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Application of (89)Zr-DFO*-immuno-PET to assess improved target engagement of a bispecific anti-amyloid-ß monoclonal antibody

PURPOSE: The recent conditional FDA approval of Aducanumab (Adu) for treating Alzheimer’s disease (AD) and the continued discussions around that decision have increased interest in immunotherapy for AD and other brain diseases. Reliable techniques for brain imaging of antibodies may guide decision-m...

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Autores principales: Stergiou, N., Wuensche, T. E., Schreurs, M., Mes, I., Verlaan, M., Kooijman, E. J. M., Windhorst, A. D., Helboe, L., Vergo, S., Christensen, S., Asuni, A. A., Jensen, A., Van Dongen, G. A. M. S., Bang-Andersen, B., Vugts, D. J., Beaino, W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10027647/
https://www.ncbi.nlm.nih.gov/pubmed/36635462
http://dx.doi.org/10.1007/s00259-023-06109-3
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author Stergiou, N.
Wuensche, T. E.
Schreurs, M.
Mes, I.
Verlaan, M.
Kooijman, E. J. M.
Windhorst, A. D.
Helboe, L.
Vergo, S.
Christensen, S.
Asuni, A. A.
Jensen, A.
Van Dongen, G. A. M. S.
Bang-Andersen, B.
Vugts, D. J.
Beaino, W.
author_facet Stergiou, N.
Wuensche, T. E.
Schreurs, M.
Mes, I.
Verlaan, M.
Kooijman, E. J. M.
Windhorst, A. D.
Helboe, L.
Vergo, S.
Christensen, S.
Asuni, A. A.
Jensen, A.
Van Dongen, G. A. M. S.
Bang-Andersen, B.
Vugts, D. J.
Beaino, W.
author_sort Stergiou, N.
collection PubMed
description PURPOSE: The recent conditional FDA approval of Aducanumab (Adu) for treating Alzheimer’s disease (AD) and the continued discussions around that decision have increased interest in immunotherapy for AD and other brain diseases. Reliable techniques for brain imaging of antibodies may guide decision-making in the future but needs further development. In this study, we used (89)Zr-immuno-PET to evaluate the targeting and distribution of a bispecific brain-shuttle IgG based on Adu with transferrin receptor protein-1 (TfR1) shuttling mechanism, mAbAdu-scFab8D3, designated Adu-8D3, as a candidate theranostic for AD. We also validated the (89)Zr-immuno-PET platform as an enabling technology for developing new antibody-based theranostics for brain disorders. METHODS: Adu, Adu-8D3, and the non-binding control construct B12-8D3 were modified with DFO*-NCS and radiolabeled with (89)Zr. APP/PS1 mice were injected with (89)Zr-labeled mAbs and imaged on days 3 and 7 by positron emission tomography (PET). Ex vivo biodistribution was performed on day 7, and ex vivo autoradiography and immunofluorescence staining were done on brain tissue to validate the PET imaging results and target engagement with amyloid-β plaques. Additionally, [(89)Zr]Zr-DFO*-Adu-8D3 was evaluated in 3, 7, and 10-month-old APP/PS1 mice to test its potential in early stage disease. RESULTS: A 7-fold higher brain uptake was observed for [(89)Zr]Zr-DFO*-Adu-8D3 compared to [(89)Zr]Zr-DFO*-Adu and a 2.7-fold higher uptake compared to [(89)Zr]Zr-DFO*-B12-8D3 on day 7. Autoradiography and immunofluorescence of [(89)Zr]Zr-DFO*-Adu-8D3 showed co-localization with amyloid plaques, which was not the case with the Adu and B12-8D3 conjugates. [(89)Zr]Zr-DFO*-Adu-8D3 was able to detect low plaque load in 3-month-old APP/PS1 mice. CONCLUSION: (89)Zr-DFO*-immuno-PET revealed high and specific uptake of the bispecific Adu-8D3 in the brain and can be used for the early detection of Aβ plaque pathology. Here, we demonstrate that (89)Zr-DFO*-immuno-PET can be used to visualize and quantify brain uptake of mAbs and contribute to the evaluation of biological therapeutics for brain diseases. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00259-023-06109-3.
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spelling pubmed-100276472023-03-22 Application of (89)Zr-DFO*-immuno-PET to assess improved target engagement of a bispecific anti-amyloid-ß monoclonal antibody Stergiou, N. Wuensche, T. E. Schreurs, M. Mes, I. Verlaan, M. Kooijman, E. J. M. Windhorst, A. D. Helboe, L. Vergo, S. Christensen, S. Asuni, A. A. Jensen, A. Van Dongen, G. A. M. S. Bang-Andersen, B. Vugts, D. J. Beaino, W. Eur J Nucl Med Mol Imaging Original Article PURPOSE: The recent conditional FDA approval of Aducanumab (Adu) for treating Alzheimer’s disease (AD) and the continued discussions around that decision have increased interest in immunotherapy for AD and other brain diseases. Reliable techniques for brain imaging of antibodies may guide decision-making in the future but needs further development. In this study, we used (89)Zr-immuno-PET to evaluate the targeting and distribution of a bispecific brain-shuttle IgG based on Adu with transferrin receptor protein-1 (TfR1) shuttling mechanism, mAbAdu-scFab8D3, designated Adu-8D3, as a candidate theranostic for AD. We also validated the (89)Zr-immuno-PET platform as an enabling technology for developing new antibody-based theranostics for brain disorders. METHODS: Adu, Adu-8D3, and the non-binding control construct B12-8D3 were modified with DFO*-NCS and radiolabeled with (89)Zr. APP/PS1 mice were injected with (89)Zr-labeled mAbs and imaged on days 3 and 7 by positron emission tomography (PET). Ex vivo biodistribution was performed on day 7, and ex vivo autoradiography and immunofluorescence staining were done on brain tissue to validate the PET imaging results and target engagement with amyloid-β plaques. Additionally, [(89)Zr]Zr-DFO*-Adu-8D3 was evaluated in 3, 7, and 10-month-old APP/PS1 mice to test its potential in early stage disease. RESULTS: A 7-fold higher brain uptake was observed for [(89)Zr]Zr-DFO*-Adu-8D3 compared to [(89)Zr]Zr-DFO*-Adu and a 2.7-fold higher uptake compared to [(89)Zr]Zr-DFO*-B12-8D3 on day 7. Autoradiography and immunofluorescence of [(89)Zr]Zr-DFO*-Adu-8D3 showed co-localization with amyloid plaques, which was not the case with the Adu and B12-8D3 conjugates. [(89)Zr]Zr-DFO*-Adu-8D3 was able to detect low plaque load in 3-month-old APP/PS1 mice. CONCLUSION: (89)Zr-DFO*-immuno-PET revealed high and specific uptake of the bispecific Adu-8D3 in the brain and can be used for the early detection of Aβ plaque pathology. Here, we demonstrate that (89)Zr-DFO*-immuno-PET can be used to visualize and quantify brain uptake of mAbs and contribute to the evaluation of biological therapeutics for brain diseases. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00259-023-06109-3. Springer Berlin Heidelberg 2023-01-13 2023 /pmc/articles/PMC10027647/ /pubmed/36635462 http://dx.doi.org/10.1007/s00259-023-06109-3 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
Stergiou, N.
Wuensche, T. E.
Schreurs, M.
Mes, I.
Verlaan, M.
Kooijman, E. J. M.
Windhorst, A. D.
Helboe, L.
Vergo, S.
Christensen, S.
Asuni, A. A.
Jensen, A.
Van Dongen, G. A. M. S.
Bang-Andersen, B.
Vugts, D. J.
Beaino, W.
Application of (89)Zr-DFO*-immuno-PET to assess improved target engagement of a bispecific anti-amyloid-ß monoclonal antibody
title Application of (89)Zr-DFO*-immuno-PET to assess improved target engagement of a bispecific anti-amyloid-ß monoclonal antibody
title_full Application of (89)Zr-DFO*-immuno-PET to assess improved target engagement of a bispecific anti-amyloid-ß monoclonal antibody
title_fullStr Application of (89)Zr-DFO*-immuno-PET to assess improved target engagement of a bispecific anti-amyloid-ß monoclonal antibody
title_full_unstemmed Application of (89)Zr-DFO*-immuno-PET to assess improved target engagement of a bispecific anti-amyloid-ß monoclonal antibody
title_short Application of (89)Zr-DFO*-immuno-PET to assess improved target engagement of a bispecific anti-amyloid-ß monoclonal antibody
title_sort application of (89)zr-dfo*-immuno-pet to assess improved target engagement of a bispecific anti-amyloid-ß monoclonal antibody
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10027647/
https://www.ncbi.nlm.nih.gov/pubmed/36635462
http://dx.doi.org/10.1007/s00259-023-06109-3
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