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RU2011129316A - Высокоаффинные человеческие антитела к pcsk9 - Google Patents

Высокоаффинные человеческие антитела к pcsk9 Download PDF

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RU2011129316A
RU2011129316A RU2011129316/10A RU2011129316A RU2011129316A RU 2011129316 A RU2011129316 A RU 2011129316A RU 2011129316/10 A RU2011129316/10 A RU 2011129316/10A RU 2011129316 A RU2011129316 A RU 2011129316A RU 2011129316 A RU2011129316 A RU 2011129316A
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tyr
asn
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Марк У. СЛИМАН
Джоэл Х. МАРТИН
Тамми Т. ХУАН
Дуглас МАКДОНАЛД
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Ридженерон Фармасьютикалз, Инк.
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Abstract

1. Антитело человека или антигенсвязывающий фрагмент антитела человека, который специфическим образом связывает человеческую пропротеинконвертазу субтилизин/кексин тип 9 («hPCSK9»), имеющую одну или более из следующих характеристик:(i) способность снижать общий сывороточный холестерин не менее чем на приблизительно 25-35% и поддерживать сниженный уровень в течение не менее чем 24-дневного периода по сравнению с уровнем до введения;(ii) способность снижать сывороточный ЛНП холестерин не менее чем на приблизительно 65-80% и поддерживать сниженный уровень в течение не менее чем 24-дневного периода по сравнению с уровнем до введения или способность снижать сывороточный ЛНП холестерин не менее чем на приблизительно 40-70% и поддерживать сниженный уровень в течение не менее чем 60-90 дней по сравнению с уровнем до введения;(iii) способность снизить уровень сывороточных триглицеридов не менее чем на приблизительно 25-40% по сравнению с уровнем до введения;(iv) достижение одного или более пп.(i)-(iii) без снижения уровня сывороточного ЛВП холестерина или снижения уровня сывороточного ЛВП холестерина не более чем на 5% по сравнению с уровнем до введения;(v) достижение одного или более пп.(i)-(iii) при незначительных изменениях или отсутствии изменений функций печени по данным измерения ALT и AST.2. Антитело или антигенсвязывающий фрагмент по п.1, содержащийдомен CDR3 (HCDR3) тяжелой цепи, выбираемый из группы, включающей последовательности SEQ ID №: 8, 32, 56, 80, 104, 128, 152, 176, 200, 224, 248, 272, 296, 320, 344, 368, 392, 416, 440, 464, 488, 512, 536, 560, 584, 608, 632, 656, 680, 704 и 728; идомен CDR3 (LCDR3) легкой цепи, выбираемый из группы, включающей последовательности SEQ ID №: 16, 40, 64, 88, 112, 136, 160, 184, 208, 232, 256, 280, 304, 328, 352, 376, 4

Claims (21)

1. Антитело человека или антигенсвязывающий фрагмент антитела человека, который специфическим образом связывает человеческую пропротеинконвертазу субтилизин/кексин тип 9 («hPCSK9»), имеющую одну или более из следующих характеристик:
(i) способность снижать общий сывороточный холестерин не менее чем на приблизительно 25-35% и поддерживать сниженный уровень в течение не менее чем 24-дневного периода по сравнению с уровнем до введения;
(ii) способность снижать сывороточный ЛНП холестерин не менее чем на приблизительно 65-80% и поддерживать сниженный уровень в течение не менее чем 24-дневного периода по сравнению с уровнем до введения или способность снижать сывороточный ЛНП холестерин не менее чем на приблизительно 40-70% и поддерживать сниженный уровень в течение не менее чем 60-90 дней по сравнению с уровнем до введения;
(iii) способность снизить уровень сывороточных триглицеридов не менее чем на приблизительно 25-40% по сравнению с уровнем до введения;
(iv) достижение одного или более пп.(i)-(iii) без снижения уровня сывороточного ЛВП холестерина или снижения уровня сывороточного ЛВП холестерина не более чем на 5% по сравнению с уровнем до введения;
(v) достижение одного или более пп.(i)-(iii) при незначительных изменениях или отсутствии изменений функций печени по данным измерения ALT и AST.
2. Антитело или антигенсвязывающий фрагмент по п.1, содержащий
домен CDR3 (HCDR3) тяжелой цепи, выбираемый из группы, включающей последовательности SEQ ID №: 8, 32, 56, 80, 104, 128, 152, 176, 200, 224, 248, 272, 296, 320, 344, 368, 392, 416, 440, 464, 488, 512, 536, 560, 584, 608, 632, 656, 680, 704 и 728; и
домен CDR3 (LCDR3) легкой цепи, выбираемый из группы, включающей последовательности SEQ ID №: 16, 40, 64, 88, 112, 136, 160, 184, 208, 232, 256, 280, 304, 328, 352, 376, 400, 424, 448, 472, 496, 520, 544, 568, 592, 616, 639, 664, 688, 712 и 736.
3. Антитело или антигенсвязывающий фрагмент по п.2, где HCDR3/LCDR3 является последовательностью SEQ ID №: 80/88 или 224/232.
4. Антитело или антигенсвязывающий фрагмент по п.2, дополнительно содержащий
домен CDR1 (HCDR1) тяжелой цепи, выбираемый из группы, включающей последовательности SEQ ID №: 4, 28, 52, 76, 100, 124, 148, 172, 196, 220, 244, 268, 292, 316, 340, 364, 388, 412, 436, 460, 484, 508, 532, 556, 580, 604, 628, 652, 676, 700 и 724;
домен CDR2 (HCDR2) тяжелой цепи, выбираемый из группы, включающей последовательности SEQ ID №: 6, 30, 54, 78, 102, 126, 150, 174, 198, 222, 246, 270, 294, 318, 342, 366, 390, 414, 438, 462, 486, 510, 534, 558, 582, 606, 630, 654, 678, 702 и 726;
домен CDR1 (HCDR1) легкой цепи, выбираемый из группы, включающей последовательности SEQ ID №: 12, 36, 60, 84, 108, 132, 156, 180, 204, 228, 252, 276, 300, 324, 348, 372, 396, 420, 444, 468, 492, 516, 540, 564, 588, 612, 636, 660, 684, 708 и 732; и
домен CDR2 (LCDR2) легкой цепи, выбираемый из группы, включающей последовательности SEQ ID №: 14, 38, 62, 86, 110, 134, 158, 182, 206, 230, 254, 278, 302, 326, 350, 374, 398, 422, 446, 470, 494, 518, 542, 566, 590, 614, 638, 662, 686, 710 и 734.
5. Антитело или антигенсвязывающий фрагмент по п.4, в котором последовательности легкой и тяжелой цепей CDR выбирают из группы, включающей
SEQ ID №: 76, 78, 80, 84, 86, 88;
SEQ ID №: 220, 222, 224, 228, 230, 232.
6. Антитело или антигенсвязывающий фрагмент по любому из вышеприведенных пунктов, где HCVR является последовательностью SEQ ID №: 90 или 218, и LCVR является последовательностью SEQ ID №: 90 или 218.
7. Антитело или антигенсвязывающий фрагмент по п.1, содержащий последовательности HCDR3 и LCDR3, где
HCDR3 содержит аминокислотную последовательность формулы X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20 (SEQ ID №: 747), где X1 - Ala, X2 - Arg или Lys, X3 - Asp, X4 - Ser или Ile, X5 - Asn или Val, X6 - Leu или Trp, X7 - Gly или Met, X8 - Asn или Val, X9 - Phe или Tyr, X10 - Asp, X11 - Leu или Met, X12 - Asp или отсутствует, X13 - Tyr или отсутствует, X14 - Tyr или отсутствует, X15 - Tyr или отсутствует, X16 - Tyr или отсутствует, X17 - Gly или отсутствует, X18 - Met или отсутствует, X19 - Asp или отсутствует и X20 - Val или отсутствует; и
LCDR3 содержит аминокислотную последовательность формулы X1-X2-X3-X4-X5-X6-X7-X8-X9 (SEQ ID №: 750), где X1 - Gln или Met, X2 - Gln, X3 - Tyr или Thr, X4 - Tyr или Leu, X5 - Thr или Gln, X6 - Thr, X7 - Pro, X8 - Tyr или Leu и X9 - Thr.
8. Антитело или антигенсвязывающий фрагмент по п.7, дополнительно содержащий HCDR1, HCDR2, LCDR1 и LCDR2, где
HCDR1 содержит аминокислотную последовательность формулы X1-X2-X3-X4-X5-X6-X7-X8 (SEQ ID №: 745), где X1 - Gly, X2 - Phe, X3 - Thr, X4 - Phe, X5 - Ser или Asn, X6 - Ser или Asn, X7 - Tyr или His и X8 - Ala или Trp;
HCDR2 содержит аминокислотную последовательность формулы X1-X2-X3-X4-X5-X6-X7-X8 (SEQ ID №: 746), где X1 - Ile, X2 - Ser или Asn, X3 - Gly или Gln, X4 - Asp или Ser, X5 - Gly, X6 - Ser или Gly, X7 - Thr или Glu и X8 - Thr или Lys;
LCDR1 содержит аминокислотную последовательность формулы X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12 (SEQ ID №: 748), где X1 - Gln, X2 - Ser, X3 - Val или Leu, X4 - Leu, X5 - His или Tyr, X6 - Arg или Ser, X7 - Ser или Asn, X8 - Asn или Gly, X9 - Asn, X10 - Arg или Asn, X11 - Asn или Tyr и X12 - Phe или отсутствует;
LCDR2 содержит аминокислотную последовательность формулы X1-X2-X3 (SEQ ID №: 749), где X1 - Trp или Leu, X2 - Ala или Gly и X3 - Ser.
9. Антитело или антигенсвязывающий фрагмент по любому из п.п.1-5, где связывание антитела или его фрагмента с вариантом белка PCSK9 составляет меньше 50% связи между антителом или его фрагментом с белком PCSK9 последовательности SEQ ID №: 755.
10. Антитело или антигенсвязывающий фрагмент по п.9, где вариант белка PCSK9 содержит не менее одной мутации остатка в позиции, выбираемой из группы, включающей S153, E159, D238 и D343; или S147, E366 и V380.
11. Антитело или антигенсвязывающий фрагмент по любому из пп.1-5, содержащий вариабельную область тяжелой цепи (HCVR), кодируемую сегментами нуклеотидной последовательности, полученными из зародышевых генных сегментов VH, DH и JH, и вариабельную область легкой цепи (LCVR), кодируемую сегментами нуклеотидной последовательности, полученными из зародышевых генных сегментов VK и JK, где зародышевыми последовательностями являются
a) ген VH 3-23, ген DH 7-27, ген JH 2, ген VK 4-1, ген JK 2; или
b) ген VH 3-7, ген DH 2-8, ген JH 6, ген VK 2-28, ген JK 4.
12. Изолированная молекула нуклеиновой кислоты, кодирующая антитело или антигенсвязывающий фрагмент в соответствии с любым из предшествующих пунктов.
13. Вектор экспрессии, содержащий молекулу нуклеиновой кислоты по п.11.
14. Способ производства антитела анти-PCSK9 человека или антигенсвязывающего фрагмента антитела, состоящий из стадий введения вектора экспрессии по п.13 в изолированную клетку-хозяин, выращивания клетки в условиях, допускающих производство антитела или его фрагмента, и получения антитела или его фрагмента, произведенного таким образом.
15. Фармацевтический состав, включающий антитело или антигенсвязывающий фрагмент в соответствии с любым из пп.1-11 и фармацевтически приемлемый носитель.
16. Фармацевтический состав по п.15, дополнительно включающий второй терапевтический агент, выбираемый из одного из ингибиторов 3-гидрокси-3-метилглутарил (HMG)-коэнзима A (CoA) редуктазы, статина, ингибитора захвата холестерина и/или реабсорбции желчных кислот, агент, повышающий катаболизм липопротеинов, или активатор фактора транскрипции LXR.
17. Способ лечения болезни или патологического состояния, которое может быть купировано, облегчено, ингибировано или предотвращено с помощью антагониста PCSK9, заключающийся в введении терапевтического количества фармацевтического состава по п.15 или 16 нуждающемуся в этом пациенту.
18. Способ в соответствии с п.17, в котором пациент является человеком, страдающим гиперхолестеринемией, гиперлипидемией, аферезом ЛВП, гетерозиготной наследственной гиперхолестеринемией, непереносимостью статинов, неконтролируемостью статинами, подверженным риску развития гиперхолестеринемии, дислипидемии, холестатического заболевания печени, нефротического синдрома, гипотироидизма, ожирения, атеросклероза и сердечнососудистых заболеваний.
19. Антитело или антигенсвязывающий фрагмент антитела в соответствии с любым из пп.1-5, применяемый для смягчения или подавления заболевания или патологического состояния, опосредованного PCSK9.
20. Применение антитела или антигенсвязывающего фрагмента антитела в соответствии с любым из пп.1-11 при производстве лекарственного препарата, применяемого для смягчения или подавления заболевания или патологического состояния, опосредованного PCSK9.
21. Применение в соответствии с п.20, при котором опосредованным PCSK9 заболеванием или состоянием является гиперхолестеринемия, гиперлипидемия, аферез ЛВП, гетерозиготная наследственная гиперхолестеринемия, непереносимость статинов, неконтролируемость статинами, риск развития гиперхолестеринемии, дислипидемия, холестатическое заболевание печени, нефротический синдром, гипотироидизм, ожирение, атеросклероз и сердечнососудистые заболевания.
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