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

EJNMMI Research, Jan 2016

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 (k a) 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.

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

Fung et al. EJNMMI Research Targeting of radiolabeled J591 antibody to PSMA-expressing tumors: optimization of imaging and therapy based on non-linear compartmental modeling Edward K. Fung 1 3 4 Sarah M. Cheal 0 1 3 Shoaib B. Fareedy 0 1 Blesida Punzalan 1 3 Volkan Beylergil 0 1 2 Jawaria Amir 0 1 Sandhya Chalasani 0 1 Wolfgang A. Weber 0 1 2 Daniel E. Spratt 1 5 Darren R. Veach 0 1 Neil H. Bander 1 6 Steven M. Larson 0 1 2 3 Pat B. Zanzonico 1 2 4 Joseph R. Osborne 0 1 2 0 Department of Radiology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, NY 10065 , USA 1 Edward K. Fung and Sarah M. Cheal are co-first authors 2 Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, NY 10065 , USA 3 Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, NY 10065 , USA 4 Department of Medical Physics, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, NY 10065 , USA 5 Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, NY 10065 , USA 6 Department of Medicine, Weill Medical College of Cornell University , 1300 York Avenue, New York, NY 10065 , USA 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. J591; PSMA; ImmunoPET; Zirconium-89; Iodine-124; Non-linear kinetic model Background Prostate-specific membrane antigen (PSMA) is an integral cell membrane glycoprotein (~100 kDa) that is present on the surface of epithelial prostate cancer (PCa) cells [ 1 ]. While PSMA is expressed in normal human prostate cells and certain other normal tissues, it is highly upregulated in PCa, making it a promising diagnostic and therapeutic target [ 2 ]. A variety of monoclonal antibodies (mAbs) specific for intracellular and extracellular epitopes of PSMA have been prepared [ 3–6 ], with two variants in particular demonstrating high (low nM) affinity and specific and efficient targeting in vivo: the murine mAb 7E11, which binds an intracellular domain of PSMA, and the humanized mAb J591, which binds to an extracellular domain of PSMA. 7E11 has been investigated clinically as a SPECT imaging agent for recurrent and metastatic PCa [7] (111In-7E11, ProstaScint™) as well as therapeutically as the Y-90 conjugate [ 8 ]. Like 7E11, J591 has also been clinically investigated in a variety of radiolabeled forms for both positron emission tomography (PET) imaging (e.g., in the form of 89Zr-J591) [ 9 ] as well as therapy (e.g., as 17 (...truncated)


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Edward K. Fung, Sarah M. Cheal, Shoaib B. Fareedy, Blesida Punzalan, Volkan Beylergil, Jawaria Amir, Sandhya Chalasani, Wolfgang A. Weber, Daniel E. Spratt, Darren R. Veach, Neil H. Bander, Steven M. Larson, Pat B. Zanzonico, Joseph R. Osborne. Targeting of radiolabeled J591 antibody to PSMA-expressing tumors: optimization of imaging and therapy based on non-linear compartmental modeling, EJNMMI Research, 2016, pp. 7, Volume 6, Issue 1, DOI: 10.1186/s13550-016-0164-0