High in-vivo Stability and First-in-human Experience with [18F]AlF-RESCA-MIRC213: A 18F-Labeled Nanobody as PET Radiotracer for Diagnosis of HER2-Positive Cancers

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 In this study, [18F]AlF-RESCA-MIRC213 was prepared at room temperature. Small-animal PET/CT and bio-distribution were performed on HER2-positive subcutaneous xenografts. Six breast cancer patients (3 HER2-positive and 3 HER2-negative patients) were included, and PET/CT images were acquired at 2 h and 4 h after injection of 222 ± 18.5 MBq of [18F]AlF-RESCA-MIRC213. All patients underwent [18F]-FDG PET/CT within a week for comparison purpose. Bio-distribution and dosimetry were calculated. Standardized uptake values (SUV) were measured in tumors and normal organs.Results [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). The 2 h cellular uptake of [18F]AlF-RESCA-MIRC213 in NCI-N87 cells was 11.22 ± 0.60 %IA/105 cells. Its binding affinity Kd value was determined to be 1.23 ± 0.58 nM using SK-OV-3 cells. After 2 h injection, the xenografted SK-OV-3 tumors could be readily detected by [18F]AlF-RESCA-MIRC213 PET with SUVmax of 4.73 ± 1.18 ID%/g and 1.70 ± 0.13 ID%/g for the blocking group (p < 0.05). No significant radioactivity was seen in the bone in tumor-bearing animals. After approved by ethics committee (No.2021KT108). First-in-human PET translational study was conducted. In six all patients, there was no adverse reactions during study. The uptake of [18F]AlF-RESCA-MIRC213 was mainly in lacrimal gland, parotid gland, submandibular gland, thyroid gland, gallbladder, kidneys, liver, and intestine. There was no significant radioactivity accumulation in the bone of cancer patients. [18F]AlF-RESCA-MIRC213 had significantly higher tumor uptake in HER2-positive lesions than that in HER2-negative lesions (SUVmax of 3.62 ± 1.56 vs. 1.41 ± 0.41, p = 0.0012) at 2 h post-injection. Kidneys received the highest radiation dose of 2.17×10-2 mGy/MBq, and the effective dose was 1.76×10-2 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.