Фаговый дисплей как универсальный метод исследования белковых взаимодействий тема диссертации и автореферата по ВАК РФ 03.00.03, доктор биологических наук Миненкова, Ольга Олеговна

• Миненкова, Ольга Олеговна
• доктор биологических наук
• 2007

Оглавление диссертации доктор биологических наук Миненкова, Ольга Олеговна

писок принятых сокращений. ведение. лава 1. ОБЗОР ЛИТЕРАТУРЫ.

1.Технология фагового дисплея.

2. Структура и биология нитчатого фага.

3. Пептидные библиотеки.

4. Дисплей пептидов и белков в составе фаговых белков pill и pVIII.

5. Минорные фаговые белки pVI, pVII и pIX.

6. Модификация фага М13 для дисплея.

7. Фаговые библиотеки "несвободной" структуры.

8. Области применения фагового дисплея.

9. Ограничения дисплея, основанного на нитчатом фаге.

10. Система литических бактериофагов.

11. Бактериофаг Т4.

12. Бактериофаг Т7.

13. Бактериофаг лямбда.

14. Дисплей на основе белка gpV.

15. Дисплей на основе белка gpD.

16. Новый дизайн векторов для библиотек кДНК.

17. Применение фагового дисплея, основанного на бактериофаге лямбда.

Введение диссертации (часть автореферата) на тему «Фаговый дисплей как универсальный метод исследования белковых взаимодействий»

Нитчатый бактериофаг М13 и умеренный литический фаг лямбда сыграли цественную роль в становлении и развитии методологии рекомбинантной ДНК. Широкое именение бактериофага М13 в экспериментальной практике молекулярно-биологических сследований (секвенирование ДНК, получение меченых проб для гибридизации, сайт-кализованный мутагенез), а также центральная роль бактериофага лямбда для развития временной концепции регуляции генов и разработка на его основе векторных систем, спользуемых для построения библиотек природных репертуаров (геномная ДНК, кДНК, елки), связаны с небольшими размерами фаговых геномов и детальным знанием биологии их бактериофагов. За последние 15 лет интерес к нитчатым бактериофагам особенно вырос связи с развитием одного из направлений генной инженерии, получившего название аговый дисплей". Эта технология основана на встраивании чужеродных нуклеотидных оследовательностей в один из генов, кодирующих оболочечные белки бактериофага. При ом производится гетерогенная смесь фаговых частиц, каждая из которых экспонирует на оверхности свой пептид, закодированный встроенным фрагментом ДНК. Физическая связь ежду экспонированным пептидом и генетической информацией о нем делает возможным лекцию специфического фага из больших библиотек и определение первичной оследовательности пептида, ответственного за связывание. Более 3 тысяч работ, убликованных к настоящему времени, описывают способы применения фагового дисплея 1 решения различных генно-инженерных задач.

Близкородственные одноцепочечные ДНК-содержащие нитчатые фаги М13, fl и fd, а кже разработанные на их основе фагмиды, размножаются на мужских клетках Е. coli, есущих F-фактор, определяющий наличие половых ворсинок, которые необходимы для , икрепления нитчатого фага при инфицировании бактерий. Фаговый капсид построен из 5-различных оболочечных белков: pVIII, pill, pVI, pVII и pIX. Чаще всего для дисплея ептидов используется основной белок оболочки нитчатого фага pVIII, представленный 2700 пиями на фаговый капсид, а также минорный белок pill, менее чувствительный к размеру тройки, но представленный только 5 копиями. Отличительной чертой морфогенеза тчатых фагов является сборка капсида, происходящая на внутренней мембране бактерии, оэтому в библиотеках, основанных на нитчатом фаге, реально представлены только такие лки и пептиды, которые могут транспортироваться через внутреннюю мембрану, сохраняя ою нативную структуру в окисляющей среде периплазматического пространства. В этой язи, использование для фагового дисплея литического фага лямбда, который собирается в топлазме и освобождается при помощи лизиса бактериальной клетки, позволяет реододевать проблемы, связанные с жизненным циклом нитчатых фагов. Развитие фагового исплея на основе бактериофага лямбда дает импульс новым приложениям техники дисплея, дним из которых является широкомасштабный скрининг больших библиотек на основе риродных репертуаров.

Настоящая работа обобщает исследования автора, выполненные в интервале времени, ответствующему периоду существования фагового дисплея. Эти исследования начинались создания первых векторных систем, основанных на основном белке оболочки нитчатого ara pVIII, и изучения пределов пептидного дисплея высокой плотности, при котором аждая молекула основного белка оболочки несет встроенный пептид. Используя пептидные иблиотеки на основе фагмиды, в данной работе была разработана универсальная стратегия зучения гуморального ответа организма на вирусную инфекцию, позволяющая получать ммунологическое изображение вируса, не имея в наличии натурального антигена. Кроме го, в данной работе описана новая векторная система на основе фага лямбда, аптированная для дисплея библиотек кДНК, н векторная система на основе минорного елка pill нитчатого фага, предназначенная для дисплея антител. Эти векторы, позволяющие ешать новые прикладные задачи молекулярной биологии, превосходят векторные системы, писанные в литературе до настоящего времени.

Цель и задачи исследования

Основной целью настоящей работы являлось: 1) создание новых векторных систем ля дисплея пептидов и белков на основе бактериофагов М13 н лямбда; 2) разработка иагностикумов вирусных заболеваний на основе пептидов, селектированных из пептидных аговых библиотек; 3) идентификация новых опухолеспецифических маркеров для терапии, иагноза и прогноза раковых заболеваний; 4) получение человеческих пухолеспецифических одноцепочечных антител для терапии и ранней диагностики нкологических заболеваний.

Для достижения поставленной цели необходимо было решить следующие основные дачи:

- исследовать возможность модификации основного белка оболочки pVIII нитчатого ara М13 и создания на его основе иммуногенных частиц;

- исследовать пределы модификации белка pVIII нитчатого фага путем мутагенеза или строек нуклеотидных последовательностей случайного состава и различной длины в ген елка р VIII;

- получить расширенную коллекцию пептидов, имитирующих антигенные етерминанты вируса гепатита С (мимотопов), для эффективного выявления ротивовирусных антител в сыворотке крови;

- разработать векторную систему для дисплея библиотек кДНК, полученных из аковых клеточных линий или образцов опухоли молочной железы, взятой от нкологических пациентов;

- провести поиск новых опухолевых антигенов путем скрининга библиотек кДНК шоротками крови онкологических пациентов;

- провести расширенный серологический анализ идентифицированных антигенов и атистическую обработку данных, подтверждающую ассоциацию между присутствием в рови специфических антител и наличием опухоли молочной железы;

- разработать новый вектор для дисплея антител, пригодный для конструирования овых библиотек, так и для аффинного созревания антител; осуществить селекцию опухолеспецифических антител из библиотек екомбинантных антител, берущих начало от лимфоцитов В, инфильтрированных в опухоль.

Научная новизна и практическая значимость работы

Впервые экспериментально доказана возможность использования основного белка болочки нитчатого бактериофага для задач фагового дисплея. Получены жизнеспособные арианты фага М13 со встройкой чужеродных пептидов в основной белок оболочки, родемонстрировано, что встроенные пептиды экспонированы на поверхности фаговой астицы и доступны для взаимодействия с антителами.

Впервые экспериментально доказано, что в системе дисплея с высокой плотностью спонированных пептидов длина встроенного пептида является основным лимитирующим актором, влияющим на жизнеспособность фаговых частиц. Было показано, что пептидная иблиотека с высокой плотностью дисплея может быть использована для селекции ецифических фагов, связывающих как моноклональные антитела, так и небольшие рганические молекулы.

Получена обширная коллекция мимотопов вируса гепатита С, послужившая базой для здания нового пептидного диагностикума этого заболевания. Диагностикум на основе лектированных пептидов позволяет классифицировать сыворотки, получившие статус еопределенных" при использовании коммерческих тест-систем в формате ELISA или SIA trip immunoblot assay).

Разработана новая техника скрининга библиотек кДНК из злокачественных опухолей помощью сывороток пациентов в формате фагового дисплея. Для эффективного дисплея блиотек кДНК разработана новая векторная система, в которой преимущественно спонируются природные белки с правильной рамкой считывания. Идентифицированы ухолевые антигены, вызывающие статистически достоверный иммунный ответ у ациентов с опухолью молочной железы.

Разработана новая векторная система дисплея рекомбинантных антител, облегчающая лекцию токсичных антител и обладающая более высокой эффективностью отбора целевых олекул. Новый вектор был использован для конструирования библиотек рекомбинантных тител, берущих начало от лимфоцитов, инфильтрированных в опухоль, и селекции ухолеспецифических антител. Продемонстрирована высокая эффективность нового метода о сравнению методами, опубликованными в литературе.

Положения, выносимые на защиту:

• Капсид нитчатого фага может быть модифицирован без нарушения его жизнеспособности. При этом увеличение длины пептидной встройки в основной белок оболочки, введение непарного числа цистеиновых остатков и увеличение положительного заряда аминоконцевого района белка рУШ негативно сказывается на жизнеспособности фага. Пептиды, встроенные между 4-м и 5-м а.о. зрелой формы основного белка оболочки, экспонированы в раствор и доступны для взаимодействия с антителами.

• Пептидная библиотека, полученная при встройке случайных пептидов длиной 8 а.о. во все копии основного белка оболочки нитчатого фага, является достаточно представительной для селекции лигандов для различных рецепторов.

• Мимотопы, имитирующие натуральные вирусные антигены, могут быть выделены из фаговых пептидных библиотек с помощью сывороток больных пациентов, даже не имея информации о болезнетворном агенте. Селектированные пептиды могут использоваться как эффективный заменитель вирусных белков в диагностических тест-системах.

• Новые векторы на основе фага лямбда, АКМ4 и ХКМ8, предназначенные для встройки фрагментов ДНК в 5 '-конец гена gpD, обеспечивают эффективный дисплей белковых доменов в составе белка Б на поверхности фага лямбда. Библиотеки кДНК эукариотических клеток, полученные при использовании этих векторов, экспонируют белковые домены преимущественно с натуральной рамкой считывания.

• Селекция опухоль-ассоциированных антигенов с помощью сывороток онкологических пациентов приводит к идентификации преимущественно цитоплазматических антигенов.

• Спонтанный иммунный ответ на антиген D7-1 при раке молочной железы растет с развитием стадии заболевания.

• Понижение уровня экспрессии рекомбинантных антител за счет введения amber-кодона приводит к повышению эффективности селекции целевых антител.

• Лимфоциты В, инфильтрированные в опухоль, могут служить источником рекомбинантных антител потенциально полезных для терапии и диагностики рака.

Публикации и апробация работы Представленные в диссертации результаты были доложены на различных нференциях и симпозиумах: Международном симпозиуме "Proceeding of seventh ternational symposium on metabolism and enzymology of nucleic acids including gene and otein engineering" (Bratislava, Czechoslovakia, 1990), Международной конференции "Medical 'otechnology immunization and AIDS" (Ленинград, 1991), Всесоюзной конференции "Новые аправления биотехнологии" (Пущино 1992), Международной конференции "Phage display" old Spring Harbor Laboratory, Long Island, New York, 1992), Международной конференции Molecular genetics of bacteria and phages" (Cold Spring Harbor Laboratory, Long Island, New ork, 1993), Международной конференции "EMBO workshop on Molecular repertoires and ehtods of selection" (Perugia, Italy, 1993), конференции Итальянской Ассоциации Генетиков GI (Associazione Genetica Italiana) (Senigallia, Italy, 1993), Международной конференции MBO-FEMS meeting on Bacterial Viruses, Molecular Biology and Biotechnology" (Gargnano, ake Garda, Italy, 1994), Конференциях Итальянской Федерации FISV (Federazione Italiana cienze della Vita) (Riva del Garda, 1999, 2000, 2001, 2002), Международном семинаре "Basic cience in ISTC Activities" (Academgorodok, Novosibirsk, 2001), Международном импозиуме "7th International Symposium on Predictive Oncology & Intervention Strategies" ice, France, 2004), Международном семинаре "Monoclonal Antibodies: Research, evelopment and Applications" (Rome, Italy, 2005), Международной конференции "2nd OM'IEO Campus Meeting on Cancer" (Milan, Italy, 2006), Международном конгрессе "25th ongress of the Interanational Association for Breast Cancer Research" (Montreal, Canada, 2006).

Представленная работа выполнена в 1988-1992 в НПО "Вектор", в 1992-1996 в боратории Молекулярной Генетики 2-го Римского университета "Tor Vergata" (Rome, aly) и в 1996-2006 в Лабораториях "Кентон" при Сигма-Тау (Pomezia, Italy).

По материалам диссертации получено 5 международных патентов и опубликовано 29 атей. и

Заключение диссертации по теме «Молекулярная биология», Миненкова, Ольга Олеговна

ВЫВОДЫ Впервые экспериментально показано, что существенная модификация основного белка оболочки нитчатого бактериофага рУШ незначительно влияет на функции этого белка и не нарушает образование жизнеспособных фаговых частиц. При этом толерантность фага к пептидным встройкам зависит от длины встроенного пептида. . Сконструирована серия векторов на основе фагов М13, fl и fdtet, обеспечивающая высокую плотность встроенных эпитопов, экспонированных на поверхности фага в составе белка pVIII. Продемонстрирована высокая эффективность новой пептидной фаговой библиотеки с высокой плотностью экспонированных пептидов при селекции специфических лигандов на примере моноклональных антител и органических молекул. . Разработан системный подход для детекции иммунного ответа на вирусную инфекцию в отсутствии натурального антигена. В результате скрининга пептидных библиотек на нитчатом фаге разработана эффективная тест-система для обнаружения противовирусных антител в крови пациентов, инфицированных вирусом гепатита С. В рамках исследования показано, что: тест-система, основанная на синтетических пептидах в форме MAP (multiple antigenic eptide) позволяет со 100% чувствительностью и 100% специфичностью выявлять пациентов, нфицированных вирусом гепатита С; предложенный набор пептидов обеспечивает высокоразрешающий серологический нализ в формате ELISA и SIA, существенно уменьшающий частоту неопределенного иагноза по сравнению с существующими коммерческими тест-системами. . Разработана новая методология модифицированного варианта техники SEREX на основе бактериофага лямбда для идентификации опухолевых антигенов при помощи скрининга библиотек сыворотками онкологических пациентов. В рамках исследования: ). сконструирована оригинальная серия векторов для дисплея кДНК на основе белка gpD ara лямбда, обеспечивающих преимущественный дисплей натуральных белковых оследовательностей; идентифицирована панель антигенов, вызывающих естественный иммунный ответ у ациентов с опухолью молочной железы; обнаружена повышенная экспрессия антигенов Т11-9, Г11-3 и Т7-1 в тканях опухоли, по равнению с нормальной молочной железой; показано, что присутствие в сыворотке пациентов антител против 4-х антигенов (D4-11, 4-19, D7-1 и Т9-27) имеет значимую ассоциацию с раком молочной железы; ). выявлена корреляция между стадией развития опухоли молочной железы и стречаемостью антител против опухоль-ассоциированного антигена D7-1, впервые дентифицированного в нашей работе.

Разработан новый вектор рКМ19 для дисплея рекомбинантных антител в формате scFv, превосходящий существующие векторные системы и разрешающий селекцию антител, токсичных для бактериальной клетки. Эффективность нового вектора была продемонстрирована при конструировании и селекции библиотек рекомбинантных антител, берущих свое начало от лимфоцитов, инфильтрированных в опухоль молочной железы.

Селектирована панель опухолеспецифических антител, потенциально полезных для разработки новых терапевтических препаратов и диагностики онкологических заболеваний.

Список научных статей, опубликованных по материалам диссертации:

Ильичев АА, Миненкова ОО, Татьков СИ, Карпышев НН, Ерошкин AM, Петренко ВА, Сандахчиев JIC. Получение жизнеспособного варианта фага М13 со встроенным чужеродным пептидом в основной белок оболочки.Доклады Академии Наук, 1989; 307: 481-483.

Petrenko VA, Ilyichev АА, Minenkova ОО, Tat'kov SI, Sandakhchiev LS. Study of M13 bacteriophage as a possible carrier of infective agent antigenic epitopes. Proceeding of seventh international symposium on metabolism and enzymology of nucleic acids including gene and proteing engineering Bratislava, Czechoslovakia (November, 1990), p.97-103.

Ильичев АА, Миненкова ОО, Татьков СИ, Карпышев НН, Ерошкин AM, Офицеров ВИ,

Акименко ЗА, Петренко ВА, Сандахчиев JIC. Использование нитчатого бактериофага

М13 в белковой инженерии. Молекулярная биология 1990; 24: 530-535.

Кищенко ГП, Миненкова ОО, Ильичев АА, Груздев ФД, Петренко ВА. Изучение структуры вирионов фага М13, содержащих молекулы химерных В-белков.

Молекулярная биология 1991; 25/6: 1497-1503.

Ilyichev АА, Minenkova ОО, Kishchenko GP, Tat'kov SI, Karpishev NN, Eroshkin AM, Ofitzerov VI, Akimenko ZA, Petrenko VA, Sandakhchiev LS. Inserting foreign peptides into the major coat protein of bacteriophage M13. FEBS Lett. 1992; 301(3): 322-4. Ерошкин AM, Миненкова ОО, Фомин ВИ, Иванисенко ВА, Ильичев АА. Анализ встроек пептидных фрагментов в основной белок оболочки бактериофагов М13, fl и fd. Молекулярная биология 1993; 27/6: 1345-1355.

Миненкова ОО, Ильичев АА, Кищенко ГР, Ильичева ТН, Хрипин ЮЛ, Орешкова СФ, Петренко ВА. Получение специфического иммуногена на основе бактериофага М13. Молекулярная биология 1993; 27/3: 561-568.

Minenkova OO, Ilyichev AA, Kishchenko GP, Petrenko VA. Design of specific immunogens using filamentous phage as the carrier. Gene. 1993; 128(1): 85-8.

Iannolo G, Minenkova O, Petruzzelli R, Cesareni G. Modifying filamentous phage capsid: Limits in the size of the major coat protein. J Mol.Biol.1995; 248: 835-844. Cesareni G, Minenkova O, Dente L, Iannolo G, Zucconi A, Helmer Citterich M, Lanfracotti A, Castagnoli L, Vetriani C. Structural and functional constraints in the display of peptides on filamentous phage capsids. in Molecular Repertoires, Chapter 6, (1995), edit. Cortese R. , Walter de Gruyter & Co, p.835-844 Iannolo G, Minenkova O, Gonfloni S, Castagnoli L, Cesareni G. Construction, exploitation and evolution of a new peptide library displayed at high density by fusion to the major coat protein of filamentous phage. Biol Chem. 1997; 378(6): 517-21. Salcini AI,Confalonieri S, Doria M, Santolini E, Tassi E, Minenkova O, Cesareni G, Pelicci PG, Di Fiore PP. Binding specificity and in vivo targets of the EH domain, a novel proteinprotein interaction module. Genes and development, 1997, 11(17), 2239-2249. Cestra G, Castagnoli L, Dente L, Minenkova O, Petrelli A, Migone N, Hoffmuller U, Schneider-Mergener J, Cesareni G. The SH3 domains of endorphilin and amphiphysin bind to the proline rich region of synaptojanin 1 at distinnct sites that display an unconventional binding specifity. J. Biol. Chem., 1999, 274(45), 32001-7. Minenkova O, De Tomassi A, Fortugno P, Gargano N, Felici F, Monaci P. Colony assay for phage-displayed libraries. Anal. Biochem. 2000, 284(2), 412-425. Zhu Z, Minenkova O, Bellintani F, De Tomassi A, Urbanelli L, Felici F, Monaci P. In vitro evolution of ligands for HCV-specific serum antibodies. Biol. Chem. 2000, 381(3), 245-254. Beghetto E, Pucci A, Minenkova O, Spadoni A, Bruno L, Buffolano W, Soldati D, Felici F, Gargano N./ Identification of a human immunodominant B-cell epitope within the GRA1 antigen of Toxoplasma gondii by phage display of cDNA libraries. Int J Parasitol. 2001; 31(14):1659-68. Minenkova O, Gargano N, De Tomassi A, Bellintani F, Pucci A, Fortugno P, Fuscaldi E, Pessi A, Rapicetta M, Miceli M, Iudicone P, Cortese R, Felici F, Monaci P. ADAM-HCV, a new-concept diagnostic assay for antibodies to hepatitis C virus in serum. Eur J Biochem. 2001; 268(17): 4758-68. v. Beghetto E, Buffolano W, Spadoni A, Del Pezzo M, Di Cristina M, Minenkova O, Petersen E, Felici F, Gargano N. Use of an Immunoglobulin G Avidity Assay Based on Recombinant Antigens for Diagnosis of Primary Toxoplasma gondii Infection during Pregnancy. J Clin Microbiol. 2003;41 (12): 5414-5418. Minenkova O, Pucci A, Pavoni E, De Tomassi A, Fortugno P, Gargano N, Cianfiiglia M, Barca S, De Placido S, Martignetti A, Felici F, Cortese R, Monaci P. Identification of tumor-associated antigens by screening pliage-displayed human cDNA libraries with sera from tumor patients. Int J Cancer. 2003; 106(4): 5 34-44. Beghetto E, Spadoni A, Buffolano W, Del Pezzo M, Minenkova O, Pavoni E, Pucci A, Cortese R, Felici F, Gargano N. Molecular dissection of the human B-cell response against Toxoplasma gondii infection by lambda display of cDNA libraries. Int J Parasitol. 2003;33(2): 163-73. Pavoni E, Vaccaro P, Pucci A, Monteriu G, Beghetto E, Barca S, Dupuis ML, De Pasquale Ceratti A, Lugini A, Cianfriglia M, Cortesi E, Felici F, Minenkova O. Identification of a panel of tumor-associated antigens from breast carcinoma cell lines, solid tumors and testis cDNA libraries displayed on lambda phage. BMC Cancer. 2004;4:78. Garufi G, Minenkova O, Passo CL, Pernice I, Felici F. Display libraries on bacteriophage lambda capsid. Biotechnol Annu Rev. 2005;11:153-90. Minenkova O, Gargano N, Vaccaro P, Garufi G, Felici F. Bacteriophage lambda surface display: Recent results open wide application perspectives/ Chapter 5 in Frontiers in DNA Research, Ed. Corey R. Woods, 2006 Nova Science Publishers, inc., New York, p.81-113. Pavoni E, Flego M, Dupuis ML, Barca S, Petronzelli F, Anastasi AM, D'Alessio V, Pelliccia A, Vaccaro P, Monteriu G, Ascione A, De Santis R, Felici F, Cianfriglia M, Minenkova O. Selection, affinity maturation, and characterization of a human scFv antibody against CEA protein. BMC Cancer 2006, 6:41 Vaccaro P, Pavoni E, Monteriu G, Andrea P, Felici F, Minenkova O. Efficient display of scFv antibodies on bacteriophage lambda. J Immunol Methods. 2006; 310(1-2): 149-58. Bellofiore P, Petronzelli F, De Martino T, Minenkova O, Bombardi V, Anastasi AM, Lindstedt R, Felici F, De Santis R, Verdoliva A. Identification and refinement of a peptide affinity ligand with unique specificity for a monoclonal anti-tenascin-C antibody by screening of a phage display library.J Chromatogr A. 2006; 1107(1-2): 182-91. Pavoni E, Pucci A, Vaccaro P, Monteriu G, Ceratti Ade P, Lugini A, Virdis RA, Cortesi E, De Gaetano A, Panunzi S, Felici F, Minenkova O. A study of the humoral immune response of breast cancer patients to a panel of human tumor antigens identified by phage display. Cancer Detect Prev. 2006; 30(3): 248-56. Pavoni E, Monteriu G, Cianfriglia M, Minenkova O. New display vector reduces biological bias for expression of antibodies inE. coli. Gene. 2007; 391(1-2): 120-9. Pavoni E, Monteriu G, Santapaola D, Petronzelli F, Anastasi AM, Pellicia A, De Santis R, Minenkova O. Tumor-infiltrating В lymphocytes as efficient source of highly specific immunoglobulins recognizing tumor cells. Submitted

Патенты:

Method of improving the antibody selection capacity in phage-display library. Inventors: MINENKOVA OLGA (IT), PAVONI EMILIANO (IT) Applicant: Sigma-Tau, SpA, Deposited 27 Dec 2005, EP05028501.4 presso L'EPO Publication: July 2007

Identification of specific tumour antigens by means of the selection of cDNA libraries with sera and the use of said antigens in diagnostic imaging techniques

Inventor: FELICI FRANCO (IT); MINENKOVA OLGA (IT)

Applicant: KENTON S R L (IT)

EC: C07K14/47A34; C12N15/10C1; (+1)

IPC: C07K14/47; C12N15/10; G01N33/574 (+6)

Publication info: US2005084857 - 2005-04-21

Identification of specific tumor antigens by means of the selection of cDNA libraries with sera and the use of said antigena in the treatment of tumors Inventor: FELICI FRANCO (IT); MINENKOVA OLGA (IT) Applicant: KENTON S R L (IT) EC: C07K14/47A34; C12N15/10C1 IPC: C07K14/47; C12N15/10; A61K38/00 (+9) Publication info: US2005069556 - 2005-03-31 Detection of infectious agents using antigen mimics Patent number: SK5362003, Publication date: 2003-09-11 Inventor: FELICI FRANCO (IT); GARGANO NICOLA (IT); MINENKOVA OLGA (IT), MONACI PAOLO (IT) Applicant: KENTON S R L (IT) Classification: - international:

C07K14/18; G01N33/576; A61K39/00; C07K14/005; G01N33/576; A61K39/00; (IPC1-7): G01N33/576; C07K7/08; C07K14/18; C12N15/10 -european:

БЛАГОДАРНОСТИ

Автор искренне благодарит ближайших коллег и соавторов исследовательских работ, исанных в представленной диссертации. В работе, выполненной в Государственном учном центре вирусологии и биотехнологии "Вектор", принимали участие академик РАН офессор J1.C. Сандахчиев, д.б.н. профессор В.А. Петренко, Г.П. Кищенко, А.М. Ерошкин, Н. Жукова, С.И. Татьков, Н.Н. Карпышев, В.И. Офицеров, З.А. Акименко, В.А. анисенко, Т.Н. Ильичева, Ю.Л. Хрипин и С.Ф. Орешкова.

Особую признательность автор выражает д.б.н. профессору А.А. Ильичеву, который ш инициатором исследования по фаговому дисплею в нашей стране и благодаря которому боты, выполненные центре вирусологии и биотехнологии "Вектор", хорошо известны за бежом.

Автор тепло благодарит профессора Второго Римского университета (II-Università di ma "Тог Vergata") Дж. Чезарени и своих коллег из лаборатории Молекулярной Генетики оаккино Янноло, Луизу Костаньоли и Лучану Денте.

Автор признательна за совместную плодотворную работу сотрудникам лаборатории нтон (Kenton, S.r.l., Pomezia (RM)) - профессору Франко Феличи, Эмильяно Павони, едео Де Томасси, Франческе Беллинтани, Джордже Монтерю, Паоле Ваккаро, Андреа 1чи, Николе Гаргано, Даниеле Сантапаола, Елизе Бегетто; сотрудникам отдела мунологии Сигма-Тау (Sigma-Tau, S.p.a., Pomezia (RM)) - Рите Де Сантис и Фьорелле тронцелли; Директору Института Молекулярной Биологии (IRBM, Pomezia) - профессору ккардо Кортезе и Паоло Моначи, а также профессору Высшего Института равоохранения (Istituto Superiore di Sanità, Roma) Маурицио Чанфрилья.

Отдельная благодарность выражается Миненкову Георгию за техническую помощь и подготовке текста и Миненкову Юрию за критическое прочтение манускрипта.

Диссертация посвящается памяти бывших коллег Сергею Головину, Льву Мамаеву и дрею Бедристову.

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