Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action

Florian Kast, Martin Schwill, Jakob C. Stüber, Svende Pfundstein, Gabriela Nagy-Davidescu, Josep M. Monné Rodríguez, Frauke Seehusen, Christian P. Richter, Annemarie Honegger, Karen Patricia Hartmann, Thomas G. Weber, Felix Kroener, Patrick Ernst, Jacob Piehler and Andreas Plückthun ()
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Florian Kast: University of Zurich
Martin Schwill: University of Zurich
Jakob C. Stüber: University of Zurich
Svende Pfundstein: University of Zurich
Gabriela Nagy-Davidescu: University of Zurich
Josep M. Monné Rodríguez: University of Zurich
Frauke Seehusen: University of Zurich
Christian P. Richter: Osnabrück University
Annemarie Honegger: University of Zurich
Karen Patricia Hartmann: University of Zurich
Thomas G. Weber: Dynamic Biosensors GmbH
Felix Kroener: Dynamic Biosensors GmbH
Patrick Ernst: University of Zurich
Jacob Piehler: Osnabrück University
Andreas Plückthun: University of Zurich

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-23948-6

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