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RU2019107788A - Анти-her2 конъюгат антитела с лекарственным средством - Google Patents

Анти-her2 конъюгат антитела с лекарственным средством Download PDF

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Publication number
RU2019107788A
RU2019107788A RU2019107788A RU2019107788A RU2019107788A RU 2019107788 A RU2019107788 A RU 2019107788A RU 2019107788 A RU2019107788 A RU 2019107788A RU 2019107788 A RU2019107788 A RU 2019107788A RU 2019107788 A RU2019107788 A RU 2019107788A
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Russia
Prior art keywords
ggfg
maleimide
amino acid
drug
antibody
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RU2019107788A
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RU2794183C2 (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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Claims (70)

1. Способ получения конъюгата антитела с лекарственным средством, включающий взаимодействие соединения, представленного следующей формулой:
(малеимид-N-ил)-(CH2)n3-C(=O)-L2-LP-NH-(CH2)n1-La-(CH2)n2-C(=O)-(NH-DX)
с анти-HER2 антителом или его реакционно-способным производным, и конъюгирование группы линкер-лекарственное средство с антителом, способом, с образованием тиоэфирной связи на участке дисульфидных связей, представленных в шарнирной части антитела,
где
n1 является целым числом от 0 до 6,
n2 является целым числом от 0 до 5,
n3 является целым числом от 2 8,
L2 представляет собой -NH-(CH2CH2-O)n4-CH2CH2-C(=O)- или одинарную связь,
где n4 является целым числом от 1 до 6,
LP представляет собой пептидный остаток, состоящий из от 2 до 7 аминокислот, выбранных из фенилаланина, глицина, валина, лизина, цитруллина, серина, глутаминовой кислоты и аспарагиновой кислоты,
La представляет собой -O- или одинарную связь, и
(малеимид-N-ил)- представляет собой группу, представленную следующей формулой:
Figure 00000001
где атом азота находится в связующем положении, и
-(NH-DX) представляет собой группу, представленную следующей формулой:
Figure 00000002
где атом азота аминогруппы в положении 1 находится в связующем положении.
2. Способ по п.1, где LP представляет собой тетрапептидный остаток -GGFG-.
3. Способ по п.1, где соединение является соединением, выбранным из следующей группы:
(малеимид-N-ил)-CH2CH2-C(=O)-GGFG-NH-CH2CH2-C(=O)-(NH-DX),
(малеимид-N-ил)-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-(NH-DX),
(малеимид-N-ил)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2-C(=O)-(NH-DX),
(малеимид-N-ил)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-(NH-DX),
(малеимид-N-ил)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2CH2CH2-C(=O)-(NH-DX),
(малеимид-N-ил)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX),
(малеимид-N-ил)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2-O-CH2-C(=O)-(NH-DX),
(малеимид-N-ил)-CH2CH2-C(=O)-NH-CH2CH2-O-CH2CH2-O-CH2CH2-C(=O)-GGFG-NH-CH2CH2-C(=O)-(NH-DX),
(малеимид-N-ил)-CH2CH2-C(=O)-NH-CH2CH2-O-CH2CH2-O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-(NH-DX),
(малеимид-N-ил)-CH2CH2-C(=O)-NH-CH2CH2-O-CH2CH2-O-CH2CH2-O-CH2CH2-O-CH2CH2-C(=O)-GGFG-NH-CH2CH2-C(=O)-(NH-DX), и
(малеимид-N-ил)-CH2CH2-C(=O)-NH-CH2CH2-O-CH2CH2-O-CH2CH2-O-CH2CH2-O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-(NH-DX).
4. Способ по п.3, где соединение является соединением, выбранным из следующей группы:
(малеимид-N-ил)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX),
(малеимид-N-ил)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2-O-CH2-C(=O)-(NH-DX), и
(малеимид-N-ил)-CH2CH2-C(=O)-NH-CH2CH2-O-CH2CH2-O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-(NH-DX).
5. Способ по п.4, где соединение представляет собой:
(малеимид-N-ил)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX).
6. Способ по п.4, где структурная группа линкер-лекарственное средство представляет собой:
(малеимид-N-ил)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2-O-CH2-C(=O)-(NH-DX).
7. Способ по п.4, где структурная группа линкер-лекарственное средство представляет собой:
(малеимид-N-ил)-CH2CH2-C(=O)-NH-CH2CH2-O-CH2CH2-O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-(NH-DX).
8. Способ по п.1, где конъюгат антитела с лекарственным средством содержит структуру линкер-лекарственное средство, представленную следующей формулой:
-(cукцинимид-3-ил-N)-(CH2)n3-C(=O)-L2-LP-NH-(CH2)n1-La-(CH2)n2-C(=O)-(NH-DX),
которая конъюгирована с анти-HER2 антителом через тиоэфирную связь, образованную на участке дисульфидных связей, представленных в шарнирной части анти-HER2 антитела.
9. Способ по п.5, где конъюгат антитела с лекарственным средством содержит структуру линкер-лекарственное средство, представленную следующей формулой:
-(cукцинимид-3-ил-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)-(NH-DX),
которая конъюгирована с анти-HER2 антителом через тиоэфирную связь, образованную на участке дисульфидных связей, представленных в шарнирной части анти-HER2 антитела.
10. Способ по п.6, где конъюгат антитела с лекарственным средством содержит структуру линкер-лекарственное средство, представленную следующей формулой:
-(cукцинимид-3-ил-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2-O-CH2-C(=O)-(NH-DX),
которая конъюгирована с анти-HER2 антителом через тиоэфирную связь, образованную на участке дисульфидных связей, представленных в шарнирной части анти-HER2 антитела.
11. Способ по п.7, где конъюгат антитела с лекарственным средством содержит структуру линкер-лекарственное средство, представленную следующей формулой:
-(cукцинимид-3-ил-N)-CH2CH2-C(=O)-NH-CH2CH2-O-CH2CH2-O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-(NH-DX),
которая конъюгирована с анти-HER2 антителом через тиоэфирную связь, образованную на участке дисульфидных связей, представленных в шарнирной части анти-HER2 антитела.
12. Способ по любому из пп. 1-11, где анти-HER2 антитело содержит тяжелую цепь, состоящую из аминокислотной последовательности, состоящей из остатков аминокислот 1-449 последовательности SEQ ID NO: 1, и легкую цепь, состоящую из аминокислотной последовательности, представленной как SEQ ID NO: 2.
13. Способ по любому из пп. 1-11, где анти-HER2 антитело содержит тяжелую цепь, состоящую из аминокислотной последовательности, представленной как SEQ ID NO: 1, и легкую цепь, состоящую из аминокислотной последовательности, представленной как SEQ ID NO: 2.
14. Способ по любому из пп. 1-11, где среднее количество структурных единиц выбранных конъюгированных структур линкер-лекарственное средство на одно антитело составляет от 2 до 8.
15. Способ по любому из пп. 1-11, где среднее количество структурных единиц выбранных конъюгированных структур линкер-лекарственное средство на одно антитело составляет от 3 до 8.
16. Способ получения конъюгат антитела с лекарственным средством, представленного следующей формулой:
Figure 00000003
где n представляет среднее количество структурных единиц конъюгированных структур линкер-лекарственное средство на одно анти-HER2 антитело,
и где анти-HER2 антитело содержит:
тяжелую цепь, состоящую из аминокислотной последовательности, состоящей из остатков аминокислот 1-449 последовательности SEQ ID NO: 1, и аминокислотной последовательности легкой цепи, состоящую из остатков аминокислот 1-214 последовательности SEQ ID NO: 2, или
аминокислотную последовательность тяжелой цепи, состоящую из последовательности SEQ ID NO: 1, и легкую цепь, состоящую из аминокислотной последовательности SEQ ID NO: 2,
и где способ включает стадии:
обработки анти-HER2 антитела в восстанавливающих условиях, а затем
взаимодействия анти-HER2 антитела с соединением, представленным следующей формулой:
Figure 00000004
.
17. Способ по п.16, где аминокислотная последовательность тяжелой цепи анти-HER2 антитела состоит из остатков аминокислот 1-449 последовательности SEQ ID NO: 1, и аминокислотная последовательность легкой цепи анти-HER2 антитела состоит из остатков аминокислот 1-214 последовательности SEQ ID NO: 2.
18. Способ по п.16, где аминокислотная последовательность тяжелой цепи анти-HER2 антитела состоит из аминокислотной последовательности SEQ ID NO: 1, и аминокислотная последовательность легкой цепи анти-HER2 антитела состоит из аминокислотной последовательности SEQ ID NO: 2.
19. Способ по любому из пп. 16-18, где значение n находится в диапазоне от 2 до 8.
20. Способ по любому из пп. 16-18, где значение n находится в диапазоне от 3 до 8.
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