An antibody that defends blood vessels against sepsis can prevent mice from succumbing to the disease, a new study shows. Instead of targeting the pathogen or the body's inflammation response as existing, unsuccessful sepsis treatments have done, this approach targets the patient's vascular response. What's more, unlike conventional therapeutic antibodies, the antibody involved here works by converting a normally harmful protein into a protective one. No specific treatment is currently available for sepsis, which affects 19 million people worldwide each year and is a leading cause of death in hospitalized patients. Sepsis involves body-wide inflammation driven by an overwhelming immune response to infection. In particular, vascular inflammation can cause blood vessels to break down and leak fluid, potentially leading to organ failure and septic shock. TIE2, a receptor found on endothelial cells lining the inside of blood vessels, has emerged as an important therapeutic target for sepsis. The receptor bolsters the endothelial barrier against vascular inflammation and leakage. However, existing compounds that stimulate TIE2 or inhibit ANG2, a secreted protein that blocks the receptor, have proven only partially effective or impractical for clinical use. Sangyeul Han and colleagues developed an unusual antibody that binds to ANG2, forming a complex that activates instead of inhibits both ANG2 and TIE2. In multiple mouse models of sepsis, the antibody prolonged survival better than did a conventional ANG2-blocking antibody. Combining the researchers' antibody with antibiotics further enhanced survival from sepsis caused by bacterial infection. Experiments showed that the antibody stabilized blood vessels, strengthened barrier function, and quelled systemic inflammation. The findings advance the antibody as a potential treatment for sepsis and possibly other diseases involving vascular leakage, such as Ebola, malaria, and anthrax. A related Focus by Samir Parikh offers additional insights.