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RU2012140451A - Композиции и способы для диагностики и лечения опухолей - Google Patents

Композиции и способы для диагностики и лечения опухолей Download PDF

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RU2012140451A
RU2012140451A RU2012140451/10A RU2012140451A RU2012140451A RU 2012140451 A RU2012140451 A RU 2012140451A RU 2012140451/10 A RU2012140451/10 A RU 2012140451/10A RU 2012140451 A RU2012140451 A RU 2012140451A RU 2012140451 A RU2012140451 A RU 2012140451A
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antibody
seq
sequence
specified
cell
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RU2595389C2 (ru
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Пол Полакис
Джиоти АСУНДИ
Рон ФАЙРСТЕЙН
Роберт Ф. КЕЛЛИ
Криста МАККАТЧЕОН
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Дженентек, Инк.
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Abstract

1. Выделенное антитело, содержащее по меньшей мере одну последовательность CDR, выбранную из группы, состоящей из:(a) последовательности CDR-L1 SEQ ID NO:7;(b) последовательности CDR-L2 SEQ ID NO:8;(c) последовательности CDR-L3 SEQ ID NO:9;(d) последовательности CDR-H1 SEQ ID NO:10;(e) последовательности CDR-H2 SEQ ID NO:11; и(f) последовательности CDR-H3 SEQ ID NO:12.2. Антитело по п.1, которое представляет собой фрагмент антитела.3. Антитело по п.1, которое представляет собой химерное или гуманизированное антитело.4. Антитело по п.1, которое конъюгировано с рост-ингибирующим средством.5. Антитело по п.1, которое конъюгировано с цитотоксическим средством.6. Антитело по п.5, где цитотоксическое средство выбрано из группы, состоящей из токсинов, антибиотиков, радиоактивных изотопов и нуклеолитических ферментов.7. Антитело по п.5, где цитотоксическим средством является токсин.8. Антитело по п.7, где токсин выбран из группы, состоящей из майтанзиноида, калихеамицина и ауристатина.9. Антитело по п.7, где токсином является майтанзиноид.10. Антитело по п.8, где ауристатином является монометилауристатин Е (ММАЕ).11. Антитело по п.1, которое продуцируется в бактериях.12. Антитело по п.1, которое продуцируется в клетках CHO.13. Антитело по п.1, индуцирующее гибель клеток, с которыми оно связывается.14. Антитело по п.1, которое ингибирует пролиферацию клеток, с которыми оно связывается.15. Антитело по п.13 или 14, где указанной клеткой является раковая клетка меланомы человека.16. Антитело по п.1, которое является детектируемо меченным.17. Выделенное антитело, содержащее последовательность VL любой из SEQ ID NO:5 или 15.18. Выделенное антитело, содержащее последовательность VH любой из SEQ ID NO:6, 16 или 17.19. Выделенное антите�

Claims (45)

1. Выделенное антитело, содержащее по меньшей мере одну последовательность CDR, выбранную из группы, состоящей из:
(a) последовательности CDR-L1 SEQ ID NO:7;
(b) последовательности CDR-L2 SEQ ID NO:8;
(c) последовательности CDR-L3 SEQ ID NO:9;
(d) последовательности CDR-H1 SEQ ID NO:10;
(e) последовательности CDR-H2 SEQ ID NO:11; и
(f) последовательности CDR-H3 SEQ ID NO:12.
2. Антитело по п.1, которое представляет собой фрагмент антитела.
3. Антитело по п.1, которое представляет собой химерное или гуманизированное антитело.
4. Антитело по п.1, которое конъюгировано с рост-ингибирующим средством.
5. Антитело по п.1, которое конъюгировано с цитотоксическим средством.
6. Антитело по п.5, где цитотоксическое средство выбрано из группы, состоящей из токсинов, антибиотиков, радиоактивных изотопов и нуклеолитических ферментов.
7. Антитело по п.5, где цитотоксическим средством является токсин.
8. Антитело по п.7, где токсин выбран из группы, состоящей из майтанзиноида, калихеамицина и ауристатина.
9. Антитело по п.7, где токсином является майтанзиноид.
10. Антитело по п.8, где ауристатином является монометилауристатин Е (ММАЕ).
11. Антитело по п.1, которое продуцируется в бактериях.
12. Антитело по п.1, которое продуцируется в клетках CHO.
13. Антитело по п.1, индуцирующее гибель клеток, с которыми оно связывается.
14. Антитело по п.1, которое ингибирует пролиферацию клеток, с которыми оно связывается.
15. Антитело по п.13 или 14, где указанной клеткой является раковая клетка меланомы человека.
16. Антитело по п.1, которое является детектируемо меченным.
17. Выделенное антитело, содержащее последовательность VL любой из SEQ ID NO:5 или 15.
18. Выделенное антитело, содержащее последовательность VH любой из SEQ ID NO:6, 16 или 17.
19. Выделенное антитело, содержащее последовательность легкой цепи любой из SEQ ID NO:3 или 13.
20. Выделенное антитело, содержащее последовательность тяжелой цепи любой из SEQ ID NO:4 или 14.
21. Выделенное антитело, содержащее последовательность VL SEQ ID NO: 15 и последовательность VH SEQ ID NO:16.
22. Выделенное антитело, содержащее последовательность VL SEQ ID NO: 15 и последовательность VH SEQ ID NO:17.
23. Клетка, продуцирующая антитело по п.1.
24. Выделенная нуклеиновая кислота, кодирующая антитело по п.1.
25. Способ идентификации первого антитела, которое связывается с антигенным эпитопом TAT419, связанным со вторым антителом, где указанным вторым антителом является антитело по п. 1, и где указанный способ включает определение способности указанного первого антитела блокировать связывание указанного второго антитела с полипептидом TAT419, где способность указанного первого антитела блокировать связывание указанного второго антитела с указанным полипептидом TAT419, по меньшей мере на 40% и при равной концентрации антител, указывает на то, что указанное первое антитело обладает способностью связываться с эпитопом, связанным с указанным вторым антителом.
26. Способ ингибирования пролиферации клетки, которая экспрессирует полипептид TAT419, где указанный способ включает приведение в контакт указанной клетки с антителом по п.1, где связывание указанного антитела с указанным полипептидом TAT419 приводит к ингибированию пролиферации указанной клетки.
27. Способ по п.26, где указанный полипептид TAT419 содержит аминокислотную последовательность SEQ ID NO:2 или ее внеклеточный домен.
28. Способ по п.26, где указанной клеткой является раковая клетка меланомы человека.
29. Способ терапевтического лечения млекопитающего, имеющего раковую опухоль, содержащую клетки, экспрессирующие полипептид TAT419, где указанный способ включает введение указанному млекопитающему терапевтически эффективного количества антитела по п.1, что позволяет осуществлять эффективное лечение указанного млекопитающего.
30. Способ по п.29, где указанный полипептид TAT419 содержит аминокислотную последовательность SEQ ID NO:2 или ее внеклеточный домен.
31. Способ по п.29, где указанными клетками являются раковые клетки меланомы человека.
32. Способ определения присутствия белка TAT419 в образце, который, как подозревается, содержит указанный белок, где указанный способ включает обработку указанного образца антителом по п. 1 и детектирование связывания указанного антитела с указанным белком в указанном образце, где связывание антитела с указанным белком является показателем присутствия указанного белка в указанном образце.
33. Способ по п.32, где указанный образец содержит клетку, предположительно, экспрессирующую указанный белок.
34. Способ по п.33, где указанной клеткой является раковая клетка меланомы человека.
35. Способ по п.32, где указанное антитело является детектируемо меченным.
36. Способ диагностики рака у млекопитающего, где указанный способ включает определение уровня экспрессии гена, кодирующего полипептид TAT419 в тест-образце клеток ткани, взятых у указанного млекопитающего, и в контрольном образце известных нормальных клеток, происходящих от той же ткани, где более высокий уровень экспрессии указанного полипептида TAT419 в тест-образце по сравнению с контрольным образцом является показателем наличия рака у млекопитающего, у которого был взят тест-образец.
37. Способ по п.36, где стадия определения уровня экспрессии гена, кодирующего указанный полипептид, включает использование олигонуклеотида в гибридизации in situ или в ОТ-ПЦР-анализе.
38. Способ по п.36, где стадия определения уровня экспрессии гена, кодирующего указанный белок, включает использование антитела в иммуногистохимическом анализе или в вестерн-блот-анализе.
39. Способ по п.36, где указанным раком является меланома человека.
40. Способ по п.36, где указанный полипептид TAT419 содержит аминокислотную последовательность SEQ ID NO:2 или ее внеклеточный домен.
41. Способ диагностики рака у млекопитающего, где указанный способ включает приведение в контакт тест-образца клеток ткани, взятых у указанного млекопитающего, с антителом по п.1, и детектирование образования комплекса между указанным антителом и белком TAT419 в тест-образце, где образование указанного комплекса является показателем наличия рака у указанного млекопитающего.
42. Способ по п. 41, где указанный тест-образец клеток ткани берут у индивидуума с подозрением на рак.
43. Способ по п. 42, где указанным раком является меланома человека.
44. Способ по п. 41, где указанный белок TAT419 содержит аминокислотную последовательность SEQ ID NO:2 или ее внеклеточный домен.
45. Способ доставки цитотоксического или диагностического средства в клетку, экспрессирующую полипептид TAT419, где указанный способ включает получение цитотоксического или диагностического средства, конъюгированного с антителом, которое связывается с указанным полипептидом TAT419 с образованием конъюгата «антитело-средство», и обработку указанной клетки указанным конъюгатом «антитело-средство».
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