Targeting different isoforms of HMGB1 leads to different beneficial effects in preclinical models of sepsis and inflammatory arthritis (100.6)

Abstract

Abstract HMGB1 is a multifunctional protein that exerts diverse proinflammatory effects when released into the extracellular milieu. Because several HMGB1 isoforms may be generated depending on the activation state of a cell, these isoforms may play distinct roles in different inflammatory disorders. To examine this, we generated a panel of fully human anti-HMGB1 monoclonal antibodies using a phage display approach. The two most potent mAbs, IA-4 and IA-6, displayed comparable binding affinity to HMGB1 (KD=30 and 39nM) and blockade of HMGB1/RAGE binding (IC50=0.9 and 1.2nM). However, only IA-4 but not IA-6 could detect HMGB1 actively secreted from LPS-treated cells. IA-4 and IA-6 were then tested in rodent models of inflammatory arthritis (rat AIA) and sepsis (mouse CLP). IA-4 reduced paw swelling in the rat AIA model (32% inhibition @ 10mg/kg, p<0.05 vs. isotype control, n=32) while IA-6 had little effect. In contrast, only IA-6 but not IA-4 prolonged survival in the mouse CLP model (@ 8mg/kg , p<0.05 vs. isotype control, n=72). IA-4 and IA-6 displayed similar pharmacokinetics and recognized recombinant rodent HMGB1 with equal affinity. In summary, these results suggest that different isoforms of HMGB1 may have distinct in vivo roles and that HMGB1 mAbs targeting these isoforms may provide tailored therapeutics.