Dosimetry Prediction for Clinical Translation of 64 Cu-Pembrolizumab ImmunoPET Targeting Human PD-1 Expression

Sci Rep. 2018 Jan 12;8(1):633. doi: 10.1038/s41598-017-19123-x.

Abstract

The immune checkpoint programmed death 1 receptor (PD-1) expressed on some tumor-infiltrating lymphocytes, and its ligand (PD-L1) expressed on tumor cells, enable cancers to evade the immune system. Blocking PD-1 with the monoclonal antibody pembrolizumab is a promising immunotherapy strategy. Thus, noninvasively quantifying the presence of PD-1 expression in the tumor microenvironment prior to initiation of immune checkpoint blockade may identify the patients likely to respond to therapy. We have developed a 64Cu-pembrolizumab radiotracer and evaluated human dosimetry. The tracer was utilized to image hPD-1 levels in two subcutaneous mouse models: (a) 293 T/hPD-1 cells xenografted into NOD-scid IL-2Rγnull mice (NSG/293 T/hPD-1) and (b) human peripheral blood mononuclear cells engrafted into NSG bearing A375 human melanoma tumors (hNSG/A375). In each mouse model two cohorts were evaluated (hPD-1 blockade with pembrolizumab [blk] and non-blocked [nblk]), for a total of four groups (n = 3-5/group). The xenograft-to-muscle ratio in the NSG/293 T/hPD-1 model at 24 h was significantly increased in the nblk group (7.0 ± 0.5) compared to the blk group (3.4 ± 0.9), p = 0.01. The radiotracer dosimetry evaluation (PET/CT ROI-based and ex vivo) in the hNSG/A375 model revealed the highest radiation burden to the liver. In summary, we validated the 64Cu-pembrolizumab tracer's specific hPD-1 receptor targeting and predicted human dosimetry.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / administration & dosage*
  • Antibodies, Monoclonal, Humanized / chemistry
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Cell Line, Tumor
  • Copper Radioisotopes / chemistry*
  • Humans
  • Melanoma / diagnostic imaging*
  • Melanoma / metabolism
  • Mice
  • Neoplasm Transplantation
  • Positron Emission Tomography Computed Tomography
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Radioactive Tracers
  • Radiometry
  • Translational Medical Research
  • Tumor Microenvironment

Substances

  • Antibodies, Monoclonal, Humanized
  • Copper Radioisotopes
  • Copper-64
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Radioactive Tracers
  • pembrolizumab