab (Tavolimab), Telazorlimab, Vonlerolizumab, Alirocumab, Bococizumab, Ebronucimab, Evolocumab, Provo Frovocimab, Ongericimab, Tafolecimab, Dostarlimab, Balstilimab, Camrelizumab, Cemiplimab , Geptanolimab, Nivolumab, Pembrolizumab, Penpulimab, Pidilizumab, Prolgolimab, Retifanlimab, Sasanri Sasanlimab, Serplulimab, Sintilimab, Spartalizumab, Tislelizumab, Toripalimab, Ezabenlimab, Zimbe Zimberelimab, Atezolizumab, Avelumab, Cosibelimab, Sugemalimab, Durvalumab, Envafolimab, Subratoc Suvratoxumab, Denosumab, Zilovertamab, Elotuzumab, Domvanalimab, Etigilimab, Ociperlimab, Tiragol Tiragolumab, Vibostolimab, Surzebiclimab, Cobolimab, Sabatolimab, Concizumab, Marstacimab, Adali Adalimumab, Golimumab, Infliximab, Certolizumab, Conatumumab, Tigatuzumab, Tezepelumab, Gatipotu Gatipotuzumab, Cabiralizumab, Bevacizumab, Brolucizumab, Ranibizumab, Olinvacimab, Icrucumab, Ramuci Ramucirumab, Caplacizumab, Abrilumab, Etrolizumab, Vedolizumab, Intetumumab, Natalizumab, Obindatamab ( Obrindatamab, Elranatamab, Linvoseltamab, Teclistamab, Epcoritamab, Glofitamab, Mosunetuzumab, Odronexta Odronextamab, Flotetuzumab, Vibecotamab, Catumaxomab, Cibisatamab, Talquetamab, Ubamatamab, Empizatamab (Emfizatamab), Blinatumomab, Amivantamab, Emicizumab, Zenocutuzumab, Zanidatamab, Tibulizumab, Naftumomab (Naptumomab), Belantamab, Pivekimab, Praluzatamab, Coltuximab, Denintuzumab, Loncastuximab, Eve Ritumomab, Inotuzumab, Epratuzumab, Moxetumomab, Brentuximab, Gemtuzumab, Vadastuximab, Lorvotuzumab, Polatuzumab, Tusamitamab, Telisotuzumab, Rovalpituzumab, Depatuxizumab, Farletuzumab , Mirvetuximab, Disitamab, Anetumab, Enfortumab, Sacituzumab, Vobarilizumab, Cadonilimab , Vudalimab, Tebotelimab, Ivonescimab, Erfonrilimab, Ozoralizumab, Faricimab, Vanucizumab ) or Navicixizumab, etc., but is not limited thereto.
본 발명에 따른 운반체-약물 접합체에 있어, 운반체와 약물은 링커를 통해 접합되는 것이 바람직하다. In the carrier-drug conjugate according to the present invention, it is preferable that the carrier and the drug are conjugated through a linker.
본 발명에서의 링커는 혈류에서는 안정(stable)하여 약물이 항체 등의 운반체로부터 분리되는 것을 막아 항원 등의 타겟에 도달할 때까지 그 구조를 유지하여 정상적인 조직에 입히는 피해를 최소화해야 하며, 이상적으로는 항체-약물 접합체 등이 전신 순환될 때는 안정하면서도 표적 세포에서는 절단되어 세포 독성 약물을 적절히 방출시켜 약물을 표적에 안전하게 전달하여 항체-약물 접합체 등이 효능과 안전성을 동시에 갖도록 하는 것이다. The linker in the present invention should be stable in the bloodstream, preventing the drug from being separated from carriers such as antibodies, maintaining its structure until it reaches the target such as antigen, and minimizing damage to normal tissues. Ideally, While the antibody-drug conjugate is stable when circulating throughout the body, it is cleaved in the target cells to appropriately release the cytotoxic drug and safely deliver the drug to the target, thereby ensuring that the antibody-drug conjugate has both efficacy and safety.
본 발명에 따른 운반체-약물 접합체는 운반체가 링커를 통해 약물, 즉 화학식 1 내지 화학식 8의 화합물과 접합된 형태인 것을 특징으로 할 수 있지만, 이에 한정되는 것은 아니다. The carrier-drug conjugate according to the present invention may be characterized in that the carrier is conjugated to the drug, that is, the compound of Formula 1 to Formula 8 through a linker, but is not limited thereto.
본 발명에 따른 운반체-약물 접합체에 있어서, 상기 화학식 1 내지 화학식 8의 화합물은 그 항암 활성 등의 특성이 변화하지 않는 한, 적절한 부위에서 링커와 연결될 수 있으며, 이에 따라 본 발명은 화학식 1 내지 화학식 8의 화합물과 링커가 연결된 약물-링커를 제공한다. In the carrier-drug conjugate according to the present invention, the compounds of Formulas 1 to 8 can be linked to a linker at an appropriate site as long as their anticancer activity and other properties do not change. Accordingly, the present invention provides compounds of Formulas 1 to 8. A drug-linker in which the compound of 8 and the linker are connected is provided.
바람직하게는 본 발명에 따른 약물-링커는 화학식 1a 내지 화학식 8a의 구조를 가질 수 있지만, 이에 한정되는 것은 아니다. 화학식 1a 내지 화학식 8a에서 L은 링커를 의미한다. Preferably, the drug-linker according to the present invention may have the structure of Formula 1a to Formula 8a, but is not limited thereto. In Formulas 1a to 8a, L refers to a linker.
본 발명에 있어서, 링커는 세포내 특정 환경 및/또는 조건에서 절단 가능한 형태 즉, 세포 내 환경에서 항체에서 약물이 링커의 절단을 통해 방출될 수 있도록 하는 것일 수 있다. In the present invention, the linker may be in a form that is cleavable in a specific intracellular environment and/or condition, that is, a drug may be released from the antibody through cleavage of the linker in the intracellular environment.
Figure PCTKR2023013502-appb-img-000002
Figure PCTKR2023013502-appb-img-000002
예를 들어, 상기 링커는 세포 내 환경 예를 들어 리소좀 또는 엔도좀에 존재하는 절단제에 의해 절단될 수 있으며, 세포 내 펩티다아제 또는 프로테아제 효소 예를 들어 리소좀 또는 엔도좀 프로테아제에 의해 절단될 수 있는 펩타이드 링커일 수 있다. 일반적으로 펩타이드 링커는 적어도 2개 이상의 아미노산 길이를 가진다. 상기 절단제는 카텝신 B 및 카텝신 D, 플라스민을 포함할 수 있으며, 펩타이드를 가수분해 하여 약물을 표적 세포 내로 방출할 수 있도록 한다. 상기 펩타이드 링커는 티올 의존성 프로테아제 카텝신-B에 의해 절단될 수 있고, 이는 암 조직에서 고발현되며, 예를 들어 Gly-Gly-Phe-Gly(GGFG), Gly-Gly-Tyr-Gly(GGYG), Phe-Leu 또는 Gly-Phe-Leu-Gly 링커 등이 사용될 수 있지만 이에 한정되는 것은 아니다. 또한, 상기 펩타이드 링커는 예를 들어 세포 내 프로테아제에 의해 절단될 수 있는 것으로, Val-Cit 링커이거나 Phe-Lys 링커일 수 있다.For example, the linker may be cleaved by a cleaving agent present in the intracellular environment, such as a lysosome or endosome, and may be a peptide that may be cleaved by an intracellular peptidase or protease enzyme, such as a lysosomal or endosomal protease. It may be a linker. Typically, peptide linkers are at least two amino acids long. The cleavage agent may include cathepsin B, cathepsin D, and plasmin, and hydrolyzes the peptide to release the drug into the target cell. The peptide linker can be cleaved by the thiol-dependent protease cathepsin-B, which is highly expressed in cancer tissues, for example, Gly-Gly-Phe-Gly (GGFG), Gly-Gly-Tyr-Gly (GGYG) , Phe-Leu or Gly-Phe-Leu-Gly linkers may be used, but are not limited thereto. Additionally, the peptide linker can be cleaved by, for example, an intracellular protease and may be a Val-Cit linker or a Phe-Lys linker.
본 발명에 있어서, 상기 절단성 링커는 pH 민감성으로, 특정 pH 값에서 가수분해에 민감할 수 있다. 일반적으로, pH 민감성 링커는 산성 조건에서 가수분해될 수 있음을 나타낸다. 예를 들어, 리소좀에서 가수분해될 수 있는 산성 불안정 링커 예를 들어, 하이드라존, 세미카바존, 티오세미카바존, 시스-아코니틱 아마이드(cis-aconitic amide), 오르쏘에스테르, 아세탈, 케탈 등일 수 있다.In the present invention, the cleavable linker is pH sensitive and may be sensitive to hydrolysis at a specific pH value. In general, pH sensitive linkers indicate that they can be hydrolyzed under acidic conditions. For example, acid labile linkers that can be hydrolyzed in lysosomes such as hydrazone, semicarbazone, thiosemicarbazone, cis-aconitic amide, orthoester, acetal, It may be ketal, etc.
또한 본 발명에 있어서, 상기 링커는 환원 조건에서 절단될 수도 있으며, 예를 들어 이황화 링커가 이에 해당할 수 있다. SATA(Nsuccinimidyl-S-acetylthioacetate), SPDP(N-succinimidyl-3- (2-pyridyldithio)propionate), SPDB(Nsuccinimidyl-3- (2-pyridyldithio)butyrate) 및 SMPT(N-succinimidyl-oxycarbonyl-alpha-methyl-alpha-(2-pyridyl-dithio) toluene)를 사용하여 다양한 이황화 결합이 형성될 수 있다.Additionally, in the present invention, the linker may be cleaved under reducing conditions, for example, a disulfide linker may correspond to this. SATA (Nsuccinimidyl-S-acetylthioacetate), SPDP (N-succinimidyl-3- (2-pyridyldithio)propionate), SPDB (Nsuccinimidyl-3- (2-pyridyldithio)butyrate) and SMPT (N-succinimidyl-oxycarbonyl-alpha-methyl) A variety of disulfide bonds can be formed using -alpha-(2-pyridyl-dithio)toluene).
상기 링커는 리소좀에서 다수 존재하거나, 또는 몇몇 종양세포에서 과발현되는 베타-글루쿠로니데이즈(βglucuronidase)에 의해 인식되어 가수분해 되는 베타-글루쿠로나이드 링커를 포함할 수 있다. 예시적으로 대한민국 특허공개공보 제2015-0137015호에 개시된 베타-글루쿠로나이드 링커, 예를 들어 자가-희생기(self-immolative group)를 포함하는 베타-글루쿠로나이드 링커가 사용될 수 있다.The linker may include a beta-glucuronide linker that is recognized and hydrolyzed by beta-glucuronidase, which exists in large numbers in lysosomes or is overexpressed in some tumor cells. For example, a beta-glucuronide linker disclosed in Korean Patent Publication No. 2015-0137015, for example, a beta-glucuronide linker containing a self-immolative group, may be used.
또한, 상기 링커는 예를 들어 비절단성 링커일 수 있으며, 항체 가수분해 단계를 통해 약물이 방출되어, 예를 들어 아미노산-링커-약물 복합체를 생산한다. 이러한 유형의 링커는 티오에테르기 또는 말레이미도카프로일기(maleimidocaproyl)일 수 있고, 혈액 내 안정성을 유지할 수 있다.Additionally, the linker may be, for example, a non-cleavable linker, and the drug is released through an antibody hydrolysis step, producing, for example, an amino acid-linker-drug complex. This type of linker can be a thioether group or maleimidocaproyl group and can maintain stability in the blood.
바람직하게는 본 발명에 따른 링커는 GGFG 또는 GGYG를 포함하는 것을 특징으로 하며, GGYG를 포함하는 링커의 경우, 타이로신(Y, Tyrosin) 측쇄(side chain)의 하이드록시기의 수소 원자가 특정 조건에서 분리가 가능한 친수성 관능기로 치환될 수 있다, 상기 친수성 관능기는 1가의 친수성 관능기가 바람직하며, 베타-글루쿠로나이드(Beta-Glucuronide) 또는 3 내지 100의 에틸렌글리콜(ethylene glycol) 반복단위를 가지는 PEG(Polyethylene Glycol)기를 가지는 에스터 또는 카보네이트 등이 예시될 수 있지만 이에 한정되는 것은 아니다. Preferably, the linker according to the present invention is characterized by containing GGFG or GGYG, and in the case of the linker containing GGYG, the hydrogen atom of the hydroxyl group of the tyrosine (Y, Tyrosin) side chain is separated under specific conditions. May be substituted with a possible hydrophilic functional group. The hydrophilic functional group is preferably a monovalent hydrophilic functional group, such as beta-glucuronide or PEG (PEG) having 3 to 100 ethylene glycol repeating units. Examples may include esters or carbonates having a polyethylene glycol (Polyethylene Glycol) group, but are not limited thereto.
더욱 바람직하게는 상기 링커는 화학식 11 또는 화학식 12의 구조를 가질 수 있지만 이에 한정되는 것은 아니다. More preferably, the linker may have the structure of Formula 11 or Formula 12, but is not limited thereto.
Figure PCTKR2023013502-appb-img-000003
Figure PCTKR2023013502-appb-img-000003
상기 화학식 12에서의 n은 3 내지 10의 정수일 수 있다. In Formula 12, n may be an integer of 3 to 10.
본 발명에 있어서, 상기 운반체-약물 접합체에서의 운반체가 항체일 경우, 상기 화학식 1 내지 화학식 8의 화합물, 또는 화학식 1a 내지 화학식 8a의 화합물인 약물 및/또는 약물-링커는 항체 내의 라이신을 통해 무작위로 접합되거나, 이황화 결합 사슬을 환원하였을 때 노출되는 시스테인을 통해 접합될 수 있다. 경우에 따라서, 유전공학적으로 제작된 태그 예를 들어, 펩타이드 또는 단백질에 존재하는 라이신이나 시스테인을 통해 약물-링커가 결합될 수 있다. In the present invention, when the carrier in the carrier-drug conjugate is an antibody, the drug and/or drug-linker, which is the compound of Formula 1 to Formula 8, or the compound of Formula 1a to Formula 8a, is randomly selected through lysine in the antibody. It can be conjugated with or through the cysteine exposed when the disulfide bond chain is reduced. In some cases, a drug-linker may be bound through a genetically engineered tag, for example, lysine or cysteine present in a peptide or protein.
또한, 본 발명은 본 발명에 따른 화학식 1 내지 화학식 8 중 어느 하나로 표시되는 화합물 또는 이의 이성질체 또는 이의 약제학적 허용염, 이의 용매화물, 또는 이를 포함하는 운반체-약물 접합체를 포함하는 암의 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a method for preventing or treating cancer, including a compound represented by any one of Formulas 1 to 8 according to the present invention, an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a carrier-drug conjugate containing the same. Provides a pharmaceutical composition for use.
또한, 본 발명의 일 구체예에 따르면, 상기 화학식 1 내지 화학식 8로 표시되는 화합물 또는 이의 이성질체 또는 이의 약제학적 허용염, 이의 용매화물, 또는 이를 포함하는 운반체-약물 접합체의 치료학적으로 유효한 양을, 이를 필요로 하는 대상 (subject)에게 투여하는 단계를 포함하는, 암의 치료 또는 예방하는 방법을 제공한다. 상기 대상 (subject)은 인간을 포함하는 포유류일 수 있다.In addition, according to one embodiment of the present invention, a therapeutically effective amount of the compound represented by Formula 1 to Formula 8 or an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a carrier-drug conjugate containing the same is used. Provides a method for treating or preventing cancer, comprising administering to a subject in need thereof. The subject may be a mammal, including humans.
본 발명에서, 상기 암은 토포이소머라제 I의 억제, 및/또는 서바이빈 (survivin), Mcl-1, XIAP 및 cIAP2로 이루어진 군에서 선택된 어느 하나 이상의 암-관련 생존 유전자 (cancer-associated survival genes)의 억제로 치료 가능한 모든 암을 포함하며, 고형암 또는 혈액암일 수 있다. 예컨대, 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 결장암, 고환암, 골수이형성증후군, 교모세포종, 구강암, 구순암, 균상식육종, 급성골수성백혈병, 급성림프구성백혈병, 기저세포암, 난소상피암, 난소생식세포암, 남성유방암, 뇌암, 뇌하수체선종, 다발성골수종, 담낭암, 담도암, 대장암, 만성골수성백혈병, 만성림프구백혈병, 망막모세포종, 맥락막흑색종, 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비부비동암, 비소세포폐암, 설암, 성상세포종, 소세포폐암, 소아뇌암, 소아림프종, 소아백혈병, 소장암, 수막종, 식도암, 신경교종, 신우암, 신장암, 심장암, 십이지장암, 악성 연부조직 암, 악성골암, 악성림프종, 악성중피종, 악성흑색종, 안암, 외음부암, 요관암, 요도암, 원발부위불명암, 위림프종, 위암, 위유암종, 위장관간질암, 윌름스암, 유방암, 육종, 음경암, 인두암, 임신융모질환, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성골암, 전이성뇌암, 종격동암, 직장암, 직장유암종, 질암, 척수암, 청신경초종, 췌장암, 침샘암, 카포시 육종, 파제트병, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 피부암, 항문암, 횡문근육종, 후두암, 흉막암, 혈액암, 및 흉선암으로 이루어진 군으로부터 선택되는 1종 이상인 것일 수 있으나, 이에 제한되지 않는다. 또한, 상기 암은 원발성암뿐 아니라 전이성암도 포함한다.In the present invention, the cancer is caused by inhibition of topoisomerase I, and/or one or more cancer-related survival genes selected from the group consisting of survivin, Mcl-1, XIAP, and cIAP2. It includes all cancers that can be treated by inhibiting genes, and may be solid cancer or blood cancer. For example, pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, oral cavity cancer, mycosis fungoides, acute myeloid leukemia, acute lymphocytic leukemia, basal cell carcinoma, ovary. Epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colon cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater cancer, bladder cancer, peritoneal cancer, Parathyroid cancer, adrenal cancer, sinonasal cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, kidney cancer, heart cancer, duodenum Cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, stomach cancer, gastric carcinoid, gastrointestinal stromal cancer, Wilms cancer. , breast cancer, sarcoma, penile cancer, oropharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cancer, acoustic neuroma, Pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleura cancer, blood cancer, and thymic cancer. It may be one or more types selected from the group consisting of, but is not limited thereto. Additionally, the cancer includes not only primary cancer but also metastatic cancer.
본 명세서에서, "환자", “피험자” 및 "대상체"는 포유동물과 같은 동물을 지칭한다. 특정 실시양태에서, 환자는 사람이다. 다른 실시양태에서, 환자는 개, 고양이, 가축(예를 들어, 말, 돼지 또는 당나귀), 침팬지 또는 원숭이와 같은, 사람이 아닌 동물이다.As used herein, “patient,” “subject,” and “subject” refer to animals, such as mammals. In certain embodiments, the patient is a human. In other embodiments, the patient is a non-human animal, such as a dog, cat, domestic animal (e.g., horse, pig, or donkey), chimpanzee, or monkey.
본 발명에서 사용되는 "치료학적으로 유효한 양"이라는 용어는 암의 치료 또는 예방에 유효한 상기 화학식 1 내지 화학식 8 중 어느 하나로 표시되는 화합물, 또는 이의 이성질체 또는 이의 약제학적 허용염, 이의 용매화물, 또는 이를 포함하는 운반체-약물 접합체의 양을 나타낸다. 구체적으로, "치료학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 질병의 종류, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 시판되는 치료제와는 순차적으로 또는 동시에 투여될 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 본 발명의 화학식 1 내지 화학식 8 중 어느 하나로 표시되는 화합물 또는 이의 이성질체 또는 및 이의 약제학적 허용염, 또는 이를 포함하는 운반체-약물 접합체는 용량 의존적인 효과를 나타내므로, 투여 용량은 환자의 상태, 연령, 성별 및 합병증 등의 다양한 요인에 따라 당업자에 의해 용이하게 결정될 수 있다. 본 발명의 약학적 조성물의 유효성분은 안전성이 우수하므로, 결정된 투여 용량 이상으로도 사용될 수 있다. The term “therapeutically effective amount” used in the present invention refers to a compound represented by any one of Formulas 1 to 8 that is effective in treating or preventing cancer, or an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or It indicates the amount of carrier-drug conjugate containing it. Specifically, “therapeutically effective amount” means an amount sufficient to treat the disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is determined by the type and severity of the individual, age, gender, type of disease, It can be determined based on factors including the activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, drugs used simultaneously, and other factors well known in the medical field. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with commercially available therapeutic agents. And it can be administered single or multiple times. Considering all of the above factors, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, and the compound represented by any of Formulas 1 to 8 of the present invention, or an isomer thereof, or a pharmaceutically acceptable salt thereof , or a carrier-drug conjugate containing it exhibits a dose-dependent effect, so the administered dose can be easily determined by a person skilled in the art depending on various factors such as the patient's condition, age, gender, and complications. Since the active ingredient of the pharmaceutical composition of the present invention has excellent safety, it can be used at a dose exceeding the determined dosage.
또한 본 발명의 일 구체예에 따르면, 본 발명은 암의 치료 또는 예방에 사용하기 위한 약제(medicament)의 제조에 사용하기 위한, 상기 화학식 1 내지 화학식 8 중 어느 하나로 표시되는 화합물 또는 이의 이성질체, 이의 약제학적 허용염, 이의 용매화물, 또는 이를 포함하는 운반체-약물 접합체의 용도 (use)를 제공한다. In addition, according to one embodiment of the present invention, the present invention provides a compound represented by any of Formulas 1 to 8, or an isomer thereof, for use in the production of a medicament for use in the treatment or prevention of cancer. Provided is a use of a pharmaceutically acceptable salt, a solvate thereof, or a carrier-drug conjugate comprising the same.
약제의 제조를 위한 상기 화학식 1 내지 화학식 8 중 어느 하나로 표시되는 화합물 또는 이의 이성질체, 이의 약제학적 허용염, 이의 용매화물, 또는 이를 포함하는 운반체-약물 접합체는 약제학적으로 허용되는 보조제, 희석제, 담체 등을 혼합할 수 있으며, 기타 활성제제와 함께 복합 제제로 제조되어 활성 성분들의 상승 작용을 가질 수 있다.For the manufacture of drugs, the compound represented by any one of Formulas 1 to 8, or an isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a carrier-drug conjugate containing the same is used as a pharmaceutically acceptable auxiliary, diluent, or carrier. etc. can be mixed, and can be prepared as a composite preparation with other active agents to have a synergistic effect of the active ingredients.
본 발명의 용도, 조성물, 치료 방법에서 언급된 사항은 서로 모순되지 않는 한 동일하게 적용된다.Matters mentioned in the uses, compositions, and treatment methods of the present invention apply equally unless they contradict each other.
본 명세서에서, 항암제에 의한 항암 효과 또는 치료 효과는 환자가 특정의 암을 앓고 있는 동안 발생하는, 암의 중증도를 감소시키거나, 종양 크기를 감소시키거나, 암의 진행을 지연 또는 둔화시키는 작용을 지칭할 수 있다.In this specification, the anticancer effect or therapeutic effect of an anticancer agent refers to the action of reducing the severity of cancer, reducing the size of a tumor, or delaying or slowing the progression of cancer that occurs while a patient is suffering from a specific cancer. It can be referred to.
예컨대 항암제에 의한 항암 효과는 인비트로(in-vitro) 및/또는 인비보(in-vivo) 상으로 암 세포에 항암제를 처리한 후 암 세포의 Cell Viability(cytotoxicity 정도 또는 세포 수의 변화)일 수 있다. 예컨대, 세포주(Cell line)나 비임상 동물모델(xenograft)을 통해 약물의 반응(drug response) 검사를 통해 간접적으로 확인할 수 있다. 또한, 암 환자에서도 항암제에 의한 항암 효과를 직접 확인하여, 이와 관련된 데이터를 도출하여 데이터베이스로 사용할 수 있다. 또한, 항암제의 투약 가이드 라인 설계시 동물모델 PK 파라미터들 및/또는 독성 프로파일(profile)을 병행하여 고려할 수 있다.For example, the anticancer effect caused by an anticancer drug may be the Cell Viability (change in the degree of cytotoxicity or number of cells) of cancer cells after treating cancer cells with an anticancer drug in-vitro and/or in-vivo. there is. For example, it can be confirmed indirectly by testing drug response using cell lines or non-clinical animal models (xenograft). In addition, cancer patients can directly confirm the anticancer effect of anticancer drugs, derive related data, and use it as a database. In addition, when designing dosing guidelines for anticancer drugs, animal model PK parameters and/or toxicity profiles can be considered in parallel.
항암제에 의한 항암 효과는 시험관내(in-vitro) 데이터인 해당 항암제의 % 최대효과(Maximum effect) 예컨대 IC50, IC60, IC70, IC80 및 IC90로부터 유추할 수도 있고, 약물의 최고 혈중농도(Cmax) 및/또는 혈중 약물농도-시간 곡선 하 면적(AUC)과 같은 생체내(in-vivo) 데이터를 통해 비임상 동물모델 및 임상 암 환자에서도 확인할 수 있다. The anticancer effect of an anticancer drug can be inferred from in-vitro data, such as the % maximum effect of the anticancer drug, such as IC 50 , IC 60 , IC 70 , IC 80 , and IC 90 , and the highest blood concentration of the drug. It can also be confirmed in non-clinical animal models and clinical cancer patients through in-vivo data such as concentration (Cmax) and/or area under the blood drug concentration-time curve (AUC).
항암제의 반응성은 항암 효과 측면에 있어서 임상적 민감도를 의미한다.The reactivity of an anticancer drug refers to clinical sensitivity in terms of anticancer effect.
항암제를 이용한 치료와 관련하여 언급할 때 "민감도" 및 "민감한"은 치료되는 종양 또는 질환의 진행을 완화 또는 감소시키는데 있어 화합물의 효과의 정도를 지칭하는 상대적 용어이다.“Sensitivity” and “sensitive” when referring to treatment with anticancer agents are relative terms that refer to the degree of effectiveness of a compound in alleviating or reducing the progression of the tumor or disease being treated.
"효과적인 환자의 항암 효과/반응"은, 예를 들어, 임의의 적합한 수단, 예컨대 유전자 발현, 세포 계수, 분석 결과 등에 의해 측정되는 바와 같은, 환자 반응에서 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 또는 그 이상의 억제일 수 있다.“Effective patient anti-cancer effect/response” refers to, e.g., 5%, 10%, 15%, 20% of patient response, as measured by any suitable means such as gene expression, cell counting, assay results, etc. , 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, or more.
본 명세서에서, 투여용량은 약효가 기대되는 용량이다. 본 발명에서 약효는 항암 효과일 수 있다. 항암제의 반응성(항암 효과)은 반응정도로서, 해당 항암제의 % 최대효과(Maximum effect) 예컨대 IC50, IC60, IC70, IC80 및 IC90, 정상세포에 대한 독성을 발휘하는 값 (LC50)일 수 있다. In this specification, the administered dose is the dose expected to have medicinal effect. In the present invention, the medicinal effect may be an anti-cancer effect. The reactivity (anti-cancer effect) of an anti-cancer drug is the degree of response, including the % maximum effect of the anti-cancer drug, such as IC 50 , IC 60 , IC 70 , IC 80 , and IC 90 , and the value of toxicity to normal cells (LC 50 ). It can be.
예컨대, 경구용 제형은 당해 기술에서 공지된 다양한 제형 기술을 사용하여 제제화될 수 있다. 예컨대, 구강 점막에 부착하는데 쓰이는 생체붕괴성 (가수분해성) 폴리머성 담체를 포함할 수 있다. 예정된 기간에 걸쳐 서서히 침식되도록 제작되고, 여기서 약물 전달은 본질적으로 전체적으로 제공된다.For example, oral dosage forms can be formulated using various formulation techniques known in the art. For example, it may include a biodegradable (hydrolyzable) polymeric carrier used to adhere to the oral mucosa. It is manufactured to erode slowly over a predetermined period of time, where drug delivery is provided essentially holistically.
경구용 제형에서 약물 전달은, 경구 약물 투여에 마주치는 약점, 예를 들면, 느린 흡수, 위장관에서 존재하는 유체에 의한 활성제의 분해 및/또는 간에서의 초회통과 불활성화를 피한다. 생체붕괴성 (가수분해성) 폴리머성 담체에 대해, 사실상 임의의 그와 같은 담체가 원하는 약물 방출 프로파일이 손상되지 않는 한 사용될 수 있고, 담체는 구강 복용량 단위로 존재하는 임의의 다른 성분과 양립가능하다. 일반적으로, 폴리머성 담체는 구강 점막의 습성 표면에 부착되는 친수성 (수용성 및 수팽윤성) 폴리머를 포함한다. 본 명세서에서 유용한 폴리머성 담체의 예는 아크릴산 폴리머(예, 카보머)가 있다. 일부 구현예에서, 경구용 제형에 편입될 수 있는 다른 성분의 비제한적인 예들은 붕해제, 희석제, 결합제, 윤활제, 풍미제, 착색제, 보존제 등이 있다. 일부 구현예에서, 구강 또는 설하 투여에 대해, 종래의 방식으로 제형화된 정제, 로젠지, 또는 겔의 형태일 수 있다. Drug delivery in oral dosage forms avoids the weaknesses encountered with oral drug administration, such as slow absorption, degradation of the active agent by fluids present in the gastrointestinal tract, and/or first-pass inactivation in the liver. With regard to biodegradable (hydrolyzable) polymeric carriers, virtually any such carrier can be used as long as the desired drug release profile is not impaired, and the carrier is compatible with any of the other ingredients present in the oral dosage unit. . Generally, polymeric carriers include hydrophilic (water-soluble and water-swellable) polymers that adhere to the wet surface of the oral mucosa. Examples of polymeric carriers useful herein include acrylic acid polymers (eg, carbomers). In some embodiments, non-limiting examples of other ingredients that can be incorporated into oral dosage forms include disintegrants, diluents, binders, lubricants, flavoring agents, colorants, preservatives, etc. In some embodiments, it may be in the form of tablets, lozenges, or gels, formulated in a conventional manner for oral or sublingual administration.
일부 구현예에서, 상기 환자의 상태가 개선되는 경우에 의사의 재량에 따라 화합물의 투여는 계속해서 제공되고; 대안적으로, 투여될 약물의 용량은 일시적으로 감소되거나 일시적으로 어떤 시간의 길이 (즉, “휴약”) 동안에 중단될 수 있다. 휴약의 길이는 2 일 내지 1 년 사이에서 변할 수 있고, 단지 예로써, 2 일, 3 일, 4 일, 5 일, 6 일, 7 일, 10 일, 12 일, 15 일, 20 일, 28 일, 35 일, 50 일, 70 일, 100 일, 120 일, 150 일, 180일, 200 일, 250 일, 280 일, 300 일, 320 일, 350 일, 또는 365 일을 포함한다. 일부 구현예에서, 휴약 동안의 용량 감소는 10%-100%이고, 단지 예로써, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 또는 100%를 포함한다.In some embodiments, administration of the compound is continued at the discretion of the physician if the patient's condition improves; Alternatively, the dose of drug to be administered may be temporarily reduced or temporarily suspended for any length of time (i.e., a “dose washout”). The length of the washout can vary between 2 days and 1 year, by way of example only: 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days. days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. In some embodiments, the dose reduction during washout is 10%-100%, and by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55 %, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
환자의 병태의 개선이 일어나면, 유지 용량은, 필요하면, 투여된다. 그 뒤에, 복용량 또는 투여 빈도, 또는 둘 모두는, 개선된 질환, 장애 또는 병태가 유지되는 수준으로, 증상의 함수로서 감소될 수 있다. 그러나 환자는 증상의 임의의 재발시 장기간에 걸쳐 간헐적 치료를 필요로 한다.Once improvement in the patient's condition occurs, maintenance doses are administered, if necessary. Thereafter, the dosage or frequency of administration, or both, can be reduced as a function of symptoms, to a level at which improved disease, disorder or condition is maintained. However, patients require intermittent treatment over a long period of time for any recurrence of symptoms.
그와 같은 양에 상응할 주어진 제제의 양은 치료가 필요한 대상체의 인자 예컨대 특정한 화합물, 질환의 중증도, 동일성 (예를 들면, 체중)에 따라 변할 것이지만, 그럼에도 불구하고 예를 들면, 투여될 제형, 투여 경로, 및 치료될 대상체를 둘러싸는 특정에 상황에 따라 당해기술에서 공지된 방식으로 일상적으로 결정될 수 있다. 일반적으로, 그러나, 성인 인간 치료에 이용된 용량은 전형적으로 0.02-5000 mg/1일, 또는 약 1-1500 mg/1일의 범위일 것이다.The amount of a given agent that will correspond to such amount will vary depending on factors such as the particular compound, the severity of the disease, and the identity (e.g., body weight) of the subject in need of treatment, but will nevertheless vary, including, for example, the formulation to be administered, the administration Depending on the route, and the particular circumstances surrounding the subject to be treated, this can be routinely determined in a manner known in the art. In general, however, doses used for treatment of adult humans will typically range from 0.02-5000 mg/day, or about 1-1500 mg/day.
본 명세서에서 1회 투여용량은 단회 용량으로 또는 동시에, 예를 들면 2, 3, 4 또는 그 초과의 하위-용량으로서 투여된 분할 용량으로 제공될 수 있다.A single dosage herein may be given as a single dose or in divided doses administered simultaneously, for example, as 2, 3, 4 or more sub-doses.
일부 구현예에서, 경구용 제형은 정확한 복용량의 단일 투여에 적합한 단위 복용 형태이다. 단위 복용 형태에서, 제형은 적절한 양의 1종 이상의 화합물을 함유하는 단위 용량으로 분할된다. 일부 구현예에서, 단위 복용량은 별개의 양의 제형을 함유하는 패장의 형태이다. 비-제한적인 예는 포장된 정제 또는 캡슐, 및 분말 바이알에서 또는 앰풀이다. 수성 서스펜션 조성물은 단일-용량 비-재밀폐가능 용기 내에서 포장될 있다. 대안적으로, 다중-용량 재밀폐가능 용기가 사용될 수 있고, 이 경우에 조성물 중 보존제를 포함하는 것이 전형적이다. In some embodiments, the oral dosage form is in unit dosage form suitable for single administration of precise doses. In unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. In some embodiments, the unit dose is in the form of a packet containing discrete amounts of dosage form. Non-limiting examples are packaged tablets or capsules, and powders in vials or in ampoules. Aqueous suspension compositions can be packaged in single-dose, non-reclosable containers. Alternatively, multi-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition.
일부 구현예에서, 비경구 주사용 제형은 부가된 보존제와 함께, 비제한적으로 앰플을 포함하는 단위 복용 형태, 또는 다중-용량 용기로 제공된다.In some embodiments, formulations for parenteral injection are provided in unit dosage form, including but not limited to ampoules, or in multi-dose containers, with an added preservative.
전형적으로 제약상 허용되는 비경구 비히클과 함께 단위 투여 주사가능한 형태로, 비경구 투여, 즉 볼루스, 정맥내, 및 종양내 주사를 위해 제조된다. 제약상 허용되는 희석제, 담체, 부형제 또는 안정화제 (Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.)와 함께 동결건조 제제 또는 수용액 형태로 임의로 혼합된다.It is typically prepared for parenteral administration, i.e., bolus, intravenous, and intratumoral injection, in unit dose injectable form with a pharmaceutically acceptable parenteral vehicle. It is optionally mixed in the form of a lyophilized preparation or aqueous solution with pharmaceutically acceptable diluents, carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.).
본 발명에 따른 화학식 1 내지 화학식 8로 표시되는 캄토테신 유도체는 기존의 캄토테신 유도체에 비해 효능, 독성, 선택성, 작용 시간, 투여, 취급, 안정성 및/또는 생산 가능성 등에서 보다 더 바람직한 성질을 가지며, (i) 내성 단백질인 Survivin 등 Bcl family를 동시에 억제하고/하거나 (ii) 유출펌프(efflux pump)의 작용을 억제하는 추가 작용 기전을 통해, 주된 약물 타겟 modulation의 효능을 극대화할 수 있는 장점이 있다. The camptothecin derivatives represented by Formulas 1 to 8 according to the present invention have more desirable properties than existing camptothecin derivatives in terms of efficacy, toxicity, selectivity, action time, administration, handling, stability and/or production potential, etc. It has the advantage of maximizing the efficacy of main drug target modulation through an additional mechanism of action that (i) simultaneously inhibits the Bcl family, such as the resistance protein Survivin, and/or (ii) inhibits the action of the efflux pump. .
나아가, 본 발명에 따른 화학식 1 내지 화학식 8 중 어느 하나로 표시되는 캄토테신 유도체를 포함하는 운반체-약물 접합체는 독성을 최소화하여 높은 안전성을 제공함과 동시에 높은 치료효능을 나타낸다는 장점이 있다. Furthermore, the carrier-drug conjugate containing a camptothecin derivative represented by any one of Formulas 1 to 8 according to the present invention has the advantage of minimizing toxicity, providing high safety, and at the same time showing high therapeutic efficacy.
도 1은 다양한 캄토테신계 항암제(SN-38, Exatecan, Dxd, FL118)의 구조식이다.Figure 1 shows structural formulas of various camptothecin-based anticancer drugs (SN-38, Exatecan, Dxd, FL118).
도 2는 FaDu 세포주에서의 화학식 2 화합물의 in vitro cytotoxicity assay 결과를 나타낸 도면이다.Figure 2 is a diagram showing the results of in vitro cytotoxicity assay of the compound of Formula 2 in FaDu cell line.
이하, 본 발명을 실시예를 통하여 보다 구체적으로 설명한다. 다만, 하기 실시예는 본 발명의 기술적 특징을 명확하게 예시하기 위한 것일 뿐 본 발명의 보호범위를 한정하는 것은 아니다.Hereinafter, the present invention will be described in more detail through examples. However, the following examples are only intended to clearly illustrate the technical features of the present invention and do not limit the scope of protection of the present invention.
실시예 1. 화학식 9 및 화학식 10의 화합물의 합성Example 1. Synthesis of compounds of formula 9 and formula 10
화학식 9에 따른 (S)-14-(아미노메틸)-7-에틸-7-하이드록시-10,13-디하이드로-11H-[1,3]디옥솔로[4,5-g]피라노[3',4':6,7]인돌리지노[1,2-b]퀴놀린-8,11(7H)-디온 (이하 ‘7MAD-MDCPT‘)은 국제공개특허공보 제2019/195665호의 실시예 4에 기재된 바와 유사하게 아래의 합성방법에 의해 제조되었다.(S)-14-(aminomethyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxolo[4,5-g]pyrano[ according to formula 9 3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione (hereinafter '7MAD-MDCPT') is an example of International Patent Publication No. 2019/195665. It was prepared by the following synthesis method similar to that described in 4.
Figure PCTKR2023013502-appb-img-000004
Figure PCTKR2023013502-appb-img-000004
또한, 화학식 10에 따른 (S)-11-(아미노메틸)-4-에틸-8-플루오로-4-하이드록시-9-메틸-1,12-디하이드로-14H-피라노[3',4':6,7] 인돌리지노[1,2-b]퀴놀린-3,14(4H)-디온은 미국 등록특허 제11,229,639호 기재된 바와 유사하게 다음과 같은 합성방법에 의해 제조되었다.In addition, (S)-11-(aminomethyl)-4-ethyl-8-fluoro-4-hydroxy-9-methyl-1,12-dihydro-14H-pyrano[3', 4':6,7] indolizino[1,2-b]quinoline-3,14(4H)-dione was prepared by the following synthetic method similar to that described in U.S. Patent No. 11,229,639.
Figure PCTKR2023013502-appb-img-000005
Figure PCTKR2023013502-appb-img-000005
실시예 2. 본 발명에 따른 캄토테신 유도체의 합성 및 물리화학적 특성Example 2. Synthesis and physicochemical properties of camptothecin derivatives according to the present invention
본 발명에 따른 화합물의 분석 조건 등은 다음과 같다 The analysis conditions for the compounds according to the present invention are as follows.
분석 조건 : U_AN_ACID, Apparatus: Agilent Infinity II; Bin. Pump: G7120A, Multisampler, VTC, DAD: Agilent G7117B, 220-320nm, PDA: 210-320nm, MSD: Agilent G6135B ESI, pos/neg 100-1000, ELSD G7102A: Evap 40℃, Neb 40℃, 가스 흐름 1.6ml/min, Column: Waters XSelect CSH C18, 50x2.1 mm, 2.5 μm, Temp: 40 ℃, Flow: 0.6 mL/min, Gradient: t0 = 5% B, t2min = 98% B, t2.7min = 98% B, Post time: 0.3 min, Eluent A: 물에 0.1% 포름산, Eluent B: 아세토니트릴에 0.1% 포름산Analysis conditions: U_AN_ACID, Apparatus: Agilent Infinity II; Bin. Pump: G7120A, Multisampler, VTC, DAD: Agilent G7117B, 220-320nm, PDA: 210-320nm, MSD: Agilent G6135B ESI, pos/neg 100-1000, ELSD G7102A: Evap 40℃, Neb 40℃, gas flow 1.6 ml/min, Column: Waters % B, Post time: 0.3 min, Eluent A: 0.1% formic acid in water, Eluent B: 0.1% formic acid in acetonitrile
산성 preparative MPLC(Luna) Acidic preparative MPLC (Luna)
기기 유형 : Reveleris™ prep MPLC; Column: Phenomenex LUNA C18(3)(150x25mm, 10μ); Flow: 40mL/min; Column temp: room temperature; Eluent A: 물에 0.1% (v/v) 포름산, Eluent B: 아세토니트릴에 0.1% 포름산 (v/v); Gradient; Detection UV: 220, 254, 340 nm, ELSD.Instrument type: Reveleris™ prep MPLC; Column: Phenomenex LUNA C18(3) (150x25mm, 10μ); Flow: 40mL/min; Column temp: room temperature; Eluent A: 0.1% (v/v) formic acid in water, Eluent B: 0.1% (v/v) formic acid in acetonitrile; Gradient; Detection UV: 220, 254, 340 nm, ELSD.
산성 preparative MPLC (Reprosil)Acid preparative MPLC (Reprosil)
기기 유형 : Reveleris™ prep MPLC; Column: Dr. Maisch Reprosil C18 150x25 mm, 10μ); Flow: 40 mL/min; Column temp: room temperature; Eluent A: 물에 0.1% (v/v) 포름산, Eluent B: 아세토니트릴에 0.1% 포름산 (v/v); Gradient; Detection UV : 220, 254, 340 nm, ELSD.Instrument type: Reveleris™ prep MPLC; Column: Dr. Maisch Reprosil C18 150x25 mm, 10μ); Flow: 40 mL/min; Column temp: room temperature; Eluent A: 0.1% (v/v) formic acid in water, Eluent B: 0.1% (v/v) formic acid in acetonitrile; Gradient; Detection UV: 220, 254, 340 nm, ELSD.
실시예 2.1 화학식 1의 캄토테신 유도체의 합성Example 2.1 Synthesis of Camptothecin Derivatives of Formula 1
글리콜산 (16.7 mg, 0.220 mmol)을 0.5 mL의 N,N-디메틸포름아미드에 용해시켰다. HOSu(25.3 mg, 0.220 mmol) 및 EDCI.HCl (42.2 mg, 0.220 mmol) 을 첨가하였다. 반응 혼합물을 실온에서 2시간 동안 교반하였다. 그런 다음 1.1 당량의 활성산 용액을 (S)-14-(아미노메틸)-7-에틸-7-하이드록시-10,13-디하이드로-11H-[1,3]디옥솔로[4,5-g]피라노[3',4':6,7]인돌리지노[1,2-b]퀴놀린-8,11(7H)-디온(화학식 9의 7MAD-MDCPT) 염산염 (91.5 mg, 0.200 mmol) 및 트리에틸아민 (0.056 mL, 0.400 mmol)을 N,N- 디메틸포름아미드 (2.5 mL)에 용해시킨 현탁액에 첨가하였다. 혼합물을 실온에서 18시간 동안 교반하였다. 반응 혼합물을 DMSO에 희석하고 가열하여 투명 용액으로 얻었다. 혼합물을 산성 분취용 MPLC(Luna10-50)로 정제하여 생성물 분획의 동결 건조 후 회백색 고체를 얻었다. 수율: 58 mg, 60%Glycolic acid (16.7 mg, 0.220 mmol) was dissolved in 0.5 mL of N,N-dimethylformamide. HOSu (25.3 mg, 0.220 mmol) and EDCI.HCl (42.2 mg, 0.220 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. Then, 1.1 equivalents of the active acid solution was added to (S)-14-(aminomethyl)-7-ethyl-7-hydroxy-10,13-dihydro-11H-[1,3]dioxolo[4,5- g]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-8,11(7H)-dione (7MAD-MDCPT of Formula 9) hydrochloride (91.5 mg, 0.200 mmol) ) and triethylamine (0.056 mL, 0.400 mmol) were added to the suspension dissolved in N,N-dimethylformamide (2.5 mL). The mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted in DMSO and heated to obtain a clear solution. The mixture was purified by acidic preparative MPLC (Luna10-50) to obtain an off-white solid after freeze-drying of the product fraction. Yield: 58 mg, 60%
Figure PCTKR2023013502-appb-img-000006
Figure PCTKR2023013502-appb-img-000006
U_AN_ACID: m/z 480.2 [M+H]+ U_AN_ACID: m/z 480.2 [M+H] +
1H NMR (400 MHz, DMSO-d6) δ 8.66 (t, J = 6.1 Hz, 1H), 7.84 (s, 1H), 7.50 (s, 1H), 7.22 (s, 1H), 6.49 (s, 1H), 6.28 (s, 2H), 5.58 (d, J = 4.9 Hz, 1H), 5.44 - 5.34 (m, 2H), 5.18 - 5.04 (m, 2H), 4.70 (d, J = 6.0 Hz, 2H), 3.96 (s, 2H), 1.92 - 1.76 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.66 (t, J = 6.1 Hz, 1H), 7.84 (s, 1H), 7.50 (s, 1H), 7.22 (s, 1H), 6.49 (s, 1H), 6.28 (s, 2H), 5.58 (d, J = 4.9 Hz, 1H), 5.44 - 5.34 (m, 2H), 5.18 - 5.04 (m, 2H), 4.70 (d, J = 6.0 Hz, 2H) ), 3.96 (s, 2H), 1.92 - 1.76 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H).
실시예 2.2 화학식 2의 캄토테신 유도체의 합성Example 2.2 Synthesis of Camptothecin Derivatives of Formula 2
D-락트산 (15.16 mg, 0.168 mmol)을 0.5 mL의 N,N-디메틸포름아미드에 용해시켰다. HOSu(19.37 mg, 0.168 mmol) 및 EDCI.HCl (32.26 mg, 0.168 mmol) 을 첨가하였다. 반응 혼합물을 실온에서 2시간 동안 교반하였다. 그런 다음 1.1당량의 활성산 용액을 7MAD-MDCPT 염산염(70 mg, 0.153 mmol) 및 트리에틸아민 (0.043 mL, 0.306 mmol)을 N,N- 디메틸포름아미드 (2.5 mL)에 용해시킨 현탁액에 첨가하였다. 혼합물을 실온에서 18시간 동안 교반하였다. 반응 혼합물을 DMSO에 희석하고 가열하여 투명 용액으로 얻었다. 혼합물을 산성 분취용 MPLC(5-40)로 두번 정제하여 생성물 분획의 동결 건조 후 회백색 고체를 얻었다. 수율: 40 mg, 53%D-lactic acid (15.16 mg, 0.168 mmol) was dissolved in 0.5 mL of N,N-dimethylformamide. HOSu (19.37 mg, 0.168 mmol) and EDCI.HCl (32.26 mg, 0.168 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. Then, 1.1 equivalents of the active acid solution was added to the suspension of 7MAD-MDCPT hydrochloride (70 mg, 0.153 mmol) and triethylamine (0.043 mL, 0.306 mmol) dissolved in N,N-dimethylformamide (2.5 mL). . The mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted in DMSO and heated to obtain a clear solution. The mixture was purified twice by acidic preparative MPLC (5-40) to give an off-white solid after freeze-drying of the product fraction. Yield: 40 mg, 53%
Figure PCTKR2023013502-appb-img-000007
Figure PCTKR2023013502-appb-img-000007
U_AN_ACID: m/z 494.2 [M+H]+ U_AN_ACID: m/z 494.2 [M+H] +
1H NMR (400 MHz, DMSO-d6) δ 8.67 (t, J = 6.1 Hz, 1H), 7.86 (s, 1H), 7.52 (s, 1H), 7.24 (s, 1H), 6.48 (s, 1H), 6.29 (s, 2H), 5.59 (d, J = 4.9 Hz, 1H), 5.44 (d, J = 14.0 Hz, 4H), 4.71 (d, J = 6.0 Hz, 2H), 4.02 - 3.93 (m, 1H), 1.93 - 1.79 (m, 2H), 1.18 (d, J = 6.8 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.67 (t, J = 6.1 Hz, 1H), 7.86 (s, 1H), 7.52 (s, 1H), 7.24 (s, 1H), 6.48 (s, 1H), 6.29 (s, 2H), 5.59 (d, J = 4.9 Hz, 1H), 5.44 (d, J = 14.0 Hz, 4H), 4.71 (d, J = 6.0 Hz, 2H), 4.02 - 3.93 ( m, 1H), 1.93 - 1.79 (m, 2H), 1.18 (d, J = 6.8 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H).
실시예 2.3 화학식 3의 캄토테신 유도체의 합성Example 2.3 Synthesis of Camptothecin Derivatives of Formula 3
(S)-3,3,3-트리플루오로-2-하이드록시프로파노산(17.29 mg, 0.120 mmol)을 2 mL의 N,N-디메틸포름아미드에 용해하고 HATU(45.6 mg, 0.120 mmol) 를 첨가하였다. 혼합물을 3분 동안 교반 한 후 7MAD-MDCPT 염산염(45.8 mg, 0.100 mmol) 및 DIPEA (0.069 ml, 0.400 mmol)를 첨가하고 반응 혼합물을 실온에서 2시간 동안 교반하였다. 반응 혼합물을 산성 분취용 MPLC(Luna10-50)로 직접 정제하고 생성물 분획물을 동결 건조하여 회백색 고체 로 생성물을 얻었다. 수율: 27 mg, 49%(S)-3,3,3-trifluoro-2-hydroxypropanoic acid (17.29 mg, 0.120 mmol) was dissolved in 2 mL of N,N-dimethylformamide and HATU (45.6 mg, 0.120 mmol). was added. The mixture was stirred for 3 minutes, then 7MAD-MDCPT hydrochloride (45.8 mg, 0.100 mmol) and DIPEA (0.069 ml, 0.400 mmol) were added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was directly purified by acidic preparative MPLC (Luna10-50) and the product fractions were freeze-dried to obtain the product as an off-white solid. Yield: 27 mg, 49%
Figure PCTKR2023013502-appb-img-000008
Figure PCTKR2023013502-appb-img-000008
U_AN_ACID: m/z 548.2 [M+H]+ U_AN_ACID: m/z 548.2 [M+H] +
1H NMR (400 MHz, DMSO-d6) δ 8.98 (d, J = 8.6 Hz, 1H), 7.87 (s, 1H), 7.53 (s, 1H), 7.24 (s, 1H), 7.20 (d, J = 6.2 Hz, 1H), 6.50 (s, 1H), 6.30 (d, J = 7.1 Hz, 2H), 5.62 (d, J = 4.9 Hz, 1H), 5.48 - 5.36 (m, 2H), 5.24 (d, J = 19.2 Hz, 1H), 5.10 (d, J = 19.2 Hz, 1H), 4.66 - 4.55 (m, 1H), 4.08 - 3.89 (m, 1H), 1.92 - 1.76 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.98 (d, J = 8.6 Hz, 1H), 7.87 (s, 1H), 7.53 (s, 1H), 7.24 (s, 1H), 7.20 (d, J = 6.2 Hz, 1H), 6.50 (s, 1H), 6.30 (d, J = 7.1 Hz, 2H), 5.62 (d, J = 4.9 Hz, 1H), 5.48 - 5.36 (m, 2H), 5.24 ( d, J = 19.2 Hz, 1H), 5.10 (d, J = 19.2 Hz, 1H), 4.66 - 4.55 (m, 1H), 4.08 - 3.89 (m, 1H), 1.92 - 1.76 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H).
실시예 2.4 화학식 4의 캄토테신 유도체의 합성Example 2.4 Synthesis of Camptothecin Derivatives of Formula 4
(R)-2-하이드록시부탄산(11.45 mg, 0.110 mmol)을 0.5 mL의 N,N-디메틸포름아미드에 용해시켰다. HOSu(12.6 mg, 0.110 mmol) 및 EDCI.HCl (21.09 mg, 0.110 mmol)을 첨가하였다. 반응 혼합물을 실온에서 2시간 동안 교반하였다. 그런 다음 1.1당량의 활성산 용액을 7MAD-MDCPT 염산염(45.8 mg, 0.100 mmol) 및 트리에틸아민 (0.028 mL, 0.200 mmol)을 N,N- 디메틸포름아미드 (2.5 mL)에 용해시킨 현탁액에 첨가하였다. 혼합물을 실온에서 18시간 동안 교반하였다. 반응 혼합물을 DMSO에 희석하고 가열하여 투명 용액으로 얻었다. 혼합물을 산성 분취용 MPLC(5-40)로 정제하여 생성물 분획의 동결 건조 후 회백색 고체를 얻었다. 수율: 28 mg, 55%(R)-2-Hydroxybutanoic acid (11.45 mg, 0.110 mmol) was dissolved in 0.5 mL of N,N-dimethylformamide. HOSu (12.6 mg, 0.110 mmol) and EDCI.HCl (21.09 mg, 0.110 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. Then, 1.1 equivalents of the active acid solution was added to the suspension of 7MAD-MDCPT hydrochloride (45.8 mg, 0.100 mmol) and triethylamine (0.028 mL, 0.200 mmol) dissolved in N,N-dimethylformamide (2.5 mL). . The mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted in DMSO and heated to obtain a clear solution. The mixture was purified by acidic preparative MPLC (5-40) to give an off-white solid after lyophilization of the product fraction. Yield: 28 mg, 55%
Figure PCTKR2023013502-appb-img-000009
Figure PCTKR2023013502-appb-img-000009
U_AN_ACID: m/z 508.4 [M+H]+ U_AN_ACID: m/z 508.4 [M+H] +
1H NMR (400 MHz, DMSO-d6) δ 8.68 (t, J = 6.1 Hz, 1H), 7.88 (s, 1H), 7.53 (s, 1H), 7.24 (s, 1H), 6.47 (s, 1H), 6.28 (s, 2H), 5.57 (d, J = 4.9 Hz, 1H), 5.43 (d, J = 14.0 Hz, 4H), 4.70 (d, J = 6.0 Hz, 2H), 4.00 - 3.91 (m, 1H), 1.92 - 1.78 (m, 3H), 1.70 - 1.61 (m, 1H), 0.94 (t, J = 7.4 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.68 (t, J = 6.1 Hz, 1H), 7.88 (s, 1H), 7.53 (s, 1H), 7.24 (s, 1H), 6.47 (s, 1H), 6.28 (s, 2H), 5.57 (d, J = 4.9 Hz, 1H), 5.43 (d, J = 14.0 Hz, 4H), 4.70 (d, J = 6.0 Hz, 2H), 4.00 - 3.91 ( m, 1H), 1.92 - 1.78 (m, 3H), 1.70 - 1.61 (m, 1H), 0.94 (t, J = 7.4 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H).
실시예 2.5 화학식 5의 캄토테신 유도체의 합성Example 2.5 Synthesis of Camptothecin Derivatives of Formula 5
글리콜산(8.37 mg, 0.110 mmol)을 0.5 mL의 N,N-디메틸포름아미드에 용해시켰다. HOSu(12.7 mg, 0.110 mmol) 및 EDCI.HCl (21.1 mg, 0.110 mmol)을 첨가하였다. 반응 혼합물을 실온에서 2시간 동안 교반하였다. 그런 다음 1.1당량의 활성산 용액을 (S)-11-(아미노메틸)-4-에틸-8-플루오로-4-하이드록시-9-메틸-1,12-디하이드로-14H-피라노[3',4':6,7] 인돌리지노[1,2-b]퀴놀린-3,14(4H)-디온 (41 mg, 0.100 mmol) 및 트리에틸아민 (0.028 mL, 0.200 mmol)을 N,N- 디메틸포름아미드 (2.5 mL)에 용해시킨 현탁액에 첨가하였다. 혼합물을 실온에서 18시간 동안 교반하였다. 반응 혼합물을 DMSO에 희석하고 가열하여 투명 용액으로 얻었다. 혼합물을 산성 분취용 MPLC(5-40)로 정제하여 생성물 분획의 동결건조 후 회백색 고체를 얻었다. 수율: 30 mg, 64%Glycolic acid (8.37 mg, 0.110 mmol) was dissolved in 0.5 mL of N,N-dimethylformamide. HOSu (12.7 mg, 0.110 mmol) and EDCI.HCl (21.1 mg, 0.110 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. Then, 1.1 equivalents of the active acid solution was added to (S)-11-(aminomethyl)-4-ethyl-8-fluoro-4-hydroxy-9-methyl-1,12-dihydro-14H-pyrano[ 3',4':6,7] indolizino[1,2-b]quinoline-3,14(4H)-dione (41 mg, 0.100 mmol) and triethylamine (0.028 mL, 0.200 mmol) were added to N was added to the suspension dissolved in N-dimethylformamide (2.5 mL). The mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted in DMSO and heated to obtain a clear solution. The mixture was purified by acidic preparative MPLC (5-40) to give an off-white solid after lyophilization of the product fraction. Yield: 30 mg, 64%
Figure PCTKR2023013502-appb-img-000010
Figure PCTKR2023013502-appb-img-000010
U_AN_ACID: m/z 468.4 [M+H]+ U_AN_ACID: m/z 468.4 [M+H] +
1H NMR (400 MHz, DMSO-d6) δ 8.76 (t, J = 6.0 Hz, 1H), 8.48 (d, J = 1.2, 8.3 Hz, 1H), 7.90 (d, J = 10.8 Hz, 1H), 7.32 (s, 1H), 6.53 (s, 1H), 5.58 (t, J = 5.7 Hz, 1H), 5.51 (s, 2H), 5.44 (s, 3H), 4.85 (d, J = 6.0 Hz, 2H), 3.84 (d, J = 5.6 Hz, 3H), 1.79 - 1.98 (m, 3H), 0.88 (t, J = 7.3 Hz, 3H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.76 (t, J = 6.0 Hz, 1H), 8.48 (d, J = 1.2, 8.3 Hz, 1H), 7.90 (d, J = 10.8 Hz, 1H) , 7.32 (s, 1H), 6.53 (s, 1H), 5.58 (t, J = 5.7 Hz, 1H), 5.51 (s, 2H), 5.44 (s, 3H), 4.85 (d, J = 6.0 Hz, 2H), 3.84 (d, J = 5.6 Hz, 3H), 1.79 - 1.98 (m, 3H), 0.88 (t, J = 7.3 Hz, 3H).
실시예 2.6 화학식 6의 캄토테신 유도체의 합성Example 2.6 Synthesis of Camptothecin Derivatives of Formula 6
D-락트산(14.9 mg, 0.165 mmol)을 0.5 mL의 N,N-디메틸포름아미드에 용해시켰다. HOSu(19.0 mg, 0.165 mmol) 및 EDCI.HCl (31.6 mg, 0.165 mmol)을 첨가하였다. 반응 혼합물을 실온에서 2시간 동안 교반하였다. 그런 다음 1.1당량의 활성산 용액을 (S)-11-(아미노메틸)-4-에틸-8-플루오로-4-하이드록시-9-메틸-1,12-디하이드로-14H-피라노[3',4':6,7] 인돌리지노[1,2-b]퀴놀린-3,14(4H)-디온 (61 mg, 0.150 mmol) 및 트리에틸아민 (0.042 mL, 0.300 mmol)을 N,N-디메틸포름아미드 (2.5 mL)에 용해시킨 현탁액에 첨가하였다. 혼합물을 실온에서 18시간 동안 교반하였다. 반응 혼합물을 DMSO에 희석하고 가열하여 투명 용액으로 얻었다. 혼합물을 산성 분취용 MPLC(5-40)로 정제하여 생성물 분획의 동결건조 후 회백색 고체를 얻었다. 수율: 37 mg, 51%D-lactic acid (14.9 mg, 0.165 mmol) was dissolved in 0.5 mL of N,N-dimethylformamide. HOSu (19.0 mg, 0.165 mmol) and EDCI.HCl (31.6 mg, 0.165 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. Then, 1.1 equivalents of the active acid solution was added to (S)-11-(aminomethyl)-4-ethyl-8-fluoro-4-hydroxy-9-methyl-1,12-dihydro-14H-pyrano[ 3',4':6,7] indolizino[1,2-b]quinoline-3,14(4H)-dione (61 mg, 0.150 mmol) and triethylamine (0.042 mL, 0.300 mmol) were added to N , was added to the suspension dissolved in N-dimethylformamide (2.5 mL). The mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted in DMSO and heated to obtain a clear solution. The mixture was purified by acidic preparative MPLC (5-40) to give an off-white solid after lyophilization of the product fraction. Yield: 37 mg, 51%
Figure PCTKR2023013502-appb-img-000011
Figure PCTKR2023013502-appb-img-000011
U_AN_ACID: m/z 481.2 [M+H]+ U_AN_ACID: m/z 481.2 [M+H] +
1H NMR (400 MHz, DMSO-d6) δ 8.75 (t, J = 6.0 Hz, 1H), 8.49 (d, J = 1.2, 8.3 Hz, 1H), 7.91 (d, J = 10.8 Hz, 1H), 7.34 (s, 1H), 6.51 (s, 1H), 5.56 (t, J = 5.7 Hz, 1H), 5.49 (s, 2H), 5.42 (s, 3H), 4.01 - 3.92 (m, 1H), 3.83 (d, J = 5.6 Hz, 3H), 1.98 - 1.78 (m, 3H), 1.16 (d, J = 6.8 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.75 (t, J = 6.0 Hz, 1H), 8.49 (d, J = 1.2, 8.3 Hz, 1H), 7.91 (d, J = 10.8 Hz, 1H) , 7.34 (s, 1H), 6.51 (s, 1H), 5.56 (t, J = 5.7 Hz, 1H), 5.49 (s, 2H), 5.42 (s, 3H), 4.01 - 3.92 (m, 1H), 3.83 (d, J = 5.6 Hz, 3H), 1.98 - 1.78 (m, 3H), 1.16 (d, J = 6.8 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H).
실시예 2.7 화학식 7의 캄토테신 유도체의 합성Example 2.7 Synthesis of Camptothecin Derivatives of Formula 7
(S)-3,3,3-트리플루오로-2-하이드록시프로파노산(20.7 mg, 0.144 mmol)을 2 mL의 N,N-디메틸포름아미드에 용해하고 HATU(54.7 mg, 0.144 mmol) 를 첨가하였다. 혼합물을 3분 동안 교반 한 후 (S)-11-(아미노메틸)-4-에틸-8-플루오로-4-하이드록시-9-메틸-1,12-디하이드로-14H-피라노[3',4':6,7] 인돌리지노[1,2-b]퀴놀린-3,14(4H)-디온 및 DIPEA (0.084 ml, 0.480 mmol)를 첨가하고 반응 혼합물을 실온에서 2시간 동안 교반하였다. 반응 혼합물을 산성 preparative MPLC(Luna10-50)로 직접 정제하고 생성물 분획물을 동결건조하여 회백색 고체로 생성물을 얻었다. 수율: 38 mg, 59%(S)-3,3,3-trifluoro-2-hydroxypropanoic acid (20.7 mg, 0.144 mmol) was dissolved in 2 mL of N,N-dimethylformamide and HATU (54.7 mg, 0.144 mmol). was added. The mixture was stirred for 3 minutes and then (S)-11-(aminomethyl)-4-ethyl-8-fluoro-4-hydroxy-9-methyl-1,12-dihydro-14H-pyrano[3 ',4':6,7] indolizino[1,2-b]quinoline-3,14(4H)-dione and DIPEA (0.084 ml, 0.480 mmol) were added and the reaction mixture was stirred at room temperature for 2 hours. did. The reaction mixture was directly purified by acidic preparative MPLC (Luna10-50), and the product fractions were lyophilized to obtain the product as an off-white solid. Yield: 38 mg, 59%
Figure PCTKR2023013502-appb-img-000012
Figure PCTKR2023013502-appb-img-000012
U_AN_ACID: m/z 536.2 [M+H]+ U_AN_ACID: m/z 536.2 [M+H] +
1H NMR (400 MHz, DMSO-d6) δ 8.97 (t, J = 6.0 Hz, 1H), 8.48 (d, J = 1.2, 8.3 Hz, 1H), 7.92 (d, J = 10.8 Hz, 1H), 7.35 (s, 1H), 6.53 (s, 1H), 5.62 (t, J = 5.7 Hz, 1H), 5.51 (s, 2H), 5.44 (s, 3H), 4.00 - 3.93 (m, 1H), 3.85 (d, J = 5.6 Hz, 3H), 1.98 - 1.79 (m, 3H), 0.87 (t, J = 7.3 Hz, 3H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.97 (t, J = 6.0 Hz, 1H), 8.48 (d, J = 1.2, 8.3 Hz, 1H), 7.92 (d, J = 10.8 Hz, 1H) , 7.35 (s, 1H), 6.53 (s, 1H), 5.62 (t, J = 5.7 Hz, 1H), 5.51 (s, 2H), 5.44 (s, 3H), 4.00 - 3.93 (m, 1H), 3.85 (d, J = 5.6 Hz, 3H), 1.98 - 1.79 (m, 3H), 0.87 (t, J = 7.3 Hz, 3H).
실시예 2.8 화학식 8의 캄토테신 유도체의 합성Example 2.8 Synthesis of Camptothecin Derivatives of Formula 8
(R)-2-하이드록시부탄산 (11.4 mg, 0.110 mmol)을 0.5 mL의 N,N-디메틸포름아미드에 용해시켰다. HOSu(12.7 mg, 0.110 mmol) 및 EDCI.HCl (21.1 mg, 0.110 mmol)을 첨가하였다. 반응 혼합물을 실온에서 2시간 동안 교반하였다. 그런 다음 1.1당량의 활성산 용액을 (S)-11-(아미노메틸)-4-에틸-8-플루오로-4-하이드록시-9-메틸-1,12-디하이드로-14H-피라노[3',4':6,7] 인돌리지노[1,2-b]퀴놀린-3,14(4H)-디온 (41 mg, 0.100 mmol) 및 트리에틸아민 (0.028 mL, 0.200 mmol)을 N,N-디메틸포름아미드 (2.5 mL)에 용해시킨 현탁액에 첨가하였다. 혼합물을 실온에서 18시간 동안 교반하였다. 반응 혼합물을 DMSO에 희석하고 가열하여 투명 용액으로 얻었다. 혼합물을 산성 분취용 MPLC(5-40)로 정제하여 생성물 분획의 동결건조 후 회백색 고체를 얻었다. 수율: 23 mg, 46%(R)-2-Hydroxybutanoic acid (11.4 mg, 0.110 mmol) was dissolved in 0.5 mL of N,N-dimethylformamide. HOSu (12.7 mg, 0.110 mmol) and EDCI.HCl (21.1 mg, 0.110 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. Then, 1.1 equivalents of the active acid solution was added to (S)-11-(aminomethyl)-4-ethyl-8-fluoro-4-hydroxy-9-methyl-1,12-dihydro-14H-pyrano[ 3',4':6,7] indolizino[1,2-b]quinoline-3,14(4H)-dione (41 mg, 0.100 mmol) and triethylamine (0.028 mL, 0.200 mmol) were added to N , was added to the suspension dissolved in N-dimethylformamide (2.5 mL). The mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted in DMSO and heated to obtain a clear solution. The mixture was purified by acidic preparative MPLC (5-40) to give an off-white solid after lyophilization of the product fraction. Yield: 23 mg, 46%
Figure PCTKR2023013502-appb-img-000013
Figure PCTKR2023013502-appb-img-000013
U_AN_ACID: m/z 496.4 [M+H]+ U_AN_ACID: m/z 496.4 [M+H] +
1H NMR (400 MHz, DMSO-d6) δ 8.76 (t, J = 6.0 Hz, 1H), 8.51 (d, J = 1.2, 8.3 Hz, 1H), 7.93 (d, J = 10.8 Hz, 1H), 7.35 (s, 1H), 6.52 (s, 1H), 5.58 (t, J = 5.7 Hz, 1H), 5.51 (s, 2H), 5.43 (s, 3H), 4.03 - 3.95 (m, 1H), 3.84 (d, J = 5.6 Hz, 3H), 1.97 - 1.78 (m, 4H), 1.72 - 1.63 (m, 1H), 0.93 (t, J = 7.4 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H). 1H NMR (400 MHz, DMSO-d 6 ) δ 8.76 (t, J = 6.0 Hz, 1H), 8.51 (d, J = 1.2, 8.3 Hz, 1H), 7.93 (d, J = 10.8 Hz, 1H) , 7.35 (s, 1H), 6.52 (s, 1H), 5.58 (t, J = 5.7 Hz, 1H), 5.51 (s, 2H), 5.43 (s, 3H), 4.03 - 3.95 (m, 1H), 3.84 (d, J = 5.6 Hz, 3H), 1.97 - 1.78 (m, 4H), 1.72 - 1.63 (m, 1H), 0.93 (t, J = 7.4 Hz, 3H), 0.87 (t, J = 7.3 Hz) , 3H).
실시예 2.9 본 발명에 따른 화합물의 물리화학적 특성Example 2.9 Physicochemical properties of compounds according to the invention
본 발명에 따른 화학식 1 내지 화학식 8의 화합물의 LogP, cLogP 및 tPSA(topological polar surface area) 값 등의 물리화학적 특성은 표 1에 기재된 바와 같다.The physicochemical properties, such as LogP, cLogP, and tPSA (topological polar surface area) values, of the compounds of Formulas 1 to 8 according to the present invention are shown in Table 1.
Figure PCTKR2023013502-appb-img-000014
Figure PCTKR2023013502-appb-img-000014
실시예 3. 본 발명에 따른 신규 캄토테신 유도체들의 cytotoxicity assay Example 3. Cytotoxicity assay of novel camptothecin derivatives according to the present invention
실시예 3.1 in vitro cytotoxicity assay 방법 Example 3.1 in vitro cytotoxicity assay method
본 발명에 따른 화학식 2의 화합물인 7MAD-MD-CPT(lactic acid)에 대하여, 하기와 같이 in vitro cytotoxicity assay를 수행하였다.For 7MAD-MD-CPT (lactic acid), a compound of formula 2 according to the present invention, an in vitro cytotoxicity assay was performed as follows.
96 well plate에 well당 3000개의 FaDu 세포주를 파종(seeding)하고 항온배양(37℃, 5% CO2)하였다. 24시간 후, 9개 농도(1000 nM부터 1/5씩 serial dilution)의 약물 100 ㎕를 셀에 처리하였다. 이 때, 화학식 2의 화합물인 7MAD-MD-CPT(lactic acid)와 대조군을 각각 처리하였다. 3000 FaDu cell lines per well were seeded in a 96 well plate and incubated at constant temperature (37°C, 5% CO 2 ). After 24 hours, 100 ㎕ of drugs at 9 concentrations (serial dilution of 1/5 from 1000 nM) were treated with the cells. At this time, 7MAD-MD-CPT (lactic acid), a compound of Formula 2, and a control group were treated, respectively.
이후, 3일 동안 항온배양(37℃, 5% CO2) 시켰다. well에 CellTiter-Glo reagent(CellTiter-Glo® Luminescent Cell Viability Assay kit (Promega, G7571)를 사용) 100 ㎕씩 추가한 후 파이펫팅해 주었다. 10분 동안 항온배양 (RT)후 luminescence를 측정하였다. 약물농도가 0일 때의 발광 값을 100%로 볼 때, 50%의 발광 값을 나타내는 농도가 IC50값이다.Afterwards, it was incubated at constant temperature (37°C, 5% CO 2 ) for 3 days. 100 ㎕ of CellTiter-Glo reagent (using CellTiter-Glo® Luminescent Cell Viability Assay kit (Promega, G7571)) was added to each well and pipetted. After incubation at temperature (RT) for 10 minutes, luminescence was measured. When considering the luminescence value when the drug concentration is 0 as 100%, the concentration that represents a luminescence value of 50% is the IC 50 value.
실시예 3.2 화학식 2 화합물의 cytotoxicity 효능 Example 3.2 Cytotoxicity efficacy of compounds of formula 2
본 발명에 따른 화학식 2 화합물의 cytotoxicity assay 결과, 모든 화합물이 매우 우수한 세포사멸 효능, 즉 항암 효능을 나타내었으며, 유사 구조체들인 PBX7014(화학식 13), PBX7016(화학식 14) 및 Dxd (reference)과 비교하였을 때, PBX7014 및 PBX7016과 동등 또는 그보다 낮은 세포독성 효능을 나타내다는 점을 확인하였다(도 2).As a result of the cytotoxicity assay of the compound of Formula 2 according to the present invention, all compounds showed very excellent cell death efficacy, that is, anticancer effect, and compared with similar structures PBX7014 (Formula 13), PBX7016 (Formula 14), and Dxd (reference). It was confirmed that it exhibited cytotoxic efficacy equivalent to or lower than that of PBX7014 and PBX7016 (Figure 2).
Figure PCTKR2023013502-appb-img-000015
Figure PCTKR2023013502-appb-img-000015
실시예 4. 항체-약물 접합체의 제조 Example 4. Preparation of antibody-drug conjugate
본 발명에 따른 화학식 1 내지 화학식 8의 화합물을 상기 화학식 11의 링커를 통해 트라스투주맙(Trastuzumab), 세툭시맙(Cetuximab), 니모투주맙(Nimotuzumab) 또는 사시투주맙(Sacituzumab)과 접합시켜 본 발명에 따른 화합물을 포함하는 항체-약물 접합체를 제조하고, 이의 항암 효능을 테스트한다. Compounds of Formulas 1 to 8 according to the present invention are conjugated with Trastuzumab, Cetuximab, Nimotuzumab or Sacituzumab through the linker of Formula 11. Antibody-drug conjugates containing the compounds according to the invention are prepared and their anticancer efficacy is tested.
상기 항체-약물 접합체의 제조는 다음과 같이 이루어진다. The preparation of the antibody-drug conjugate is carried out as follows.
트라스트주맙, 세툭시맙, 니모투주맙 또는 사시투주맙을 PD-10 desalting column을 이용하여 Reduction buffer(150 mM NaCl, 50 mM Histidine pH 6.0)로 Buffer exchange 후 27.5 μM의 항체에 825 μM TCEP을 25℃에서 2시간 처리하여 항체의 Disulfide bond를 환원시켰다.After buffer exchange of trastuzumab, cetuximab, nimotuzumab or sacituzumab with reduction buffer (150 mM NaCl, 50 mM Histidine pH 6.0) using a PD-10 desalting column, 825 μM TCEP was added to 27.5 μM of antibody for 25 days. Disulfide bond of the antibody was reduced by treatment at ℃ for 2 hours.
이후 PD-10 desalting column을 이용하여 여분의 TCEP을 제거하고, 15% DMSO를 포함하는 Reaction buffer (25mM Histidine pH6.0)에서 165μM의 화학식 11의 링커를 가지는 화학식 1a 내지 화학식 8a의 약물-링커와 13.8 μM의 환원된 항체를 25℃에서 1시간 반응하여 conjugation 반응을 진행하였다. Afterwards, excess TCEP was removed using a PD-10 desalting column, and drug-linkers of Formulas 1a to 8a having 165 μM of the linker of Formula 11 were added in Reaction buffer (25mM Histidine pH6.0) containing 15% DMSO. Conjugation reaction was performed by reacting 13.8 μM of the reduced antibody at 25°C for 1 hour.
이때 약물 항체 비율(DAR)은 약 8이다. Conjugation 반응 후 여분의 약물-링커를 PD-10 desalting column을 이용하여 제거하고 최종 항체-약물 접합체를 수득하였다.At this time, the drug-to-antibody ratio (DAR) is about 8. After the conjugation reaction, excess drug-linker was removed using a PD-10 desalting column, and the final antibody-drug conjugate was obtained.

Claims (10)

  1. 화학식 1 내지 화학식 8 중 어느 하나로 표시되는 화합물, 이의 이성질체, 이의 약제학적 허용염 또는 이의 용매화물:Compounds represented by any one of Formulas 1 to 8, isomers thereof, pharmaceutically acceptable salts thereof, or solvates thereof:
    Figure PCTKR2023013502-appb-img-000016
    Figure PCTKR2023013502-appb-img-000016
  2. 제1항에 따른 화학식 1 내지 화학식 8 중 어느 하나의 화합물, 이의 약제학적 허용염, 또는 이의 용매화물을 포함하는 운반체-약물 접합체(Carrier-Drug Conjugate).A carrier-drug conjugate comprising any one of the compounds of Formulas 1 to 8 according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof.
  3. 제2항에 있어서, 상기 운반체는 항체, 펩타이드, 리피바디, 또는 압타머인 것을 특징으로 하는 운반체-약물 접합체.The carrier-drug conjugate according to claim 2, wherein the carrier is an antibody, peptide, lipibody, or aptamer.
  4. 제3항에 있어서, 상기 운반체-약물 접합체는 운반체가 링커를 통해 약물과 접합된 형태인 것을 특징으로 하는 운반체-약물 접합체.The carrier-drug conjugate according to claim 3, wherein the carrier is conjugated to the drug through a linker.
  5. 제4항에 있어서, 상기 링커는 GGFG 또는 GGYG를 포함하는 것을 특징으로 하는 운반체-약물 접합체.The carrier-drug conjugate according to claim 4, wherein the linker comprises GGFG or GGYG.
  6. 제3항에 있어서, 상기 운반체는 4-1BB, 5T4, 인테그린 (integrin), 액티빈 (Activin), 아밀로이드 베타(amyloid beta), 안지오포에틴(안지오포에틴 1 또는 2), 안지오포에틴 유사물질3, B세포 성숙화 항원 (B cell maturation antigen, BCMA), B세포 활성인자 (B-cell activating factor, BAFF), B7-H3, 보체5 (complement 5), CCR4, CCR5, CCL11, CD2, CD3, CD4, CD6, CD11a, CD16A, CD19, CD20, CD22, CD25, CD27, CD28, CD30, CD32B, CD33, CD38, CD40, CD45, CD46, CD47, CD52, CD56, CD62, CD70, CD73, CD74, CD79b, CD80, CD105, CD123, CD154, CD166, CD262, CD278, CD319, CD326, 태아성암항원 (Carcinoembryonic antigen, CEA), CGRP, 클라우딘18 (Claudin-18), c-Met, CSF-1, CSF-1 수용체, CTLA4, DLL3, EGF 수용체, 혈우병 인자, Fc 수용체, FGF23, 폴레이트 (folate) 수용체, GD2, 글루코코르티코이드 유도 TNF 수용체 (Glucocorticoid-induced TNF receptor, GITR), 글리피칸 3 (Glypican 3), GM-CSF, HER2, HER3, TROP2, 간세포성장인자 (Hepatocyte Growth Factor, HGF), 인터페론 수용체, 인터페론 감마, IgE, IGF-1 수용체, 인터루킨1, 인터루킨2 수용체, 인터루킨4, 인터루킨4 수용체, 인터루킨5, 인터루킨5 수용체, 인터루킨6, 인터루킨6 수용체, 인터루킨8, 인터루킨12/23, 인터루킨13, 인터루킨17A, 인터루킨17수용체A, 인터루킨23, 인터루킨31 수용체, 인터루킨36 수용체, 림프구활성화유전자3 (Lymphocyte-activation gene 3, LAG3), 라이실 산화효소 유사체 2 (Lysyl oxidase homolog 2, LOXL2), 메소텔린 (Mesothelin), 뮤신1 (Mucin-1), 뮤신16 (Mucin-16), 넥틴4 (Netin-4), 신경성장인자 (Nerve Growth Factor, NGF), OX40, 전구단백질 전환효소 유형9 (Proprotein Convertase Subtilisin/Kexin type 9, PCSK9), PD-1, PD-L1, 포스포리파제 C (Phospholipase C), RANKL (Receptor activator of nuclear factors kappa B ligand), 티로신-단백질 키나제 막횡단 수용체 (Tyrosine-protein kinase transmembrane receptor, ROR1), 시알산 결합 Ig-유사 렉틴 15 (Sialic acid binding ig-like lectin 15, Siglec-15), 전환성장인자 베타(Transforming growth factor beta, TGFβ), TIGIT (T-cell innunoreceptor with immunoglobulin and ITIM domain), T세포 면역글로블린 및 뮤신-도메인 함유물질 3 (T cell immunoglobulin and mucin-domain containing-3, Tim-3), 조직인자 (Tissue factor), 조직인자경로억제제 (Tissue factor pathway inhibitor, TFPI), TORP-2, 종양괴사인자(tumor necrosis factor, TNF), 흉선 기질상 림포포이에틴 (Thymic stromal lymphopoietin, TSLB), 큰포식세포집락자극인자 (Colony stimulating factor 1 receptor, CSF1R), 혈관내피세포성장인자 (Vascular endothelial growth factor, VEGF), VEGF 수용체 및 vWF(von Willebrand Factor)로 구성된 군에서 선택된 하나 이상의 물질(항원)과 특이적으로 결합하는 항체, 펩타이드, 리피바디, 또는 압타머인 것을 특징으로 하는 운반체-약물 접합체.The method of claim 3, wherein the carrier is 4-1BB, 5T4, integrin, Activin, amyloid beta, angiopoietin (angiopoietin 1 or 2), angiopoietin analogue. 3, B cell maturation antigen (BCMA), B-cell activating factor (BAFF), B7-H3, complement 5, CCR4, CCR5, CCL11, CD2, CD3, CD4, CD6, CD11a, CD16A, CD19, CD20, CD22, CD25, CD27, CD28, CD30, CD32B, CD33, CD38, CD40, CD45, CD46, CD47, CD52, CD56, CD62, CD70, CD73, CD74, CD79b, CD80, CD105, CD123, CD154, CD166, CD262, CD278, CD319, CD326, Carcinoembryonic antigen (CEA), CGRP, Claudin-18, c-Met, CSF-1, CSF-1 receptor , CTLA4, DLL3, EGF receptor, hemophilia factor, Fc receptor, FGF23, folate receptor, GD2, Glucocorticoid-induced TNF receptor (GITR), Glypican 3, GM- CSF, HER2, HER3, TROP2, Hepatocyte Growth Factor (HGF), interferon receptor, interferon gamma, IgE, IGF-1 receptor, interleukin 1, interleukin 2 receptor, interleukin 4, interleukin 4 receptor, interleukin 5, interleukin 5 receptor, interleukin 6, interleukin 6 receptor, interleukin 8, interleukin 12/23, interleukin 13, interleukin 17A, interleukin 17 receptor A, interleukin 23, interleukin 31 receptor, interleukin 36 receptor, lymphocyte-activation gene 3 , LAG3), Lysyl oxidase homolog 2 (LOXL2), Mesothelin, Mucin-1, Mucin-16, Netin-4, nerve Nerve Growth Factor (NGF), OX40, Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9), PD-1, PD-L1, Phospholipase C, RANKL (Receptor activator of nuclear factors kappa B ligand), Tyrosine-protein kinase transmembrane receptor (ROR1), Sialic acid binding ig-like lectin 15 (Sialic acid binding ig-like lectin 15, Siglec-15), Transforming growth factor beta (TGFβ), TIGIT (T-cell innunoreceptor with immunoglobulin and ITIM domain), T cell immunoglobulin and mucin-domain containing-3, Tim -3), Tissue factor, Tissue factor pathway inhibitor (TFPI), TORP-2, tumor necrosis factor (TNF), Thymic stromal lymphopoietin , TSLB), colony stimulating factor 1 receptor (CSF1R), vascular endothelial growth factor (VEGF), VEGF receptor, and vWF (von Willebrand Factor). A carrier-drug conjugate characterized in that it is an antibody, peptide, lipibody, or aptamer that specifically binds to a substance (antigen).
  7. 제3항에 있어서, 상기 운반체는 항체인 것을 특징으로 하는 운반체-약물 접합체.The carrier-drug conjugate according to claim 3, wherein the carrier is an antibody.
  8. 제7항에 있어서, 상기 항체는 우렐루맙 (Urelumab), 우토밀루맙 (Utomilumab), 벱텔로비맙 (Bebtelovimab), 아두카누맙 (Aducanumab), 바피네주맙 (Bapinezumab), 크레네주맙 (Crenezumab), 도나네맙 (Donanemab), 간테네루맙 (Gantenerumab), 레카네맙 (Lecanemab), 솔라네주맙 (Solanezumab), 네스바쿠맙 (Nesvacumab), 에비나쿠맙 (Evinacumab), 에놉리투주맙 (Enoblituzumab), 옴부르타맙 (Omburtamab), 벨리무맙 (Belimumab), 이아나루맙 (Ianalumab), 타발루맙 (Tabalumab), 베르틸리무맙 (Bertilimumab), 모가물리주맙 (Mogamulizumab), 레론리맙 (Leronlimab), 시필리주맙 (Siplizumab), 포랄루맙 (Foralumab), 무로모납-CD3(Muromonab-CD3), 오텔릭시주맙 (Otelixizumab), 테플리주맙 (Teplizumab), 이발리주맙 (Ibalizumab), 트레갈리주맙 (Tregalizumab), 자노리무맙 (Zanolimumab), 이톨리주맙 (Itolizumab), 에팔리주맙 (Efalizumab), 이네빌리주맙 (Inebilizumab), 타파시타맙 (Tafasitamab), 토시투모맙 (Tositumomab), 오크렐리주맙(Ocrelizumab), 오파투무맙 (Ofatumumab), 리툭시맙 (Rituximab), 우블리툭시맙 (Ublituximab), 벨투주맙(Veltuzumab), 에프라투주맙 (Epratuzumab), 바실릭시맙 (Basiliximab), 다클리주맙 (Daclizumab), 바르릴루맙 (Varlilumab), 룰리주맙 (Lulizumab), 이라투무맙 (Iratumumab), 린투주맙 (Lintuzumab), 다라투무맙 (Daratumumab), 펠자르타맙 (Felzartamab), 이사툭시맙 (Isatuximab), 메자키타맙(Mezagitamab), 블레셀루맙 (Bleselumab), 다쎄투주맙 (Dacetuzumab), 이스칼리맙 (Iscalimab), 루카투무맙 (Lucatumumab), 미타잘리맙 (Mitazalimab), 소티갈리맙 (Sotigalimab), 다피롤리주맙 (Dapirolizumab), 아파미스타맙 (Apamistamab), 리구팔리맙 (Ligufalimab), 마그롤리맙 (Magrolimab), 알렘투주맙 (Alemtuzumab), 크리잔리주맙 (Crizanlizumab), 인클라쿠맙 (Inclacumab), 쿠사투주맙 (Cusatuzumab), 올레클루맙 (Oleclumab), 밀라투주맙 (Milatuzumab), 갈릭시맙 (Galiximab), 카로툭시맙 (Carotuximab), 아데카투무맙 (Adecatumumab), 엡티네주맙 (Eptinezumab), 에레누맙 (Erenumab), 프레마네주맙 (Fremanezumab), 갈카네주맙 (Galcanezumab), 졸베툭시맙 (Zolbetuximab), 오나르투주맙 (Onartuzumab), 에쿨리주맙 (Eculizumab), 포젤리맙 (Pozelimab), 라불리주맙 (Ravulizumab), 라크노투주맙 (Lacnotuzumab), 악사틸리맙(Axatilimab), 카비랄리주맙 (Cabiralizumab), 에막투주맙 (Emactuzumab), 이필리무맙 (Ipilimumab), 쿠아본리맙 (Quavonlimab), 트레멜리무맙 (Tremelimumab), 잘리프레리맙 (Zalifrelimab), 세툭시맙(Cetuximab), 데파툭시주맙 (Depatuxizumab), 푸툭시맙 (Futuximab), 임가투주맙 (Imgatuzumab), 마투주맙(Matuzumab), 모도특시맙 (Modotuximab), 네씨투무맙 (Necitumumab), 니모투주맙 (Nimotuzumab), 파니투무맙(Panitumumab), 토무조툭시맙 (Tomuzotuximab), 잘루투무맙 (Zalutumumab), 바토클리맙(Batoclimab), 니포칼리맙 (Nipocalimab), 로자놀릭시주맙 (Rozanolixizumab), 부로수맙 (Burosumab), 팔레투주맙 (Farletuzumab), 디누툭시맙 (Dinutuximab), 낙시타맙(Naxitamab), 라기필리맙 (Ragifilimab), 김실루맙 (Gimsilumab), 렌질루맙 (Lenzilumab), 마브릴리무맙 (Mavrilimumab), 나밀루맙 (Namilumab), 오틸리맙 (Otilimab), 플론마를리맙 (Plonmarlimab), 코드리투주맙 (Codrituzumab), 마르게툭시맙 (Margetuximab), 페르투주맙 (Pertuzumab), 트라스투주맙 (Trastuzumab), 다토포타맙(Datopotamab), 파트리투맙 (Patritumab), 세리반투맙 (Seribantumab), 둘리고투주맙 (Duligotuzumab), 피클라투주맙 (Ficlatuzumab), 릴로투무맙 (Rilotumumab), 알롬필리맙 (Alomfilimab), 아니프롤루맙 (Anifrolumab), 에마팔루맙 (Emapalumab), 리겔리주맙 (Ligelizumab), 오말리주맙 (Omalizumab), 씩수투무맙(Cixutumumab), 달로투주맙 (Dalotuzumab), 피키투무맙 (Figitumumab), 가니투맙 (Ganitumab), 테프로투무맙(Teprotumumab), 베르메키맙 (Bermekimab), 카나기누맙 (Canakinumab), 게보키주맙 (Gevokizumab), 브리아키누맙 (Briakinumab), 우스테키누맙 (Ustekinumab), 안루킨주맙 (Anrukinzumab), 쎈다키맙 (Cendakimab), 레브리키주맙 (Lebrikizumab), 트랄로키누맙 (Tralokinumab), 브로달루맙 (Brodalumab), 비메키주맙 (Bimekizumab), 익세키주맙 (Ixekizumab), 세쿠기누맙 (Secukinumab), 브라지쿠맙 (Brazikumab), 구셀쿠맙 (Guselkumab), 미리키주맙 (Mirikizumab), 리산키주맙 (Risankizumab), 틸드라키주맙 (Tildrakizumab), 네몰리주맙(Nemolizumab), 임시돌리맙 (Imsidolimab), 스페솔리맙 (Spesolimab), 파스콜리주맙 (Pascolizumab), 두필루맙 (Dupilumab), 데페모키맙 (Depemokimab), 메폴리주맙 (Mepolizumab), 레슬리주맙 (Reslizumab), 벤랄리주맙 (Benralizumab), 클라자키주맙 (Clazakizumab), 올로키주맙 (Olokizumab), 실툭시맙 (Siltuximab), 시루쿠맙 (Sirukumab), 질티베키맙 (Ziltivekimab), 레빌리맙 (Levilimab), 사릴루맙 (Sarilumab), 사트랄리주맙(Satralizumab), 토씰리주맙 (Tocilizumab), 아비투주맙 (Abituzumab), 파베젤리맙 (Favezelimab), 피안리맙 (Fianlimab), 이에라밀리맙 (Ieramilimab), 렐라틀리맙 (Relatlimab), 심투주맙 (Simtuzumab), 아바고보맙 (Abagovomab), 오레고보맙 (Oregovomab), 타네주맙 (Tanezumab), 이븍솔리맙 (Ivuxolimab), 로카틴리맙 (Rocatinlimab), 타볼리맙(Tavolimab), 델라조를리맙 (Telazorlimab), 본레롤리주맙 (Vonlerolizumab), 알리로쿠맙 (Alirocumab), 보코씨주맙 (Bococizumab), 에브로누씨맙 (Ebronucimab), 에볼로쿠맙 (Evolocumab), 프로보씨맙 (Frovocimab), 온게리씨맙 (Ongericimab), 타폴레씨맙 (Tafolecimab), 도스타를리맙 (Dostarlimab), 발스틸리맙 (Balstilimab), 캄렐리주맙 (Camrelizumab), 쎄미플리맙 (Cemiplimab), 겝타놀리맙 (Geptanolimab), 니볼루맙 (Nivolumab), 펨브롤리주맙 (Pembrolizumab), 펜풀리맙 (Penpulimab), 피딜리주맙 (Pidilizumab), 프롤골리맙(Prolgolimab), 레티판리맙 (Retifanlimab), 사산리맙 (Sasanlimab), 세르플루리맙 (Serplulimab), 신틸리맙(Sintilimab), 스파르탈리주맙 (Spartalizumab), 티슬렐리주맙 (Tislelizumab), 토리팔리맙 (Toripalimab), 에자벤리맙 (Ezabenlimab), 짐베렐리맙 (Zimberelimab), 아테졸리주맙 (Atezolizumab), 아벨루맙 (Avelumab), 코시벨리맙 (Cosibelimab), 수게말리맙 (Sugemalimab), 두르발루맙 (Durvalumab), 엔바폴리맙(Envafolimab), 수브라톡수맙 (Suvratoxumab), 데노수맙 (Denosumab), 질로베르타맙 (Zilovertamab), 엘로투주맙 (Elotuzumab), 돔바날리맙 (Domvanalimab), 에티길리맙(Etigilimab), 오씨페를리맙 (Ociperlimab), 티라골루맙 (Tiragolumab), 비보스톨리맙 (Vibostolimab), 수르제비씰리맙 (Surzebiclimab), 코볼리맙 (Cobolimab), 사바톨리맙 (Sabatolimab), 콘씨주맙(Concizumab), 마르스타씨맙 (Marstacimab), 아달리무맙 (Adalimumab), 골리무맙 (Golimumab), 인플릭시맙(Infliximab), 쎄르톨리주맙(Certolizumab), 코나투무맙 (Conatumumab), 티가투주맙(Tigatuzumab), 테제펠루맙 (Tezepelumab), 가티포투주맙 (Gatipotuzumab), 카비랄리주맙 (Cabiralizumab), 베바씨주맙 (Bevacizumab), 브롤루씨주맙 (Brolucizumab), 라니비주맙 (Ranibizumab), 올린바씨맙(Olinvacimab), 이크루쿠맙 (Icrucumab), 라무씨루맙 (Ramucirumab), 카프라씨주맙 (Caplacizumab), 아부릴루맙 (Abrilumab), 에트롤리주맙 (Etrolizumab), 베돌리주맙 (Vedolizumab), 인테투무맙 (Intetumumab), 나탈리주맙 (Natalizumab), 오브린다타맙 (Obrindatamab), 엘라나타맙 (Elranatamab), 린보셀타맙(Linvoseltamab), 테클리스타맙 (Teclistamab), 엡코리타맙 (Epcoritamab), 글로피타맙 (Glofitamab), 모수네투주맙 (Mosunetuzumab), 오드로넥스타맙 (Odronextamab), 플로테투주맙 (Flotetuzumab), 비베코타맙(Vibecotamab), 카투막소맙 (Catumaxomab), 씨비사타맙 (Cibisatamab), 탈쿠에타맙 (Talquetamab), 우바마타맙 (Ubamatamab), 엠피자타맙 (Emfizatamab), 블리나투모맙 (Blinatumomab), 아미반타맙 (Amivantamab), 에미씨주맙 (Emicizumab), 제노쿠투주맙 (Zenocutuzumab), 자니다타맙 (Zanidatamab), 티불리주맙 (Tibulizumab), 나프투모맙 (Naptumomab), 벨란타맙 (Belantamab), 피베키맙(Pivekimab), 프랄루자타맙 (Praluzatamab), 콜툭시맙 (Coltuximab), 데닌투주맙 (Denintuzumab), 론카스툭시맙 (Loncastuximab), 이브리투모맙(Ibritumomab), 이노투주맙 (Inotuzumab), 에프라투주맙 (Epratuzumab), 목세투모맙 (Moxetumomab), 브렌툭시맙 (Brentuximab), 겜투주맙 (Gemtuzumab), 바다스툭시맙 (Vadastuximab), 로보투주맙 (Lorvotuzumab), 폴라투주맙 (Polatuzumab), 투사마타맙 (Tusamitamab), 텔리소투주맙 (Telisotuzumab), 로발피투주맙 (Rovalpituzumab), 데파툭시주맙 (Depatuxizumab), 파를레투주맙 (Farletuzumab), 미르베툭시맙 (Mirvetuximab), 디시타맙 (Disitamab), 아네투맙 (Anetumab), 엔포르투맙 (Enfortumab), 사씨투주맙 고비테칸 (Sacituzumab), 보바릴리주맙(Vobarilizumab), 카도닐리맙 (Cadonilimab), 부달리맙 (Vudalimab), 테보텔리맙 (Tebotelimab), 이보네스씨맙 (Ivonescimab),에르폰릴리맙 (Erfonrilimab), 오조랄리주맙 (Ozoralizumab), 파리시맙 (Faricimab), 바누씨주맙(Vanucizumab) 및 나비씩시주맙 (Navicixizumab)으로 구성된 군에서 선택된 1종 이상인 것을 특징으로 하는 운반체-약물 접합체.The method of claim 7, wherein the antibody is Urelumab, Utomilumab, Bebtelovimab, Aducanumab, Bapinezumab, Crenezumab, Donanemab, Gantenerumab, Lecanemab, Solanezumab, Nesvacumab, Evinacumab, Enoblituzumab, Omburtamab (Omburtamab), Belimumab, Ianalumab, Tabalumab, Bertilimumab, Mogamulizumab, Leronlimab, Siplizumab ), Foralumab, Muromonab-CD3, Otelixizumab, Teplizumab, Ibalizumab, Tregalizumab, Zano Zanolimumab, Itolizumab, Efalizumab, Inebilizumab, Tafasitamab, Tositumomab, Ocrelizumab, Opatu Ofatumumab, Rituximab, Ublituximab, Veltuzumab, Epratuzumab, Basiliximab, Daclizumab, Var Varlilumab, Lulizumab, Iratumumab, Lintuzumab, Daratumumab, Felzartamab, Isatuximab, Mezakitamab (Mezagitamab), Bleselumab, Dacetuzumab, Iscalimab, Lucatumumab, Mitazalimab, Sotigalimab, Dapirolizumab ( Dapirolizumab, Apamistamab, Ligufalimab, Magrolimab, Alemtuzumab, Crizanlizumab, Inclacumab, Cusatuzumab ), Oleclumab, Milatuzumab, Galiximab, Carotuximab, Adecatumumab, Eptinezumab, Erenumab , Fremanezumab, Galcanezumab, Zolbetuximab, Onartuzumab, Eculizumab, Pozelimab, Ravulizumab ), Lacnotuzumab, Axatilimab, Cabiralizumab, Emactuzumab, Ipilimumab, Quavonlimab, Tremelimumab , Zalifrelimab, Cetuximab, Depatuxizumab, Futuximab, Imgatuzumab, Matuzumab, Modotuximab , Necitumumab, Nimotuzumab, Panitumumab, Tomuzotuximab, Zalutumumab, Batoclimab, Nipocalimab ), Rozanolixizumab, Burosumab, Farletuzumab, Dinutuximab, Naxitamab, Ragipilimab, Gimsilumab, Lenzilumab, Mavrilimumab, Namilumab, Otilimab, Plonmarlimab, Codrituzumab, Margetuximab, Pertu Pertuzumab, Trastuzumab, Datopotamab, Patritumab, Seribantumab, Duligotuzumab, Ficlatuzumab, Rilotumumab (Rilotumumab), Alomfilimab, Anifrolumab, Emapalumab, Ligelizumab, Omalizumab, Cixutumumab, Dalotuzumab ), Figitumumab, Ganitumab, Teprotumumab, Bermekimab, Canakinumab, Gevokizumab, Briakinumab , Ustekinumab, Anrukinzumab, Cendakimab, Lebrikizumab, Tralokinumab, Brodalumab, Bimekizumab , Ixekizumab, Secukinumab, Brazikumab, Guselkumab, Mirikizumab, Risankizumab, Tildrakizumab, yes Nemolizumab, Imsidolimab, Spesolimab, Pascolizumab, Dupilumab, Depemokimab, Mepolizumab, Reslizumab ( Reslizumab, Benralizumab, Clazakizumab, Olokizumab, Siltuximab, Sirukumab, Ziltivekimab, Levilimab , Sarilumab, Satralizumab, Tocilizumab, Abituzumab, Favezelimab, Fianlimab, Ieramilimab, Relatlimab, Simtuzumab, Abagovomab, Oregovomab, Tanezumab, Ivuxolimab, Rocatinlimab, Tavolimab ( Tavolimab, Telazorlimab, Vonlerolizumab, Alirocumab, Bococizumab, Ebronucimab, Evolocumab, Provoc Frovocimab, Ongericimab, Tafolecimab, Dostarlimab, Balstilimab, Camrelizumab, Cemiplimab, Geptanolimab, Nivolumab, Pembrolizumab, Penpulimab, Pidilizumab, Prolgolimab, Retifanlimab, Sasanlimab (Sasanlimab), Serplulimab, Sintilimab, Spartalizumab, Tislelizumab, Toripalimab, Ezabenlimab, Zimberelli Zimberelimab, Atezolizumab, Avelumab, Cosibelimab, Sugemalimab, Durvalumab, Envafolimab, Subratoxumab (Suvratoxumab), Denosumab, Zilovertamab, Elotuzumab, Domvanalimab, Etigilimab, Ociperlimab, Tiragolumab (Tiragolumab), Vibostolimab, Surzebiclimab, Cobolimab, Sabatolimab, Concizumab, Marstacimab, Adalimumab (Adalimumab), Golimumab, Infliximab, Certolizumab, Conatumumab, Tigatuzumab, Tezepelumab, Gatipotuzumab (Gatipotuzumab), Cabiralizumab, Bevacizumab, Brolucizumab, Ranibizumab, Olinvacimab, Icrucumab, Ramucirumab (Ramucirumab), Caplacizumab, Abrilumab, Etrolizumab, Vedolizumab, Intetumumab, Natalizumab, Obrindatamab ), Elranatamab, Linvoseltamab, Teclistamab, Epcoritamab, Glofitamab, Mosunetuzumab, Odronextamab (Odronextamab), Flotetuzumab, Vibecotamab, Catumaxomab, Cibisatamab, Talquetamab, Ubamatamab, Empizatamab ( Emfizatamab, Blinatumomab, Amivantamab, Emicizumab, Zenocutuzumab, Zanidatamab, Tibulizumab, Naftumomab ( Naptumomab, Belantamab, Pivekimab, Praluzatamab, Coltuximab, Denintuzumab, Loncastuximab, Ibri Ibritumomab, Inotuzumab, Epratuzumab, Moxetumomab, Brentuximab, Gemtuzumab, Vadastuximab, Robo Lorvotuzumab, Polatuzumab, Tusamitamab, Telisotuzumab, Rovalpituzumab, Depatuxizumab, Farletuzumab, Mirvetuximab, Disitamab, Anetumab, Enfortumab, Sacituzumab, Vobarilizumab, Cadonilimab, Vudalimab, Tebotelimab, Ivonescimab, Erfonrilimab, Ozoralizumab, Faricimab, Vanucizumab and Navicixizumab.
  9. 제1항에 따른 캄토테신 유도체, 또는 제2항 내지 제8항 중 어느 한 항에 따른 운반체-약물 접합체를 함유하는 암 예방 또는 치료용 약제학적 조성물.A pharmaceutical composition for preventing or treating cancer containing the camptothecin derivative according to claim 1 or the carrier-drug conjugate according to any one of claims 2 to 8.
  10. 제9항에 있어서, 상기 암은 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 결장암, 고환암, 골수이형성증후군, 교모세포종, 구강암, 구순암, 균상식육종, 급성골수성백혈병, 급성림프구성백혈병, 기저세포암, 난소상피암, 난소생식세포암, 남성유방암, 뇌암, 뇌하수체선종, 다발성골수종, 담낭암, 담도암, 대장암, 만성골수성백혈병, 만성림프구백혈병, 망막모세포종, 맥락막흑색종, 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비부비동암, 비소세포폐암, 설암, 성상세포종, 소세포폐암, 소아뇌암, 소아림프종, 소아백혈병, 소장암, 수막종, 식도암, 신경교종, 신우암, 신장암, 심장암, 십이지장암, 악성 연부조직 암, 악성골암, 악성림프종, 악성중피종, 악성흑색종, 안암, 외음부암, 요관암, 요도암, 원발부위불명암, 위림프종, 위암, 위유암종, 위장관간질암, 윌름스암, 유방암, 3중 음성 유방암(TNBC), 육종, 음경암, 인두암, 임신융모질환, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성골암, 전이성뇌암, 종격동암, 직장암, 직장유암종, 질암, 척수암, 청신경초종, 췌장암, 침샘암, 카포시 육종, 파제트병, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 피부암, 항문암, 횡문근육종, 후두암, 흉막암, 혈액암, 및 흉선암으로 구성된 군에서 선택된 1종 이상인 것을 특징으로 하는 약제학적 조성물. The method of claim 9, wherein the cancer is pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, oral cavity cancer, mycosis fungoides, acute myeloid leukemia, and acute lymphoblastic Leukemia, basal cell cancer, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colon cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla of Vater. Cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, sinonasal cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, pediatric brain cancer, pediatric lymphoma, pediatric leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvis cancer, Kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, stomach cancer, gastric carcinoid , gastrointestinal stromal cancer, Wilms cancer, breast cancer, triple negative breast cancer (TNBC), sarcoma, penile cancer, pharyngeal cancer, gestational trophoblastic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinum. Cancer, rectal cancer, rectal carcinoid, vaginal cancer, spinal cord cancer, acoustic neuroma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer , a pharmaceutical composition characterized in that it is one or more selected from the group consisting of rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymic cancer.
PCT/KR2023/013502 2022-09-08 2023-09-08 Novel camptothecin derivatives and carrier-drug conjugate comprising same WO2024054089A1 (en)

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US5342947A (en) * 1992-10-09 1994-08-30 Glaxo Inc. Preparation of water soluble camptothecin derivatives
KR20210006362A (en) * 2018-04-06 2021-01-18 시애틀 지네틱스, 인크. Camptothecin peptide conjugates
WO2021067861A1 (en) * 2019-10-04 2021-04-08 Seagen Inc. Camptothecin peptide conjugates
KR20220027828A (en) * 2019-04-26 2022-03-08 이뮤노젠 아이엔씨 camptothecin derivatives
WO2022170971A1 (en) * 2021-02-09 2022-08-18 苏州宜联生物医药有限公司 Bioactive substance conjugate, preparation method therefor and use thereof

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US5342947A (en) * 1992-10-09 1994-08-30 Glaxo Inc. Preparation of water soluble camptothecin derivatives
KR20210006362A (en) * 2018-04-06 2021-01-18 시애틀 지네틱스, 인크. Camptothecin peptide conjugates
KR20220027828A (en) * 2019-04-26 2022-03-08 이뮤노젠 아이엔씨 camptothecin derivatives
WO2021067861A1 (en) * 2019-10-04 2021-04-08 Seagen Inc. Camptothecin peptide conjugates
WO2022170971A1 (en) * 2021-02-09 2022-08-18 苏州宜联生物医药有限公司 Bioactive substance conjugate, preparation method therefor and use thereof

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