放射性免疫治疗用抗 CD66 抗体：使用基于生理学的药代动力学模型改善生物分布。
Radioimmunotherapy with anti-CD66 antibody: improving the biodistribution using a physiologically based pharmacokinetic model.
机构信息
Klinik für Nuklearmedizin, Universität Ulm, Ulm, Germany.
出版信息
J Nucl Med. 2010 Mar;51(3):484-91. doi: 10.2967/jnumed.109.067546. Epub 2010 Feb 11.
UNLABELLED
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 (111)In-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 (90)Y-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 R(2) > 0.91), and the estimated parameters were in a physiologically reasonable range. The median deviation of the predicted and measured (90)Y-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 (90)Y-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.
目的
为了改进抗 CD66 抗体的放射免疫疗法，开发了一种基于生理学的药代动力学（PBPK）模型，该模型能够描述生物分布，并在不同剂量的抗 CD66 抗体之间进行推断。
方法
测量了 8 例急性白血病患者的（111）In 标记抗 CD66 抗体的生物分布。将数据拟合到 2 个 PBPK 模型中。模型 A 纳入了抗体结合的有效值，模型 B 则明确描述了单价和二价结合。使用校正的 Akaike 信息准则选择最佳模型。通过比较模拟和（90）Y-抗 CD66 血清测量结果来验证模型的预测能力。使用模拟确定导致最佳治疗分布的抗体量（范围 0.1-4 mg）。
结果
数据更支持模型 B。所选模型的拟合效果良好（调整后的 R²＞0.91），估计参数在生理合理范围内。预测的和测量的（90）Y-抗 CD66 血清浓度值和停留时间的中位数偏差分别为 24%（范围 17%-31%）和 9%（范围 1%-64%）。验证后的模型预测了不同的剂量学和治疗设置的生物分布。模拟的最小（0.1 mg）抗体量导致最有利的治疗生物分布。
结论
所开发的模型能够充分描述抗 CD66 抗体的生物分布，并准确预测（90）Y-抗 CD66 抗体的时间-活性血清曲线和治疗血清停留时间。模拟表明，通过减少给予的抗体量可以改善抗 CD66 抗体的放射免疫疗法；例如，使用 0.27 mg 的抗 CD66 抗体，红骨髓的停留时间可以增加 1.9±0.3 倍。
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