Targeting of radiolabeled J591 antibody to PSMA-expressing tumors: Optimization of imaging and therapy based on non-linear compartmental modeling Journal Article

Authors: Fung, E. K.; Cheal, S. M.; Fareedy, S. B.; Punzalan, B.; Beylergil, V.; Amir, J.; Chalasani, S.; Weber, W. A.; Spratt, D. E.; Veach, D. R.; Bander, N. H.; Larson, S. M.; Zanzonico, P. B.; Osborne, J. R.
Article 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 (124I-J591 and 89Zr-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 89Zr-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 124I-J591 and 89Zr-J591 yielded similar model-derived values of the total antigen concentration and internalization rate. The association equilibrium constant (ka) was twofold higher for 124I, but there was a ~tenfold greater tumoral efflux rate of 124I from tumor compared to that of 89Zr. Plots of surface-bound and internalized radiotracers indicate similar behavior up to 24 h p.i. for both 124I-J591 and 89Zr-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 × 1012 (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 124I-J591 and 89Zr-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. © 2016, Fung et al.
Keywords: controlled study; human cell; nonhuman; positron emission tomography; mouse; animal experiment; animal model; prostate cancer; monoclonal antibody j591; prostate specific membrane antigen; isotope labeling; xenograft; radioactivity; iodine 124; zirconium-89; zirconium 89; compartment model; j591; immunopet; nonlinear system; psma; iodine-124; human; priority journal; article; lncap cell line; non-linear kinetic model
Journal Title: EJNMMI Research
Volume: 6
Issue: 1
ISSN: 2191-219X
Publisher: Springer  
Date Published: 2016-01-22
Start Page: 7
Language: English
DOI: 10.1186/s13550-016-0164-0
PROVIDER: scopus
PMCID: PMC4723373
PUBMED: 26801327
Notes: Article -- Export Date: 3 March 2016 -- Source: Scopus
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MSK Authors
  1. Joseph R Osborne
    57 Osborne
  2. Darren Veach
    60 Veach
  3. Pat B Zanzonico
    246 Zanzonico
  4. Steven M Larson
    779 Larson
  5. Sarah Marie Cheal
    25 Cheal
  6. Daniel Eidelberg Spratt
    83 Spratt
  7. Wolfgang Andreas Weber
    149 Weber
  8. Edward Komin Fung
    7 Fung
  9. Jawaria   Amir
    1 Amir