RU2016129624A - Биспецифичные антитела против гаптена/против рецептора гематоэнцефалического барьера, их комплексы и их применение в качестве челноков гематоэнцефалического барьера - Google Patents

Биспецифичные антитела против гаптена/против рецептора гематоэнцефалического барьера, их комплексы и их применение в качестве челноков гематоэнцефалического барьера Download PDF

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RU2016129624A
RU2016129624A RU2016129624A RU2016129624A RU2016129624A RU 2016129624 A RU2016129624 A RU 2016129624A RU 2016129624 A RU2016129624 A RU 2016129624A RU 2016129624 A RU2016129624 A RU 2016129624A RU 2016129624 A RU2016129624 A RU 2016129624A
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receptor
haptenylated
cargo
blood
brain barrier
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RU2016129624A
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RU2016129624A3 (ru
RU2693438C2 (ru
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Ульрих БРИНКМАНН
Гай ГЕОРГЕС
Олаф МУНДИГЛЬ
Енс НИВЁНЕР
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Ф. Хоффманн-Ля Рош Аг
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Claims (39)

1. Применение ковалентного конъюгата, содержащего:
i) биспецифичное антитело, которое имеет первый функционал связывания, который специфично связывается с гаптенилированным грузом, и второй функционал связывания, который специфично связывается с рецептором гематоэнцефалического барьера, и
ii) гаптенилированный груз,
где гаптенилированный груз специфично связывается первым функционалом связывания,
где ковалентный конъюгат имеет ковалентную связь между гаптенилированным грузом и первым функционалом связывания, который специфично связывается с гаптенилированным грузом, и
где гаптенилированный груз выбран из группы, состоящей из биотинилированных грузов, теофиллинированных грузов, дигоксигенилированных грузов, карборанилированных грузов, флуоресцеинилированных грузов, хеликарилированных грузов и бромдезоксиуридинилированных грузов,
для целевой доставки гаптенилированного груза через гематоэнцефалический барьер.
2. Применение по п. 1, где применение предназначено для целевой доставки свободного (т.е. выделенного) гаптенилированного груза через гематоэнцефалический барьер.
3. Применение по п. 1, где рецептор гематоэнцефалического барьера выбран из группы, состоящей из рецептора трансферрина (TfR), рецептора инсулина, рецептора инсулиноподобного фактора роста (рецептор IGF), белка 8, родственного рецептору липопротеина низкой плотности (LRP8), белка 1, родственного рецептору липопротеина низкой плотности (LRP1), и фактора роста, подобного гепаринсвязывающему эпидермальному фактору роста (HB-EGF).
4. Применение по п. 1, где рецептор гематоэнцефалического барьера представляет собой рецептор трансферрина или белок 8, родственный рецептору липопротеина низкой плотности.
5. Применение по п. 1, где биспецифичное антитело не имеет эффекторной функции.
6. Применение по п. 1, где биспецифичное антитело содержит:
а) один сайт связывания для гаптенилированного груза и один сайт связывания для рецептора гематоэнцефалического барьера или
б) два сайта связывания для гаптенилированного груза и один сайт связывания для рецептора гематоэнцефалического барьера, или
в) один сайт связывания для гаптенилированного груза и два сайта связывания для рецептора гематоэнцефалического барьера, или
г) два сайта связывания для гаптенилированного груза и два сайта связывания для рецептора гематоэнцефалического барьера.
7. Применение по п. 1, где биспецифичное антитело содержит остаток цистеина в остатке амиокислоты в CDR2 антитела, при этом CDR2 определяется согласно Kabat.
8. Применение по любому из пп. 1-7, где ковалентная связь образуется между остатком цистеина в CDR2 антитела и тиольной группой в гаптенилированном грузе.
9. Ковалентный конъюгат, содержащий:
i) биспецифичное антитело, которое имеет первый функционал связывания, который специфично связывается с гаптенилированным грузом, и второй функционал связывания, который специфично связывается с рецептором гематоэнцефалического барьера, и
ii) гаптенилированный груз,
где гаптенилированный груз специфично связывается первым функционалом связывания,
где ковалентный конъюгат имеет ковалентную связь между гаптенилированным грузом и первым функционалом связывания, который специфично связывается с гаптенилированным грузом, и
где гаптенилированный груз выбран из группы, состоящей из биотинилированных грузов, теофиллинированных грузов, дигоксигенилированных грузов, карборанилированных грузов, флуоресцеинилированных грузов, хеликарилированных грузов и бромдезоксиуридинилированных грузов.
10. Конъюгат по п. 9, где рецептор гематоэнцефалического барьера выбран из группы, состоящей из рецептора трансферрина (TfR), рецептора инсулина, рецептора инсулиноподобного фактора роста (рецептор IGF), белка 8, родственного рецептору липопротеина низкой плотности (LRP8), белка 1, родственного рецептору липопротеина низкой плотности (LRP1), и фактора роста, подобного гепаринсвязывающему эпидермальному фактору роста (HB-EGF).
11. Конъюгат по п. 9, где рецептор гематоэнцефалического барьера представляет собой рецептор трансферрина или белок 8, родственный рецептору липопротеина низкой плотности.
12. Конъюгат по п. 9, где биспецифичное антитело не имеет эффекторной функции.
13. Конъюгат по п. 9, где биспецифичное антитело содержит:
а) один сайт связывания для гаптенилированного груза и один сайт связывания для рецептора гематоэнцефалического барьера или
б) два сайта связывания для гаптенилированного груза и один сайт связывания для рецептора гематоэнцефалического барьера, или
в) один сайт связывания для гаптенилированного груза и два сайта связывания для рецептора гематоэнцефалического барьера, или
г) два сайта связывания для гаптенилированного груза и два сайта связывания для рецептора гематоэнцефалического барьера.
14. Конъюгат по п. 9, где биспецифичное антитело содержит остаток цистеина в остатке аминокислоты в CDR2 антитела, при этом CDR2 определяется согласно Kabat.
15. Конъюгат по п. 9, где ковалентная связь образуется между остатком цистеина в CDR2 антитела и тиольной группой в гаптенилированном грузе.
16. Конъюгат по п. 9, где CDR2 представляет собой CDR2 тяжелой цепи, и цистеин находится в положении 52b или 53 согласно нумерации по Kabat.
17. Конъюгат по п. 9, где CDR2 представляет собой CDR2 легкой цепи, и цистеин находится в положении 55 или 51 согласно нумерации по Kabat.
18. Фармацевтическая композиция, содержащая конъюгат по любому из пп. 9-17 и фармацевтически приемлемый носитель.
19. Конъюгат по любому из пп. 9-17 для применения в качестве лекарственного средства.
20. Конъюгат по любому из пп. 9-17 для лечения рака или неврологического расстройства.
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