Iron and Hemolysis and Hematoma
Treatment of Marmoset Intracerebral Hemorrhage with Humanized Anti-HMGB1 mAb
by Dengli Wang 1ORCID,Daiki Ousaka 1ORCID,Handong Qiao 1,Ziyi Wang 2,3ORCID,Kun Zhao 3,Shangze Gao 4,Keyue Liu 1,Kiyoshi Teshigawara 1,Kenzo Takada 5 andMasahiro Nishibori 6,*
Department of Pharmacology, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama 7008558, Japan
Research Fellow of Japan Society for the Promotion of Science, Tokyo 1020083, Japan
Department of Molecular Biology and Biochemistry, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 7008558, Japan
School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China Sapporo Laboratory, EVEC, Inc., Sapporo 0606642, Japan
Department of Translational Research and Drug Development, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 7008558, Japan
Cells 2022, 11(19), 2970; https://doi.org/10.3390/cells11192970
Received: 23 August 2022 / Revised: 9 September 2022 / Accepted: 15 September 2022 / Published: 23 September 2022
(This article belongs to the Special Issue High Mobility Group Box-1 (HMGB1) in a Neuroimmune Crosstalk)
Abstract
Intracerebral hemorrhage (ICH) is recognized as a severe 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 in a rat ICH model. Therefore, we developed a humanized anti-HMGB1 mAb (OKY001) for clinical use. The present study
examined whether and how the humanized anti-HMGB1 mAb ameliorates ICH injury in common marmosets. The results show that administration of humanized anti-HMGB1 mAb inhibited HMGB1 release from the brain into plasma, in association with a decrease of 4-
hydroxynonenal (4-HNE) accumulation and a decrease in cerebral iron deposition. In addition, humanized anti-HMGB1 mAb treatment resulted in a reduction in brain injury volume at 12 d after ICH induction. Our in vitro experiment showed that recombinant
HMGB1 inhibited hemoglobin uptake by macrophages through CD163 in the presence of haptoglobin, suggesting that the release of excess HMGB1 from the brain may induce a delay in hemoglobin scavenging, thereby allowing the toxic effects of hemoglobin, heme,
and Fe2+ to persist. Finally, humanized anti-HMGB1 mAb reduced body weight loss and improved behavioral performance after ICH. Taken together, these results suggest that intravenous injection of humanized anti-HMGB1 mAb has potential as a novel
therapeutic strategy for ICH.

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