PET imaging of an optimized anti-PD-L1 probe 68Ga-NODAGA-BMS986192 in immunocompetent mice and non-human primates

Huimin Zhou; Guangfa Bao; Ziqiang Wang; Buchuan Zhang; Dan Li; Lixing Chen; Xiaoyun Deng; Bo Yu; Jun Zhao; Xiaohua Zhu

doi:10.1186/s13550-022-00906-x

PET imaging of an optimized anti-PD-L1 probe ⁶⁸Ga-NODAGA-BMS986192 in immunocompetent mice and non-human primates

EJNMMI Res. 2022 Jun 13;12(1):35. doi: 10.1186/s13550-022-00906-x.

Authors

Huimin Zhou¹, Guangfa Bao¹, Ziqiang Wang¹, Buchuan Zhang¹, Dan Li¹, Lixing Chen¹, Xiaoyun Deng¹, Bo Yu¹, Jun Zhao^{1

2

3}, Xiaohua Zhu⁴

Affiliations

¹ Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China.
² Department of Anatomy, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.
³ Cell Architecture Research Center, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China.
⁴ Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China. evazhu@vip.sina.com.

Abstract

Background: Adnectin is a protein family derived from the 10th type III domain of human fibronectin (¹⁰Fn3) with high-affinity targeting capabilities. Positron emission tomography (PET) probes derived from anti-programmed death ligand-1 (PD-L1) Adnectins, including ¹⁸F- and ⁶⁸Ga-labeled BMS-986192, are recently developed for the prediction of patient response to immune checkpoint blockade. The ⁶⁸Ga-labeled BMS-986192, in particular, is an attractive probe for under-developed regions due to the broader availability of ⁶⁸Ga. However, the pharmacokinetics and biocompatibility of ⁶⁸Ga-labeled BMS-986192 are still unknown, especially in non-human primates, impeding its further clinical translation.

Methods: We developed a variant of ⁶⁸Ga-labeled BMS-986192 using 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA) as the radionuclide-chelator. The resultant probe, ⁶⁸Ga-NODAGA-BMS986192, was evaluated in terms of targeting specificity using a bilateral mouse tumor model inoculated with wild-type B16F10 and B16F10 transduced with human PD-L1 (hPD-L1-B16F10). The dynamic biodistribution and radiation dosimetry of this probe were also investigated in non-human primate cynomolgus.

Results: ⁶⁸Ga-NODAGA-BMS986192 was prepared with a radiochemical purity above 99%. PET imaging with ⁶⁸Ga-NODAGA-BMS986192 efficiently delineated the hPD-L1-B16F10 tumor at 1 h post-injection. The PD-L1-targeting capability of this probe was further confirmed using in vivo blocking assay and ex vivo biodistribution studies. PET dynamic imaging in both mouse and cynomolgus models revealed a rapid clearance of the probe via the renal route, which corresponded to the low background signals of the PET images. The probe also exhibited a favorable radiation dosimetry profile with a total-body effective dose of 6.34E-03 mSv/MBq in male cynomolgus.

Conclusions: ⁶⁸Ga-NODAGA-BMS986192 was a feasible and safe tool for the visualization of human PD-L1. Our study also provided valuable information on the potential of targeted PET imaging using Adnectin-based probes.

Keywords: 68Ga; Adnectin; BMS-986192; Cynomolgus; PD-L1; PET imaging.

Abstract

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