89Zr-Immuno-PET: Toward a Noninvasive Clinical Tool to Measure Target Engagement of Therapeutic Antibodies In Vivo

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.