Improved Modeling of In Vivo Kinetics of Slowly Diffusing Radiotracers for Tumor Imaging

Abstract

Large-molecule tracers, such as labeled antibodies, have shown success in immuno-PET for imaging of specific cell surface biomarkers. However, previous work has shown that localization of such tracers shows high levels of heterogeneity in target tissues, due to both the slow diffusion and the high affinity of these compounds. In this work, we investigate the effects of subvoxel spatial heterogeneity on measured time–activity curves in PET imaging and the effects of ignoring diffusion limitation on parameter estimates from kinetic modeling. Methods Partial differential equations (PDE) were built to model a radially symmetric reaction-diffusion equation describing the activity of immuno-PET tracers. The effects of slower diffusion on measured time–activity curves and parameter estimates were measured in silico, and a modified Levenberg–Marquardt algorithm with Bayesian priors was developed to accurately estimate parameters from diffusion-limited data. This algorithm was applied to immuno-PET data of mice implanted with prostate stem cell antigen–overexpressing tumors and injected with 124I-labeled A11 anti–prostate stem cell antigen minibody. Results Slow diffusion of tracers in linear binding models resulted in heterogeneous localization in silico but no measurable differences in time–activity curves. For more realistic saturable binding models, measured time–activity curves were strongly dependent on diffusion rates of the tracers. Fitting diffusion-limited data with regular compartmental models led to parameter estimate bias in an excess of 1,000% of true values, while the new model and fitting protocol could accurately measure kinetics in silico. In vivo imaging data were also fit well by the new PDE model, with estimates of the dissociation constant (Kd) and receptor density close to in vitro measurements and with order of magnitude differences from a regular compartmental model ignoring tracer diffusion limitation. Conclusion Heterogeneous localization of large, high-affinity compounds can lead to large differences in measured time–activity curves in immuno-PET imaging, and ignoring diffusion limitations can lead to large errors in kinetic parameter estimates. Modeling of these systems with PDE models with Bayesian priors is necessary for quantitative in vivo measurements of kinetics of slow-diffusion tracers.

Cerenkov Luminescence Imaging as a Modality to Evaluate Antibody-Based PET Radiotracers

“…To accomplish this comparison of methods, we used 64 Cu-NODAGA-PSMA-IgG and 64 Cu-NODAGA-PSMA-Mb as radiotracers for imaging in our preclinical model system. Previous studies have shown that the optimal signalto-background ratios are attainable within a window of 12-48 h with formats of imaging probes similar to those in this study (ViolaVillegas et al (37); Wilks et al (38)). The radiotracers were administered intravenously to cohorts of 5 mice harboring bilateral PSMA-positive CWR22Rv1 and PSMAnegative PC-3 xenografts and serially imaged up to 48 and 72 h for the 64 Cu-NODAGA-PSMA-Mb and 64 Cu-NODAGA-PSMAIgG, respectively.…”

Practical Immuno-PET Radiotracer Design Considerations for Human Immune Checkpoint Imaging

“…Although radiolabeled antibodies are a powerful tool in the drug development process, antibody-based immuno-PET radiotracers have several clinical drawbacks including long clearance times and high background signal, which require patients to return to the hospital several days after radiotracer injection for imaging (29,30). Furthermore, we have recently shown that anti-PD-L1 antibodies have limited tumor penetration (31) and that the Fc region of anti-PD-L1 monoclonal antibodies can mediate unintended T cell depletion (27).…”

Dual-Isotope Cryoimaging Quantitative Autoradiography: Investigating Antibody–Drug Conjugate Distribution and Payload Delivery Through Imaging

“…3C). Both tumor types demonstrated significant heterogeneity in the distribution of the antibody signal ( 111 In), as expected for compounds of high molecular weight (19,20).…”