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

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 (I-124-J591 and Zr-89-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 Zr-89-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 mu M.hours) of administered tracer in tumor as a function of the administered dose of antibody. Results: The comparison of I-124-J591 and Zr-89-J591 yielded similar model-derived values of the total antigen concentration and internalization rate. The association equilibrium constant (k(a)) was twofold higher for I-124, but there was a similar to tenfold greater tumoral efflux rate of I-124 from tumor compared to that of Zr-89. Plots of surface-bound and internalized radiotracers indicate similar behavior up to 24 h p.i. for both I-124-J591 and Zr-89-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 x 10(12) (for doses from 60 to 240 mu g) 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 (12)4I-J591 and Zr-89-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.