RU2018120695A - Связывающие молекулы, специфичные в отношении asct2, и их применения - Google Patents

Связывающие молекулы, специфичные в отношении asct2, и их применения Download PDF

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RU2018120695A
RU2018120695A RU2018120695A RU2018120695A RU2018120695A RU 2018120695 A RU2018120695 A RU 2018120695A RU 2018120695 A RU2018120695 A RU 2018120695A RU 2018120695 A RU2018120695 A RU 2018120695A RU 2018120695 A RU2018120695 A RU 2018120695A
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antibody
seq
binding fragment
amino acid
acid sequence
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RU2018120695A
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RU2710194C2 (ru
RU2710194C9 (ru
RU2018120695A3 (ru
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Набенду ПОР
БОРРОК Мартин Дж., III
Партха ЧОВДХУРИ
Эмиль Ф. МИКЕЛОТТИ
Дэвид А. ТАЙС
Роберт Е. ХОЛЛИНГСВОРТ
Чиэнь-Ин ЧАН
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МЕДИММЬЮН, ЭлЭлСи
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • 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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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
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    • 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
    • A61K47/68—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
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
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    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
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    • G01N33/57492—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds localized on the membrane of tumor or cancer cells
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Claims (20)

1. Антитело или его антиген-связывающий фрагмент, которые специфично связываются с эпитопом транспортного белка 2 переноса нейтральных аминокислот (ASCT2), где антитело или антиген-связывающий фрагмент содержат три определяющих комплементарность участка тяжелой цепи (HCDR) вариабельного участка тяжелой цепи (VH) и три определяющих комплементарность участка легкой цепи (LCDR) вариабельного участка легкой цепи (VL); где антитело или его антиген-связывающий фрагмент содержат HCDR1, чья аминокислотная последовательность приведена в SEQ ID NO: 10 или SEQ ID NO: 16; HCDR2 с аминокислотной последовательностью, приведенной в SEQ ID NO: 11 или SEQ ID NO: 17; HCDR3 с аминокислотной последовательностью, приведенной в SEQ ID NO: 12 или SEQ ID NO: 18; LCDR1 с аминокислотной последовательностью, приведенной в SEQ ID NO: 13 или SEQ ID NO: 19; LCDR2 с аминокислотной последовательностью, приведенной в SEQ ID NO: 14 или SEQ ID NO: 20; и LCDR3 с аминокислотной последовательностью, приведенной в SEQ ID NO: 15 или SEQ ID NO: 21.
2. Антитело или антиген-связывающий фрагмент по п. 1, где VH содержит аминокислотную последовательность, выбранную из SEQ ID NO: 1; SEQ ID NO: 3; SEQ ID NO: 5 и SEQ ID NO: 7; и где VL содержит аминокислотную последовательность, выбранную из SEQ ID NO: 2; SEQ ID NO: 4; SEQ ID NO: 6 и SEQ ID NO: 8.
3. Антитело или антиген-связывающий фрагмент по любому одному из пп. 1 или 2, где VH содержит аминокислотную последовательность, приведенную в SEQ ID NO: 5, а VL содержит аминокислотную последовательность, приведенную в SEQ ID NO: 6.
4. Антитело или антиген-связывающий фрагмент по любому одному из пп. 1 или п. 2, где VH содержит аминокислотную последовательность SEQ ID NO: 7, а VL содержит аминокислотную последовательность SEQ ID NO: 8.
5. Антитело или антиген-связывающий фрагмент по любому одному из пп. 1-4, где антитело или антиген-связывающий фрагмент содержат константный участок IgG, содержащий вставку цистеина (C) между серином (S) в положении 239 и валином (V) в положении 240.
6. Антитело или антиген-связывающий фрагмент по п. 5, где антитело содержит тяжелую цепь с аминокислотной последовательностью, приведенной в SEQ ID NO: 9.
7. Антитело или антиген-связывающий фрагмент по любому одному из пп. 1-6, где при связывании антитела с ASCT2 на клеточной поверхности антитело поглощается клеткой.
8. Антитело или антиген-связывающий фрагмент по любому одному из пп. 1-8, которые содержат константный участок легкой цепи, выбранный из группы, состоящей из константного участка каппа-цепи человека и константного участка лямбда-цепи человека.
9. Антитело или антиген-связывающий фрагмент по п. 9, где антитело содержит константный участок каппа-цепи человека, приведенный в SEQ ID NO: 26.
10. Антитело или антиген-связывающий фрагмент по любому одному из пп. 1-9, дополнительно конъюгированные с цитотоксином, выбранным из группы, состоящей из противомикробного средства, терапевтического средства, пролекарства, пептида, белка, фермента, липида, модификатора биологического ответа, фармацевтического средства, лимфокина, гетерологичного антитела, фрагмента гетерологичного антитела, детектируемой метки, полиэтиленгликоля (PEG), радиоизотопа и комбинации двух или более из любых указанных цитотоксинов.
11. Антитело или антиген-связывающий фрагмент по п. 10, которые конъюгированы с цитотоксином.
12. Антитело или антиген-связывающий фрагмент по п. 11, где цитотоксин выбирают из производного тубулизина и пирролобензодиазепина.
13. Антитело или антиген-связывающий фрагмент по п. 12, где производное тубулизина представляет собой тубулизин AZ1508.
14. Антитело или антиген-связывающий фрагмент по п. 12, где пирролобензодиазепин выбирают из SG3315 и SG3249.
15. Антитело или антиген-связывающий фрагмент по любому одному из пп. 1-14, где антитело связывается с ASCT2 человека и ASCT2 макака-крабоеда.
16. Антитело или антиген-связывающий фрагмент по любому одному из пп. 1-15, где антитело специфично не связывается с ASCT1 человека.
17. Фармацевтическая композиция, содержащая антитело или антиген-связывающий фрагмент по любому одному из пп. 1-16 и фармацевтически приемлемый носитель.
18. Полинуклеотид или комбинация полинуклеотидов, кодирующие антитело или его антиген-связывающий фрагмент по любому одному из пп. 1-16.
19. Способ получения антитела или его антиген-связывающего фрагмента по любому одному из пп. 1-16, включающий в себя культивирование хозяина, содержащего полинуклеотид по п. 18.
20. Способ лечения онкологического заболевания, характеризующегося сверхэкспрессией ASCT2 у субъекта, причем способ включает введение субъекту, нуждающемуся в лечении, эффективного количества антитела или антиген-связывающего фрагмента по любому одному из пп. 1-16 или фармацевтической композиции по п. 1.
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