⁸⁹Zr-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 ⁸⁹Zr-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 ⁸⁹Zr-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 ⁸⁹Zr-immuno-PET. Methods: Data from clinical studies with 4 ⁸⁹Zr-labeled intact IgG1 antibodies were collected, resulting in a total of 128 PET scans (1–7 d after injection from 36 patients: ⁸⁹Zr-obinutuzumab [n = 9], ⁸⁹Zr-cetuximab [n = 7], ⁸⁹Zr-huJ591 [n = 10], and ⁸⁹Zr-trastuzumab [n = 10] [denoted as ⁸⁹Zr-anti-CD20, ⁸⁹Zr-anti-EGFR, ⁸⁹Zr-anti-PSMA and ⁸⁹Zr-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: ⁸⁹Zr-anti-CD20, ⁸⁹Zr-anti-EGFR, and ⁸⁹Zr-anti-HER2; liver: ⁸⁹Zr-anti-CD20; lung: ⁸⁹Zr-anti-CD20, ⁸⁹Zr-anti-EGFR, and ⁸⁹Zr-anti-PSMA; spleen: ⁸⁹Zr-anti-EGFR and ⁸⁹Zr-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 μL⋅g⁻¹⋅h⁻¹, respectively. For ⁸⁹Zr-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 ⁸⁹Zr-immuno-PET at multiple time points. These results form a crucial base for measurement of target engagement by therapeutic antibodies in vivo with ⁸⁹Zr-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.

⁸⁹ Zr-immuno-PET是一种有前途的无创临床工具，可测量单克隆抗体（mAb）的靶标结合情况，以预测正常组织的毒性和对肿瘤的疗效。量化^89种Zr-immuno-PET的应用将需要超越SUV，因为总摄入量可能包含非目标特异性的显着贡献。非特异性摄取是可逆的（例如血容量）或不可逆的摄取（由于mAb降解后⁸⁹ Zr残留）。这项研究的目的是评估正常组织中非特异性的摄取，这是使用⁸⁹ Zr-immuno-PET量化正常组织和肿瘤中靶标结合的第一步。方法：来自临床研究的数据包括4 ⁸⁹收集了Zr标记的完整IgG1抗体，总共进行了128次PET扫描（注射后1-7 d，来自36位患者）：⁸⁹ Zr-obinutuzumab [ n = 9]，⁸⁹ Zr-cetuximab [ n = 7]，⁸⁹ Zr -huJ591 [ ñ = 10]，和⁸⁹ Zr的曲妥珠单抗[ ñ = 10] [表示为⁸⁹ Zr的抗CD20，⁸⁹ Zr的抗EGFR，⁸⁹ Zr的抗PSMA和⁸⁹ Zr的抗HER2，分别]）。非特异性摄取被定义为在没有已知靶标表达的组织中测量的摄取。用Patlak图形评估传递常数，以估计可逆性（V_t）和不可逆（ K _i）对肾脏，肝脏，肺和脾脏总摄取量的贡献。：每组织结合所有的mAb没有靶表达（肾计算基线值⁸⁹ Zr的抗CD20， ⁸⁹ Zr的抗EGFR，和⁸⁹：;肝Zr的抗HER2 ⁸⁹ Zr的抗CD20;肺： ⁸⁹的Zr -抗CD20， ⁸⁹ Zr的抗EGFR，和⁸⁹ Zr的抗PSMA;脾： ⁸⁹ Zr的抗EGFR和⁸⁹ Zr的抗HER2）。结果：对于肾，肝，肺和脾，基线V _t为0.20、0.24、0.09和0.24 mL·cm ^-3基线K _i分别为0.7、1.1、0.2和0.5μL·g ^-1· h ^-1。对于⁸⁹ Zr-抗PSMA，肾脏的K _i值提高了4倍，表明有靶标参与。在这种情况下，注射后1、3和7天，非特异性摄取分别占肾脏总信号的66％，34％和22％。结论：这项研究表明，可以在多个时间点使用⁸⁹ Zr-immuno-PET定量分析无靶标表达的组织对mAb的非特异性吸收。这些结果为测量体内^89种治疗性抗体对靶标结合的关键基础Zr免疫PET。对于将来的研究，需要在注射后1天或更多天进行至少3次扫描的试验阶段，以评估随时间变化的非特异性摄取，以优化研究设计以检测靶标参与度。