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Sci Transl Med. 2016 Apr 20;8(335):335ra55. doi: 10.1126/scitranslmed.aad9260.

Amelioration of sepsis by TIE2 activation-induced vascular protection.

Author information

1
Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea. Center for Vascular Research, Institute for Basic Science, Daejeon 305-701, Republic of Korea. gykoh@kaist.ac.kr syhan69@gmail.com.
2
Center for Vascular Research, Institute for Basic Science, Daejeon 305-701, Republic of Korea. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
3
Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea.
4
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
5
Graduate School of Nanoscience and Technology, KAIST, Daejeon 305-701, Republic of Korea.
6
School of Life Sciences and Technologies, Korea University, Seoul 136-701, Republic of Korea.
7
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
8
Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
9
Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), 69121 Heidelberg, Germany. Department of Vascular Biology and Tumor Angiogenesis (CBTM), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
10
Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), 69121 Heidelberg, Germany.
11
Center for Vascular Research, Institute for Basic Science, Daejeon 305-701, Republic of Korea. Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea. gykoh@kaist.ac.kr syhan69@gmail.com.

Abstract

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.

PMID:
27099174
DOI:
10.1126/scitranslmed.aad9260
[Indexed for MEDLINE]

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