Early phase I study of a 99m Tc labeled anti-PD-L1 sdAb in SPECT/CT assessment of programmed death ligand-1 expression in non-small cell lung cancer

Purpose: Immunotherapy with checkpoint inhibitor programmed cell death 1 (PD-1)/programmed death ligand (PD-L1) antibodies demonstrates improvements in treatment of advanced non-small cell lung cancer (NSCLC). Treatment stratification depends on immunohistochemical (IHC) PD-L1 measurement on biopsy material which is invasive and does not account for spatiotemporal heterogeneity. Non-invasive imaging methods for PD-L1 expression measurement are of potential value. Using a single domain antibody (sdAb), NM-01, against PD-L1, radiolabeled site-specifically with technetium-99m ( 99m Tc) for single photon emission computed tomography (SPECT) imaging, we aimed to assess the safety, radiation dosimetry and imaging characteristics of this radiopharmaceutical and correlate tumor uptake with IHC PD-L1 expression.

Methods: Sixteen patients with NSCLC were recruited. Primary tumor PD-L1 expression was measured by IHC. Anti-PD-L1 sdAb was radiolabeled with the 99m Tc. Administered activity was 3.8-10.4 MBq/kg, corresponding to 100 µg or 400 µg of anti-PD-L1 sdAb. Whole body planar and thoracic SPECT/CT scans were performed at 1 and 2h post-injection in all patients and 5 patients had additional imaging at 10mins, 3 and 24h for radiation dosimetry calculations. All patients were monitored for adverse events. Primary tumor SPECT parameters were correlated with IHC results.

Results: No drug-related adverse events occurred in this study. The mean effective dose was 8.84×10 ^-3 ± 9.33×10 ^-4 mSv/MBq (mean 3.59 ± 0.74 mSv per patient). Scans showed an expected biodistribution of PD-L1, including kidneys, spleen, liver and bone marrow. SPECT primary tumor-blood pool ratios(T:BP) varied from 1.24 to 2.3 (mean=1.79) at 1h and 1.24 to 3.53 (mean=2.22) at 2h (p=0.005). 2h primary T:BP ratios correlated with IHC PD-L1 expression (r=0.68, p=0.014). 2h T:BP was lower in tumors with ≤1% PD-L1 expression (1.89 vs 2.49, p=0.048). Nodal and bone metastases showed tracer uptake. Heterogeneity (>20%) between primary tumor and nodal T:BP was present in 4 of 12 patients.

Conclusions: This first in human study demonstrates that 99mTc-labeled anti-PD-L1-sdAb SPECT/CT imaging is safe and associated with acceptable dosimetry. Tumor uptake is readily visible against background tissues, particularly at 2h when the T:BP ratio correlates with IHC PD-L1 expression.