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Immuno-PET Imaging to Assess Target Engagement: Experience from (89)Zr-Anti-HER3 mAb (GSK2849330) in Patients with Solid Tumors

PET imaging with radiolabeled drugs provides information on tumor uptake and dose-dependent target interaction to support selection of an optimal dose for future efficacy testing. In this immuno-PET study of the anti–human epidermal growth factor receptor (HER3) mAb GSK2849330, we investigated the b...

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Autores principales: Menke-van der Houven van Oordt, C. Willemien, McGeoch, Adam, Bergstrom, Mats, McSherry, Iain, Smith, Deborah A., Cleveland, Matthew, Al-Azzam, Wasfi, Chen, Liangfu, Verheul, Henk, Hoekstra, Otto S., Vugts, Danielle J., Freedman, Immanuel, Huisman, Marc, Matheny, Chris, van Dongen, Guus, Zhang, Sean
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Society of Nuclear Medicine 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604691/
https://www.ncbi.nlm.nih.gov/pubmed/30733323
http://dx.doi.org/10.2967/jnumed.118.214726
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author Menke-van der Houven van Oordt, C. Willemien
McGeoch, Adam
Bergstrom, Mats
McSherry, Iain
Smith, Deborah A.
Cleveland, Matthew
Al-Azzam, Wasfi
Chen, Liangfu
Verheul, Henk
Hoekstra, Otto S.
Vugts, Danielle J.
Freedman, Immanuel
Huisman, Marc
Matheny, Chris
van Dongen, Guus
Zhang, Sean
author_facet Menke-van der Houven van Oordt, C. Willemien
McGeoch, Adam
Bergstrom, Mats
McSherry, Iain
Smith, Deborah A.
Cleveland, Matthew
Al-Azzam, Wasfi
Chen, Liangfu
Verheul, Henk
Hoekstra, Otto S.
Vugts, Danielle J.
Freedman, Immanuel
Huisman, Marc
Matheny, Chris
van Dongen, Guus
Zhang, Sean
author_sort Menke-van der Houven van Oordt, C. Willemien
collection PubMed
description PET imaging with radiolabeled drugs provides information on tumor uptake and dose-dependent target interaction to support selection of an optimal dose for future efficacy testing. In this immuno-PET study of the anti–human epidermal growth factor receptor (HER3) mAb GSK2849330, we investigated the biodistribution and tumor uptake of (89)Zr-labeled GSK2849330 and evaluated target engagement as a function of antibody mass dose. Methods: (89)Zr-GSK2849330 distribution was monitored in 6 patients with HER3-positive tumors not amenable to standard treatment. Patients received 2 administrations of (89)Zr-GSK2849330. Imaging after tracer only was performed at baseline; dose-dependent inhibition of (89)Zr-GSK2849330 uptake in tumor tissues was evaluated 2 wk later using increasing doses of unlabeled GSK2849330 in combination with the tracer. Up to 3 PET scans (2 hours post infusion [p.i.] and days 2 and 5 p.i.) were performed after tracer administration. Biodistribution and tumor targeting were assessed visually and quantitatively using SUV. The 50% and 90% inhibitory mass doses (ID(50) and ID(90)) of target-mediated antibody uptake were calculated using a Patlak transformation. Results: At baseline, imaging with tracer showed good tumor uptake in all evaluable patients. Predosing with unlabeled mAb reduced the tumor uptake rate in a dose-dependent manner. Saturation of (89)Zr-mAb uptake by tumors was seen at the highest dose (30 mg/kg). Despite the limited number of patients, an exploratory ID(50) of 2 mg/kg and ID(90) of 18 mg/kg have been determined. Conclusion: In this immuno-PET study, dose-dependent inhibition of tumor uptake of (89)Zr-GSK2849330 by unlabeled mAb confirmed target engagement of mAb to the HER3 receptor. This study further validates the use of immuno-PET to directly visualize tissue drug disposition in patients with a noninvasive approach and to measure target engagement at the site of action, offering the potential for dose selection.
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spelling pubmed-66046912019-07-10 Immuno-PET Imaging to Assess Target Engagement: Experience from (89)Zr-Anti-HER3 mAb (GSK2849330) in Patients with Solid Tumors Menke-van der Houven van Oordt, C. Willemien McGeoch, Adam Bergstrom, Mats McSherry, Iain Smith, Deborah A. Cleveland, Matthew Al-Azzam, Wasfi Chen, Liangfu Verheul, Henk Hoekstra, Otto S. Vugts, Danielle J. Freedman, Immanuel Huisman, Marc Matheny, Chris van Dongen, Guus Zhang, Sean J Nucl Med Oncology PET imaging with radiolabeled drugs provides information on tumor uptake and dose-dependent target interaction to support selection of an optimal dose for future efficacy testing. In this immuno-PET study of the anti–human epidermal growth factor receptor (HER3) mAb GSK2849330, we investigated the biodistribution and tumor uptake of (89)Zr-labeled GSK2849330 and evaluated target engagement as a function of antibody mass dose. Methods: (89)Zr-GSK2849330 distribution was monitored in 6 patients with HER3-positive tumors not amenable to standard treatment. Patients received 2 administrations of (89)Zr-GSK2849330. Imaging after tracer only was performed at baseline; dose-dependent inhibition of (89)Zr-GSK2849330 uptake in tumor tissues was evaluated 2 wk later using increasing doses of unlabeled GSK2849330 in combination with the tracer. Up to 3 PET scans (2 hours post infusion [p.i.] and days 2 and 5 p.i.) were performed after tracer administration. Biodistribution and tumor targeting were assessed visually and quantitatively using SUV. The 50% and 90% inhibitory mass doses (ID(50) and ID(90)) of target-mediated antibody uptake were calculated using a Patlak transformation. Results: At baseline, imaging with tracer showed good tumor uptake in all evaluable patients. Predosing with unlabeled mAb reduced the tumor uptake rate in a dose-dependent manner. Saturation of (89)Zr-mAb uptake by tumors was seen at the highest dose (30 mg/kg). Despite the limited number of patients, an exploratory ID(50) of 2 mg/kg and ID(90) of 18 mg/kg have been determined. Conclusion: In this immuno-PET study, dose-dependent inhibition of tumor uptake of (89)Zr-GSK2849330 by unlabeled mAb confirmed target engagement of mAb to the HER3 receptor. This study further validates the use of immuno-PET to directly visualize tissue drug disposition in patients with a noninvasive approach and to measure target engagement at the site of action, offering the potential for dose selection. Society of Nuclear Medicine 2019-07 /pmc/articles/PMC6604691/ /pubmed/30733323 http://dx.doi.org/10.2967/jnumed.118.214726 Text en © 2019 by the Society of Nuclear Medicine and Molecular Imaging. Immediate Open Access: Creative Commons Attribution 4.0 International License (CC BY) allows users to share and adapt with attribution, excluding materials credited to previous publications. License: https://creativecommons.org/licenses/by/4.0/. Details: http://jnm.snmjournals.org/site/misc/permission.xhtml.
spellingShingle Oncology
Menke-van der Houven van Oordt, C. Willemien
McGeoch, Adam
Bergstrom, Mats
McSherry, Iain
Smith, Deborah A.
Cleveland, Matthew
Al-Azzam, Wasfi
Chen, Liangfu
Verheul, Henk
Hoekstra, Otto S.
Vugts, Danielle J.
Freedman, Immanuel
Huisman, Marc
Matheny, Chris
van Dongen, Guus
Zhang, Sean
Immuno-PET Imaging to Assess Target Engagement: Experience from (89)Zr-Anti-HER3 mAb (GSK2849330) in Patients with Solid Tumors
title Immuno-PET Imaging to Assess Target Engagement: Experience from (89)Zr-Anti-HER3 mAb (GSK2849330) in Patients with Solid Tumors
title_full Immuno-PET Imaging to Assess Target Engagement: Experience from (89)Zr-Anti-HER3 mAb (GSK2849330) in Patients with Solid Tumors
title_fullStr Immuno-PET Imaging to Assess Target Engagement: Experience from (89)Zr-Anti-HER3 mAb (GSK2849330) in Patients with Solid Tumors
title_full_unstemmed Immuno-PET Imaging to Assess Target Engagement: Experience from (89)Zr-Anti-HER3 mAb (GSK2849330) in Patients with Solid Tumors
title_short Immuno-PET Imaging to Assess Target Engagement: Experience from (89)Zr-Anti-HER3 mAb (GSK2849330) in Patients with Solid Tumors
title_sort immuno-pet imaging to assess target engagement: experience from (89)zr-anti-her3 mab (gsk2849330) in patients with solid tumors
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604691/
https://www.ncbi.nlm.nih.gov/pubmed/30733323
http://dx.doi.org/10.2967/jnumed.118.214726
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