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Noninvasive Detection of HER2 Expression in Gastric Cancer by 64Cu-NOTA-Trastuzumab in PDX Mouse Model and in Patients
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-09-25 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00673 Xiaoyi Guo 1 , Hua Zhu 1 , Nina Zhou 1 , Zuhua Chen 2 , Teli Liu 1 , Fei Liu 1 , Xiaoxia Xu 1 , Hongjun Jin 3 , Lin Shen 2 , Jing Gao 2 , Zhi Yang 1
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-09-25 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00673 Xiaoyi Guo 1 , Hua Zhu 1 , Nina Zhou 1 , Zuhua Chen 2 , Teli Liu 1 , Fei Liu 1 , Xiaoxia Xu 1 , Hongjun Jin 3 , Lin Shen 2 , Jing Gao 2 , Zhi Yang 1
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The purpose of this study was to establish the quality control and quantify the novel 64Cu-NOTA-Trastuzumab in gastric cancer patient-derived xenografts (PDX) mice models and patients by applying the molecular imaging technique. Trastuzumab was labeled with 64Cu using NCS-Bz-NOTA as bifunctional chelator, and hIgG1 was labeled with the same procedures as a negative control agent. HER2-positive (case 176, n = 12) and HER2-negative (case 168, n = 3) PDX models were established and validated by Western blot, DNA amplification, and immunohistochemistry (IHC). Both models were conducted for micro-PET imaging by tail injection of 18.5 MBq of 64Cu-NOTA-Trastuzumab or 64Cu-NOTA-hIgG1. Radioprobe uptake in tumor and main organs was quantified by region of interested (ROI) analysis of the micro-PET images and autoradiography. Finally, gastric cancer patients were enrolled in preliminary 64Cu-NOTA-Trastuzumab PET/CT scans. NOTA-Trastuzumab was efficiently radiolabeled with 64Cu over a 99% radiochemical purity and 17.5 GBq/μmol specific activity. The immune activity was preserved as the nonmodified antibody, and the radiopharmaceutical proved to be stable for up to 5 half-decay lives of 64Cu both in vitro and in vivo. Two serials of PDX gastric cancer models were successfully established: case 176 for HER2 positive and case 168 for HER2 negative. In micro-PET imaging studies, 64Cu-NOTA-Trastuzumab exhibits a significant higher tumor uptake (11.45 ± 0.42 ID%/g) compared with 64Cu-NOTA-IgG1 (3.25 ± 0.28 ID%/g, n = 5, p = 0.0004) at 36 h after intravenous injection. Lower level uptake of 64Cu-NOTA-Trastuzumab (6.35 ± 0.48 ID%/g) in HER2-negative PDX tumor models further confirmed specific binding of the radioprobe. Interestingly, the coinjection of 2.0 mg of Trastuzumab (15.52 ± 1.97 ID%/g) or 2.0 mg of hIgG1 (15.64 ± 3.54 ID%/g) increased the 64Cu-NOTA-Trastuzumab tumor uptake in PDX tumor (HER2+) models compared with 64Cu-NOTA-Trastuzumab alone (p < 0.05) at 36 h postinjection. There were good correlations between micro-PET images and IHC (n = 4) and autoradiography in PDX (HER2+) tumor tissues. Therefore, 64Cu-NOTA-Trastuzumab successfully translated to clinical PET imaging, and 64Cu-NOTA-Trastuzumab PET/CT scan in gastric cancer patients showed good detection ability. In conclusion, we reported quality control and application of novel 64Cu-NOTA-Trastuzumab for HER2 expression in PDX gastric cancer mice models and gastric cancer patients. Moreover, 64Cu-NOTA-Trastuzumab holds great potential for noninvasive PET detection, staging, and follow-up of HER2 expression in gastric cancer.
中文翻译：
在PDX小鼠模型和患者中通过64 Cu-NOTA-曲妥珠单抗无创检测胃癌中HER2的表达
这项研究的目的是建立应用分子成像技术在胃癌患者异种移植（PDX）小鼠模型和患者中建立新颖的64 Cu-NOTA-曲妥珠单抗的质量控制并进行定量。使用NCS-Bz-NOTA作为双功能螯合剂，曲妥珠单抗用64 Cu标记，hIgG1用与阴性对照试剂相同的步骤标记。建立了HER2阳性（案例176，n = 12）和HER2阴性（案例168，n = 3）PDX模型，并通过Western印迹，DNA扩增和免疫组化（IHC）进行了验证。通过对18.5 MBq的64 Cu-NOTA-曲妥珠单抗或64的尾部注射进行两种模型的微型PET成像Cu-NOTA-hIgG1。通过对微型PET图像和放射自显影的目标区域（ROI）分析来量化肿瘤和主要器官中的放射性探针吸收。最后，对胃癌患者进行了初步的64 Cu-NOTA-曲妥珠单抗PET / CT扫描。用99％放射化学纯度和17.5 GBq /μmol比活度的64 Cu有效地对NOTA-曲妥珠单抗进行了放射性标记。免疫活性被保留为未修饰的抗体，并且在体外和体内，放射性药物被证明在64 Cu的多达5个半衰期中是稳定的。成功建立了两个系列的PDX胃癌模型：HER2阳性的病例176和HER2阴性的病例168。在微型PET成像研究中，64的Cu-NOTA-曲妥珠单抗表现出显著更高的肿瘤摄取（11.45±0.42 ID％/ g），用比较64的Cu-NOTA-IgG1的（3.25±0.28 ID％/克，Ñ = 5，p = 0.0004）在36小时后静脉注射。在HER2阴性的PDX肿瘤模型中64 Cu-NOTA-曲妥珠单抗的较低水平摄取（6.35±0.48 ID％/ g）进一步证实了放射性探针的特异性结合。有趣的是，在PDX肿瘤（HER2 +）模型中，共注射2.0 mg曲妥珠单抗（15.52±1.97 ID％/ g）或2.0 mg hIgG1（15.64±3.54 ID％/ g）共同注射64 Cu-NOTA-曲妥珠单抗。与单独使用64 Cu-NOTA-曲妥珠单抗相比（p<0.05）在注射后36小时。在PDX（HER2 +）肿瘤组织中，微型PET图像与IHC（n = 4）和放射自显影之间存在良好的相关性。因此，64 Cu-NOTA-曲妥珠单抗成功地转化为临床PET显像，并且64 Cu-NOTA-曲妥珠单抗PET / CT扫描在胃癌患者中显示出良好的检测能力。总之，我们报道了PDX胃癌小鼠模型和胃癌患者中HER2表达的新型64 Cu-NOTA-曲妥珠单抗的质量控制和应用。此外，64 Cu-NOTA-曲妥珠单抗在胃癌的无创PET检测，分期和HER2表达的随访方面具有巨大潜力。
更新日期：2018-09-25
中文翻译：
在PDX小鼠模型和患者中通过64 Cu-NOTA-曲妥珠单抗无创检测胃癌中HER2的表达
这项研究的目的是建立应用分子成像技术在胃癌患者异种移植（PDX）小鼠模型和患者中建立新颖的64 Cu-NOTA-曲妥珠单抗的质量控制并进行定量。使用NCS-Bz-NOTA作为双功能螯合剂，曲妥珠单抗用64 Cu标记，hIgG1用与阴性对照试剂相同的步骤标记。建立了HER2阳性（案例176，n = 12）和HER2阴性（案例168，n = 3）PDX模型，并通过Western印迹，DNA扩增和免疫组化（IHC）进行了验证。通过对18.5 MBq的64 Cu-NOTA-曲妥珠单抗或64的尾部注射进行两种模型的微型PET成像Cu-NOTA-hIgG1。通过对微型PET图像和放射自显影的目标区域（ROI）分析来量化肿瘤和主要器官中的放射性探针吸收。最后，对胃癌患者进行了初步的64 Cu-NOTA-曲妥珠单抗PET / CT扫描。用99％放射化学纯度和17.5 GBq /μmol比活度的64 Cu有效地对NOTA-曲妥珠单抗进行了放射性标记。免疫活性被保留为未修饰的抗体，并且在体外和体内，放射性药物被证明在64 Cu的多达5个半衰期中是稳定的。成功建立了两个系列的PDX胃癌模型：HER2阳性的病例176和HER2阴性的病例168。在微型PET成像研究中，64的Cu-NOTA-曲妥珠单抗表现出显著更高的肿瘤摄取（11.45±0.42 ID％/ g），用比较64的Cu-NOTA-IgG1的（3.25±0.28 ID％/克，Ñ = 5，p = 0.0004）在36小时后静脉注射。在HER2阴性的PDX肿瘤模型中64 Cu-NOTA-曲妥珠单抗的较低水平摄取（6.35±0.48 ID％/ g）进一步证实了放射性探针的特异性结合。有趣的是，在PDX肿瘤（HER2 +）模型中，共注射2.0 mg曲妥珠单抗（15.52±1.97 ID％/ g）或2.0 mg hIgG1（15.64±3.54 ID％/ g）共同注射64 Cu-NOTA-曲妥珠单抗。与单独使用64 Cu-NOTA-曲妥珠单抗相比（p<0.05）在注射后36小时。在PDX（HER2 +）肿瘤组织中，微型PET图像与IHC（n = 4）和放射自显影之间存在良好的相关性。因此，64 Cu-NOTA-曲妥珠单抗成功地转化为临床PET显像，并且64 Cu-NOTA-曲妥珠单抗PET / CT扫描在胃癌患者中显示出良好的检测能力。总之，我们报道了PDX胃癌小鼠模型和胃癌患者中HER2表达的新型64 Cu-NOTA-曲妥珠单抗的质量控制和应用。此外，64 Cu-NOTA-曲妥珠单抗在胃癌的无创PET检测，分期和HER2表达的随访方面具有巨大潜力。
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