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

BACKGROUND: Adnectin is a protein family derived from the 10th type III domain of human fibronectin ((10)Fn3) with high-affinity targeting capabilities. Positron emission tomography (PET) probes derived from anti-programmed death ligand-1 (PD-L1) Adnectins, including (18)F- and (68)Ga-labeled BMS-986192, are recently developed for the prediction of patient response to immune checkpoint blockade. The (68)Ga-labeled BMS-986192, in particular, is an attractive probe for under-developed regions due to the broader availability of (68)Ga. However, the pharmacokinetics and biocompatibility of (68)Ga-labeled BMS-986192 are still unknown, especially in non-human primates, impeding its further clinical translation. METHODS: We developed a variant of (68)Ga-labeled BMS-986192 using 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA) as the radionuclide–chelator. The resultant probe, (68)Ga-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: (68)Ga-NODAGA-BMS986192 was prepared with a radiochemical purity above 99%. PET imaging with (68)Ga-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: (68)Ga-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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13550-022-00906-x.