(89)Zr-immuno-PET: Toward a noninvasive clinical tool to measure target engagement of therapeutic antibodies in vivo Journal Article
| Authors: | Jauw, Y. W. S.; O'Donoghue, J. A.; Zijlstra, J. M.; Hoekstra, O. S.; Willemien Menke-van der Houven van Oordt, C.; Morschhauser, F.; Carrasquillo, J. A.; Zweegman, S.; Pandit-Taskar, N.; Lammertsma, A. A.; Van Dongen, G. A. M. S.; Boellaard, R.; Weber, W. A.; Huisman, M. C. |
| Article Title: | (89)Zr-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. COPYRIGHT © 2019 by the Society of Nuclear Medicine and Molecular Imaging. |
| Keywords: | clinical article; controlled study; human tissue; unclassified drug; positron emission tomography; epidermal growth factor receptor 2; in vivo study; molecular imaging; cetuximab; monoclonal antibodies; colorectal carcinoma; prostate cancer; prostate specific membrane antigen; nonhodgkin lymphoma; drug research; drug uptake; blood sampling; stomach cancer; trastuzumab; immunoglobulin g1 antibody; epidermal growth factor receptor antibody; zirconium 89; immunopharmacology; 89zr; immuno-pet; cd20 antibody; human; priority journal; article; immunoradiometric assay; obinutuzumab; antineoplastic monoclonal antibody; huj 591 |
| Journal Title: | Journal of Nuclear Medicine |
| Volume: | 60 |
| Issue: | 12 |
| ISSN: | 0161-5505 |
| Publisher: | Society of Nuclear Medicine |
| Date Published: | 2019-12-01 |
| Start Page: | 1825 |
| End Page: | 1832 |
| Language: | English |
| DOI: | 10.2967/jnumed.118.224568 |
| PUBMED: | 31147401 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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140Carrasquillo -
173Weber
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