Total-Body PET and Highly Stable Chelators Together Enable Meaningful ⁸⁹Zr-Antibody PET Studies up to 30 Days After Injection

Abstract

See an invited perspective on this article on page 451. The use of 89 Zr-antibody PET imaging to measure antibody biodistribution and tissue pharmacokinetics is well established, but current PET systems lack the sensitivity needed to study 89 Zr-labeled antibodies beyond 2-3 isotope half-lives (7-10 d), after which a poor signal-to-noise ratio is problematic. However, studies across many weeks are desirable to better match antibody circulation half-life in human and nonhuman primates. These studies investigated the technical feasibility of using the primate mini-EXPLORER PET scanner, making use of its high sensitivity and 45-cm axial field of view, for total-body imaging of 89 Zr-labeled antibodies in rhesus monkeys up to 30 d after injection. Methods: A humanized monoclonal IgG antibody against the herpes simplex viral protein glycoprotein D (gD) was radiolabeled with 89 Zr via 1 of 4 chelator-linker combinations (benzyl isothiocyanate-DFO [DFO-Bz-NCS], where DFO is desferrioxamine B; DFO-squaramide; DFO*-Bz-NCS, where DFO* is desferrioxamine*; and DFO*-squaramide). The pharmacokinetics associated with these 4 chelator-linker combinations were compared in 12 healthy young male rhesus monkeys (∼1-2 y old, ∼3 ± 1 kg). Each animal was initially injected intravenously with unlabeled antibody in a peripheral vessel in the right arm (10 mg/kg, providing therapeutic-level antibody concentrations), immediately followed by approximately 40 MBq of one of the 89 Zr-labeled antibodies injected intravenously in a peripheral vessel in the left arm. All animals were imaged 6 times over a period of 30 d, with an initial 60-min dynamic scan on day 0 (day of injection) followed by static scans of 30-45 min on approximately days 3, 7, 14, 21, and 30, with all acquired using a single bed position and images reconstructed using time-offlight list-mode ordered-subsets expectation maximization. Activity concentrations in various organs were extracted from the PET images using manually defined regions of interest. Results: Excellent image quality was obtained, capturing the initial distribution phase in the whole-body scan; later time points showed residual 89 Zr mainly in the liver. Even at 30 d after injection, representing approximately 9 half-lives of 89 Zr and with a total residual activity of only 20-40 kBq in the animal, the image quality was sufficient to readily identify activity in the liver, kidneys, and upper and lower limb joints. Significant differences were noted in late time point liver uptake, bone uptake, and whole-body clearance between chelator-linker types, whereas little variation (±10%) was observed within each type. Conclusion: These studies demonstrate the ability to image 89 Zr-radiolabeled antibodies up to 30 d after injection while maintaining satisfactory image quality, as provided by the primate mini-EXPLORER with high sensitivity and long axial field of view. Quantification demonstrated potentially important differences in the behavior of the 4 chelators. This finding supports further investigation.

Improved non-invasive positron emission tomographic imaging of chemotherapy-induced tumor cell death using Zirconium-89-labeled APOMAB®

“…The results of this study indicated that DFOSq had better stability in vivo and an improved tumor to background imaging quality than DFO-NCS (Rudd et al 2016). In addition, recent data indicate that DFOSq has an improved shelf life compared to DFO-NCS (Berg et al 2020). Hence, since we intended to employ DFOSq as the bifunctional chelator for conjugating chDAB4 in a future clinical study, we wished to test its attributes for this task in comparison to the industry standard, DFO-NCS.…”

The Added Value of Diagnostic and Theranostic PET Imaging for the Treatment of CNS Tumors

“…PET also has higher sensitivity, which is particularly beneficial for patients, as it requires lower radiation doses. A next leap forward herein is the recent introduction of advanced whole-body PET scanners as their larger field of view further increases the sensitivity, resulting in better image quality and more accurate assessment of tracer biodistribution at a low count rate [9,10].…”

“…In recent years, several molecular imaging techniques, notably nuclear techniques such as Positron Emission Tomography (PET), have been developed that conjoin both diagnostic and theranostic applications to directly link molecular biology with molecular diagnosis and molecular targeted therapy [7,8]. In our review, we appreciate these developments at multiple levels, with special consideration for the added value in the challenging field of neuro-oncology, where PET imaging not only can serve as a sensitive diagnostic tool enabling non-invasive studies of tumor characteristics at multiple sites over time, but can also serve as an in vivo theranostic tool guiding drug development and drug delivery studies by display of target expression and target binding behind the assumedly intact blood-brain barrier (BBB) [9,10].…”

Recent progress in the molecular imaging of therapeutic monoclonal antibodies

“…Satisfactory image quality was obtained even at 30 days post injection, representing approximately 9-fold half-lives of 89 Zr to identify the activity of anti-gD IgG in different organs like liver, kidneys, and bone joints ( Fig. 6 ) [ 72 ].

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