Structural insights into the clustering and activation of Tie2 receptor mediated by Tie2 agonistic antibody

Gyunghee Jo, Jeomil Bae, Ho Jeong Hong, Ah-reum Han, Do-Kyun Kim, Seon Pyo Hong, Jung A Kim, Sangkyu Lee, Gou Young Koh () and Ho Min Kim ()
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Gyunghee Jo: Korea Advanced Institute of Science and Technology (KAIST)
Jeomil Bae: Center for Vascular Research, IBS
Ho Jeong Hong: Institute for Basic Science (IBS)
Ah-reum Han: Institute for Basic Science (IBS)
Do-Kyun Kim: Institute for Basic Science (IBS)
Seon Pyo Hong: Center for Vascular Research, IBS
Jung A Kim: Korea Advanced Institute of Science and Technology (KAIST)
Sangkyu Lee: Center for Cognition and Sociality, IBS
Gou Young Koh: Korea Advanced Institute of Science and Technology (KAIST)
Ho Min Kim: Korea Advanced Institute of Science and Technology (KAIST)

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

Abstract: Abstract Angiopoietin (Angpt)-Tie receptor 2 (Tie2) plays key roles in vascular development and homeostasis as well as pathological vascular remodeling. Therefore, Tie2-agonistic antibody and engineered Angpt1 variants have been developed as potential therapeutics for ischemic and inflammatory vascular diseases. However, their underlying mechanisms for Tie2 clustering and activation remain elusive and the poor manufacturability and stability of Angpt1 variants limit their clinical application. Here, we develop a human Tie2-agonistic antibody (hTAAB), which targets the membrane proximal fibronectin type III domain of Tie2 distinct from the Angpt-binding site. Our Tie2/hTAAB complex structures reveal that hTAAB tethers the preformed Tie2 homodimers into polygonal assemblies through specific binding to Tie2 Fn3 domain. Notably, the polygonal Tie2 clustering induced by hTAAB is critical for Tie2 activation and are resistant to antagonism by Angpt2. Our results provide insight into the molecular mechanism of Tie2 clustering and activation mediated by hTAAB, and the structure-based humanization of hTAAB creates a potential clinical application.

Date: 2021
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DOI: 10.1038/s41467-021-26620-1

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