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 = 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.

Keywords: 89Zr; immuno-PET; molecular imaging; monoclonal antibodies; positron emission tomography.