Strategy for the development of targeted agents for therapy of HER2-positive breast cancer

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. 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. 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. 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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