WO2020031936A1 - 抗体－薬物コンジュゲートとチューブリン阻害剤の組み合わせ - Google Patents

抗体－薬物コンジュゲートとチューブリン阻害剤の組み合わせ Download PDF

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Publication number
WO2020031936A1
WO2020031936A1 PCT/JP2019/030635 JP2019030635W WO2020031936A1 WO 2020031936 A1 WO2020031936 A1 WO 2020031936A1 JP 2019030635 W JP2019030635 W JP 2019030635W WO 2020031936 A1 WO2020031936 A1 WO 2020031936A1
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Prior art keywords
antibody
pharmaceutical composition
drug conjugate
composition according
seq
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/JP2019/030635
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English (en)
French (fr)
Japanese (ja)
Inventor
祐輔 扇谷
千晶 石井
泰樹 鎌井
潔 杉原
翔太郎 長瀬
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Daiichi Sankyo Co Ltd
Original Assignee
Daiichi Sankyo Co Ltd
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Publication date
Priority to US17/266,465 priority Critical patent/US12497465B2/en
Priority to AU2019320336A priority patent/AU2019320336B2/en
Priority to EP19847036.1A priority patent/EP3834843A4/en
Priority to JP2020535747A priority patent/JP7458981B2/ja
Priority to KR1020217006189A priority patent/KR20210042120A/ko
Priority to CN201980052170.5A priority patent/CN112512587A/zh
Priority to EA202190471A priority patent/EA202190471A1/ru
Priority to CA3108754A priority patent/CA3108754A1/en
Application filed by Daiichi Sankyo Co Ltd filed Critical Daiichi Sankyo Co Ltd
Priority to BR112021001750-0A priority patent/BR112021001750A2/pt
Publication of WO2020031936A1 publication Critical patent/WO2020031936A1/ja
Anticipated expiration legal-status Critical
Priority to JP2024043043A priority patent/JP2024075668A/ja
Priority to JP2024158824A priority patent/JP2024178243A/ja
Priority to AU2025226765A priority patent/AU2025226765A1/en
Ceased legal-status Critical Current

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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention provides a pharmaceutical composition characterized in that a specific antibody-drug conjugate and a tubulin inhibitor are administered in combination, and / or a combination of a specific antibody-drug conjugate and a tubulin inhibitor. And administered to an individual.
  • Non-Patent Documents 1 and 2 Tubulin inhibitors, by affecting microtubule dynamics, G 2 phase of the cell cycle of cell division was stopped at (mitotic preparation stage) and / or M phase (mitosis), induces cell death by apoptosis Thus, it is an agent that suppresses the growth of cancer cells (Non-Patent Documents 1 and 2).
  • Tubulin inhibitors include drugs that affect microtubule dynamics by promoting tubulin polymerization (tubulin polymerization accelerators) and drugs that affect microtubule dynamics by inhibiting tubulin polymerization (Tubulin polymerization inhibitors).
  • Paclitaxel, Docetaxel, Cabazitaxel, etc. are known as tubulin polymerization accelerators.
  • the tubulin polymerization inhibitor eribulin (Vincristine), vinblastine (Vinblastine), vinorelbine (Vinolebine), vindesine (Vindesine), monomethylauristatin E (Monomethyl Auristatin E and a component of MA)
  • Brentuximab vedotin which is an antibody-drug conjugate
  • trastuzumab emtansine which is an antibody-drug conjugate comprising DM1
  • An antibody-drug conjugate in which a cytotoxic drug is bound to an antibody that expresses on the surface of a cancer cell and binds to an antigen that can be internalized in the cell is selected for cancer cells.
  • ADC Antibody-Drug Conjugate
  • antibody-drug conjugates comprising a derivative of an antibody and a derivative of exotecan, which is a topoisomerase I inhibitor, are known (Patent Documents 1 to 7, Non-Patent Documents 8 to 11). .
  • Patent Documents 1 to 7 describe that the above antibody-drug conjugate can be administered together with various cancer therapeutic agents.
  • the antibody-drug conjugate (antibody-drug conjugate having a derivative of exatecan as a component) used in the present invention exhibits an excellent antitumor effect even when used alone.
  • the present invention provides a pharmaceutical composition characterized in that a specific antibody-drug conjugate and a tubulin inhibitor are administered in combination, and / or a combination of a specific antibody-drug conjugate and a tubulin inhibitor. It is an object of the present invention to provide a therapeutic method characterized by being administered to an individual.
  • the present inventors have conducted intensive studies in order to solve the above-mentioned problems, and found that the combination of a specific antibody-drug conjugate and a tubulin inhibitor shows an excellent combination effect. Heading, the present invention has been completed.
  • the present invention provides the following [1] to [344].
  • the antibody-drug conjugate has the formula
  • a pharmaceutical composition which is an antibody-drug conjugate in which a drug linker represented by (1) and an antibody are bound by a thioether bond.
  • the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.
  • the antibody in the antibody-drug conjugate is an anti-HER2 antibody.
  • the anti-HER2 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 1 to 449 in SEQ ID NO: 1 and a light chain having the amino acid sequence of amino acids 1 to 214 in SEQ ID NO: 2.
  • the anti-HER3 antibody is an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 3 and a light chain having the amino acid sequence of SEQ ID NO: 4.
  • the anti-TROP2 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 470 in SEQ ID NO: 5 and a light chain having the amino acid sequence of amino acids 21 to 234 in SEQ ID NO: 6.
  • the pharmaceutical composition according to [2], wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.
  • the anti-B7-H3 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 471 in SEQ ID NO: 7 and a light chain having the amino acid sequence of amino acids 21 to 233 in SEQ ID NO: 8.
  • the pharmaceutical composition according to [15]. [17] The pharmaceutical composition according to [16], wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted.
  • the anti-GPR20 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 472 in SEQ ID NO: 9 and a light chain having the amino acid sequence of amino acids 21 to 234 in SEQ ID NO: 10.
  • the anti-CDH6 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 471 in SEQ ID NO: 11 and a light chain having the amino acid sequence of amino acids 21 to 233 in SEQ ID NO: 12.
  • tubulin inhibitor according to any one of [1] to [26], wherein the tubulin inhibitor is eribulin or a pharmacologically acceptable salt thereof, or an antibody-drug conjugate in which eribulin and an antibody are bound via a linker.
  • Pharmaceutical composition [30] The pharmaceutical composition according to [29], wherein the tubulin inhibitor is eribulin mesylate.
  • the pharmaceutical composition according to item. [32] Breast, stomach, colon, lung, esophagus, salivary gland, gastroesophageal junction adenocarcinoma, biliary tract, Paget disease, pancreatic, ovarian, bladder, prostate, And the pharmaceutical composition according to any one of [1] to [31] for at least one treatment selected from the group consisting of uterine carcinosarcoma. [33] The pharmaceutical composition according to [32], for treating breast cancer. [34] The pharmaceutical composition according to [32], for treating gastric cancer.
  • the pharmaceutical composition according to [39], wherein the drug resistance factor is ABCG2.
  • a pharmaceutical composition, wherein the antibody-drug conjugate and the tubulin inhibitor are administered in combination, The antibody-drug conjugate has the formula
  • the anti-HER2 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 1 to 449 in SEQ ID NO: 1 and a light chain having the amino acid sequence of amino acids 1 to 214 in SEQ ID NO: 2.
  • the pharmaceutical composition according to [42], wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.
  • the pharmaceutical composition according to [47], wherein the anti-HER3 antibody is an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 3 and a light chain having the amino acid sequence of SEQ ID NO: 4.
  • the anti-TROP2 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 470 in SEQ ID NO: 5 and a light chain having the amino acid sequence of amino acids 21 to 234 in SEQ ID NO: 6.
  • the pharmaceutical composition according to [42], wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.
  • the anti-B7-H3 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 471 in SEQ ID NO: 7 and a light chain having the amino acid sequence of amino acids 21 to 233 in SEQ ID NO: 8.
  • the pharmaceutical composition according to [55] is deleted.
  • the anti-GPR20 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 472 in SEQ ID NO: 9 and a light chain having the amino acid sequence of amino acids 21 to 234 in SEQ ID NO: 10.
  • the anti-CDH6 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 471 in SEQ ID NO: 11 and a light chain having the amino acid sequence of amino acids 21 to 233 in SEQ ID NO: 12.
  • tubulin inhibitor according to any one of [41] to [66], wherein the tubulin inhibitor is eribulin or a pharmacologically acceptable salt thereof, or an antibody-drug conjugate in which eribulin and an antibody are bound via a linker.
  • Pharmaceutical composition [70] The pharmaceutical composition according to [69], wherein the tubulin inhibitor is eribulin mesylate.
  • the pharmaceutical composition according to [72] for treating breast cancer.
  • the pharmaceutical composition according to [79], wherein the drug resistance factor is ABCG2.
  • the antibody-drug conjugate has the formula
  • a therapeutic method wherein the antibody is a drug conjugate in which the drug linker represented by (1) and the antibody are bound by a thioether bond.
  • the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.
  • the anti-HER2 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 1 to 449 in SEQ ID NO: 1 and a light chain having the amino acid sequence of amino acids 1 to 214 in SEQ ID NO: 2.
  • the therapeutic method according to [82], wherein the antibody in the antibody-drug conjugate is an anti-HER3 antibody.
  • the therapeutic method according to [87], wherein the anti-HER3 antibody is an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 3 and a light chain having the amino acid sequence of SEQ ID NO: 4.
  • the therapeutic method according to [82], wherein the antibody in the antibody-drug conjugate is an anti-TROP2 antibody.
  • the anti-TROP2 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 470 in SEQ ID NO: 5 and a light chain having the amino acid sequence of amino acids 21 to 234 in SEQ ID NO: 6.
  • the therapeutic method according to [82], wherein the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody.
  • the anti-B7-H3 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 471 in SEQ ID NO: 7 and a light chain having the amino acid sequence of amino acids 21 to 233 in SEQ ID NO: 8. A method according to [95].
  • the anti-GPR20 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 472 in SEQ ID NO: 9 and a light chain having the amino acid sequence of amino acids 21 to 234 in SEQ ID NO: 10.
  • the anti-CDH6 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 471 in SEQ ID NO: 11 and a light chain having the amino acid sequence of amino acids 21 to 233 in SEQ ID NO: 12.
  • tubulin inhibitor according to any one of [81] to [106], wherein the tubulin inhibitor is eribulin or a pharmacologically acceptable salt thereof, or an antibody-drug conjugate in which eribulin and an antibody are bound via a linker.
  • Treatment method [110] The treatment method according to [109], wherein the tubulin inhibitor is eribulin mesylate.
  • the treatment method according to [112] for treating breast cancer.
  • a therapeutic method which is an antibody-drug conjugate represented by the formula: [122] The therapeutic method according to [121], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody. [123] The therapeutic method according to [122], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.
  • the anti-HER2 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 1 to 449 in SEQ ID NO: 1 and a light chain having the amino acid sequence of amino acids 1 to 214 in SEQ ID NO: 2.
  • the therapeutic method according to [123] wherein the anti-HER2 antibody is an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 1 and a light chain having the amino acid sequence of SEQ ID NO: 2.
  • [128] [127] The therapeutic method of [127], wherein the anti-HER3 antibody is an antibody comprising a heavy chain having the amino acid sequence of SEQ ID NO: 3 and a light chain having the amino acid sequence of SEQ ID NO: 4.
  • the anti-TROP2 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 470 in SEQ ID NO: 5 and a light chain having the amino acid sequence of amino acids 21 to 234 in SEQ ID NO: 6.
  • the anti-B7-H3 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 471 in SEQ ID NO: 7 and a light chain having the amino acid sequence of amino acids 21 to 233 in SEQ ID NO: 8. A method according to [135].
  • [137] [136] The therapeutic method according to [136], wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted. [138] The therapeutic method according to any one of [135] to [137], wherein the average number of drug linkers per antibody in the antibody-drug conjugate ranges from 3.5 to 4.5. [139] The therapeutic method according to [122], wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody. [140] The anti-GPR20 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 472 in SEQ ID NO: 9 and a light chain having the amino acid sequence of amino acids 21 to 234 in SEQ ID NO: 10. [139] The treatment method according to [139].
  • the anti-CDH6 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 471 in SEQ ID NO: 11 and a light chain having the amino acid sequence of amino acids 21 to 233 in SEQ ID NO: 12.
  • tubulin inhibitor is eribulin or a pharmacologically acceptable salt thereof, or an antibody-drug conjugate in which eribulin and an antibody are bound via a linker.
  • treatment method [150] The treatment method according to [149], wherein the tubulin inhibitor is eribulin mesylate.
  • the treatment method according to [152] for treating breast cancer.
  • A indicates a binding position with the antibody
  • the antibody-drug conjugate of [162] wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.
  • the anti-HER2 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 1 to 449 in SEQ ID NO: 1 and a light chain having the amino acid sequence of amino acids 1 to 214 in SEQ ID NO: 2.
  • the antibody-drug conjugate according to [168] wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-HER3 antibody is deleted.
  • the anti-TROP2 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 470 in SEQ ID NO: 5 and a light chain having the amino acid sequence of amino acids 21 to 234 in SEQ ID NO: 6.
  • the antibody-drug conjugate of [172], wherein the anti-TROP2 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.
  • the anti-B7-H3 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 471 in SEQ ID NO: 7 and a light chain having the amino acid sequence of amino acids 21 to 233 in SEQ ID NO: 8.
  • the anti-GPR20 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 472 in SEQ ID NO: 9 and a light chain having the amino acid sequence of amino acids 21 to 234 in SEQ ID NO: 10.
  • the anti-CDH6 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 471 in SEQ ID NO: 11 and a light chain having the amino acid sequence of amino acids 21 to 233 in SEQ ID NO: 12.
  • [185] The antibody-drug conjugate of [184], wherein the anti-CDH6 antibody has a deletion of a lysine residue at the carboxyl terminus of the heavy chain.
  • the tubulin inhibitor is any one of [161] to [186], wherein the tubulin inhibitor is eribulin or a pharmacologically acceptable salt thereof, or an antibody-drug conjugate in which eribulin and an antibody are bound via a linker.
  • Antibody-drug conjugates [190] The antibody-drug conjugate of [189], wherein the tubulin inhibitor is eribulin mesylate.
  • the anti-HER2 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 1 to 449 in SEQ ID NO: 1 and a light chain having the amino acid sequence of amino acids 1 to 214 in SEQ ID NO: 2.
  • the anti-TROP2 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 470 in SEQ ID NO: 5 and a light chain having the amino acid sequence of amino acids 21 to 234 in SEQ ID NO: 6.
  • the anti-B7-H3 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 471 in SEQ ID NO: 7 and a light chain having the amino acid sequence of amino acids 21 to 233 in SEQ ID NO: 8.
  • the anti-GPR20 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 472 in SEQ ID NO: 9 and a light chain having the amino acid sequence of amino acids 21 to 234 in SEQ ID NO: 10.
  • [221] The antibody-drug conjugate of [220], wherein the anti-GPR20 antibody lacks a lysine residue at the carboxyl terminus of the heavy chain.
  • the anti-CDH6 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 471 in SEQ ID NO: 11 and a light chain having the amino acid sequence of amino acids 21 to 233 in SEQ ID NO: 12.
  • [227] The antibody-drug conjugate of any one of [201] to [226], wherein the tubulin inhibitor is paclitaxel, docetaxel, cabazitaxel, or a pharmaceutically acceptable salt thereof, or nab-paclitaxel.
  • [229] The any one of [201] to [226], wherein the tubulin inhibitor is eribulin or a pharmacologically acceptable salt thereof, or an antibody-drug conjugate in which eribulin and an antibody are bound via a linker. Antibody-drug conjugates.
  • [230] 229. The antibody-drug conjugate of [229], wherein the tubulin inhibitor is eribulin mesylate.
  • [234] The antibody-drug conjugate of [232] for the treatment of gastric cancer.
  • [235] The antibody-drug conjugate of [232] for the treatment of lung cancer.
  • [236] The antibody-drug conjugate of [232] for the treatment of ovarian cancer.
  • [237] The antibody-drug conjugate according to any one of [201] to [236], wherein a tubulin inhibitor suppresses a decrease in the expression of a drug susceptibility factor caused by administration of the antibody-drug conjugate. .
  • [238] 237. The antibody-drug conjugate according to [237], wherein the drug sensitivity factor is SLFN11.
  • A indicates a binding position with the antibody
  • an antibody-drug conjugate in which a drug linker represented by (1) and an antibody are bound by a thioether bond [242] The use according to [241], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.
  • the antibody in the antibody-drug conjugate is an anti-HER2 antibody.
  • the anti-HER2 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 1 to 449 in SEQ ID NO: 1 and a light chain having the amino acid sequence of amino acids 1 to 214 in SEQ ID NO: 2. Use according to [243]. [245] The use according to [243], wherein the anti-HER2 antibody is an antibody comprising a heavy chain consisting of the amino acid sequence of SEQ ID NO: 1 and a light chain consisting of the amino acid sequence of SEQ ID NO: 2. [246] The use according to any one of [243] to [245], wherein the average number of drug linkers per antibody in the antibody-drug conjugate ranges from 7 to 8.
  • the anti-TROP2 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 470 in SEQ ID NO: 5 and a light chain having the amino acid sequence of amino acids 21 to 234 in SEQ ID NO: 6. Use according to [251].
  • the antibody in the antibody-drug conjugate is an anti-B7-H3 antibody [256].
  • the anti-B7-H3 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 471 in SEQ ID NO: 7 and a light chain having the amino acid sequence of amino acids 21 to 233 in SEQ ID NO: 8. Use according to [255].
  • [257] The use according to [256], wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-B7-H3 antibody is deleted. [258] The use according to any one of [255] to [257], wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate ranges from 3.5 to 4.5. [259] Use according to [242], wherein the antibody in the antibody-drug conjugate is an anti-GPR20 antibody. [260] The anti-GPR20 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 472 in SEQ ID NO: 9 and a light chain having the amino acid sequence of amino acids 21 to 234 in SEQ ID NO: 10. Use according to [259].
  • [261] The use according to [260], wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-GPR20 antibody is deleted.
  • [262] Use according to any one of [259] to [261], wherein the average number of drug linkers per antibody in the antibody-drug conjugate ranges from 7 to 8.
  • [263] Use according to [242], wherein the antibody in the antibody-drug conjugate is an anti-CDH6 antibody.
  • the anti-CDH6 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 471 in SEQ ID NO: 11 and a light chain having the amino acid sequence of amino acids 21 to 233 in SEQ ID NO: 12. Use according to [263].
  • [265] The use according to [264], wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.
  • [266] Use according to any of [263] to [265], wherein the average number of drug linkers per antibody in the antibody-drug conjugate is in the range of 7 to 8.
  • [267] The use according to any one of [241] to [266], wherein the tubulin inhibitor is paclitaxel, docetaxel, cabazitaxel, or a pharmaceutically acceptable salt thereof, or nab-paclitaxel.
  • [268] The use according to [267], wherein the tubulin inhibitor is paclitaxel.
  • tubulin inhibitor is eribulin or a pharmacologically acceptable salt thereof, or an antibody-drug conjugate in which eribulin and an antibody are bound via a linker.
  • tubulin inhibitor is eribulin mesylate.
  • [273] Use according to [272] for the treatment of breast cancer.
  • [274] Use according to [272] for the treatment of gastric cancer.
  • [275] Use according to [272] for the treatment of lung cancer.
  • [276] Use according to [272] for the treatment of ovarian cancer.
  • [277] The use according to any one of [241] to [276], wherein a tubulin inhibitor suppresses a decrease in the expression of a drug susceptibility factor caused by administration of the antibody-drug conjugate.
  • the drug sensitivity factor is SLFN11.
  • [280] The use according to [279], wherein the drug resistance factor is ABCG2.
  • an antibody-drug conjugate represented by [282] The use according to [281], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody, an anti-HER3 antibody, an anti-TROP2 antibody, an anti-B7-H3 antibody, an anti-GPR20 antibody, or an anti-CDH6 antibody.
  • [283] The use according to [282], wherein the antibody in the antibody-drug conjugate is an anti-HER2 antibody.
  • the anti-HER2 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 1 to 449 in SEQ ID NO: 1 and a light chain having the amino acid sequence of amino acids 1 to 214 in SEQ ID NO: 2.
  • the anti-TROP2 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 470 in SEQ ID NO: 5 and a light chain having the amino acid sequence of amino acids 21 to 234 in SEQ ID NO: 6. Use according to [291].
  • the anti-B7-H3 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 471 in SEQ ID NO: 7 and a light chain having the amino acid sequence of amino acids 21 to 233 in SEQ ID NO: 8. Use according to [295].
  • the anti-GPR20 antibody is an antibody comprising a heavy chain having the amino acid sequence of amino acids 20 to 472 in SEQ ID NO: 9 and a light chain having the amino acid sequence of amino acids 21 to 234 in SEQ ID NO: 10. Use according to [299].
  • [305] The use according to [304], wherein the lysine residue at the carboxyl terminus of the heavy chain of the anti-CDH6 antibody is deleted.
  • [306] The use according to any one of [303] to [305], wherein the average number of drug linkers bound per antibody in the antibody-drug conjugate ranges from 7 to 8.
  • [307] The use according to any one of [281] to [306], wherein the tubulin inhibitor is paclitaxel, docetaxel, cabazitaxel, or a pharmaceutically acceptable salt thereof, or nab-paclitaxel.
  • [308] The use according to [307], wherein the tubulin inhibitor is paclitaxel.
  • tubulin inhibitor is eribulin or a pharmacologically acceptable salt thereof, or an antibody-drug conjugate in which eribulin and an antibody are bound via a linker.
  • tubulin inhibitor is eribulin mesylate.
  • Use according to [312] for treating breast cancer.
  • the drug sensitivity factor is SLFN11.
  • a pharmaceutical composition wherein the antibody-drug conjugate and the tubulin inhibitor are administered in combination, 1) the tubulin inhibitor suppresses a decrease in the expression of a drug susceptibility factor caused by administration of the antibody-drug conjugate, and / or 2) that the tubulin inhibitor suppresses an increase in the expression of a drug resistance factor caused by administration of the antibody-drug conjugate;
  • a pharmaceutical composition characterized in that: [322] The pharmaceutical composition according to [321], wherein the drug sensitivity factor is SLFN11. [323] The pharmaceutical composition according to [321] or [322], wherein the drug resistance factor is ABCG2. [324] The pharmaceutical composition according to any one of [321] to [323], wherein the drug in the antibody-drug conjugate has a topoisomerase I inhibitory action. [325]
  • the antibody-drug conjugate has the formula
  • A indicates a binding position with the antibody
  • the antibody-drug conjugate has the formula
  • a method of treatment wherein the antibody-drug conjugate and the tubulin inhibitor are administered in combination to an individual in need of such treatment, 1) the tubulin inhibitor suppresses a decrease in the expression of a drug susceptibility factor caused by administration of the antibody-drug conjugate, and / or 2) that the tubulin inhibitor suppresses an increase in the expression of a drug resistance factor caused by administration of the antibody-drug conjugate;
  • a method of treatment characterized in that: [328] [327] The treatment method of [327], wherein the drug sensitivity factor is SLFN11.
  • the therapeutic method according to any one of [327] to [329], which is an antibody-drug conjugate represented by the formula: [333]
  • An antibody-drug conjugate for treating a disease which is administered in combination with a tubulin inhibitor, comprising: 1) the tubulin inhibitor suppresses a decrease in the expression of a drug susceptibility factor caused by administration of the antibody-drug conjugate, and / or 2) that the tubulin inhibitor suppresses an increase in the expression of a drug resistance factor caused by administration of the antibody-drug conjugate;
  • An antibody-drug conjugate characterized in that: [334] The antibody-drug conjugate of [333], wherein the drug sensitivity factor is SLFN11.
  • the antibody-drug conjugate according to any one of [333] to [335], which is an antibody-drug conjugate in which the drug linker represented by and the antibody are bound by a thioether bond. [338]
  • the antibody-drug conjugate has the formula
  • the antibody-drug conjugate according to any one of [333] to [335], which is an antibody-drug conjugate represented by the formula: [339]
  • Use of an antibody-drug conjugate for the manufacture of a medicament for treating a disease when administered in combination with a tubulin inhibitor comprising: 1) the tubulin inhibitor suppresses a decrease in the expression of a drug susceptibility factor caused by administration of the antibody-drug conjugate, and / or 2) that the tubulin inhibitor suppresses an increase in the expression of a drug resistance factor caused by administration of the antibody-drug conjugate; Characterized by the use.
  • a pharmaceutical composition and / or a specific antibody-drug conjugate and a tubulin inhibitor are characterized in that a specific antibody-drug conjugate and a tubulin inhibitor are administered in combination. Can be provided to an individual in combination.
  • FIG. 3 shows the amino acid sequence of the heavy chain of the anti-HER2 antibody (SEQ ID NO: 1).
  • FIG. 3 is a view showing an amino acid sequence of an anti-HER2 antibody light chain (SEQ ID NO: 2).
  • FIG. 4 shows the amino acid sequence of the heavy chain of the anti-HER3 antibody (SEQ ID NO: 3).
  • FIG. 4 is a view showing an amino acid sequence of an anti-HER3 antibody light chain (SEQ ID NO: 4).
  • FIG. 9 shows the amino acid sequence of the heavy chain of the anti-TROP2 antibody (SEQ ID NO: 5).
  • FIG. 9 is a view showing an amino acid sequence of an anti-TROP2 antibody light chain (SEQ ID NO: 6).
  • FIG. 7 shows the amino acid sequence of the heavy chain of the anti-B7-H3 antibody (SEQ ID NO: 7).
  • FIG. 9 shows the amino acid sequence of the light chain of the anti-B7-H3 antibody (SEQ ID NO: 8).
  • FIG. Tumor growth inhibition in mice implanted subcutaneously with JIMT-1 cells in the single-agent administration group of antibody-drug conjugate (1) and Eribulin @ mesylate, and in the combination administration group of antibody-drug conjugate (1) and Eribulin @ mesylate It is a figure showing an effect.
  • FIG. 1 Inhibition of tumor growth in mice implanted subcutaneously with NCI-N87 cells in the antibody-drug conjugate (1) and Eribulin @ mesylate alone, and in the combination of antibody-drug conjugate (1) and Eribulin @ mesylate It is a figure showing an effect.
  • FIG. 9 is a view showing an amino acid sequence of an anti-GPR20 antibody heavy chain (SEQ ID NO: 9).
  • FIG. 9 is a view showing an amino acid sequence of an anti-GPR20 antibody light chain (SEQ ID NO: 10).
  • FIG. 11 shows the amino acid sequence of the heavy chain of the anti-CDH6 antibody (SEQ ID NO: 11).
  • FIG. 9 is a view showing an amino acid sequence of an anti-CDH6 antibody light chain (SEQ ID NO: 12).
  • FIG. 1 The tumor growth inhibitory effects of the antibody-drug conjugate (2) and Paclitaxel alone and the combined administration of antibody-drug conjugate (2) and Paclitaxel in mice implanted subcutaneously with JIMT-1 cells were investigated.
  • FIG. 1 The tumor growth inhibitory effect of the antibody-drug conjugate (3) and Paclitaxel alone and the combined administration of the antibody-drug conjugate (3) and Paclitaxel in mice into which OV-90 cells were subcutaneously transplanted was evaluated.
  • Antibody-Drug Conjugate The antibody-drug conjugate used in the present invention has the formula
  • A indicates a binding position with the antibody
  • a partial structure comprising a linker and a drug in the antibody-drug conjugate is referred to as a “drug linker”.
  • This drug linker is a thiol group (in other words, a sulfur atom of a cysteine residue) generated at a disulfide bond site between antibody chains (at two heavy chains and heavy chains and at two heavy chains and light chains). Is bound to.
  • the drug linker of the present invention is a topoisomerase I inhibitor, exatecan (IUPAC name: (1S, 9S) -1-amino-9-ethyl-5-fluoro-1,2,3,9,12,15-hexahydro-).
  • the antibody-drug conjugate used in the present invention can be represented by the following formula.
  • n has the same meaning as the so-called average number of drug bonds (DAR; Drug-to-Antibody Ratio), and indicates the average number of drug linker bonds per antibody.
  • the antibody-drug conjugate used in the present invention has a linker moiety that is cleaved after being transferred into a cancer cell, formula
  • the above compounds are considered to be the main antitumor activity of the antibody-drug conjugate used in the present invention and have been confirmed to have topoisomerase I inhibitory activity (Ogitani Y. et al., Clinical Cancer Research. , 2016, Oct 15; 22 (20): 5097-5108, Epub 2016 Mar 29).
  • Topoisomerase I is an enzyme involved in the synthesis of DNA by converting the higher order structure of DNA by cutting and rejoining a single strand of DNA. Therefore, a drug having a topoisomerase I inhibitory activity inhibits the synthesis of DNA, thereby halting cell division in the S phase (DNA synthesis phase) of the cell cycle, and inducing cell death by apoptosis. Can be suppressed.
  • tubulin inhibitors by affecting microtubule dynamics, G 2 phase of the cell cycle of cell division was stopped at (mitotic preparation stage) and / or M phase (mitosis), cell death by apoptosis The induction can suppress the growth of cancer cells (Dumontet C, et al., Nat Rev Drug Discov. 2010 Oct; 9 (10): 790-803.) (Mukhtar E, et al., Mol Cancer Ther. 2014 Feb: 13 (2): 275-284.).
  • the antibody-drug conjugate used in the present invention (a drug having an inhibitory effect on topoisomerase I as a main body of antitumor activity) is administered in combination with a tubulin inhibitor to form the S phase of the cell cycle. and for stopping the composite cell division in phase 2 and / or M phase G, it can exhibit excellent combined effect (antitumor effect).
  • the antibody-drug conjugate used in the present invention is also known to have a bystander effect (Ogitani Y. et al., Cancer Science (2016) 107, 1039-1046).
  • This bystander effect is that after the antibody-drug conjugate used in the present invention is internalized in the target-expressing cancer cells, the compound is released, and the cancer-target cells in the vicinity do not express the target. Are also exerted by exerting an antitumor effect.
  • This bystander effect is exhibited as an excellent antitumor effect even when the antibody-drug conjugate according to the present invention is used in combination with a tubulin inhibitor.
  • the antibody in the antibody-drug conjugate used in the present invention may be derived from any species, but is preferably an antibody derived from human, rat, mouse, and rabbit. is there. When the antibody is derived from a species other than human, it is preferable to use a well-known technique to chimerize or humanize the antibody.
  • the antibody of the present invention may be a polyclonal antibody or a monoclonal antibody, but a monoclonal antibody is preferred.
  • the antibody in the antibody-drug conjugate used in the present invention preferably has the property of being able to target cancer cells, and has the property of recognizing cancer cells, the property of binding to cancer cells, Those having the property of being taken up into cells and being internalized, and / or the activity of killing cancer cells are preferred.
  • Antibody uptake into cancer cells can be achieved by (1) an assay that visualizes the antibody taken up into cells with a fluorescent microscope using a secondary antibody (fluorescent label) that binds to the therapeutic antibody (Cell Death Differentiation (2008 ) 15, 751-761), (2) Assay (Molecular Biology of the Cell Vol. 15, 5268- 5282, ⁇ December ⁇ 2004), or (3) a Mab-ZAP assay using an immunotoxin that binds to a therapeutic antibody to release the toxin and suppress cell proliferation when taken up into cells (Bio Technologys 28: 162- 165, ⁇ January 2000 ⁇ ).
  • the immunotoxin a recombinant complex protein of the catalytic region of diphtheria toxin and protein G can be used.
  • the antitumor activity of the antibody can be confirmed in vitro by measuring the activity of suppressing cell proliferation.
  • a cancer cell line overexpressing a target protein of an antibody is cultured, the antibody is added to the culture system at various concentrations, and the inhibitory activity on focus formation, colony formation and spheroid proliferation can be measured.
  • antitumor activity can be confirmed by administering an antibody to a nude mouse transplanted with a cancer cell line that highly expresses a target protein and measuring the change in the cancer cell.
  • the antibody itself has an antitumor effect, but since the antibody-drug conjugate has a compound exhibiting an antitumor effect bound thereto, the antitumor effect of the antibody itself is not essential.
  • the antibody has a property of being internalized and transferred into cancer cells.
  • the antibody in the antibody-drug conjugate used in the present invention can be obtained by known means. For example, it can be obtained by immunizing an animal with a polypeptide serving as an antigen, collecting and purifying an antibody produced in a living body, using a method usually used in this field.
  • the origin of the antigen is not limited to humans, and animals can be immunized with antigens derived from non-human animals such as mice and rats.
  • antibodies that can be applied to human diseases can be selected by testing the cross-reactivity between the obtained antibody that binds to the heterologous antigen and the human antigen.
  • a hybridoma can be established by fusing an antibody-producing cell that produces an antibody against an antigen with a myeloma cell to obtain a monoclonal antibody.
  • the antigen can be obtained by causing a host cell to produce a gene encoding an antigen protein by genetic manipulation. Specifically, a vector capable of expressing an antigen gene may be prepared, introduced into a host cell to express the gene, and the expressed antigen may be purified. Antibodies can also be obtained by using a method of immunizing an animal with an antigen-expressing cell or a cell line expressing an antigen by the above-described genetic manipulation.
  • the antibody in the antibody-drug conjugate used in the present invention may be a recombinant antibody artificially modified for the purpose of, for example, reducing heterologous antigenicity to humans, for example, a chimeric antibody, a humanized ( (Humanized) antibody, or an antibody having only the gene sequence of a human-derived antibody, that is, a human antibody.
  • a chimeric antibody for example, a humanized ( (Humanized) antibody, or an antibody having only the gene sequence of a human-derived antibody, that is, a human antibody.
  • chimeric antibody examples include antibodies in which the variable region and the constant region of the antibody are different from each other, for example, a chimeric antibody in which the variable region of a mouse or rat-derived antibody is conjugated to a human-derived constant region (Proc. Natl. Acad . Sci. USA, 81, 6851-6855, (1984)).
  • humanized antibody an antibody (Nature (1986) @ 321, @ p.522-525) in which only the complementarity determining region (CDR; complementarity determining region) of a heterologous antibody is incorporated into a human-derived antibody, In addition to the CDR sequences of the antibody, the amino acid residues of some of the frameworks of the heterologous antibody were also transplanted into a human antibody (WO 90/07861), a gene conversion mutagenesis strategy. And humanized antibodies (US Pat. No. 5,821,337).
  • CDR complementarity determining region
  • an antibody As a human antibody, an antibody (Tomizuka, K. et al., Nature Genetics (1997) 16, p.1) prepared using a human antibody-producing mouse having a human chromosome fragment containing human antibody heavy and light chain genes. 133-143; Kuroiwa, Y. et. Al., Nucl. Acids Res. (1998) 26, p.3447-3448; Yoshida, H. et. Al., Animal Cell Technology: Basic and Applied Aspects vol.10, p.69-73 (Kitagawa, Y., atsuMatsuda, T. and Iijima, S. eds.), Kluwer Academic Publishers, 1999; Tomizuka, K. et.
  • an antibody obtained by phage display selected from a human antibody library (Wormstone, I. M. et. Al, Investigative Ophthalmology & Visual230Science. (2002) 43 (7), p.2301-2308; Carmen, S. et al., Briefings in Functional Genomics and Proteomics (2002), 1 (2), p. 189-203; Siriwardena, D. et.al, Ophthalmology (2002) 109 (3), p. 427-431, etc. See also).
  • Antibodies in the antibody-drug conjugate used in the present invention also include modified antibodies.
  • modified product means that the antibody of the present invention has been subjected to chemical or biological modification.
  • Chemical modifications include those having a chemical moiety attached to the amino acid backbone, a chemical moiety attached to an N-linked or O-linked carbohydrate chain, and the like.
  • Biologically modified forms include post-translational modifications (eg, addition of N-linked or O-linked sugar chains, N-terminal or C-terminal processing, deamidation, aspartic acid isomerization, methionine oxidation, etc. ) And those obtained by adding a methionine residue to the N-terminus by expression using a prokaryotic host cell.
  • those labeled to enable detection or isolation of the antibody or antigen according to the present invention for example, an enzyme label, a fluorescent label, and an affinity label are also included in the meaning of such a modified form.
  • a modified antibody according to the present invention is useful for improving antibody stability and blood retention, reducing antigenicity, detecting or isolating an antibody or antigen, and the like.
  • the antibody-dependent cytotoxic activity by controlling the modification of the sugar chain bound to the antibody according to the present invention (glycosylation, defucosification, etc.).
  • Techniques for controlling the sugar chain modification of antibodies include WO 99/54342, WO 00/61739, WO 02/31140, WO 2007/133855, and WO 2013/120066. Nos. Are known, but not limited to these.
  • the antibody according to the present invention also includes an antibody in which the sugar chain modification is regulated.
  • the antibody according to the present invention also includes the modified antibody and a functional fragment of the antibody, and has a deletion in which one or two amino acids have been deleted at the carboxyl terminus of the heavy chain, and amidation
  • the deletion for example, a heavy chain in which a proline residue at the carboxyl terminal site is amidated
  • the deletion at the carboxyl terminus of the heavy chain of the antibody according to the present invention is not limited to the above types.
  • the two heavy chains constituting the antibody according to the present invention may be any one of the heavy chains selected from the group consisting of full-length and the above-described deletion, or a combination of any two heavy chains. It may be something.
  • the antibody of the present invention preferably has a carboxyl-terminal at both of the two heavy chains. In which one amino acid residue is deleted.
  • IgG immunoglobulin G
  • IgG1, IgG2, IgG3, IgG4 IgG1 or IgG2
  • IgG1 or IgG2 IgG2
  • the antibody in the antibody-drug conjugate used in the present invention is not particularly limited.
  • anti-HER2 antibody refers to an activity that specifically binds to HER2 (Human ⁇ Epidermal ⁇ Growth ⁇ Factor ⁇ Receptor ⁇ Type ⁇ 2; @ ErbB-2), and preferably internalizes in HER2 expressing cells by binding to HER2. 1 shows an antibody having
  • anti-HER2 antibody examples include trastuzumab (US Pat. No. 5,821,337) and pertuzumab (International Publication No. 01/00245), and preferably trastuzumab.
  • the “anti-HER3 antibody” specifically binds to HER3 (Human Epidermal Growth Factor Receptor Type 3; ErbB-3), and preferably has an activity of being internalized in HER3 expressing cells by binding to HER3. 1 shows an antibody having
  • anti-HER3 antibody examples include patrizumab (Patritumab; @ U3-1287), U1-59 (WO2007 / 0777028), MM-121 (Seribantuab), and anti-ERBB3 antibodies described in WO2008 / 100624, RG. -7116 (Lumretuzumab) and LJM-716 (Elgemtumab), and preferably, patrizumab and U1-59.
  • the “anti-TROP2 antibody” specifically binds to TROP2 (TACSTD2: Tumor-associated calcium signal transducer 2; EGP-1), and preferably internalizes in TROP2-expressing cells by binding to TROP2. 1 shows an antibody having the activity of TROP2 (TACSTD2: Tumor-associated calcium signal transducer 2; EGP-1), and preferably internalizes in TROP2-expressing cells by binding to TROP2. 1 shows an antibody having the activity of
  • anti-TROP2 antibody examples include hTINA1-H1L1 (WO 2015/098099).
  • the “anti-B7-H3 antibody” specifically binds to B7-H3 (B cell antigen # 7 homolog 3; PD-L3; CD276), and preferably binds to B7-H3. 2 shows an antibody having an activity of internalizing B7-H3 expressing cells.
  • anti-B7-H3 antibody examples include M30-H1-L4 (WO 2014/057687).
  • the “anti-GPR20 antibody” refers to an antibody that specifically binds to GPR20 (G protein-coupled receptor) 20 and preferably has an activity of being internalized in GPR20-expressing cells by binding to GPR20. .
  • anti-GPR20 antibody h046-H4e / L7 (WO 2018/135501).
  • anti-CDH6 antibody refers to an antibody that specifically binds to CDH6 (Cadherin-6), and preferably has an activity of binding to CDH6 to be internalized in CDH6-expressing cells.
  • anti-CDH6 antibody H01L02 (WO 2018/212136).
  • a drug linker intermediate used for preparing the antibody-drug conjugate according to the present invention is represented by the following formula.
  • the above drug linker intermediate is N- [6- (2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl) hexanoyl] glycylglycyl-L-phenylalanyl-N-[(2- ⁇ [(1S, 9S) -9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H, 12H-benzo [ de] pyrano [3 ′, 4 ′: 6,7] indolizino [1,2-b] quinolin-1-yl] amino ⁇ -2-oxoethoxy) methyl] glycinamide, WO 2014/057687, WO 2015/098099, WO 2015/115091, WO 2015/155998, and WO 2019/009.
  • the description of the equal sign 4947 can be prepared as a reference.
  • the antibody-drug conjugate used in the present invention can be produced by reacting the above-mentioned drug linker intermediate with an antibody having a thiol group (also referred to as a sulfhydryl group).
  • An antibody having a sulfhydryl group can be obtained by a method well known to those skilled in the art (Hermanson, G. T, Bioconjugate Techniques, pp.56-136, pp.456-493, Academic Press (1996)).
  • a reducing agent such as tris (2-carboxyethyl) phosphine hydrochloride (TCEP) is used in an amount of 0.3 to 3 molar equivalents per one intrachain disulfide in an antibody
  • TCEP tris (2-carboxyethyl) phosphine hydrochloride
  • EDTA ethylenediaminetetraacetic acid
  • an antibody-drug conjugate in which 2 to 8 drugs are bound per antibody by using 2 to 20 molar equivalents of the drug linker intermediate per antibody having a sulfhydryl group. it can.
  • the average number of drug bonds per antibody molecule of the produced antibody-drug conjugate is calculated, for example, by measuring the UV absorbance of the antibody-drug conjugate and its conjugate precursor at two wavelengths of 280 nm and 370 nm. (UV method), or a method in which each fragment obtained by treating an antibody-drug conjugate with a reducing agent is quantified by HPLC measurement and calculated (HPLC method).
  • anti-HER2 antibody-drug conjugate refers to an antibody-drug conjugate in which the antibody in the antibody-drug conjugate according to the present invention is an anti-HER2 antibody.
  • the anti-HER2 antibody preferably comprises a heavy chain consisting of the amino acid sequence of amino acids 1 to 449 in SEQ ID NO: 1 and a light chain consisting of the amino acid sequence of amino acids 1 to 214 in SEQ ID NO: 2.
  • the average number of drug linkers bound per antibody of the anti-HER2 antibody-drug conjugate is preferably from 2 to 8, more preferably from 3 to 8, even more preferably from 7 to 8, Even more preferably from 7.5 to 8, and even more preferably about 8.
  • An anti-HER2 antibody-drug conjugate can be produced with reference to the description of WO 2015/115091 and the like.
  • anti-HER3 antibody-drug conjugate refers to an antibody-drug conjugate in which the antibody in the antibody-drug conjugate according to the present invention is an anti-HER3 antibody.
  • the anti-HER3 antibody is preferably CDRH1 consisting of the amino acid sequence of amino acids 26 to 35 in SEQ ID NO: 3, CDRH2 consisting of the amino acid sequence of amino acids 50 to 65 in SEQ ID NO: 3, and A heavy chain comprising CDRH3 consisting of the amino acid sequence of amino acids 98 to 106; CDRL1 consisting of the amino acid sequence of amino acids 24 to 39 in SEQ ID NO: 4; An antibody comprising CDRL2 consisting of an amino acid sequence, and a light chain comprising CDRL3 consisting of the amino acid sequence of amino acids 95 to 103 in SEQ ID NO: 4, More preferably, a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence of amino acids 1 to 117 in SEQ ID NO: 3, and a light chain consisting of the amino acid sequence of amino acids 1 to 113 in SEQ ID NO: 4 An antibody comprising a light chain comprising a region, Still more preferably, an antibody comprising a heavy chain consisting of the amino acid sequence of SEQ ID
  • the average number of drug linkers bound per antibody of the anti-HER3 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 8, even more preferably 7 to 8, Even more preferably from 7.5 to 8, and even more preferably about 8.
  • An anti-HER3 antibody-drug conjugate can be produced with reference to the description in WO 2015/155998 and the like.
  • anti-TROP2 antibody-drug conjugate refers to an antibody-drug conjugate in which the antibody in the antibody-drug conjugate according to the present invention is an anti-TROP2 antibody.
  • the anti-TROP2 antibody is preferably CDRH1 consisting of the amino acid sequence of amino acids 50 to 54 in SEQ ID NO: 5, CDRH2 consisting of the amino acid sequence of amino acids 69 to 85 in SEQ ID NO: 5, and CDRH2 consisting of the amino acid sequence of amino acids 69 to 85 in SEQ ID NO: 5, and A heavy chain comprising CDRH3 comprising the amino acid sequence of amino acids Nos. 118-129; CDRL1 comprising the amino acid sequence of amino acids Nos. 44-54 in SEQ ID No.
  • the average number of drug linkers bound per antibody of the anti-TROP2 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 5, and even more preferably 3.5 to 4. 5 and even more preferably about 4.
  • An anti-TROP2 antibody-drug conjugate can be produced with reference to the description of WO 2015/098099 and the like.
  • anti-B7-H3 antibody-drug conjugate refers to an antibody-drug conjugate in which the antibody in the antibody-drug conjugate according to the present invention is an anti-B7-H3 antibody.
  • the anti-B7-H3 antibody is preferably CDRH1 consisting of the amino acid sequence of amino acids 50 to 54 in SEQ ID NO: 7, CDRH2 consisting of the amino acid sequence of amino acids 69 to 85 in SEQ ID NO: 7, and SEQ ID NO: 7, a heavy chain comprising CDRH3 consisting of the amino acid sequence of amino acids 118 to 130; SEQ ID NO: 8, CDRL1 consisting of the amino acid sequence of amino acids 44 to 53; An antibody comprising CDRL2 comprising the amino acid sequence of SEQ ID NO: 8 and a light chain comprising CDRL3 comprising the amino acid sequence of amino acids 108 to 116 in SEQ ID NO: 8, More preferably, a heavy chain comprising a heavy chain variable region consisting of the amino acid sequence of amino acids 20 to 141 in SEQ ID NO: 7, and a light chain variable region consisting of the amino acid sequence of amino acids 21 to 128 in SEQ ID NO: 8 A light chain comprising a region, Even more preferably, an antibody comprising a heavy chain
  • the average number of drug linker bonds per antibody of the anti-B7-H3 antibody-drug conjugate is preferably 2 to 8, more preferably 3 to 5, and even more preferably 3.5 to 5. 4.5, and even more preferably about 4.
  • the anti-B7-H3 antibody-drug conjugate used in the present invention can be produced by referring to the description in WO 2014/057687 and the like.
  • anti-GPR20 antibody-drug conjugate refers to an antibody-drug conjugate in which the antibody in the antibody-drug conjugate according to the present invention is an anti-GPR20 antibody.
  • the anti-GPR20 antibody is preferably CDRH1 consisting of the amino acid sequence of amino acids 45 to 54 in SEQ ID NO: 9, CDRH2 consisting of the amino acid sequence of amino acids 69 to 78 in SEQ ID NO: 9, and CDRH2 consisting of the amino acid sequence of amino acids 69 to 78 in SEQ ID NO: 9.
  • An antibody comprising a light chain comprising a region Still more preferably, an antibody comprising a heavy chain consisting of the amino acid sequence of amino acids 20 to 472 in SEQ ID NO: 9 and a light chain consisting of the amino acid sequence of amino acids 21 to 234 in SEQ ID NO: 10, or , Wherein the
  • the average number of drug linkers bound per antibody of the anti-GPR20 antibody-drug conjugate is preferably from 2 to 8, more preferably from 3 to 8, even more preferably from 7 to 8, Even more preferably from 7.5 to 8, and even more preferably about 8.
  • An anti-GPR20 antibody-drug conjugate can be produced by referring to the description in WO2018 / 135501 and the like.
  • anti-CDH6 antibody-drug conjugate refers to an antibody-drug conjugate in which the antibody in the antibody-drug conjugate according to the present invention is an anti-CDH6 antibody.
  • the anti-CDH6 antibody is preferably CDRH1 consisting of the amino acid sequence of amino acids 45 to 54 in SEQ ID NO: 11, CDRH2 consisting of the amino acid sequence of amino acids 69 to 78 in SEQ ID NO: 11, and CDRH1 consisting of the amino acid sequence of amino acids 69 to 78 in SEQ ID NO: 11.
  • a heavy chain comprising CDRH3 comprising the amino acid sequence of amino acids Nos. 118-130; CDRL1 comprising the amino acid sequence of amino acids Nos. 44-54 in SEQ ID No.
  • An antibody comprising a light chain comprising a region Still more preferably, an antibody comprising a heavy chain consisting of the amino acid sequence of amino acids 20 to 471 in SEQ ID NO: 11 and a light chain consisting of the amino acid sequence of amino acids 21 to 233 in SEQ ID NO: 12, or , Wherein the lysine residue at the carboxyl terminus of the heavy chain of the antibody is deleted.
  • the average number of drug linkers bound per antibody of the anti-CDH6 antibody-drug conjugate is preferably from 2 to 8, more preferably from 3 to 8, even more preferably from 7 to 8, Even more preferably from 7.5 to 8, and even more preferably about 8.
  • An anti-CDH6 antibody-drug conjugate can be produced with reference to the description in WO2018 / 212136 and the like.
  • tubulin inhibitor by affecting microtubule dynamics, cell division in G 2 phase of the cell cycle (division preparation phase) and / or M phase (mitosis) It is an agent that suppresses the growth of cancer cells by stopping it and inducing cell death by apoptosis (Dumontet C, et al., Nat Rev Drug Discov. 2010 Oct; 9 (10): 790-803.) (Mukhtar E, et al., Mol Cancer Ther. 2014 Feb: 13 (2): 275-284.).
  • Tubulin inhibitors include agents that affect microtubule dynamics by promoting tubulin polymerization (referred to as “tubulin polymerization accelerators” in the present invention) and microtubules by inhibiting tubulin polymerization. There are drugs that affect the dynamics (referred to as “tubulin polymerization inhibitors” in the present invention).
  • Taxanes (paclitaxel, docetaxel, cabazitaxel, etc.) and the like are known as tubulin polymerization accelerators.
  • tubulin polymerization inhibitors include halichondrins (such as eribulin), vinca alkaloids (such as vincristine, vinblastine, vinorelbine, and vindesine), dolastatins (such as MMAE and MMAF), and maytansinoids (such as DM1 and DM4).
  • halichondrins such as eribulin
  • vinca alkaloids such as vincristine, vinblastine, vinorelbine, and vindesine
  • dolastatins such as MMAE and MMAF
  • maytansinoids such as DM1 and DM4
  • a conjugate of any of these drugs with albumin for example, nab-paclitaxel which is a conjugate of paclitaxel and albumin
  • Drug conjugates eg, brentuximab vedotin, an antibody-drug conjugate in which MMAE and anti-CD30 antibody are bound via a linker, and an antibody-drug conjugate in which DM1 and an anti-HER2 antibody are bound via a linker
  • CDX-011 WO 2006/071441, etc.
  • Conjugated antibody-drug conjugate I GN-853 (WO 2017/049149 etc.), RG-7596 (US 2017/304438 etc.), which is an antibody-drug conjugate in which MMAE and anti-CD79b antibody are bound via a linker, DM4 and SAR-3419, an antibody-drug conjugate in which an anti-CD19 antibody is bound via a linker (US Patent Publication No.
  • tubulin inhibitors suitably used in the present invention
  • examples of the tubulin polymerization accelerator include taxanes or pharmacologically acceptable salts thereof, or a conjugate of a taxane and albumin, More preferably, paclitaxel, docetaxel, cabazitaxel, or a pharmaceutically acceptable salt thereof, or nab-paclitaxel can be mentioned, and even more preferably, paclitaxel, docetaxel trihydrate, or cabazitaxel acetone. Examples thereof include Japanese products and nab-paclitaxel, and even more preferably, paclitaxel.
  • tubulin inhibitors preferably used in the present invention, as the tubulin polymerization inhibitor, halichonds or their pharmacologically acceptable salts, or halichondrin and an antibody bound via a linker
  • an antibody-drug conjugate can be mentioned, and more preferably, an antibody-drug conjugate in which eribulin or a pharmaceutically acceptable salt thereof, or eribulin and an antibody bound via a linker (for example, eribulin and anti-FOLR1) MORAb-202, which is an antibody-drug conjugate linked to an antibody via a linker (US Publication No. 2017/252458, etc.), and even more preferably eribulin mesylate (Eribulin @ mesylate) Can be mentioned.
  • eribulin mesylate Eribulin @ mesylate
  • the “pharmacologically acceptable salt” in the present invention may be either an acid addition salt or a base addition salt.
  • the acid addition salts include lower alkane sulfonates such as cansylates (camphorsulfonates), mesylates (methanesulfonates), trifluoromethanesulfonates, and ethanesulfonates; (P-toluenesulfonate) and aryl sulfonates such as benzenesulfonate; inorganic acid salts such as phosphate, nitrate, perchlorate and sulfate; hydrochloride, hydrobromide, Hydrohalides such as hydroiodide and hydrofluoride; acetate, malate, fumarate, succinate, citrate, tartrate, oxalate, maleate, etc.
  • amino acid salts such as ornithate, glutamate and aspartate.
  • the base addition salt include alkali metal salts such as sodium salt, potassium salt and lithium salt; alkaline earth metal salts such as calcium salt and magnesium salt; inorganic salts such as ammonium salt; dibenzylamine salt, morpholine salt and phenyl Glycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, diethanolamine salt, N-benzyl-N- (2 Organic amine salts such as -phenylethoxy) amine salt, piperazine salt, tetramethylammonium salt and tris (hydroxymethyl) aminomethane salt; and amino acid salts such as arginine salt.
  • pharmacologically acceptable salts may exist as solvates, and these solvates are also included in the “pharmacologically acceptable salts” in the present invention.
  • solvates include, for example, hydrates (eg, 0.5 hydrate, 1 hydrate, 2 hydrate, 3 hydrate), ethanol solvate, and acetone solvate. it can.
  • compositions and therapeutic methods characterized in that the antibody-drug conjugate according to the present invention and a tubulin inhibitor are administered in combination are described.
  • the pharmaceutical composition and the therapeutic method of the present invention are characterized in that the antibody-drug conjugate and the tubulin inhibitor are contained as active ingredients in different preparations, respectively, and are administered simultaneously or at different times.
  • the antibody-drug conjugate and the tubulin inhibitor may be contained in a single preparation as active ingredients and administered.
  • the pharmaceutical composition and treatment method of the present invention can be used for treating cancer, and are preferably breast cancer, stomach cancer (sometimes called gastric adenocarcinoma), colorectal cancer (colorectal cancer) And colon cancer and rectal cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), esophageal cancer, head and neck cancer (including salivary gland cancer and pharyngeal cancer) , Gastroesophageal junction adenocarcinoma, biliary tract cancer (including bile duct cancer), Paget disease, pancreatic cancer, ovarian cancer, uterine carcinosarcoma, urothelial cancer, prostate cancer, bladder cancer Gastrointestinal stromal tumor, cervical cancer, squamous cell carcinoma, peritoneal cancer, liver cancer, hepatocellular carcinoma, endometrial cancer, kidney cancer, vulvar cancer, thyroid cancer, penis Selected from the group consisting of cancer, leukemia, malignant lymphoma, plasmacytoma, my
  • antibody-drug conjugates used in the present invention in particular, what kind of antibody-drug conjugate is suitable is determined by examining the type of cancer and a tumor marker. Can be.
  • an anti-HER2 antibody-drug conjugate can be suitably used.
  • anti-HER3 antibody-drug conjugate can be used.
  • the expression of TROP2 is confirmed in the cancer
  • the anti-TROP2 antibody-drug conjugate can be suitably used, and the expression of B7-H3 is confirmed in the cancer.
  • an anti-B7-H3 antibody-drug conjugate can be preferably used, and when expression of GPR20 has been confirmed in cancer, an anti-GPR20 antibody-drug conjugate can be suitably used.
  • an anti-CDH6 antibody-drug conjugate can be suitably used.
  • the presence or absence of HER2, HER3, TROP2, B7-H3, GPR20, and CDH6 and other tumor markers can be determined, for example, by collecting a tumor tissue from a cancer patient and using a formalin-fixed paraffin-embedded specimen (FFPE) Inspection at gene product (protein) level by chemical (IHC) method, flow cytometer, western blot method, etc., or in situ hybridization method (ISH), quantitative PCR method (q-PCR), microarray analysis, etc. Or by examining the cell-free blood circulating tumor DNA (ctDNA) from a cancer patient and using a method such as next-generation sequencing (NGS). You can also.
  • FFPE formalin-fixed paraffin-embedded specimen
  • composition and the therapeutic method of the present invention can be suitably used for mammals, but can be more preferably used for humans.
  • the antitumor effect of the pharmaceutical composition and the treatment method of the present invention is, for example, a model in which cancer cells are transplanted into a test animal, a tumor volume is reduced by applying the pharmaceutical composition and the treatment method of the present invention. It can be confirmed by measuring the life extension effect.
  • the antibody-drug conjugate and tubulin inhibitor used in the present invention were compared with the antitumor effect of each of the antibody-drug conjugate and the tubulin inhibitor used alone in the present invention by comparing them with the antitumor effect of each of them. The effect of the combination can be confirmed.
  • the combined effect of the pharmaceutical composition and the treatment method of the present invention can also be determined from a change in the expression level of a drug sensitivity factor and / or a drug resistance factor.
  • drug sensitivity in the case where a subject is administered with the antibody-drug conjugate used in the present invention and the tubulin inhibitor alone, in the case of combined administration, or in the case of no administration (control)
  • the expression levels of the factor and / or drug resistance factor are compared. Then, if it can be confirmed that the tubulin inhibitor suppresses the decrease in the expression of the drug susceptibility factor caused by administration of the antibody-drug conjugate used in the present invention, the combined effect of the antibody-drug conjugate and the tubulin inhibitor It can be determined that there is.
  • SLFN11 is known to be a susceptibility factor for topoisomerase I inhibitors (Zoppoli G. et al., Proc Natl Acad Sci U S A. 2012; 109 (39): 15030-5).
  • a tubulin inhibitor suppresses an increase in the expression of a drug resistance factor caused by administration of the antibody-drug conjugate used in the present invention, the combined effect of the antibody-drug conjugate and the tubulin inhibitor It can be determined that there is.
  • An example of such a drug resistance factor is ABCG2.
  • ABCG2 is known to be a drug resistance factor (transporter) released from the antibody-drug conjugate according to the present invention (Nagai Y. et al., Xenobiotica. 2019; 49 (9): 1086) -96).
  • the expression levels of the drug sensitivity factor and / or the drug resistance factor at the gene (RNA or the like) level can be compared, and the expression levels at the protein level can also be compared.
  • the pharmaceutical composition and the treatment method of the present invention can delay the growth of cancer cells, suppress the proliferation, and can destroy cancer cells. By these actions, in a cancer patient, it is possible to achieve a relief from symptoms caused by the cancer and an improvement in QOL, thereby achieving a therapeutic effect while maintaining the life of the cancer patient. Even in cases where the cancer cells are not destroyed, cancer patients can achieve longer QOL while achieving higher QOL by suppressing and controlling the proliferation of cancer cells.
  • composition of the present invention can be applied to a patient as a systemic therapy, or applied locally to a cancer tissue to expect a therapeutic effect.
  • compositions of the present invention can be administered containing one or more pharmaceutically compatible ingredients.
  • Pharmaceutically compatible components are appropriately selected from pharmaceutical additives and the like usually used in this field, depending on the dose and concentration of the antibody-drug conjugate and tubulin inhibitor used in the present invention. And can be applied.
  • the antibody-drug conjugate used in the present invention is administered as a pharmaceutical composition comprising a buffer such as a histidine buffer, an excipient such as sucrose or trehalose, and a surfactant such as polysorbate 80 or 20.
  • the pharmaceutical composition containing the antibody-drug conjugate used in the present invention can be preferably used as an injection, and more preferably, can be used as an aqueous injection or a lyophilized injection. Still more preferably, it can be used as a lyophilized injection.
  • the pharmaceutical composition containing the antibody-drug conjugate used in the present invention is an aqueous injection, it can be suitably administered by intravenous infusion after dilution with an appropriate diluent.
  • the diluting solution include a glucose solution and a physiological saline solution, preferably a glucose solution, and more preferably a 5% glucose solution.
  • the pharmaceutical composition containing the antibody-drug conjugate used in the present invention is a lyophilized injection, it is preferably dissolved in water for injection, and then diluted with an appropriate diluent, and then injected into a vein.
  • the diluting solution include a glucose solution and a physiological saline solution, preferably a glucose solution, and more preferably a 5% glucose solution.
  • Introduction routes that can be used to administer the pharmaceutical compositions of the present invention include, for example, intravenous, intradermal, subcutaneous, intramuscular, and intraperitoneal routes, preferably intravenous. Routes can be mentioned.
  • the antibody-drug conjugate used in the present invention can be administered to a human at intervals of 1 to 180 days, preferably 1 week, 2 weeks, 3 weeks, or 4 weeks. Once every three weeks, and even more preferably once every three weeks. Further, the antibody-drug conjugate used in the present invention can be administered at a dose of about 0.001 to 100 mg / kg per dose, preferably 0.8 to 12.4 mg / dose. / Kg dose. When the antibody-drug conjugate used in the present invention is an anti-ER2 antibody-drug conjugate, it is preferably 0.8 mg / kg, 1.6 mg / kg, 3.2 mg / kg, 5 mg / dose.
  • a dose of 0.4 mg / kg, 6.4 mg / kg, 7.4 mg / kg, or 8 mg / kg can be administered once every three weeks.
  • the antibody-drug conjugate used in the present invention is an anti-HER3 antibody-drug conjugate, it is preferably 1.6 mg / kg, 3.2 mg / kg, 4.8 mg / kg, 5 times per dose.
  • a dose of 6.6 mg / kg, 6.4 mg / kg, 8.0 mg / kg, 9.6 mg / kg, or 12.8 mg / kg can be administered once every three weeks.
  • the antibody-drug conjugate used in the present invention is an anti-TROP2 antibody-drug conjugate
  • it is preferably 0.27 mg / kg, 0.5 mg / kg, 1.0 mg / kg, 2 times per dose.
  • a dose of 0.0 mg / kg, 4.0 mg / kg, 6.0 mg / kg, or 8.0 mg / kg can be administered once every three weeks.
  • the tubulin inhibitor according to the present invention can be administered to a human at an interval of 1 to 180 days, preferably once a week, two weeks, three weeks, or four weeks. Can be administered at regular intervals. Further, the tubulin inhibitor according to the present invention can be administered at a dose of about 0.001 to 100 mg / kg per dose. When the tubulin inhibitor according to the present invention is paclitaxel, it is preferable to administer a dose of 100, 125, 135, 175 or 260 mg / m 2 (body surface area) once a week or three times a week.
  • Intravenous administration can be performed at intervals of one time (when administered once a week, administration is performed for three consecutive weeks and then the drug is stopped on the fourth week).
  • the tubulin inhibitor according to the present invention is eribulin mesylate, it is preferably intravenously administered at a dose of 1.4 mg / m 2 (body surface area) at a time, once a week. (Dose for 3 consecutive weeks after administration for 2 consecutive weeks).
  • the pharmaceutical composition and the therapeutic method of the present invention may further contain a cancer therapeutic agent other than the antibody-drug conjugate and the tubulin inhibitor according to the present invention.
  • the pharmaceutical composition and the therapeutic method of the present invention can be administered in combination with other cancer therapeutic agents, whereby the antitumor effect can be enhanced.
  • the other cancer therapeutic agent used for such a purpose may be administered to an individual simultaneously or separately with the pharmaceutical composition of the present invention, or may be administered at different intervals. May be done.
  • Such a cancer therapeutic agent is not limited as long as it has an antitumor activity.
  • irinotecan (Irinotecan, CPT-11), cisplatin, carboplatin, oxaliplatin (Oxaliplatin), Fluorouracil (5-FU), Gemcitabine (Gemcitabine), Capecitabine (Capecitabine), Doxorubicin (Doxorubicin), Epirubicin (Epirubicin), Cymphomycomicin Tegafur, Gimeracil, Oteracil (Ote) acil), Cetuximab (Cetuximab), Panitumumab (Panitumumab), Bevacizumab (Bevacizumab), Ramucirumab (Ramucirumab), Regorafenib (Regorafenib), Triflurinib Erlotinib), afatinib (Afatinib), methotrexate (Methotrexate), pemetrexed (Pemetrexed), tamoxifen (Ir
  • the pharmaceutical composition and treatment method of the present invention can be used in combination with radiation therapy.
  • a cancer patient receives radiation therapy before and / or after receiving treatment with the pharmaceutical composition of the present invention, or at the same time.
  • compositions and treatment methods of the present invention can also be used as adjuvant chemotherapy in combination with surgery.
  • the pharmaceutical composition of the present invention may be administered for the purpose of reducing the size of a tumor before surgery (referred to as preoperative adjuvant chemotherapy or neoadjuvant therapy) and prevent tumor recurrence after surgery. It may be administered for a purpose (referred to as postoperative adjuvant chemotherapy or adjuvant therapy).
  • Example 1 Preparation of Antibody-Drug Conjugate A humanized anti-HER2 antibody (a heavy chain comprising the amino acid sequence of amino acids 1 to 449 in SEQ ID NO: 1) An antibody comprising a light chain consisting of the amino acid sequence of amino acids 1 to 214 in SEQ ID NO: 2)
  • antibody-drug conjugate (1) in which a drug linker represented by and an anti-HER2 antibody were bound by a thioether bond was produced.
  • the DAR of the antibody-drug conjugate (1) is 7.7 or 7.8.
  • Example 2 Antitumor test (1) Mice: Female BALB / c nude mice of 5-6 weeks of age (Charles River Japan) were used for the experiment.
  • Paclitaxel was dissolved in cremophor and ethanol (1: 1), diluted with physiological saline, and then administered to the tail vein at a volume of 10 or 20 mL / kg.
  • Eribulin mesylate was diluted with physiological saline, and a 10 mL / kg solution was administered into the tail vein.
  • KPL-4 cells a human breast cancer strain obtained from Kawasaki Medical University's Dr. Junichi Kobayashi (British Journal of Cancer, (1999) 79 (5/6) .707-717), were suspended in physiological saline for 1.5 hours. ⁇ 10 7 cells were implanted subcutaneously into the right side of female nude mice, and randomized into groups 17 days after the implantation (Day 0). Antibody-drug conjugate (1) (DAR: 7.8) was administered to Day 0 via the tail vein at a dose of 7.5 mg / kg.
  • DAR Antibody-drug conjugate (1)
  • Paclitaxel was administered to Day 0 and Day 7 at a dose of 15 mg / kg in the tail vein, and Eribulin mesylate was administered to Day 0 and Day 4 at a dose of 0.8 mg / kg in the tail vein.
  • a solvent administration group was set as each single agent and combined administration group, and a control group.
  • FIG. 9 shows the results of the combination use of the antibody-drug conjugate (1) and Paclitaxel.
  • the tumor growth inhibition rate (Tumor ⁇ Growth ⁇ Inhibition; TGI) on the last day of the test with the administration of Paclitaxel alone was 48%.
  • the TGI by single administration of the antibody-drug conjugate (1) was 87%.
  • the combined administration of the antibody-drug conjugate (1) and Paclitaxel showed a significantly superior tumor growth inhibitory effect as compared to the single administration of Paclitaxel (P ⁇ 0.01 (calculated by Dunnett's test).
  • FIG. 10 shows the results of the combination use of antibody-drug conjugate (1) and Eribulin mesylate.
  • TGI by single administration of Eribulin @ mesylate was 91%.
  • the TGI by single administration of the antibody-drug conjugate (1) was 87%.
  • the combined administration of the antibody-drug conjugate (1) and Eribulin @ mesylate showed a significantly better tumor growth inhibitory effect than the single administration of Eribulin @ mesylate (P ⁇ 0.05).
  • Tumor growth inhibitory effect significantly superior to that of conjugate (1) alone was observed (P ⁇ 0.05), and the combined effect was very strong in which tumor disappearance was observed in all cases. (TGI, 100%).
  • the horizontal axis represents the number of days after cell transplantation, and the vertical axis represents the tumor volume.
  • no remarkable findings such as weight loss were observed in any of the single agent and combination administration groups.
  • Example 3 Antitumor test (2) Human breast cancer strain JIMT-1 cells purchased from DSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH) were suspended in physiological saline, and 5 ⁇ 10 6 cells were subcutaneously transplanted into the right body of female nude mice 13 days after transplantation. Grouping was performed randomly (Day 0). Antibody-drug conjugate (1) (DAR: 7.7) was administered to Day 0 at a dose of 10 mg / kg via the tail vein. Paclitaxel was administered to Day 0, Day 7, and Day 14 at a dose of 15 mg / kg via the tail vein. Eribulin mesylate was administered to Day 0 and Day 3 at a dose of 0.8 mg / kg in the tail vein. A solvent administration group was set as each single agent and combined administration group, and a control group.
  • DAR Human breast cancer strain JIMT-1 cells purchased from DSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH) were suspended in physiological saline, and 5 ⁇ 10 6 cells were subcutaneously
  • FIG. 11 shows the results of the combination use of the antibody-drug conjugate (1) and Paclitaxel.
  • TGI by single administration of Paclitaxel was 30%.
  • the TGI by single administration of the antibody-drug conjugate (1) was 73%.
  • the combined administration of the antibody-drug conjugate (1) and Paclitaxel showed a significantly superior tumor growth inhibitory effect than the single administration of Paclitaxel (P ⁇ 0.001).
  • a significantly superior tumor growth inhibitory effect was observed than the single agent administration of gate (1) (P ⁇ 0.001), and the TGI was 97%.
  • no remarkable findings such as weight loss were observed in any of the single agent and combination administration groups.
  • FIG. 12 shows the results of the combination use of ⁇ ⁇ antibody-drug conjugate (1) and Eribulin mesylate.
  • TGI by single administration of Eribulin @ mesylate was 73%.
  • the TGI by single administration of the antibody-drug conjugate (1) was 73%.
  • the combined administration of the antibody-drug conjugate (1) and Eribulin @ mesylate showed a significantly better tumor growth inhibitory effect than the single administration of Eribulin @ mesylate (P ⁇ 0.05).
  • the tumor growth inhibitory effect significantly superior to that of the conjugate (1) alone was observed (P ⁇ 0.001), and the TGI was 97%.
  • no remarkable findings such as weight loss were observed in any of the single agent and combination administration groups.
  • Example 4 Antitumor test (3) Human gastric cancer strain NCI-N87 cells purchased from ATCC (American Type Culture Collection) were suspended in physiological saline, and 1 ⁇ 10 7 cells were subcutaneously transplanted into the right side of female nude mice, and 6 days after transplantation, they were randomly performed. Grouping was performed (Day 0). Antibody-drug conjugate (1) (DAR: 7.8) was administered to Day 0 via the tail vein at a dose of 1 mg / kg. Paclitaxel was administered to Day 0 and Day 7 at a dose of 15 mg / kg in the tail vein, and Eribulin mesylate was administered to Day 0 and Day 4 at a dose of 0.4 mg / kg in the tail vein. A solvent administration group was set as each single agent and combined administration group, and a control group.
  • DAR Antibody-drug conjugate (1)
  • FIG. 13 shows the results of the combination use of the antibody-drug conjugate (1) and Paclitaxel.
  • TGI by single administration of Paclitaxel was 50%.
  • the TGI by single administration of the antibody-drug conjugate (1) was 45%.
  • the combined administration of the antibody-drug conjugate (1) and Paclitaxel showed a significantly superior tumor growth inhibitory effect than the single administration of Paclitaxel (P ⁇ 0.001).
  • a tumor growth inhibitory effect significantly superior to single agent administration of gate (1) was observed (P ⁇ 0.001), and TGI was 82%.
  • no remarkable findings such as weight loss were observed in any of the single agent and combination administration groups.
  • FIG. 14 shows the results of the combination use of antibody-drug conjugate (1) and Eribulin mesylate.
  • TGI by single administration of Eribulin @ mesylate was 64%.
  • the TGI by single administration of the antibody-drug conjugate (1) was 45%.
  • the combined administration of the antibody-drug conjugate (1) and Eribulin @ mesylate showed a significantly better tumor growth inhibitory effect than the single administration of Eribulin @ mesylate (P ⁇ 0.01).
  • Tumor growth inhibitory effect significantly superior to that of conjugate (1) alone was observed (P ⁇ 0.001), and TGI was 77%.
  • no remarkable findings such as weight loss were observed in any of the single agent and combination administration groups.
  • Example 5 Antitumor test (4) Human breast cancer strain MDA-MB-453 cells purchased from the ATCC were suspended in Matrigel basement membrane matrix (Matrigel), and 1 ⁇ 10 7 cells were subcutaneously transplanted into the right side of female nude mice, and randomly 7 days after transplantation. Grouping was performed (Day 0). Antibody-drug conjugate (1) (DAR: 7.8) was administered to Day 0 via the tail vein at a dose of 0.5 mg / kg. Paclitaxel was administered to Day 0 and Day 7 at a dose of 15 mg / kg via the tail vein. A solvent administration group was set as each single agent and combined administration group, and a control group.
  • DAR Antibody-drug conjugate (1)
  • FIG. 15 shows the results of the combination use of the antibody-drug conjugate (1) and Paclitaxel.
  • TGI by single administration of Paclitaxel was 96%.
  • TGI by single administration of the antibody-drug conjugate (1) was 75%.
  • the combined administration of the antibody-drug conjugate (1) and Paclitaxel showed a significantly better tumor growth inhibitory effect than the single administration of the antibody-drug conjugate (1) (P ⁇ 0.01).
  • TGI was 100%.
  • no remarkable findings such as weight loss were observed in any of the single agent and combination administration groups.
  • Example 6 Antitumor test (5) Human gastric cancer cell line SNU-1 cells purchased from the ATCC were suspended in Matrigel, and 1 ⁇ 10 7 cells were subcutaneously transplanted into the right side of female nude mice, and randomized 28 days after transplantation (Day 0). .
  • Antibody-drug conjugate (1) (DAR: 7.8) was administered to Day 0 via the tail vein at a dose of 10 mg / kg.
  • Paclitaxel was administered to Day 0 and Day 7 at a dose of 15 mg / kg via the tail vein.
  • a solvent administration group was set as each single agent and combined administration group, and a control group.
  • FIG. 16 shows the results of the combination use of the antibody-drug conjugate (1) and Paclitaxel.
  • TGI by single administration of Paclitaxel was 58%.
  • TGI by single administration of the antibody-drug conjugate (1) was 79%.
  • the combined administration of the antibody-drug conjugate (1) and Paclitaxel showed a significantly superior tumor growth inhibitory effect (P ⁇ 0.01) compared to single administration of Paclitaxel, and the TGI was 87%. Was.
  • no remarkable findings such as weight loss were observed in any of the single agent and combination administration groups.
  • Example 7 Antitumor test (6) Human lung cancer cell line NCI-H441 cells purchased from ATCC were suspended in Matrigel and 5 ⁇ 10 6 cells were subcutaneously transplanted into the right side of female nude mice, and randomized 7 days after transplantation (Day 0) .
  • Antibody-drug conjugate (1) (DAR: 7.8) was administered to Day 0 via the tail vein at a dose of 10 mg / kg.
  • Paclitaxel was administered to Day 0 and Day 7 at a dose of 15 mg / kg via the tail vein.
  • a solvent administration group was set as each single agent and combined administration group, and a control group.
  • FIG. 17 shows the results of the combination use of the antibody-drug conjugate (1) and Paclitaxel.
  • TGI by single administration of Paclitaxel was 55%.
  • TGI by single administration of the antibody-drug conjugate (1) was 92%.
  • the combined administration of the antibody-drug conjugate (1) and Paclitaxel showed a significantly superior tumor growth inhibitory effect than the single administration of Paclitaxel (P ⁇ 0.001).
  • a significantly superior tumor growth inhibitory effect was observed than the single agent administration of gate (1) (P ⁇ 0.01), and TGI was 99%. No significant findings such as weight loss were observed in any of the single agent and combination administration groups.
  • Example 8 Production of antibody-drug conjugate (2) According to the production method described in WO 2015/155998, an anti-HER3 antibody (an antibody comprising a heavy chain consisting of the amino acid sequence of SEQ ID NO: 3 and a light chain consisting of the amino acid sequence of SEQ ID NO: 4) is used. Using the formula
  • antibody-drug conjugate (2) An antibody-drug conjugate in which the drug linker represented by and the anti-HER3 antibody were bound by a thioether bond was produced.
  • the DAR of antibody-drug conjugate (2) is 7.6.
  • Example 9 Preparation of antibody-drug conjugate (3) According to the production method described in WO2018 / 212136, an anti-CDH6 antibody (a heavy chain comprising the amino acid sequences of amino acids 20 to 471 in SEQ ID NO: 11 and the amino acids of amino acids 21 to 233 in SEQ ID NO: 12) Antibody comprising a light chain consisting of a sequence)
  • antibody-drug conjugate (3) in which the drug linker represented by and the anti-CDH6 antibody were bound by a thioether bond was produced.
  • the DAR of the antibody-drug conjugate (3) is 7.8.
  • Example 10 Antitumor test (7) Human breast cancer strain JIMT-1 cells purchased from DSMZ were suspended in physiological saline, and 5 ⁇ 10 6 cells were subcutaneously transplanted into the right side of female nude mice, and randomized into groups 10 days after transplantation ( Day 0).
  • Antibody-drug conjugate (2) (DAR: 7.6) was administered to Day 0, Day 7, and Day 14 at a dose of 10 mg / kg via the tail vein.
  • Paclitaxel was administered to Day 0 and Day 7 at a dose of 15 mg / kg via the tail vein.
  • a solvent administration group was set as each single agent and combined administration group, and a control group.
  • FIG. 22 shows the results of the combination use of the antibody-drug conjugate (2) and Paclitaxel.
  • TGI by single administration of Paclitaxel was 36%.
  • TGI by single administration of the antibody-drug conjugate (2) was 69%.
  • P ⁇ 0.001 a significantly superior tumor growth inhibitory effect was observed as compared with the single administration of Paclitaxel.
  • a tumor growth inhibitory effect significantly superior to that of the single agent administration of gate (2) was observed (P ⁇ 0.001), and TGI was 97%. No significant findings such as weight loss were observed in any of the single agent and combination administration groups.
  • Example 11 Antitumor test (8) Human ovarian cancer cell line OV-90 cells purchased from ATCC were suspended in Matrigel, and 2.5 ⁇ 10 6 cells were subcutaneously transplanted into the right body of female nude mice, and randomly grouped 15 days after transplantation. (Day 0). Antibody-drug conjugate (3) (DAR: 7.8) was administered to Day 0 via the tail vein at a dose of 10 mg / kg. Paclitaxel was administered to Day 0, Day 7, and Day 14 at a dose of 15 mg / kg via the tail vein. A solvent administration group was set as each single agent and combined administration group, and a control group.
  • DAR Antibody-drug conjugate (3)
  • FIG. 23 shows the results of the combination use of the antibody-drug conjugate (3) and Paclitaxel.
  • TGI by single administration of Paclitaxel was 80%
  • TGI by single administration of antibody-drug conjugate (3) was 97%
  • TGI by combined administration of antibody-drug conjugate (3) and Paclitaxel was 99%.
  • Met In the combined administration of the antibody-drug conjugate (3) and Paclitaxel, a significantly superior tumor growth inhibitory effect was observed on Day 27 as compared with the administration of Paclitaxel alone (P ⁇ 0.001).
  • a tumor growth inhibitory effect significantly superior to that of the single agent administration of the antibody-drug conjugate (3) was observed on Day 38 (P ⁇ 0.01 (calculated by Student ⁇ s ⁇ t-test)).
  • no remarkable findings such as weight loss were observed in any of the single agent and combination administration groups.
  • Example 12 RNA expression analysis Human breast cancer strain JIMT-1 cells were transplanted into nude mice, and antibody-drug conjugate (1), Paclitaxel or Eribulin mesylate alone administration group, antibody-drug conjugate (1) A combined administration group of Paclitaxel or the antibody-drug conjugate (1) and Eribulin mesylate, and a Control group are set. Tumors before and after drug administration are collected and used for RNA expression analysis. Tumors are incubated overnight in RNAlater RNA Stabilization Reagent after weighing and stored at -80 ° C after RNAlater removal.
  • the library is analyzed using an Illina NextSeq 500/550 High Output Kit v2.5 with an Illina NextSeq 500 or 550 sequencer, and a base call file is output.
  • the obtained base call file is bcl2fastq ver. 2.
  • the read of the fastq file is based on the reference sequence of the transcript based on the human reference genome GRCh37 assembly, STAR ver. Alignment was performed using 2.5.3a15, and the number of reads for each gene was determined using RSEM ver. Estimate according to 1.3.016. Gene expression levels were determined using EBSeq ver. Using 1.22.0, it is shown as a normalized Transcripts Per Kilobase Million (TPM) value using the median ratio between samples normalization method.
  • TPM Trans
  • the average TPM of the SLFN11 gene after administration of the antibody-drug conjugate (1) alone is lower than the average TPM of the SLFN11 gene in the tumors of the Control group.
  • the average TPM value of the SLFN11 gene after the combined administration of the antibody-drug conjugate (1) and Paclitaxel or after the combined administration of the antibody-drug conjugate (1) and Eribulin @ mesylate is better than that of the antibody-drug conjugate (1). It is confirmed that the TPM of the SLFN11 gene after the single agent administration is higher than the average TPM value.
  • the average TPM of the ABCG2 gene after administration of the antibody-drug conjugate (1) as a single agent is higher than the average TPM of the ABCG2 gene in the tumors of the Control group.
  • the average TPM value of the ABCG2 gene after the combined administration of the antibody-drug conjugate (1) and Paclitaxel or after the combined administration of the antibody-drug conjugate (1) and Eribulin @ mesylate is better than that of the antibody-drug conjugate (1).
  • the ABCG2 gene after administration of the single agent was confirmed to be lower than the average TPM value.
  • Example 13 Protein expression analysis Human breast cancer strain JIMT-1 cells were transplanted into nude mice, and antibody-drug conjugate (1), Paclitaxel or Eribulin mesylate alone administration group, antibody-drug conjugate (1) A combined administration group of Paclitaxel or the antibody-drug conjugate (1) and Eribulin mesylate, and a Control group are set. Tumors before and after drug administration are collected and used for protein expression analysis. The tumor excised from the mouse is disrupted and dissolved in a RIPA buffer, and the supernatant after centrifugation is collected as a tumor lysate.
  • the SLFN11 protein expression and ⁇ -Actin expression in the obtained tumor lysate were detected using a simple western system (Wes or Peggy Sue), and were compared with Compass for SW ver. 4. Calculate the peak area value using 0.0.
  • the SLFN11 protein expression level ratio of each tumor lysate is calculated by the following formula.
  • SLFN11 protein expression level ratio (peak area value of SLFN11 protein at each time point / peak area value of ⁇ -Actin at each time point) / (peak area value of SLFN11 protein at Day0 / peak area value of ⁇ -Actin at Day0)
  • the expression level of SLFN11 protein in the single agent administration group of the antibody-drug conjugate (1) was higher than that of the antibody-drug conjugate (1) in combination with Paclitaxel or the antibody-drug conjugate (1) and Eribulin mesylate. It is confirmed that the SLFN11 protein expression level in the combined administration group shows a higher value.
  • SEQ ID NO: 1 amino acid sequence of anti-HER2 antibody heavy chain
  • SEQ ID NO: 2 amino acid sequence of anti-HER2 antibody light chain
  • SEQ ID NO: 3 amino acid sequence of heavy chain of anti-HER3 antibody
  • SEQ ID NO: 4 amino acid sequence of light chain of anti-HER3 antibody
  • SEQ ID NO: 5 amino acid sequence of anti-TROP2 antibody heavy chain
  • SEQ ID NO: 6 amino acid sequence of anti-TROP2 antibody light chain
  • SEQ ID NO: 10 amino acid sequence of anti-GPR20 antibody light chain
  • SEQ ID NO: 11 amino acid sequence of anti-CDH6 antibody heavy chain
  • SEQ ID NO: 12 amino acid sequence of anti-CDH6 antibody light chain

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PCT/JP2019/030635 2018-08-06 2019-08-05 抗体－薬物コンジュゲートとチューブリン阻害剤の組み合わせ Ceased WO2020031936A1 (ja)

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EA202190471A EA202190471A1 (ru) 2018-08-06 2019-08-05 Комбинация конъюгата антитела-лекарственного средства и ингибитора тубулина
EP19847036.1A EP3834843A4 (en) 2018-08-06 2019-08-05 COMBINATION OF ANTIBODY-DRUG CONJUGATE AND TUBULIN INHIBITOR
JP2020535747A JP7458981B2 (ja) 2018-08-06 2019-08-05 抗体－薬物コンジュゲートとチューブリン阻害剤の組み合わせ
KR1020217006189A KR20210042120A (ko) 2018-08-06 2019-08-05 항체-약물 콘주게이트와 튜불린 저해제의 조합
CN201980052170.5A CN112512587A (zh) 2018-08-06 2019-08-05 抗体药物缀合物和微管蛋白抑制剂的组合
CA3108754A CA3108754A1 (en) 2018-08-06 2019-08-05 Combination of antibody-drug conjugate and tubulin inhibitor
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020240467A1 (en) * 2019-05-29 2020-12-03 Daiichi Sankyo Company, Limited Dosage of an antibody-drug conjugate
EP3673918A4 (en) * 2017-08-23 2021-05-19 Daiichi Sankyo Company, Limited PREPARATION OF AN ANTIBODY INGREDIENT CONJUGATE AND LYOPHILIZATION FOR IT
WO2021200131A1 (ja) * 2020-03-30 2021-10-07 国立研究開発法人国立がん研究センター 抗体薬物複合体
WO2022099762A1 (zh) * 2020-11-12 2022-05-19 博瑞生物医药（苏州）股份有限公司 一种抗体偶联物中间体及其制备方法
WO2022126569A1 (zh) * 2020-12-18 2022-06-23 上海复旦张江生物医药股份有限公司 一种靶向b7-h3的抗体药物偶联物、其制备方法及应用
JP2023545096A (ja) * 2020-10-09 2023-10-26 アストラゼネカ ユーケー リミテッド 抗体－薬物コンジュゲート及びｐａｒｐ１選択的阻害薬の組み合わせ
US11806405B1 (en) 2021-07-19 2023-11-07 Zeno Management, Inc. Immunoconjugates and methods
WO2024190815A1 (ja) * 2023-03-14 2024-09-19 第一三共株式会社 抗ｃｄｈ６抗体－薬物コンジュゲートとｖｅｇｆ阻害剤の組み合わせ
WO2024204679A1 (ja) * 2023-03-31 2024-10-03 第一三共株式会社 抗ＣＤＨ６抗体－薬物コンジュゲートとＨＩＦ－２α阻害剤の組み合わせ

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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CN118955615A (zh) * 2022-07-05 2024-11-15 上海药明合联生物技术有限公司 偶联连接子
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Citations (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990007861A1 (en) 1988-12-28 1990-07-26 Protein Design Labs, Inc. CHIMERIC IMMUNOGLOBULINS SPECIFIC FOR p55 TAC PROTEIN OF THE IL-2 RECEPTOR
US5821337A (en) 1991-06-14 1998-10-13 Genentech, Inc. Immunoglobulin variants
WO1999054342A1 (en) 1998-04-20 1999-10-28 Pablo Umana Glycosylation engineering of antibodies for improving antibody-dependent cellular cytotoxicity
WO2000061739A1 (fr) 1999-04-09 2000-10-19 Kyowa Hakko Kogyo Co., Ltd. Methode de regulation de l'activite d'une molecule immunologiquement fonctionnelle
WO2001000245A2 (en) 1999-06-25 2001-01-04 Genentech, Inc. HUMANIZED ANTI-ErbB2 ANTIBODIES AND TREATMENT WITH ANTI-ErbB2 ANTIBODIES
WO2002031140A1 (en) 2000-10-06 2002-04-18 Kyowa Hakko Kogyo Co., Ltd. Cells producing antibody compositions
WO2006071441A2 (en) 2004-11-30 2006-07-06 Curagen Corporation Antibodies directed to gpnmb and uses thereof
WO2007002222A2 (en) 2005-06-20 2007-01-04 Psma Development Company, Llc Psma antibody-drug conjugates
WO2007077028A2 (en) 2005-12-30 2007-07-12 U3 Pharma Ag Antibodies directed to her-3 and uses thereof
US20070183971A1 (en) 2004-08-30 2007-08-09 Biotest Ag Immunoconjugates targeting syndecan-1 expressing cells and use thereof
WO2007133855A2 (en) 2006-03-27 2007-11-22 University Of Maryland Biotechnology Institute Glycoprotein synthesis and remodeling by enzymatic transglycosylation
WO2008100624A2 (en) 2007-02-16 2008-08-21 Merrimack Pharmaceuticals, Inc. Antibodies against erbb3 and uses thereof
WO2009052431A2 (en) 2007-10-19 2009-04-23 Seattle Genetics, Inc. Cd19 binding agents and uses thereof
WO2010124797A1 (en) 2009-04-29 2010-11-04 Bayer Schering Pharma Aktiengesellschaft Anti-mesothelin immunoconjugates and uses therefor
WO2013120066A1 (en) 2012-02-10 2013-08-15 University Of Maryland, Baltimore Chemoenzymatic glycoengineering of antibodies and fc fragments thereof
WO2014057687A1 (ja) 2012-10-11 2014-04-17 第一三共株式会社 抗体－薬物コンジュゲート
WO2014061277A1 (ja) 2012-10-19 2014-04-24 第一三共株式会社 親水性構造を含むリンカーで結合させた抗体－薬物コンジュゲート
US20150071949A1 (en) 2003-05-20 2015-03-12 Immunogen, Inc. Cytotoxic agents comprising new maytansinoids (dm4)
WO2015098099A1 (ja) 2013-12-25 2015-07-02 第一三共株式会社 抗ｔｒｏｐ２抗体－薬物コンジュゲート
WO2015115091A1 (ja) 2014-01-31 2015-08-06 第一三共株式会社 抗ｈｅｒ２抗体－薬物コンジュゲート
WO2015146132A1 (ja) 2014-03-26 2015-10-01 第一三共株式会社 抗ｃｄ９８抗体－薬物コンジュゲート
WO2015155998A1 (en) 2014-04-10 2015-10-15 Daiichi Sankyo Company, Limited Anti-her3 antibody-drug conjugate
WO2015155976A1 (ja) 2014-04-10 2015-10-15 第一三共株式会社 抗ｈｅｒ２抗体－薬物コンジュゲート
WO2017049149A1 (en) 2015-09-17 2017-03-23 Immunogen, Inc. Therapeutic combinations comprising anti-folr1 immunoconjugates
JP2017524364A (ja) * 2014-08-12 2017-08-31 ノバルティス アーゲー 抗ｃｄｈ６抗体薬物コンジュゲート
US20170252458A1 (en) 2016-03-02 2017-09-07 Eisai Co., Ltd. Eribulin-based antibody-drug conjugates and methods of use
US20170304438A1 (en) 2014-09-23 2017-10-26 Genentech, Inc. METHODS OF USING ANTI-CD79b IMMUNOCONJUGATES
WO2018135501A1 (ja) 2017-01-17 2018-07-26 第一三共株式会社 抗ｇｐｒ２０抗体及び抗ｇｐｒ２０抗体－薬物コンジュゲート
JP2018520140A (ja) * 2015-06-25 2018-07-26 イミューノメディクス、インコーポレイテッドＩｍｍｕｎｏｍｅｄｉｃｓ， Ｉｎｃ． 抗ｈｌａ‐ｄｒまたは抗ｔｒｏｐ‐２抗体と微小管阻害剤、ｐａｒｐ阻害剤、ブルトンキナーゼ阻害剤またはホスホイノシチド３‐キナーゼ阻害剤との併用は癌の治療効果を有意に改善する
WO2018212136A1 (ja) 2017-05-15 2018-11-22 第一三共株式会社 抗ｃｄｈ６抗体及び抗ｃｄｈ６抗体－薬物コンジュゲート
WO2019044947A1 (ja) 2017-08-31 2019-03-07 第一三共株式会社 抗体－薬物コンジュゲートの改良製造方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103239455A (zh) 2012-12-24 2013-08-14 苏州大学 有协同治疗效果和高载药量的多组分纳米药物的制备方法
AU2016286898B2 (en) 2015-06-29 2022-12-08 Daiichi Sankyo Company, Limited Method for selectively manufacturing antibody-drug conjugate
JP2018537536A (ja) 2015-12-09 2018-12-20 ナント ホールディングス アイピー エルエルシーＮａｎｔ Ｈｏｌｄｉｎｇｓ ＩＰ， ＬＬＣ Ｈｅｒ２陽性転移性乳癌の治療のための組成物および方法
KR20250040100A (ko) 2016-12-12 2025-03-21 다이이찌 산쿄 가부시키가이샤 항체-약물 콘주게이트와 면역 체크 포인트 저해제의 조합

Patent Citations (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990007861A1 (en) 1988-12-28 1990-07-26 Protein Design Labs, Inc. CHIMERIC IMMUNOGLOBULINS SPECIFIC FOR p55 TAC PROTEIN OF THE IL-2 RECEPTOR
US5821337A (en) 1991-06-14 1998-10-13 Genentech, Inc. Immunoglobulin variants
WO1999054342A1 (en) 1998-04-20 1999-10-28 Pablo Umana Glycosylation engineering of antibodies for improving antibody-dependent cellular cytotoxicity
WO2000061739A1 (fr) 1999-04-09 2000-10-19 Kyowa Hakko Kogyo Co., Ltd. Methode de regulation de l'activite d'une molecule immunologiquement fonctionnelle
WO2001000245A2 (en) 1999-06-25 2001-01-04 Genentech, Inc. HUMANIZED ANTI-ErbB2 ANTIBODIES AND TREATMENT WITH ANTI-ErbB2 ANTIBODIES
WO2002031140A1 (en) 2000-10-06 2002-04-18 Kyowa Hakko Kogyo Co., Ltd. Cells producing antibody compositions
US20150071949A1 (en) 2003-05-20 2015-03-12 Immunogen, Inc. Cytotoxic agents comprising new maytansinoids (dm4)
US20070183971A1 (en) 2004-08-30 2007-08-09 Biotest Ag Immunoconjugates targeting syndecan-1 expressing cells and use thereof
WO2006071441A2 (en) 2004-11-30 2006-07-06 Curagen Corporation Antibodies directed to gpnmb and uses thereof
WO2007002222A2 (en) 2005-06-20 2007-01-04 Psma Development Company, Llc Psma antibody-drug conjugates
WO2007077028A2 (en) 2005-12-30 2007-07-12 U3 Pharma Ag Antibodies directed to her-3 and uses thereof
WO2007133855A2 (en) 2006-03-27 2007-11-22 University Of Maryland Biotechnology Institute Glycoprotein synthesis and remodeling by enzymatic transglycosylation
WO2008100624A2 (en) 2007-02-16 2008-08-21 Merrimack Pharmaceuticals, Inc. Antibodies against erbb3 and uses thereof
WO2009052431A2 (en) 2007-10-19 2009-04-23 Seattle Genetics, Inc. Cd19 binding agents and uses thereof
WO2010124797A1 (en) 2009-04-29 2010-11-04 Bayer Schering Pharma Aktiengesellschaft Anti-mesothelin immunoconjugates and uses therefor
WO2013120066A1 (en) 2012-02-10 2013-08-15 University Of Maryland, Baltimore Chemoenzymatic glycoengineering of antibodies and fc fragments thereof
WO2014057687A1 (ja) 2012-10-11 2014-04-17 第一三共株式会社 抗体－薬物コンジュゲート
WO2014061277A1 (ja) 2012-10-19 2014-04-24 第一三共株式会社 親水性構造を含むリンカーで結合させた抗体－薬物コンジュゲート
WO2015098099A1 (ja) 2013-12-25 2015-07-02 第一三共株式会社 抗ｔｒｏｐ２抗体－薬物コンジュゲート
WO2015115091A1 (ja) 2014-01-31 2015-08-06 第一三共株式会社 抗ｈｅｒ２抗体－薬物コンジュゲート
WO2015146132A1 (ja) 2014-03-26 2015-10-01 第一三共株式会社 抗ｃｄ９８抗体－薬物コンジュゲート
WO2015155976A1 (ja) 2014-04-10 2015-10-15 第一三共株式会社 抗ｈｅｒ２抗体－薬物コンジュゲート
WO2015155998A1 (en) 2014-04-10 2015-10-15 Daiichi Sankyo Company, Limited Anti-her3 antibody-drug conjugate
JP2017524364A (ja) * 2014-08-12 2017-08-31 ノバルティス アーゲー 抗ｃｄｈ６抗体薬物コンジュゲート
US20170304438A1 (en) 2014-09-23 2017-10-26 Genentech, Inc. METHODS OF USING ANTI-CD79b IMMUNOCONJUGATES
JP2018520140A (ja) * 2015-06-25 2018-07-26 イミューノメディクス、インコーポレイテッドＩｍｍｕｎｏｍｅｄｉｃｓ， Ｉｎｃ． 抗ｈｌａ‐ｄｒまたは抗ｔｒｏｐ‐２抗体と微小管阻害剤、ｐａｒｐ阻害剤、ブルトンキナーゼ阻害剤またはホスホイノシチド３‐キナーゼ阻害剤との併用は癌の治療効果を有意に改善する
WO2017049149A1 (en) 2015-09-17 2017-03-23 Immunogen, Inc. Therapeutic combinations comprising anti-folr1 immunoconjugates
US20170252458A1 (en) 2016-03-02 2017-09-07 Eisai Co., Ltd. Eribulin-based antibody-drug conjugates and methods of use
WO2018135501A1 (ja) 2017-01-17 2018-07-26 第一三共株式会社 抗ｇｐｒ２０抗体及び抗ｇｐｒ２０抗体－薬物コンジュゲート
WO2018212136A1 (ja) 2017-05-15 2018-11-22 第一三共株式会社 抗ｃｄｈ６抗体及び抗ｃｄｈ６抗体－薬物コンジュゲート
WO2019044947A1 (ja) 2017-08-31 2019-03-07 第一三共株式会社 抗体－薬物コンジュゲートの改良製造方法

Non-Patent Citations (32)

* Cited by examiner, † Cited by third party
Title
"79", BRITISH JOURNAL OF CANCER, vol. 10, no. 5/6, 1999, pages 707 - 717
ALLEY, S. C. ET AL., CURRENT OPINION IN CHEMICAL BIOLOGY, vol. 14, 2010, pages 529 - 537
ANALYTICAL BIOCHEMISTRY, vol. 360, 2007, pages 75 - 83
BIO TECHNIQUES, vol. 28, January 2000 (2000-01-01), pages 162 - 165
CARMEN, S., BRIEFINGS IN FUNCTIONAL GENOMICS AND PROTEOMICS, vol. 1, no. 2, 2002, pages 189 - 203
CELL DEATH AND DIFFERENTIATION, vol. 15, 2008, pages 751 - 761
DAMLE N. K., EXPERT OPIN. BIOL. THER., vol. 4, 2004, pages 1445 - 1452
DOI T ET AL., LANCET ONCOL, vol. 18, 2017, pages 1512 - 22
DUCRY, L. ET AL., BIOCONJUGATE CHEM, vol. 21, 2010, pages 5 - 13
DUMONTET C ET AL., NAT REV DRUG DISCOV, vol. 9, no. 10, October 2010 (2010-10-01), pages 790 - 803
HERMANSON, G. T: "Bioconjugate Techniques", 1996, ACADEMIC PRESS, pages: 56 - 136,456-493
HOWARD A. ET AL., J CLIN ONCOL, vol. 29, pages 398 - 405
JOURNAL OF CHROMATOGRAPHY A, vol. 705, 1995, pages 129 - 134
KENNET, R.: "Monoclonal Antibodies", 1980, PLENUM PRESS, pages: 365 - 367
KOHLERMILSTEIN, NATURE, vol. 256, 1975, pages 495 - 497
KUROIWA, Y., NUCL. ACIDS RES., vol. 26, 1998, pages 3447 - 3448
MOLECULAR BIOLOGY OF THE CELL, vol. 15, December 2004 (2004-12-01), pages 5268 - 5282
MUKHTAR E ET AL., MOL CANCER THER, vol. 13, no. 2, February 2014 (2014-02-01), pages 275 - 284
NAGAI Y. ET AL., XENOBIOTICA, vol. 49, no. 9, 2019, pages 1086 - 96
NATURE, vol. 321, 1986, pages 522 - 525
OGITANI Y. ET AL., CANCER SCIENCE, vol. 107, 2016, pages 1039 - 1046
OGITANI Y. ET AL., CLINICAL CANCER RESEARCH, vol. 22, no. 20, 2016, pages 5097 - 5108
OGITANI Y. ET AL., CLINICAL CANCER RESEARCH, vol. 22, no. 20, 29 March 2016 (2016-03-29), pages 5097 - 5108
PROC. NATL. ACAD. SCI. USA, vol. 81, 1984, pages 6851 - 6855
See also references of EP3834843A4
SENTER P. D. ET AL., NATURE BIOTECHNOLOGY, vol. 30, 2012, pages 631 - 637
SIRIWARDENA, D., OPHTHALMOLOGY, vol. 109, no. 3, 2002, pages 427 - 431
TAKEGAWA N ET AL., INT. J. CANCER, vol. 141, 2017, pages 1682 - 1689
TOMIZUKA, K. ET AL., NATURE GENETICS, vol. 16, 1997, pages 133 - 143
TOMIZUKA, K., PROC. NATL. ACAD. SCI. USA, vol. 97, 2000, pages 722 - 727
WORMSTONE, I. M., INVESTIGATIVE OPHTHALMOLOGY VISUAL SCIENCE, vol. 43, no. 7, 2002, pages 2301 - 2308
ZOPPOLI G. ET AL., PROC NATL ACAD SCI U S A., vol. 109, no. 39, 2012, pages 15030 - 5

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WO2021200131A1 (ja) * 2020-03-30 2021-10-07 国立研究開発法人国立がん研究センター 抗体薬物複合体
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US12285492B2 (en) 2021-07-19 2025-04-29 Immunome, Inc. Immunoconjugates and methods
WO2024190815A1 (ja) * 2023-03-14 2024-09-19 第一三共株式会社 抗ｃｄｈ６抗体－薬物コンジュゲートとｖｅｇｆ阻害剤の組み合わせ
WO2024204679A1 (ja) * 2023-03-31 2024-10-03 第一三共株式会社 抗ＣＤＨ６抗体－薬物コンジュゲートとＨＩＦ－２α阻害剤の組み合わせ

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