Medhus Astrid, Schink Kay Oliver, Longva Ane Sager, Engebraaten Olav, Berg Kristian, Weyergang Anette
Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
Institute of Basic Medical Science, University of Oslo, Oslo, Norway.
Ther Adv Med Oncol. 2025 Apr 24;17:17588359251332473. doi: 10.1177/17588359251332473. eCollection 2025.
In the era of personalized cancer therapy, antibody-drug conjugates (ADCs) have become one of the fastest-emerging groups of anticancer drugs. ADCs consist of an antibody coupled to a cytotoxic payload by a chemical linker, designed to be cleaved off intracellularly. Understanding the intracellular trafficking and processing of ADCs is crucial for elucidating their mechanism of action.
This study aimed to compare trastuzumab deruxtecan (T-DXd) to ado-trastuzumab emtansine (T-DM1) with emphasis on Rab GTPase-regulated intracellular trafficking and its impact on ADC efficacy.
The efficacy of T-DXd and T-DM1 was assessed in a panel of HER2-positive cell lines. Correlations between ADC efficacy and the expression of HER2 and Rab GTPases were evaluated. Functional studies, including knockdown (KD), overexpression, and microscopy, were performed to evaluate the impact of Rab GTPases on ADC cytotoxicity.
In contrast to T-DM1, T-DXd efficacy was found not to correlate to HER2 expression in a panel of HER2-positive cell lines. However, a correlation to RAB5A expression was found for T-DXd efficacy, although not as strong as for T-DM1. Altering the expression of RAB5 in our model system confirmed RAB5 to have an impact on both T-DXd and T-DM1 cytotoxicity, but more on T-DM1. In addition, RAB4a was found to influence T-DXd sensitivity, but not T-DM1, indicating differences in intracellular processing between T-DXd and T-DM1.
The study demonstrates that ADC design significantly influences intracellular trafficking and processing. The linker design, in particular, plays a major role in determining the intracellular fate of an ADC.
在个性化癌症治疗时代，抗体药物偶联物（ADC）已成为发展最快的抗癌药物类别之一。ADC由通过化学连接子与细胞毒性载荷偶联的抗体组成，设计为在细胞内裂解。了解ADC的细胞内运输和加工对于阐明其作用机制至关重要。
本研究旨在比较曲妥珠单抗德曲妥珠单抗（T-DXd）和ado-曲妥珠单抗恩美曲妥珠单抗（T-DM1），重点关注Rab GTP酶调节的细胞内运输及其对ADC疗效的影响。
在一组HER2阳性细胞系中评估T-DXd和T-DM1的疗效。评估ADC疗效与HER2和Rab GTP酶表达之间的相关性。进行功能研究，包括敲低（KD）、过表达和显微镜检查，以评估Rab GTP酶对ADC细胞毒性的影响。
与T-DM1不同，在一组HER2阳性细胞系中发现T-DXd疗效与HER2表达无关。然而，发现T-DXd疗效与RAB5A表达相关，尽管不如T-DM1强。在我们的模型系统中改变RAB5的表达证实RAB5对T-DXd和T-DM1细胞毒性均有影响，但对T-DM1的影响更大。此外，发现RAB4a影响T-DXd敏感性，但不影响T-DM1，表明T-DXd和T-DM1在细胞内加工方面存在差异。
该研究表明ADC设计显著影响细胞内运输和加工。特别是连接子设计在决定ADC的细胞内命运方面起主要作用。
