RU2019121267A - АНТИ-CD79b АНТИТЕЛА И ИММУНОКОНЪЮГАТЫ И СПОСОБЫ ИХ ПРИМЕНЕНИЯ - Google Patents
АНТИ-CD79b АНТИТЕЛА И ИММУНОКОНЪЮГАТЫ И СПОСОБЫ ИХ ПРИМЕНЕНИЯ Download PDFInfo
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- RU2019121267A RU2019121267A RU2019121267A RU2019121267A RU2019121267A RU 2019121267 A RU2019121267 A RU 2019121267A RU 2019121267 A RU2019121267 A RU 2019121267A RU 2019121267 A RU2019121267 A RU 2019121267A RU 2019121267 A RU2019121267 A RU 2019121267A
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- antibody
- immunoconjugate
- seq
- variable domain
- agent
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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Claims (101)
1. Полинуклеотид, кодирующий анти-CD79b антитело,
где антитело содержит
вариабельный домен тяжелой цепи, содержащий последовательность SEQ ID NO:208, и
вариабельный домен легкой цепи, содержащий последовательность SEQ ID NO:207.
2. Вектор, содержащий полинуклеотид по п.1.
3. Клетка-хозяин, содержащая вектор по п.2.
4. Клетка-хозяин по п.3, которая представляет собой эукариотическую клетку-хозяин.
5. Иммуноконъюгат, содержащий анти-CD79b антитело, ковалентно соединенное с цитотоксическим средством,
где антитело содержит вариабельный домен тяжелой цепи, содержащий последовательность SEQ ID NO:208, и вариабельный домен легкой цепи, содержащий последовательность SEQ ID NO:207.
6. Иммуноконъюгат по п.5, где цитотоксическое средство выбрано из группы, состоящей из токсина, терапевтического средства, молекулы лекарственного средства, антибиотика, радиоактивного изотопа и нуклеолитического фермента.
7. Иммуноконъюгат, содержащий формулу: Ab-(L-D)р, где:
a) Ab представляет собой анти-CD-79b антитело, где антитело содержит вариабельный домен тяжелой цепи, содержащий последовательность SEQ ID NO:208, и вариабельный домен легкой цепи, содержащий последовательность SEQ ID NO:207;
b) L представляет собой линкерную группу;
c) D представляет собой молекулу лекарственного средства и
d) p варьируется от примерно 1 до примерно 20.
8. Иммуноконъюгат по п.7, где L включает линкер, выбранный из одного или более из: 6-малеимидокапроила (MC), малеимидопропаноила (MP), валина-цитруллина (val-cit), аланина-фенилаланина (ala-phe), п-аминобензилоксикарбонила (PAB), N-сукцинимидил-4-(2-пиридилтио)пентаноата (SPP), N-сукцинимидил-4-(N-малеимидометил)циклогексан-1-карбоксилата (SMCC), N-гидроксисукцинимидный эфир 4-(2-пиридилтио)масляной кислоты (SPDB) и N-сукцинимидил-(4-йодацетил)аминобензоата (SIAB).
9. Иммуноконъюгат по п.7 или 8, где D выбран из группы, состоящей из майтанзиноида, ауристатина и доластатина.
10. Иммуноконъюгат по п.9, где D представляет собой ауристатин и где D включает формулу DE или DF:
и где каждый R2 и R6 представляет собой метил;
каждый R3 и R4 представляет собой изопропил;
R5 представляет собой H и метил;
R7 представляет собой втор-бутил;
каждый R8 независимо выбран из CH3, O-CH3, OH и H;
R9 представляет собой H;
R10 представляет собой арил;
Z представляет собой –O– или –NH–;
R11 представляет собой H, C1-C8 алкил или –(CH2)2–O–(CH2)2–O–(CH2)2–O–CH3 и
R18 представляет собой –C(R8)2–C(R8)2–арил.
11. Иммуноконъюгат по п.9, где D представляет собой доластатин.
12. Иммуноконъюгат по п.7, где D представляет собой MMAE и MMAF.
13. Иммуноконъюгат по п.9, где D представляет собой майтанзиноид.
14. Иммуноконъюгат по п.13, где D выбран из группы, состоящей из DM1, DM3 и DM4.
15. Иммуноконъюгат по любому из пп.7-14, где L содержит val-cit, MC, PAB и/или MC-PAB.
16. Иммуноконъюгат по любому из пп.7-15, где L содержит MC-val-cit-PAB.
17. Иммуноконъюгат по п.7, где иммуноконъюгат содержит структуру, выбранную из группы, состоящей из:
где Val представляет собой валин и Cit представляет собой цитруллин.
18. Иммуноконъюгат по п.17, где иммуноконъюгат содержит структуру
19. Иммуноконъюгат по любому из пп.7-18, где p варьируется от примерно 1 до примерно 8.
20. Иммуноконъюгат по любому из пп.7-19, где p варьируется от примерно 2 до примерно 5.
21. Иммуноконъюгат, содержащий формулу:
где Val представляет собой валин;
Cit представляет собой цитруллин;
p варьируется от примерно 2 до примерно 5 и
Ab представляет собой анти-CD79b антитело,
где антитело содержит вариабельный домен тяжелой цепи, содержащий последовательность SEQ ID NO:208, и вариабельный домен легкой цепи, содержащий последовательность SEQ ID NO:207.
22. Композиция, содержащая анти-CD79b антитело, где антитело содержит вариабельный домен тяжелой цепи, содержащий последовательность SEQ ID NO:208, и вариабельный домен легкой цепи, содержащий последовательность SEQ ID NO:207.
23. Композиция, содержащая иммуноконъюгат по любому из пп.5-21.
24. Применение эффективного количества анти-CD79b антитела для получения лекарственного средства для лечения индивидуума, страдающего злокачественным В-клеточным пролиферативным расстройством,
где антитело содержит вариабельный домен тяжелой цепи, содержащий последовательность SEQ ID NO:208, и вариабельный домен легкой цепи, содержащий последовательность SEQ ID NO:207.
25. Применение эффективного количества иммуноконъюгата по любому из пп.5-21 для получения лекарственного средства для лечения индивидуума, страдающего злокачественным В-клеточным пролиферативным расстройством.
26. Применение по п.24 или 25, где указанное злокачественное В-клеточное пролиферативное расстройство выбрано из группы, состоящей из лимфомы, миеломы, неходжкинской лимфомы (НХЛ), диффузной крупноклеточной B-клеточной лимфомы (DLBCL), агрессивной НХЛ, бессимптомной лимфомы, фолликулярной лимфомы (FL), рецидивирующей агрессивной НХЛ, рецидивирующей бессимптомной НХЛ, рецидивирующей НХЛ, не поддающейся лечению НХЛ, не поддающейся лечению бессимптомной НХЛ, хронического лимфоцитарного лейкоза (ХЛЛ), мелкоклеточной лимфоцитарной лимфомы, лейкоза, ретикулоэндотелиоза (РЭ), острого лимфоцитарного лейкоза (ОЛЛ) и лимфомы клеток коры головного мозга.
27. Применение по п.26, где злокачественное В-клеточное пролиферативное расстройство представляет собой неходжкинскую лимфому (НХЛ).
28. Применение по п.26, где злокачественное В-клеточное пролиферативное расстройство представляет собой диффузную крупноклеточную B-клеточную лимфому (DLBCL).
29. Применение по п.26, где злокачественное В-клеточное пролиферативное расстройство представляет собой рецидивирующий НХЛ или не поддающийся лечению НХЛ.
30. Применение по п.26, где злокачественное В-клеточное пролиферативное расстройство представляет собой фолликулярную лимфому (FL).
31. Применение по любому из пп.24-30, где лекарственное средство используется в комбинации с эффективным количеством другого терапевтического средства.
32. Применение по п.31, где терапевтическое средство выбрано из группы, состоящей из антитела, химиотерапевтического средства, цитотоксического средства, антиангиогенного агента, иммунодепрессанта, пролекарства, цитокина, антагониста цитокина, цитотоксической лучевой терапии, кортикостероида, раковой вакцины и ингибирующего рост средства.
33. Применение по п.31, где терапевтическое средство выбрано из группы, состоящей из одного или более из: тамоксифена, летрозола, экcеместана, анастрозола, иринотекана, цетуксимаба, фульвестранта, винорелбина, эрлотиниба, бевацизумаба, винкристина, мезилата иматиниба, сорафиниба, лапатиниба, трастузумаба, цисплатина, гемцитабина, метотрексата, винбластина, карбоплатина, паклитаксела, 5-фторурацила, доксорубицина, бортезомиба, мелфалана, преднизона, преднизолона и доцетаксела.
34. Применение по п.31, где терапевтическое средство представляет собой анти-CD20 антитело.
35. Применение по п.31, где терапевтическое средство представляет собой анти-CD20 антитело и где злокачественное В-клеточное пролиферативное расстройство представляет собой диффузную крупноклеточную B-клеточную лимфому (DLBCL).
36. Применение по п.31, где терапевтическое средство представляет собой анти-CD20 антитело и где злокачественное В-клеточное пролиферативное расстройство представляет собой фолликулярную лимфому (FL).
37. Применение по любому из пп.34-36, где анти-СD20 антитело представляет собой ритуксимаб.
38. Применение по п.32, где терапевтическое средство представляет собой химиотерапевтическое средство.
39. Применение п.38, где химиотерапевтическое средство включает один или более из циклофосфамида, гидроксидаунорубицина, винкристина, преднизона или преднизолона.
40. Применение п.38, где химиотерапевтический агент включает циклофосфамид, доксорубицин, преднизон или преднизолон.
41. Применение п.34, где лекарственное средство используется в комбинации с эффективным количеством химиотерапевтического агента.
42. Применение п.41, где химиотерапевтический агент включает циклофосфамид, доксорубицин, преднизон или преднизолон.
43. Применение п.43, где химиотерапевтический агент включает циклофосфамид, доксорубицин, преднизон или преднизолон.
44. Применение п.42, в котором злокачественное В-клеточное пролиферативное заболевание представляет собой диффузную крупноклеточную В-клеточную лимфому (DLBCL).
45. Применение по любому из пп.41-44, где анти-CD20 антитело представляет собой ритуксимаб.
46. Способ in vitro определения присутствия CD79b в биологическом образце, предположительно содержащем CD79b, включающий
приведение указанного образца в in vitro контакт с анти-CD79b антителом и
определение уровня связывания указанного антитела с CD79b в образце,
где антитело содержит вариабельный домен тяжелой цепи, содержащий последовательность SEQ ID NO:208, и вариабельный домен легкой цепи, содержащий последовательность SEQ ID NO:207, и
где связывание указанного антитела с CD79b в образце является показателем присутствия CD79b в образце.
47. Способ получения иммуноконъюгата, содержащего Формулу I:
Ab-(L-D)p I
где Ab представляет собой анти-CD79b антитело,
где антитело содержит вариабельный домен тяжелой цепи, содержащий последовательность SEQ ID NO:208, и вариабельный домен легкой цепи, содержащий последовательность SEQ ID NO:207;
где D представляет собой молекулу лекарственного средства, выбранную из группы, состоящей из майтанзиноида, ауристатина и доластатина;
где антитело связано посредством одного или нескольких цистеиновых остатков с помощью линкерной группы (L) с D;
где p варьирует от примерно 1 до примерно 20 и
где способ включает стадии:
(a) взаимодействия цистеинового остатка антитела с линкерным реагентом с образованием промежуточного соединения антитело-линкер Ab-L и
(b) взаимодействия Ab-L с активированной молекулой лекарственного средства D с образованием иммуноконъюгата;
или включает стадии:
(c) взаимодействия нуклеофильной группы молекулы лекарственного средства с линкерным реагентом с образованием промежуточного соединения лекарственное средство–линкер D-L и
(d) взаимодействия D-L с цистеиновым остатком антитела; таким образом, с образованием иммуноконъюгата.
48. Способ по п.47, дополнительно включающий стадию экспрессии антитела в клетке яичников китайского хомячка (CHO).
49. Способ по п.47 или 48, дополнительно включающий стадию обработки экспрессируемого антитела восстановителем.
50. Способ по п.49, где указанный восстановитель представляет собой TCEP и DTT.
51. Способ по п.49 или 50, дополнительно включающий стадию обработки экспрессируемого антитела окислителем после обработки восстановителем.
52. Способ по п.51, где указанный окислитель выбран из сульфата меди, дегидроаскорбиновой кислоты и воздуха.
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US95005207P | 2007-07-16 | 2007-07-16 | |
US60/950,052 | 2007-07-16 | ||
US2513708P | 2008-01-31 | 2008-01-31 | |
US61/025,137 | 2008-01-31 | ||
US3279008P | 2008-02-29 | 2008-02-29 | |
US61/032,790 | 2008-02-29 | ||
US5470908P | 2008-05-20 | 2008-05-20 | |
US61/054,709 | 2008-05-20 |
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