RU2011108928A - Конъюгаты "производное калихеамицина-носитель" - Google Patents
Конъюгаты "производное калихеамицина-носитель" Download PDFInfo
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Abstract
1. Способ получения конъюгатов "мономерное цитотоксическое лекарственное средство/носитель" с низким содержанием низкоконъюгированной фракции (LCF), имеющих формулу: ! Pr(-Х-W)m, ! где Pr представляет собой белковый носитель; ! Х представляет собой линкер, включающий продукт реакции любой реакционноспособной группы, которая может взаимодействовать с белковым носителем; ! W представляет собой цитотоксическое лекарственное средство; ! m означает среднюю нагрузку для продукта очищенного конъюгата, такую, при которой указанное цитотоксическое лекарственное средство составляет 7-9% по массе конъюгата; и ! (-Х-W)m представляет собой производное цитотоксического лекарственного средства, ! где указанный способ включает стадии: ! (1) добавления производного цитотоксического лекарственного средства к белковому носителю, где указанное производное цитотоксического лекарственного средства составляет 4,5-11% по массе белкового носителя; ! (2) инкубирования указанного производного цитотоксического лекарственного средства и белкового носителя в ненуклеофильном и совместимом с белком буферном растворе, имеющем рН примерно от 7 до 9, с продуцированием конъюгата "мономерное цитотоксическое лекарственное средство/носитель", где указанный раствор, кроме того, содержит (а) органический сорастворитель и (b) добавку, содержащую, по крайней мере, одну С6-С18-карбоновую кислоту или ее соль, и где указанное инкубирование осуществляют при температуре в пределах примерно от 30°С до 35°С в течение периода времени примерно от 15 мин до 24 ч; и ! (3) хроматографии конъюгата, полученного на стадии (2), для отделения конъюгатов "производное мономерного цито
Claims (25)
1. Способ получения конъюгатов "мономерное цитотоксическое лекарственное средство/носитель" с низким содержанием низкоконъюгированной фракции (LCF), имеющих формулу:
Pr(-Х-W)m,
где Pr представляет собой белковый носитель;
Х представляет собой линкер, включающий продукт реакции любой реакционноспособной группы, которая может взаимодействовать с белковым носителем;
W представляет собой цитотоксическое лекарственное средство;
m означает среднюю нагрузку для продукта очищенного конъюгата, такую, при которой указанное цитотоксическое лекарственное средство составляет 7-9% по массе конъюгата; и
(-Х-W)m представляет собой производное цитотоксического лекарственного средства,
где указанный способ включает стадии:
(1) добавления производного цитотоксического лекарственного средства к белковому носителю, где указанное производное цитотоксического лекарственного средства составляет 4,5-11% по массе белкового носителя;
(2) инкубирования указанного производного цитотоксического лекарственного средства и белкового носителя в ненуклеофильном и совместимом с белком буферном растворе, имеющем рН примерно от 7 до 9, с продуцированием конъюгата "мономерное цитотоксическое лекарственное средство/носитель", где указанный раствор, кроме того, содержит (а) органический сорастворитель и (b) добавку, содержащую, по крайней мере, одну С6-С18-карбоновую кислоту или ее соль, и где указанное инкубирование осуществляют при температуре в пределах примерно от 30°С до 35°С в течение периода времени примерно от 15 мин до 24 ч; и
(3) хроматографии конъюгата, полученного на стадии (2), для отделения конъюгатов "производное мономерного цитотоксического лекарственного средства/белковый носитель", имеющих нагрузку цитотоксическим лекарственным средством, составляющую в пределах 4-10 мас.%, и содержание низкоконъюгированной фракции (LCF), составляющее ниже 10% от неконъюгированного белкового носителя, производного цитотоксического лекарственного средства и агрегированных конъюгатов.
2. Способ по п.1, где указанный белковый носитель выбран из группы, состоящей из гормонов, факторов роста, антител, фрагментов антител, миметиков антител, и их генетически или ферментативно сконструированных аналогов.
3. Способ по п.1, где указанным белковым носителем является антитело.
4. Способ по п.3, где указанное антитело выбрано из группы, состоящей из моноклонального антитела, химерного антитела, человеческого антитела, гуманизированного антитела, одноцепочечного антитела, Fab-фрагмента и F(ab)2-фрагмента.
5. Способ по п.4, где указанное гуманизированное антитело направлено против антигена клеточной поверхности CD22.
6. Способ по п.5, где указанным гуманизированным анти-CD22 антителом является CDR-привитое антитело, которое включает вариабельную область легкой цепи 5/44-gL1 (SEQ ID NO:19) и вариабельную область тяжелой цепи 5/44-gH7 (SEQ ID NO:27).
7. Способ по п.5, где указанным гуманизированным анти-CD22 антителом является CDR-привитое антитело, содержащее легкую цепь, имеющую последовательность, представленную в SEQ ID NO:28.
8. Способ по п.5, где указанным гуманизированным анти-CD22 антителом является CDR-привитое антитело, содержащее тяжелую цепь, имеющую последовательность, представленную в SEQ ID NO:30.
9. Способ по п.5, где указанным гуманизированным анти-CD22 антителом является CDR-привитое антитело, содержащее легкую цепь, имеющую последовательность, представленную в SEQ ID NO:28, и тяжелую цепь, имеющую последовательность, представленную в SEQ ID NO:30.
10. Способ по п.5, где указанным гуманизированным анти-CD22 антителом является CDR-привитое антитело, которое представляет собой вариант антитела, полученный в соответствии с протоколом осуществления аффинного созревания, и обладающий повышенной специфичностью к человеческому CD22.
11. Способ по п.1, где указанным цитотоксическим лекарственным средством является ингибитор полимеризации тубулина.
12. Способ по п.1, где указанным цитотоксическим лекарственным средством является алкилирующий агент, который связывается с ДНК и разрушает ее.
13. Способ по п.1, где указанным цитотоксическим лекарственным средством является ингибитор синтеза белка.
14. Способ по п.1, где указанным цитотоксическим лекарственным средством является ингибитор тирозинкиназы.
15. Способ по п.1, где указанное цитотоксическое лекарственное средство выбрано из калихеамицинов, тиотепы, таксанов, винкристина, даунорубицина, доксорубицина, эпирубицина, эсперамицинов, актиномицина, аутрамицина, азасеринов, блеомицинов, тамоксифена, идарубицина, доластатинов/ауристатинов, гемиастерлинов и маитанзиноидов.
16. Способ по п.1, где указанным цитотоксическим лекарственным средством является калихеамицин.
17. Способ по п.16, где указанным калихеамицином является гамма-калихеамицин или N-ацетил-гамма-калихеамицин.
18. Способ по п.1, где указанное цитотоксическое лекарственное средство имеет функциональный 3-меркапто-3-метилбутаноилгидразид.
19. Способ по п.1, где указанным линкером является гидролизуемый линкер, способный высвобождать цитотоксическое лекарственное средство из указанного конъюгата после его связывания и проникновения в клетки-мишени.
20. Способ по п.19, где указанным гидролизуемым линкером является 4-(4-ацетилфенокси)бутановая кислота (AcBut).
21. Способ по п.1, где добавкой, используемой в стадии (2)(b), является октановая кислота или ее соль.
22. Способ по п.1, где добавкой, используемой в стадии (2)(b), является декановая кислота или ее соль.
23. Способ по п.1, где указанным методом хроматографического разделения на стадии (3) является эксклюзионная хроматография (SEC).
24. Способ по п.1, где указанным методом хроматографического разделения на стадии (3) является ВЭЖХ, ЖЭХБ или хроматография на Сефакриле S-200.
25. Способ по п.1, где указанным методом хроматографического разделения на стадии (3) является гидрофобная хроматография (ГФХ).
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