Antibodies to mannose-binding lectin and factor XI Inhibit Shiga toxin-induced kidney injury additively in a murine model

BACKGROUND: Enterohemorrhagic HUS (eHUS), triggered by Shiga toxin (STX), is a thrombotic microangiopathy and major cause of acute kidney injury (AKI) in children. Of those hospitalized, ~65% require dialysis, while others may suffer seizures, neurocognitive deficits from cerebral ischemia, other organ failure ( ~ 30%), and death (3-5%). Long-term sequelae include chronic kidney disease, hypertension, insulin-dependent diabetes, and neurocognitive impairment. No therapeutic agents are effective and/or approved by the Food and Drug Administration, or similar bodies. METHODS: We have identified two potential therapeutic targets-mannose-binding lectin-2 (MBL2) of the lectin complement pathway and clotting factor XIa (FXIa) of the intrinsic coagulation pathway. We previously reported the importance of MBL2 in a mouse model of Shiga Toxin-induced kidney injury, using 3F8, a mouse anti-human MBL2 antibody, and procoagulant activity in an endothelial monolayer model. We now report important roles for both clotting factor XI and MBL2 in this model, employing 3G3, a humanized anti-FXIa antibody, and 3F8 together. RESULTS: The antibody combination is superior to either antibody alone in reducing glomerular platelet deposition, and to 3F8 in reducing fibrin deposition. Only the combination is effective in lowering AKI, hemolysis, and weight loss. CONCLUSION: The antibody combination may have therapeutic application in affected children. IMPACT: Enterohemorrhagic hemolytic uremic syndrome causes acute renal failure in 65% of affected children, seizures and neurocognitive deficits from cerebral ischemic events in 3-5%, other organ system failure in 20-30%, and death in 3-5%. There presently exists no specific therapy, only supportive care. We have found in our mouse model of Shiga Toxin-induced kidney injury that monoclonal antibodies against the mannose binding lectin-2 (MBL2) of the lectin complement pathway, and factor XI/XIa of the contact coagulation pathway show clear benefit used singly, but even greater benefit in combination. The combination offers promise for an effective first specific therapy.