PET imaging of an optimized anti-PD-L1 probe 68Ga-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 F-18- and Ga-68-labeled BMS-986192, are recently developed for the prediction of patient response to immune checkpoint blockade. The Ga-68-labeled BMS-986192, in particular, is an attractive probe for under-developed regions due to the broader availability of Ga-68. However, the pharmacokinetics and biocompatibility of Ga-68-labeled BMS-986192 are still unknown, especially in non-human primates, impeding its further clinical translation. Methods We developed a variant of Ga-68-labeled BMS-986192 using 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA) as the radionuclide-chelator. The resultant probe, Ga-68-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 Ga-68-NODAGA-BMS986192 was prepared with a radiochemical purity above 99%. PET imaging with Ga-68-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 Ga-68-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.

Automated summary

This study developed a variant of Ga-68-labeled BMS-986192, Ga-68-NODAGA-BMS986192, which demonstrated good targeting specificity and achieved favorable imaging results in a tumor model. The probe exhibited rapid clearance through the renal route and showed low background signals. The study also provided valuable information on the probe's biocompatibility and radiation dosimetry in non-human primates.