Radioimmunotherapy with Anti-CD66 Antibody: Improving the Biodistribution Using a Physiologically Based Pharmacokinetic Model

To improve radioimmunotherapy with anti-CD66 antibody, a physiologically based pharmacokinetic (PBPK) model was developed that was capable of describing the biodistribution and extrapolating between different doses of anti-CD66 antibody. Methods: The biodistribution of the 111In-labeled anti-CD66 antibody of 8 patients with acute leukemia was measured. The data were fitted to 2 PBPK models. Model A incorporated effective values for antibody binding, and model B explicitly described mono- and bivalent binding. The best model was selected using the corrected Akaike information criterion. The predictive power of the model was validated comparing simulations and 90Y-anti-CD66 serum measurements. The amount of antibody (range, 0.1–4 mg) leading to the most favorable therapeutic distribution was determined using simulations. Results: Model B was better supported by the data. The fits of the selected model were good (adjusted R2 > 0.91), and the estimated parameters were in a physiologically reasonable range. The median deviation of the predicted and measured 90Y-anti-CD66 serum concentration values and the residence times were 24% (range, 17%−31%) and 9% (range, 1%−64%), respectively. The validated model predicted considerably different biodistributions for dosimetry and therapeutic settings. The smallest (0.1 mg) simulated amount of antibody resulted in the most favorable therapeutic biodistribution. Conclusion: The developed model is capable of adequately describing the anti-CD66 antibody biodistribution and accurately predicting the time–activity serum curve of 90Y-anti-CD66 antibody and the therapeutic serum residence time. Simulations indicate that an improvement of radioimmunotherapy with anti-CD66 antibody is achievable by reducing the amount of administered antibody; for example, the residence time of the red marrow could be increased by a factor of 1.9 ± 0.3 using 0.27 mg of anti-CD66 antibody.

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