Han S, Lee SJ, Kim KE, Lee HS, Oh N, Park I, Ko E, Oh SJ, Lee YS, Kim D, Lee S, Lee DH, Lee KH, Chae SY, Lee JH, Kim SJ, Kim HC, Kim S, Kim SH, Kim C, Nakaoka Y, He Y, Augustin HG, Hu J, Song PH, Kim YI, Kim P, Kim I and Koh GY
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.
Fig. 7. ABTAA blunts cytokine storm and ANG2 surge in sepsis.
(A to E) Fc, ABA (AB), or ABTAA (AT) (10 mg/kg) was given at 6 hours after CLP (indicated by arrows), and blood samples and lungs were collected at indicated time points. (A to C) Temporal changes of TNF-α, IL-6, and ANG2 concentrations in serum after CLP (each group, n = 6 to 8). (D and E) Representative images and comparison (each group, n = 3 to 4) of colocalization of Fc, ABA, or ABTAA with lung ECs (arrowheads). Lungs were harvested at 2 hours after antibody injection, and the injected antibodies were directly detected by anti-human IgG secondary antibody. (F) Total, free, and antibody-bound ANG2 in serum at 18 hours after CLP with pretreatment of Fc, ABA, REGN 910 (RGN), or ABTAA (10 mg/kg) 1 hour before CLP. Each group, n = 5 to 6. (G) A schematic model showing how ABTAA induces ANG2 clustering, resulting in clustering and activation of TIE2 receptors on ECs in sepsis. Ultimately, ANG2 sequestering and TIE2 activation by ABTAA reduces vascular leakage, protects glycocalyx, and suppresses inflammatory responses. Scale bars, 20 μm. Bars indicate means ± SEM. *P < 0.05 versus Fc; #P < 0.05 versus AB.
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