Protection of endothelial integrity has been recognized as a frontline approach to alleviating sepsis progression, yet no effective agent for preserving endothelial integrity is available. Using an unusual anti-angiopoietin 2 (ANG2) antibody, ABTAA (ANG2-binding and TIE2-activating antibody), we show that activation of the endothelial receptor TIE2 protects the vasculature from septic damage and provides survival benefit in three sepsis mouse models. Upon binding to ANG2, ABTAA triggers clustering of ANG2, assembling an ABTAA/ANG2 complex that can subsequently bind and activate TIE2. Compared with a conventional ANG2-blocking antibody, ABTAA was highly effective in augmenting survival from sepsis by strengthening the endothelial glycocalyx, reducing cytokine storms, vascular leakage, and rarefaction, and mitigating organ damage. Together, our data advance the role of TIE2 activation in ameliorating sepsis progression and open a potential therapeutic avenue for sepsis to address the lack of sepsis-specific treatment.

Background:The angiogenic growth factor angiopoietin-2 regulates angiogenesis through Tie2 and integrins. Results: An angiopoietin-2 mutant fails to bind to integrin, but not Tie2, and to mediate cell migration. Conclusion: Tie2-independent angiopoietin-2 association with integrin is critical for migration of tumor and endothelial cells. Significance: Understanding the mechanism of angiopoietin-2 interaction with integrin is essential for angiogenesis and cancer invasion.