Department of Nuclear Therapy and Diagnostic, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia.
Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, Tomsk, Russia.
Theranostics. 2023 Sep 4;13(14):4858-4871. doi: 10.7150/thno.86770. eCollection 2023.
The determination of tumor human epidermal growth factor receptor type 2 (HER2) status is of increasing importance with the recent approval of more efficacious HER2-targeted treatments. There is a lack of suitable methods for clinical HER2 expression assessment. Affibody molecules are small affinity proteins ideal for imaging detection of receptors, which are engineered using a small (molecular weight 6.5 kDa) nonimmunoglobulin scaffold. Labeling of Affibody molecules with positron emitters enabled the development of sensitive and specific agents for molecular imaging. The development of probes for SPECT would permit the use of Affibody-based imaging in regions where PET is not available. In this first-in-human study, we evaluated the safety, biodistribution, and dosimetry of the Tc-ZHER2:41071 Affibody molecule developed for SPECT/CT imaging of HER2 expression. : Thirty-one patients with primary breast cancer were enrolled and divided into three cohorts (injected with 500, 1000, or 1500 µg ZHER2:41071) comprising at least five patients with high (positive) HER2 tumor expression (IHC score 3+ or 2+ and ISH positive) and five patients with low (IHC score 2+ or 1+ and ISH negative) or absent HER2 tumor expression. Patients were injected with 451 ± 71 MBq Tc-ZHER2:4107. Planar scintigraphy was performed after 2, 4, 6 and 24 h, and SPECT/CT imaging followed planar imaging 2, 4 and 6 h after injection. : Injections of Tc-ZHER2:41071 were well tolerated and not associated with adverse events. Normal organs with the highest accumulation were the kidney and liver. The effective dose was 0.019 ± 0.004 mSv/MBq. Injection of 1000 µg provided the best standard discrimination between HER2-positive and HER2-low or HER2-negative tumors 2 h after injection (SUV 16.9 ± 7.6 3.6 ± 1.4, p < 0.005). The Tc-ZHER2:41071 uptake in HER2-positive lymph node metastases (SUV 6.9 ± 2.4, n = 5) was significantly (p < 0.05) higher than that in HER2-low/negative lymph nodes (SUV 3.5 ± 1.2, n = 4). Tc-ZHER2:41071 visualized hepatic metastases in a patient with liver involvement. : Injections of Tc-ZHER2:41071 appear safe and exhibit favorable dosimetry. The protein dose of 1000 µg provides the best discrimination between HER2-positive and HER2-low/negative expression of HER2 according to the definition used for current HER2-targeting drugs.
人表皮生长因子受体 2 型（HER2）肿瘤的测定随着最近批准的更有效的 HER2 靶向治疗的应用变得越来越重要。目前缺乏用于临床 HER2 表达评估的合适方法。亲和体分子是用于受体成像检测的理想的小亲和力蛋白，它们是使用小（分子量 6.5 kDa）非免疫球蛋白支架来设计的。用正电子发射体对亲和体分子进行标记，从而开发出了用于分子成像的敏感和特异性试剂。SPECT 探针的开发将允许在无法使用 PET 的区域使用基于亲和体的成像。在这项首次人体研究中，我们评估了 Tc-ZHER2:41071 亲和体分子用于 HER2 表达 SPECT/CT 成像的安全性、生物分布和剂量学。31 名患有原发性乳腺癌的患者被纳入并分为三组（注射 500、1000 或 1500 µg ZHER2:41071），每组至少有 5 名高（阳性）HER2 肿瘤表达（免疫组化评分 3+或 2+且 ISH 阳性）和 5 名低（免疫组化评分 2+或 1+且 ISH 阴性）或无 HER2 肿瘤表达的患者。患者注射 451±71MBq Tc-ZHER2:4107。在注射后 2、4、6 和 24 小时进行平面闪烁显像，在注射后 2、4 和 6 小时进行 SPECT/CT 成像。Tc-ZHER2:41071 的注射耐受良好，与不良事件无关。具有最高累积量的正常器官是肾脏和肝脏。有效剂量为 0.019±0.004mSv/MBq。注射 1000µg 在注射后 2 小时提供了最佳的 HER2 阳性与 HER2 低或 HER2 阴性肿瘤之间的标准区分（SUV 16.9±7.6与 3.6±1.4，p<0.005）。HER2 阳性淋巴结转移（SUV 6.9±2.4，n=5）中的 Tc-ZHER2:41071 摄取明显（p<0.05）高于 HER2 低/阴性淋巴结（SUV 3.5±1.2，n=4）。Tc-ZHER2:41071 在一名有肝受累的患者中可视化了肝转移。Tc-ZHER2:41071 的注射似乎是安全的，并且具有良好的剂量学特性。根据当前用于 HER2 靶向药物的定义，1000µg 的蛋白剂量提供了最佳的 HER2 阳性与 HER2 低/阴性表达之间的区分。
