Стратегия разработки таргетных препаратов для терапии HER2-позитивного рака молочной железы

Цель исследования – определить современные стратегии, достижения и проблемы в разработке таргетных HER2-направленных терапевтических конъюгатов и текущие клинические результаты терапии на их основе.

Материал и методы. Изучено 247 литературных источников в пределах 7 лет, из которых для обзора отобрано 60. Поиск источников проведен в информационных базах данных Scopus (n=35), PubMed (n=121), WOS (n=91). Для получения полнотекстовых документов использованы электронные ресурсы PubMed Central (PMC), Science Direct, Research Gate.

Результаты. Перспективность применения терапевтических HER2-направленных конъюгатов клинически подтверждена для таких препаратов, как трастузумаб эмтанзин (T-DM1, Kadcyla®), трастузумаб дерукстекан (T-DXd, Enhertu®). Разработка новых HER2-направленных конъюгатов включает ряд подходов, направленных на улучшение характеристик препаратов и повышение эффективности терапии: увеличение аффинности связывания с мишенью, одновременное блокирование двух доменов HER2, различные механизмы цитотоксического воздействия на опухолевую клетку (ингибирование тубулина, РНК-полимеразы II, ДНКтопоизомеразы I, повреждение ДНК), увеличение соотношения цитотоксических агентов на молекулу антитела, использование «эффекта свидетеля», повышение стабильности конъюгата в кровотоке. На стадии клинических исследований изучаются такие препараты, как трастузумаб дуокармазин (SYD985), Диситамаб ведотин (RC48, Aidixi®), Занидатамаб зоводотин (ZW49), ARX788, MRG002.

Заключение. Совершенствование конструкции и понимание нюансов взаимодействия таргетных конъюгатов и опухоли способствуют новым клиническим успехам, что может обеспечить не только преимущество в выживании по сравнению с традиционной терапией, но и значительно улучшить качество жизни пациентов с HER2-положительным статусом.

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