Amelioration of sepsis by TIE2 activation-induced vascular protection

• Published in: Science translational medicine Vol. 8; no. 335; p. 335ra55
• Main Authors: Han, Sangyeul, Lee, Seung-Jun, Kim, Kyung Eun, Lee, Hyo Seon, Oh, Nuri, Park, Inwon, Ko, Eun, Oh, Seung Ja, Lee, Yoon-Sook, Kim, David, Lee, Seungjoo, Lee, Dae Hyun, Lee, Kwang-Hoon, Chae, Su Young, Lee, Jung-Hoon, Kim, Su-Jin, Kim, Hyung-Chan, Kim, Seokkyun, Kim, Sung Hyun, Kim, Chungho, Nakaoka, Yoshikazu, He, Yulong, Augustin, Hellmut G, Hu, Junhao, Song, Paul H, Kim, Yong-In, Kim, Pilhan, Kim, Injune, Koh, Gou Young
• Format: Journal Article
• Language: English
• Published: United States 20.04.2016
• Subjects: Angiopoietin-2 - metabolism; Animals; Antibodies - therapeutic use; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Human Umbilical Vein Endothelial Cells; Humans; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; Neutrophil Infiltration - drug effects; Receptor, TIE-2 - metabolism; Ribonuclease, Pancreatic - metabolism; Sepsis - drug therapy; Sepsis - metabolism; Vesicular Transport Proteins - metabolism
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.aad9260

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.