دورية أكاديمية
An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity
| العنوان: | An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity |
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| المؤلفون: | 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 |
| المصدر: | Nature Communications ; volume 14, issue 1 ; ISSN 2041-1723 |
| بيانات النشر: | Springer Science and Business Media LLC |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, Multidisciplinary |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1038/s41467-023-37029-3 |
| الإتاحة: | https://doi.org/10.1038/s41467-023-37029-3Test https://www.nature.com/articles/s41467-023-37029-3.pdfTest https://www.nature.com/articles/s41467-023-37029-3Test |
| حقوق: | https://creativecommons.org/licenses/by/4.0Test ; https://creativecommons.org/licenses/by/4.0Test |
| رقم الانضمام: | edsbas.9EB0EA4A |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41467-023-37029-3 |
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