RU2016145445A - Конъюгат антитела и лекарственного средства и его применение для лечения рака - Google Patents
Конъюгат антитела и лекарственного средства и его применение для лечения рака Download PDFInfo
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- RU2016145445A RU2016145445A RU2016145445A RU2016145445A RU2016145445A RU 2016145445 A RU2016145445 A RU 2016145445A RU 2016145445 A RU2016145445 A RU 2016145445A RU 2016145445 A RU2016145445 A RU 2016145445A RU 2016145445 A RU2016145445 A RU 2016145445A
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- antibody
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Claims (126)
1. Конъюгат "антитело - лекарственное средство" следующей формулы (I):
или его фармацевтически приемлемая соль,
где:
Ab представляет собой антитело против [мишени] или антитело против антигена, или его [мишень]-связывающий фрагмент или его антигенсвязывающий фрагмент;
L представляет собой линкер;
D представляет собой лекарственную группировку следующей формулы (II):
где:
R1 представляет собой Н или ОН;
R2 представляет собой группу: (С1-С6)алкил, СООН, СОО-((С1-С6)алкил) или тиазолил;
R3 представляет собой Н или (С1-С6)алкил;
А представляет собой:
- группу формулы -Het-Alk-, где Alk представляет собой (С1-С8)алкандиил и связан с NR3, a Het представляет собой гетероцикл, возможно, замещенный группой (С1-С6)алкил и содержащий по меньшей мере один атом азота, при этом указанный атом азота связан с L, или
- группу формулы -Aa-Ab- где Аа связан с L и представляет собой О или NR9, где R9 представляет собой Н или (С1-С6)алкил, а Ab связан с NR3 и представляет собой:
СН2СН2-, где каждый из Х1, Х2, Х3 и Х4 независимо от других представляет собой О или NR8; каждый из а1, а2, а3 и а4 независимо от других представляет собой 0 или 1; a R8 представляет собой Н или (С1-С6)алкил,
волнистая линия указывает на точку присоединения к L; и
n составляет от 1 до 12.
2. Конъюгат "антитело - лекарственное средство" по п. 1, где [мишень] или антиген указанного антитела против [мишени], или антитела против антигена согласно изобретению, или его [мишень]- или антигенсвязывающего фрагмента выбраны среди CD19, CD20, CD22, CD25, CD30, CD33, CD40, CD56, CD64, CD70, CD74, CD79, CD105, CD138, CD174, CD205, CD227, CD326, CD340, MUC16, GPNMB, PSMA, Cripto, ED-B, TMEFF2, EphB2, EphA2, FAP, интегрина av, мезотелина, EGFR, TAG-72, GD2, CAIX, 5T4, HER1, HER3, HER2, IGF-1R, Axl и их внеклеточных мембранных фрагментов (ECD, от англ. extracellular domains).
3. Конъюгат "антитело - лекарственное средство" по п. 1, где указанная [мишень] или антиген указанного антитела против [мишени], или антитела против антигена согласно изобретению, или его [мишень]- или антигенсвязывающего фрагмента выбраны среди HER2, IGF-1R и белка Axl, предпочтительно человеческого HER2, человеческого IGF-1R и человеческого белка Axl, а также их внеклеточных мембранных фрагментов (ECD).
4. Конъюгат "антитело - лекарственное средство" по п. 1, где указанное Ab представляет собой антитело или его антигенсвязывающий фрагмент, способные связываться с человеческим IGF-1R, выбранные среди:
i) антител 208F2, 212A11, 214F8, 219D6 и 213В10;
ii) антител, которые конкурируют за связывание с IGF-1R с антителами из i); и
iii) антител, которые связываются с тем же эпитом IGF-1R, что и антитела i).
5. Конъюгат "антитело - лекарственное средство" по п. 1, где указанное Ab представляет собой антитело или его антигенсвязывающий фрагмент, способные связываться с человеческим IGF-1R, выбранные среди:
i) антитела, которое содержит три CDR участка тяжелой цепи последовательностей SEQ ID NO 1, 2 и 3 и три CDR участка легкой цепи последовательностей SEQ ID NO 4, 5 и 6;
ii) антитела, которое конкурирует за связывание IGF-1R с антителом из i); и
iii) антитела, которое связывается с тем же эпитопом IGF-1R, что и антитело из i).
6. Конъюгат "антитело - лекарственное средство" по п. 1, где Ab содержит:
a) вариабельный домен тяжелой цепи (VH) последовательности SEQ ID NO 33, где указанная последовательность SEQ ID NO 33 содержит по меньшей мере 1 обратную мутацию, выбранную среди остатков 20, 34, 35, 38, 48, 50, 59, 61, 62, 70, 72, 74, 76, 77, 79, 82 или 95; и
b) вариабельный домен легкой цепи (VL) последовательности SEQ ID NO 35, где указанная последовательность SEQ ID NO 35 содержит по меньшей мере 1 обратную мутацию, выбранную среди остатков 22, 53, 55, 65, 71, 72, 77 или 87.
7. Конъюгат "антитело - лекарственное средство" по п. 1, где указанное Ab представляет собой антитело или его антигенсвязывающий фрагмент, способные связываться с человеческим белком Axl, выбранные среди:
i) антитела, которое содержит три CDR участка тяжелой цепи последовательностей SEQ ID NO 59, 60 и 61 и три CDR участка легкой цепи последовательностей SEQ ID NO 56, 57 и 58;
ii) антитела, которое конкурирует за связывание Axl с антителом из i); и
iii) антитела, которое связывается с тем же эпитопом Axl, что и антитело из i).
8. Конъюгат "антитело - лекарственное средство" по п. 1, где указанное Ab представляет собой антитело или его антигенсвязывающий фрагмент, способные связываться с человеческим HER2, состоящие из трастузумаба.
9. Конъюгат "антитело - лекарственное средство" по п. 1, где L представляет собой линкер следующей формулы (III):
где:
L2 представляет собой (С4-С10)циклоалкил-карбонил, (С2-С6)алкил, (С2-С6)алкил-карбонил,
W представляет собой аминокислотный блок; w представляет собой целое число от 0 до 5;
звездочка указывает на точку присоединения к D; и
волнистая линия указывает на точку присоединения к Ab.
10. Конъюгат "антитело - лекарственное средство" по п. 9, где L2 имеет следующую формулу:
где:
звездочка указывает на точку присоединения к (W)w; и
волнистая линия указывает на точку присоединения к атому азота малеимидной группировки.
11. Конъюгат "антитело - лекарственное средство" по п. 9, где w равно 0; или w равно 2, a (W)w выбран среди:
где:
звездочка указывает на точку присоединения к (Y)y; и
волнистая линия указывает на точку присоединения к L2.
12. Конъюгат "антитело - лекарственное средство" по п. 9, где L выбран среди:
где звездочка указывает на точку присоединения к D, а волнистая линия указывает на точку присоединения к Ab.
13. Конъюгат "антитело - лекарственное средство" по п. 1, где А представляет собой группу формулы -Аа-Ab-, в которой Аа является таким, как определено в п. 1, а Ab представляет собой группу:
- фенил-(С1-С2)алкандиил, или
- гетероцикл-(С1-С2)алкандиил, возможно, замещенную группой (C1-С6)алкил (особенно незамещенную), при этом гетероцикл представляет собой насыщенное, ненасыщенное или ароматическое кольцо с 5 или 6 членами, содержащее 1 или 2 атома азота, выбранное, в частности, среди пиридина, пиперидина и имидазола и предпочтительно представляющее собой пиридин.
14. Конъюгат "антитело - лекарственное средство" по п. 1, где А представляет собой группу следующей формулы:
где:
R9 является таким, как определено в п. 1, a m представляет собой целое число от 1 до 8, и где предпочтительно R9 представляет собой Н или Me, a m равен 1 или 2,
волнистая линия указывает на точку присоединения к L, и
звездочка указывает на точку присоединения к NR3.
15. Конъюгат "антитело - лекарственное средство" по п. 1, где (L-D) выбран среди:
где волнистая линия указывает на точку присоединения к Ab.
16. Конъюгат "антитело - лекарственное средство" по п. 1, имеющий формулу, выбранную среди:
и его фармацевтически приемлемая соль,
где Ab представляет собой антитело против [мишени] или антитело против антигена, или его [мишень]-связывающий фрагмент или его антигенсвязывающий фрагмент.
17. Конъюгат "антитело - лекарственное средство" по п. 16, где [мишень] указанного антитела против [мишени] или антиген указанного антитела против антигена или его [мишень]-связывающего фрагмента или его антигенсвязывающего фрагмента выбраны среди CD19, CD20, CD22, CD25, CD30, CD33, CD40, CD56, CD64, CD70, CD74, CD79, CD105, CD138, CD174, CD205, CD227, CD326, CD340, MUC16, GPNMB, PSMA, Cripto, ED-B, TMEFF2, EphB2, EphA2, FAP, интегрина av, мезотелина, EGFR, TAG-72, GD2, CAIX, 5T4, HER1, HER3, HER2, IGF-1R, Axl и их внеклеточных мембранных фрагментов (ECD).
18. Конъюгат "антитело - лекарственное средство" по п. 16, где [мишень] указанного антитела против [мишени] или антиген указанного антитела против антигена выбраны среди HER2, IGF-1R и белка Axl, предпочтительно человеческого HER2, человеческого IGF-1R и человеческого белка Axl.
19. Конъюгат "антитело - лекарственное средство" по п. 16, где указанное Ab представляет собой антитело или его антигенсвязывающий фрагмент и выбрано среди:
a) Ab или его антигенсвязывающего фрагмента, способного связываться с человеческим IGF-1R, выбранного среди:
i) антител 208F2, 212А11, 214F8, 219D6 и 213В10;
ii) антител, которые конкурируют за связывание с IGF-1R с антителами из i); и
iii) антител, которые связываются с тем же эпитом IGF-1R, что и антитела из i),
b) Ab или его антигенсвязывающего фрагмента, способного связываться с человеческим IGF-1R, выбранного среди:
i) антитела, которое содержит три CDR участка тяжелой цепи последовательностей SEQ ID NO 1, 2 и 3 и три CDR участка легкой цепи последовательностей SEQ ID NO 4, 5 и 6;
ii) антитела, которое конкурирует за связывание IGF-1R с антителом из i); и
iii) антитела, которое связывается с тем же эпитопом IGF-1R, что и антитело из i),
c) Ab, которое содержит:
i) вариабельный домен тяжелой цепи (VH) последовательности SEQ ID NO 33, где указанная последовательность SEQ ID NO 33 содержит по меньшей мере 1 обратную мутацию, выбранную среди остатков 20, 34, 35, 38, 48, 50, 59, 61, 62, 70, 72, 74, 76, 77, 79, 82 или 95; и
ii) вариабельный домен легкой цепи (VL) последовательности SEQ ID NO 35, где указанная последовательность SEQ ID NO 35 содержит по меньшей мере 1 обратную мутацию, выбранную среди остатков 22, 53, 55, 65, 71, 72, 77 или 87,
d) Ab или его антигенсвязывающего фрагмента, способного связываться с человеческим белком Axl, выбранного среди:
i) антитела, которое содержит три CDR тяжелой цепи последовательностей SEQ ID NO 59, 60 и 61 и три CDR легкой цепи последовательностей SEQ ID NO 56, 57 и 58;
ii) антитела, которое конкурирует за связывание Axl с антителом из i); и
iii) антитела, которое связывается с тем же эпитопом Axl, что и антитело из i), и
е) Ab или его антигенсвязывающего фрагмента, способного связываться с человеческим HER2, состоящего из трастузумаба или пертузумаба.
20. Конъюгат "антитело - лекарственное средство" по п. 1, где n составляет 2.
21. Конъюгат "антитело - лекарственное средство" по п. 1, где n составляет 4.
22. Конъюгат "антитело - лекарственное средство" по любому из пп. 1-21 для применения в качестве лекарственного препарата.
23. Композиция, содержащая по меньшей мере один конъюгат "антитело - лекарственное средство" по любому из пп. 1-21.
24. Композиция по п. 23, дополнительно содержащая фармацевтически приемлемый носитель.
25. Композиция по п. 23 или 24 для применения в лечении [мишень]- или антигенэкспрессирующего рака, где указанная [мишень] или антиген предпочтительно выбраны среди CD19, CD20, CD22, CD25, CD30, CD33, CD40, CD56, CD64, CD70, CD74, CD79, CD105, CD138, CD174, CD205, CD227, CD326, CD340, MUC16, GPNMB, PSMA, Cripto, ED-B, TMEFF2, EphB2, EphA2, FAP, интегрина av, мезотелина, EGFR, TAG-72, GD2, CAIX, 5T4, HER2, IGF-1R, Axl и их внеклеточных мембранных фрагментов (ECD).
26. Композиция по п. 23 или 24 для применения в лечении HER2-, IGF-1R- или Axl-экспрессирующего рака.
27. Композиция по п. 25, где указанный [мишень]- или антигенэкспрессирующий рак представляет собой рак, выбранный среди рака молочной железы, толстой кишки, карциномы пищевода, гепатоцеллюлярного рака, рака желудка, глиомы, рака легких, меланомы, остеосаркомы, рака яичников, предстательной железы, рабдомиосаркомы, рака почек, щитовидной железы, эндометрия матки, мезотелиомы, плоскоклеточной карциномы ротовой полости, саркомы Капоши, острой лейкемии, колоректальной карциномы, меланомы, протоковой аденокарциномы поджелудочной железы и любого рака с лекарственной устойчивостью.
28. Способ лечения [мишень]- или антигенэкспрессирующего рака у субъекта, нуждающегося в этом, включающий введение субъекту эффективного количества по меньшей мере одного конъюгата "антитело - лекарственное средство" по любому из пп. 1-21 или композиции по п. 23 или 24.
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