RU2017134348A - Конъюгаты антитело-лекарственное средство на основе криптофицина с новыми саморасщепляющимися линкерами - Google Patents

Конъюгаты антитело-лекарственное средство на основе криптофицина с новыми саморасщепляющимися линкерами Download PDF

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RU2017134348A
RU2017134348A RU2017134348A RU2017134348A RU2017134348A RU 2017134348 A RU2017134348 A RU 2017134348A RU 2017134348 A RU2017134348 A RU 2017134348A RU 2017134348 A RU2017134348 A RU 2017134348A RU 2017134348 A RU2017134348 A RU 2017134348A
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conjugate
antibody
conjugate according
alkyl
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RU2017134348A
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М. Кристиан ШТАЙНКУЛЕР
М. Паола ГАЛЛИНАРИ
Бьянка ОССВАЛЬД
Норберт ЗЕВАЛЬД
Маркус РИТЦЕФЕЛЬД
Марсель ФРЕЗЕ
Эдуард ФИГЕРАС
Лилла ПЕТО
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Эксирис С.Р.Л.
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • 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
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6863—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from stomach or intestines cancer cell
    • 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
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    • 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
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Claims (40)

1. Конъюгат формулы (I)
Figure 00000001
(I)
где R является -CO-CH2-X-(A)n-B
где X выбран из группы, состоящей из NRa, где Ra выбран из группы, состоящей из H и C1-C10-алкила и O;
A является саморасщепляющимся линкером,
n является 0 или 1;
B выбран из группы, состоящей из пептида, полипептида/белка и антитела
и его фармацевтически приемлемые соли.
2. Конъюгат по п.1, где антитело является моноклональным антителом или нанотелом.
3. Конъюгат по п.2, где нанотело выбрано из группы, состоящей из однодоменного антитела и антитела Верблюжьих.
4. Конъюгат антитело-лекарственное средство (ADC) по п.2, где моноклональное антитело выбрано из группы, состоящей из трастузумаба, гемтузумаба, брентуксимаба, ритуксимаба, цетуксимаба, панитумумаба, офатумумаба, обинутузумаба, пертузумаба.
5. Конъюгат по п.1, где пептид B связывается с рецепторами соматостатина.
6. Конъюгат (PDC) по п.5, где пептид выбран из группы, состоящей из октреотида, пасиреотида или ланреотида.
7. Конъюгат по любому из пп.1-6, где саморасщепляющийся линкер A является остатком формулы (II)
Figure 00000002
(II)
где R1 выбран из группы, состоящей из H, (C1-C10)-алкила, R2, необязательно, вместе с R1, является остатком боковой цепи аминокислоты, R3 выбран из группы, состоящей из H, (C1-C10)-алкила, R4, необязательно, вместе с R3, является остатком боковой цепи аминокислоты.
8. Конъюгат по любому из пп.1-6, где саморасщепляющийся линкер A выбран из группы, состоящей из
Figure 00000003
и
Figure 00000004
9. Конъюгат по п.7, имеющий формулу (III)
Figure 00000005
(III)
где R1, R2, R3 и R4 являются такими, как определено выше, X выбран из группы, состоящей из NH, N-(C1-C10)-алкила, O; mAb представляет собой моноклональное антитело, или нанотело, или пептид, или полипептид.
10. Конъюгат по п.7 формулы (IV)
Figure 00000006
(IV)
11. Конъюгат по п.1 формулы (V)
Figure 00000007
(V)
где R1 выбран из группы, состоящей из H, (C1-C10)-алкила, R4, необязательно, вместе с R1, является остатком боковой цепи аминокислоты; X выбран из группы, состоящей из NH, N-(C1-C10)-алкила O; mAb представляет собой моноклональное антитело, пептид или полипептид.
12. Конъюгат по п.6 формулы (VI)
Figure 00000008
(VI)
13. Фармацевтическая композиция, содержащая конъюгат по любому из пп.1-12 в качестве активного ингредиента в смеси по меньшей мере с одним фармацевтически приемлемым наполнителем и/или эксципиентом.
14. Конъюгат по любому из пп.1-12 для применения в качестве лекарственного средства.
15. Конъюгат для применения по п.14 для терапевтического лечения заболевания, выбранного из группы, состоящей из злокачественного новообразования, или аутоиммунного заболевания, или инфекционного заболевания.
16. Конъюгат по любому из пп.1-12 для применения в качестве диагностического средства.
17. Конъюгат для применения по п.16 для диагностики заболевания, выбранного из группы, состоящей из злокачественного новообразования, или аутоиммунного заболевания, или инфекционного заболевания.
RU2017134348A 2015-03-17 2016-03-15 Конъюгаты антитело-лекарственное средство на основе криптофицина с новыми саморасщепляющимися линкерами RU2017134348A (ru)

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EP15159327.4 2015-03-17
EP15159327.4A EP3069734A1 (en) 2015-03-17 2015-03-17 Cryptophycin-based antibody-drug conjugates with novel self-immolative linkers
PCT/EP2016/055599 WO2016146638A1 (en) 2015-03-17 2016-03-15 Cryptophycin-based antibody-drug conjugates with novel self-immolative linkers

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RU2017134348A3 RU2017134348A3 (ru) 2019-08-27

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US (1) US20180078656A1 (ru)
EP (2) EP3069734A1 (ru)
JP (1) JP2018517762A (ru)
KR (1) KR20180006879A (ru)
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