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RU2018144315A - КОНЪЮГАТЫ АНТИТЕЛА К cMet И ЛЕКАРСТВЕННОГО СРЕДСТВА И СПОСОБЫ ИХ ПРИМЕНЕНИЯ - Google Patents

КОНЪЮГАТЫ АНТИТЕЛА К cMet И ЛЕКАРСТВЕННОГО СРЕДСТВА И СПОСОБЫ ИХ ПРИМЕНЕНИЯ Download PDF

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RU2018144315A
RU2018144315A RU2018144315A RU2018144315A RU2018144315A RU 2018144315 A RU2018144315 A RU 2018144315A RU 2018144315 A RU2018144315 A RU 2018144315A RU 2018144315 A RU2018144315 A RU 2018144315A RU 2018144315 A RU2018144315 A RU 2018144315A
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seq
amino acid
acid sequence
cdr
cmet
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RU2740996C2 (ru
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Эдвард Б. РАЙЛИ
Луи НАУМОВСКИ
Кристиан Б. АЛЛАН
Цзеи ВАН
Марк Г. АНДЕРСОН
Дэниел Е. АФАР
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Эббви Байотерапьютикс Инк.
Эббви Инк.
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Claims (62)

1. Конъюгат антитела к cMet и лекарственного средства ("ADC"), содержащий антимитотическое средство, связанное с антителом к cMet посредством линкера, где ADC характеризуется структурой формулы (I):
(I) [D-L-XY-]n-Ab,
или соответствующей ей соли, где
D представляет собой антимитотическое средство;
L представляет собой линкер;
Ab представляет собой антитело к cMet;
XY представляет собой ковалентную связь, связывающую линкер L с антителом Ab; и
n представляет собой целое число в диапазоне от 2 до 8;
где
L предусматривает валин-цитруллиновый (vc) линкер и характеризуется структурой формулы (IVb.2):
Figure 00000001
D представляет собой монометилауристатин E ("MMAE"), и ADC структурной формулы (I) характеризуется следующей структурой:
Figure 00000002
; и
Ab предусматривает антитело к cMet, которое содержит (i) VH-цепь, содержащую три CDR; и (ii) VL-цепь, содержащую три CDR, где
CDR №1 VH имеет аминокислотную последовательность: GYIFTAYTMH (SEQ ID NO: 112), CDR №2 VH имеет аминокислотную последовательность: WIKPNNGLANYAQKFQG (SEQ ID NO: 113), CDR №3 VH имеет аминокислотную последовательность: SEITTEFDY (SEQ ID NO: 114), CDR №1 VL имеет аминокислотную последовательность: KSSESVDSYANSFLH (SEQ ID NO: 115), CDR №2 VL имеет аминокислотную последовательность: RASTRES (SEQ ID NO: 116), и CDR №3 VL имеет аминокислотную последовательность: QQSKEDPLT (SEQ ID NO: 117),
и (iii) модифицированную шарнирную область, имеющую аминокислотную последовательность PKSCDCHCPPCP (SEQ ID NO: 170).
2. ADC по п. 1, где антитело к cMet содержит VH-цепь с SEQ ID NO: 78 и VL-цепь с SEQ ID NO: 79 или 81.
3. ADC по п. 1, где антитело к cMet содержит тяжелую цепь с SEQ ID NO: 86 или 88 и легкую цепь с SEQ ID NO: 87.
4. Фармацевтическая композиция, содержащая ADC по п. 3 и фармацевтически приемлемый носитель.
5. Фармацевтическая композиция по п. 4, характеризующаяся соотношением лекарственного средства и антитела ("DAR"), составляющим приблизительно 3,1.
6. Конъюгат антитела к cMet и лекарственного средства ("ADC"), содержащий сшивающее ДНК средство, связанное с антителом к cMet посредством линкера, где ADC характеризуется структурой формулы (I):
(I) [D-L-XY-]n-Ab,
или соответствующей ей соли, где
D представляет собой сшивающее ДНК средство;
L представляет собой линкер;
Ab представляет собой антитело к cMet;
XY представляет собой ковалентную связь, связывающую линкер L с антителом Ab; и
n представляет собой целое число в диапазоне от 2 до 8;
где
L предусматривает валин-аланиновый (va) линкер и характеризуется структурой формулы (IVd.3):
Figure 00000003
D представляет собой димер пирролобензодиазепина ("PBD"), и ADC структурной формулы (I) характеризуется следующей структурой:
Figure 00000004
Ab предусматривает антитело к cMet, которое содержит (i) VH-цепь, содержащую три CDR; и (ii) VL-цепь, содержащую три CDR, где
CDR №1 VH имеет аминокислотную последовательность: GYIFTAYTMH (SEQ ID NO: 173), CDR №2 VH имеет аминокислотную последовательность: WIKPNNGLANYAQKFQG (SEQ ID NO: 174), CDR №3 VH имеет аминокислотную последовательность: SEITTEFDY (SEQ ID NO: 175), CDR №1 VL имеет аминокислотную последовательность: KSSESVDSYANSFLH (SEQ ID NO: 176), CDR №2 VL имеет аминокислотную последовательность: RASTRES (SEQ ID NO: 177), и CDR №3 VL имеет аминокислотную последовательность: QQSKEDPLT (SEQ ID NO: 178),
и (iii) модифицированную шарнирную область, имеющую аминокислотную последовательность PKSCDCHCPPCP (SEQ ID NO: 170).
7. ADC по п. 6, где антитело к cMet содержит VH-цепь с SEQ ID NO: 78 и VL-цепь с SEQ ID NO: 79 или 81.
8. ADC по п. 6, где антитело к cMet содержит тяжелую цепь с SEQ ID NO: 171 и легкую цепь с SEQ ID NO: 172.
9. Способ лечения рака, представляющего собой солидную опухоль, при котором сверхэкспрессируется cMet, предусматривающий введение субъекту-человеку, у которого имеется указанный рак, фармацевтической композиции, содержащей конъюгат антитела к cMet и лекарственного средства ("ADC") и фармацевтически приемлемый носитель, где фармацевтическую композицию вводят в количестве и в течение периода времени, достаточных для обеспечения терапевтического эффекта, и где ADC характеризуется структурой формулы (I):
(I) [D-L-XY-]n-Ab,
или соответствующей ей соли, где
D представляет собой антимитотическое средство;
L представляет собой линкер;
Ab представляет собой антитело к cMet;
XY представляет собой ковалентную связь, связывающую линкер L с антителом Ab; и
n представляет собой целое число в диапазоне от 2 до 8;
где
L предусматривает валин-цитруллиновый (vc) линкер и характеризуется структурой формулы (IVb.2):
Figure 00000005
D представляет собой монометилауристатин E ("MMAE"), и ADC структурной формулы (I) характеризуется следующей структурой:
Figure 00000002
; и
Ab предусматривает антитело к cMet, которое содержит (i) VH-цепь, содержащую три CDR; и (ii) VL-цепь, содержащую три CDR, где
CDR №1 VH имеет аминокислотную последовательность: GYIFTAYTMH (SEQ ID NO: 112), CDR №2 VH имеет аминокислотную последовательность: WIKPNNGLANYAQKFQG (SEQ ID NO: 113), CDR №3 VH имеет аминокислотную последовательность: SEITTEFDY (SEQ ID NO: 114), CDR №1 VL имеет аминокислотную последовательность: KSSESVDSYANSFLH (SEQ ID NO: 115), CDR №2 VL имеет аминокислотную последовательность: RASTRES (SEQ ID NO: 116), и CDR №3 VL имеет аминокислотную последовательность: QQSKEDPLT (SEQ ID NO: 117),
и (iii) модифицированную шарнирную область, имеющую аминокислотную последовательность PKSCDCHCPPCP (SEQ ID NO: 170).
10. Способ по п. 9, где антитело к cMet содержит VH-цепь с SEQ ID NO: 78 и VL-цепь с SEQ ID NO: 79 или 81.
11. Способ по п. 9, где антитело к cMet содержит тяжелую цепь с SEQ ID NO: 86 или 88 и легкую цепь с SEQ ID NO: 87.
12. Способ по п. 9, где рак, характеризующийся сверхэкспрессией cMet, представляет собой немелкоклеточный рак легкого ("NSCLC").
13. Способ по п. 12, где NSCLC представляет собой плоскоклеточный NSCLC или аденокарциному.
14. Способ по п. 13, где плоскоклеточный NSCLC характеризуется IHC-показателем, составляющим от 2+ до 3+, у биоптата.
15. Способ по п. 13, где биоптат ткани опухоли, представляющей собой аденокарциному, характеризуется IHC-показателем, составляющим 3+, и/или H-показателем, превышающим 225.
16. Способ по п. 9, где ADC, нацеливающийся на cMet, вводят в дополнение к дополнительному противораковому средству.
17. Способ по п. 16, где дополнительное противораковое средство представляет собой ингибитор рецептора эпидермального фактора роста ("EGFR").
18. Способ по п. 17, где дополнительное противораковое средство представляет собой эрлотиниб.
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