Phase I Study of 68Ga-HER2-Nanobody for PET/CT Assessment of HER2 Expression in Breast Carcinoma
Phase I Study of 68Ga-HER2-Nanobody for PET/CT Assessment of HER2 Expression in Breast Carcinoma
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DOI：
10.2967/jnumed.115.162024
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发表时间：
2016-01-01
影响因子：
9.3
通讯作者：
Lahoutte, Tony
中科院分区：
文献类型：
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作者：
Keyaerts, Marleen;Xavier, Catarina;Lahoutte, Tony
人表皮生长因子受体2（HER 2）状态是乳腺癌中指导治疗的主要肿瘤特征之一。抗HER 2治疗在HER 2阳性乳腺癌患者中具有明显的生存优势。原发肿瘤和转移瘤之间的HER 2表达的异质性已被反复描述，导致需要在疾病过程中重新评估HER 2状态。为了避免由于肿瘤异质性而具有潜在偏倚的重复活检，已经开发了针对HER 2的纳米抗体作为分子成像的探针。纳米抗体来源于独特的仅重链抗体，是最小的抗原结合抗体片段，具有PET成像的理想特性。主要目的是评估安全性、生物分布和剂量测定。次要目的是研究肿瘤靶向潜力。方法：共纳入20例原发性或转移性乳腺癌患者（HER 2免疫组化评估评分为2+或3+）。通过NOTA衍生物用Ga-68标记抗HER 2纳米抗体。给药活性为53-174 MBq（平均107 MBq）。在给药后10、60和90 min进行PET/CT扫描，用于剂量测定评估。进行体格评价和血液分析以进行安全性评价。使用MIM软件分析11个器官的生物分布;使用OUNDA/EXM评估剂量学。在原发性和转移性病变中评估肿瘤靶向潜力。结果：未发生不良反应。观察到快速的血液清除，注射后1小时血液中仅残留10%的注射活性。摄取主要见于肾脏、肝脏和肠道。有效剂量为0.043 mSv/MBq，平均每例患者4.6 mSv。关键器官为膀胱壁，剂量为0.406 mGy/MBq。在转移性疾病患者中，在大多数确定的疾病部位显示示踪剂蓄积远高于背景水平。原发性病变在示踪剂累积方面变化更大。结论：Ga-68-HER 2-纳米抗体PET/CT是一种安全的程序，其辐射剂量与其他常规使用的PET示踪剂相当。它的生物分布是有利的，在肾脏、肝脏和肠道中摄取最高，但在通常容纳原发性乳腺癌或肿瘤转移的所有其他器官中的背景水平非常低。与正常周围组织相比，HER 2阳性转移灶中的示踪剂积累较高，需要在II期试验中进一步评估。
Human epidermal growth factor receptor 2 (HER2) status is one of the major tumor characteristics in breast cancer to guide therapy. Anti-HER2 treatment has clear survival advantages in HER2-positive breast carcinoma patients. Heterogeneity in HER2 expression between primary tumor and metastasis has repeatedly been described, resulting in the need to reassess HER2 status during the disease course. To avoid repeated biopsy with potential bias due to tumor heterogeneity, Nanobodies directed against HER2 have been developed as probes for molecular imaging. Nanobodies, which are derived from unique heavy-chain-only antibodies, are the smallest antigen-binding antibody fragments and have ideal characteristics for PET imaging. The primary aims were assessment of safety, biodistribution, and dosimetry. The secondary aim was to investigate tumor-targeting potential. Methods: In total, 20 women with primary or metastatic breast carcinoma (score of 2+ or 3+ on HER2 immunohistochemical assessment) were included. Anti-HER2-Nanobody was labeled with Ga-68 via a NOTA derivative. Administered activities were 53-174 MBq (average, 107 MBq). PET/CT scans for dosimetry assessment were obtained at 10, 60, and 90 min after administration. Physical evaluation and blood analysis were performed for safety evaluation. Biodistribution was analyzed for 11 organs using MIM software; dosimetry was assessed using OUNDA/EXM. Tumor-targeting potential was assessed in primary and metastatic lesions. Results: No adverse reactions occurred. A fast blood clearance was observed, with only 10% of injected activity remaining in the blood at 1 h after injection. Uptake was seen mainly in the kidneys, liver, and intestines. The effective dose was 0.043 mSv/MBq, resulting in an average of 4.6 mSv per patient. The critical organ was the urinary bladder wall, with a dose of 0.406 mGy/MBq. In patients with metastatic disease, tracer accumulation well above the background level was demonstrated in most identified sites of disease. Primary lesions were more variable in tracer accumulation. Conclusion: Ga-68-HER2-Nanobody PET/CT is a safe procedure with a radiation dose comparable to other routinely used PET tracers. Its biodistribution is favorable, with the highest uptake in the kidneys, liver, and intestines but very low background levels in all other organs that typically house primary breast carcinoma or tumor metastasis. Tracer accumulation in HER2-positive metastases is high, compared with normal surrounding tissues, and warrants further assessment in a phase ll trial.