Amelioration of sepsis by TIE2 activation-induced vascular protection.
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.
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.
Sangyeul
S
Han
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.
Seung-Jun
SJ
Lee
Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea.
Kyung Eun
KE
Kim
Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea.
Hyo Seon
HS
Lee
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
Nuri
N
Oh
Graduate School of Nanoscience and Technology, KAIST, Daejeon 305-701, Republic of Korea.
Inwon
I
Park
Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea.
Eun
E
Ko
Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea.
Seung Ja
SJ
Oh
Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea.
Yoon-Sook
YS
Lee
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
David
D
Kim
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
Seungjoo
S
Lee
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
Dae Hyun
DH
Lee
Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea.
Kwang-Hoon
KH
Lee
Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea.
Su Young
SY
Chae
Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea.
Jung-Hoon
JH
Lee
Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea.
Su-Jin
SJ
Kim
Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea.
Hyung-Chan
HC
Kim
Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea.
Seokkyun
S
Kim
Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea.
Sung Hyun
SH
Kim
School of Life Sciences and Technologies, Korea University, Seoul 136-701, Republic of Korea.
Chungho
C
Kim
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Yoshikazu
Y
Nakaoka
Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
Yulong
Y
He
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.
Hellmut G
HG
Augustin
Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), 69121 Heidelberg, Germany.
Junhao
J
Hu
Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea.
Paul H
PH
Song
Samsung Advanced Institute of Technology, Suwon, 446-712, Republic of Korea.
Yong-In
YI
Kim
Graduate School of Nanoscience and Technology, KAIST, Daejeon 305-701, Republic of Korea.
Pilhan
P
Kim
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea.
Injune
I
Kim
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.
Gou Young
GY
Koh
D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D020556:Neutrophil Infiltration / Q000187:drug effects; D042787:Receptor, TIE-2 / Q000378:metabolism*; D012259:Ribonuclease, Pancreatic / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000378:metabolism
D042702:Angiopoietin-2; D000906:Antibodies; C555023:VPS51 protein, human; D033921:Vesicular Transport Proteins; D042787:Receptor, TIE-2; C099439:Ang2 protein, mouse; D012259:Ribonuclease, Pancreatic