Preclinical pharmacokinetics and biodistribution studies of ⁸⁹Zr-labeled pembrolizumab for human dosimetry estimation

Objectives Pembrolizumab is a clinically-available humanized monoclonal antibody that targets programmed cell death protein (PD-1) on the surface of activated T and B cells. Currently, pembrolizumab is approved for the treatment of advanced melanoma and non-small cell lung cancer. In some instances, severe toxicities have been detected in patients treated with pembrolizumab, which have been linked to the accumulation of antibody in off-target tissues. In this study, we evaluate the pharmacokinetics, biodistribution, and dosimetry of pembrolizumab in vivo using positron emission tomography (PET) imaging.

Methods Pembrolizumab was conjugated with the chelator desferrioxamine (Df) before radiolabeling with the long-lived isotope ⁸⁹Zr (t_1/2 = 3.3 days). Long-term whole-body tracking of the radiolabeled antibody was accomplished in three rodent models, including Balb/c mice, Sprague Dawley rats, and PBL mice (NSG mice reconstituted with human peripheral blood mononuclear cells). Data obtained from PET scans and biodistribution studies were extrapolated to predict radiation dose estimates for humans.

Results ⁸⁹Zr-Df-Pembrolizumab stayed in circulation throughout the study and accumulated the greatest in liver (3.40±0.68 %ID/g for mice and 0.87±0.06 %ID/g for rats at 168 h p.i.) and spleen tissues (4.10±0.41 %ID/g mice and 0.71±0.05 %ID/g rats). Relatively high doses were estimated to these organs (0.958±0.077 mGy/MBq for the liver and 0.109±0.103 mGy/MBq for spleen using rat data) as well as to the urinary bladder wall (0.578±0.006 mGy/MBq), resulting from the initial clearance routes of this agent. Despite these high uptakes, the total body absorbed doses for humans were found to be within safe limits, at a total body effective dose of 0.540±0.008 mSv/MBq. The use of PBL mice allowed for a more clinically relevant comparison to be made.

Conclusions The low total body and major organ doses found in this study indicate the potential use of ⁸⁹Zr-Df-Pembrolizumab for the clinical selection of patients that may benefit from anti-PD-1 therapy and the development of more advanced dosing strategies in the future. The techniques in this study may be further applied to other antibodies for better understanding of the pharmacokinetics, biodistributions, and dosimetry for future clinical applications.

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