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

Abstract

89 Zr-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 89 Zr-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 89 Zr-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 89 Zr-immuno-PET. Methods: Data from clinical studies with 4 89 Zr-labeled intact IgG1 antibodies were collected, resulting in a total of 128 PET scans (1-7 d after injection from 36 patients: 89 Zr-obinutuzumab [n 5 9], 89 Zr-cetuximab [n 5 7], 89 Zr-huJ591 [n 5 10], and 89 Zr-trastuzumab [n 5 10] [denoted as 89 Zr-anti-CD20, 89 Zr-anti-EGFR, 89 Zr-anti-PSMA and 89 Zr-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: 89 Zr-anti-CD20, 89 Zr-anti-EGFR, and 89 Zr-anti-HER2; liver: 89 Zr-anti-CD20; lung: 89 Zr-anti-CD20, 89 Zr-anti-EGFR, and 89 Zranti-PSMA; spleen: 89 Zr-anti-EGFR and 89 Zr-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 89 Zr-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 89 Zr-immuno-PET at multiple time points. These results form a crucial base for measurement of target engagement by therapeutic antibodies in vivo with 89 Zr-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.

Recent progress in the molecular imaging of therapeutic monoclonal antibodies

“…When conjugated with other reagents like drugs or radionuclides, more efficient cell death can be achieved. Assessment of antibody-antigen interaction is therefore important for understanding the efficacy and toxicity of mAb or immunoconjugate treatment [ 83 ]. In vitro binding affinity of mAbs can be detected by methods as described for serum mAb concentrations including ELISA [ 84 ] and SPR assay [ 85 , 86 ], so they will not be specified here.…”

Noninvasive quantification of target availability during therapy using paired-agent fluorescence tomography

“…The development of molecular imaging strategies using targeted agents has often been viewed as a promising avenue for assessing drug targets noninvasively 11 , 12 . Yet, the irregular and variable vasculature in solid tumors presents a persistent challenge for isolating and quantifying receptor availability in these pathologies 8 , 13 - 15 . Specifically, the rates at which the agent transports between the vascular and extra-vascular spaces, and the rates at which it binds and becomes dissociated from the receptor, among other factors 16 - 19 , all play a role in determining total agent accumulation.…”

Synthesis of a novel 89Zr-labeled HER2 affibody and its application study in tumor PET imaging

“…Current selection of patients for targeted therapy is mainly dependent on the status of HER2, determined by biopsy using immunohistochemistry or fluorescence in situ hybridization [8]. However, the invasive method may not be reliable because the HER2 expression is heterogeneous in the tumors and varies during the progress of the disease [9]. Almost 20% of the outcomes was inaccurate [10].…”