{"title":"免疫PET和使用89Zr或211At标记的抗胰蛋白酶-1抗体的靶向α-治疗:胰腺导管腺癌的Theranos方法。","authors":"Tadashi Watabe, Kazuya Kabayama, Sadahiro Naka, Ryuku Yamamoto, Kazuko Kaneda, Satoshi Serada, Kazuhiro Ooe, Atsushi Toyoshima, Yang Wang, Hiromitsu Haba, Kenta Kurimoto, Takanori Kobayashi, Eku Shimosegawa, Noriyuki Tomiyama, Koichi Fukase, Tetsuji Naka","doi":"10.2967/jnumed.123.266313","DOIUrl":null,"url":null,"abstract":"<p><p>Glypican-1 (GPC1) is overexpressed in several solid cancers and is associated with tumor progression, whereas its expression is low in normal tissues. This study aimed to evaluate the potential of an anti-GPC1 monoclonal antibody (GPC1 mAb) labeled with <sup>89</sup>Zr or <sup>211</sup>At as a theranostic target in pancreatic ductal adenocarcinoma. <b>Methods:</b> GPC1 mAb clone 01a033 was labeled with <sup>89</sup>Zr or <sup>211</sup>At with a deferoxamine or decaborane linker, respectively. The internalization ability of GPC1 mAb was evaluated by fluorescence conjugation using a confocal microscope. PANC-1 xenograft mice (<i>n</i> = 6) were intravenously administered [<sup>89</sup>Zr]GPC1 mAb (0.91 ± 0.10 MBq), and PET/CT scanning was performed for 7 d. Uptake specificity was confirmed through a comparative study using GPC1-positive (BxPC-3) and GPC1-negative (BxPC-3 GPC1-knockout) xenografts (each <i>n</i> = 3) and a blocking study. DNA double-strand breaks were evaluated using the γH2AX antibody. The antitumor effect was evaluated by administering [<sup>211</sup>At]GPC1 mAb (∼100 kBq) to PANC-1 xenograft mice (<i>n</i> = 10). <b>Results:</b> GPC1 mAb clone 01a033 showed increased internalization ratios over time. One day after administration, a high accumulation of [<sup>89</sup>Zr]GPC1 mAb was observed in the PANC-1 xenograft (SUV<sub>max</sub>, 3.85 ± 0.10), which gradually decreased until day 7 (SUV<sub>max</sub>, 2.16 ± 0.30). The uptake in the BxPC-3 xenograft was significantly higher than in the BxPC-3 GPC1-knockout xenograft (SUV<sub>max</sub>, 4.66 ± 0.40 and 2.36 ± 0.36, respectively; <i>P</i> = 0.05). The uptake was significantly inhibited in the blocking group compared with the nonblocking group (percentage injected dose per gram, 7.3 ± 1.3 and 12.4 ± 3.0, respectively; <i>P</i> = 0.05). DNA double-strand breaks were observed by adding 150 kBq of [<sup>211</sup>At]GPC1 and were significantly suppressed by the internalization inhibitor (dynasore), suggesting a substantial contribution of the internalization ability to the antitumor effect. Tumor growth suppression was observed in PANC-1 mice after the administration of [<sup>211</sup>At]GPC1 mAb. Internalization inhibitors (prochlorperazine) significantly inhibited the therapeutic effect of [<sup>211</sup>At]GPC1 mAb, suggesting an essential role in targeted α-therapy. <b>Conclusion:</b> [<sup>89</sup>Zr]GPC1 mAb PET showed high tumoral uptake in the early phase after administration, and targeted α-therapy using [<sup>211</sup>At]GPC1 mAb showed tumor growth suppression. GPC1 is a promising target for future applications for the precise diagnosis of pancreatic ductal adenocarcinoma and GPC1-targeted theranostics.</p>","PeriodicalId":16758,"journal":{"name":"Journal of Nuclear Medicine","volume":null,"pages":null},"PeriodicalIF":9.1000,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10690121/pdf/","citationCount":"0","resultStr":"{\"title\":\"Immuno-PET and Targeted α-Therapy Using Anti-Glypican-1 Antibody Labeled with <sup>89</sup>Zr or <sup>211</sup>At: A Theranostic Approach for Pancreatic Ductal Adenocarcinoma.\",\"authors\":\"Tadashi Watabe, Kazuya Kabayama, Sadahiro Naka, Ryuku Yamamoto, Kazuko Kaneda, Satoshi Serada, Kazuhiro Ooe, Atsushi Toyoshima, Yang Wang, Hiromitsu Haba, Kenta Kurimoto, Takanori Kobayashi, Eku Shimosegawa, Noriyuki Tomiyama, Koichi Fukase, Tetsuji Naka\",\"doi\":\"10.2967/jnumed.123.266313\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Glypican-1 (GPC1) is overexpressed in several solid cancers and is associated with tumor progression, whereas its expression is low in normal tissues. This study aimed to evaluate the potential of an anti-GPC1 monoclonal antibody (GPC1 mAb) labeled with <sup>89</sup>Zr or <sup>211</sup>At as a theranostic target in pancreatic ductal adenocarcinoma. <b>Methods:</b> GPC1 mAb clone 01a033 was labeled with <sup>89</sup>Zr or <sup>211</sup>At with a deferoxamine or decaborane linker, respectively. The internalization ability of GPC1 mAb was evaluated by fluorescence conjugation using a confocal microscope. PANC-1 xenograft mice (<i>n</i> = 6) were intravenously administered [<sup>89</sup>Zr]GPC1 mAb (0.91 ± 0.10 MBq), and PET/CT scanning was performed for 7 d. Uptake specificity was confirmed through a comparative study using GPC1-positive (BxPC-3) and GPC1-negative (BxPC-3 GPC1-knockout) xenografts (each <i>n</i> = 3) and a blocking study. DNA double-strand breaks were evaluated using the γH2AX antibody. The antitumor effect was evaluated by administering [<sup>211</sup>At]GPC1 mAb (∼100 kBq) to PANC-1 xenograft mice (<i>n</i> = 10). <b>Results:</b> GPC1 mAb clone 01a033 showed increased internalization ratios over time. One day after administration, a high accumulation of [<sup>89</sup>Zr]GPC1 mAb was observed in the PANC-1 xenograft (SUV<sub>max</sub>, 3.85 ± 0.10), which gradually decreased until day 7 (SUV<sub>max</sub>, 2.16 ± 0.30). The uptake in the BxPC-3 xenograft was significantly higher than in the BxPC-3 GPC1-knockout xenograft (SUV<sub>max</sub>, 4.66 ± 0.40 and 2.36 ± 0.36, respectively; <i>P</i> = 0.05). The uptake was significantly inhibited in the blocking group compared with the nonblocking group (percentage injected dose per gram, 7.3 ± 1.3 and 12.4 ± 3.0, respectively; <i>P</i> = 0.05). DNA double-strand breaks were observed by adding 150 kBq of [<sup>211</sup>At]GPC1 and were significantly suppressed by the internalization inhibitor (dynasore), suggesting a substantial contribution of the internalization ability to the antitumor effect. Tumor growth suppression was observed in PANC-1 mice after the administration of [<sup>211</sup>At]GPC1 mAb. Internalization inhibitors (prochlorperazine) significantly inhibited the therapeutic effect of [<sup>211</sup>At]GPC1 mAb, suggesting an essential role in targeted α-therapy. <b>Conclusion:</b> [<sup>89</sup>Zr]GPC1 mAb PET showed high tumoral uptake in the early phase after administration, and targeted α-therapy using [<sup>211</sup>At]GPC1 mAb showed tumor growth suppression. GPC1 is a promising target for future applications for the precise diagnosis of pancreatic ductal adenocarcinoma and GPC1-targeted theranostics.</p>\",\"PeriodicalId\":16758,\"journal\":{\"name\":\"Journal of Nuclear Medicine\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":9.1000,\"publicationDate\":\"2023-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10690121/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Nuclear Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.2967/jnumed.123.266313\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Nuclear Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2967/jnumed.123.266313","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING","Score":null,"Total":0}
Immuno-PET and Targeted α-Therapy Using Anti-Glypican-1 Antibody Labeled with 89Zr or 211At: A Theranostic Approach for Pancreatic Ductal Adenocarcinoma.
Glypican-1 (GPC1) is overexpressed in several solid cancers and is associated with tumor progression, whereas its expression is low in normal tissues. This study aimed to evaluate the potential of an anti-GPC1 monoclonal antibody (GPC1 mAb) labeled with 89Zr or 211At as a theranostic target in pancreatic ductal adenocarcinoma. Methods: GPC1 mAb clone 01a033 was labeled with 89Zr or 211At with a deferoxamine or decaborane linker, respectively. The internalization ability of GPC1 mAb was evaluated by fluorescence conjugation using a confocal microscope. PANC-1 xenograft mice (n = 6) were intravenously administered [89Zr]GPC1 mAb (0.91 ± 0.10 MBq), and PET/CT scanning was performed for 7 d. Uptake specificity was confirmed through a comparative study using GPC1-positive (BxPC-3) and GPC1-negative (BxPC-3 GPC1-knockout) xenografts (each n = 3) and a blocking study. DNA double-strand breaks were evaluated using the γH2AX antibody. The antitumor effect was evaluated by administering [211At]GPC1 mAb (∼100 kBq) to PANC-1 xenograft mice (n = 10). Results: GPC1 mAb clone 01a033 showed increased internalization ratios over time. One day after administration, a high accumulation of [89Zr]GPC1 mAb was observed in the PANC-1 xenograft (SUVmax, 3.85 ± 0.10), which gradually decreased until day 7 (SUVmax, 2.16 ± 0.30). The uptake in the BxPC-3 xenograft was significantly higher than in the BxPC-3 GPC1-knockout xenograft (SUVmax, 4.66 ± 0.40 and 2.36 ± 0.36, respectively; P = 0.05). The uptake was significantly inhibited in the blocking group compared with the nonblocking group (percentage injected dose per gram, 7.3 ± 1.3 and 12.4 ± 3.0, respectively; P = 0.05). DNA double-strand breaks were observed by adding 150 kBq of [211At]GPC1 and were significantly suppressed by the internalization inhibitor (dynasore), suggesting a substantial contribution of the internalization ability to the antitumor effect. Tumor growth suppression was observed in PANC-1 mice after the administration of [211At]GPC1 mAb. Internalization inhibitors (prochlorperazine) significantly inhibited the therapeutic effect of [211At]GPC1 mAb, suggesting an essential role in targeted α-therapy. Conclusion: [89Zr]GPC1 mAb PET showed high tumoral uptake in the early phase after administration, and targeted α-therapy using [211At]GPC1 mAb showed tumor growth suppression. GPC1 is a promising target for future applications for the precise diagnosis of pancreatic ductal adenocarcinoma and GPC1-targeted theranostics.
期刊介绍:
The Journal of Nuclear Medicine (JNM), self-published by the Society of Nuclear Medicine and Molecular Imaging (SNMMI), provides readers worldwide with clinical and basic science investigations, continuing education articles, reviews, employment opportunities, and updates on practice and research. In the 2022 Journal Citation Reports (released in June 2023), JNM ranked sixth in impact among 203 medical journals worldwide in the radiology, nuclear medicine, and medical imaging category.