Immuno-PET and Targeted α-Therapy Using Anti-Glypican-1 Antibody Labeled with 89Zr or 211At: A Theranostic Approach for Pancreatic Ductal Adenocarcinoma

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

Immuno-PET and Targeted α-Therapy Using Anti-Glypican-1 Antibody Labeled with ⁸⁹Zr or ²¹¹At: A Theranostic Approach for Pancreatic Ductal Adenocarcinoma

J Nucl Med. 2023 Dec 1;64(12):1949-1955. doi: 10.2967/jnumed.123.266313.

Authors

Tadashi Watabe^{1

2}, Kazuya Kabayama^{2

3

4}, Sadahiro Naka⁵, Ryuku Yamamoto³, Kazuko Kaneda^{2

4}, Satoshi Serada⁶, Kazuhiro Ooe², Atsushi Toyoshima², Yang Wang⁷, Hiromitsu Haba⁷, Kenta Kurimoto⁵, Takanori Kobayashi⁸, Eku Shimosegawa⁹, Noriyuki Tomiyama^{2

10}, Koichi Fukase^{2

3

4}, Tetsuji Naka^{6

11}

Affiliations

¹ Department of Nuclear Medicine and Tracer Kinetics, Graduate School of Medicine, Osaka University, Suita, Japan; watabe.tadashi.med@osaka-u.ac.jp.
² Institute for Radiation Sciences, Osaka University, Suita, Japan.
³ Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Japan.
⁴ Forefront Research Center, Graduate School of Science, Osaka University, Toyonaka, Japan.
⁵ Department of Pharmacy, Osaka University Hospital, Suita, Japan.
⁶ Institute for Biomedical Sciences Molecular Pathophysiology, Iwate Medical University, Yahaba, Japan.
⁷ Nishina Center for Accelerator-Based Science, RIKEN, Saitama, Japan.
⁸ Department of Nuclear Medicine and Tracer Kinetics, Graduate School of Medicine, Osaka University, Suita, Japan.
⁹ Department of Molecular Imaging in Medicine, Graduate School of Medicine, Osaka University, Suita, Japan.
¹⁰ Department of Radiology, Graduate School of Medicine, Osaka University, Suita, Japan; and.
¹¹ Division of Allergy and Rheumatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Yahaba, Japan.

Abstract

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 (SUV_max, 3.85 ± 0.10), which gradually decreased until day 7 (SUV_max, 2.16 ± 0.30). The uptake in the BxPC-3 xenograft was significantly higher than in the BxPC-3 GPC1-knockout xenograft (SUV_max, 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.

Keywords: astatine; glypican-1; immuno-PET; pancreatic ductal adenocarcinoma; targeted α-therapy; theranostics; zirconium.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinoma, Pancreatic Ductal* / diagnostic imaging
Carcinoma, Pancreatic Ductal* / therapy
Cell Line, Tumor
DNA
Glypicans / metabolism
Humans
Mice
Pancreatic Neoplasms* / diagnostic imaging
Pancreatic Neoplasms* / pathology
Pancreatic Neoplasms* / therapy
Positron Emission Tomography Computed Tomography
Positron-Emission Tomography
Precision Medicine
Zirconium

Substances

Glypicans
DNA
Zirconium