Department of Nuclear Medicine, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
Nanomab Technology Limited, Shanghai, People's Republic of China.
J Nucl Med. 2019 Sep;60(9):1213-1220. doi: 10.2967/jnumed.118.224170. Epub 2019 Feb 22.
Immunotherapy with checkpoint inhibitor programmed cell death 1 (PD-1)/programmed death ligand-1 (PD-L1) antibodies demonstrates improvements in treatment of advanced non-small cell lung cancer. Treatment stratification depends on immunohistochemical PD-L1 measurement of biopsy material, an invasive method that does not account for spatiotemporal heterogeneity. Using a single-domain antibody, NM-01, against PD-L1, radiolabeled site-specifically with Tc for SPECT imaging, we aimed to assess the safety, radiation dosimetry, and imaging characteristics of this radiopharmaceutical and correlate tumor uptake with PD-L1 immunohistochemistry results. Sixteen patients (mean age, 61.7 y; 11 men) with non-small cell lung cancer were recruited. Primary tumor PD-L1 expression was measured by immunohistochemistry. NM-01 was radiolabeled with [Tc(OH)(CO)] complex binding to its C-terminal hexahistidine tag. Administered activity was 3.8-10.4 MBq/kg, corresponding to 100 μg or 400 μg of NM-01. Whole-body planar and thoracic SPECT/CT scans were obtained at 1 and 2 h after injection in all patients, and 5 patients underwent additional imaging at 10 min, 3 h, and 24 h for radiation dosimetry calculations. All patients were monitored for adverse events. No drug-related adverse events occurred in this study. The mean effective dose was 8.84 × 10 ± 9.33 × 10 mSv/MBq (3.59 ± 0.74 mSv per patient). Tracer uptake was observed in the kidneys, spleen, liver, and bone marrow. SPECT primary tumor-to-blood-pool ratios (T:BP) varied from 1.24 to 2.3 (mean, 1.79) at 1 h and 1.24 to 3.53 (mean, 2.22) at 2 h ( = 0.005). Two-hour primary T:BP ratios correlated with PD-L1 immunohistochemistry results ( = 0.68, = 0.014). Two-hour T:BP was lower in tumors with ≤1% PD-L1 expression (1.89 vs. 2.49, = 0.048). Nodal and bone metastases showed tracer uptake. Heterogeneity (>20%) between primary tumor and nodal T:BP was present in 4 of 13 patients. This first-in-human study demonstrates that Tc-labeled anti-PD-L1-single-domain antibody SPECT/CT imaging is safe and associated with acceptable dosimetry. Tumor uptake is readily visible against background tissues, particularly at 2 h when the T:BP ratio correlates with PD-L1 immunohistochemistry results.
免疫疗法联合检查点抑制剂程序性细胞死亡蛋白 1（PD-1）/程序性死亡配体-1（PD-L1）抗体在治疗晚期非小细胞肺癌方面显示出改善作用。治疗分层取决于对活检材料进行免疫组织化学 PD-L1 检测，这是一种侵入性方法，无法考虑时空异质性。我们使用针对 PD-L1 的单域抗体 NM-01，该抗体与 Tc 特异性结合进行 SPECT 成像，旨在评估这种放射性药物的安全性、辐射剂量学和成像特征，并将肿瘤摄取与 PD-L1 免疫组织化学结果相关联。 招募了 16 名（平均年龄 61.7 岁；11 名男性）患有非小细胞肺癌的患者。通过免疫组织化学测量原发性肿瘤 PD-L1 的表达。NM-01 用 [Tc(OH)(CO)] 复合物标记，该复合物与 C 末端六组氨酸标签结合。给药活度为 3.8-10.4 MBq/kg，相当于 NM-01 的 100 μg 或 400 μg。所有患者在注射后 1 小时和 2 小时进行全身平面和胸部 SPECT/CT 扫描，5 名患者在 10 分钟、3 小时和 24 小时进行额外的成像，以计算辐射剂量学。所有患者均监测不良事件。 在这项研究中未发生与药物相关的不良事件。平均有效剂量为 8.84×10±9.33×10 mSv/MBq（每位患者 3.59±0.74 mSv）。在肾脏、脾脏、肝脏和骨髓中观察到示踪剂摄取。1 小时时 SPECT 原发性肿瘤与血池比（T:BP）从 1.24 到 2.3（平均值，1.79）变化，2 小时时从 1.24 到 3.53（平均值，2.22）变化（ = 0.005）。2 小时时原发性 T:BP 比值与 PD-L1 免疫组织化学结果相关（ = 0.68， = 0.014）。在 PD-L1 表达≤1%的肿瘤中，2 小时时 T:BP 比值较低（1.89 比 2.49， = 0.048）。淋巴结和骨转移显示示踪剂摄取。13 名患者中有 4 名在原发性肿瘤和淋巴结 T:BP 之间存在异质性（>20%）。 这项首次人体研究表明，Tc 标记的抗 PD-L1 单域抗体 SPECT/CT 成像安全且具有可接受的剂量学。肿瘤摄取在背景组织中很容易看到，尤其是在 2 小时时，T:BP 比值与 PD-L1 免疫组织化学结果相关。
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