89Zr-Immuno-PET: Toward a Noninvasive Clinical Tool to Measure Target Engagement of Therapeutic Antibodies In Vivo
89Zr-Immuno-PET: Toward a Noninvasive Clinical Tool to Measure Target Engagement of Therapeutic Antibodies In Vivo
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DOI：
10.2967/jnumed.118.224568
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发表时间：
2019-12-01
影响因子：
9.3
通讯作者：
Huisman, Marc C.
中科院分区：
文献类型：
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作者：
Jauw, Yvonne W. S.;O'Donoghue, Joseph A.;Huisman, Marc C.
zr -89- immune - pet是一种很有前途的无创临床工具，可以测量单克隆抗体（mab）的靶向性，以预测正常组织中的毒性和肿瘤中的疗效。zr -89免疫pet的定量将需要超越suv，因为总摄取可能包含重要的非目标特异性贡献。非特异性摄取是可逆的（如血容量）或不可逆的（由于单克隆抗体降解后zr -89残留）。本研究的目的是评估正常组织中的非特异性摄取，作为使用zr -89免疫pet定量正常组织和肿瘤中靶标参与的关键第一步。方法：收集4种zr -89标记的完整IgG1抗体的临床研究数据，共128次PET扫描（注射后1-7 d）， 36例患者：Zr-89-obinutuzumab [n = 9]， zr -89-西妥昔单抗[n = 7], Zr-89-huJ591 [n = 10]， zr -89-曲妥珠单抗[n = 10][分别为zr -89-抗cd20， zr -89-抗egfr， zr -89-抗psma和zr -89-抗her2])。非特异性摄取被定义为在没有已知目标表达的组织中测量的摄取。使用Patlak传递常数的图形评价来估计可逆（V-t）和不可逆（K-i）对肾、肝、肺和脾总测量摄取的贡献。结合所有无靶表达的单克隆抗体（肾脏：zr -89-抗cd20、zr -89-抗egfr和zr -89-抗her2；肝脏：zr -89-抗cd20；肺：zr -89-抗cd20、zr -89-抗egfr和zr -89-抗psma；脾脏：zr -89-抗egfr和zr -89-抗her2）计算每个组织的基线值。结果：肾、肝、肺、脾的基线V-t分别为0.20、0.24、0.09、0.24 mL.cm(-3)，基线K-i分别为0.7、1.1、0.2、0.5 μ L.g(-1).h（-1）。对于Zr-89-anti-PSMA，观察到肾脏的K-i高4倍，表明目标接合。在本例中，注射后1、3和7 d，非特异性摄取分别占肾脏总信号的66%、34%和22%。结论：本研究表明，使用zr -89- immune - pet可以在多个时间点量化无目标表达组织对单克隆抗体的非特异性摄取。这些结果为使用zr -89- immune - pet在体内测量治疗性抗体的靶向性提供了重要的基础。对于未来的研究，需要在注射后1天或更长时间内进行至少3次扫描的试点阶段，以评估非特异性摄取作为时间的函数，以优化研究设计，以检测目标接触。
Zr-89-immuno-PET is a promising noninvasive clinical tool that measures target engagement of monoclonal antibodies (mAbs) to predict toxicity in normal tissues and efficacy in tumors. Quantification of Zr-89-immuno-PET will need to move beyond SUVs, since total uptake may contain a significant non-target-specific contribution. Nonspecific uptake is reversible (e.g., blood volume) or irreversible (due to Zr-89-residualization after mAb degradation). The aim of this study was to assess nonspecific uptake in normal tissues as a first critical step toward quantification of target engagement in normal tissues and tumors using Zr-89-immuno-PET. Methods: Data from clinical studies with 4 Zr-89-labeled intact IgG1 antibodies were collected, resulting in a total of 128 PET scans (1-7 d after injection from 36 patients: Zr-89-obinutuzumab [n = 9], Zr-89-cetuximab [n = 7], Zr-89-huJ591 [n = 10], and Zr-89-trastuzumab [n = 10] [denoted as Zr-89-anti-CD20, Zr-89-anti-EGFR, Zr-89-anti-PSMA and Zr-89-anti-HER2, respectively]). Nonspecific uptake was defined as uptake measured in tissues without known target expression. Patlak graphical evaluation of transfer constants was used to estimate the reversible (V-t) and irreversible (K-i) contributions to the total measured uptake for the kidney, liver, lung, and spleen. Baseline values were calculated per tissue combining all mAbs without target expression (kidney: Zr-89-anti-CD20, Zr-89-anti-EGFR, and Zr-89-anti-HER2; liver: Zr-89-anti-CD20; lung: Zr-89-anti-CD20, Zr-89-anti-EGFR, and Zr-89-anti-PSMA; spleen: Zr-89-anti-EGFR and Zr-89-anti-HER2). Results: For the kidney, liver, lung, and spleen, baseline V-t was 0.20, 0.24, 0.09, and 0.24 mL.cm(-3), respectively, and baseline K-i was 0.7, 1.1, 0.2 and 0.5 mu L.g(-1).h(-1), respectively. For Zr-89-anti-PSMA, a 4-fold higher K-i was observed for the kidney, indicating target engagement. In this case, nonspecific uptake accounted for 66%, 34%, and 22% of the total signal in the kidney at 1, 3, and 7 d after injection, respectively. Conclusion: This study shows that nonspecific uptake of mAbs for tissues without target expression can be quantified using Zr-89-immuno-PET at multiple time points. These results form a crucial base for measurement of target engagement by therapeutic antibodies in vivo with Zr-89-immuno-PET. For future studies, a pilot phase including at least 3 scans at 1 or more days after injection is required to assess nonspecific uptake as a function of time, to optimize study design for detection of target engagement.