Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action
Autor(en): | Kast, Florian Schwill, Martin Stueber, Jakob C. Pfundstein, Svende Nagy-Davidescu, Gabriela Rodriguez, Josep M. Monne Seehusen, Frauke Richter, Christian P. Honegger, Annemarie Hartmann, Karen Patricia Weber, Thomas G. Kroener, Felix Ernst, Patrick Piehler, Jacob Pluckthun, Andreas |
Stichwörter: | BINDING-PROTEINS; CANCER; EXPRESSION; EXTRACELLULAR DOMAIN; GENERATION; GROWTH-FACTOR RECEPTOR; HER2; INHIBITION; Multidisciplinary Sciences; RESISTANCE; Science & Technology - Other Topics; STRUCTURAL BASIS | Erscheinungsdatum: | 2021 | Herausgeber: | NATURE RESEARCH | Journal: | NATURE COMMUNICATIONS | Volumen: | 12 | Ausgabe: | 1 | Zusammenfassung: | 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. HER2 acts an oncogenic driver in numerous cancers. Here, the authors design an anti-HER2 biparatopic and tetravalent IgG fusion with inhibitory effects in a xenograft model. |
ISSN: | 20411723 | DOI: | 10.1038/s41467-021-23948-6 |
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geprüft am 02.05.2024