Journal article
Preclinical Pharmacokinetics and Biodistribution Studies of Zr-89-Labeled Pembrolizumab
The Journal of nuclear medicine (1978), Vol.58(1), pp.162-168
01/01/2017
DOI: 10.2967/jnumed.116.177857
PMCID: PMC5209640
PMID: 27493273
Abstract
Pembrolizumab is a humanized monoclonal antibody targeting programmed cell death protein 1 (PD-1) found on T and pro-B cells. Pembrolizumab prevents PD-1 ligation by both PD-L1 and PD-L2, preventing the immune dysregulation that otherwise occurs when T-cells encounter cells expressing these ligands. Clinically, PD-1 blockade elicits potent antitumor immune responses, and antibodies blocking PD-1 ligation, including pembrolizumab, have recently received Food and Drug Administration approval for the treatment of advanced melanoma, renal cell cancer, and non small cell lung cancer. Methods: In this study, we evaluated the pharmacokinetics, biodistribution, and dosimetry of pembrolizumab in vivo, accomplished through radiolabeling with the positron emitter Zr-89. PET imaging was used to evaluate the whole-body distribution of Zr-89-deferoxamine (Df)-pembrolizumab in two rodent models (mice and rats). Data obtained from PET scans and biodistribution studies were extrapolated to humans to estimate the dosimetry of the tracer. As a proof of concept, the biodistribution of Zr-89-Df-pembrolizumab was further investigated in a humanized murine model. Results: The tracer remained stable in blood circulation throughout the study and accumulated the greatest in liver and spleen tissues. Both mice and rats showed similar biodistribution and pharmacokinetics of Zr-89-Df-pembrolizumab. In the humanized mouse model, T-cell infiltration into the salivary and lacrimal glands could be successfully visualized. Conclusion: These data will augment our understanding of the pharmacokinetics and biodistribution of radiolabeled pembrolizumab in vivo, while providing detailed dosimetry data that may lead to better dosing strategies in the future. These findings further demonstrate the utility of noninvasive in vivo PET imaging to dynamically track T-cell checkpoint receptor exprespion and localization in a humanized mouse model.
Details
- Title: Subtitle
- Preclinical Pharmacokinetics and Biodistribution Studies of Zr-89-Labeled Pembrolizumab
- Creators
- Christopher G. England - University of Wisconsin–MadisonEmily B. Ehlerding - University of Wisconsin–MadisonReinier Hernandez - University of Wisconsin–MadisonBrian T. Rekoske - University of Wisconsin–MadisonStephen A. Graves - University of Wisconsin–MadisonHaiyan Sun - University of Wisconsin–MadisonGlenn Liu - University of Wisconsin Carbone Cancer CenterDouglas G. Mcneel - University of Wisconsin Carbone Cancer CenterTodd E. Barnhart - University of Wisconsin–MadisonWeibo Cai - University of Wisconsin Carbone Cancer Center
- Resource Type
- Journal article
- Publication Details
- The Journal of nuclear medicine (1978), Vol.58(1), pp.162-168
- Publisher
- Soc Nuclear Medicine Inc
- DOI
- 10.2967/jnumed.116.177857
- PMID
- 27493273
- PMCID
- PMC5209640
- ISSN
- 0161-5505
- eISSN
- 1535-5667
- Number of pages
- 7
- Grant note
- T32GM008349 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) DGE-1256259 / National Science Foundation; National Science Foundation (NSF) University of Wisconsin-Madison 125246-RSG-13-099-01-CCE / American Cancer Society 1R01CA169365; P30CA014520; T32CA009206; T32GM08349; T32GM07215; T32GM008505 / National Institutes of Health (NIBIB/NCI); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01CA169365 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 01/01/2017
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Radiology; Radiation Oncology
- Record Identifier
- 9984383905502771
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