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RU2016123597A - Анти-her2 конъюгат антитела с лекарственным средством - Google Patents

Анти-her2 конъюгат антитела с лекарственным средством Download PDF

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Publication number
RU2016123597A
RU2016123597A RU2016123597A RU2016123597A RU2016123597A RU 2016123597 A RU2016123597 A RU 2016123597A RU 2016123597 A RU2016123597 A RU 2016123597A RU 2016123597 A RU2016123597 A RU 2016123597A RU 2016123597 A RU2016123597 A RU 2016123597A
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Prior art keywords
cancer
antibody
conjugate
drug
succinimid
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RU2016123597A
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English (en)
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RU2016123597A3 (ru
RU2683780C2 (ru
RU2683780C3 (ru
Inventor
Хиройуки НАИТО
Юсуке ОГИТАНИ
Такеси МАСУДА
Такаси НАКАДА
Масао Йосида
Синдзи АСИДА
Кодзи МОРИТА
Хидеки МИЯЗАКИ
Юдзи КАСУЯ
Итиро ХАЯКАВА
Юки АБЕ
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Дайити Санкио Компани, Лимитед
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    • C07—ORGANIC CHEMISTRY
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    • 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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Claims (122)

1. Конъюгат антитела с лекарственным средством, где противоопухолевое соединение, представленное следующей формулой:
[Формула 1]
Figure 00000001
конъюгировано с анти-HER2 антителом через связующую группу, имеющую структуру, представленную следующей формулой:
-L1-L2-LP-NH-(CH2)n1-La-(CH2)n2-C(=O)-
через тиоэфирную связь, которая формируется на дисульфидной связующей группе, присутствующей в шарнирной части анти-HER2 антитела,
где
анти-HER2 антитело соединено с концом L1,
противоопухолевое соединение соединено с карбонильной группой -(CH2)n2-C(=O)- части с атомом азота аминогруппы в положении 1 в качестве связующего положения,
где
n1 является целым числом от 0 до 6,
n2 является целым числом от 0 до 5,
L1 является -(Сукцинимид-3-ил-N)-(CH2)n3-C(=O)-,
где n3 является целым числом от 2 до 8,
L2 является -NH-(CH2CH2-O)n4-CH2CH2-C(=O)- или одинарной связью,
где n4 является целым числом от 1 до 6,
LP является пептидным остаток, состоящим из от 2 до 7 аминокислот,
La является -O- или одинарной связью, и
-(Сукцинимид-3-ил-N)- имеет структуру, представленную следующей формулой:
[Формула 2]
Figure 00000002
,
которая соединена с анти-HER2 антителом в положении 3, и соединена с метиленовой группой в связующей структуре, содержащей эту структуру, на атоме азота в положении 1.

2. Конъюгат антитела с лекарственным средством по п.1, где пептидным остатком LP является пептидный остаток, содержащий аминокислоту, выбранную из фенилаланина, глицина, валина, лизина, цитруллина, серина, глутаминовой кислоты и аспарагиновой кислоты.

3. Конъюгат антитела с лекарственным средством по п.1 или 2, где LP является пептидным остатком, выбранным из следующей группы:
-GGF-
-DGGF-
-(D-)D-GGF-
-EGGF-
-GGFG-
-SGGF-
-KGGF-
-DGGFG-
-GGFGG-
-DDGGFG-
-КДGGFG-
-GGFGGGF-
где "(D-)D" является D-аспарагиновой кислотой.

4. Конъюгат антитела с лекарственным средством по п.1 или 2, где LP является пептидным остатком, содержащим 4 аминокислоты.

5. Конъюгат антитела с лекарственным средством по любому из пп.1-4, где LP является тетрапептидным остатком -GGFG-.

6. Конъюгат антитела с лекарственным средством по любому из пп.1-5, где n3 является целым числом от 2 до 5 и L2 является одинарной связью.

7. Конъюгат антитела с лекарственным средством по любому из пп.1-5, где n3 является целым числом от 2 до 5, L2 является -NH-(CH2CH2-O)n4-CH2CH2-C(=O)- и n4 равно 2 или 4.

8. Конъюгат антитела с лекарственным средством по любому из пп.1-7, где -NH-(CH2)n1-La-(CH2)n2-C(=O)- является подструктурой, имеющей длину цепи от 4 до 7 атомов.

9. Конъюгат антитела с лекарственным средством по любому из пп.1-7, где -NH-(CH2)n1-La-(CH2)n2-C(=O)- является подструктурой, имеющей длину цепи 5 или 6 атомов.

10. Конъюгат антитела с лекарственным средством по любому из пп.1-9, где -NH-(CH2)n1-La-(CH2)n2-C(=O)- является любым из следующей группы:
-NH-CH2CH2-C(=O)-
-NH-CH2CH2CH2-C(=O)-
-NH-CH2CH2CH2CH2-C(=O)-
-NH-CH2CH2CH2CH2CH2-C(=O)-
-NH-CH2-O-CH2-C(=O)-
-NH-CH2CH2-O-CH2-C(=O)-
-NH-CH2CH2-O-C(=O)-

11. Конъюгат антитела с лекарственным средством по п.10, где -NH-(CH2)n1-La-(CH2)n2-C(=O)- является любым из следующей группы:
-NH-CH2CH2CH2-C(=O)-
-NH-CH2-O-CH2-C(=O)-
-NH-CH2CH2-O-CH2-C(=O)-

12. Конъюгат антитела с лекарственным средством по любому из пп.1-9, где структурой лекарственное средство-связующая группа, содержащей лекарственное средство, связанное с -L1-L2-LP-NH-(CH2)n1-La-(CH2)n2-C(=O)-, является одна из структур лекарственное средство-связующая группа, выбранных из следующей группы:
-(Сукцинимид-3-ил-N)-CH2CH2-C(=O)-GGFG-NH-CH2CH2-C(=O)-(NH-DX)
-(Сукцинимид-3-ил-N)-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-(NH-DX)
-(Сукцинимид-3-ил-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2-C(=O)-(NH-DX)
-(Сукцинимид-3-ил-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-(NH-DX)
-(Сукцинимид-3-ил-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2CH2CH2-C(=O)-(NH-DX)
-(Сукцинимид-3-ил-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX)
-(Сукцинимид-3-ил-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2-O-CH2-C(=O)-(NH-DX)
-(Сукцинимид-3-ил-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2-O-C(=O)-(NH-DX)
-(Сукцинимид-3-ил-N)-CH2CH2-C(=O)-NH-CH2CH2-O-CH2CH2-O-CH2CH2-C(=O)-GGFG-NH-CH2CH2-C(=O)-(NH-DX)
-(Сукцинимид-3-ил-N)-CH2CH2-C(=O)-NH-CH2CH2-O-CH2CH2-O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-(NH-DX)
-(Сукцинимид-3-ил-N)-CH2CH2-C(=O)-NH-CH2CH2-O-CH2CH2-O-CH2CH2-O-CH2CH2-O-CH2CH2-C(=O)-GGFG-NH-CH2CH2-C(=O)-(NH-DX)
-(Сукцинимид-3-ил-N)-CH2CH2-C(=O)-NH-CH2CH2-O-CH2CH2-O-CH2CH2-O-CH2CH2-O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-(NH-DX)
где -(Сукцинимид-3-ил-N)- имеет структуру, представленную следующей формулой:
[Формула 3]
Figure 00000003
,
которая соединена с анти-HER2 антителом в положении 3 и соединена с метиленовой группой в связующей структуре, содержащей эту структуру на атоме азота в положении 1,
-(NH-DX) является группой, представленной следующей формулой:
[Формула 4]
Figure 00000004
,
где атом азота аминогруппы в положении 1 является связующим положением, и
-GGFG- является тетрапептидным остатком -Gly-Gly-Phe-Gly-.

13. Конъюгат антитела с лекарственным средством по п.12, где структурой лекарственное средство-связующая группа является одна из структур лекарственное средство-связующая группа, выбранных из следующей группы:
-(Сукцинимид-3-ил-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX)
-(Сукцинимид-3-ил-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2-O-CH2-C(=O)-(NH-DX)
-(Сукцинимид-3-ил-N)-CH2CH2-C(=O)-NH-CH2CH2-O-CH2CH2-O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-(NH-DX)

14. Конъюгат антитела с лекарственным средством, где противоопухолевое соединение представлено следующей формулой:
[Формула 5]
Figure 00000005
и конъюгировано с анти-HER2 антителом через связующую группу, имеющую структуру, представленную следующей формулой:
-L1-L2-LP-NH-(CH2)n1-La-(CH2)n2-C(=O)-
через тиоэфирную связь, которая образуется на дисульфидной связи, присутствующей в шарнирной части анти-HER2 антитела,
где
анти-HER2 антитело соединено с концом L1,
противоопухолевое соединение соединено с карбонильной группой -(CH2)n2-C(=O)- группы,
где
n1 является целым числом от 0 до 6,
n2 является целым числом от 0 до 5,
L1 является -(Сукцинимид-3-ил-N)-(CH2)n3-C(=O)-,
где n3 является целым числом от 2 до 8,
L2 является -NH-(CH2CH2-O)n4-CH2CH2-C(=O)- или одинарной связью,
где n4 является целым числом от 1 до 6,
LP является тетрапептидным остатком -GGFG-,
La является -O- или одинарной связью, и
-(Сукцинимид-3-ил-N)- имеет структуру, представленную следующей формулой:
[Формула 6]
Figure 00000006
,
которая соединена с анти-HER2 антителом в положении 3 и соединена с метиленовой группой в связующей структуре, содержащей эту структуру, на атоме азота в положении 1.

15. Конъюгат антитела с лекарственным средством по п.14, где
n1 равно 3, n2 равно 0, n3 равно 2, L2 является -NH-(CH2CH2-O)n4-CH2CH2-C(=O)-, n4 равно 2 и La является одинарной связью,
n1 равно 1, n2 равно 1, n3 равно 5, L2 является одинарной связью и La является -O-, или
n1 равно 2, n2 равно 1, n3 равно 5, L2 является одинарной связью и La является -O-.

16. Конъюгат антитела с лекарственным средством по п.14 или 15, где n3 равно 2 или 5 и L2 является одинарной связью.

17. Конъюгат антитела с лекарственным средством по п.14 или 15, где n3 равно 2 или 5, L2 является -NH-(CH2CH2-O)n4-CH2CH2-C(=O)- и n4 равно 2 или 4.

18. Конъюгат антитела с лекарственным средством по любому из пп.14-17, где -NH-(CH2)n1-La-(CH2)n2-C(=O)- является любой из следующих групп:
-NH-CH2CH2CH2-C(=O)-
-NH-CH2-O-CH2-C(=O)-
-NH-CH2CH2-O-CH2-C(=O)-

19. Конъюгат антитела с лекарственным средством по любому из пп.1-18, где среднее количество единиц выбранной одной структуры лекарственное средство-связующая группа, конъюгированной с молекулой антитела составляет от 1 до 10.

20. Конъюгат антитела с лекарственным средством по любому из пп.1-18, где среднее количество единиц выбранной одной структуры лекарственное средство-связующая группа, конъюгированной с молекулой антитела составляет от 2 до 8.

21. Конъюгат антитела с лекарственным средством по любому из пп.1-18, где среднее количество единиц выбранной одной структуры лекарственное средство-связующая группа, конъюгированной с молекулой антитела составляет от 3 до 8.

22. Лекарственное средство, содержащее конъюгат антитела с лекарственным средством по любому из пп.1-21, его соль или его гидрат.

23. Противоопухолевое лекарственное средство и/или противораковое лекарственное средство, содержащее конъюгат антитела с лекарственным средством по любому из пп.1-21, его соль или его гидрат.

24. Противоопухолевое лекарственное средство и/или противораковое лекарственное средство по п.23, предназначенное для использования при раке легкого, уротелиальном раке, раке ободочной и прямой кишки, раке предстательной железы, раке яичников, раке поджелудочной железы, раке молочной железы, раке мочевого пузыря, раке желудка, гастроинтестинальной стромальной опухоли, раке шейки матки, раке пищевода, плоскоклеточном раке, перитонеальном раке, раке печени, печеночно-клеточном раке, раке толстой кишки, раке прямой кишки, раке ободочной и прямой кишки, раке эндометрия, раке матки, раке слюнной железы, раке почки, раке вульвы, раке щитовидной железы, раке полового члена, лейкемии, злокачественной лимфоме, плазмоцитоме, миеломе или саркоме.

25. Фармацевтическая композиция, содержащая конъюгат антитела с лекарственным средством по любому из пп.1-21, его соль или его гидрат, в качестве активного компонента, и фармацевтические приемлемый наполнитель.

26. Фармацевтическая композиция по п.25, предназначенная для использования при раке легкого, уротелиальном раке, раке ободочной и прямой кишки, раке предстательной железы, раке яичников, раке поджелудочной железы, раке молочной железы, раке мочевого пузыря, раке желудка, гастроинтестинальной стромальной опухоли, раке шейки матки, раке пищевода, плоскоклеточном раке, перитонеальном раке, раке печени, печеночно-клеточном раке, раке толстой кишки, раке прямой кишки, раке ободочной и прямой кишки, раке эндометрия, раке матки, раке слюнной железы, раке почки, раке вульвы, раке щитовидной железы, раке полового члена, лейкемии, злокачественной лимфоме, плазмоцитоме, миеломе или саркоме.

27. Способ лечения опухоли и/или рака, включающий введение конъюгата антитела с лекарственным средством по любому из пп.1-21, его соли или его гидрата.
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