The fate of an antibody labelled with zirconium-89 in cynomolgus macaques

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-labelled anti-KLH human IgG and its metabolites to confirm their non-specific/physiological accumulation in healthy cynomolgus macaques. Methods Selected IgG was conjugated to desferrioxamine (DFO), labelled with ⁸⁹Zr, and injected into healthy cynomolgus macaques (9–16 MBq of ⁸⁹Zr-IgG/head). 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-Fab, as well as that of [⁸⁹Zr]Zr-DFO and [⁸⁹Zr]Zr-oxalate, the expected metabolites of ⁸⁹Zr-IgG, was also assessed. Results After ⁸⁹Zr-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-IgG radioactivity accumulated in the renal cortex. Relatively high accumulation in the kidneys was also observed in ⁸⁹Zr-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-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-IgG.