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。

IF 9.1 1区 医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING Journal of Nuclear Medicine Pub Date : 2023-12-01 DOI:10.2967/jnumed.123.266313
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
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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. 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引用次数: 0

摘要

Glypian-1(GPC1)在几种实体癌中过表达,并与肿瘤进展有关,而其在正常组织中的表达较低。本研究旨在评估用89Zr或211At标记的抗GPC1单克隆抗体(GPC1mAb)作为胰腺导管腺癌的治疗靶点的潜力。方法:分别用89Zr和211At标记GPC1mAb克隆01a033,用去铁胺或十硼烷连接子标记。使用共聚焦显微镜通过荧光缀合评价GPC1mAb的内化能力。PANC-1异种移植物小鼠(n=6)静脉注射[89Zr]GPC1 mAb(0.91 ± 0.10MBq),并进行PET/CT扫描7天。通过使用GPC1阳性(BxPC-3)和GPC1阴性(BxPC-3-GPC1敲除)异种移植物(每个n=3)的比较研究和阻断研究来确认摄取特异性。使用γH2AX抗体评估DNA双链断裂。通过向PANC-1异种移植物小鼠(n=10)施用[211At]GPC1 mAb(~100kBq)来评估抗肿瘤效果。结果:GPC1 mAb克隆01a033显示出随时间增加的内化比率。给药一天后,在PANC-1异种移植物中观察到[89Zr]GPC1 mAb的高积累(SUVmax,3.85 ± 0.10),其逐渐降低直到第7天(SUVmax,2.16 ± 0.30)。BxPC-3异种移植物中的摄取显著高于BxPC-3GPC1敲除异种移植物(SUVmax,4.66 ± 0.40和2.36 ± 0.36;P=0.05)。与非阻断组相比,阻断组的摄取受到显著抑制(每克注射剂量的百分比,7.3 ± 1.3和12.4 ± 3.0;P=0.05)。通过添加150kBq的[211At]GPC1观察到DNA双链断裂,并且被内化抑制剂(dynasole)显著抑制,表明内化能力对抗肿瘤效果有显著贡献。在给予[211At]GPC1mAb后,在PANC-1小鼠中观察到肿瘤生长抑制。内化抑制剂(普氯哌嗪)显著抑制[211At]GPC1 mAb的治疗作用,表明其在靶向α治疗中发挥重要作用。结论:[89Zr]GPC1 mAb PET在给药后早期显示出高肿瘤摄取,使用[211At]GPC1单克隆抗体的靶向α治疗显示出肿瘤生长抑制。GPC1是胰腺导管腺癌精确诊断和GPC1靶向治疗的一个有前途的靶点。
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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.

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来源期刊
Journal of Nuclear Medicine
Journal of Nuclear Medicine 医学-核医学
CiteScore
13.00
自引率
8.60%
发文量
340
审稿时长
1 months
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.
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