RU2016141267A - Антитела против egfr и конъюгаты антитело-лекарственное средство - Google Patents
Антитела против egfr и конъюгаты антитело-лекарственное средство Download PDFInfo
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- RU2016141267A RU2016141267A RU2016141267A RU2016141267A RU2016141267A RU 2016141267 A RU2016141267 A RU 2016141267A RU 2016141267 A RU2016141267 A RU 2016141267A RU 2016141267 A RU2016141267 A RU 2016141267A RU 2016141267 A RU2016141267 A RU 2016141267A
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- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 title claims 19
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- IEDXPSOJFSVCKU-HOKPPMCLSA-N [4-[[(2S)-5-(carbamoylamino)-2-[[(2S)-2-[6-(2,5-dioxopyrrolidin-1-yl)hexanoylamino]-3-methylbutanoyl]amino]pentanoyl]amino]phenyl]methyl N-[(2S)-1-[[(2S)-1-[[(3R,4S,5S)-1-[(2S)-2-[(1R,2R)-3-[[(1S,2R)-1-hydroxy-1-phenylpropan-2-yl]amino]-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl]-3-methoxy-5-methyl-1-oxoheptan-4-yl]-methylamino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]-N-methylcarbamate Chemical compound CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCc1ccc(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN2C(=O)CCC2=O)C(C)C)cc1)C(C)C IEDXPSOJFSVCKU-HOKPPMCLSA-N 0.000 claims 6
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Classifications
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- C—CHEMISTRY; METALLURGY
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Claims (97)
1. Антитело против рецептора эпидермального фактора роста человека (против hEGFR) или его антигенсвязывающая часть, которые
a) связываются с эпитопом в аминокислотной последовательности CGADSYEMEEDGVRKC (SEQ ID NO: 45) или конкурируют со вторым антителом против hEGFR за связывание с вариантом III рецептора эпидермального фактора роста (EGFRvIII) (SEQ ID NO: 33) в конкурентном анализе связывания, где второе антитело против EGFR содержит вариабельный домен тяжелой цепи, содержащий аминокислотную последовательность, указанную в SEQ ID NO: 1, и вариабельный домен легкой цепи, содержащий аминокислотную последовательность, указанную в SEQ ID NO: 5;
b) связываются с EGFR(1-525) (SEQ ID NO: 47) с константной диссоциации (Kd) приблизительно 1×10-6 M или менее при определении с использованием поверхностного плазмонного резонанса; и
c) ингибируют рост опухоли в анализе с ксенотрансплантатом немелкоклеточной карциномы легкого (NSCLC) человека in vivo с % ингибированием роста опухоли (TGI%) по меньшей мере приблизительно 50% относительно IgG-антитела человека, которое не является специфичным к EGFR, где IgG-антитело человека вводят в анализе с ксенотрансплантатом NSCLC в той же дозе и с той же частотой, что и антитело против hEGFR или его антигенсвязывающая часть.
2. Антитело или его антигенсвязывающая часть по п.1, которые связываются с EGFR (1-525) (SEQ ID NO: 47) c Kd от приблизительно 1×10-6 M до приблизительно 1×10-10 M при определении с использованием поверхностного плазмонного резонанса.
3. Антитело или его антигенсвязывающая часть по п.1, которые связываются с EGFR (1-525) (SEQ ID NO: 47) с Kd от приблизительно 1×10-6 M до приблизительно 1×10-7 M при определении с использованием поверхностного плазмонного резонанса.
4. Антитело или его антигенсвязывающая часть по любому из пп.1-3, которые связываются с EGFRvIII (SEQ ID NO: 33) с Kd приблизительно 8,2×10-9 M или менее при определении с использованием поверхностного плазмонного резонанса.
5. Антитело или его антигенсвязывающая часть по любому из пп.1-3, которые связываются с EGFRvIII (SEQ ID NO: 33) с Kd от приблизительно 8,2×10-9 M до приблизительно 6,3×10-10 M при определении с использованием поверхностного плазмонного резонанса.
6. Антитело или его антигенсвязывающая часть по любому из пп.1-3, которые связываются с EGFRvIII (SEQ ID NO: 33) с Kd от приблизительно 8,2×10-9 M до приблизительно 2,0×10-9 M при определении с использованием поверхностного плазмонного резонанса.
7. Антитело или его антигенсвязывающая часть по любому из пп.1-6, которые ингибируют рост опухоли по меньшей мере приблизительно на 60% в анализе с ксенотрансплантатом немелкоклеточной карциномы легкого (NSCLC) человека in vivo относительно IgG-антитела человека, которое не является специфичным к EGFR.
8. Антитело или его антигенсвязывающая часть по любому из пп.1-6, которые ингибируют рост опухоли по меньшей мере приблизительно на 70% в анализе с ксенотрансплантатом немелкоклеточной карциномы легкого (NSCLC) человека in vivo относительно IgG-антитела человека, которое не является специфичным к EGFR.
9. Антитело или его антигенсвязывающая часть по любому из пп.1-6, которые ингибируют рост опухоли по меньшей мере приблизительно на 80% в анализе с ксенотрансплантатом немелкоклеточной карциномы легкого (NSCLC) человека in vivo относительно IgG-антитела человека, которое не является специфичным к EGFR.
10. Антитело или его антигенсвязывающая часть по любому из пп.1-9, где антитело или его антигенсвязывающая часть содержат домен CDR3 тяжелой цепи, содержащий аминокислотную последовательность, указанную в SEQ ID NO: 12, домен CDR2 тяжелой цепи, содержащий аминокислотную последовательность, указанную в SEQ ID NO: 11, и домен CDR1 тяжелой цепи, содержащий аминокислотную последовательность, указанную в SEQ ID NO: 10; и домен CDR3 легкой цепи, содержащий аминокислотную последовательность, указанную в SEQ ID NO: 8, домен CDR2 легкой цепи, содержащий аминокислотную последовательность, указанную в SEQ ID NO: 7, и домен CDR1 легкой цепи, содержащий аминокислотную последовательность, указанную в SEQ ID NO: 6.
11. Антитело или его антигенсвязывающая часть по любому из пп.1-9, где антитело или его антигенсвязывающая часть содержат вариабельную область тяжелой цепи, содержащую аминокислотную последовательность, указанную в SEQ ID NO: 9, и вариабельную область легкой цепи, содержащую аминокислотную последовательность, указанную в SEQ ID NO: 5.
12. Антитело или его антигенсвязывающая часть по любому из пп.1-9, содержащее тяжелую цепь, содержащую аминокислотную последовательность, указанную в SEQ ID NO: 15, и легкую цепь, содержащую аминокислотную последовательность, указанную в SEQ ID NO: 13.
13. Антитело против hEGFR или его антигенсвязывающая часть, содержащие
домен CDR3 легкой цепи, содержащий аминокислотную последовательность, указанную в SEQ ID NO: 40, домен CDR2 легкой цепи, содержащий аминокислотную последовательность, указанную в SEQ ID NO: 39, и домен CDR1 легкой цепи, содержащий аминокислотную последовательность, указанную в SEQ ID NO: 38; и
домен CDR3 тяжелой цепи, содержащий аминокислотную последовательность, указанную в SEQ ID NO: 37, домен CDR2 тяжелой цепи, содержащий аминокислотную последовательность, указанную в SEQ ID NO: 36, и домен CDR1 тяжелой цепи, содержащий аминокислотную последовательность, указанную в SEQ ID NO: 35.
14. Антитело против hEGFR или его антигенсвязывающая часть, содержащие вариабельную область тяжелой цепи, содержащую аминокислотную последовательность, выбранную из группы, состоящей из 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76 и 78; и вариабельную область легкой цепи, содержащую аминокислотную последовательность, выбранную из группы, состоящей из 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77 и 79.
15. Антитело против hEGFR или его антигенсвязывающая часть, содержащие
набор CDR тяжелой цепи (CDR1, CDR2 и CDR3), выбранный из группы, состоящей из SEQ ID NO: 10, 11 и 12; SEQ ID NO: 16, 17 и 18; SEQ ID NO: 10, 11 и 19; SEQ ID NO: 20, 11 и 12; SEQ ID NO: 21, 3 и 22; SEQ ID NO: 16, 17 и 19; SEQ ID NO: 2, 3 и 4; SEQ ID NO: 10, 3 и 12; SEQ ID NO: 80, 11 и 18; SEQ ID NO: 80, 3 и 18; SEQ ID NO: 20, 3 и 12; SEQ ID NO: 80, 11 и 12; и SEQ ID NO: 81, 11 и 22; и
набор CDR легкой цепи (CDR1, CDR2 и CDR3), выбранный из группы, состоящей из SEQ ID NO: 6, 7 и 8; SEQ ID NO: 23, 24 и 25; SEQ ID NO: 26, 27 и 28; SEQ ID NO: 29, 30 и 31; SEQ ID NO: 6, 7 и 84; SEQ ID NO: 82, 83 и 31; и SEQ ID NO: 82, 27 и 85,
где антитело или его антигенсвязывающая часть не содержат ни набора CDR тяжелой цепи SEQ ID NO: 2, 3 и 4, ни набора CDR легкой цепи SEQ ID NO: 6, 7 и 8.
16. Антитело или его антигенсвязывающая часть по любому из пп.1-15, содержащие константную область тяжелой цепи, содержащую аминокислотную последовательность, указанную в SEQ ID NO: 41, и/или константную область легкой цепи, содержащую аминокислотную последовательность, указанную в SEQ ID NO: 43.
17. Антитело или его антигенсвязывающая часть по любому из пп.1-15, где антитело или его антигенсвязывающая часть содержат константный домен тяжелой цепи иммуноглобулина, выбранный из группы, состоящей из константного домена IgG человека, константного домена IgM человека, константного домена IgE человека и константного домена IgA человека.
18. Антитело или его антигенсвязывающая часть по п.17, где константный домен IgG выбран из группы, состоящей из константного домена IgG1, константного домена IgG2, константного домена IgG3 и константного домена IgG4.
19. Антитело или его антигенсвязывающая часть по любому из пп.1-18, где антитело представляет собой полиспецифическое антитело.
20. Антитело или его антигенсвязывающая часть по любому из пп.1-19, где его антигенсвязывающая часть выбрана из группы, состоящей из Fab, Fabʹ, F(abʹ)2, Fv, связанного дисульфидной связью Fv, scFv, однодоменного антитела и диантитела.
21. Антитело или его антигенсвязывающая часть по любому из пп.1-20, где антитело или его антигенсвязывающая часть конъюгированы с визуализирующим средством.
22. Антитело или его антигенсвязывающая часть по п.21, где визуализирующее средство выбрано из группы, состоящей из радиоактивной метки, фермента, флуоресцентной метки, люминесцентной метки, биолюминесцентной метки, магнитной метки и биотина.
23. Антитело или его антигенсвязывающая часть по п.22, где радиоактивная метка представляет собой индий.
24. Фармацевтическая композиция, содержащая антитело или его антигенсвязывающую часть по любому из пп.1-23 и фармацевтически приемлемый носитель.
25. Конъюгат антитело-лекарственное средство (ADC), содержащий антитело или его антигенсвязывающую часть по любому из пп.1-23, конъюгированные по меньшей мере с одним лекарственным средством.
26. ADC по п.25, где по меньшей мере одно лекарственное средство выбрано из группы, состоящей из антиапоптотического средства, ингибитора митоза, противоопухолевого антибиотика, иммуномодулирующего средства, нуклеиновой кислоты для генной терапии, алкилирующего средства, антиангиогенного средства, антиметаболита, борсодержащего средства, хемопротективного средства, гормонального средства, антигормонального средства, кортикостероида, фотоактивного лекарственного средства, олигонуклеотида, радионуклидного средства, радиосенсибилизатора, ингибитора топоизомеразы и ингибитора тирозинкиназы.
27. ADC по п.26, где ингибитор митоза выбран из группы, состоящей из доластатина, ауристатина, майтанзиноида и алкалоида растений.
28. ADC по п.27, где ауристатин представляет собой монометилауристатин F (MMAF) или монометилауристатин E (MMAE).
29. ADC по п.27, где майтанзиноид выбран из группы, состоящей из DM1, DM2, DM3 и DM4.
30. ADC по п.26, где противоопухолевый антибиотик выбран из группы, состоящей из актиномицина, антрациклина, калихеамицина и дуокармицина.
31. Фармацевтическая композиция, содержащая смесь ADC, содержащую множество ADC по любому из пп.25-30 и фармацевтически приемлемый носитель.
32. Фармацевтическая композиция по п.31, где смесь ADC имеет среднее соотношение лекарственного средства и антитела (DAR) от 2 до 4.
33. Фармацевтическая композиция по п.31, где смесь ADC содержит ADC, каждый из которых имеет DAR от 2 до 8.
34. Способ лечения индивидуума, имеющего злокачественную опухоль, включающий введение индивидууму фармацевтической композиции по любому из пп.24 или 31-33, так чтобы происходило лечение индивидуума, имеющего злокачественную опухоль.
35. Способ по п.34, где злокачественная опухоль выбрана из группы, состоящей из рака молочной железы, рака легкого, глиобластомы, рака предстательной железы, рака поджелудочной железы, рака толстого кишечника, рака головы и шеи и рака почки.
36. Способ по п.34, где злокачественная опухоль представляет собой плоскоклеточную карциному.
37. Способ по п.36, где плоскоклеточная карцинома представляет собой плоскоклеточный рак легкого или плоскоклеточный рак головы и шеи.
38. Способ по п.34, где злокачественная опухоль представляет собой тройной отрицательный рак молочной железы.
39. Способ по п.34, где злокачественная опухоль представляет собой немелкоклеточный рак легкого.
40. Способ по любому из пп.34-39, где злокачественная опухоль характеризуется наличием сверхэкспрессии EGFR.
41. Способ ингибирования или снижения роста солидной опухоли у индивидуума, имеющего солидную опухоль, причем указанный способ включает введение фармацевтической композиции по любому из пп.24 или 31-33 индивидууму, имеющему солидную опухоль, так чтобы происходило ингибирование или снижение роста солидной опухоли.
42. Способ ингибирования или снижения роста солидной опухоли у индивидуума, имеющего солидную опухоль, причем указанный способ включает введение индивидууму, имеющему солидную опухоль, эффективного количества антитела или ADC по любому из пп.1-23 или 25-30, так чтобы происходило ингибирование или снижение роста солидной опухоли.
43. Способ по п.41 или 42, где солидная опухоль представляет собой солидную опухоль, экспрессирующую EGFR, или солидную опухоль, положительную по EGFRvIII.
44. Способ по п.41 или 42, где солидная опухоль представляет собой солидную опухоль, сверхэкспрессирующую EGFR.
45. Способ по любому из пп. 41-44, где солидная опухоль представляет собой немелкоклеточную карциному легких или глиобластому.
46. Способ по любому из пп.34-45, где антитело, ADC или фармацевтическую композицию вводят в комбинации с дополнительным средством или дополнительным способом терапии.
47. Способ по п.46, где дополнительное средство выбрано из группы, состоящей из антитела против PD1, антитела против CTLA-4, темозоломида, ингибитора bcl-xl, ибрутиниба, дувелисиба, иделалисиба, венетоклакса и ингибитора никотинамидфосфорибозилтрансферазы (NAMPT).
48. Способ по п.46, где дополнительная терапия представляет собой лучевую терапию.
49. Способ по п.46, где дополнительное средство представляет собой химиотерапевтическое средство.
50. Выделенная нуклеиновая кислота, кодирующая антитело или его антигенсвязывающую часть по любому из пп.1-23.
51. Вектор, содержащий нуклеиновую кислоту по п.50.
52. Клетка-хозяин, содержащая вектор по п.51.
53. Клетка-хозяин по п.52, которая представляет собой прокариотическую или эукариотическую клетку.
54. Клетка-хозяин по п.53, где эукариотическая клетка выбрана из группы, состоящей из клетки животного, клетки простейшего, клетки растения и клетки гриба.
55. Клетка-хозяин по п.54, где клетка животного выбрана из группы, состоящей из клетки млекопитающего, клетки насекомого и клетки птицы.
56. Клетка-хозяин по п.55, где клетка млекопитающего выбрана из группы, состоящей из клетки CHO, клетки COS и клетки Sp2/0.
57. Конъюгат антитело против hEGFR-лекарственное средство (ADC), содержащий антитело против hEGFR, конъюгированное с ауристатином, где антитело содержит домен CDR3 тяжелой цепи, содержащий аминокислотную последовательность SEQ ID NO: 12, домен CDR2 тяжелой цепи, содержащий аминокислотную последовательность SEQ ID NO: 11, и домен CDR1 тяжелой цепи, содержащий аминокислотную последовательность SEQ ID NO: 10; и домен CDR3 легкой цепи, содержащий аминокислотную последовательность SEQ ID NO: 8, домен CDR2 легкой цепи, содержащий аминокислотную последовательность SEQ ID NO: 7, и домен CDR1 легкой цепи, содержащий аминокислотную последовательность SEQ ID NO: 6.
58. ADC по п.57, где антитело содержит вариабельную область тяжелой цепи, содержащую аминокислотную последовательность, указанную в SEQ ID NO: 9, и вариабельную область легкой цепи, содержащую аминокислотную последовательность SEQ ID NO: 5.
59. ADC по п.57 или 58, где антитело содержит константный домен тяжелой цепи иммуноглобулина IgG.
60. ADC по п.59, где IgG представляет собой константный домен тяжелой цепи иммуноглобулина IgG1 или IgG4.
61. ADC по любому из пп.57-60, где ауристатин представляет собой монометилауристатин F (MMAF) или монометилауристатин E (MMAE).
62. ADC по п.57 или 58, где антитело содержит тяжелую цепь, содержащую аминокислотную последовательность SEQ ID NO: 15, и содержит легкую цепь, содержащую аминокислотную последовательность SEQ ID NO: 13.
63. ADC по п.61, где антитело ковалентно связано с ауристатином через линкер, содержащий малеимидокапроил, валин-цитруллин, п-аминобензиловый спирт (mc-vc-PABA).
64. ADC по любому из пп.57-63, где ADC содержит радиоактивную метку.
65. ADC по п.64, где радиоактивная метка представляет собой индий.
66. Фармацевтическая композиция, содержащая ADC по любому из пп.57-65 и фармацевтически приемлемый носитель.
67. Фармацевтическая композиция, содержащая смесь ADC, содержащую ADC по любому из пп.57-65, где средний диапазон соотношений лекарственного средства и антитела (DAR) в смеси ADC составляет от 2 до 4.
68. Фармацевтическая композиция, содержащая смесь ADC, содержащую конъюгаты антитело против hEGFR-лекарственное средство (ADC), и фармацевтически приемлемый носитель, где смесь ADC имеет среднее соотношение лекарственного средства и антитела (DAR) от 2 до 4 и где указанный ADC содержит монометилауристатин E (MMAE), конъюгированный с антителом против hEGFR, содержащим домен CDR3 тяжелой цепи, содержащий аминокислотную последовательность SEQ ID NO: 12, домен CDR2 тяжелой цепи, содержащий аминокислотную последовательность SEQ ID NO: 11, и домен CDR1 тяжелой цепи, содержащий аминокислотную последовательность SEQ ID NO: 10; и домен CDR3 легкой цепи, содержащий аминокислотную последовательность SEQ ID NO: 8, домен CDR2 легкой цепи, содержащий аминокислотную последовательность SEQ ID NO: 7, и домен CDR1 легкой цепи, содержащий аминокислотную последовательность SEQ ID NO: 6.
69. Фармацевтическая композиция по п.68, где вариабельная область тяжелой цепи антитела содержит аминокислотную последовательность, указанную в SEQ ID NO: 9, и вариабельная область легкой цепи антитела против EGFR содержит аминокислотную последовательность, указанную в SEQ ID NO: 5.
70. Фармацевтическая композиция по п.68 или 69, где антитело содержит константный домен тяжелой цепи иммуноглобулина IgG.
71. Фармацевтическая композиция по п.70, где IgG представляет собой константный домен тяжелой цепи иммуноглобулина IgG1 или IgG4.
72. Фармацевтическая композиция по п.68 или 69, где антитело содержит тяжелую цепь, содержащую аминокислотную последовательность, указанную в SEQ ID NO: 15, и легкую цепь, содержащую аминокислотную последовательность SEQ ID NO: 13.
73. Фармацевтическая композиция по любому из пп.68-72, где MMAE конъюгирован с антителом через линкер, содержащий малеимидокапроил, val-cit, PABA.
74. Способ лечения индивидуума, имеющего злокачественную опухоль, включающий введение индивидууму фармацевтической композиции по любому из пп.68-73, так чтобы происходило лечение индивидуума, имеющего злокачественную опухоль.
75. Способ по п.74, где злокачественная опухоль выбрана из группы, состоящей из рака молочной железы, рака легкого, глиобластомы, рака предстательной железы, рака поджелудочной железы, рака толстого кишечника, рака головы и шеи и рака почки.
76. Способ по п.74, где злокачественная опухоль представляет собой плоскоклеточную карциному.
77. Способ по п.76, где плоскоклеточная карцинома представляет собой плоскоклеточный рак легкого или плоскоклеточный рак головы и шеи.
78. Способ по п.74, где злокачественная опухоль представляет собой тройной отрицательный рак молочной железы.
79. Способ по п.74, где злокачественная опухоль представляет собой немелкоклеточный рак легкого.
80. Способ по любому из пп.74-79, где злокачественная опухоль характеризуется наличием сверхэкспрессии EGFR.
81. Способ ингибирования или снижения роста солидной опухоли у индивидуума, имеющего солидную опухоль, причем указанный способ включает введение фармацевтической композиции по любому из пп.66-73 индивидууму, имеющему солидную опухоль, так чтобы происходило ингибирование или снижение роста солидной опухоли.
82. Способ по п.81, где солидная опухоль представляет собой немелкоклеточную карциному легких или глиобластому.
83. Способ по п.81, где солидная опухоль представляет собой плоскоклеточную карциному.
84. Способ по любому из пп.81-83, где солидная опухоль представляет собой положительную по EGFRvIII солидную опухоль или представляет собой экспрессирующую EGFR солидную опухоль.
85. Способ по любому из пп.81-83, где солидная опухоль сверхэкспрессирует EGFR.
86. Способ по любому из пп.74-85, где фармацевтическую композицию вводят в комбинации с дополнительным средством или дополнительной терапией.
87. Способ по п.86, где дополнительное средство выбрано из группы, состоящей из антитела против PD1, антитела против CTLA-4, темозоломида, ингибитора bcl-xl, ибрутиниба, дувелисиба, иделалисиба, венетоклакса и ингибитора никотинамидфосфорибозилтрансферазы (NAMPT).
88. Способ по п.86, где дополнительная терапия представляет собой лучевую терапию.
89. Способ по п.86, где дополнительное средство представляет собой химиотерапевтическое средство.
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