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An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity
Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase that plays an oncogenic role in breast, gastric and other solid tumors. However, anti-HER2 therapies are only currently approved for the treatment of breast and gastric/gastric esophageal junction cancers and treatment res...
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
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Nature Publishing Group UK
2023
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| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10011572/ https://www.ncbi.nlm.nih.gov/pubmed/36914633 http://dx.doi.org/10.1038/s41467-023-37029-3 |
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| author | Weisser, Nina E. Sanches, Mario Escobar-Cabrera, Eric O’Toole, Jason Whalen, Elizabeth Chan, Peter W. Y. Wickman, Grant Abraham, Libin Choi, Kate Harbourne, Bryant Samiotakis, Antonios Rojas, Andrea Hernández Volkers, Gesa Wong, Jodi Atkinson, Claire E. Baardsnes, Jason Worrall, Liam J. Browman, Duncan Smith, Emma E. Baichoo, Priya Cheng, Chi Wing Guedia, Joy Kang, Sohyeong Mukhopadhyay, Abhishek Newhook, Lisa Ohrn, Anders Raghunatha, Prajwal Zago-Schmitt, Matteo Schrag, Joseph D. Smith, Joel Zwierzchowski, Patricia Scurll, Joshua M. Fung, Vincent Black, Sonia Strynadka, Natalie C. J. Gold, Michael R. Presta, Leonard G. Ng, Gordon Dixit, Surjit |
| author_facet | Weisser, Nina E. Sanches, Mario Escobar-Cabrera, Eric O’Toole, Jason Whalen, Elizabeth Chan, Peter W. Y. Wickman, Grant Abraham, Libin Choi, Kate Harbourne, Bryant Samiotakis, Antonios Rojas, Andrea Hernández Volkers, Gesa Wong, Jodi Atkinson, Claire E. Baardsnes, Jason Worrall, Liam J. Browman, Duncan Smith, Emma E. Baichoo, Priya Cheng, Chi Wing Guedia, Joy Kang, Sohyeong Mukhopadhyay, Abhishek Newhook, Lisa Ohrn, Anders Raghunatha, Prajwal Zago-Schmitt, Matteo Schrag, Joseph D. Smith, Joel Zwierzchowski, Patricia Scurll, Joshua M. Fung, Vincent Black, Sonia Strynadka, Natalie C. J. Gold, Michael R. Presta, Leonard G. Ng, Gordon Dixit, Surjit |
| author_sort | Weisser, Nina E. |
| collection | PubMed |
| description | Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase that plays an oncogenic role in breast, gastric and other solid tumors. However, anti-HER2 therapies are only currently approved for the treatment of breast and gastric/gastric esophageal junction cancers and treatment resistance remains a problem. Here, we engineer an anti-HER2 IgG1 bispecific, biparatopic antibody (Ab), zanidatamab, with unique and enhanced functionalities compared to both trastuzumab and the combination of trastuzumab plus pertuzumab (tras + pert). Zanidatamab binds adjacent HER2 molecules in trans and initiates distinct HER2 reorganization, as shown by polarized cell surface HER2 caps and large HER2 clusters, not observed with trastuzumab or tras + pert. Moreover, zanidatamab, but not trastuzumab nor tras + pert, elicit potent complement-dependent cytotoxicity (CDC) against high HER2-expressing tumor cells in vitro. Zanidatamab also mediates HER2 internalization and downregulation, inhibition of both cell signaling and tumor growth, antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP), and also shows superior in vivo antitumor activity compared to tras + pert in a HER2-expressing xenograft model. Collectively, we show that zanidatamab has multiple and distinct mechanisms of action derived from the structural effects of biparatopic HER2 engagement. |
| format | Online Article Text |
| id | pubmed-10011572 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2023 |
| publisher | Nature Publishing Group UK |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-100115722023-03-15 An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity Weisser, Nina E. Sanches, Mario Escobar-Cabrera, Eric O’Toole, Jason Whalen, Elizabeth Chan, Peter W. Y. Wickman, Grant Abraham, Libin Choi, Kate Harbourne, Bryant Samiotakis, Antonios Rojas, Andrea Hernández Volkers, Gesa Wong, Jodi Atkinson, Claire E. Baardsnes, Jason Worrall, Liam J. Browman, Duncan Smith, Emma E. Baichoo, Priya Cheng, Chi Wing Guedia, Joy Kang, Sohyeong Mukhopadhyay, Abhishek Newhook, Lisa Ohrn, Anders Raghunatha, Prajwal Zago-Schmitt, Matteo Schrag, Joseph D. Smith, Joel Zwierzchowski, Patricia Scurll, Joshua M. Fung, Vincent Black, Sonia Strynadka, Natalie C. J. Gold, Michael R. Presta, Leonard G. Ng, Gordon Dixit, Surjit Nat Commun Article Human epidermal growth factor receptor 2 (HER2) is a receptor tyrosine kinase that plays an oncogenic role in breast, gastric and other solid tumors. However, anti-HER2 therapies are only currently approved for the treatment of breast and gastric/gastric esophageal junction cancers and treatment resistance remains a problem. Here, we engineer an anti-HER2 IgG1 bispecific, biparatopic antibody (Ab), zanidatamab, with unique and enhanced functionalities compared to both trastuzumab and the combination of trastuzumab plus pertuzumab (tras + pert). Zanidatamab binds adjacent HER2 molecules in trans and initiates distinct HER2 reorganization, as shown by polarized cell surface HER2 caps and large HER2 clusters, not observed with trastuzumab or tras + pert. Moreover, zanidatamab, but not trastuzumab nor tras + pert, elicit potent complement-dependent cytotoxicity (CDC) against high HER2-expressing tumor cells in vitro. Zanidatamab also mediates HER2 internalization and downregulation, inhibition of both cell signaling and tumor growth, antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP), and also shows superior in vivo antitumor activity compared to tras + pert in a HER2-expressing xenograft model. Collectively, we show that zanidatamab has multiple and distinct mechanisms of action derived from the structural effects of biparatopic HER2 engagement. Nature Publishing Group UK 2023-03-13 /pmc/articles/PMC10011572/ /pubmed/36914633 http://dx.doi.org/10.1038/s41467-023-37029-3 Text en © The Author(s) 2023 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 Weisser, Nina E. Sanches, Mario Escobar-Cabrera, Eric O’Toole, Jason Whalen, Elizabeth Chan, Peter W. Y. Wickman, Grant Abraham, Libin Choi, Kate Harbourne, Bryant Samiotakis, Antonios Rojas, Andrea Hernández Volkers, Gesa Wong, Jodi Atkinson, Claire E. Baardsnes, Jason Worrall, Liam J. Browman, Duncan Smith, Emma E. Baichoo, Priya Cheng, Chi Wing Guedia, Joy Kang, Sohyeong Mukhopadhyay, Abhishek Newhook, Lisa Ohrn, Anders Raghunatha, Prajwal Zago-Schmitt, Matteo Schrag, Joseph D. Smith, Joel Zwierzchowski, Patricia Scurll, Joshua M. Fung, Vincent Black, Sonia Strynadka, Natalie C. J. Gold, Michael R. Presta, Leonard G. Ng, Gordon Dixit, Surjit An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity |
| title | An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity |
| title_full | An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity |
| title_fullStr | An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity |
| title_full_unstemmed | An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity |
| title_short | An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity |
| title_sort | anti-her2 biparatopic antibody that induces unique her2 clustering and complement-dependent cytotoxicity |
| topic | Article |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10011572/ https://www.ncbi.nlm.nih.gov/pubmed/36914633 http://dx.doi.org/10.1038/s41467-023-37029-3 |
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