Treatment of intracerebral hemorrhage with humanized a-HMGB1 mAb in non-human primate brain

Abstract

Intracerebral hemorrhage (ICH) is recognized as a serious clinical problem lacking effective treatment. High mobility group box-1 (HMGB1) exhibits inflammatory cytokine-like activity once released into the extracellular space from the nuclei. We previously demonstrated that intravenous injection of rat anti-HMGB1 monoclonal antibody (mAb) remarkably ameliorated brain injury induced by hemorrhage in the striatum of rat. In the present study, we examined whether and how humanized anti-HMGB1 mAb (OKY001) effects on ICH injury in common marmoset. The results show that administration of OKY001 inhibited the release of HMGB1 from brain into plasma, which was associated with the decrease of 4-HNE adduct accumulation in the brain and plasma. Besides, brain injury volume was ameliorated by treatment of OKY001 at 12 d after ICH induction. In vitro experiment showed that haptoglobin increased the uptake of hemoglobin and HMGB1 by THP1 cell respectively. However, recombinant HMGB1 inhibited the uptake of hemoglobin by THP1 cell, which suggested that abundant HMGB1 released form the brain impeded the absorption of hematoma. Moreover, OKY001 reduced body weight loss and improved the behavioral performance. Taken together, these results suggest that intravenous injection of OKY001 has potential as a novel therapeutic strategy for ICH disease.