Targeting of radiolabeled J591 antibody to PSMA-expressing tumors: optimization of imaging and therapy based on non-linear compartmental modeling.
Targeting of radiolabeled J591 antibody to PSMA-expressing tumors: optimization of imaging and therapy based on non-linear compartmental modeling.
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DOI：
10.1186/s13550-016-0164-0
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发表时间：
2016-12
期刊：
影响因子：
3.2
通讯作者：
Osborne JR
中科院分区：
文献类型：
--
作者：
Fung EK;Cheal SM;Fareedy SB;Punzalan B;Beylergil V;Amir J;Chalasani S;Weber WA;Spratt DE;Veach DR;Bander NH;Larson SM;Zanzonico PB;Osborne JR
我们应用非线性免疫动力学模型定量比较两种放射性标记形式的人源化抗前列腺特异性膜抗原（PSMA）单克隆抗体J591（124 I-J591和89 Zr-J591）在皮下LNCaP人前列腺癌（PCa）异种移植物中的绝对抗体摄取和转换。使用该模型，我们研究了剂量对肿瘤和血浆正电子发射断层扫描（PET）衍生的时间-活性曲线的影响。我们还试图预测放射免疫治疗的最佳靶向指数（整合肿瘤与整合血浆活性浓度的比值）。使用具有非线性转移速率的房室模型，从注射后96小时的PET图像中推导出肿瘤中抗体内化和周转的平衡速率。此外，我们对注射了89 Zr-J591抗体剂量（从抗原亚饱和到饱和）的LNCaP荷瘤小鼠组进行了连续成像，以检查使用非线性方法的适用性，并推导出肿瘤中给药示踪剂的时间积分浓度（以μM/小时计）作为抗体给药剂量的函数。124 I-J591和89 Zr-J591的比较产生了相似的总抗原浓度和内化率的模型衍生值。124 I的结合平衡常数（ka）高出两倍，但与89 Zr相比，124 I从肿瘤中的肿瘤外排率高出约十倍。表面结合和内化的放射性示踪剂的图表明直至24 h p.i.对于124 I-J591和89 Zr-J591，在p.i. J591/PSMA复合物周转的估计值为3.9-90.5 × 1012（剂量为60 - 240 μg）分子/小时/克肿瘤（20%的受体内化/小时）。使用定量房室模型方法，表面结合和内化率显示124 I-J591和89 Zr-J591形式相似，如预期。肿瘤放射性清除率的巨大差异可能是由于残留锆与非残留碘的不同捕获。我们的非线性模型被发现是上级传统的线性模型。这一发现和计算出的肿瘤中的活性持续时间对患者的放射免疫治疗和其他基于抗体的治疗具有重要意义。
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. 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. 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). 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.