JP6871858B2 - 抗体薬物コンジュゲート - Google Patents
抗体薬物コンジュゲート Download PDFInfo
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- JP6871858B2 JP6871858B2 JP2017540224A JP2017540224A JP6871858B2 JP 6871858 B2 JP6871858 B2 JP 6871858B2 JP 2017540224 A JP2017540224 A JP 2017540224A JP 2017540224 A JP2017540224 A JP 2017540224A JP 6871858 B2 JP6871858 B2 JP 6871858B2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
- C07K5/06052—Val-amino acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
- A61K47/6813—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin the drug being a peptidic cytokine, e.g. an interleukin or interferon
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6871—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting an enzyme
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
Description
YはOHまたはNH2であり、
R4はOH、NH2、F、Cl、Br、I、OR5であり、ここで、R5はC1〜C4アルキルである〕
のドラスタチン誘導体部分を含む化合物を提供する。
Abはモノクローナル抗体であり、
L1はコネクターであり、
L2はリンカーであり、
Dは式II
YはOまたはNHであり、波線は結合点を示し、
Xは−CH2N3または
の構造を有する活性物質であり、
nは1〜8の整数である〕
の構造を有する抗体薬物コンジュゲートまたはその薬学的に許容される塩を提供する。
Abはモノクローナル抗体であり、
L1はコネクターであり、
L2はリンカーであり、
Dは式II:
YはOまたはNHであり、波線は結合点を示し、
Xは−CH2N3または
の構造を有する活性物質であり、
nは1〜8の整数である〕
の構造を有する抗体薬物コンジュゲートまたはその薬学的に許容される塩を合成する方法であって、抗体上のLysと式III
Gは−F、−Cl、−Br、−I、−N3、−OR、SR、−ONRR、RC(=O)O−およびRSO2−O−から成る群から選択され;そして
Rは場合により置換されていてよいアルキルまたは場合により置換されていてよいアリールであり、
m=0または1である〕
を反応させることを含む、方法を提供する。
本発明は、ペプチドに基づくリンカー部分が、そのC末端に、制御された様式で抗体上のCysまたはLysのいずれか一方と反応する結合点を有する、ADC(抗体薬物コンジュゲート)のような化合物およびコンジュゲートを提供する。Lys接合については、例えば、DAR(薬物抗体比)は2である。Cys上で接合が起こるとき、大部分のコンジュゲートのDAR(薬物抗体比)は4である。
酸をDCM(塩化メチレン)に溶解し、必要ならば、溶解を助けるためにDMF(N,N’−ジメチルホルムアミド)を添加した。N−ヒドロキシスクシンイミド(1.5当量)を添加し、その後EDC.HCl(1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド)(1.5当量)を添加した。酸の大部分が消費されるまで、反応混合物を室温で1時間撹拌した。反応の進行をRP−HPLCにより観察した。混合物をその後DCMで希釈し、クエン酸(10%水溶液)および飽和食塩水で順次洗浄した。有機層を乾燥させ、濃縮乾固した。粗生成物を任意に、RP−HPLCまたはシリカゲルカラムクロマトグラフィーにより精製した。
化合物37(261mg、0.52mmol)のDMF(6mL)溶液に、HATU(217mg、0.57mmol)、DIEA(362μL、2.08mmol)およびアミン36(213mg、0.52mmol)を添加した。混合物を30分間撹拌し、その後ピペリジン400μLを添加し、10分間撹拌した。混合物を蒸発させ、HPLCにより精製し、化合物38(171mg、60%)を得た。MS m/z 548.3(M+H)。
化合物39(37mg、0.15mmol)のDMF(4mL)溶液に、HATU(59mg、0.15mmol)、DIEA(108μL、0.6mmol)およびアミン38(102mg、0.15mmol)を添加した。混合物を30分間撹拌し、その後蒸発乾固させた。残渣を2mLのDCMに溶解させ、その後1mLのTFAを添加し、10分間撹拌した。混合物を蒸発させ、HPLCにより精製し、化合物40(94mg、78%)を得た。MS m/z 673.4(M+H)。
化合物41(85mg、0.12mmol)のDMF(2mL)溶液に、HATU(48mg、0.12mmol)、DIEA(83μL、0.48mmol)およびアミン40(94mg、0.12mmol)を添加した。混合物を30分間撹拌し、その後NaOH(90mg)の水溶液(1mL)を添加し、30分間撹拌した。混合物をHPLCにより精製し、化合物4(86mg、58%)を得た。MS m/z 1239.7(M+H)。
化合物41(1000mg、1.67mmol)のDMF(20mL)溶液に、HATU(640mg、1.68mmol)、DIEA(870μL、5.00mmol)およびアミン45(535mg、1.67mmol)を添加した。混合物を30分間撹拌し、その後蒸発させ、HPLCにより精製し、化合物46(1140mg、70%)を得た。MS m/z 865.5(M+H)。
化合物46(500mg、0.57mmol)のDMA(10mL)溶液に、ビス(p−ニトロフェニル)カーボネート(210mg、0.69mmol)およびDIEA(35μL、0.2mmol)を添加した。混合物を18時間撹拌し、その後100mLのエーテルを添加し、析出物をろ過により回収し、化合物47(500mg、85%)を得た。MS m/z 1030.6(M+H)。
化合物47(125mg、0.12mmol)のDMF(4mL)溶液に、HOBt(7mg、0.05mmol)、DIEA(21μL、0.12mmol)およびアミン48(40mg、0.12mmol)を添加した。混合物を16時間撹拌し、その後200μLのピペリジンを添加し、10分間撹拌した。混合物を蒸発させ、HPLCにより精製し、化合物49(72mg、60%)を得た。MS m/z 1005.6(M+H)。
化合物49(30mg、0.027mmol)のDCM(2mL)溶液に、DIEA(15μL、0.086mmol)、DIEA(50μL、0.288mmol)および無水物50(19mg、0.027mmol)を添加した。混合物を30分間撹拌し、その後蒸発させ、HPLCにより精製し、化合物6(32mg、88%)を得た。MS m/z 1347.5(M+H)。
化合物46(120mg、0.12mmol)のDMF(3mL)溶液に、K2CO3(118mg、0.85mmol)およびブロモアセテート51(35mg、0.18mmol)を添加した。混合物を16時間撹拌し、その後蒸発させた。残渣を2mLのDCMに溶解させ、ろ過し、2mLのTFAを添加した。20分後、混合物を蒸発させ、HPLCにより精製し、化合物52(92mg、83%)を得た。MS m/z 923.5(M+H)。
化合物52(92mg、0.1mmol)のDMF(2mL)溶液に、HATU(38mg、0.1mmol)、DIEA(70μL、0.4mmol)およびboc−ヒドラジン(15mg、0.12mmol)を添加した。混合物を30分間撹拌し、その後蒸発乾固させた。残渣を2mLのDCMに溶解し、1mLのTFAを添加し、10分間撹拌した。混合物を蒸発させ、HPLCにより精製し、化合物53(82mg、78%)を得た。MS m/z 937.5(M+H)。
化合物54(53mg、0.156mmol)のDCM(2mL)溶液に、DIC(10mg、0.078mmol)を添加し、10分間撹拌した。その後DIEA(54μL、0.312mmol)およびアミン53(82mg、0.078mmol)を添加し、混合物を15分間撹拌した。混合物を蒸発させ、HPLCにより精製し、化合物9(62mg、63%)を得た。MS m/z 1260.5(M+H)。
Claims (9)
- 式I:
Abはモノクローナル抗体であり、
L1はコネクターであり、
L1−L2は、
L2はアミノ酸、ペプチド、−(CH2)n−、−(CH2CH2O)n−、−(C=O)、−Val−Cit−、−Val−Ala−、−Ala−Ala−Asn−、−Ala−Val−Asn−、−(C=O)CH2CH2(C=O)−、−(C=O)CH2CH2O)−、−(CH2CH2O)n−CH2CH2NH−、−(C=O)−CH2−、
Dは式II:
YはOまたはNHであり、
XはCH2N3である)
の構造を有する活性物質であり、
nは1〜8の整数である〕
を含む抗体薬物コンジュゲート(ADC)またはその薬学的に許容される塩。 - YがOHである、請求項1に記載の化合物またはその薬学的に許容される塩。
- YがNH2である、請求項1に記載の化合物またはその薬学的に許容される塩。
- 式I:
Abはモノクローナル抗体であり、
L 1 はコネクターであり、
L 1 −L 2 は、
L2が、
−(C=O)−、−CH2(C=O)−、−Cit−Val−(C=O)CH2CH2(C=O)−、Asn−Ala−Ala−(C=O)CH2CH2(C=O)、−Asn−Val−Ala−(C=O)CH2CH2(C=O)−、−Cit−Val−(C=O)CH2CH2OCH2CH2OCH2CH2−、−Cit−Val−(C=O)CH2CH2OCH2CH2OCH2CH2NH−、−Asn−Ala−Ala−(C=O)CH2CH2O(CH2CH2O)nCH2CH2NH(C=O)−、
Dは式II:
YはOまたはNHであり、
XはCH 2 N 3 である)
の構造を有する活性物質であり、
nは1〜8の整数である〕
を含む、抗体薬物コンジュゲート(ADC)またはその薬学的に許容される塩。 - YがNHである、請求項2に記載の抗体薬物コンジュゲート(ADC)またはその薬学的に許容される塩。
- YがOである、請求項2に記載の抗体薬物コンジュゲート(ADC)またはその薬学的に許容される塩。
- 式I:
Abはモノクローナル抗体であり、
Abと一体となった−L1−L2が、
L 2 はアミノ酸、ペプチド、−(CH 2 ) n −、−(CH 2 CH 2 O) n −、−(C=O)、−Val−Cit−、−Val−Ala−、−Ala−Ala−Asn−、−Ala−Val−Asn−、−(C=O)CH 2 CH 2 (C=O)−、−(C=O)CH 2 CH 2 O)−、−(CH 2 CH 2 O) n −CH 2 CH 2 NH−、−(C=O)−CH 2 −、
Dは式II:
YはOまたはNHであり、
XはCH 2 N 3 である)
の構造を有する活性物質であり、
nは1〜8の整数である〕
を含む、抗体薬物コンジュゲート(ADC)またはその薬学的に許容される塩。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US201562108894P | 2015-01-28 | 2015-01-28 | |
US62/108,894 | 2015-01-28 | ||
PCT/US2016/015482 WO2016123412A1 (en) | 2015-01-28 | 2016-01-28 | Antibody drug conjugates |
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JP2018512376A JP2018512376A (ja) | 2018-05-17 |
JP2018512376A5 JP2018512376A5 (ja) | 2019-03-07 |
JP6871858B2 true JP6871858B2 (ja) | 2021-05-19 |
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US (1) | US10590165B2 (ja) |
EP (2) | EP4137159A1 (ja) |
JP (1) | JP6871858B2 (ja) |
CN (1) | CN107849090A (ja) |
CA (1) | CA2975383C (ja) |
ES (1) | ES2918425T3 (ja) |
WO (1) | WO2016123412A1 (ja) |
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EP3925627A1 (en) | 2012-05-15 | 2021-12-22 | Concortis Biosystems, Corp | Drug-conjugates and uses thereof |
CA2934030A1 (en) | 2013-10-15 | 2015-04-23 | Sorrento Therapeutics Inc. | Drug-conjugates with a targeting molecule and two different drugs |
ES2916722T3 (es) | 2013-12-27 | 2022-07-05 | Zymeworks Inc | Sistemas de enlace que contienen sulfonamida para conjugados de fármacos |
IL287645B2 (en) | 2014-09-17 | 2024-04-01 | Zymeworks Bc Inc | Cytotoxic and anti-mitotic compounds and methods for their use |
US10590165B2 (en) | 2015-01-28 | 2020-03-17 | Sorrento Therapeutics, Inc. | Antibody drug conjugates |
CN106729743B (zh) * | 2015-11-23 | 2021-09-21 | 四川科伦博泰生物医药股份有限公司 | 抗ErbB2抗体-药物偶联物及其组合物、制备方法和应用 |
CN107029244B (zh) * | 2016-02-04 | 2021-04-27 | 浙江昭华生物医药有限公司 | 抗her2抗体-药物偶联物及其应用 |
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WO2018069851A2 (en) * | 2016-10-11 | 2018-04-19 | Sorrento Therapeutics, Inc. | C-met antibody drug conjugate |
CN108285487B (zh) * | 2017-01-08 | 2021-02-19 | 浙江昭华生物医药有限公司 | 抗5t4抗体-药物偶联物及其应用 |
CN110312730A (zh) | 2017-04-19 | 2019-10-08 | 四川科伦博泰生物医药股份有限公司 | 细胞毒素和偶联物、 其用途和制备方法 |
KR20200017519A (ko) * | 2017-06-20 | 2020-02-18 | 소렌토 쎄라퓨틱스, 인코포레이티드 | Cd38 항체 약물 접합체 |
CN107744592B (zh) * | 2017-09-15 | 2020-04-28 | 四川大学 | 抗cd56抗体与海兔毒素偶联复合物及其制备方法和用途 |
FR3112547B1 (fr) * | 2020-07-20 | 2023-01-20 | Mc Saf | Composés capables de se lier à des protéines et conjugués obtenus à partir de ces composés |
EP4301418A1 (en) | 2021-03-03 | 2024-01-10 | Sorrento Therapeutics, Inc. | Antibody-drug conjugates comprising an anti-bcma antibody |
WO2023173026A1 (en) | 2022-03-10 | 2023-09-14 | Sorrento Therapeutics, Inc. | Antibody-drug conjugates and uses thereof |
TW202400247A (zh) * | 2022-05-10 | 2024-01-01 | 美商索倫多醫療公司 | 包含抗folr1抗體之抗體藥物結合物 |
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