title: Preclinical Pharmacokinetics and Biodistribution Studies of 89Zr-Labeled Pembrolizumab.
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 emitter89Zr. PET imaging was used to evaluate the whole-body distribution of89Zr-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 of89Zr-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 of89Zr-Df-pembrolizumab. In the humanized mouse model, T-cell infiltration into the salivary and lacrimal glands could be successfully visualized.
  
  
  CONCLUSIONS
  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 expression and localization in a humanized mouse model.
authors: Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin.
authors: Christopher G
authors: CG
authors: England
authors: Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin.
authors: Emily B
authors: EB
authors: Ehlerding
authors: Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin.
authors: Reinier
authors: R
authors: Hernandez
authors: Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin.
authors: Brian T
authors: BT
authors: Rekoske
authors: Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin.
authors: Stephen A
authors: SA
authors: Graves
authors: Department of Radiology, University of Wisconsin-Madison, Madison, Wisconsin; and.
authors: Haiyan
authors: H
authors: Sun
authors: Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin.|University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
authors: Glenn
authors: G
authors: Liu
authors: Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin.|University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
authors: Douglas G
authors: DG
authors: McNeel
authors: Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin.
authors: Todd E
authors: TE
authors: Barnhart
authors: Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin wcai@uwhealth.org.|Department of Radiology, University of Wisconsin-Madison, Madison, Wisconsin; and.|University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
authors: Weibo
authors: W
authors: Cai
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics; D058948:Cell Tracking / Q000379:methods*; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008813:Mice, Inbred ICR; D009928:Organ Specificity; D049268:Positron-Emission Tomography / Q000379:methods*; D011868:Radioisotopes / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D014018:Tissue Distribution; D014915:Whole-Body Counting; D015040:Zirconium / Q000493:pharmacokinetics*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D015040:Zirconium; C582435:pembrolizumab
keywords: 89Zr; dosimetry; pembrolizumab; positron emission tomography (PET); programmed cell death protein 1 (PD-1)