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RU2011153288A - Способы конъюгации - Google Patents

Способы конъюгации Download PDF

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Publication number
RU2011153288A
RU2011153288A RU2011153288/10A RU2011153288A RU2011153288A RU 2011153288 A RU2011153288 A RU 2011153288A RU 2011153288/10 A RU2011153288/10 A RU 2011153288/10A RU 2011153288 A RU2011153288 A RU 2011153288A RU 2011153288 A RU2011153288 A RU 2011153288A
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RU
Russia
Prior art keywords
effector
mixture
linker
maytansinoid
cell
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RU2011153288/10A
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English (en)
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RU2595424C2 (ru
Inventor
Бренда А. КЕЛЛОГ
Раджиева Сингх
Рави В. Дж. Чари
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Иммьюноджен, Инк.
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Publication of RU2011153288A publication Critical patent/RU2011153288A/ru
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Publication of RU2595424C2 publication Critical patent/RU2595424C2/ru

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
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Abstract

1. Способ приготовления очищенного конъюгата в растворе, при этом конъюгат включает эффекторную или репортерную молекулу, соединенную со связывающимся с клетками агентом, включающий этапы: (а) связывания эффекторной или репортерной молекулы с бифункциональным линкерным реагентом для ковалентного присоединения линкера к эффекторной или репортерной молекуле и приготовления таким образом неочищенной первой смеси, содержащей эффекторные или репортерные молекулы, связанные с линкером, (б) конъюгацию связывающегося с клетками агента с эффекторной или репортерной молекулой, связанной с линкером, путем реакции неочищенной первой смеси со связывающимся с клетками агентом для приготовления второй смеси и (в) воздействие на вторую смесь путем тангенциальной поточной фильтрации, диализа, гелевой фильтрации, адсорбционной хроматографии, селективного осаждения или их комбинации для получения очищенного конъюгата.2. Способ по п.1, отличающийся тем, что этап (б) выполняют в растворе с рН от около 4 до около 9.3. Способ по п.1, отличающийся тем, что вторая смесь на этапе (б) по большей части свободна от нежелаемых поперечно-сшитых гидролизованных частиц, образовавшихся в результате внутримолекулярных или межмолекулярных реакций.4. Способ по п.1, отличающийся тем, что эффекторная молекула является цитотоксичным агентом.5. Способ по п.4, отличающийся тем, что цитотоксичный агент является майтансиноидом, таксаном, СС1065 или их аналогом.6. Способ по п.4, отличающийся тем, что цитотоксичный агент является майтансиноидом.7. Способ по п.6, отличающийся тем, что майтансиноид включает в себя тиоловую группу.8. Способ по п.6, отличающийся тем,

Claims (17)

1. Способ приготовления очищенного конъюгата в растворе, при этом конъюгат включает эффекторную или репортерную молекулу, соединенную со связывающимся с клетками агентом, включающий этапы: (а) связывания эффекторной или репортерной молекулы с бифункциональным линкерным реагентом для ковалентного присоединения линкера к эффекторной или репортерной молекуле и приготовления таким образом неочищенной первой смеси, содержащей эффекторные или репортерные молекулы, связанные с линкером, (б) конъюгацию связывающегося с клетками агента с эффекторной или репортерной молекулой, связанной с линкером, путем реакции неочищенной первой смеси со связывающимся с клетками агентом для приготовления второй смеси и (в) воздействие на вторую смесь путем тангенциальной поточной фильтрации, диализа, гелевой фильтрации, адсорбционной хроматографии, селективного осаждения или их комбинации для получения очищенного конъюгата.
2. Способ по п.1, отличающийся тем, что этап (б) выполняют в растворе с рН от около 4 до около 9.
3. Способ по п.1, отличающийся тем, что вторая смесь на этапе (б) по большей части свободна от нежелаемых поперечно-сшитых гидролизованных частиц, образовавшихся в результате внутримолекулярных или межмолекулярных реакций.
4. Способ по п.1, отличающийся тем, что эффекторная молекула является цитотоксичным агентом.
5. Способ по п.4, отличающийся тем, что цитотоксичный агент является майтансиноидом, таксаном, СС1065 или их аналогом.
6. Способ по п.4, отличающийся тем, что цитотоксичный агент является майтансиноидом.
7. Способ по п.6, отличающийся тем, что майтансиноид включает в себя тиоловую группу.
8. Способ по п.6, отличающийся тем, что майтансиноид является DM1.
9. Способ по п.6, отличающийся тем, что майтансиноид является DM4.
10. Способ по п.1, отличающийся тем, что связывающийся с клетками агент является интерферонами, интерлейкином 2, (IL-2), интерлейкином 3 (IL-3), интерлейкином 4 (IL-4), интерлейкином 6 (IL-6), инсулином, EGF, TGF-a, FGF, G-CSF, VEGF, MCSF, GM-CSF, трансферрином или антителами.
11. Способ по п.10, отличающийся тем, что связывающийся с клетками агент является антителом.
12. Способ по п.11, отличающийся тем, что антитело является моноклональным антителом.
13. Способ по п.11, отличающийся тем, что антитело является человеческим или гуманизированным моноклональным антителом.
14. Способ по п.10, отличающийся тем, что антитело является MY9, анти-В4, ЕрСАМ, CD2, CD3, CD4, CD5, CD6, CD11, CD19, CD20, CD22, CD26, CD30, CD33, CD37, CD38, CD40, CD44, CD56, CD79, CD105, CD138, EphA рецепторами, EphB рецепторами, EGFR, EGFRvIII, HER2, HER3, мезотелином, крипто, альфаvбета3, альфаvбета5; альфаvбета6 интегрином или С242.
15. Способ по п.13, отличающийся тем, что человеческое или гуманизированное антитело является Му9-6, В4, С242, N901, DS6, EphA2 рецепторами, CD38, IGF-IR, CNTO 95, В-В4, трастузумабом, пертузумабом, биватузумабом, зибротузумабом или ритуксимабом.
16. Способ по п.1, отличающийся тем, что линкер является расщепляемым или нерасщепляемым линкером.
17. Способ по п.1, отличающийся тем, что репортерная молекула является радиоизотопом.
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DK2437790T3 (da) 2019-05-20
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HRP20190898T1 (hr) 2019-08-09
IL286056B2 (en) 2023-08-01
IL274599B (en) 2021-09-30
RU2016130501A3 (ru) 2020-01-29
BRPI1010620A2 (pt) 2016-03-15
CN102448500A (zh) 2012-05-09
US20110003969A1 (en) 2011-01-06
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BRPI1010620B8 (pt) 2021-05-25
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JP7262507B2 (ja) 2023-04-21
SI2437790T1 (sl) 2019-07-31
US20170002096A1 (en) 2017-01-05
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US20210163625A1 (en) 2021-06-03
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US8624003B2 (en) 2014-01-07
JP2024099722A (ja) 2024-07-25
KR20200090974A (ko) 2020-07-29
MX2011012794A (es) 2012-05-08
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US11498979B2 (en) 2022-11-15
KR102139019B1 (ko) 2020-07-28

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