RU2005125430A - Терапевтические полипептиды, их гомологи, их фрагментыи и их применение для модуляции агрегации, опосредованной тромбоцитами - Google Patents

Терапевтические полипептиды, их гомологи, их фрагментыи и их применение для модуляции агрегации, опосредованной тромбоцитами Download PDF

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RU2005125430A
RU2005125430A RU2005125430/13A RU2005125430A RU2005125430A RU 2005125430 A RU2005125430 A RU 2005125430A RU 2005125430/13 A RU2005125430/13 A RU 2005125430/13A RU 2005125430 A RU2005125430 A RU 2005125430A RU 2005125430 A RU2005125430 A RU 2005125430A
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Prior art keywords
polypeptide construct
construct according
polypeptide
platelet
formation
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RU2005125430/13A
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English (en)
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RU2357974C2 (ru
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Карен СИЛАНС (BE)
Карен СИЛАНС
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Аблинкс Н.В. (Be)
Аблинкс Н.В.
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Priority claimed from PCT/BE2003/000190 external-priority patent/WO2004041867A2/en
Priority claimed from PCT/BE2003/000194 external-priority patent/WO2004041863A2/en
Application filed by Аблинкс Н.В. (Be), Аблинкс Н.В. filed Critical Аблинкс Н.В. (Be)
Publication of RU2005125430A publication Critical patent/RU2005125430A/ru
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Claims (34)

1. Полипептидная конструкция, включающая по меньшей мере, одно однодоменное антитело, направленное против любого из vWF, A1 домена vWF, A1 домена активированного vWF, A3 домена vWF, gplb и коллагена.
2. Полипептидная конструкция по п.1, дополнительно включающая, по меньшей мере, одно однодоменное антитело, направленное против одного или более сывороточных белков.
3. Полипептидная конструкция по п.2, в которой указанный, по меньшей мере, один сывороточный белок является любым из сывороточного альбумина, иммуноглобулинов сыворотки, тироксин-связывающего белка, трансферрина или фибриногена и их фрагментов.
4. Полипептидная конструкция по п.2, в которой, по меньшей мере, одно однодоменное антитело, направленное против одного или более сывороточных белков, соответствует последовательности, представленной любой из SEQ ID NO: с 16 по 19 и с 49 по 61.
5. Полипептидная конструкция по п.2, соответствующая последовательности, представленной любой из SEQ ID NO: с 13 по 15 и с 42 по 45.
6. Полипептидная конструкция по п.1, в которой, по меньшей мере, одно однодоменное антитело представляет собой гуманизированную последовательность.
7. Полипептидная конструкция по п.6, в которой, по меньшей мере, одно однодоменное антитело соответствует последовательности, представленной любой из SEQ ID NO: с 38 по 41 и с 42 по 45.
8. Полипептидная конструкция п.1, соответствующая последовательности, представленной любой из SEQ ID NO: с 8 по 12, с 20 по 22, с 32 по 34 и с 46 по 47.
9. Полипептидная конструкция по п.1, в которой, по меньшей мере, одно однодоменное антитело является антителом VHH Camelidae.
10. Полипептидная конструкция по п.1, в которой, по меньшей мере, одно однодоменное антитело соответствует последовательности, представленной любой из SEQ ID NO: с 1 по 7, с 23 по 31, с 35 по 37 и с 62 по 65.
11. Полипептидная конструкция по п.1, в которой указанное однодоменное антитело является гомологичной последовательностью, функциональной частью или функциональной частью гомологичной последовательности полноразмерного однодоменного антитела.
12. Полипептидная конструкция по п.1, где указанная полипептидная конструкция является гомологичной последовательностью указанной полипептидной конструкции, ее функциональной частью, или гомологичной последовательностью ее функциональной части.
13. Нуклеиновая кислота, кодирующая полипептидную конструкцию по любому из пп.1-12.
14. Композиция, содержащая полипептидную конструкцию по п.1 и, по меньшей мере, один тромболитический агент, для одновременного, последовательного или раздельного введения пациенту.
15. Композиция по п.14, в которой указанный тромболитический агент является любым из стафилокиназы, тканевого активатора плазминогена, стрептокиназы, одноцепочечной стрептокиназы, урокиназы и комплекса ацил-плазминогена и стрептокиназы.
16. Полипептидная конструкция по любому из пп.1-12 для применения в лечении, профилактике и/или облегчении симптомов нарушений, связанных с опосредованной тромбоцитами агрегацией или ее дисфункцией.
17. Применение полипептидной конструкции по любому из пп.1-12 для получения лекарственного средства для лечения, профилактики и/или облегчения симптомов нарушений, связанных с опосредованной тромбоцитами агрегацией или ее дисфункцией.
18. Полипептидная конструкция по п.16, где названные нарушения являются любыми из возникающих в результате кратковременного ишемического повреждения головного мозга, нестабильной или стабильной стенокардии, грудной жабы, инсульта головного мозга, инфаркта миокарда, закупорки периферических артерий, рестеноза, шунтирования коронарных сосудов, замены сердечного клапана или оперативных вмешательств на сердце, таких как ангиопластика, эндопротезирование, эндартерэктомия сонной артерии или атерэктомия.
19. Полипептидная конструкция по п.16, где названные нарушения являются любыми из возникающих в результате образования неокклюзивных тромбов, образования окклюзивных тромбов, образования артериальных тромбов, острой коронарной окклюзии, рестеноза, рестеноза после РСТА или эндопротезирования, образования тромбов в стенозированных артериях, гиперплазии после ангиопластики, атерэктомии или эндопротезирования артерий, окклюзивного синдрома сосудистой системы или потери проницаемости больных артерий.
20. Применение по п.17, где названные нарушения являются любыми из возникающих в результате кратковременного ишемического повреждения головного мозга, нестабильной или стабильной стенокардии, грудной жабы, инсульта головного мозга, инфаркта миокарда, закупорки периферических артерий, рестеноза, шунтирования коронарных сосудов, замены сердечного клапана или оперативных вмешательств на сердце, таких как ангиопластика, эндопротезирование, эндартерэктомия сонной артерии или атерэктомия.
21. Применение по п.17, где названные нарушения являются любыми из возникающих в результате образования неокклюзивных тромбов, образования окклюзивных тромбов, образования артериальных тромбов, острой коронарной окклюзии, рестеноза, рестеноза после РСТА или эндопротезирования, образования тромбов в стенозированных артериях, гиперплазии после ангиопластики, атерэктомии или эндопротезирования артерий, окклюзивного синдрома сосудистой системы или потери проницаемости больных артерий.
22. Полипептидная конструкция по п.16, где указанное нарушение представляет собой образование бляшки или тромба в условиях высокого срезывающего напряжения.
23. Полипептидная конструкция по п.16, где указанная полипептидная конструкция вводится внутривенно, подкожно, перорально, сублингвально, местно, назально, вагинально, ректально или в виде ингаляции.
24. Композиция, включающая полипептидную конструкцию по любому из пп.1-12, и фармацевтически приемлемый наполнитель.
25. Способ получения полипептида по любому из пп.1-12, включающий
а) культивирование клеток-хозяев, содержащих нуклеиновую кислоту, способную кодировать полипептид по любому из пп.1-12, в условиях, обеспечивающих экспрессию полипептидов, и
б) извлечение полученного полипептида из культуры.
26. Способ по п.25, где указанные клетки-хозяева являются бактериями или дрожжами.
27. Способ обработки инвазивных медицинских устройств для предотвращения опосредованной тромбоцитами агрегации вокруг участка вмешательства, заключающийся в нанесении на названные устройства полипептидной конструкции по любому из пп.1-12.
28. Инвазивное медицинское устройство для избегания опосредованной тромбоцитами агрегации вокруг участка вмешательства, где указанное устройство покрыто полипептидной конструкцией по любому из пп.1-12.
29. Способ идентификации агента, модулирующего опосредованную тромбоцитами агрегацию, включающий в себя
а) контактирование полипептидной конструкции по любому из пп.1-12 с полипептидом, соответствующим ее мишени, или его фрагментом в присутствии и в отсутствие потенциального модулятора в условиях, обеспечивающих связывание названных полипептидов, и
б) измерение связывания между полипептидами на стадии (а), где уменьшение связывания в присутствии названного потенциального модулятора по отношению к связыванию в отсутствие названного потенциального модулятора идентифицирует названный потенциальный модулятор в качестве агента, модулирующего опосредованную тромбоцитами агрегацию.
30. Набор для скрининга на агенты, модулирующие опосредованную тромбоцитами агрегацию, в соответствии со способом по п.29.
31. Неизвестный агент, модулирующий опосредованную тромбоцитами агрегацию, идентифицированный в соответствии со способом по п.29.
32. Способ диагностики заболеваний или нарушений, характеризующихся дисфункцией опосредованной тромбоцитами агрегации, включающий в себя
а) контактирование образца с полипептидной конструкцией по любому из пп.1-12,
и
б) детектирование связывания указанной полипептидной конструкции с указанным образцом, и
в) сравнение связывания, зарегистрированного на стадии (б), со стандартом, где различие в связывании по отношению к указанному образцу является диагностическим признаком для заболевания или нарушения, характеризующегося дисфункцией опосредованной тромбоцитами агрегации.
33. Набор для диагностики заболевания или нарушения, характеризующегося дисфункцией опосредованной тромбоцитами агрегации, в соответствии со способом по п.32.
34. Набор по п.30 или 33, включающий в себя полипептидную конструкцию по любому из пп.1-12.
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US20060149041A1 (en) 2006-07-06
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