oncotomskСибирский онкологический журналSiberian journal of oncology1814-48612312-3168Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences10.21294/1814-4861-2025-24-3-135-148oncotomsk-3671Research ArticleОБЗОРЫREVIEWSСтратегия разработки таргетных препаратов для терапии HER2-позитивного рака молочной железыStrategy for the development of targeted agents for therapy of HER2-positive breast cancerhttps://orcid.org/0000-0001-5097-9737БоденкоВ. В.BodenkoV. V.

Боденко Виталина Васильевна - лаборант-исследователь научно-образовательной лаборатории химико-фармацевтических исследований, ФГБОУ ВО «Сибирский ГМУ» Минздрава России; инженер научно-исследовательского центра «Онкотераностика» исследовательской школы химических и биомедицинских технологий, ФГАОУ ВО Национальный исследовательский ТПУ; лаборант-исследователь отделения радионуклидной терапии и диагностики, НИИО, Томский НИМЦ РАН. SPIN-код: 8061-0837. Researcher ID (WOS): AEU-7385-2022. Author ID (Scopus): 57212209719.

634050, Томск, Московский тракт, 2; 634034, Томск, пр. Ленина, 43А; 634009, Томск, пер. Кооперативный, 5

Vitalina V. Bodenko - Laboratory research assistant, Scientific and Educational Laboratory of Chemical and Pharmaceutical Research, Siberian State Medical University of the Ministry of Health of Russia; Engineer, Research Center of Oncotheranostics, Research School of Chemistry & Applied Biomedical Sciences, National Research TPU; Laboratory research assistant, Department of Nuclear Therapy and Diagnostics, Cancer Research Institute, Tomsk NRMC, RAS. Researcher ID (WOS): AEU-7385-2022. Author ID (Scopus): 57212209719.

2, Moskovsky trakt, Tomsk, 634050; 43А, Lenina St., Tomsk, 634034; 5, Kooperativny St., Tomsk, 634009

bodenkovitalina@gmail.comhttps://orcid.org/0000-0003-1176-2441ЛарькинаМ. С.LarkinaM. S.

Ларькина Мария Сергеевна - доктор фармацевтических наук, профессор кафедры фармацевтического анализа, ФГБОУ ВО «Сибирский государственный медицинский университет» Минздрава России; профессор исследовательской школы химических и биомедицинских технологий, ФГАОУ ВО Национальный исследовательский ТПУ. SPIN-код: 2812-7907. Author ID (Scopus): 57194542755.

634050, Томск, Московский тракт, 2; 634034, Томск, пр. Ленина, 43А

Maria S. Larkina - DSc, Professor, Department of Pharmaceutical Analysis, Siberian State Medical University of the Ministry of Health of Russia; Professor, Research School of Chemistry & Applied Biomedical Sciences, National Research TPU. Author ID (Scopus): 57194542755.

2, Moskovsky trakt, Tomsk, 634050; 43А, Lenina St., Tomsk, 634034

https://orcid.org/0000-0002-5040-931XТретьяковаМ. С.TretyakovaM. S.

Третьякова Мария Сергеевна - кандидат биологических наук, младший научный сотрудник Научно-исследовательского центра «Онкотераностика» исследовательской школы химических и биомедицинских технологий, ФГАОУ ВО Национальный исследовательский ТПУ; младший научный сотрудник лаборатории биологии опухолевой прогрессии, НИИО, Томский НИМЦ РАН. SPIN-код: 5207-8330. Researcher ID (WOS): AAL-6195-2021. Author ID (Scopus): 56967923800.

634034, Томск, пр. Ленина, 43А; 634009, Томск, пер. Кооперативный, 5

Maria S. Tretyakova - PhD, Junior Researcher, Research Center of Oncotheranostics, Research School of Chemistry & Applied Biomedical Sciences, National Research TPU; Junior Researcher, Laboratory of Cancer Progression Biology, Cancer Research Institute, NRMC, RAS. Researcher ID (WOS): AAL-6195-2021. Author ID (Scopus): 56967923800.

43А, Lenina St., Tomsk, 634034; 5, Kooperativny St., Tomsk, 634009

https://orcid.org/0000-0002-2153-7945БелоусовМ. В.BelousovM. V.

Белоусов Михаил Валерьевич - доктор фармацевтических наук, профессор, заведующий кафедрой фармацевтического анализа, ФГБОУ ВО «Сибирский государственный медицинский университет» Минздрава России; профессор исследовательской школы химических и биомедицинских технологий, ФГАОУ ВО Национальный исследовательский ТПУ. SPIN-код: 8185-8117. Researcher ID (WOS): Q-3827-2016. Author ID (Scopus): 55808990700.

634050, Томск, Московский тракт, 2; 634034, Томск, пр. Ленина, 43А

Mikhail V. Belousov - DSc, Professor, Head of the Department of Pharmaceutical Analysis, Siberian State Medical University of the Ministry of Health of Russia; Professor, Research School of Chemistry & Applied Biomedical Sciences, National Research TPU. Researcher ID (WOS): Q-3827-2016. Author ID (Scopus): 55808990700.

2, Moskovsky trakt, Tomsk, 634050; 43А, Lenina St., Tomsk, 634034

https://orcid.org/0000-0002-5524-9546ЧерновВ. И.ChernovV. I.

Чернов Владимир Иванович - доктор медицинских наук, профессор, член-корреспондент РАН, заместитель директора по научной и инновационной работе, заведующий отделением радионуклидной терапии и диагностики, НИИО, Томский НИМЦ РАН; ведущий инженер лаборатории No 31 ядерного реактора, ФГАОУ ВО Национальный исследовательский ТПУ. SPIN-код: 6301-3612. Researcher ID (WOS): B-6789-2016. Author ID (Scopus): 7201429550.

634034, Томск, пр. Ленина, 43А; 634009, Томск, пер. Кооперативный, 5

Vladimir I. Chernov - MD, DSc, Professor, Corresponding Member of the Russian Academy of Sciences, Deputy Director for Scientific and Innovative Activities, Head of the Department of Nuclear Therapy and Diagnostics, Cancer Research Institute, Tomsk NRMC, RAS; Leading Engineer, Laboratory No. 31 of Nuclear Research Reactor, National Research TPU. Researcher ID (WOS): B-6789-2016. Author ID (Scopus): 7201429550.

43А, Lenina St., Tomsk, 634034; 5, Kooperativny St., Tomsk, 634009

ФГБОУ ВО «Сибирский государственный медицинский университет» Минздрава России Россия; ФГАОУ ВО «Национальный исследовательский Томский политехнический университет»; Научно-исследовательский институт онкологии, Томский национальный исследовательский медицинский центр Российской академии наукРоссияSiberian State Medical University of the Ministry of Health of Russia; National Research Tomsk Polytechnic University; Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of SciencesRussian FederationФГБОУ ВО «Сибирский государственный медицинский университет» Минздрава России Россия; ФГАОУ ВО «Национальный исследовательский Томский политехнический университет»РоссияSiberian State Medical University of the Ministry of Health of Russia; National Research Tomsk Polytechnic UniversityRussian FederationФГАОУ ВО «Национальный исследовательский Томский политехнический университет»; Научно-исследовательский институт онкологии, Томский национальный исследовательский медицинский центр Российской академии наукРоссияNational Research Tomsk Polytechnic University; Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of SciencesRussian Federation202504082025243135148Copyright © Боденко В.В., Ларькина М.С., Третьякова М.С., Белоусов М.В., Чернов В.И., 20252025Боденко В.В., Ларькина М.С., Третьякова М.С., Белоусов М.В., Чернов В.И.Bodenko V.V., Larkina M.S., Tretyakova M.S., Belousov M.V., Chernov V.I.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.siboncoj.ru/jour/article/view/3671

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

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

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

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.

The objective of the study: to identify current strategies, achievements, and challenges in developing HER2-targeted therapeutic conjugates and assess clinical outcomes of therapies based on them.

Material and Methods

Material and Methods. A total of 247 publications over the past 7 years were analyzed. Finally, 60 were selected for the review. The sources were searched in Scopus (n=35), PubMed (n=321) and WOS (n=91) databases. Electronic resources, such as PubMed Central (PMC), ScienceDirect and ResearchGate were used to obtain the full-text articles.

Results

Results. The therapeutic potential of HER2-targeted conjugates has been confirmed in clinical trials for drugs, such as trastuzumab emtansine (T-DM1, Kadcyla®) and trastuzumab deruxtecan (T-DXd, Enhertu®). The development of new HER2-targeted conjugates involves several approaches to improve drug characteristics and therapeutic efficacy: increasing binding affinity to the target, simultaneous blocking of two HER2 domains, various mechanisms of cytotoxic effects on tumor cells (inhibition of tubulin, RNA polymerase II, and DNA topoisomerase I), enhancing the ratio of cytotoxic agents per antibody molecule and improving the conjugate stability in the bloodstream. Trastuzumab duocarmazine (SYD985), disitamab vedotin (RC48, Aidixi®), zanidatamab zovodotin (ZW49), ARX788 and MRG002 are all currently being studied in clinical trials.

Conclusion

Conclusion. Improvements in the design and understanding of drug-tumor interactions contribute to new clinical advances that may provide not only a survival advantage over traditional therapy, but also significantly improve the quality of life of patients with HER2-positive tumors.

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The authors declare that there are no conflicts of interest present.