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Article: An MMP-9 exclusive neutralizing antibody attenuates blood-brain barrier breakdown in mice with stroke and reduces stroke patient-derived MMP-9 activity

TitleAn MMP-9 exclusive neutralizing antibody attenuates blood-brain barrier breakdown in mice with stroke and reduces stroke patient-derived MMP-9 activity
Authors
KeywordsAntibody therapy
Blood-brain barrier
Intracranial hemorrhage
Ischemic stroke
MMP-9
Issue Date7-Mar-2023
PublisherElsevier
Citation
Pharmacological Research, 2023, v. 190 How to Cite?
Abstract

Rapid upregulation of matrix metalloproteinase 9 (MMP-9) leads to blood-brain barrier (BBB) breakdown following stroke, but no MMP-9 inhibitors have been approved in clinic largely due to their low specificities and side effects. Here, we explored the therapeutic potential of a human IgG monoclonal antibody (mAb), L13, which was recently developed with exclusive neutralizing specificity to MMP-9, nanomolar potency, and biological function, using mouse stroke models and stroke patient samples. We found that L13 treatment at the onset of reperfusion following cerebral ischemia or after intracranial hemorrhage (ICH) significantly reduced brain tissue injury and improved the neurological outcomes of mice. Compared to control IgG, L13 substantially attenuated BBB breakdown in both types of stroke model by inhibiting MMP-9 activity-mediated degradations of basement membrane and endothelial tight junction proteins. Importantly, these BBB-protective and neuroprotective effects of L13 in wild-type mice were comparable to Mmp9 genetic deletion and fully abolished in Mmp9 knockout mice, highlighting the in vivo target specificity of L13. Meanwhile, ex vivo co-incubation with L13 significantly neutralized the enzymatic activities of human MMP-9 in the sera of ischemic and hemorrhagic stroke patients, or in the peri-hematoma brain tissues from hemorrhagic stroke patients. Overall, we demonstrated that MMP-9 exclusive neutralizing mAbs constitute a potential feasible therapeutic approach for both ischemic and hemorrhagic stroke.


Persistent Identifierhttp://hdl.handle.net/10722/331507
ISSN
2023 Impact Factor: 9.1
2023 SCImago Journal Rankings: 2.160
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorJi, YB-
dc.contributor.authorGao, Q-
dc.contributor.authorMa, YZ-
dc.contributor.authorWang, F-
dc.contributor.authorTan, XX-
dc.contributor.authorSong, DP-
dc.contributor.authorHoo, RLC-
dc.contributor.authorWang, ZN-
dc.contributor.authorGe, X-
dc.contributor.authorHan, HJ-
dc.contributor.authorGuo, FY-
dc.contributor.authorChang, JL-
dc.date.accessioned2023-09-21T06:56:27Z-
dc.date.available2023-09-21T06:56:27Z-
dc.date.issued2023-03-07-
dc.identifier.citationPharmacological Research, 2023, v. 190-
dc.identifier.issn1043-6618-
dc.identifier.urihttp://hdl.handle.net/10722/331507-
dc.description.abstract<p>Rapid upregulation of matrix metalloproteinase 9 (MMP-9) leads to blood-brain barrier (BBB) breakdown following stroke, but no MMP-9 inhibitors have been approved in clinic largely due to their low specificities and side effects. Here, we explored the therapeutic potential of a human IgG monoclonal antibody (mAb), L13, which was recently developed with exclusive neutralizing specificity to MMP-9, nanomolar potency, and biological function, using mouse stroke models and stroke patient samples. We found that L13 treatment at the onset of reperfusion following cerebral ischemia or after intracranial hemorrhage (ICH) significantly reduced brain tissue injury and improved the neurological outcomes of mice. Compared to control IgG, L13 substantially attenuated BBB breakdown in both types of stroke model by inhibiting MMP-9 activity-mediated degradations of basement membrane and endothelial tight junction proteins. Importantly, these BBB-protective and neuroprotective effects of L13 in wild-type mice were comparable to Mmp9 genetic deletion and fully abolished in Mmp9 knockout mice, highlighting the in vivo target specificity of L13. Meanwhile, ex vivo co-incubation with L13 significantly neutralized the enzymatic activities of human MMP-9 in the sera of ischemic and hemorrhagic stroke patients, or in the peri-hematoma brain tissues from hemorrhagic stroke patients. Overall, we demonstrated that MMP-9 exclusive neutralizing mAbs constitute a potential feasible therapeutic approach for both ischemic and hemorrhagic stroke.<br></p>-
dc.languageeng-
dc.publisherElsevier-
dc.relation.ispartofPharmacological Research-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectAntibody therapy-
dc.subjectBlood-brain barrier-
dc.subjectIntracranial hemorrhage-
dc.subjectIschemic stroke-
dc.subjectMMP-9-
dc.titleAn MMP-9 exclusive neutralizing antibody attenuates blood-brain barrier breakdown in mice with stroke and reduces stroke patient-derived MMP-9 activity-
dc.typeArticle-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1016/j.phrs.2023.106720-
dc.identifier.scopuseid_2-s2.0-85149759858-
dc.identifier.volume190-
dc.identifier.eissn1096-1186-
dc.identifier.isiWOS:000954975100001-
dc.identifier.issnl1043-6618-

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