Abstract
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Objectives: The use of 89Zr-immuno-PET imaging to measure antibody biodistribution and tissue pharmacokinetics has become well established, but current PET systems lack the sensitivity needed to study 89Zr antibodies beyond 2-3 isotope half-lives (7-10 days), after which poor signal-to-noise becomes problematic. However, studies of several weeks duration would be highly desirable to better match the antibodies' potential circulatory half-life in primates, including humans. Here we investigate the technical feasibility of using the mini-EXPLORER PET scanner, making use of its 15% peak sensitivity and 45 cm axial field-of-view, to enable total-body imaging of 89Zr-labeled antibodies in rhesus monkeys up to 30 days post-injection. Methods: Humanized monoclonal IgG antibodies against the herpes simplex viral protein gD were labeled with 89Zr via one of three chelator-linker combinations. The pharmacokinetics associated with each chelator were compared using a cohort of nine healthy male rhesus monkeys (~ 2-3 years of age, ~ 3 +/- 1 kg). Each animal was injected intravenously (IV) with ~ 37 MBq of one of the 89Zr-labeled antibodies along with a separate IV injection of unlabeled antibody at a 10 mg/kg dose (to provide therapeutic-level antibody concentrations), and imaged six times over a period of 30 days on the mini-EXPLORER PET scanner. Scan durations ranged from 60 minutes on day 0, 45 minutes on day 30, to 30 minutes for intermediate days, all acquired with a single bed position. Images were reconstructed using a time-of-flight listmode OSEM algorithm that includes all corrections except scatter correction. CT images were also acquired immediately following the PET scan for each animal on all scan days and co-registered to the PET images. Activity concentrations in the liver and whole-body were extracted from the PET images using manually defined regions-of-interest.
Results: Excellent image quality was obtained, capturing the initial distribution phase in a whole-body scan. Later time points showed residual 89Zr in the liver reflecting normal hepatic clearance. Even at 30 days post-injection, representing ~9 half-lives of 89Zr and with a total residual activity in the animals of only 20 - 40 kBq, the image quality was sufficient to readily identify the (presumably non-specific) signal in the liver, kidneys, and joints. Significant differences in late time-point liver uptake and whole-body clearance were observed between the three chelators, while little variation (+/- 10%) was observed within each chelator group.
Conclusions: We demonstrated the ability to image 89Zr-labeled antibodies up to 30 days post-injection while maintaining satisfactory image quality provided by the mini-EXPLORER's high sensitivity and long axial field-of-view. Quantification demonstrated potentially important differences in the behavior of the three chelators. Future studies will include comparisons with assay-based pharmacokinetics and quantifying the signal in bone to characterize the suitability of each chelator for long duration immuno-PET studies. Acknowledgements: We thank the staff of the UC Davis Center for Molecular and Genomic Imaging and the California National Primate Research Center Multimodal Imaging Core (NIH grant #OD011107).