A physiologically based pharmacokinetic (PBPK) model to characterize and predict the disposition of monoclonal antibody CC49 and its single chain Fv constructs.
UNLABELLED Recently, we developed a physiologically based pharmacokinetic model capable of predicting antibody biodistribution in humans by scaling up from mice. By applying this model to anticarcinoembryonic antigen murine antibody ZCE025, we address several critical issues in radioimmunodetection and radioimmunotherapy, including the optimal antibody doses, the desirable antibody form for cancer detection, the optimal combinations of antibody forms and radionuclides for cancer treatment and the effectiveness of the modality. METHODS Under the baseline conditions of a standard 70-kg man with a 20-g tumor embedded in the liver, the model was used to: (a) estimate absorbed doses in tumor and normal tissues, (b) determine dose-dependent antibody uptake in the tumor, (c) simulate tumor-to-background antibody concentration ratio and (d) calculate therapeutic ratios for different antibody forms and radionuclides. Sensitivity analysis further enabled us to determine antibody delivery barriers and to assess the modality under average and favorable tumor physiological conditions. RESULTS By using ZCE025 under the baseline conditions, the model found that Fab was the most suitable form for cancer diagnosis, while 131l combined with F(ab')2 provided the highest tumor-to-bone marrow therapeutic ratio for cancer treatment. Sensitivity analysis showed that antibody permeability was the major barrier for antibody accretion in tumors. It also demonstrated that normal tissue antigen expression at a level lower than in the tumor had little effect on the therapeutic ratio. CONCLUSION The model demonstrates that: (a) for radioimmunodetection, the most effective antibody form (Fab for ZCE025) was the lower mol weight form, yet not sensitive enough for hepatic metastasis detection; and (b) for radioimmunotherapy, a relatively fast-clearing antibody form (F(ab')2 for ZCE025) in combination with long half-life beta(-)-emitters was optimal, yet inadequate as the sole therapeutic modality for solid tumors.