title: Targeting of radiolabeled J591 antibody to PSMA-expressing tumors: optimization of imaging and therapy based on non-linear compartmental modeling.
abstract: BACKGROUND
  We applied a non-linear immunokinetic model to quantitatively compare absolute antibody uptake and turnover in subcutaneous LNCaP human prostate cancer (PCa) xenografts of two radiolabeled forms of the humanized anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 ((124)I-J591 and (89)Zr-J591). Using the model, we examined the impact of dose on the tumor and plasma positron emission tomography (PET)-derived time-activity curves. We also sought to predict the optimal targeting index (ratio of integrated-tumor-to-integrated-plasma activity concentrations) for radioimmunotherapy.
  
  
  METHODS
  The equilibrium rates of antibody internalization and turnover in the tumors were derived from PET images up to 96 h post-injection using compartmental modeling with a non-linear transfer rate. In addition, we serially imaged groups of LNCaP tumor-bearing mice injected with (89)Zr-J591 antibody doses ranging from antigen subsaturating to saturating to examine the suitability of using a non-linear approach and derived the time-integrated concentration (in μM∙hours) of administered tracer in tumor as a function of the administered dose of antibody.
  
  
  RESULTS
  The comparison of (124)I-J591 and (89)Zr-J591 yielded similar model-derived values of the total antigen concentration and internalization rate. The association equilibrium constant (k a) was twofold higher for (124)I, but there was a ~tenfold greater tumoral efflux rate of (124)I from tumor compared to that of (89)Zr. Plots of surface-bound and internalized radiotracers indicate similar behavior up to 24 h p.i. for both (124)I-J591 and (89)Zr-J591, with the effect of differential clearance rates becoming apparent after about 35 h p.i. Estimates of J591/PSMA complex turnover were 3.9-90.5 × 10(12) (for doses from 60 to 240 μg) molecules per hour per gram of tumor (20 % of receptors internalized per hour).
  
  
  CONCLUSIONS
  Using quantitative compartmental model methods, surface binding and internalization rates were shown to be similar for both (124)I-J591 and (89)Zr-J591 forms, as expected. The large difference in clearance rates of the radioactivity from the tumor is likely due to differential trapping of residualizing zirconium versus non-residualizing iodine. Our non-linear model was found to be superior to a conventional linear model. This finding and the calculated activity persistence time in tumor have important implications for radioimmunotherapy and other antibody-based therapies in patients.
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. funge@mskcc.org.|Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. funge@mskcc.org.
authors.forename: Edward K
authors.initials: EK
authors.lastname: Fung
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. cheals@mskcc.org.|Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. cheals@mskcc.org.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Cheal
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. fareedys@mskcc.org.
authors.forename: Shoaib B
authors.initials: SB
authors.lastname: Fareedy
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. punzalab@mskcc.org.
authors.forename: Blesida
authors.initials: B
authors.lastname: Punzalan
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. vbeylergil@metrohealth.org.|Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. vbeylergil@metrohealth.org.
authors.forename: Volkan
authors.initials: V
authors.lastname: Beylergil
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. jawaria.amir01@gmail.com.
authors.forename: Jawaria
authors.initials: J
authors.lastname: Amir
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. chalass1@mskcc.org.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Chalasani
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. weberw@mskcc.org.|Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. weberw@mskcc.org.
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Weber
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. sprattda@med.umich.edu.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Spratt
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. veachd@mskcc.org.
authors.forename: Darren R
authors.initials: DR
authors.lastname: Veach
authors.affiliation: Department of Medicine, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY, 10065, USA. nhbander@med.cornell.edu.
authors.forename: Neil H
authors.initials: NH
authors.lastname: Bander
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. larsons@mskcc.org.|Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. larsons@mskcc.org.|Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. larsons@mskcc.org.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Larson
authors.affiliation: Department of Medical Physics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. zanzonip@mskcc.org.|Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. zanzonip@mskcc.org.
authors.forename: Pat B
authors.initials: PB
authors.lastname: Zanzonico
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. osbornej@mskcc.org.|Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA. osbornej@mskcc.org.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Osborne
keywords: ImmunoPET; Iodine-124; J591; Non-linear kinetic model; PSMA; Zirconium-89