Xue Qin1,2, Xiaoyi Guo2, Tianyu Liu3, Liqiang Li2,3, Nina Zhou2, Xiaopan Ma1,2, Xiangxi Meng2, Jiayue Liu2, Hua Zhu4,5, Bing Jia6, Zhi Yang7,8. 1. Guizhou University School of Medicine, Guizhou University, Guiyang, 550025, China. 2. Key Laboratory of Carcinogenesis and Translational Research, (Ministry of Education/Beijing), Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China. 3. Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing, 100191, China. 4. Guizhou University School of Medicine, Guizhou University, Guiyang, 550025, China. zhuhuananjing@163.com. 5. Key Laboratory of Carcinogenesis and Translational Research, (Ministry of Education/Beijing), Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China. zhuhuananjing@163.com. 6. Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing, 100191, China. jiabing@bjmu.edu.cn. 7. Guizhou University School of Medicine, Guizhou University, Guiyang, 550025, China. pekyz@163.com. 8. Key Laboratory of Carcinogenesis and Translational Research, (Ministry of Education/Beijing), Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing, 100142, China. pekyz@163.com.
Abstract
PURPOSE: [18F]AlF-RESCA was introduced as a core particularly useful for 18F-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 18F-labeled anti-HER2 nanobody MIRC213 as a PET radiotracer for imaging HER2-positive cancers. METHODS: MIRC213 was produced by E. coli and conjugated with ( ±)-H3RESCA-Mal. [18F]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 [18F]AlF-RESCA-MIRC213 (1.85-3.7 MBq/kg) in six breast cancer patients (3 HER2-positive and 3 HER2-negative). All patients underwent [18F]-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. [18F]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 [18F]AlF-RESCA-MIRC213 in NCI-N87 cells was 11.22 ± 0.60 AD%/105 cells. Its binding affinity Kd value was determined to be 1.23 ± 0.58 nM. Small-animal PET/CT with [18F]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 [18F]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. [18F]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 × 10-1 mGy/MBq, and the effective dose was 1.56 × 10-2 mSv/MBq. CONCLUSIONS: [18F]AlF-RESCA-MIRC213 could be prepared with high radiolabeling yield under mild conditions. [18F]AlF-RESCA-MIRC213 has relatively high stability both in vitro and in vivo. The results from clinical transformation suggest that [18F]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.
PURPOSE: [18F]AlF-RESCA was introduced as a core particularly useful for 18F-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 18F-labeled anti-HER2 nanobody MIRC213 as a PET radiotracer for imaging HER2-positive cancers. METHODS: MIRC213 was produced by E. coli and conjugated with ( ±)-H3RESCA-Mal. [18F]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 [18F]AlF-RESCA-MIRC213 (1.85-3.7 MBq/kg) in six breast cancer patients (3 HER2-positive and 3 HER2-negative). All patients underwent [18F]-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. [18F]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 [18F]AlF-RESCA-MIRC213 in NCI-N87 cells was 11.22 ± 0.60 AD%/105 cells. Its binding affinity Kd value was determined to be 1.23 ± 0.58 nM. Small-animal PET/CT with [18F]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 [18F]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. [18F]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 × 10-1 mGy/MBq, and the effective dose was 1.56 × 10-2 mSv/MBq. CONCLUSIONS: [18F]AlF-RESCA-MIRC213 could be prepared with high radiolabeling yield under mild conditions. [18F]AlF-RESCA-MIRC213 has relatively high stability both in vitro and in vivo. The results from clinical transformation suggest that [18F]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.
Authors: F Cardoso; A Costa; L Norton; E Senkus; M Aapro; F André; C H Barrios; J Bergh; L Biganzoli; K L Blackwell; M J Cardoso; T Cufer; N El Saghir; L Fallowfield; D Fenech; P Francis; K Gelmon; S H Giordano; J Gligorov; A Goldhirsch; N Harbeck; N Houssami; C Hudis; B Kaufman; I Krop; S Kyriakides; U N Lin; M Mayer; S D Merjaver; E B Nordström; O Pagani; A Partridge; F Penault-Llorca; M J Piccart; H Rugo; G Sledge; C Thomssen; L Van't Veer; D Vorobiof; C Vrieling; N West; B Xu; E Winer Journal: Breast Date: 2014-09-20 Impact factor: 4.380