Radionuclide-Aided Improvement of the Therapeutic Efficacy of Novel Antibody–Drug Conjugates against HER2-Expressing Cancers

Antibody-drug conjugates (ADCs) have drawn a lot of attention in the field of cancer therapy due to their improved efficacy and reduced side effects compared to traditional therapeutic antibodies or chemotherapeutics. However, cancer patients still develop resistance against ADCs and there is an urgent need for the development of strategies to reinforce ADC efficacy. Radiolabeling of an antibody with therapeutic radioisotopes (e.g., ¹⁷⁷Lu or ²²⁵Ac) can be considered an option. Herein, we synthesized radiolabeled ADCs and evaluated their potential therapeutic efficacies in vitro and in vivo for cancer therapy. New trastuzumab-based ADCs utilizing fendiline or gemifloxacin as drug moieties were developed, and they were decorated with therapeutic radionuclide ¹⁷⁷Lu or ²²⁵Ac. Anticancer effects of radiolabeled ADCs were evaluated using human epidermal growth factor receptor 2 (HER2) expressing cancer cells and compared to that of cold ADCs. Radiolabeled versions of newly synthesized ADCs showed significantly improved anticancer efficacy compared to unlabeled ADCs, especially when they were armed with ²²⁵Ac, demonstrating the great potential of radiolabeled ADCs in cancer therapy. This study offers an effective strategy for improving the therapeutic efficacy of ADCs by fortifying them with radionuclides.