Investigating the Fate of Zirconium-89 Labelled Antibody in Cynomolgus Macaques

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 Zr (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 Zr, 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, Zr-labelled Fab, as well as that of [Zr]Zr-DFO and [Zr]Zr-oxalate, the expected metabolites of Zr- labelled IgG, was also assessed.

Results: After Zr-labelled IgG injection, the SUV in the heart, vertebral body, and muscle decreased, in line with the Zr 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 Zr- labelled IgG radioactivity accumulated in the renal cortex. Relatively high accumulation in the kidneys was also observed in Zr- labelled Fab-injected macaques, and renal autoradiographs of these animals showed that the renal cortex was the preferred accumulation site. However, [Zr]Zr-DFO was rapidly excreted into the urine, whereas [Zr]Zr-oxalate was highly accumulated in the epiphysis of the long bones and vertebral body.

Conclusion: In the non-human primate cynomolgus macaque, Zr- labelled IgG accumulated in the kidneys and the liver. However, [Zr]Zr-DFO and Zr 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 Zr- labelled IgG.