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RU2013128444A - Новые модуляторы и способы их применения - Google Patents

Новые модуляторы и способы их применения Download PDF

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Publication number
RU2013128444A
RU2013128444A RU2013128444/10A RU2013128444A RU2013128444A RU 2013128444 A RU2013128444 A RU 2013128444A RU 2013128444/10 A RU2013128444/10 A RU 2013128444/10A RU 2013128444 A RU2013128444 A RU 2013128444A RU 2013128444 A RU2013128444 A RU 2013128444A
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RU
Russia
Prior art keywords
variable region
seq
indicated
antibody
heavy chain
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Application number
RU2013128444/10A
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English (en)
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RU2592672C2 (ru
RU2592672C9 (ru
Inventor
Йоханнес ХЭМПЛ
Скотт Дж. ДИЛЛА
Орит ФУРД
Роберт А. СТАЛ
Original Assignee
СтемСентРкс, Инк.
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Priority claimed from PCT/US2011/050451 external-priority patent/WO2012031280A2/en
Application filed by СтемСентРкс, Инк. filed Critical СтемСентРкс, Инк.
Publication of RU2013128444A publication Critical patent/RU2013128444A/ru
Publication of RU2592672C2 publication Critical patent/RU2592672C2/ru
Application granted granted Critical
Publication of RU2592672C9 publication Critical patent/RU2592672C9/ru

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Abstract

1. Антитело, включающее химерное, CDR-привитое, гуманизированное или рекомбинантное человеческое антитело или его фрагмент, которое(ый) специфически связывается с человеческим EFNA4 (эфрин А4) и которое(ый) конкурирует за связывание с человеческим EFNA4 с антителом, содержащим:а) вариабельную область тяжелой цепи, указанную как SEQ ID NO:113, и вариабельную область легкой цепи, указанную как SEQ ID NO:115;б) вариабельную область тяжелой цепи, указанную как SEQ ID NO:121, и вариабельную область легкой цепи, указанную как SEQ ID NO:123; илив) вариабельную область тяжелой цепи, указанную как SEQ ID NO:137, и вариабельную область легкой цепи, указанную как SEQ ID NO:139.2. Антитело по п.1, которое представляет собой нейтрализующее или истощающее антитело.3. Антитело по п.1, которое представляет собой интернализованное антитело.4. Антитело по п.1, содержащее по меньшей мере одну вариабельную область тяжелой цепи и по меньшей мере одну вариабельную область легкой цепи, где по меньшей мере одна вариабельная область тяжелой цепи содержит три CDR, указанные как SEQ ID NO:12, 25 и 38.5. Антитело по п.1, содержащее по меньшей мере одну вариабельную область тяжелой цепи и по меньшей мере одну вариабельную область легкой цепи, где по меньшей мере одна вариабельная область тяжелой цепи содержит три CDR, указанные как SEQ ID NO:51, 74 и 87.6. Антитело по п.1, содержащее:а) вариабельную область тяжелой цепи, содержащую три CDR, указанные как SEQ ID NO:12, 25 и 38; иб) вариабельную область легкой цепи, содержащую три CDR, указанные как SEQ ID NO:51, 74 и 87.7. Антитело по п.1, содержащее вариабельную область тяжелой цепи, имеющую аминокислотную последовательность, которая по меньшей мере на 60% идентична SEQ ID NO:157, и вариабельную

Claims (32)

1. Антитело, включающее химерное, CDR-привитое, гуманизированное или рекомбинантное человеческое антитело или его фрагмент, которое(ый) специфически связывается с человеческим EFNA4 (эфрин А4) и которое(ый) конкурирует за связывание с человеческим EFNA4 с антителом, содержащим:
а) вариабельную область тяжелой цепи, указанную как SEQ ID NO:113, и вариабельную область легкой цепи, указанную как SEQ ID NO:115;
б) вариабельную область тяжелой цепи, указанную как SEQ ID NO:121, и вариабельную область легкой цепи, указанную как SEQ ID NO:123; или
в) вариабельную область тяжелой цепи, указанную как SEQ ID NO:137, и вариабельную область легкой цепи, указанную как SEQ ID NO:139.
2. Антитело по п.1, которое представляет собой нейтрализующее или истощающее антитело.
3. Антитело по п.1, которое представляет собой интернализованное антитело.
4. Антитело по п.1, содержащее по меньшей мере одну вариабельную область тяжелой цепи и по меньшей мере одну вариабельную область легкой цепи, где по меньшей мере одна вариабельная область тяжелой цепи содержит три CDR, указанные как SEQ ID NO:12, 25 и 38.
5. Антитело по п.1, содержащее по меньшей мере одну вариабельную область тяжелой цепи и по меньшей мере одну вариабельную область легкой цепи, где по меньшей мере одна вариабельная область тяжелой цепи содержит три CDR, указанные как SEQ ID NO:51, 74 и 87.
6. Антитело по п.1, содержащее:
а) вариабельную область тяжелой цепи, содержащую три CDR, указанные как SEQ ID NO:12, 25 и 38; и
б) вариабельную область легкой цепи, содержащую три CDR, указанные как SEQ ID NO:51, 74 и 87.
7. Антитело по п.1, содержащее вариабельную область тяжелой цепи, имеющую аминокислотную последовательность, которая по меньшей мере на 60% идентична SEQ ID NO:157, и вариабельную область легкой цепи, имеющую аминокислотную последовательность, которая по меньшей мере на 60% идентична SEQ ID NO:159.
8. Антитело по п.7, содержащее вариабельную область тяжелой цепи, указанную как SEQ ID NO:157, и вариабельную область легкой цепи, указанную как SEQ ID NO:159.
9. Антитело по п.1, содержащее по меньшей мере одну вариабельную область тяжелой цепи и по меньшей мере одну вариабельную область легкой цепи, где по меньшей мере одна вариабельная область тяжелой цепи содержит три CDR, указанные как SEQ ID NO:14, 27 и 40.
10. Антитело по п.1, содержащее по меньшей мере одну вариабельную область тяжелой цепи и по меньшей мере одну вариабельную область легкой цепи, где по меньшей мере одна вариабельная область тяжелой цепи содержит три CDR, указанные как SEQ ID NO:53, 76 и 89.
11. Антитело по п.1, содержащее:
а) вариабельную область тяжелой цепи, содержащую три CDR, указанные как SEQ ID NO:14, 27 и 40; и
б) вариабельную область легкой цепи, содержащую три CDR, указанные как SEQ ID NO:53, 76 и 89.
12. Антитело по п.1, содержащее вариабельную область тяжелой цепи, имеющую аминокислотную последовательность, которая по меньшей мере на 60% идентична SEQ ID NO:161, и вариабельную область легкой цепи, имеющую аминокислотную последовательность, которая по меньшей мере на 60% идентична SEQ ID NO:163.
13. Антитело по п.12, содержащее вариабельную область тяжелой цепи, указанную как SEQ ID NO:161, и вариабельную область легкой цепи, указанную как SEQ ID NO:163.
14. Антитело по п.1, содержащее вариабельную область тяжелой цепи, указанную как SEQ ID NO:113, 121, 137, 157 или 161.
15. Антитело по п.1, содержащее вариабельную область легкой цепи, указанную как SEQ ID NO:115, 123, 139, 159 или 163.
16. Антитело по п.1, содержащее:
а) вариабельную область тяжелой цепи, указанную как SEQ ID NO:113 или 157, и вариабельную область легкой цепи, указанную как SEQ ID NO:115 или 159;
б) вариабельную область тяжелой цепи, указанную как SEQ ID NO:121 или 161, и вариабельную область легкой цепи, указанную как SEQ ID NO:123 или 163; или
в) вариабельную область тяжелой цепи, указанную как SEQ ID NO:137, и вариабельную область легкой цепи, указанную как SEQ ID NO:139.
17. Антитело, включающее химерное, CDR-привитое или гуманизированное антитело или его фрагмент, которое(ый) специфически связывается с эпитопом человеческого лиганда эфрина А, указанным как SEQ ID NO:164.
18. Антитело, включающее химерное, CDR-привитое или гуманизированное антитело или его фрагмент, которое(ый) специфически связывается с эпитопом человеческого лиганда эфрина А, указанным как SEQ ID NO:165.
19. Конъюгат антитела, содержащий химерное, CDR-привитое, гуманизированное или рекомбинантное человеческое антитело или его фрагмент, которое(ый) специфически связывается с EFNA4, где антитело конъюгировано, связано или иным образом соединено с цитотоксическим агентом.
20. Конъюгат антитела по п.19, где химерное, CDR-привитое, гуманизированное или рекомбинантное человеческое антитело или его фрагмент представляет собой антитело по любому из пп.1-18.
21. Фармацевтическая композиция, содержащая антитело по любому из пп.1-18, где антитело возможно конъюгировано, связано или иным образом соединено с цитотоксическим агентом.
22. Нуклеиновая кислота, кодирующая вариабельную область тяжелой цепи, указанную как SEQ ID NO:113, 121, 137, 157 или 161, или вариабельную область легкой цепи, указанную как SEQ ID NO:115, 123, 139, 159 или 163.
23. Вектор, содержащий нуклеиновую кислоту по п.22.
24. Клетка-хозяин, содержащая нуклеиновую кислоту по п.22.
25. Способ лечения EFNA-ассоциированного расстройства, включающий введение нуждающемуся в этом субъекту терапевтически эффективного количества композиции, содержащей химерное, CDR-привитое, гуманизированное или рекомбинантное человеческое антитело или его фрагмент, который(ое) специфически связывается с человеческим EFNA4 и возможно конъюгирован(о), связан(о) или иным образом соединен(о) с цитотоксическим агентом.
26. Способ по п.25, где химерное, CDR-привитое, гуманизированное или рекомбинантное человеческое антитело или его фрагмент представляет собой антитело по любому из пп.1-18.
27. Способ по п.25, где EFNA-ассоциированное расстройство представляет собой пролиферативное расстройство.
28. Способ по п.27, где пролиферативное расстройство представляет собой опухолевое расстройство.
29. Способ по п.28, где опухолевое расстройство включает солидную опухоль.
30. Способ по п.29, где опухолевое расстройство представляет собой рак молочной железы, рак яичника, колоректальный рак, рак печени или рак легкого.
31. Способ по п.28, где опухолевое расстройство включает гематологическое злокачественное заболевание.
32. Способ по п.31, где гематологическое злокачественное заболевание представляет собой лейкоз.
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