6ZQK

HER2-binding scFv-Fab fusion 841

Summary for 6ZQK

• Entry DOI: 10.2210/pdb6zqk/pdb
• Descriptor: 841 heavy chain, 841 light chain, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: antibody, her2, scfv-fab fusion, antitumor protein
• Biological source: Mus musculus; More
• Total number of polymer chains: 4
• Total formula weight: 149779.84

Authors

Kast, F.,Schwill, M.,Stueber, J.C.,Pfundstein, S.,Nagy-Davidescu, G.,Monne Rodriguez, J.M.,Seehusen, F.,Richter, C.P.,Honegger, A.,Hartmann, K.P.,Weber, T.G.,Kroener, F.,Ernst, P.,Piehler, J.,Plueckthun, A. (deposition date: 2020-07-09, release date: 2021-06-30, Last modification date: 2024-11-20)

Primary citation

Kast, F.,Schwill, M.,Stuber, J.C.,Pfundstein, S.,Nagy-Davidescu, G.,Rodriguez, J.M.M.,Seehusen, F.,Richter, C.P.,Honegger, A.,Hartmann, K.P.,Weber, T.G.,Kroener, F.,Ernst, P.,Piehler, J.,Pluckthun, A.
Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action.
Nat Commun, 12:3790-3790, 2021

PubMed 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.

PubMed: 34145240
DOI: 10.1038/s41467-021-23948-6

Experimental method

X-RAY DIFFRACTION (2.2 Å)