RU2017118225A - Антитела к PD-1 и способы их применения - Google Patents
Антитела к PD-1 и способы их применения Download PDFInfo
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- RU2017118225A RU2017118225A RU2017118225A RU2017118225A RU2017118225A RU 2017118225 A RU2017118225 A RU 2017118225A RU 2017118225 A RU2017118225 A RU 2017118225A RU 2017118225 A RU2017118225 A RU 2017118225A RU 2017118225 A RU2017118225 A RU 2017118225A
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- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims 3
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- 150000001413 amino acids Chemical class 0.000 claims 1
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- 229960003005 axitinib Drugs 0.000 claims 1
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical group CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 claims 1
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- C—CHEMISTRY; METALLURGY
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
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- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
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- C—CHEMISTRY; METALLURGY
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
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- C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
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Claims (45)
1. Выделенное антагонистическое антитело, которое специфически связывается с PD-1 (белок 1 программируемой клеточной гибели) и содержит:
вариабельный участок тяжелой цепи (VH), содержащий VH определяющую комплементарность область один (CDR1), VH CDR2 и VH CDR3 из VH, имеющего аминокислотную последовательность, выбранную из группы, состоящей из SEQ ID NO: 3, SEQ ID NO: 4; SEQ ID NO: 5; и SEQ ID NO: 6; и
вариабельный участок легкой цепи (VL), содержащий VL CDR1, VL CDR2 и VL CDR3 из VL, имеющего аминокислотную последовательность, выбранную из группы, состоящей из SEQ ID NO: 2; SEQ ID NO:7; SEQ ID NO: 8; и SEQ ID NO: 9.
2. Выделенное антагонистическое антитело по п. 1, которое содержит VH CDR1, содержащую аминокислотную последовательность SEQ ID NO: 13, 14 или 15, VH CDR2, содержащую аминокислотную последовательность SEQ ID NO: 16, 17, 24, 25, 27, 28, 35 или 36, VH CDR3, содержащую аминокислотную последовательность, представленную в SEQ ID NO: 18, 23, 26 или 37, VL CDR1, содержащую аминокислотную последовательность, представленную в SEQ ID NO: 10, 22, 30 или 32, VL CDR2, содержащую аминокислотную последовательность, представленную в SEQ ID NO: 11, 20 или 33, и VL CDR3, содержащую аминокислотную последовательность, представленную в SEQ ID NO: 12, 21, 31 или 34.
3. Выделенное антагонистическое антитело по п. 1 или 2, которое содержит VH, содержащий аминокислотную последовательность, представленную в SEQ ID NO: 3, 4, 5 или 6, или его вариант с одной или несколькими консервативными аминокислотными заменами остатков, не входящих в CDR.
4. Выделенное антагонистическое антитело по п. 3, которое содержит VL, содержащий аминокислотную последовательность, представленную в SEQ ID NO: 2, 7, 8 или 9, или его вариант с одной или несколькими аминокислотными заменами аминокислот, не входящих в CDR.
5. Выделенное антагонистическое антитело по любому из пп. 1-4, которое содержит VH, содержащий аминокислотную последовательность, представленную в SEQ ID NO: 3, 4, 5 или 6, и VL, содержащий аминокислотную последовательность, представленную в SEQ ID NO: 2, 7, 8 или 9.
6. Выделенное антагонистическое антитело по любому из пп. 1-5, которое содержит тяжелую цепь, содержащую аминокислотную последовательность, представленную в SEQ ID NO: 29 или 38, и легкую цепь, содержащую аминокислотную последовательность, представленную в SEQ ID NO: 39.
7. Выделенное антагонистическое антитело по любому из пп. 1-5, которое содержит константную область.
8. Выделенное антагонистическое антитело по п. 7, которое имеет изотип, выбранный из группы, состоящей из IgG2, IgG2Δa, IgG4, IgG4Δb, IgG4Δc, IgG4 S228P, IgG4Δb S228P и IgG4Δc S228P.
9. Выделенное антагонистическое антитело по п. 7, где константная область представляет собой IgG4 S228P.
10. Выделенное антагонистическое антитело по п. 1, где каждый CDR антитела определен в соответствии с определением по Kabat, с определением по Chothia, с комбинацией определений по Kabat и по Chothia, с AbM определением или с контактным определением CDR.
11. Выделенное антагонистическое антитело, которое специфически связывается с PD-1 и конкурирует за связывание с PD-1 с антителом по п. 1, и/или связывается с эпитопом, который является таким же или перекрывается с эпитопом на PD-1, распознаваемым антителом по п. 1.
12. Выделенное анти-PD-1 антитело, которое содержит VH CDR1, содержащую аминокислотную последовательность SEQ ID NO: 13, VH CDR2, содержащую аминокислотную последовательность SEQ ID NO: 17, VH CDR3, содержащую аминокислотную последовательность, представленную в SEQ ID NO: 23, VL CDR1, содержащую аминокислотную последовательность, представленную в SEQ ID NO: 10, VL CDR2, содержащую аминокислотную последовательность, представленную в SEQ ID NO: 20, и VL CDR3, содержащую аминокислотную последовательность, представленную в SEQ ID NO: 21.
13. Выделенное антитело по любому из пп. 1-12, которое способствует секреции IFNγ (интерферон-гамма) и/или TNF (фактор некроза опухоли) из Т-клеток.
14. Выделенное антитело по любому из пп. 1-13, которое способствует пролиферации Т-клеток.
15. Выделенное антитело по любому из пп. 1-14, которое ингибирует рост опухоли.
16. Выделенное антитело по любому из пп. 1-15, которое связывается с человеческим PD-1 и мышиным PD-1.
17. Выделенное антитело по п. 16, которое связывается с человеческим PD-1 с аффинностью примерно 0,73 нМ при 25°С, при измерении при помощи поверхностного плазмонного резонанса.
18. Выделенная клеточная линия, которая продуцирует антитело по любому из пп. 1-17.
19. Выделенная нуклеиновая кислота, кодирующая антитело по любому из пп. 1-17.
20. Рекомбинантный экспрессионный вектор, содержащий нуклеиновую кислоту по п. 19.
21. Клетка-хозяин, содержащая экспрессионный вектор по п. 20.
22. Гибридома, способная продуцировать антитело по любому из пп. 1-17.
23. Способ получения антагонистического антитела к PD-1, включающий: культивирование клеточной линии, которая рекомбинантно продуцирует антитело по любому из пп. 1-17, в условиях, в которых продуцируется антитело; и выделение антитела.
24. Способ получения антагонистического антитела к PD-1, включающий: культивирование клеточной линии, содержащей нуклеиновую кислоту, кодирующую антитело, содержащее тяжелую цепь, содержащую аминокислотную последовательность, представленную в SEQ ID NO: 29 или 38, и легкую цепь, содержащую аминокислотную последовательность, представленную в SEQ ID NO: 39, в условиях, в которых продуцируется антитело; и выделение антитела.
25. Способ по п. 24, где тяжелая и легкая цепи антитела кодируются отдельными векторами.
26. Способ по п. 24, где тяжелая и легкая цепи антитела кодируются одним и тем же вектором.
27. Фармацевтическая композиция, содержащая антитело по любому из пп. 1-17 и фармацевтически приемлемый носитель.
28. Набор для лечения рака, содержащий фармацевтическую композицию по п. 27.
29. Способ лечения рака у субъекта, нуждающегося в этом, включающий введение этому субъекту эффективного количества антитела к PD-1 по любому из пп. 1-17 или фармацевтической композиции по п. 27, так что у субъекта улучшаются один или более симптомов, ассоциированных с раком.
30. Способ по п. 29, где рак выбран из группы, состоящей из рака желудка, саркомы, лимфомы, лимфомы Ходжкина, лейкемии, рака головы и шеи, плоскоклеточного рака головы и шеи, рака вилочковой железы, эпителиального рака, рака слюнной железы, рака печени, рака желудка, рака щитовидной железы, рака легкого, рака яичника, рака молочной железы, рака предстательной железы, рака пищевода, рака поджелудочной железы, глиомы, лейкемии, множественной миеломы, почечно-клеточной карциномы, рака мочевого пузыря, рака шейки матки, хориокарциномы, рака толстой кишки, рака полости рта, рака кожи и меланомы.
31. Способ по п. 29 или 30, где субъект представляет собой взрослого пациента, ранее получавшего лечение, с местнораспространенной или метастатической меланомой, с плоскоклеточным раком головы и шеи (SCHNC), с карциномой яичника, с саркомой или с рецидивирующей или рефрактерной классической лимфомой Ходжкина (cHL).
32. Способ по любому из пп. 29-31, где антитело к PD-1 вводят в дозе примерно 0,5 мг/кг, примерно 1,0 мг/кг, примерно 3,0 мг/кг или примерно 10 мг/кг.
33. Способ по любому из пп. 29-32, где антитело к PD-1 вводят один раз каждые 7, 14, 21 или 28 суток.
34. Способ по любому из пп. 29-33, где антитело к PD-1 вводят внутривенно или подкожно.
35. Способ по любому из пп. 29-34, который дополнительно включает введение эффективного количества второго терапевтического агента.
36. Способ по п. 35, где второй терапевтический агент выбран из группы, состоящей из анти-CTLA4 (антиген 4, ассоциированный с цитотоксическими Т-лимфоцитами) антитела, анти-4-1ВВ антитела, второго PD-1 антагониста, анти-PD-L1 (лиганд 1 белка программируемой клеточной гибели) антитела, анти-TIM3 антитела, анти-LAG3 антитела, анти-TIGIT (Т-клеточный иммунорецептор с Ig и ITIM (тирозиновый ингибиторный мотив иммунорецептора)) доменами) антитела, анти-ОХ40 антитела, анти-GITR (индуцируемый глюкокортикоидами, родственный TNFR белок) антитела, ингибитора тирозинкиназы и ингибитора ALK (киназа анапластической лимфомы).
37. Способ по п. 36, где ингибитор тирозинкиназы представляет собой акситиниб или палбоциклиб.
38. Способ по п. 36, где ингибитор ALK представляет собой сунитиниб или кризотиниб.
39. Способ лечения рака у субъекта, нуждающегося в этом, включающий введение субъекту (1) эффективного количества антитела к PD-1 по любому из пп. 1-17 или фармацевтической композиции по п. 27 и (2) эффективного количества вакцины, способной вызывать иммунный ответ против клеток рака.
40. Способ увеличения иммуногенности или терапевтического эффекта вакцины, вводимой субъекту для лечения рака, включающий введение субъекту, получающему эту вакцину, эффективного количества антитела к PD-1 по любому из пп. 1-17 или фармацевтической композиции по п. 27.
41. Способ по п. 39 или 40, где рак выбран из группы, состоящей из рака молочной железы, рака желудка, рака печени, рака легкого, рака яичника, рака поджелудочной железы, рака предстательной железы и колоректального рака.
42. Способ по п. 39 или 40, дополнительно включающий введение субъекту эффективного количества одного или более других иммуномодуляторов.
43. Способ по п. 42, где другие иммуномодуляторы выбраны из группы, состоящей из ингибитора рецептора протеинкиназы, антагониста CTLA-4, агониста CD40 и агониста TLR9 (Toll-подобный рецептор 9).
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