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RU2018134379A - Олигонуклеотиды для понижения экспрессии pd-l1 - Google Patents

Олигонуклеотиды для понижения экспрессии pd-l1 Download PDF

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RU2018134379A
RU2018134379A RU2018134379A RU2018134379A RU2018134379A RU 2018134379 A RU2018134379 A RU 2018134379A RU 2018134379 A RU2018134379 A RU 2018134379A RU 2018134379 A RU2018134379 A RU 2018134379A RU 2018134379 A RU2018134379 A RU 2018134379A
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conjugate
oligonucleotide
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oligonucleotide according
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RU2018134379A
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RU2747822C2 (ru
RU2018134379A3 (ru
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Люкке ПЕДЕРСЕН
Хассан ЯВАНБАКХТ
Малене ЯКЕРОТТ
Сёрен ОТТОСЕН
Суфалон ЛУАНГСЭЙ
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Ф. Хоффманн-Ля Рош Аг
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Claims (26)

1. Конъюгат антисмыслового олигонуклеотида, содержащий:
а. олигонуклеотид (область А), содержащий непрерывную нуклеотидную последовательность из 10-30 нуклеотидов в длину с по меньшей мере 90%-ной комплементарностью с нуклеиновой кислотой-мишенью PD-L1;
и
б. по меньшей мере одну конъюгатную группировку, нацеленную на рецептор асиалогликопротеина (область С), ковалентно присоединенную к олигонуклеотиду в а).
2. Конъюгат олигонуклеотида по п. 1, в котором непрерывная нуклеотидная последовательность является комплементарной нуклеиновой кислоте-мишени, выбранной из группы, состоящей из SEQ ID NO: 1, SEQ ID NO: 2 и/или SEQ ID NO: 3.
3. Конъюгат олигонуклеотида по п. 1 или 2, в котором непрерывная нуклеотидная последовательность является комплементарной подпоследовательности нуклеиновой кислоты-мишени, где данная подпоследовательность выбрана из группы, состоящей из положения 371-3068, 5467-12107 и 15317-19511 на SEQ ID NO: 1.
4. Конъюгат олигонуклеотида по пп. 1-3, в котором непрерывная нуклеотидная последовательность является комплементарной подпоследовательности нуклеиновой кислоты-мишени, где данная подпоследовательность выбрана из группы, состоящей из A221, A360, A180, A160 и A269.
5. Конъюгат олигонуклеотида по пп. 1-4, где олигонуклеотид содержит последовательность, выбранную из SEQ ID NO: 466, 640, 342, 287 и 566.
6. Конъюгат олигонуклеотида по пп. 1-5, где непрерывная нуклеотидная последовательность содержит один или более чем один модифицированный нуклеозид, такой как один или более чем один нуклеозид, модифицированный 2'-сахаром.
7. Конъюгат олигонуклеотида по 6, в котором один или более чем один нуклеозид, модифицированный 2'-сахаром, независимо выбран из группы, состоящей из нуклеозидов 2'-O-алкил-РНК, 2'-O-метил-РНК, 2'-алкокси-РНК, 2'-O-метоксиэтил-РНК, 2'-амино-ДНК, 2'-фтор-ДНК, арабинонуклеиновой кислоты (ANA), 2'-фтор-ANA и LNA.
8. Конъюгат олигонуклеотида по любому из пп. 6 или 7, в котором все модифицированные нуклеозиды представляют собой нуклеозиды LNA.
9. Конъюгат олигонуклеотида по любому из пп. 1-8, в котором непрерывная нуклеотидная последовательность содержит по меньшей мере одну модифицированную межнуклеозидную связь, такую как по меньшей мере одна фосфоротиоатная межнуклеозидная связь.
10. Конъюгат олигонуклеотида по любому из пп. 1-9, в котором олигонуклеотид представляет собой гэпмер.
11. Конъюгат олигонуклеотида по п. 10, в котором гэпмер имеет формулу 5'-D'-F-G-F'-3' или 5'-F-G-F'-D''-3', где область F и F' независимо содержит 1-7 модифицированных нуклеозидов, G представляет собой область из 6-16 нуклеозидов, которая способна рекрутировать РНКазу Н, и область D' или D'' является опционной и содержит 0-5 нуклеозидов, связанных фосфодиэфирной связью.
12. Конъюгат олигонуклеотида по любому из пп. 1-11, в котором конъюгатная группировка, нацеленная на рецептор асиалогликопротеина, содержит по меньшей мере одну углеводную группировку, выбранную из группы, состоящей из галактозы, галактозамина, N-формил-галактозамина, N-ацетилгалактозамина, N-пропионил-галактозамина, N-н-бутаноил-галактозамина и N-изобутаноилгалактозамина.
13. Конъюгат олигонуклеотида по любому из пп. 1-12, в котором конъюгатная группировка, нацеленная на рецептор асиалогликопротеина, является одновалентной, двухвалентной, трехвалентной или четырехвалентной.
14. Конъюгат олигонуклеотида по любому из пп. 1-13, в котором конъюгатная группировка, нацеленная на рецептор асиалогликопротеина, является трехвалентной N-ацетилгалактозаминной (GalNAc) группировкой.
15. Конъюгат олигонуклеотида по любому из пп. 1-14, в котором конъюгатная группировка, нацеленная на рецептор асиалогликопротеина, представляет собой трехвалентную GalNAc группировку на Фиг. 3.
16. Конъюгат олигонуклеотида по любому из пп. 1-15, где конъюгат олигонуклеотида выбран из CMP ID NO: 766_2, 767_2, 768_2, 769_2 и 770_2.
17. Антисмысловой олигонуклеотид, содержащий олигонуклеотид или непрерывную нуклеотидную последовательность по любому из пп. 1-11.
18. Фармацевтическая композиция, содержащая конъюгат олигонуклеотида по пп. 1-16 или олигонуклеотиды по п. 17 и фармацевтически приемлемый разбавитель, растворитель, носитель, соль и/или адъювант.
19. Способ in vivo или in vitro модулирования экспрессии PD-L1 в клетке-мишени, которая экспрессирует PD-L1, причем указанный способ включает введение в указанную клетку конъюгата олигонуклеотида по пп. 1-16 или олигонуклеотидов по п. 17 в эффективном количестве.
20. Применение конъюгата олигонуклеотида по пп. 1-16 или олигонуклеотида по п. 17 или фармацевтической композиции по п. 18 для восстановления иммунного ответа против вируса или паразита.
21. Применение по п. 20, при котором восстановление иммунного ответа представляет собой увеличение в печени уровня Т-клеток CD8+, специфичных в отношении одного или более чем одного антигена HBV, по сравнению с контролем.
22. Применение конъюгата олигонуклеотида по пп. 1-16 или олигонуклеотида по п. 17 или фармацевтической композиции по п. 18 для лечения или предупреждения вирусных инфекций печени, таких как HBV, HCV и HDV; паразитарных инфекций, таких как малярия, токсоплазмоз, лейшманиоз и трипаносомоз; или рака печени или метастазов в печени.
23. Применение конъюгата олигонуклеотида по пп. 1-16 или олигонуклеотидов по п. 17 или фармацевтической композиции по п. 18 для получения лекарственного средства для лечения или предупреждения вирусных инфекций печени, таких как инфекции HBV, HCV и HDV; паразитарных инфекций, таких как малярия, токсоплазмоз, лейшманиоз и трипаносомоз; или рака печени, или метастазов в печени.
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