Amelioration of sepsis by TIE2 activation–induced vascular protection

Vascular protection through TIE2 activation is a potential treatment strategy to ameliorate sepsis. Antibody TIEs sepsis up in knots Sepsis, or severe systemic inflammation caused by infection, has a high mortality despite the availability of antibiotic treatment, and more specific therapies are urgently needed. One of the difficult-to-treat and potentially life-threatening components of sepsis is vascular disintegration and leakage. Han et al. have discovered an antibody, called ABTAA, which binds to a ligand called angiopoietin 2 (ANG2) in the vasculature, but then activates it instead of blocking its activity like standard antibodies. When ABTAA binds to ANG2, it causes clustering of ANG2 and subsequently its receptor TIE2 at the site, and the resulting signaling cascade protects the vascular walls and blunts the damaging effects of sepsis, greatly increasing survival in mouse models of the disease. 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.