Kang Chi Soo, Kim Do Hyeon, Lim Hwisoo, Kim Sunkyo, Almaslamani Muath, Kang Choong Mo, Woo Sang-Keun
Division of Applied RI, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea.
Radiological and Medico-Oncological Sciences, University of Science and Technology, Daejeon 34113, Republic of Korea.
Mol Pharm. 2025 Jul 7;22(7):3793-3802. doi: 10.1021/acs.molpharmaceut.5c00043. Epub 2025 May 31.
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., Lu or Ac) 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 Lu or Ac. 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 Ac, 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.
抗体药物偶联物（ADCs）因其与传统治疗性抗体或化疗药物相比具有更高的疗效和更低的副作用，在癌症治疗领域备受关注。然而，癌症患者仍会对ADCs产生耐药性，因此迫切需要开发增强ADCs疗效的策略。用治疗性放射性同位素（如镥或锕）对抗体进行放射性标记可被视为一种选择。在此，我们合成了放射性标记的ADCs，并在体外和体内评估了它们在癌症治疗中的潜在疗效。开发了以新的曲妥珠单抗为基础、利用芬地林或吉米沙星作为药物部分的ADCs，并对它们进行了治疗性放射性核素镥或锕的修饰。使用表达人表皮生长因子受体2（HER2）的癌细胞评估了放射性标记的ADCs的抗癌效果，并与未标记的ADCs进行了比较。新合成的ADCs的放射性标记版本与未标记的ADCs相比，显示出显著提高的抗癌疗效，尤其是当它们带有锕时，这证明了放射性标记的ADCs在癌症治疗中的巨大潜力。本研究提供了一种通过用放射性核素强化ADCs来提高其治疗效果的有效策略。
