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RU2016150377A - Сайт-специфичная конъюгация линкерных лекарственных препаратов с антителами и получаемые в результате adc - Google Patents

Сайт-специфичная конъюгация линкерных лекарственных препаратов с антителами и получаемые в результате adc Download PDF

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RU2016150377A
RU2016150377A RU2016150377A RU2016150377A RU2016150377A RU 2016150377 A RU2016150377 A RU 2016150377A RU 2016150377 A RU2016150377 A RU 2016150377A RU 2016150377 A RU2016150377 A RU 2016150377A RU 2016150377 A RU2016150377 A RU 2016150377A
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antibody
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Герардус Йозеф Андреас АРИАНС
Руди Герардус Элизабет КАУМАНС
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Синтон Байофармасьютикалс Б. В.
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    • C12Y304/17021—Glutamate carboxypeptidase II (3.4.17.21)
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    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
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Claims (25)

1. Соединение конъюгат антитело-лекарственный препарат, в котором линкерный лекарственный препарат сайт-специфичным образом конъюгирован с антителом через встроенный цистеин в одной или более позициях указанного антитела, выбранных из 40, 41 и 89 тяжелой цепи (согласно нумерации Kabat); и 40 и 41 легкой цепи (согласно нумерации Kabat).
2. Соединение по п. 1, в котором указанный встроенный цистеин находится в одной или более позициях указанного антитела, выбранных из 40 и 41 тяжелой цепи и 40 и 41 легкой цепи в части Fab указанного антитела.
3. Соединение по п. 1 или 2, дополнительно содержащее встроенный цистеин в позиции 375 в части Fc указанного антитела (согласно нумерации Eu).
4. Соединение по любому из пп. 1-3, в котором указанный линкерный лекарственный препарат содержит производную дуокармицина.
5. Соединение конъюгат антитело-лекарственный препарат, в котором линкерный лекарственный препарат сайт-специфичным образом конъюгирован с антителом или связывающим антиген фрагментом антитела через встроенный цистеин в одной или более позициях указанного антитела, выбранных из 40, 41 и 89 тяжелой цепи (согласно нумерации Kabat); 152, 153, 155, 171, 247, 297, 339, 375 и 376 тяжелой цепи (согласно нумерации Eu); и 40, 41, 165 и 168 легкой цепи (согласно нумерации Kabat), при этом указанный линкерный лекарственный препарат содержит производную дуокармицина.
6. Соединение по любому из пп. 1-5 с формулой (I)
Figure 00000001
,
при этом n составляет 0-3, m представляет среднее DAR от 1 до 6, R1 выбирается из
Figure 00000002
,
y равно 1-16, и R2 выбирается из
Figure 00000003
.
7. Соединение по п. 6, в котором n составляет 0-1, m представляет среднее DAR от 1,5 до 2, R1 представляет собой
Figure 00000004
y равно 1-4, и R2 выбирается из
Figure 00000005
.
8. Соединение по любому из пп. 1-7 с формулой (II)
Figure 00000006
.
9. Соединение по любому из пп. 1-8, в котором указанное антитело связывается с антигеном-мишенью, который экспрессирован в или на клеточной мембране опухолевой клетки, и при этом указанное антитело поглощается клеткой после связывания с указанной целью.
10. Соединение по любому из пп. 1-9, в котором указанное антитело представляет собой антитело против аннексина A1, антитело против CD115, антитело против CD123, антитело против CLL-1, антитело против c-MET, антитело против MUC1, антитело против PSMA, антитело против 5T4 или антитело против TF.
11. Соединение по любому из пп. 1-10, в котором указанное антитело представляет собой моноклональное антитело против PSMA или моноклональное антитело против 5T4.
12. Соединение по п. 11, в котором указанный линкерный лекарственный препарат конъюгирован в позиции 41 вариабельной области тяжелой цепи указанного антитела против PSMA, предпочтительно, при этом тяжелая цепь указанного антитела против PSMA содержит последовательность аминокислот с SEQ ID, NO:2, и легкая цепь указанного антитела против PSMA содержит последовательность аминокислот с SEQ ID NO:5.
13. Соединение по п. 11, в котором указанный линкерный лекарственный препарат конъюгирован в позиции 41 вариабельной области тяжелой цепи указанного антитела против 5T4, предпочтительно, при этом тяжелая цепь указанного антитела против 5T4 содержит последовательность аминокислот с SEQ ID NO:8, и легкая цепь указанного антитела против 5T4 содержит последовательность аминокислот SEQ ID NO:11.
14. Фармацевтическая композиция, содержащая соединение по любому из пп. 1-13 и один или более фармацевтически приемлемых эксципиентов, предпочтительно, в форме лиофилизированного порошка.
15. Соединение по любому из пп. 1-13 или фармацевтическая композиция по п. 14 для применения в качестве медикамента.
16. Соединение по любому из пп. 1-13 или фармацевтическая композиция по п. 14 для применения в лечении человеческих солидных опухолей и гематологических злокачественных образований.
17. Соединение или фармацевтическая композиция по п. 16, при этом человеческие солидные опухоли выбираются из группы, состоящей из рака груди, рака желудка, рака ободочной и прямой кишки, рака уротелия, рака яичников, рака матки, рака легких, мезотелиомы, рака печени, рака поджелудочной железы и рака простаты.
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