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RU2012147286A - Гуманизированные антитела к фактору d и их применения - Google Patents

Гуманизированные антитела к фактору d и их применения Download PDF

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RU2012147286A
RU2012147286A RU2012147286/10A RU2012147286A RU2012147286A RU 2012147286 A RU2012147286 A RU 2012147286A RU 2012147286/10 A RU2012147286/10 A RU 2012147286/10A RU 2012147286 A RU2012147286 A RU 2012147286A RU 2012147286 A RU2012147286 A RU 2012147286A
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seq
sequence
antibody
variable domain
factor
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RU2678802C2 (ru
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Херрен ВУ
Санджая Сингх
Сек Чунг ФУНГ
Линг-линг АН
Генри Б. Лоуман
Роберт Ф. КЕЛЛИ
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Дженентек, Инк.
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Abstract

1. Вариабельный домен гуманизированного антитела, включающий аминокислотную последовательность вариабельного домена тяжелой цепи, выбранную из группы, состоящей из: SEQ ID NO: 6; SEQ ID NO: 8; SEQ ID NO: 10 и SEQ ID NO: 12.2. Вариабельный домен гуманизированного антитела, включающий аминокислотную последовательность вариабельного домена легкой цепи, выбранную из группы, состоящей из SEQ ID NO: 5; SEQ ID NO: 7; SEQ ID NO: 9 и SEQ ID NO: 11.3. Вариабельный домен по п.2, в котором аминокислота в положении 104 последовательности SEQ ID NO: 7 представляет собой валин или лейцин.4. Гуманизированное антитело к фактору D, включающее последовательность вариабельного домена SEQ ID NO:5 и последовательность вариабельного домена в SEQ ID NO: 6.5. Гуманизированное антитело к фактору D, включающее последовательность вариабельного домена SEQ ID NO: 7 и последовательность вариабельного домена в SEQ ID NO: 8.6. Гуманизированное антитело к фактору D по п.5, включающее последовательность вариабельного домена SEQ ID NO: 7, в котором аминокислота в положении 104 последовательности SEQ ID NO: 7 представляет собой валин или лейцин, и последовательность вариабельного домена SEQ ID NO: 8.7. Гуманизированное антитело к фактору D, включающее последовательность вариабельного домена SEQ ID NO: 9 и последовательность вариабельного домена в SEQ ID NO: 10.8. Гуманизированное антитело к фактору D, включающее последовательность вариабельного домена SEQ ID NO: 11 и последовательность вариабельного домена в SEQ ID NO: 12.9. Гуманизированное антитело к фактору D, имеющее вариабельный участок легкой цепи, включающий участок CDR-L1, имеющий последовательность SEQ ID NO: 16; участок CDR-L2, имеющий последовательность SEQ ID NO: 17, 21 или 23, и участок CDR-L3, имеющий последователь

Claims (31)

1. Вариабельный домен гуманизированного антитела, включающий аминокислотную последовательность вариабельного домена тяжелой цепи, выбранную из группы, состоящей из: SEQ ID NO: 6; SEQ ID NO: 8; SEQ ID NO: 10 и SEQ ID NO: 12.
2. Вариабельный домен гуманизированного антитела, включающий аминокислотную последовательность вариабельного домена легкой цепи, выбранную из группы, состоящей из SEQ ID NO: 5; SEQ ID NO: 7; SEQ ID NO: 9 и SEQ ID NO: 11.
3. Вариабельный домен по п.2, в котором аминокислота в положении 104 последовательности SEQ ID NO: 7 представляет собой валин или лейцин.
4. Гуманизированное антитело к фактору D, включающее последовательность вариабельного домена SEQ ID NO:5 и последовательность вариабельного домена в SEQ ID NO: 6.
5. Гуманизированное антитело к фактору D, включающее последовательность вариабельного домена SEQ ID NO: 7 и последовательность вариабельного домена в SEQ ID NO: 8.
6. Гуманизированное антитело к фактору D по п.5, включающее последовательность вариабельного домена SEQ ID NO: 7, в котором аминокислота в положении 104 последовательности SEQ ID NO: 7 представляет собой валин или лейцин, и последовательность вариабельного домена SEQ ID NO: 8.
7. Гуманизированное антитело к фактору D, включающее последовательность вариабельного домена SEQ ID NO: 9 и последовательность вариабельного домена в SEQ ID NO: 10.
8. Гуманизированное антитело к фактору D, включающее последовательность вариабельного домена SEQ ID NO: 11 и последовательность вариабельного домена в SEQ ID NO: 12.
9. Гуманизированное антитело к фактору D, имеющее вариабельный участок легкой цепи, включающий участок CDR-L1, имеющий последовательность SEQ ID NO: 16; участок CDR-L2, имеющий последовательность SEQ ID NO: 17, 21 или 23, и участок CDR-L3, имеющий последовательность SEQ ID NO: 18, 22 или 24.
10. Гуманизированное антитело к фактору D, имеющее вариабельный участок тяжелой цепи CDR-H1, имеющий последовательность SEQ ID NO: 13 или 25; участок CDR-H2, имеющий последовательность SEQ ID NO: 14; и участок CDR-H3, имеющий последовательность SEQ ID NO: 15 или 20.
11. Полипептид, включающий следующую аминокислотную последовательность: QX1QLVQSGX2E LKKPGASVKV SCKASGYTFT SYGMNWVX3QA PGQGLEWMGW INTYTGETTYADDFKGRFVF SLDTSVSTAY LQISSLKAED TAX4YYCX5REG GVNNWGQGTL VTVSS (SEQ ID NO: 27), где X1 представляет собой I или V; X2 представляет собой P или S; X3 представляет собой K или R; X4 представляет собой T или V; и X5 представляет собой E или A.
12. Полипептид, включающий следующую аминокислотную последовательность: DIQX6TQSPSSLSX7SVGDRVTITCITSTDIDDDMNWYQQKPGKX8PKLLIX9DGNT LRPGVPSRFSX10SGSGX11DFTLTISSLQPEDVATYYCLQSDSLPYTFGQGTKLEIK (SEQ ID NO: 26), где X6 представляет собой V или M; X7 представляет собой M или A; X8 представляет собой P или V; X9 представляет собой S или Y; X10 представляет собой S или G и X11 представляет собой A или T.
13. Полипептид, включающий аминокислотную последовательность SEQ ID NO: 6, 8, 10 или 12.
14. Полипептид, включающий аминокислотную последовательность SEQ ID NO: 5, 7, 9 или 11.
15. Полипептид по п.12, в котором аминокислота в положении 104 последовательности SEQ ID NO: 26 представляет собой валин или лейцин.
16. Гуманизированное антитело, включающее полипептид по п.11.
17. Гуманизированное антитело по п.16, дополнительно включающее полипептид по п.12 или 15.
18. Фрагмент антитела по любому из п.п.1-10, 16, 17, 3 или 6.
19. Выделенная нуклеиновая кислота, включающая последовательность SEQ ID NO: 4.
20. Выделенная нуклеиновая кислота, кодирующая антитело по любому из п.п.1-10, 16, 17, 3 или 6.
21. Выделенная нуклеиновая кислота, кодирующая полипептид по любому из п.п.11-14.
22. Вектор, включающий нуклеиновую кислоту по п.20.
23. Вектор, включающий нуклеиновую кислоту по п.21.
24. Клеточная линия, включающая вектор по п.22 или 23.
25. Композиция, включающая антитело по любому из п.п.1-10, 16 или 17.
26. Применение композиции по п.25 для лечения нарушений, опосредованных системой комплемента.
27. Применение по п.26, где нарушение представляет собой глазное заболевание, такое как возрастная дегенерация желтого пятна или диабетическая ретинопатия.
28. Полипептид по п.14, в котором аминокислота в положении 104 последовательности SEQ ID NO: 7 представляет собой валин или лейцин.
29. Способ получения гуманизированного антитела к фактору D или его фрагмента по любому из п.п.1-10, 16, 17, 3 или 6.
30. Антитело, которое конкурирует с мышиным антителом 166-32, и/или с клонами #56, #111, #250 или #416 гуманизированного антитела к фактору D, и/или с антителом, включающим вариабельный домен или HVR-последовательности клонов #56, #111, #250 или #416 гуманизированного антитела к фактору D.
31. Антитело, которое связывается с тем же эпитопом, что и мышиное антитело 166-32, и/или клоны #56, #111, #250 или #416 гуманизированного антитела к фактору D, и/или антитело, включающее вариабельный домен или HVR-последовательности клонов #56, #111, #250 или #416 гуманизированного антитела к фактору D.
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