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A novel high mobili...
A novel high mobility group box 1 neutralizing chimeric antibody attenuates drug-induced liver injury and postinjury inflammation in mice
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- Lundbäck, Peter (författare)
- Karolinska Institute
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- Lea, Jonathan D. (författare)
- University of Liverpool
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- Sowinska, Agnieszka (författare)
- Karolinska Institute
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- Ottosson, Lars (författare)
- Karolinska Institutet,Karolinska Institute
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- Fürst, Camilla Melin (författare)
- Karolinska Institutet,Lund University,Lunds universitet,Proteinkemi, Malmö,Forskargrupper vid Lunds universitet,Protein Chemistry, Malmö,Lund University Research Groups
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- Steen, Johanna (författare)
- Karolinska Institute
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- Aulin, Cecilia (författare)
- Karolinska Institute
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- Clarke, Joanna I. (författare)
- University of Liverpool
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- Kipar, Anja (författare)
- University of Liverpool
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- Klevenvall, Lena (författare)
- Karolinska Institutet,Karolinska Institute
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- Yang, Huan (författare)
- Feinstein Institute for Medical Research
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- Palmblad, Karin (författare)
- Karolinska Institutet,Karolinska Institute
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- Park, B. Kevin (författare)
- University of Liverpool
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- Tracey, Kevin J. (författare)
- Feinstein Institute for Medical Research
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- Blom, Anna M. (författare)
- Lund University,Lunds universitet,Proteinkemi, Malmö,Forskargrupper vid Lunds universitet,Protein Chemistry, Malmö,Lund University Research Groups
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- Andersson, Ulf (författare)
- Karolinska Institutet,Karolinska Institute
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- Antoine, Daniel J. (författare)
- University of Liverpool
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- Erlandsson Harris, Helena (författare)
- Karolinska Institutet,Karolinska Institute
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(creator_code:org_t)
- 2016-09-01
- 2016
- Engelska 12 s.
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Ingår i: Hepatology. - : Ovid Technologies (Wolters Kluwer Health). - 0270-9139 .- 1527-3350. ; 64:5, s. 1699-1710
- Relaterad länk:
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http://dx.doi.org/10... (free)
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https://doi.org/10.1...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
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- Acetaminophen (APAP) overdoses are of major clinical concern. Growing evidence underlines a pathogenic contribution of sterile postinjury inflammation in APAP-induced acute liver injury (APAP-ALI) and justifies development of anti-inflammatory therapies with therapeutic efficacy beyond the therapeutic window of the only current treatment option, N-acetylcysteine (NAC). The inflammatory mediator, high mobility group box 1 (HMGB1), is a key regulator of a range of liver injury conditions and is elevated in clinical and preclinical APAP-ALI. The anti-HMGB1 antibody (m2G7) is therapeutically beneficial in multiple inflammatory conditions, and anti-HMGB1 polyclonal antibody treatment improves survival in a model of APAP-ALI. Herein, we developed and investigated the therapeutic efficacy of a partly humanized anti-HMGB1 monoclonal antibody (mAb; h2G7) and identified its mechanism of action in preclinical APAP-ALI. The mouse anti-HMGB1 mAb (m2G7) was partly humanized (h2G7) by merging variable domains of m2G7 with human antibody-Fc backbones. Effector function-deficient variants of h2G7 were assessed in comparison with h2G7 in vitro and in preclinical APAP-ALI. h2G7 retained identical antigen specificity and comparable affinity as m2G7. 2G7 treatments significantly attenuated APAP-induced serum elevations of alanine aminotransferase and microRNA-122 and completely abrogated markers of APAP-induced inflammation (tumor necrosis factor, monocyte chemoattractant protein 1, and chemokine [C-X-C motif] ligand 1) with prolonged therapeutic efficacy as compared to NAC. Removal of complement and/or Fc receptor binding did not affect h2G7 efficacy. Conclusion: This is the first report describing the generation of a partly humanized HMGB1-neutralizing antibody with validated therapeutic efficacy and with a prolonged therapeutic window, as compared to NAC, in APAP-ALI. The therapeutic effect was mediated by HMGB1 neutralization and attenuation of postinjury inflammation. These results represent important progress toward clinical implementation of HMGB1-specific therapy as a means to treat APAP-ALI and other inflammatory conditions. (Hepatology 2016;64:1699-1710).
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Gastroenterologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Gastroenterology and Hepatology (hsv//eng)
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- art (ämneskategori)
- ref (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Lundbäck, Peter
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Lea, Jonathan D.
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Sowinska, Agnies ...
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Ottosson, Lars
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Fürst, Camilla M ...
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Steen, Johanna
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Aulin, Cecilia
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Clarke, Joanna I ...
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Kipar, Anja
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Klevenvall, Lena
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Yang, Huan
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Palmblad, Karin
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Park, B. Kevin
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Tracey, Kevin J.
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Blom, Anna M.
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Andersson, Ulf
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Antoine, Daniel ...
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Erlandsson Harri ...
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- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Gastroenterologi
- Artiklar i publikationen
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Hepatology
- Av lärosätet
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Lunds universitet
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Karolinska Institutet