Head-to-head comparison of peptide-based and nanobody-based radiotracers in detecting PD-L1 expression in non-small cell lung cancer.

Background: Immunotherapy based on programmed cell death protein receptor 1 and its ligand (PD-1/PD-L1) has become an important method for treating non-small cell lung cancer (NSCLC). Peptide-based and nanobody-based PET tracers offer potential advantages in PD-L1 detection, yet their comparative tumor uptake and biodistribution remain unclear. This study aimed to evaluate and compare [Ga]Ga-DOTA-WL12 (a peptide-based tracer) and [Ga]Ga-NOTA-RW102 (a nanobody-based tracer) in assessing PD-L1 expression in primary and metastatic NSCLC, providing insights for future radiotracer design and theranostic applications.

Methods: Ten patients diagnosed with NSCLC underwent [Ga]Ga-DOTA-WL12 and [Ga]Ga-NOTA-RW102 PET/CT scans, with four of these patients also receiving [F]FDG PET/CT scans. The tracer uptakes, quantified by maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), and target-to-background ratio (TBR), were compared between [Ga]Ga-DOTA-WL12 and [Ga]Ga-NOTA-RW102 PET/CT.

Results: DOTA-WL12 and NOTA-RW102 exhibited favorable binding affinities with PD-L1, with equilibrium dissociation constant (K) values of 0.2 nM and 0.0047 nM, respectively. Subsequent human studies revealed significant variations (P < 0.05) in the uptake of [Ga]Ga-DOTA-WL12 and [Ga]Ga-NOTA-RW102 across the liver (SUVmean: 20.43 ± 4.26 vs. 6.12 ± 1.36, p = 0.015), kidney (SUVmean: 2.40 ± 0.34 vs. 22.37 ± 2.88, P = 0.015), spleen (SUVmean: 2.44 ± 0.67 vs. 18.49 ± 3.90, P = 0.015), and lung background (SUVmean: 0.18 ± 0.12 vs. 1.09 ± 0.29, P = 0.015). Meanwhile, we found that the correlation between SUVmax and PD-L1 TPS was significantly stronger with [Ga]Ga-DOTA-WL12 compared to [Ga]Ga-NOTA-RW102 (P < 0.0001, r = 0.9471 vs. P = 0.0241, r = 0.5235).

Conclusion: The uptake of peptide-based [Ga]Ga-DOTA-WL12 was more strongly correlated with PD-L1 TPS in primary and metastatic tumor lesions compared to [Ga]Ga-NOTA-RW102. They also displayed different distribution, suggesting that peptide-based and nanobody-based radiotracers may have different clinical implications, particularly in radiotherapy.