RU2010150348A - Антитела к рецептору конечных продуктов глубокого гликирования (rage) и их применение - Google Patents
Антитела к рецептору конечных продуктов глубокого гликирования (rage) и их применение Download PDFInfo
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- RMZNXRYIFGTWPF-UHFFFAOYSA-N 2-nitrosoacetic acid Chemical compound OC(=O)CN=O RMZNXRYIFGTWPF-UHFFFAOYSA-N 0.000 title 1
- 125000003275 alpha amino acid group Chemical group 0.000 claims abstract 17
- 239000000427 antigen Substances 0.000 claims abstract 4
- 102000036639 antigens Human genes 0.000 claims abstract 4
- 108091007433 antigens Proteins 0.000 claims abstract 4
- 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 abstract 2
- 101001014223 Homo sapiens MAPK/MAK/MRK overlapping kinase Proteins 0.000 claims abstract 2
- 102000049409 human MOK Human genes 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims 10
- 208000024827 Alzheimer disease Diseases 0.000 claims 4
- 239000000203 mixture Substances 0.000 claims 4
- 102000014914 Carrier Proteins Human genes 0.000 claims 3
- 108091008324 binding proteins Proteins 0.000 claims 3
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- 102000039446 nucleic acids Human genes 0.000 claims 2
- 108020004707 nucleic acids Proteins 0.000 claims 2
- 150000007523 nucleic acids Chemical class 0.000 claims 2
- 102000004169 proteins and genes Human genes 0.000 claims 2
- 108090000623 proteins and genes Proteins 0.000 claims 2
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- 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
- 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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Abstract
1. Выделенное моноклональное антитело, содержащее антигенсвязывающий домен, где указанное антитело способно связывать эпитоп молекулы RAGE человека, где указанный антигенсвязывающий домен содержит, по меньшей мере, одну CDR, содержащую аминокислотную последовательность, выбранную из: ! a) группы аминокислотных последовательностей CDR-H3, состоящей из последовательностей SEQ ID NO: 4, 12 и 20; модифицированных аминокислотных последовательностей CDR, имеющих идентичность последовательности с одной из указанных последовательностей, составляющую, по меньшей мере, 50%; и/или ! b) группы аминокислотных последовательностей CDR-L3, состоящей из последовательностей SEQ ID NO: 8, 16 и 24; и модифицированных аминокислотных последовательностей CDR, имеющих идентичность последовательности с одной из указанных последовательностей, составляющую, по меньшей мере, 50%. ! 2. Антитело по п. 1, дополнительно содержащее, по меньшей мере, одну CDR, содержащую аминокислотную последовательность, выбранную из группы CDR-H1, состоящей из последовательностей SEQ ID NO: 2, 10, 18; или выбранную из группы CDR-H2, состоящей из последовательностей SEQ ID NO: 3, 11, 19; или выбранную из группы CDR-L1, состоящей из последовательностей SEQ ID NO: 6, 14, 22; или выбранную из группы CDR-L2, состоящей из последовательностей SEQ ID NO: 7, 15, 23; ! и модифицированных аминокислотных последовательностей CDR, имеющих идентичность последовательности с одной из указанных последовательностей, составляющую, по меньшей мере, 50%. ! 3. Антитело по п. 2, содержащее, по меньшей мере, 3 CDR, которые выбраны из набора CDR вариабельного домена, состоящего из: ! ! или набора вариабельных доменов, в котором, по меньшей мере, одна из указанных 3 CDR
Claims (20)
1. Выделенное моноклональное антитело, содержащее антигенсвязывающий домен, где указанное антитело способно связывать эпитоп молекулы RAGE человека, где указанный антигенсвязывающий домен содержит, по меньшей мере, одну CDR, содержащую аминокислотную последовательность, выбранную из:
a) группы аминокислотных последовательностей CDR-H3, состоящей из последовательностей SEQ ID NO: 4, 12 и 20; модифицированных аминокислотных последовательностей CDR, имеющих идентичность последовательности с одной из указанных последовательностей, составляющую, по меньшей мере, 50%; и/или
b) группы аминокислотных последовательностей CDR-L3, состоящей из последовательностей SEQ ID NO: 8, 16 и 24; и модифицированных аминокислотных последовательностей CDR, имеющих идентичность последовательности с одной из указанных последовательностей, составляющую, по меньшей мере, 50%.
2. Антитело по п. 1, дополнительно содержащее, по меньшей мере, одну CDR, содержащую аминокислотную последовательность, выбранную из группы CDR-H1, состоящей из последовательностей SEQ ID NO: 2, 10, 18; или выбранную из группы CDR-H2, состоящей из последовательностей SEQ ID NO: 3, 11, 19; или выбранную из группы CDR-L1, состоящей из последовательностей SEQ ID NO: 6, 14, 22; или выбранную из группы CDR-L2, состоящей из последовательностей SEQ ID NO: 7, 15, 23;
и модифицированных аминокислотных последовательностей CDR, имеющих идентичность последовательности с одной из указанных последовательностей, составляющую, по меньшей мере, 50%.
3. Антитело по п. 2, содержащее, по меньшей мере, 3 CDR, которые выбраны из набора CDR вариабельного домена, состоящего из:
или набора вариабельных доменов, в котором, по меньшей мере, одна из указанных 3 CDR представляет собой модифицированную аминокислотную последовательность CDR, имеющую идентичность последовательности с исходной последовательностью, составляющую, по меньшей мере, 50%.
4. Антитело по п. 3, в котором указанные, по меньшей мере, два набора CDR вариабельных доменов, выбраны из группы, состоящей из:
набора VH 7F9 и набора VL 7F9;
набора VH 4E5 и VL 4E5 и
набора VH 11E6 и набора VL 11E6.
5. Антитело по любому из предшествующих пунктов, дополнительно содержащее акцепторный каркас человека.
6. Антитело по п. 1, содержащее, по меньшей мере, один вариабельный домен тяжелой цепи, выбранный из последовательностей SEQ ID NO: 56 и 57; и/или, по меньшей мере, один вариабельный домен легкой цепи, выбранный из последовательностей SEQ ID NO: 58 и 59.
7. Антитело по п. 6, в котором указанный связывающий белок содержит, по меньшей мере, одну мутацию в каркасе, выбранную из группы, состоящей из:
(положения последовательности тяжелой цепи): 1, 2, 68, 70, 72, 76, 85, 89, 95;
(положения последовательности легкой цепи): 11, 13, 43, 49, 58, 70, 87.
8. Антитело по п. 1, в котором указанный связывающий белок содержит, по меньшей мере, один
вариабельный домен (с мутацией в каркасе), имеющий аминокислотную последовательность, выбранную из группы, состоящей из:
вариабельный домен (с мутацией в каркасе), имеющий аминокислотную последовательность, выбранную из группы, состоящей из:
(последовательностей тяжелой цепи) SEQ ID NO: 62, 67, 68 и 69;
(последовательностей легкой цепи) SEQ ID NO: 63, 64, 65 и 66.
9. Антитело по п. 1, которое выбрано из группы, состоящей из антител 11E6, 4E5 и 7F9.
10. Выделенная нуклеиновая кислота, кодирующая аминокислотную последовательность антитела по любому из пп. 1-9.
11. Вектор, содержащий выделенную нуклеиновую кислоту по п. 10.
12. Клетка-хозяин, содержащая вектор по п. 11.
13. Способ получения белка, способного связывать RAGE, включающий культивирование клетки-хозяина по п. 12 в культуральной среде в условиях, достаточных для продуцирования связывающего белка, способного связывать RAGE.
14. Белок, полученный способом по п. 13.
15. Композиция для высвобождения антитела, где указанная композиция содержит
(a) препарат, где указанный препарат содержит антитело по пп. 1-9 в кристаллизованной форме в качестве ингредиента; и
(b) по меньшей мере, один полимерный носитель.
16. Фармацевтическая композиция, содержащая антитело по любому из пп. 1-9 и фармацевтически приемлемый носитель.
17. Способ лечения млекопитающего, включающий в себя стадию введения млекопитающему эффективного количества композиции по п. 15 или 16.
18. Способ по п. 17, в котором способ представляет собой способ лечения неврологических заболеваний, выбранных из группы, включающей боковой амиотрофический склероз, повреждение плечевого сплетения, повреждение головного мозга, включая травматическое повреждение головного мозга, церебральный паралич, атаксию Фридриха, синдром Гийена-Барре, лейкодистрофию, рассеянный склероз, постполиомиелитный синдром, расщепление позвоночника, повреждение спинного мозга, спинальную мышечную атрофию, опухоль спинного мозга, инсульт, поперечный миелит, деменцию, сенильную деменцию, умеренное когнитивное нарушение, деменцию, связанную с болезнью Альцгеймера, хорею Хантингтона, позднюю дискинезию, гиперкинезию, манию, болезнь Паркинсона, синдром Стила-Ричарда, синдром Дауна, бульбоспинальный паралич, травму нервов, васкулярный амилоидоз, церебральную геморрагию I с амилоидозом, воспаление головного мозга, атаксию Фридриха, острую спутанность сознания, амиотрофический боковой склероз, глаукому, болезнь Альцгеймера, диабетическую нефропатию, сепсис, ревматоидный артрит и родственные воспалительные заболевания.
19. Способ по п. 17, в котором способ представляет собой способ лечения болезни Альцгеймера.
20. Способ по п. 19, в котором композиция содержит 11E6.
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