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Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action
The receptor tyrosine kinase HER2 acts as oncogenic driver in numerous cancers. Usually, the gene is amplified, resulting in receptor overexpression, massively increased signaling and unchecked proliferation. However, tumors become frequently addicted to oncogenes and hence are druggable by targeted...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213836/ https://www.ncbi.nlm.nih.gov/pubmed/34145240 http://dx.doi.org/10.1038/s41467-021-23948-6 |
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author | Kast, Florian Schwill, Martin Stüber, Jakob C. Pfundstein, Svende Nagy-Davidescu, Gabriela Rodríguez, Josep M. Monné Seehusen, Frauke Richter, Christian P. Honegger, Annemarie Hartmann, Karen Patricia Weber, Thomas G. Kroener, Felix Ernst, Patrick Piehler, Jacob Plückthun, Andreas |
author_facet | Kast, Florian Schwill, Martin Stüber, Jakob C. Pfundstein, Svende Nagy-Davidescu, Gabriela Rodríguez, Josep M. Monné Seehusen, Frauke Richter, Christian P. Honegger, Annemarie Hartmann, Karen Patricia Weber, Thomas G. Kroener, Felix Ernst, Patrick Piehler, Jacob Plückthun, Andreas |
author_sort | Kast, Florian |
collection | PubMed |
description | The receptor tyrosine kinase HER2 acts as oncogenic driver in numerous cancers. Usually, the gene is amplified, resulting in receptor overexpression, massively increased signaling and unchecked proliferation. However, tumors become frequently addicted to oncogenes and hence are druggable by targeted interventions. Here, we design an anti-HER2 biparatopic and tetravalent IgG fusion with a multimodal mechanism of action. The molecule first induces HER2 clustering into inactive complexes, evidenced by reduced mobility of surface HER2. However, in contrast to our earlier binders based on DARPins, clusters of HER2 are thereafter robustly internalized and quantitatively degraded. This multimodal mechanism of action is found only in few of the tetravalent constructs investigated, which must target specific epitopes on HER2 in a defined geometric arrangement. The inhibitory effect of our antibody as single agent surpasses the combination of trastuzumab and pertuzumab as well as its parental mAbs in vitro and it is effective in a xenograft model. |
format | Online Article Text |
id | pubmed-8213836 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-82138362021-07-01 Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action Kast, Florian Schwill, Martin Stüber, Jakob C. Pfundstein, Svende Nagy-Davidescu, Gabriela Rodríguez, Josep M. Monné Seehusen, Frauke Richter, Christian P. Honegger, Annemarie Hartmann, Karen Patricia Weber, Thomas G. Kroener, Felix Ernst, Patrick Piehler, Jacob Plückthun, Andreas Nat Commun Article The receptor tyrosine kinase HER2 acts as oncogenic driver in numerous cancers. Usually, the gene is amplified, resulting in receptor overexpression, massively increased signaling and unchecked proliferation. However, tumors become frequently addicted to oncogenes and hence are druggable by targeted interventions. Here, we design an anti-HER2 biparatopic and tetravalent IgG fusion with a multimodal mechanism of action. The molecule first induces HER2 clustering into inactive complexes, evidenced by reduced mobility of surface HER2. However, in contrast to our earlier binders based on DARPins, clusters of HER2 are thereafter robustly internalized and quantitatively degraded. This multimodal mechanism of action is found only in few of the tetravalent constructs investigated, which must target specific epitopes on HER2 in a defined geometric arrangement. The inhibitory effect of our antibody as single agent surpasses the combination of trastuzumab and pertuzumab as well as its parental mAbs in vitro and it is effective in a xenograft model. Nature Publishing Group UK 2021-06-18 /pmc/articles/PMC8213836/ /pubmed/34145240 http://dx.doi.org/10.1038/s41467-021-23948-6 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Kast, Florian Schwill, Martin Stüber, Jakob C. Pfundstein, Svende Nagy-Davidescu, Gabriela Rodríguez, Josep M. Monné Seehusen, Frauke Richter, Christian P. Honegger, Annemarie Hartmann, Karen Patricia Weber, Thomas G. Kroener, Felix Ernst, Patrick Piehler, Jacob Plückthun, Andreas Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action |
title | Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action |
title_full | Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action |
title_fullStr | Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action |
title_full_unstemmed | Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action |
title_short | Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action |
title_sort | engineering an anti-her2 biparatopic antibody with a multimodal mechanism of action |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213836/ https://www.ncbi.nlm.nih.gov/pubmed/34145240 http://dx.doi.org/10.1038/s41467-021-23948-6 |
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