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 [68Ga]Ga-DOTA-WL12 (a peptide-based tracer) and [68Ga]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 [68Ga]Ga-DOTA-WL12 and [68Ga]Ga-NOTA-RW102 PET/CT scans, with four of these patients also receiving [18F]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 [68Ga]Ga-DOTA-WL12 and [68Ga]Ga-NOTA-RW102 PET/CT. Results DOTA-WL12 and NOTA-RW102 exhibited favorable binding affinities with PD-L1, with equilibrium dissociation constant (KD) values of 0.2 nM and 0.0047 nM, respectively. Subsequent human studies revealed significant variations (P < 0.05) in the uptake of [68Ga]Ga-DOTA-WL12 and [68Ga]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 [68Ga]Ga-DOTA-WL12 compared to [68Ga]Ga-NOTA-RW102 (P < 0.0001, r = 0.9471 vs. P = 0.0241, r = 0.5235). Conclusion The uptake of peptide-based [68Ga]Ga-DOTA-WL12 was more strongly correlated with PD-L1 TPS in primary and metastatic tumor lesions compared to [68Ga]Ga-NOTA-RW102. They also displayed different distribution, suggesting that peptide-based and nanobody-based radiotracers may have different clinical implications, particularly in radiotherapy.

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

期刊论文
发表日期：

2025年5月8日

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Yanfei Wu,
Hao Wang,
Yue Gu,
You Zhang,
Guanglei Li,
Yuan Huang,
Min Cao,
Xiaofeng Chen,
Yihui Guan,
Dong Xu,
Weijun Wei,
Fang Xie

摘要

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 [⁶⁸Ga]Ga-DOTA-WL12 (a peptide-based tracer) and [⁶⁸Ga]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 [⁶⁸Ga]Ga-DOTA-WL12 and [⁶⁸Ga]Ga-NOTA-RW102 PET/CT scans, with four of these patients also receiving [¹⁸F]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 [⁶⁸Ga]Ga-DOTA-WL12 and [⁶⁸Ga]Ga-NOTA-RW102 PET/CT.

Results

DOTA-WL12 and NOTA-RW102 exhibited favorable binding affinities with PD-L1, with equilibrium dissociation constant (K_D) values of 0.2 nM and 0.0047 nM, respectively. Subsequent human studies revealed significant variations (P < 0.05) in the uptake of [⁶⁸Ga]Ga-DOTA-WL12 and [⁶⁸Ga]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 [⁶⁸Ga]Ga-DOTA-WL12 compared to [⁶⁸Ga]Ga-NOTA-RW102 (P < 0.0001, r = 0.9471 vs. P = 0.0241, r = 0.5235).

Conclusion

The uptake of peptide-based [⁶⁸Ga]Ga-DOTA-WL12 was more strongly correlated with PD-L1 TPS in primary and metastatic tumor lesions compared to [⁶⁸Ga]Ga-NOTA-RW102. They also displayed different distribution, suggesting that peptide-based and nanobody-based radiotracers may have different clinical implications, particularly in radiotherapy.