start-ver=1.4 cd-journal=joma no-vol=11 cd-vols= no-issue=19 article-no= start-page=2970 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20220923 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Treatment of Marmoset Intracerebral Hemorrhage with Humanized Anti-HMGB1 mAb en-subtitle= kn-subtitle= en-abstract= kn-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. en-copyright= kn-copyright= en-aut-name=WangDengli en-aut-sei=Wang en-aut-mei=Dengli kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=OusakaDaiki en-aut-sei=Ousaka en-aut-mei=Daiki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=QiaoHandong en-aut-sei=Qiao en-aut-mei=Handong kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=WangZiyi en-aut-sei=Wang en-aut-mei=Ziyi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=ZhaoKun en-aut-sei=Zhao en-aut-mei=Kun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=GaoShangze en-aut-sei=Gao en-aut-mei=Shangze kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=LiuKeyue en-aut-sei=Liu en-aut-mei=Keyue kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TeshigawaraKiyoshi en-aut-sei=Teshigawara en-aut-mei=Kiyoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=TakadaKenzo en-aut-sei=Takada en-aut-mei=Kenzo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=NishiboriMasahiro en-aut-sei=Nishibori en-aut-mei=Masahiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Department of Pharmacology, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Pharmacology, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Pharmacology, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Research Fellow of Japan Society for the Promotion of Science kn-affil= affil-num=5 en-affil=Department of Molecular Biology and Biochemistry, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=6 en-affil=School of Pharmaceutical Sciences, Tsinghua University kn-affil= affil-num=7 en-affil=Department of Pharmacology, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Pharmacology, Faculty of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=9 en-affil=Sapporo Laboratory, EVEC, Inc. kn-affil= affil-num=10 en-affil=Department of Translational Research and Drug Development, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=intracerebral hemorrhage kn-keyword=intracerebral hemorrhage en-keyword=HMGB1 kn-keyword=HMGB1 en-keyword=antibody therapy kn-keyword=antibody therapy en-keyword=non-human primate kn-keyword=non-human primate END