RU2483080C2 - Антитела и иммуноконъюгаты и их применение - Google Patents

Антитела и иммуноконъюгаты и их применение Download PDF

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RU2483080C2
RU2483080C2 RU2009119976/10A RU2009119976A RU2483080C2 RU 2483080 C2 RU2483080 C2 RU 2483080C2 RU 2009119976/10 A RU2009119976/10 A RU 2009119976/10A RU 2009119976 A RU2009119976 A RU 2009119976A RU 2483080 C2 RU2483080 C2 RU 2483080C2
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antibody
immunoconjugate
amino acid
seq
acid sequence
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RU2009119976/10A
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RU2009119976A (ru
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Марк С. Деннис
Бонни РУБИНФЕЛД
Пол Полакис
Айя Якобовиц
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Дженентек, Инк.
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Abstract

Изобретение относится к области иммунологии. Предложено гуманизированное антитело, специфичное к STEAP-1, которое содержит тяжелую и легкую цепи с охарактеризованными аминокислотными последовательностями 6 CDR и каркасной областью FR1 тяжелой цепи. Описан способ детектирования STEAP-1, фармацевтическая композиция и иммуноконъюгат, а также цистеин-встроенное антитело на основе указанного антитела. Раскрыты: способ лечения рака, связанного с увеличенной экспрессией STEAP-1, а также фармацевтическая композиция и варианты иммуноконъюгата с использованием цистеин-встроенного антитела. Использование изобретения обеспечивает новые антитела к STEAP-1, что может найти применение в медицине. 12 н. и 44 з.п. ф-лы, 45 ил., 2 табл., 9 пр.

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Claims (56)

1. Гуманизированное моноклональное антитело, которое связывается с STEAP-1, содержащее тяжелую цепь (НС), содержащую:
(1) HVR-H1, содержащий аминокислотную последовательность SEQ ID NO:14;
(2) HVR-H2, содержащий аминокислотную последовательность SEQ ID NO:15;
(3) HVR-H3, содержащий аминокислотную последовательность SEQ ID NO:16; и
(4) HC-FR1, содержащий аминокислотную последовательность SEQ ID NO:25; и
легкую цепь (LC), содержащую:
(1) HVR-L1, содержащий аминокислотную последовательность SEQ ID NO:11;
(2) HVR-L2, содержащий аминокислотную последовательность SEQ ID NO:12; и
(3) HVR-L3, содержащий аминокислотную последовательность SEQ ID NO:13.
2. Антитело по п.1, дополнительно содержащее по меньшей мере один, два или три каркасных района (FR), выбранных из
(1) HC-FR2, содержащего аминокислотную последовательность SEQ ID NO:22, 75 или 76;
(2) HC-FR3, содержащего аминокислотную последовательность SEQ ID NO:23, 78 или 79; и
(3) HC-FR4, содержащего аминокислотную последовательность SEQ ID NO:24.
3. Антитело по п.1, в котором указанная LC содержит SEQ ID NO:6.
4. Антитело по п.1, где указанная НС содержит SEQ ID NO:10.
5. Антитело по п.3, где указанная НС содержит SEQ ID NO:10.
6. Антитело по п.1, где указанное антитело является фрагментом антитела, выбранным из фрагментов Fab, Fab'-SH, Fv, scFv или (Fab')2.
7. Способ детектирования присутствия STEAP-1 в биологической пробе, предусматривающий приведение биологической пробы в контакт с антителом по п.1 в условиях, допускающих связывание указанного антитела с STEAP-1, и детектирование того, образуется ли комплекс между антителом и STEAP-1.
8. Способ по п.7, где биологическая проба получена из организма пациента, предположительно имеющего клеточно-пролиферативное нарушение предстательной железы, легкого, ободочной кишки, мочевого пузыря, яичника или саркомы Юинга.
9. Иммуноконъюгат для применения в лечении и детектировании клеточно-пролиферативных нарушений, ассоциированных с увеличенной экспрессией STEAP-1, содержащий антитело по п.1, ковалентно связанное с цитотоксическим агентом.
10. Иммуноконъюгат по п.9, где цитотоксический агент выбран из токсина, химиотерапевтического агента, лекарственного средства, антибиотика, радиоактивного изотопа и нуклеолитического фермента.
11. Иммуноконъюгат по п.10, где иммуноконъюгат имеет формулу Ab-(L-D)p, и где:
(a) Ab означает антитело по п.1;
(b) L означает линкер;
(c) D означает лекарственное средство; и
(d) p изменяется в интервале приблизительно от 1 до 20.
12. Иммуноконъюгат по п.11, где L выбран из 6-малеимидокапроила (МС), малеимидопропаноила (МР), валин-цитруллина (val-cit), аланин-фенилаланина (ala-phe), п-аминобензилоксикарбонила (РАВ), N-сукцинимидил-4-(2-пиридилтио)пентаноата (SPP), N-сукцинимидил-4-(N-малеимидометил)циклогексан-1-карбоксилата (SMCC), N-сукцинимидил-(4-иодацетил)аминобензоата (SIAB) и 6-малеимидокапроил-валин-цитруллин-п-аминобензилоксикарбонила (MC-vc-PAB).
13. Иммуноконъюгат по п.11, где D выбран из ауристатина и доластатина.
14. Иммуноконъюгат по п.13, где D означает группу лекарственного средства формулы DE или DF
Figure 00000379

Figure 00000380

и где каждый из R2 и R6 означает метил, каждый из R3 и R4 означает изопропил, R5 означает Н, R7 означает втор-бутил, каждый R8 независимо выбран из СН3, O-СН3, ОН и Н; R9 означает Н; R10 означает арил; Z означает -О- или -NH-; R11 означает Н, C1-C8-алкил или - (СН2)2-O-(СН2)2-O-(СН2)2-O-СН3; и R18 означает -С(R8)2-С(R8)2-арил; и
p изменяется в интервале приблизительно от 1 до 8.
15. Иммуноконъюгат по п.11, имеющий активность, связанную с уничтожением клеток in vitro или in vivo.
16. Иммуноконъюгат по п.11, имеющий формулу Ab-(L-MMAE)p, где L означает линкер, а p изменяется в интервале от 2 до 5.
17. Иммуноконъюгат по п.16, где L содержит val-cit.
18. Иммуноконъюгат по п.16, где L содержит МС.
19. Иммуноконъюгат по п.16, где L содержит РАВ.
20. Иммуноконъюгат по п.16, где L содержит MC-vc-PAB.
21. Иммуноконъюгат по п.11, где D означает майтансиноид.
22. Иммуноконъюгат по п.21, где D выбран из DM1, DM3 и DM4.
23. Иммуноконъюгат по п.21, где указанный линкер присоединен к антителу через тиоловую группу на антителе.
24. Иммуноконъюгат по п.21, где указанный линкер, L, выбран из N-сукцинимидил-4-(2-пиридилтио)пентаноата (SPP), N-сукцинимидил-4-(N-малеимидометил)циклогексан-1-карбоксилата (SMCC) и N-сукцинимидил-(4-иодацетил)аминобензоата (SIAB).
25. Иммуноконъюгат по п.24, где D является DM4.
26. Иммуноконъюгат по п.25, где L содержит SPP.
27. Иммуноконъюгат по п.25, где L содержит SMCC.
28. Иммуноконъюгат по п.25, где p составляет от 2 до 6.
29. Фармацевтическая композиция для лечения и детектирования клеточно-пролиферативных нарушений, ассоциированных с увеличенной экспрессией STEAP-1, содержащая эффективное количество иммуноконъюгата по любому из пп.11 и 16-20 и фармацевтически приемлемый носитель.
30. Способ лечения клеточно-пролиферативного нарушения, ассоциированного с увеличенной экспрессией STEAP-1, предусматривающий введение индивидууму эффективного количества фармацевтической композиции по п.29.
31. Способ по п.30, где клеточно-пролиферативное нарушение выбрано из клеточно-пролиферативного нарушения предстательной железы, легкого, ободочной кишки, мочевого пузыря, яичника и саркомы Юинга.
32. Цистеин-встроенное антитело для применения в лечении и детектировании клеточно-пролиферативных нарушений, ассоциированных с увеличенной экспрессией STEAP-1, представляющее собой антитело по п.1, содержащее тяжелую цепь и легкую цепь, где один или более аминокислотных остатков в константной области указанной тяжелой цепи и/или легкой цепи заменены одним или несколькими аминокислотными остатками свободного цистеина, имеющими величину реакционной способности тиолов в интервале от 0,6 до 1,0.
33. Антитело по п.32, где один или более аминокислотных остатков свободного цистеина расположены в легкой цепи.
34. Антитело по п.32, где один или более аминокислотных остатков свободного цистеина расположены в тяжелой цепи.
35. Иммуноконъюгат для применения в лечении и детектировании клеточно-пролиферативных нарушений, ассоциированных с увеличенной экспрессией STEAP-1, содержащий антитело по п.32, ковалентно связанное с цитотоксическим агентом.
36. Иммуноконъюгат по п.35, где цитотоксический агент выбран из токсина, химиотерапевтического агента, лекарственного средства, антибиотика, радиоактивного изотопа и нуклеолитического фермента.
37. Антитело по п.32, ковалентно присоединенное к захватывающей метке, детектируемой метке или твердому носителю.
38. Иммуноконъюгат для применения в лечении и детектировании клеточно-пролиферативных нарушений, ассоциированных с увеличенной экспрессией STEAP-1, содержащий антитело по п.32, где указанное антитело ковалентно присоединено к лекарственному средству ауристатину или майтансиноиду.
39. Иммуноконъюгат для применения в лечении и детектировании клеточно-пролиферативных нарушений, ассоциированных с увеличенной экспрессией STEAP-1, содержащий антитело по п.32 (Ab) и лекарственное средство ауристатин или майтансиноид (D), причем антитело присоединено через один или более аминокислотных остатков свободного цистеина линкерной частью (L) к D; при этом соединение имеет формулу I:
Figure 00000381

где p изменяется в интервале от 1 до 4.
40. Иммуноконъюгат по п.39, где p составляет приблизительно 2.
41. Иммуноконъюгат по п.39, где L имеет формулу
-Aa-Ww-Yy-,
в которой -А- означает удлиняющее звено, ковалентно связанное с цистеиновым тиолом цистеин-встроенного антитела (Ab);
а равно 0 или 1;
каждый -W- независимо означает аминокислотное звено;
w означает целое число, находящееся в интервале от 0 до 12;
-Y- означает спейсерное звено, ковалентно присоединенное к лекарственной части; и
y равно 0, 1 или 2.
42. Иммуноконъюгат по п.41, имеющий формулу:
Figure 00000382

где РАВ означает пара-аминобензилкарбамоил, и R17 означает двухвалентный радикал, выбранный из (СН2)r, С3-C8 карбоциклила, O-(СН2)r, арилена, (CH2)r-арилена, -арилен-(СН2)r-, (СН2)r-(С3-С8 карбоциклила), (С3-C8 карбоциклил)-(СН3)r, С3-C8 гетероциклила, (СН2)r-(С3-C8 гетероциклила), -(С3-C8 гетероциклил)-(СН2)r, (CH2)rC(O)NRb(CH2)r-, -(СН2СН2О)r-, -(CH2CH2O)rCH2-, (CH2)rC(O)NRb(CH2CH2O)r-, -(CH2)rC(O)NRb(CH2CH2O)rCH2-, (CH2CH2O)rC(O)NRb(CH2CH2O)r-, -(CH2CH2O)rC(O)NRb(CH2CH2O)rCH2- и -(CH2CH2O)rC(O)NRb(CH2)r-; где Rb означает Н, C1-С6 алкил, фенил или бензил; и r независимо означает целое число, находящееся в интервале от 1 до 10.
43. Иммуноконъюгат по п.41, где Ww является валин-цитруллином.
44. Иммуноконъюгат по п.42, где R17 является (СН2)5 или (СН2)2.
45. Иммуноконъюгат по п.41, имеющее формулу:
Figure 00000383
46. Иммуноконъюгат по п.39, где D является ММАЕ, имеющим структуру:
Figure 00000384

где волнистой линией показан сайт присоединения к линкеру L.
47. Фармацевтическая композиция для лечения и детектирования клеточно-пролиферативных нарушений, ассоциированных с увеличенной экспрессией STEAP-1, содержащая эффективное количество иммуноконъюгата по п.38 и фармацевтически приемлемый разбавитель, носитель или эксципиент.
48. Способ лечения рака, ассоциированного с увеличенной экспрессией STEAP-1, предусматривающий введение пациенту фармацевтической композиции по п.47.
49. Способ по п.48, где рак выбран из группы, состоящей из рака предстательной железы, рака легкого, рака ободочной кишки, рака мочевого пузыря, рака яичника и саркомы Юинга.
50. Способ по п.48, где пациенту вводят химиотерапевтический агент в комбинации с иммуноконъюгатом, где химиотерапевтический агент выбран из летрозола, цисплатина, карбоплатина, таксола, паклитаксела, оксалиплатина, доксетаксела, 5-ФУ, лейковорина, лапатиниба и гемцитабина.
51. Антитело по п.32, содержащее цистеин в одном или нескольких положениях, выбранных из 15, 43, 110, 144, 168 и 205 легкой цепи, в соответствии с нумерацией Кабата, и 41, 88, 115, 118, 120, 171, 172, 282, 375 и 400 тяжелой цепи, в соответствии с нумерацией EU.
52. Антитело по п.51, где цистеин находится в положении 205 легкой цепи.
53. Антитело по п.51, где цистеин находится в положении 118 тяжелой цепи.
54. Иммуноконъюгат по п.39, где D является DM4, имеющим структуру:
Figure 00000385

где волнистой линией показан сайт присоединения к линкеру L.
55. Иммуноконъюгат для применения в лечении и детектировании клеточно-пролиферативных нарушений, ассоциированных с увеличенной экспрессией STEAP-1, выбранное из структур:
Figure 00000386

Figure 00000387

Figure 00000388

Figure 00000389

Figure 00000390

где Val означает валин; Cit означает цитруллин; p равно 1, 2, 3 или 4; и Ab означает анти-STEAP-1-антитело по п.32.
56. Антитело по п.1, где LC содержит
(1) район легкой цепи, содержащий аминокислотную последовательность SEQ ID NO:90;
(2) район легкой цепи, содержащий аминокислотную последовательность SEQ ID NO:92;
(3) район легкой цепи, содержащий аминокислотную последовательность SEQ ID NO:93;
(4) район легкой цепи, содержащий аминокислотную последовательность SEQ ID NO:94;
(5) район легкой цепи, содержащий аминокислотную последовательность SEQ ID NO:95;
(6) район легкой цепи, содержащий аминокислотную последовательность SEQ ID NO:96;
(7) район легкой цепи, содержащий аминокислотную последовательность SEQ ID NO:97;
(8) район легкой цепи, содержащий аминокислотную последовательность SEQ ID NO:98;
(9) район легкой цепи, содержащий аминокислотную последовательность SEQ ID NO:99;
(10) район легкой цепи, содержащий аминокислотную последовательность SEQ ID NO:100; или
(11) район легкой цепи, содержащий аминокислотную последовательность SEQ ID NO:101.
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PT2845866T (pt) 2017-08-09
SI2845866T1 (sl) 2017-07-31
ES2636089T3 (es) 2017-10-05
DK2061814T3 (da) 2012-08-27
SI2502938T1 (sl) 2015-05-29
CO6180431A2 (es) 2010-07-19
NZ576132A (en) 2012-04-27
CY1113074T1 (el) 2016-04-13
KR20090078360A (ko) 2009-07-17
US20150166674A1 (en) 2015-06-18
CR10734A (es) 2009-06-25
CA2667019A1 (en) 2008-05-02
WO2008052187A2 (en) 2008-05-02
US20180106809A1 (en) 2018-04-19
IL197928A0 (en) 2011-08-01
TWI428347B (zh) 2014-03-01
TW200825105A (en) 2008-06-16
EP2845866A1 (en) 2015-03-11
LT2845866T (lt) 2017-07-10
US20090280056A1 (en) 2009-11-12
ZA201002209B (en) 2012-08-29
MA30910B1 (fr) 2009-11-02

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