RU2333919C2 - Снижение иммуногенности слитых белков - Google Patents

Снижение иммуногенности слитых белков Download PDF

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RU2333919C2
RU2333919C2 RU2003129523/13A RU2003129523A RU2333919C2 RU 2333919 C2 RU2333919 C2 RU 2333919C2 RU 2003129523/13 A RU2003129523/13 A RU 2003129523/13A RU 2003129523 A RU2003129523 A RU 2003129523A RU 2333919 C2 RU2333919 C2 RU 2333919C2
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Стефен Д. Джиллиз
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Abstract

Изобретение относится к биотехнологии и иммунологии. Предложен терапевтически активный слитый белок со сниженной иммуногенностью. Белок состоит из двух белков, происходящих от белков человека, соединенных через область слияния. При этом соединительная область, которая перекрывает или окружает область слияния в пределах от 1 до 25 аминокислотных остатков, содержит модификацию, удаляющую Т-клеточный эпитоп, в норме отсутствующий у человека. Предложено применение слитого белка для получения фармацевтической композиции для лечения опухоли. Предложена нуклеиновая кислота, кодирующая слитый белок. Описан способ снижения иммуногенности слитого белка путем введения замен соответствующих аминокислот. Использование изобретения позволяет снизить способность соединительного эпитопа терапевтически активного слитого белка связываться с молекулами главного комплекса гистосовместимости (МНС) класса II, что в конечном итоге снижает взаимодействие эпитопа с рецепторами Т-клеток и может найти применение в медицине для предотвращения иммунологических расстройств, возникающих при введении терапевтически активного белка, немодифицированного в соединительной области. 4 н. и 19 з.п. ф-лы.

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Claims (23)

1. Терапевтически активный слитый белок со сниженной иммуногенностью, состоящий из двух белков, происходящих от человеческого, соединенных друг с другом через область слияния, причем соединительная область в пределах от 1 до 25 аминокислотных остатков, окружающая или перекрывающая область слияния, содержит модификацию, удаляющую Т-клеточный эпитоп, в норме отсутствующий в организме человека, выбранную из группы, состоящей из:
(i) сайта N-связанного гликозилирования, который представляет собой Asn-X-Ser/Thr, где Х представляет собой аминокислоту,
(ii) последовательность аминокислот Ala-Thr-Ala-Thr вместо Leu-Ser-Leu-Ser в случае, если компонент слияния представлен IgG, или
(iii) мутацию Thr, Ala или Pro вместо Leu, Val, IIe, Met, Phe, Tyr или Trp.
2. Слитый белок по п.1, отличающийся тем, что Х представляет собой Gly.
3. Слитый белок по п.1, отличающийся тем, что соединительная область содержит спейсер или линкер.
4. Слитый белок по п.1, отличающийся тем, что один компонент слитого белка представляет собой альбумин.
5. Слитый белок по п.1, отличающийся тем, что один компонент слитого белка обладает активностью цитокина или гормона.
6. Слитый белок по п.1, отличающийся тем, что один компонент слитого белка представляет собой IgG или его фрагмент.
7. Слитый белок по п.1, отличающийся тем, что один компонент слитого белка представляет собой IgG или его фрагмент, а другой компонент представляет собой белок, обладающий активностью цитокина или гормона.
8. Слитый белок по п.7, отличающийся тем, что С-конец указанного IgG или его фрагмента соединен с N-концом другого компонента.
9. Слитый белок по п.7, отличающийся тем, что фрагмент IgG представляет собой Fc-молекулу.
10. Слитый белок по п.7, отличающийся тем, что IgG или его фрагмент содержит последовательности аминокислот от двух изотипов антител.
11. Слитый белок по п.10, отличающийся тем, что IgG или его фрагмент содержит последовательности аминокислот IgG1 и IgG2.
12. Слитый белок по п.11, отличающийся тем, что IgG или его фрагмент представляет собой изотип IgG2, измененный в шарнирной области до IgG1.
13. Слитый белок по п.8, представляющий собой huKS-IL2, включающий в соединительной области в последовательности IgG вместо последовательности Leu-Ser-Leu-Ser последовательность Ala-Thr-Ala-Thr.
14. Слитый белок по п.8, представляющий собой Fc-IL12-IL2, включающий в соединительной области в последовательности IgG вместо последовательности Leu-Ser-Leu-Ser последовательность Ala-Thr-Ala-Thr.
15. Слитый белок по п.8, представляющий собой Fc-IL12-IL2, включающий в первых положениях в молекуле IL2 сайт гликозилирования Asn-Gly.
16. Слитый белок по п.8, представляющий собой Fc-EPO, включающий в соединительной области в последовательности IgG вместо последовательности Leu-Ser-Leu-Ser последовательность Ala-Thr-Ala-Thr.
17. Слитый белок по п.16, представляющий собой Fc-EPO, в котором IgG представляет собой IgG2, содержащий шарнирную область IgG1.
18. Применение терапевтически активного слитого белка, как он определен в любом из пп.13-15, для получения фармацевтической композиции для лечения опухоли.
19. Нуклеиновая кислота, кодирующая слитый белок, как он определен в любом из пп.1-17.
20. Способ снижения иммуногенности слитого белка, охарактеризованного в п.1, путем удаления Т-клеточного эпитопа, в норме отсутствующего в организме человека, включающий модифицирование соединительной области, окружающей или перекрывающей область слияния в пределах от 1 до 25 аминокислотных остатков, методом, выбранным из группы, состоящей из:
(i) введения сайта N-связанного гликозилирования, который представляет собой Asn-X-Ser/Thr, где Х представляет собой аминокислоту,
(ii) замены последовательности аминокислот Leu-Ser-Leu-Ser на последовательность аминокислот Ala-Thr-Ala-Thr в случае, если компонент слияния представляет собой IgG, или
(iii) замены аминокислоты Leu, Val, Ile, Met, Phe, Tyr или Trp на Thr, Ala или Pro;
21. Способ по п.20, отличающийся тем, что Х представляет собой Gly.
22. Способ по п.20, отличающийся тем, что один компонент слияния представляет собой IgG или его фрагмент.
23. Способ по п.20, отличающийся тем, что один компонент слияния представляет собой IgG или его фрагмент, а другой компонент слияния представляет собой цитокин.
RU2003129523/13A 2001-03-30 2002-03-30 Снижение иммуногенности слитых белков RU2333919C2 (ru)

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