Synthesis and Preclinical Evaluation of a 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, Dasa Lipovsek, Samuel J. Bonacorsi, Adam Smith, Katja Steiger, Christina Aulehner, Angela M. Krackhardt, Wolfgang A. Weber

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Blocking the interaction of the immune checkpoint molecule programmed cell death protein-1 and its ligand, PD-L1, using specific antibodies has been a major breakthrough for immune oncology. Whole-body PD-L1 expression PET imaging may potentially allow for a better prediction of response to programmed cell death protein-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 labeling 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 performed in NaOAc-buffer at pH 5.5 (50C, 15 min). In vitro stability in human serum at 37C was analyzed using radio-thin layer chromatography and radio-high-performance liquid chromatography. 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 a negative control. Immunohistochemical staining studies, biodistribution studies, and small-animal PET studies of 68Ga-BMS-986192 were performed using PD-L1–positive and PD-L1–negative U-698-M–bearing NSG mice. Results: 68Ga-BMS-986192 was obtained with quantitative radiochemical yields of more than 97% and with high radiochemical purity. In vitro stability in human serum was at least 95% after 4 h 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 immunohistochemistry staining. In vivo, 68Ga-BMS-986192 uptake was high at 1 h after injection in PD-L1–positive tumors (9.0 6 2.1 percentage injected dose [%ID]/g) and kidneys (56.9 6 9.2 %ID/g), with negligible uptake in other tissues. PD-L1–negative tumors demonstrated only background uptake of radioactivity (0.6 6 0.1 %ID/g). Coinjection of an excess of unlabeled 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 demonstrates 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.

Original languageEnglish
Pages (from-to)1228-1234
Number of pages7
JournalJournal of Nuclear Medicine
Volume62
Issue number9
DOIs
StatePublished - 2021
Externally publishedYes

Keywords

  • F-BMS-986192
  • Ga-BMS-986192
  • Ga-adnectin
  • PD-1/PD-L1 checkpoint inhibitors
  • PD-L1 PET imaging

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