89Zr-immuno-PET: Toward a noninvasive clinical tool to measure target engagement of therapeutic antibodies in vivo

Abstract

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 5 9], 89Zr-cetuximab [n 5 7], 89Zr-huJ591 [n 5 10], and 89Zr-trastuzumab [n 5 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 (Vt) and irreversible (Ki) 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 Vt was 0.20, 0.24, 0.09, and 0.24 mL.cm−3, respectively, and baseline Ki was 0.7, 1.1, 0.2 and 0.5 μL.g−1.h−1, respectively. For 89Zr-anti-PSMA, a 4-fold higher Ki 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.