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Circulating Microvesicle-Associated Inducible Nitric Oxide Synthase Is a Novel Therapeutic Target to Treat Sepsis: Current Status and Future Considerations.
Webber, Robert J; Sweet, Richard M; Webber, Douglas S.
  • Webber RJ; Research & Diagnostic Antibodies, Las Vegas, NV 89117, USA.
  • Sweet RM; School of Medicine, University of California, San Francisco, CA 94143, USA.
  • Webber DS; Renal Department, Zuckerberg San Francisco General Hospital, San Francisco, CA 94110, USA.
Int J Mol Sci ; 22(24)2021 Dec 13.
Article in English | MEDLINE | ID: covidwho-1599176
ABSTRACT
To determine whether mitigating the harmful effects of circulating microvesicle-associated inducible nitric oxide (MV-A iNOS) in vivo increases the survival of challenged mice in three different mouse models of sepsis, the ability of anti-MV-A iNOS monoclonal antibodies (mAbs) to rescue challenged mice was assessed using three different mouse models of sepsis. The vivarium of a research laboratory Balb/c mice were challenged with an LD80 dose of either lipopolysaccharide (LPS/endotoxin), TNFα, or MV-A iNOS and then treated at various times after the challenge with saline as control or with an anti-MV-A iNOS mAb as a potential immunotherapeutic to treat sepsis. Each group of mice was checked daily for survivors, and Kaplan-Meier survival curves were constructed. Five different murine anti-MV-A iNOS mAbs from our panel of 24 murine anti-MV-A iNOS mAbs were found to rescue some of the challenged mice. All five murine mAbs were used to genetically engineer humanized anti-MV-A iNOS mAbs by inserting the murine complementarity-determining regions (CDRs) into a human IgG1,kappa scaffold and expressing the humanized mAbs in CHO cells. Three humanized anti-MV-A iNOS mAbs were effective at rescuing mice from sepsis in three different animal models of sepsis. The effectiveness of the treatment was both time- and dose-dependent. Humanized anti-MV-A iNOS rHJ mAb could rescue up to 80% of the challenged animals if administered early and at a high dose. Our conclusions are that MV-A iNOS is a novel therapeutic target to treat sepsis; anti-MV-A iNOS mAbs can mitigate the harmful effects of MV-A iNOS; the neutralizing mAb's efficacy is both time- and dose-dependent; and a specifically targeted immunotherapeutic for MV-A iNOS could potentially save tens of thousands of lives annually and could result in improved antibiotic stewardship.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Sepsis / Nitric Oxide Synthase Type II / Cell-Derived Microparticles Type of study: Prognostic study Limits: Animals / Humans Language: English Year: 2021 Document Type: Article Affiliation country: Ijms222413371

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Sepsis / Nitric Oxide Synthase Type II / Cell-Derived Microparticles Type of study: Prognostic study Limits: Animals / Humans Language: English Year: 2021 Document Type: Article Affiliation country: Ijms222413371