A novel high mobility group box 1 neutralizing chimeric antibody attenuates drug-induced liver injury and postinjury inflammation in mice

Research output: Contribution to journalArticle

Abstract

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).

Details

Authors
  • Peter Lundbäck
  • Jonathan D. Lea
  • Agnieszka Sowinska
  • Lars Ottosson
  • Camilla Melin Fürst
  • Johanna Steen
  • Cecilia Aulin
  • Joanna I. Clarke
  • Anja Kipar
  • Lena Klevenvall
  • Huan Yang
  • Karin Palmblad
  • B. Kevin Park
  • Kevin J. Tracey
  • Anna M. Blom
  • Ulf Andersson
  • Daniel J. Antoine
  • Helena Erlandsson Harris
Organisations
External organisations
  • University of Liverpool
  • Karolinska Institutet
  • Feinstein Institute for Medical Research
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Gastroenterology and Hepatology
Original languageEnglish
Pages (from-to)1699-1710
Number of pages12
JournalHepatology
Volume64
Issue number5
Publication statusPublished - 2016 Nov 1
Publication categoryResearch
Peer-reviewedYes