High in-vivo stability in preclinical and first-in-human experiments with [18F]AlF-RESCA-MIRC213: a 18F-labeled nanobody as PET radiotracer for diagnosis of HER2-positive cancers
High in-vivo stability in preclinical and first-in-human experiments with [18F]AlF-RESCA-MIRC213: a 18F-labeled nanobody as PET radiotracer for diagnosis of HER2-positive cancers
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[18F]AlF-RESCA-MIRC213 在临床前和首次人体实验中具有高体内稳定性：18F 标记的纳米抗体作为 PET 放射性示踪剂，用于诊断 HER2 阳性癌症
DOI：
10.1007/s00259-022-05967-7
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发表时间：
2022-09-21
影响因子：
9.1
通讯作者：
Yang, Zhi
中科院分区：
文献类型：
--
作者：
Qin, Xue;Guo, Xiaoyi;Yang, Zhi
[F-18]AlF-RESCA是一种特别适用于热敏性生物分子F-18标记的核心材料。但目前尚未见相关的转化研究报道。在此，我们报道了f -18标记的抗her2纳米体MIRC213作为her2阳性癌症成像的PET放射性示踪剂的首次人体评估。方法利用大肠杆菌制备MIRC213，与(+/-)- h (3)RESCA-Mal偶联。[F-18]室温制备AlF-RESCA-MIRC213。采用放射性高效液相色谱法测定其放射化学纯度和稳定性。在NCI-N87 （HER2 +）和MCF-7 （HER2-）细胞中进行了细胞摄取，并在SK-OV-3 （HER2 +）细胞中验证了细胞结合亲和力。对SK-OV-3、NCI-N87和MCF-7荷瘤小鼠分别于注射后30 min、1 h和2 h进行小动物PET/CT检查。阻断实验中，过量的MIRC213与放射性示踪剂共同注射。注射后2 h对SKOV-3和MCF-7荷瘤小鼠进行生物分布。在临床研究中，对6例乳腺癌患者（3例her2阳性和3例her2阴性）注射[F-18]AlF-RESCA-MIRC213 （1.85-3.7 MBq/kg）后2 h和4 h的PET/CT图像进行采集。所有患者均在一周内行[F-18]-FDG PET/CT进行组织选择。计算分布和剂量学。在肿瘤和正常器官中测量标准化摄取值（SUV）。结果制备的MIRC213纯度为bb0 95%，用RESCA修饰得到RESCA-MIRC213。[F-18]AlF-RESCA-MIRC213在室温下20 min内制备完成，放射化学产率为50.48 +/- 7.6%，放射化学纯度为bbb98 % (n >0)， 6 h后在PBS（88%）和5% HSA（92%）中均保持稳定。[F-18]AlF-RESCA-MIRC213在NCI-N87细胞中2 h的细胞摄取为11.22 +/- 0.60 AD%/10(5)个细胞。测定其结合亲和力K-d值为1.23 +/- 0.58 nM。含有[F-18]AlF-RESCA-MIRC213的小动物PET/CT能明显区分SK-OV-3和NCI-N87肿瘤与MCF-7肿瘤，注射后2小时，阻断组在SK-OV-3肿瘤中摄取4.73 +/- 1.18 ID%/g，显著降低至1.70 +/- 0.13 ID%/g （p < 0.05）。在荷瘤动物中未见明显的骨放射性。6例乳腺癌患者在研究期间均未出现不良反应。[F-18]AlF-RESCA-MIRC213的摄取主要发生在泪腺、腮腺、颌下腺、甲状腺、胆囊、肾脏、肝脏和肠道。在癌症患者中没有明显的骨放射性积累。[F-18]注射后2小时，AlF-RESCA-MIRC213在her2阳性患者病变中的肿瘤摄取明显高于her2阴性患者病变（SUVmax为3.62 +/- 1.56 vs. 1.41 +/- 0.41, p = 0.0012）。肾脏接受的最高辐射剂量为2.42 × 10(-1) mGy/MBq，有效剂量为1.56 × 10(-2) mSv/MBq。结论在温和的条件下，制备出[F-18]AlF-RESCA-MIRC213具有较高的放射性标记收率。[F-18]AlF-RESCA-MIRC213在体外和体内均具有较高的稳定性。临床转化结果表明，[F-18]AlF-RESCA-MIRC213 PET/CT具有良好的药代动力学和剂量学特征，是一种有前景的新型PET示踪剂，可用于her2阳性癌症的无创诊断。
Purpose [F-18]AlF-RESCA was introduced as a core particularly useful for F-18-labeling of heat-sensitive biomolecules. However, no translational studies have been reported up to now. Herein, we reported the first-in-human evaluation of an F-18-labeled anti-HER2 nanobody MIRC213 as a PET radiotracer for imaging HER2-positive cancers. Methods MIRC213 was produced by E. coli and conjugated with ( +/-)-H(3)RESCA-Mal. [F-18]AlF-RESCA-MIRC213 was prepared at room temperature. Its radiochemical purity and stability of were determined by radio-HPLC with the size-exclusion chromatographic column. Cell uptake was performed in NCI-N87 (HER2 +) and MCF-7 (HER2-) cells and the cell-binding affinity was verified in SK-OV-3 (HER2 +) cells. Small-animal PET/CT was performed using SK-OV-3, NCI-N87, and MCF-7 tumor-bearing mice at 30 min, 1 h, and 2 h post-injection. For blocking experiment, excess MIRC213 was co-injected with radiotracer. Biodistribution were performed on SKOV-3 and MCF-7 tumor-bearing mice at 2 h post-injection. For clinical study, PET/CT images were acquired at 2 h and 4 h after injection of [F-18]AlF-RESCA-MIRC213 (1.85-3.7 MBq/kg) in six breast cancer patients (3 HER2-positive and 3 HER2-negative). All patients underwent [F-18]-FDG PET/CT within a week for tissue selection purpose. Distribution and dosimetry were calculated. Standardized uptake values (SUV) were measured in tumors and normal organs. Results MIRC213 was produced with > 95% purity and modified with RESCA to obtain RESCA-MIRC213. [F-18]AlF-RESCA-MIRC213 was prepared within 20 min at room temperature with the radiochemical yield of 50.48 +/- 7.6% and radiochemical purity of > 98% (n > 10), and remained stable in both PBS (88%) and 5% HSA (92%) after 6 h. The 2 h cellular uptake of [F-18]AlF-RESCA-MIRC213 in NCI-N87 cells was 11.22 +/- 0.60 AD%/10(5) cells. Its binding affinity K-d value was determined to be 1.23 +/- 0.58 nM. Small-animal PET/CT with [F-18]AlF-RESCA-MIRC213 can clearly differentiate SK-OV-3 and NCI-N87 tumors from MCF-7 tumors and background with a high uptake of 4.73 +/- 1.18 ID%/g and substantially reduced to 1.70 +/- 0.13 ID%/g for the blocking group (p < 0.05) in SK-OV-3 tumors at 2 h post-injection. No significant bone radioactivity was seen in the tumor-bearing animals. In all six breast cancer patients, there was no adverse reaction during study. The uptake of [F-18]AlF-RESCA-MIRC213 was mainly in lacrimal gland, parotid gland, submandibular gland, thyroid gland, gallbladder, kidneys, liver, and intestines. There was no significant bone radioactivity accumulation in cancer patients. [F-18]AlF-RESCA-MIRC213 had significantly higher tumor uptake in lesions from HER2-positive patients than that lesions from HER2-negative patients (SUVmax of 3.62 +/- 1.56 vs. 1.41 +/- 0.41, p = 0.0012) at 2 h post-injection. The kidneys received the highest radiation dose of 2.42 x 10(-1) mGy/MBq, and the effective dose was 1.56 x 10(-2) mSv/MBq. Conclusions [F-18]AlF-RESCA-MIRC213 could be prepared with high radiolabeling yield under mild conditions. [F-18]AlF-RESCA-MIRC213 has relatively high stability both in vitro and in vivo.The results from clinical transformation suggest that [F-18]AlF-RESCA-MIRC213 PET/CT is a safe procedure with favorable pharmacokinetics and dosimetry profile, and it is a promising new PET radiotracer for noninvasive diagnosis of HER2-positive cancers.