title: Cerenkov Luminescence Imaging as a Modality to Evaluate Antibody-Based PET Radiotracers.
abstract: Antibodies, and engineered antibody fragments, labeled with radioisotopes are being developed as radiotracers for the detection and phenotyping of diseases such as cancer. The development of antibody-based radiotracers requires extensive characterization of their in vitro and in vivo properties, including their ability to target tumors in an antigen-selective manner. In this study, we investigated the use of Cerenkov luminescence imaging (CLI) as compared with PET as a modality for evaluating the in vivo behavior of antibody-based radiotracers.
  
  
  METHODS
  The anti-prostate-specific membrane antigen (PSMA) huJ591 antibody (IgG; 150 kDa) and its minibody (Mb; 80 kDa) format were functionalized with the chelator 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA) and radiolabeled with the positron-emitting radionuclide64Cu (half-life, 12.7 h). Immunoreactive preparations of the radiolabeled antibodies were injected into NCr nu/nu mice harboring PSMA-positive CWR22Rv1 and PSMA-negative PC-3 tumor xenografts. Tumor targeting was evaluated by both PET and CLI.
  
  
  RESULTS
  64Cu-NODAGA-PSMA-IgG and64Cu-NODAGA-PSMA-Mb retained the ability to bind cell surface PSMA, and both radiotracers exhibited selective uptake into PSMA-positive tumors. Under the experimental conditions used, PSMA-selective uptake of64Cu-NODAGA-PSMA-IgG and64Cu-NODAGA-PSMA-Mb was observed by CLI as early as 3 h after injection, with tumor-to-background ratios peaking at 24 (IgG) and 16 (Mb) h after injection. Targeting data generated by CLI correlated with that generated by PET and necropsy.
  
  
  CONCLUSIONS
  CLI provided a rapid and simple assessment of the targeting specificity and pharmacokinetics of the antibody-based PET radiotracers that correlated well with the behavior observed by standard PET imaging. Moreover, CLI provided clear discrimination between uptake kinetics of an intact IgG and its small-molecular-weight derivative Mb. These data support the use of CLI for the evaluation of radiotracer performance.
authors.affiliation: Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Jimson W
authors.initials: JW
authors.lastname: D'Souza
authors.affiliation: Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Harvey
authors.initials: H
authors.lastname: Hensley
authors.affiliation: Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.|Nuclear Medicine, Department of Diagnostic Imaging, Fox Chase Cancer Center, Philadelphia, Pennsylvania; and.
authors.forename: Mohan
authors.initials: M
authors.lastname: Doss
authors.affiliation: ImaginAb Inc., Inglewood, California.
authors.forename: Charles
authors.initials: C
authors.lastname: Beigarten
authors.affiliation: ImaginAb Inc., Inglewood, California.
authors.forename: Michael
authors.initials: M
authors.lastname: Torgov
authors.affiliation: ImaginAb Inc., Inglewood, California.
authors.forename: Tove
authors.initials: T
authors.lastname: Olafsen
authors.affiliation: Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.|Nuclear Medicine, Department of Diagnostic Imaging, Fox Chase Cancer Center, Philadelphia, Pennsylvania; and.
authors.forename: Jian Q
authors.initials: JQ
authors.lastname: Yu
authors.affiliation: Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania matthew.robinson@fccc.edu.
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Robinson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D008163:Luminescent Measurements / Q000379:methods*; D008297:Male; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D049268:Positron-Emission Tomography / Q000379:methods*; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
chemical_list: D000911:Antibodies, Monoclonal; D019275:Radiopharmaceuticals
keywords: Cerenkov luminescence imaging (CLI); ImmunoPET; antibody