HER2-targeted dual radiotracer approach with clinical potential for noninvasive imaging of trastuzumab-resistance caused by epitope masking

作者：Liqiang Li, Tianyu Liu, Linqing Shi, Xin Zhang, Xiaoyi Guo, Biao Hu, Meinan Yao, Hua Zhu, Zhi Yang, Bing Jia, Fan Wang · 发表于：Theranostics · 年份：2022 · DOI：10.7150/thno.74154 · 被引用次数：33 · 研究领域：Monoclonal and Polyclonal Antibodies Research、HER2/EGFR in Cancer Research、Peptidase Inhibition and Analysis

The decreased HER2-accessibility by epitope masking is a primary trastuzumab-resistance mechanism. In this study, we developed a HER2-targeted dual radiotracer approach to predict the HER2-trastuzumab engagement noninvasively. Methods: Two novel HER2-specific VHHs, MIRC208 and MIRC213, were acquired by immunizing alpaca with human HER2 protein, and were site-specifically labeled with 99m Tc. Biodistribution and SPECT/CT imaging studies were performed in mice bearing HER2-positive and HER2-negative tumors. The HER2 binding sites of 99m Tc-MIRC208 and 99m Tc-MIRC213 were investigated by cell binding and SPECT/CT imaging studies. We evaluated the therapeutic predictive ability of our dual-radiotracer imaging approach for trastuzumab treatment in mice bearing MUC4-positive tumors (trastuzumab-resistant JIMT-1 and 87MUC4) and MUC4-negative tumors (trastuzumab-sensitive 7HER2 and NCI-N87). The preliminary clinical studies of 99m Tc-MIRC208 were performed in two patients with HER2-positive breast tumors. Results: 99m Tc-MIRC208 and 99m Tc-MIRC213 clearly visualized HER2-positive tumors, but not HER2-negative tumors. 99m Tc-MIRC208 competes with trastuzumab for HER2-binding while 99m Tc-MIRC213 recognizes HER2 on an epitope that is not masked by MUC4. The SPECT/CT studies with 99m Tc-MIRC208 and 99m Tc-MIRC213 clearly showed that the MUC4-negative and trastuzumab-sensitive 7HER2 and NCI-N87 tumors had very similar tumor uptake with the SUV208/SUV213 (2 h) ratios of 1.11 0.17 in 7HER2...