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RU2013154264A - Конъюгаты белок-активное вещество и способ их получения - Google Patents

Конъюгаты белок-активное вещество и способ их получения Download PDF

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Publication number
RU2013154264A
RU2013154264A RU2013154264/15A RU2013154264A RU2013154264A RU 2013154264 A RU2013154264 A RU 2013154264A RU 2013154264/15 A RU2013154264/15 A RU 2013154264/15A RU 2013154264 A RU2013154264 A RU 2013154264A RU 2013154264 A RU2013154264 A RU 2013154264A
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RU
Russia
Prior art keywords
protein
active substance
amino acid
conjugate according
acid motif
Prior art date
Application number
RU2013154264/15A
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English (en)
Other versions
RU2613906C2 (ru
Inventor
Йонгжу КИМ
Таекио ПАРК
Сангхо ВУ
Хиангсук ЛИ
Юнгун КИМ
Йонгун ЧО
Доохван ДЖУНГ
Санянг КИМ
Хиюнджин КВОН
Киюман ОХ
Юнсео ЧУНГ
Юн-хее ПАРК
Original Assignee
Легокем Биосайенсис, Инк.
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Publication of RU2013154264A publication Critical patent/RU2013154264A/ru
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Publication of RU2613906C2 publication Critical patent/RU2613906C2/ru

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    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/48—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase
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Abstract

1. Конъюгат белок-активное вещество, содержащий белок, имеющий аминокислотный мотив, который может распознаваться с помощью изопреноид-трансферазы, где активное вещество ковалентно связано с белком в аминокислотном мотиве.2. Конъюгат белок-активное вещество по п. 1, где белок содержит модификацию, выбранную из группы, состоящей по существу из:(i) делеции на карбоксильном конце белка;(ii) вставки олигопептида или полипептида на карбоксильном конце белка, а также(iii) делеции на карбоксильном конце белка и вставки олигопептида или полипептида на карбоксильном конце белка;где модификация присоединена к аминокислотному мотиву.3. Конъюгат белок-активное вещество по п. 1, в котором белок представляет собой антитело или фрагмент антигенного полипептида.4. Конъюгат белок-активное вещество по п. 3, в котором белок представляет собой моноклональное антитело.5. Конъюгат белок-активное вещество по п. 4, в котором по меньшей мере одна легкая цепь и/или по меньшей мере одна тяжелая цепь моноклонального антитела содержит аминокислотную область, имеющую аминокислотный мотив.6. Конъюгат белок-активное вещество по п. 1, в котором изопреноид-трансфераза представляет собой FTase или GGTase.7. Конъюгат белок-активное вещество по п. 1, где активное вещество представляет собой лекарственное вещество, токсин, аффинный лиганд, детекторный зонд или их комбинацию.8. Конъюгат белок-активное вещество по п. 1, в котором аминокислотный мотив представляет собой СААХ, ХХСС, ХСХС или СХХ, где С представляет собой цистеин, А представляет собой алифатическую аминокислоту, и X представляет собой аминокислоту, которая определяет субстратную специфичность изопрен

Claims (40)

1. Конъюгат белок-активное вещество, содержащий белок, имеющий аминокислотный мотив, который может распознаваться с помощью изопреноид-трансферазы, где активное вещество ковалентно связано с белком в аминокислотном мотиве.
2. Конъюгат белок-активное вещество по п. 1, где белок содержит модификацию, выбранную из группы, состоящей по существу из:
(i) делеции на карбоксильном конце белка;
(ii) вставки олигопептида или полипептида на карбоксильном конце белка, а также
(iii) делеции на карбоксильном конце белка и вставки олигопептида или полипептида на карбоксильном конце белка;
где модификация присоединена к аминокислотному мотиву.
3. Конъюгат белок-активное вещество по п. 1, в котором белок представляет собой антитело или фрагмент антигенного полипептида.
4. Конъюгат белок-активное вещество по п. 3, в котором белок представляет собой моноклональное антитело.
5. Конъюгат белок-активное вещество по п. 4, в котором по меньшей мере одна легкая цепь и/или по меньшей мере одна тяжелая цепь моноклонального антитела содержит аминокислотную область, имеющую аминокислотный мотив.
6. Конъюгат белок-активное вещество по п. 1, в котором изопреноид-трансфераза представляет собой FTase или GGTase.
7. Конъюгат белок-активное вещество по п. 1, где активное вещество представляет собой лекарственное вещество, токсин, аффинный лиганд, детекторный зонд или их комбинацию.
8. Конъюгат белок-активное вещество по п. 1, в котором аминокислотный мотив представляет собой СААХ, ХХСС, ХСХС или СХХ, где С представляет собой цистеин, А представляет собой алифатическую аминокислоту, и X представляет собой аминокислоту, которая определяет субстратную специфичность изопреноид-трансферазы.
9. Конъюгат белок-активное вещество по п. 1, в котором аминокислотный мотив ковалентно связан с активным веществом через по меньшей мере один линкер.
10. Конъюгат белок-активное вещество по п. 9, в котором линкер представляет собой изопренильное производное, которое может узнаваться изопреноид-трансферазой.
11. Конъюгат белок-активное вещество по п. 9, отличающийся тем, что линкер представлен следующей формулой (I):
Figure 00000001
где P1 и Y независимо представляют собой группу, содержащую первую функциональную группу (FG1), FG1 выбирается из группы, состоящей из: ацетилена, азида, альдегида, гидроксиламина, гидразина, кетона, нитробензофуразана (NBD), дансила, флуоресцеина, биотина и родамина,
L1 представляет собой (CH2)rXq(CH2)p,
X представляет собой кислород, серу, -NR1-, -C(O)NR1, -NR1C(O)-, -NR1SO2-, -SO2NR1-, -(СН=CH)- или ацетилен,
R1 представляет собой водород, C1-6 -алкил, C1-6 -алкил арил или C1-6 -алкил гетероарил,
r и p независимо представляют собой целое число от 0 до 6,
q представляет собой целое число от 0 до 1, и
N представляет собой целое число от 1 до 4.
12. Конъюгат белок-активное вещество по любому из пп. 9-11, в котором активное вещество прикреплено к группе, содержащей вторую функциональную группу (FG2), которая может реагировать с FG1, где FG2 выбирается из группы, состоящей из: ацетилена, гидроксиламина, азида, альдегида, гидразина, кетона и амина.
13. Конъюгат белок-активное вещество по п. 12, где активное вещество присоединено к группе, содержащей FG2 через -(CH2)rXq(CH2)p- или -[ZCH2CH2O(CH2CH2O)wCH2CH2Z]-, в которой
X представляет собой кислород, серу, -NR1-, -C(O)NR1-, -NR1C(O)-, -NR1SO2- или -SO2NR1-,
Ζ представляет собой кислород, серу или NR1,
R1 представляет собой водород, C1-6 -алкил, C1-6 -алкил арил или C1-6 -алкил гетероарил,
r и p независимо представляют собой целое число от 0 до 6,
q представляет собой целое число от 0 до 1, и
w представляет собой целое число от 0 до 6.
14. Конъюгат белок-активное вещество по п. 13, в котором -(CH2)rXq(CH2)p- или -[ZCH2CH2O(CH2CH2O)wCH2CH2Z]- прикреплены к (i) пептиду(ам), который (которые) может(могут) быть расщеплен(ы) посредством катепсина В, или (ii) глюкурониду, который может быть расщеплен посредством β-глюкуронидазы.
15. Конъюгат белок-активное вещество по п. 14, где пептид, который может быть расщеплен посредством катепсина В, представляет собой
Figure 00000002
16. Конъюгат белок-активное вещество по п. 14, в котором глюкуронид, который может быть расщеплен посредством β-глюкуронидазы, представляет собой
Figure 00000003
17. Способ получения конъюгата белок-активное вещество по п. 1, включающий:
(а) экспрессию белка, имеющего аминокислотный мотив, который может распознаваться с помощью изопреноид-трансферазы;
(b) ферментативное взаимодействие с применением изопреноид-трансферазы, экспрессируемого белка по меньшей мере с одним изосубстратом, имеющим первую функциональную группу (FG1), с получением, таким образом, функционализированного белка;
(c) присоединение второй функциональной группы (FG2) к активному веществу, с получением, таким образом, функционализированного активного вещества; и
(d) взаимодействие функционализированного белка с функционализированным активным веществом, с получением, таким образом, конъюгата белок-активное вещество по п. 1.
18. Способ по п. 17, в котором аминокислотный мотив находится на карбоксильном конце белка.
19. Способ по п. 17, в котором аминокислотный мотив представляет собой СААХ, ХХСС, ХСХС или СХХ, где С представляет собой цистеин, А представляет собой алифатическую аминокислоту, и X представляет собой аминокислоту, которая определяет субстратную специфичность изопреноид-трансферазы.
20. Способ по п. 19, в котором аминокислотный мотив представляет собой СААХ, и где способ дополнительно включает удаление ААХ из аминокислотного мотива после стадии (b).
21. Способ по п. 17, в котором FG2 прикреплен к активному веществу по меньшей мере одним линкером.
22. Способ по любому из пп. 17-21, в котором реакция между функционализированным белком и функционализированным активным веществом представляет собой реакцию клик-химии или образование гидразона и/или оксима.
23. Способ по п. 22, в котором FG1 представляет собой азидную группу, и FG2 представляет собой ацетиленовую группу, или где FG1 представляет собой ацетиленовую группу, и FG2 представляет собой азидную группу.
24. Способ по п. 22, в котором FG1 представляет собой альдегидную или кетонную группу, и FG2 представляет собой гидразин или гидроксиламин, или где FG1 представляет собой гидразин или гидроксиламин, и FG2 представляет собой альдегид или кетон.
25. Способ получения конъюгата белок-активное вещество по п. 1, в котором способ включает:
(a) экспрессию белка, имеющего аминокислотный мотив, который может распознаваться с помощью изопреноид-трансферазы;
(b) присоединение изосубстрата изопреноид-трансферазы к активному веществу, и
(c) ферментативное взаимодействие с применением изопреноид-трансферазы экспрессированного белка с активным веществом, присоединенным к изосубстрату.
26. Способ по п. 25, в котором аминокислотный мотив находится на карбоксильном конце белка.
27. Способ по п. 25, в котором аминокислотный мотив представляет собой СААХ, ХХСС, ХСХС или СХХ, где С представляет собой цистеин, А представляет собой алифатическую аминокислоту, и X представляет собой аминокислоту, которая определяет субстратную специфичность изопреноид-трансферазы.
28. Способ по любому из пп. 25-27, в котором изосубстрат прикреплен к активному веществу посредством по меньшей мере одного линкера.
29. Композиция, содержащая конъюгат белок-активное вещество по любому из пп. 1-16.
30. Композиция по п. 29, где композиция представляет собой гомогенную смесь конъюгата белок-активное вещество.
31. Композиция по п. 30, в которой белок представляет собой антитело или фрагмент антигенного полипептида.
32. Способ доставки активного вещества к клетке-мишени у субъекта, включающий введение конъюгата белок-активное вещество по любому из пп. 1-16 или композиции по любому из пп. 29-31 субъекту.
33. Способ по п. 32, в котором клетка-мишень представляет собой раковую клетку.
34. Способ по п. 32, в котором клетка-мишень представляет собой клетку, содержащую патогенный агент.
35. Способ по п. 34, в котором патогенный агент представляет собой вирус, бактерии, грибы или паразит.
36. Способ лечения субъекта, нуждающегося в этом, включающий введение терапевтически эффективное количество конъюгата белок-активное вещество по любому из пп. 1-16 или композиции по любому из пп. 29-31 субъекту.
37. Способ по п. 36, в котором субъект страдает от рака.
38. Способ по п. 36, в котором субъект страдает от инфекции с патогенным агентом.
39. Способ по п. 38, в котором патогенный агент представляет собой вирус, бактерии, грибы или паразит.
40. Конъюгат белок-активное вещество, композиция или способ по любому из пп. 1-39, в котором активное вещество представляет собой иммуномодулирующее соединение, противоопухолевое средство, противовирусное средство, антибактериальное средство, антигрибковый агент или антипаразитарный агент.
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