RU2018111205A - Терапевтические комбинации, содержащие анти-folr1 иммуноконъюгаты - Google Patents
Терапевтические комбинации, содержащие анти-folr1 иммуноконъюгаты Download PDFInfo
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Claims (45)
1. Способ лечения пациента, больного раком, включающий введение указанному пациенту, нуждающемуся в этом
(a) иммуноконъюгата, который связывается с рецептором фолиевой кислоты 1 (FOLR1), причем указанный иммуноконъюгат содержит (i) антитело или его антигенсвязывающий фрагмент, содержащий последовательность SEQ ID NO: 9 определяющей комплементарность области (CDR)1 вариабельной области тяжелой цепи (VH), последовательность SEQ ID NO: 10 CDR2 VH и последовательность SEQ ID NO: 12 CDR3 VH, и последовательность SEQ ID NO:6 CDR1 вариабельной области легкой цепи (VL), последовательность SEQ ID NO: 7 CDR2 VL, последовательность SEQ ID NO: 8 CDR3 VL, и (ii) майтанзиноид, причем указанный майтанзиноид связан с антителом или его антигенсвязывающим фрагментом посредством сульфо- SPDB, и
(b) анти-ФРЭС агент, агент на основе платины или доксорубицин.
2. Способ по п. 1, отличающийся тем, что иммуноконъюгат вводят в комбинации с анти-ФРЭС агентом.
3. Способ по п. 1, отличающийся тем, что иммуноконъюгат вводят в комбинации с агентом на основе платины.
4. Способ по п. 1, отличающийся тем, что иммуноконъюгат вводят в комбинации с доксорубицином.
5. Способ лечения пациента, больного раком, включающий введение указанному пациенту, нуждающемуся в этом
(а) иммуноконъюгата, который связывается с рецептором фолиевой кислоты 1 (FOLR1), причем указанный иммуноконъюгат содержит (i) антитело или его антигенсвязывающий фрагмент, содержащий последовательность SEQ ID NO: 9 определяющей комплементарность области (CDR)1 вариабельной области тяжелой цепи (VH), последовательность SEQ ID NO: 10 CDR2 VH и последовательность SEQ ID NO: 12 CDR3 VH, и последовательность SEQ ID NO: 6 CDR1 вариабельной области легкой цепи (VL), последовательность SEQ ID NO: 7 CDR2 VL, последовательность SEQ ID NO: 8 CDR3 VL, и (ii) майтанзиноид, причем указанный майтанзиноид связан с антителом или его антигенсвязывающий фрагментом посредством сульфо- SPDB,
(b) (i) анти-ФРЭС агент и агент на основе платины;
(ii) анти-ФРЭС агент и доксорубицин; или
(iii) агент на основе платины и доксорубицин; причем иммуноконъюгат линкер, причем линкер представляет собой сульфо-SPDB.
6. Способ по любому из пп. 1, 2 и 5, отличающийся тем, что анти-ФРЭС агент представляет собой бевацизумаб.
7. Способ по любому из пп. 1, 3, 5 и 6, отличающийся тем, что агент на основе платины представляет собой карбоплатин.
8. Способ по любому из пп. 1, 4 или 5, отличающийся тем, что доксорубицин представляет собой пегилированный липосомальный доксорубицин (PLD).
9. Способ по любому из пп. 1-8, отличающийся тем, что иммуноконъюгат, который связывается с FOLR1, содержит антитело или его антигенсвязывающий фрагмент, который содержит VH, содержащую последовательность SEQ ID NO: 3, и VL, содержащую последовательность SEQ ID NO: 5.
10. Способ по любому из пп. 1-9, отличающийся тем, что иммуноконъюгат содержит антитело, содержащее (i) тяжелую цепь, содержащую аминокислотную последовательность SEQ ID NO: 13, и (ii) а легкую цепь, содержащую аминокислотную последовательность SEQ ID NO: 15, и при этом майтанзиноид представляет собой DM4.
11. Способ по любому из пп. 1-10, отличающийся тем, что иммуноконъюгат содержит антитело, содержащее (i) тяжелую цепь, содержащую аминокислотную последовательность, идентичную аминокислотной последовательности тяжелой цепи, кодируемой плазмидой, депонированной Американской коллекции типовых культур (АТСС) под номером РТА-10772, и (ii) легкая цепь содержит аминокислотную последовательность, идентичную аминокислотной последовательности легкой цепи, кодируемой плазмидой, депонированной Американской коллекции типовых культур (АТСС) под номером РТА-10774, и при этом майтанзиноид представляет собой DM4.
12. Способ по любому из пп. 1-10, отличающийся тем, что майтанзиноид представляет собой DM4.
13. Способ по любому из пп. 1-12, отличающийся тем, что иммуноконъюгат вводят один раз каждые три недели в дозе 6 мг/кг скорректированного идеального веса тела (AIBW).
14. Способ по любому из пп. 1-12, отличающийся тем, что иммуноконъюгат вводят один раз каждые четыре недели в дозе 5 мг/кг скорректированного идеального веса тела (AIBW) или один раз каждые четыре недели в дозе 6 мг/кг скорректированного идеального веса тела (AIBW).
15. Способ по любому из пп. 6, 7 или 9-13, отличающийся тем, что бевацизумаб вводят один раз каждые три недели в дозе 15 мг/кг.
16. Способ по любому из пп. 6, 7 или 9-13, отличающийся тем, что бевацизумаб вводят два раза каждые четыре недели в дозе 10 мг/кг.
17. Способ по любому из пп. 7 или 9-13, отличающийся тем, что карбоплатин вводят один раз каждые три недели в дозе, дающей площадь под кривой (AUC) 5 мг/мл⋅мин или 6 мг/мл⋅мин.
18. Способ по любому из пп. 8-14, отличающийся тем, что PLD вводят один раз каждые четыре недели в дозе 40 мг/м2 или один раз каждые четыре недели в дозе 30 мг/м2.
19. Способ по любому из пп. 1-18, отличающийся тем, что иммуноконъюгат содержит от примерно 1 майтанзиноида на антитело до примерно 8 майтанзионидов на антитело, при этом необязательно иммуноконъюгат содержит от примерно 3 майтанзионидов на антитело до примерно 4 майтанзионидов на антитело.
20. Способ по любому из пп. 1-19, который дополнительно включает введение пациенту стероида, причем стероид вводят в глазной капле.
21. Способ по любому из пп. 1-20, отличающийся тем, что рак представляет собой рак яичников, перитонеальный рак, рак фаллопиевых труб, рак эндометрия или рак легких.
22. Способ по п. 21, отличающийся тем, что рак представляет собой рак яичников, перитонеальный рак или рак эндометрия, причем необязательно рак яичников является устойчивым к препаратам платины.
23. Способ по любому из пп. 1-22, отличающийся тем, что рак экспрессирует FOLR1.
24. Способ по п.23, отличающийся тем, что экспрессию FOLR1 измеряют с помощью иммуногистохимии (ИГХ).
25. Способ по п. 24, отличающийся тем, что по меньшей мере 50% клеток в образце, полученном от пациента, имеют иммуногистохимический показатель (ИГХ) равный по меньшей мере 2.
26. Способ по п. 24, отличающийся тем, что по меньшей мере 75% клеток в образце, полученном от пациента, имеют иммуногистохимический показатель (ИГХ) равный по меньшей мере 2.
27. Способ по п. 24, отличающийся тем, что по меньшей мере 50% клеток в образце, полученном от пациента, имеют иммуногистохимический показатель (ИГХ) равный по меньшей мере 3.
28. Способ по п. 24, отличающийся тем, что по меньшей мере 75% клеток в образце, полученном от пациента, имеют иммуногистохимический показатель (ИГХ) равный по меньшей мере 3.
29. Способ по любому из пп. 1-28, отличающийся тем, что иммуноконъюгат и анти-ФРЭС агент, агент на основе платины, доксорубицин, или их комбинации вводят в отдельных фармацевтических композициях.
30. Способ по любому из пп. 1-29, отличающийся тем, что рак ранее лечили бевацизумабом.
31. Способ по любому из пп. 1-29, отличающийся тем, что рак ранее не лечили бевацизумабом.
32. Способ по любому из пп. 1-31, отличающийся тем, что рак является первично невосприимчивым к лечению препаратами платины.
33. Способ по любому из пп. 1-31, отличающийся тем, что рак устойчив к препаратам платины.
34. Способ по любому из пп. 1-31, отличающийся тем, что рак является чувствительным к препаратам платины.
35. Способ по любому из пп. 1-12 или 31-34, отличающийся тем, что что введение представляет собой терапию первой линии.
36. Способ по любому из пп. 1-34, отличающийся тем, что введение представляет собой терапию второй линии.
37. Способ по любому из пп. 1-34, отличающийся тем, что введение представляет собой терапию третьей линии.
38. Способ по любому из пп. 1-34, отличающийся тем, что введение представляет собой терапию четвертой линии.
39. Способ по любому из пп. 1-34, отличающийся тем, что введение представляет собой терапию пятой линии.
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| US201562250756P | 2015-11-04 | 2015-11-04 | |
| US62/250,756 | 2015-11-04 | ||
| PCT/US2016/052231 WO2017049149A1 (en) | 2015-09-17 | 2016-09-16 | Therapeutic combinations comprising anti-folr1 immunoconjugates |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| RU2844017C1 (ru) * | 2020-06-22 | 2025-07-23 | Национальный Исследовательский Институт Здравоохранения | Полигетероциклические конъюгаты и их фармацевтическое применение |
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