The anti-interleukin-6 antibody ALD518-P18 mitigates murine kidney ischemia–reperfusion injury

Abstract

Abstract Interleukin-6 (IL-6) is a key pleiotropic cytokine implicated in kidney injury; however, the therapeutic potential of IL-6 blockade against acute ischemia–reperfusion injury (IRI) remains uncertain, with previous murine studies yielding conflicting results. This study investigated the protective effects of the high-affinity chimeric anti-IL-6 monoclonal antibody, cALD518-P18, in a non-transplant mouse model of warm renal IRI (22 min ischemia, 24 h reperfusion). Male C57BL/6 mice received a single 40 mg/kg dose of cALD518-P18 or an isotype control, administered either intraperitoneally 30 min before ischemia or intravenously immediately after ischemia. At 24 h, control mice exhibited significant kidney dysfunction (serum creatinine, urea), injury, and inflammation, consistent with elevated pro-inflammatory IL-6 trans-signalling (soluble IL-6R (sIL-6R) and tubular STAT3 phosphorylation (pSTAT3)). Treatment with cALD518-P18, in both regimens, significantly protected the kidneys from IRI, demonstrating improved renal function and reduced tissue damage. The antibody attenuated inflammation, endothelial activation and pSTAT3 signalling, significantly downregulating gene expression of the acute tubular stress marker NGAL. These findings confirm the pathogenic role of IL-6 and highlight its early blockade with cALD518-P18 as a promising therapeutic strategy to improve outcomes in acute kidney injury and transplantation.