RU2016102116A - Конъюгаты антител с лекарственными агентами, обладающие улучшенной стабильностью, и их применение - Google Patents

Конъюгаты антител с лекарственными агентами, обладающие улучшенной стабильностью, и их применение Download PDF

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RU2016102116A
RU2016102116A RU2016102116A RU2016102116A RU2016102116A RU 2016102116 A RU2016102116 A RU 2016102116A RU 2016102116 A RU2016102116 A RU 2016102116A RU 2016102116 A RU2016102116 A RU 2016102116A RU 2016102116 A RU2016102116 A RU 2016102116A
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antibody
conjugate
agent according
drug agent
group
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RU2016102116A
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RU2670748C2 (ru
RU2670748C9 (ru
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Юн Мин КИМ
Мин Чи КО
Чэ Ён КИМ
Чу Хи КИМ
Кюн Тюк МУН
Тэ Хэ СОН
Чэ Хён ОМ
Чин Вон ДЖУН
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Аблбио
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    • A61K47/6891—Pre-targeting systems involving an antibody for targeting specific cells
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    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
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    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
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    • C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
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Claims (23)

1. Конъюгат антитела с лекарственным агентом, содержащий цитотоксическое вещество, присоединенное к N-концевому аминокислотному остатку тяжелой или легкой цепи антитела.
2. Конъюгат антитела с лекарственным агентом по п. 1, в котором цитотоксическое вещество присоединено к N-концевой α-аминогруппе тяжелой или легкой цепи антитела.
3. Конъюгат антитела с лекарственным агентом по п. 2, в котором цитотоксическое вещество присоединено к антителу реакционноспособной группой цитотоксического вещества, способной к образованию поперечной сшивки с указанной α-аминогруппой.
4. Конъюгат антитела с лекарственным агентом по п. 3, в котором реакционноспособную группу, способную к образованию поперечной сшивки с указанной α-аминогруппой, выбирают из группы, состоящей из изотиоцианатной, изоцианатной, ацилазидной, N-гидроксисукцинимидэфирной (NHS-эфирной), сульфонилхлоридной, альдегидной, глиоксальной, эпоксидной, оксирановой, карбонатной, арилгалогенидной, имидоэфирной, карбодиимидной, ангидридной и фторфенилэфирной групп.
5. Конъюгат антитела с лекарственным агентом по п. 1, в котором антитело включает полноразмерные молекулы антител или фрагменты антител, содержащие домены, связывающие антиген.
6. Конъюгат антитела с лекарственным агентом по п. 5, в котором антитело выбирают из группы, состоящей из IgG, scFv, Fv, Fab, Fab' и F(ab')2.
7. Конъюгат антитела с лекарственным агентом по п. 1, в котором цитотоксическое вещество выбирают из группы, состоящей из ингибиторов образования структуры микротрубочек, ингибиторов мейоза, ингибиторов РНК-полимеразы, ингибиторов топоизомеразы, агентов, интеркалирующих в ДНК, агентов, алкилирующих ДНК, ингибиторов функций рибосом, радиоактивных изотопов и токсинов.
8. Конъюгат антитела с лекарственным агентом по п. 7, в котором цитотоксическое вещество выбирают из группы, состоящей из мейтансиноида, ауристатина, долостатина, тубулизина, калихеамицина, пирролобензодиазепинов, доксорубицина, дуокамицина, карбоплатина (параплатина), цисплатина, циклофосфамида, ифосфамида, нидрана, азотистого иприта (мехлорэтамина-HCl), блеомицина, митомицина С, цитарабина, фторурацила, гемцитабина, триметрексата, метотрексата, этопозида, винбластина, винорелбина, алимты, алтретамина, прокарбазина, таксола, таксотера,
топотекана, иринотекана, трихотецена, СС1065, альфа-аманитина, других энединовых антибиотиков, экзотоксинов и растительных токсинов.
9. Конъюгат антитела с лекарственным агентом по п. 8, в котором ауристатин представлен монометилауристатином Е или монометилауристатином F.
10. Конъюгат антитела с лекарственным агентом по п. 1, в котором антитело специфично связывается с антигеном поверхности раковых клеток.
11. Конъюгат антитела с лекарственным агентом по п. 10, в котором антиген поверхности раковых клеток выбирают из группы, состоящей из CD19, CD20, CD30, CD33, CD37, CD22, CD56, CD70, CD74, CD138, Muc-16, мезотелина, HER2, HER3, гликопротеина NMB (GPNMB), IGF-1R, антигена созревания В-клеток (ВСМА), PSMA (мембранного антигена, характерного для предстательной железы), ЕрСАМ (молекулы адгезии эпителиальных клеток) и EGFR (рецептора фактора роста эпидермиса).
12. Конъюгат антитела с лекарственным агентом по п. 1, в котором антитело выбирают из группы, состоящей из антител против HER2, антител против CD30, антител против CD56, антител против GPNMB (гликопротеина NMB).
13. Конъюгат антитела с лекарственным агентом по п. 12, в котором антитело выбирают из группы, состоящей из трастузумаба, лорвотузумаба, брентуксимаба и глембатумумаба.
14. Конъюгат антитела с лекарственным агентом, содержащий иммуносупрессивный агент, присоединенный к N-концевому аминокислотному остатку тяжелой или легкой цепи антитела.
15. Способ получения конъюгата антитела с лекарственным агентом по любому из пп. 1-14, включающий присоединение цитотоксического вещества или иммуносупрессивного агента к N-концевой α-аминогруппе тяжелой или легкой цепи антитела путем обеспечения взаимодействия антитела с цитотоксическим веществом или иммуносупрессивным агентом, содержащим реакционноспособную группу, способную образовывать поперечную сшивку с α-аминогруппой.
16. Способ по п. 15, включающий также отделение конъюгата антитела с лекарственным агентом от прочих продуктов реакции, в том числе молекул антитела и цитотоксического или иммуносупрессивного вещества, не образовавших конъюгата.
17. Способ по п. 15, в котором реакционноспособную группу, способную образовывать поперечную сшивку с указанной α-аминогруппой, выбирают из группы, состоящей из изотиоцианатной, изоцианатной, ацилазидной, N-гидроксисукцинимидэфирной (NHS-эфирной), сульфонилхлоридной, альдегидной, глиоксальной, эпоксидной, оксирановой, карбонатной, арилгалогенидной, имидоэфирной,
карбодиимидной, ангидридной и фторфенилэфирной групп.
18. Фармацевтическая композиция для лечения ракового заболевания, содержащая конъюгат антитела с лекарственным агентом по любому из пп. 1-13.
19. Фармацевтическая композиция для лечения аутоиммунного заболевания, содержащая конъюгат антитела с лекарственным агентом по п. 14.
20. Способ лечения рака, включающий введение конъюгата антитела с лекарственным агентом по любому из пп. 1-13 индивиду, у которого подозревается наличие ракового заболевания.
21. Способ лечения аутоиммунного заболевания, включающий введение конъюгата антитела с лекарственным агентом по п. 14 индивиду, у которого подозревается наличие аутоиммунного заболевания.
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