HER2-targeted dual radiotracer approach with clinical potential for noninvasive imaging of trastuzumab-resistance caused by epitope masking.
HER2-targeted dual radiotracer approach with clinical potential for noninvasive imaging of trastuzumab-resistance caused by epitope masking.
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HER2靶向双放射性示踪剂方法具有临床潜力，可用于表位掩蔽引起的曲妥珠单抗耐药性的无创成像
DOI：
10.7150/thno.74154
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发表时间：
2022
期刊：
影响因子：
12.4
通讯作者：
Wang, Fan
中科院分区：
文献类型：
--
作者：
Li, Liqiang;Liu, Tianyu;Shi, Linqing;Zhang, Xin;Guo, Xiaoyi;Hu, Biao;Yao, Meinan;Zhu, Hua;Yang, Zhi;Jia, Bing;Wang, Fan
原理：表位掩蔽导致的HER2可及性降低是曲妥珠单抗耐药的主要机制。在这项研究中，我们开发了一种针对HER2的双放射示踪剂方法来非侵入性地预测HER2-曲妥珠单抗的结合。方法：用人HER2蛋白免疫羊驼，获得两种新的HER2特异性VHH：MIRC208和MIRC213，并用99mTc进行定位标记。对HER2阳性和HER2阴性肿瘤的小鼠进行了生物分布和SPECT/CT成像研究。通过细胞结合和SPECT/CT显像研究了99mTC-MIRC208和99mTC-MIRC213的HER2结合部位。我们评估了我们的双放射示踪成像方法对于曲妥珠单抗治疗MUC4阳性肿瘤(曲妥珠单抗耐药的JIMT-1和87MUC4)和MUC4阴性肿瘤(曲妥珠单抗敏感的7HER2和NCI-N87)的小鼠的治疗预测能力。对2例HER2阳性乳腺肿瘤患者进行了99mTC-MIRC208的初步临床研究。结果：99mTC-MIRC208和99mTC-MIRC213可清晰显示HER2阳性肿瘤，但不能显示HER2阴性肿瘤。99mTC-MIRC208与曲妥珠单抗竞争HER2结合，而99mTC-MIRC213识别未被MUC4掩蔽的表位上的HER2。99mTC-MIRC208和99mTC-MIRC213的SPECT/CT研究表明，MUC4阴性和曲妥珠单抗敏感的7HER2和NCI-N87肿瘤具有非常相似的肿瘤摄取，7HER2和NCI-N87的SUV208/SUV213(2小时)比值分别为1.11±0.17和1.25±0.22。然而，MUC4阳性的JIMT-1肿瘤显示SUV208/SUV213(2 H)比值降低(0.63±0.07)，这与曲妥珠单抗治疗的低应答率有很好的相关性。在表达MUC4的NCI-N87细胞中，SUV208/SUV213(2 H)比值降至0.72±0.02，导致曲妥珠单抗敏感性降低，进一步支持SUV208/SUV213(2 H)比值与曲妥珠单抗敏感性之间的相关性。注射后2小时99mTC-MIRC208 SPECT可清晰显示HER2阳性原发灶和转移灶。结论：总体而言，我们证明了在曲妥珠单抗治疗前，双示踪剂显影策略是一种有效的非侵入性癌症患者选择方法。99mTC-MIRC213 SPECT用于定量肿瘤HER2的表达并筛查HER2阳性的癌症患者，而99mTC-MIRC208 SPECT用于确定曲妥珠单抗对HER2的可及性。SUV208/SUV213(2小时)比值是决定曲妥珠单抗治疗疗效的重要生物标志物。
Rationale: 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 99mTc. Biodistribution and SPECT/CT imaging studies were performed in mice bearing HER2-positive and HER2-negative tumors. The HER2 binding sites of 99mTc-MIRC208 and 99mTc-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 99mTc-MIRC208 were performed in two patients with HER2-positive breast tumors. Results: 99mTc-MIRC208 and 99mTc-MIRC213 clearly visualized HER2-positive tumors, but not HER2-negative tumors. 99mTc-MIRC208 competes with trastuzumab for HER2-binding while 99mTc-MIRC213 recognizes HER2 on an epitope that is not masked by MUC4. The SPECT/CT studies with 99mTc-MIRC208 and 99mTc-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 and 1.25 ± 0.22 in NCI-N87. However, the MUC4-positive JIMT-1 tumors showed the decreased SUV208/SUV213 (2 h) ratio (0.63 ± 0.07), which correlated well with the low response rate to trastuzumab therapy. The SUV208/SUV213 (2 h) ratio was reduced to 0.72 ± 0.02 in MUC4-expressing NCI-N87 cells, and resulting in the decreased trastuzumab sensitivity, further supporting the correlation between the SUV208/SUV213 (2 h) ratio and trastuzumab-sensitivity. The primary and metastatic HER2-positive lesions of patients were clearly visualized by 99mTc-MIRC208 SPECT at 2 h post injection. Conclusion: Overall, we demonstrated that the dual radiotracer imaging strategy is a valid noninvasive approach for the cancer patient selection before trastuzumab therapy. 99mTc-MIRC213 SPECT is utilized to quantify the tumor HER2 expression and screen HER2-positive cancer patients, while 99mTc-MIRC208 SPECT is used to determine the HER2-accessibility of trastuzumab. The SUV208/SUV213 (2 h) ratio is an important biomarker to determine the responsiveness of trastuzumab therapy.
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影响因子：
8.8
作者：
通讯作者：
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针对早期 HER2 阳性乳腺癌的个性化治疗。
DOI：
10.1038/s41571-019-0299-9
发表时间：
2020-04
期刊：
Nature reviews. Clinical oncology
影响因子：
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作者：
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影响因子：
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