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Journal of Nuclear Medicine

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OtherBasic Science (Animal or Phantoms)

Synthesis and Preclinical Evaluation of 68Ga-labeled Adnectin, 68Ga-BMS-986192 as a PET Agent for Imaging PD-L1 Expression

Stephanie Robu, Antonia Richter, Dario Gosmann, Christof Seidl, David Leung, Wendy Hayes, Daniel Cohen, Paul Morin, David J Donnelly, Daša Lipovšek, Samuel J Bonacorsi, Adam Smith, Katja Steiger, Christina Aulehner, Angela M Krackhardt and Wolfgang A Weber
Journal of Nuclear Medicine January 2021, jnumed.120.258384; DOI: https://doi.org/10.2967/jnumed.120.258384
Stephanie Robu
1 Technical University of Munich, Department of Nuclear Medicine, Klinikum rechts der Isar, Germany;
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Antonia Richter
1 Technical University of Munich, Department of Nuclear Medicine, Klinikum rechts der Isar, Germany;
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Dario Gosmann
2 Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Clinic and Policlinic for Internal Medicine III, Germany;
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Christof Seidl
1 Technical University of Munich, Department of Nuclear Medicine, Klinikum rechts der Isar, Germany;
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David Leung
3 Bristol-Myers Squibb Research and Development, United States;
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Wendy Hayes
3 Bristol-Myers Squibb Research and Development, United States;
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Daniel Cohen
3 Bristol-Myers Squibb Research and Development, United States;
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Paul Morin
3 Bristol-Myers Squibb Research and Development, United States;
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David J Donnelly
4 Bristol-Myers Squibb, United States;
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Daša Lipovšek
3 Bristol-Myers Squibb Research and Development, United States;
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Samuel J Bonacorsi
3 Bristol-Myers Squibb Research and Development, United States;
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Adam Smith
3 Bristol-Myers Squibb Research and Development, United States;
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Katja Steiger
5 Technical University of Munich, School of Medicine, Institute of Pathology, Germany;
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Christina Aulehner
2 Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Clinic and Policlinic for Internal Medicine III, Germany;
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Angela M Krackhardt
6 Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Clinic and Policlinic for Internal Medicine III; German Cancer Consortium (DKTK), partner-site Munich; and German Cancer Research Center (DKFZ) Heidelberg, Germany, Germany;
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Wolfgang A Weber
7 Technical University of Munich, Department of Nuclear Medicine, Klinikum rechts der Isar; German Cancer Consortium (DKTK), partner-site Munich; and German Cancer Research Center (DKFZ) Heidelberg, Germany
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Abstract

Blocking the interaction of the immune checkpoint molecules programmed cell death protein-1 (PD-1) and its ligand, PD-L1, using specific antibodies has been a major breakthrough for immune oncology. Whole-body PD-L1 expression positron emission tomography (PET) imaging may potentially allow for a better prediction of response to PD-1 targeted therapies. Imaging of PD-L1 expression is feasible by PET with the Adnectin protein 18F-BMS-986192. However, radiofluorination of proteins, such as BMS-986192 remains complex and labelling yields are low. The goal of this study was therefore the development and preclinical evaluation of a 68Ga-labeled Adnectin protein (68Ga- BMS-986192) to facilitate clinical trials. Methods: 68Ga-labeling of DOTA-conjugated Adnectin (BXA-206362) was carried out in NaOAc-buffer at pH 5.5 (50°C, 15min). In vitro stability in human serum at 37°C was analyzed using Radio-thin layer chromatography (Radio-TLC) and Radio-high performance liquid chromatography (Radio-HPLC). PD-L1 binding assays were performed using the transduced PD-L1 expressing lymphoma cell line U-698-M and wild-type U-698-M cells as negative control. Immunohistochemical staining studies, biodistribution and small animal PET studies of 68Ga-BMS-986192 were carried out using PD-L1-positive and negative U-698-M-bearing NSG mice. Results: 68Ga-BMS-986192 was obtained with quantitative radiochemical yields (RCYs) >97% and with high radiochemical purity (RCP). In vitro stability in human serum was ≥ 95% after 4h of incubation. High and specific binding of 68Ga-BMS-986192 to human PD-L1-expressing cancer cells was confirmed, which closely correlates with the respective PD-L1 expression level determined by flow cytometry and IHC staining. In vivo, 68Ga-BMS-986192 uptake was high in PD-L1+ tumors (9.0±2.1%ID/g at 1hp.i.) and kidneys (56.9±9.2% ID/g at 1hp.i.) with negligible uptake in other tissues. PD-L1 negative tumors demonstrated only background uptake of radioactivity (0.6±0.1% ID/g). Co-injection of an excess of unlabelled Adnectin reduced tumor uptake of PD-L1 by more than 80%. Conclusion: 68Ga-BMS-986192 enables easy radiosynthesis and shows excellent in vitro and in vivo PD-L1 targeting characteristics. The high tumor uptake combined with low background accumulation at early imaging time points demonstrate the feasibility of 68Ga-BMS-986192 for imaging of PD-L1 expression in tumors and is encouraging for further clinical applications of PD-L1 ligands.

  • Molecular Imaging
  • PET
  • Radiopharmaceuticals
  • 18F-BMS-986192
  • 68Ga-Adnectin
  • 68Ga-BMS-986192
  • PD-1/PD-L1 checkpoint inhibitors
  • PD-L1 PET Imaging
  • Copyright © 2021 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

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Journal of Nuclear Medicine: 62 (3)
Journal of Nuclear Medicine
Vol. 62, Issue 3
March 1, 2021
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Synthesis and Preclinical Evaluation of 68Ga-labeled Adnectin, 68Ga-BMS-986192 as a PET Agent for Imaging PD-L1 Expression
Stephanie Robu, Antonia Richter, Dario Gosmann, Christof Seidl, David Leung, Wendy Hayes, Daniel Cohen, Paul Morin, David J Donnelly, Daša Lipovšek, Samuel J Bonacorsi, Adam Smith, Katja Steiger, Christina Aulehner, Angela M Krackhardt, Wolfgang A Weber
Journal of Nuclear Medicine Jan 2021, jnumed.120.258384; DOI: 10.2967/jnumed.120.258384

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Synthesis and Preclinical Evaluation of 68Ga-labeled Adnectin, 68Ga-BMS-986192 as a PET Agent for Imaging PD-L1 Expression
Stephanie Robu, Antonia Richter, Dario Gosmann, Christof Seidl, David Leung, Wendy Hayes, Daniel Cohen, Paul Morin, David J Donnelly, Daša Lipovšek, Samuel J Bonacorsi, Adam Smith, Katja Steiger, Christina Aulehner, Angela M Krackhardt, Wolfgang A Weber
Journal of Nuclear Medicine Jan 2021, jnumed.120.258384; DOI: 10.2967/jnumed.120.258384
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Keywords

  • molecular imaging
  • PET
  • radiopharmaceuticals
  • 18F-BMS-986192
  • 68Ga-Adnectin
  • 68Ga-BMS-986192
  • PD-1/PD-L1 checkpoint inhibitors
  • PD-L1 PET Imaging
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