Ocular Biodistribution of 89Zr-Bevacizumab in New Zealand Rabbits Determined Using PET/MRI: A Feasibility Study

Abstract

Background: Despite studies on positron emission tomography/magnetic resonance imaging (PET/MRI) in oncological imaging with high soft-tissue contrast resolution, PET/MRI has not been studied in ophthalmology. 89 Zr-bevacizumab, designed as a probe for PET, targets vascular endothelial growth factor, which is highly expressed in ocular angiogenesis. Intravitreal injections of bevacizumab agents have curative effects on ocular disease. Objectives: To study the ocular biodistribution of 89 Zr-bevacizumab in New Zealand rabbits using PET/MRI. Materials and Methods: 89 Zr-bevacizumab, synthesized from conjugated bevacizumab and 89 Zr-oxalate, and the purity of radiolabeled antibodies were determined using radio high-performance liquid chromatography (radio-HPLC). Instant thin-layer chromatography (ITLC) was utilized to differentiate the labeled product from aggregates and unlabeled 89 Zr. 89 Zr-bevacizumab was injected 2 mm from the left limbus into the vitreous humor of six normal New Zealand white rabbits. Micro-PET was utilized for dynamic imaging from 5 minutes to 60 minutes postinjection and for static imaging at 4 hours, 24 hours, 48 hours, 120 hours, and 144 hours (10-minutes scans) postinjection. PET/MRI scans were fused using PMOD software. Results: 89 Zr-bevacizumab with a radiochemical purity of 93.21% was monitored via PET imaging. Radioactivity levels in the eyes plateaued approximately 5 minutes after administration of 89 Zr-bevacizumab, and the measured vitreous values decreased from 340.52 ± 41.6% injected dose (ID)/g to 21.53 ± 3.39%ID/g by 144 hours. The half-life of the drug in the eye was calculated for 84.25 hours. Conclusion:89 Zr-bevacizumab could be monitored in animals by PET imaging, and the radiolabel exhibited high sensitivity in the vitreous body. Radioactivity levels in the eyes plateaued approximately 5 minutes after administration. This study clearly demonstrates the biodistribution of 89 Zr-bevacizumab.

Ocular Half-Life of Intravitreal Biologics in Humans and Other Species: Meta-Analysis and Model-Based Prediction

“…about one t 1/2 for a typical IgG) and the t 1/2 estimate being inconsistent with the terminal elimination phase. Our reanalysis of the experimental observations (Liu et al, Figure 5B) suggests a t 1/2 value of 5.1 d that is well in line with the body of literature evidence. e PET/CT imaging study with 124 l-labeled ranibizumab and bevacizumab. f In a previous study conducted by Giansanti et al, the VH t 1/2 of infliximab was estimated to be 8.5 d. This value was disregarded because the study was described as a pilot experiment in a limited number of animals. g t -test of the means: p < 0.001. Ratio of the means ± SEM: 1.8 ± 0.1. …”

“…about one t 1/2 for a typical IgG) and the t 1/2 estimate being inconsistent with the terminal elimination phase. Our reanalysis of the experimental observations (Liu et al, 39 Figure 5B) suggests a t 1/2 value of 5.1 d that is well in line with the body of literature evidence. e PET/CT imaging study with 124 l-labeled ranibizumab and bevacizumab.…”

“… a Roche: unpublished study (data on file). b CA: compartmental analysis; NCA: noncompartmental analysis; n/a: not available. c n : number of values compiled. d In a recent PET/MRI imaging study, Liu et al reported an ocular t 1/2 value of 3.5 d for 89 Zr-bevacizumab in New Zealand rabbits. This value was disregarded because the study suffers from methodological weaknesses, such as the short observation period (6 d, i.e.…”

“…In a recent PET/MRI imaging study, Liu et al reported an ocular t 1/2 value of 3.5 d for 89 Zr-bevacizumab in New Zealand rabbits. This value was disregarded because the study suffers from methodological weaknesses, such as the short observation period (6 d, i.e.…”

“…We illustrate this approach for the anti-VEGF molecules aflibercept and brolucizumab, as well as larger experimental molecules (PEGylated Fabs). 39 reported an ocular t 1/2 value of 3.5 d for 89 Zr-bevacizumab in New Zealand rabbits. This value was disregarded because the study suffers from methodological weaknesses, such as the short observation period (6 d, i.e.…”