Investigating the fate of Zirconium-89 labelled antibody in cynomolgus macaques

IF 3.6 4区医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING

Nuclear medicine and biology Pub Date : 2025-02-14 DOI:10.1016/j.nucmedbio.2025.109001

Takanori Sasaki , Sadaaki Kimura , Akihiro Noda , Yoshihiro Murakami , Sosuke Miyoshi , Masaru Akehi , Kazuhiko Ochiai , Masami Watanabe , Takahiro Higuchi , Eiji Matsuura

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Abstract

Background

Preclinical pharmacokinetic studies of therapeutic antibodies in non-human primates are desired because of the difficulty in extrapolating ADME data from animal models to humans. We evaluated the pharmacokinetics of ⁸⁹Zr (Zirconium-89) -labelled anti-KLH human IgG and its metabolites to confirm their non-specific/physiological accumulation in healthy cynomolgus macaques. The anti-KLH antibody was used as a negative control, ensuring that the observed distribution reflected general IgG behavior rather than antigen-specific accumulation. This provides a valuable reference for comparing the biodistribution of targeted antibodies.

Methods

Selected IgG was conjugated to desferrioxamine (DFO), labelled with ⁸⁹Zr, and injected into healthy cynomolgus macaques. PET/CT images at the whole-body level were acquired at different time points, and standard uptake values (SUV) in regions of interest, such as the heart, liver, spleen, kidneys, bone, and muscles, were calculated. The distribution of a shortened antibody variant, ⁸⁹Zr-labelled Fab, as well as that of [⁸⁹Zr]Zr-DFO and [⁸⁹Zr]Zr-oxalate, the expected metabolites of ⁸⁹Zr- labelled IgG, was also assessed.

Results

After ⁸⁹Zr-labelled IgG injection, the SUV in the heart, vertebral body, and muscle decreased, in line with the ⁸⁹Zr concentration decrease in the circulation, whereas radioactivity increased over time in the kidneys and liver. Autoradiography of the renal sections indicated that most of the ⁸⁹Zr- labelled IgG radioactivity accumulated in the renal cortex. Relatively high accumulation in the kidneys was also observed in ⁸⁹Zr- labelled Fab-injected macaques, and renal autoradiographs of these animals showed that the renal cortex was the preferred accumulation site. However, [⁸⁹Zr]Zr-DFO was rapidly excreted into the urine, whereas [⁸⁹Zr]Zr-oxalate was highly accumulated in the epiphysis of the long bones and vertebral body.

Conclusion

In the non-human primate cynomolgus macaque, ⁸⁹Zr- labelled IgG accumulated in the kidneys and the liver. However, [⁸⁹Zr]Zr-DFO and ⁸⁹Zr did not accumulate in these organs. This preclinical pharmacokinetic study performed with human IgG in a non-human primate model using PET is of great significance as it sheds light on the basic fate and distribution of ⁸⁹Zr- labelled IgG.

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来源期刊

Nuclear medicine and biology 医学-核医学

CiteScore

6.00

自引率

9.70%

发文量

479

审稿时长

51 days

期刊介绍： Nuclear Medicine and Biology publishes original research addressing all aspects of radiopharmaceutical science: synthesis, in vitro and ex vivo studies, in vivo biodistribution by dissection or imaging, radiopharmacology, radiopharmacy, and translational clinical studies of new targeted radiotracers. The importance of the target to an unmet clinical need should be the first consideration. If the synthesis of a new radiopharmaceutical is submitted without in vitro or in vivo data, then the uniqueness of the chemistry must be emphasized. These multidisciplinary studies should validate the mechanism of localization whether the probe is based on binding to a receptor, enzyme, tumor antigen, or another well-defined target. The studies should be aimed at evaluating how the chemical and radiopharmaceutical properties affect pharmacokinetics, pharmacodynamics, or therapeutic efficacy. Ideally, the study would address the sensitivity of the probe to changes in disease or treatment, although studies validating mechanism alone are acceptable. Radiopharmacy practice, addressing the issues of preparation, automation, quality control, dispensing, and regulations applicable to qualification and administration of radiopharmaceuticals to humans, is an important aspect of the developmental process, but only if the study has a significant impact on the field. Contributions on the subject of therapeutic radiopharmaceuticals also are appropriate provided that the specificity of labeled compound localization and therapeutic effect have been addressed.