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RU2013141976A - Новые модуляторы и способы их применения - Google Patents

Новые модуляторы и способы их применения Download PDF

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RU2013141976A
RU2013141976A RU2013141976/10A RU2013141976A RU2013141976A RU 2013141976 A RU2013141976 A RU 2013141976A RU 2013141976/10 A RU2013141976/10 A RU 2013141976/10A RU 2013141976 A RU2013141976 A RU 2013141976A RU 2013141976 A RU2013141976 A RU 2013141976A
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seq
variable region
residues
antibody
heavy chain
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RU2013141976/10A
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RU2627176C2 (ru
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Орит ФУРД
Скотт Дж. ДИЛЛА
Роберт А. СТАЛЛ
Алекс БЭНКОВИЧ
Александра Лейда Лиана ЛАЗЕТИК
Джеффри БЕРНШТЕЙН
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СтемСентРкс, Инк.
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Abstract

1. Выделенное антитело, которое специфически связывается с PTK7 (протеинтирозинкиназа 7) человека и конкурирует за связывание с PTK7 человека с антителом, содержащим:а) вариабельную область легкой цепи, представленную в SEQ ID NO: 48, и вариабельную область тяжелой цепи, представленную в SEQ ID NO: 49; илиб) вариабельную область легкой цепи, представленную в SEQ ID NO: 50, и вариабельную область тяжелой цепи, представленную в SEQ ID NO: 51.2. Антитело по п. 1, ингибирующее связывание контрольного антитела по меньшей мере на примерно 40%.3. Антитело по п. 1, представляющее собой нейтрализирующее, истощающее и/или интернализованное антитело.4. Антитело по п. 1, которое специфически связывается с изоформой PTK7, выбранной из группы, состоящей из изоформы a, изоформы b, изоформы с и изоформы d.5. Антитело по п. 1, представляющее собой моноклональное, химерное, CDR-привитое, гуманизированное или рекомбинантное человеческое антитело, или его фрагмент.6. 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, представленные как остатки 26-35 из SEQ ID NO: 49, остатки 53-59 из SEQ ID NO: 49 и остатки 98-120 из SEQ ID NO: 49.7. 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 легкой цепи содержит три CDR, представленные как остатки 24-32 из SEQ ID NO: 48, остатки 50-56 из SEQ ID NO: 48 и остатки 89-107 из SEQ ID NO: 48.8. Антитело по п. 1, содержащееа) вариабельную область тяжелой цепи, содержащую три CDR, представленные как остатки 26-35

Claims (28)

1. Выделенное антитело, которое специфически связывается с PTK7 (протеинтирозинкиназа 7) человека и конкурирует за связывание с PTK7 человека с антителом, содержащим:
а) вариабельную область легкой цепи, представленную в SEQ ID NO: 48, и вариабельную область тяжелой цепи, представленную в SEQ ID NO: 49; или
б) вариабельную область легкой цепи, представленную в SEQ ID NO: 50, и вариабельную область тяжелой цепи, представленную в SEQ ID NO: 51.
2. Антитело по п. 1, ингибирующее связывание контрольного антитела по меньшей мере на примерно 40%.
3. Антитело по п. 1, представляющее собой нейтрализирующее, истощающее и/или интернализованное антитело.
4. Антитело по п. 1, которое специфически связывается с изоформой PTK7, выбранной из группы, состоящей из изоформы a, изоформы b, изоформы с и изоформы d.
5. Антитело по п. 1, представляющее собой моноклональное, химерное, CDR-привитое, гуманизированное или рекомбинантное человеческое антитело, или его фрагмент.
6. 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, представленные как остатки 26-35 из SEQ ID NO: 49, остатки 53-59 из SEQ ID NO: 49 и остатки 98-120 из SEQ ID NO: 49.
7. 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 легкой цепи содержит три CDR, представленные как остатки 24-32 из SEQ ID NO: 48, остатки 50-56 из SEQ ID NO: 48 и остатки 89-107 из SEQ ID NO: 48.
8. Антитело по п. 1, содержащее
а) вариабельную область тяжелой цепи, содержащую три CDR, представленные как остатки 26-35 из SEQ ID NO: 49, остатки 53-59 из SEQ ID NO: 49 и остатки 98-120 из SEQ ID NO: 49; и
б) вариабельную область легкой цепи, содержащую три CDR, представленные как остатки 24-32 из SEQ ID NO: 48, остатки 50-56 из SEQ ID NO: 48 и остатки 89-107 из SEQ ID NO: 48.
9. Антитело по п. 1, содержащее вариабельную область тяжелой цепи, имеющую аминокислотную последовательность, которая по меньшей мере на 60% идентична SEQ ID NO: 63, и вариабельную область легкой цепи, имеющую аминокислотную последовательность, которая по меньшей мере на 60% идентична SEQ ID NO: 62.
10. Антитело по п. 9, содержащее вариабельную область тяжелой цепи, представленную в SEQ ID NO: 63, и вариабельную область легкой цепи, представленную в SEQ ID NO: 62.
11. 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, представленные как остатки 26-33 из SEQ ID NO: 51, остатки 51-58 из SEQ ID NO: 51 и остатки 97-119 из SEQ ID NO: 51.
12. 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 легкой цепи содержит три CDR, представленные как остатки 24-36 из SEQ ID NO: 50, остатки 54-60 из SEQ ID NO: 50 и остатки 93-111 из SEQ ID NO: 50.
13. Антитело по п.1, содержащее
а) вариабельную область тяжелой цепи, содержащую три CDR, представленные как остатки 26-33 из SEQ ID NO: 51, остатки 51-58 из SEQ ID NO: 51 и остатки 97-119 из SEQ ID NO: 51; и
б) вариабельную область легкой цепи, содержащую три CDR, представленные как остатки 24-36 из SEQ ID NO: 50, остатки 54-60 из SEQ ID NO: 50 и остатки 93-111 из SEQ ID NO: 50.
14. Антитело по п. 1, содержащее вариабельную область тяжелой цепи, имеющую аминокислотную последовательность, которая по меньшей мере на 60% идентична SEQ ID NO: 65, и вариабельную область легкой цепи, имеющую аминокислотную последовательность, которая по меньшей мере на 60% идентична SEQ ID NO: 64.
15. Антитело по п. 14, содержащее вариабельную область тяжелой цепи, представленную в SEQ ID NO: 65, и вариабельную область легкой цепи, представленную в SEQ ID NO: 64.
16. Антитело по п. 1, содержащее вариабельную область тяжелой цепи, представленную в SEQ ID NO: 49, 51, 63 или 65, и/или вариабельную область легкой цепи, представленную в SEQ ID NO: 48, 50, 62 или 64.
17. Антитело по п. 1, содержащее
а) вариабельную область тяжелой цепи, представленную как SEQ ID NO: 49 или 63, и вариабельную область легкой цепи, представленную как SEQ ID NO: 48 или 62; или
б) вариабельную область тяжелой цепи, представленную как SEQ ID NO: 51 или 65, и вариабельную область легкой цепи, представленную как SEQ ID NO: 50 или 64.
18. Конъюгат антитела, содержащий химерное, CDR-привитое, гуманизированное или рекомбинантное человеческое антитело или его фрагмент, которое(ый) специфически связывается с PTK7, причем это антитело конъюгировано, связано или иным образом ассоциировано с цитотоксическим агентом, и где это химерное, CDR-привитое, гуманизированное или рекомбинантное человеческое антитело или его фрагмент возможно представляет собой антитело по любому из пп. 1-17.
19. Фармацевтическая композиция, содержащая антитело по любому из пп. 1-17 или конъюгат антитела по п. 18.
20. Нуклеиновая кислота, кодирующая вариабельную область тяжелой цепи, представленную в SEQ ID NO: 49, 51, 63 или 65, и/или вариабельную область легкой цепи, представленную в SEQ ID NO: 48, 50, 62 или 64.
21. Вектор или клетка-хозяин, содержащий(ая) нуклеиновую кислоту по п. 20.
22. Клетка-хозяин, содержащая нуклеиновую кислоту по п. 20.
23. Способ лечения рака у субъекта, включающий введение этому субъекту терапевтически эффективной дозы конъюгата антитела, содержащего анти-PTK7 антитело, конъюгированное, связанное или иным образом ассоциированное с цитотоксическим агентом.
24 Способ обнаружения, диагностики или мониторинга рака у субъекта, включающий стадии:
(а) приведения клеток субъекта в контакт с анти-PTK7 антителом; и
(б) обнаружения анти-PTK7 антитела на опухоль-инициирующих клетках.
25. Способ по п. 23 или 24, где рак представляет собой рак молочной железы, рак яичников, колоректальный рак, рак поджелудочной железы, рак легкого или рак кожи.
26. Способ снижения частоты появления опухоль-инициирующих клеток у субъекта, включающий введение этому субъекту конъюгата анти-PTK7 антитела, содержащего анти-РТК7 антитело, конъюгированное, связанное или иным образом ассоциированное с цитотоксическим агентом, в количестве, эффективном для снижения частоты появления опухоль-инициирующих клеток у субъекта.
27. Способ идентификации, выделения или обогащения популяции опухоль-инициирующих клеток, включающий стадии (а) приведения клеток в контакт с анти-PTK7 антителом; и (б) селекции опухоль-инициирующих клеток, с которыми связано анти-PTK7 антитело.
28. Способ по любому из пп. 23, 24, 26 и 27, где анти-PTK7 антитело содержит антитело по любому из пп. 1-17.
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