Mitigation of septic shock in mice and rhesus monkeys by human chorionic gonadotrophin-related oligopeptides

Abstract

SummaryThe marked improvement of several immune-mediated inflammatory diseases during pregnancy has drawn attention to pregnancy hormones as potential therapeutics for such disorders. Low molecular weight fractions derived from the pregnancy hormone human chorionic gonadotrophin (hCG) have remarkable potent immunosuppressive effects in mouse models of diabetes and septic shock. Based on these data we have designed a set of oligopeptides related to the primary structure of hCG and tested these in models of septic shock in mice and rhesus monkeys. We demonstrate that mice exposed to lipopolysaccharide (LPS) and treated subsequently with selected tri-, tetra-, penta-and hepta-meric oligopeptides (i.e. MTR, VVC, MTRV, LQGV, AQGV, VLPALP, VLPALPQ) are protected against fatal LPS-induced septic shock. Moreover, administration of a cocktail of three selected oligopeptides (LQGV, AQGV and VLPALP) improved the pathological features markedly and nearly improved haemodynamic parameters associated with intravenous Escherichia coli-induced septic shock in rhesus monkeys. These data indicate that the designed hCG-related oligopeptides may present a potential treatment for the initial hyperdynamic phase of septic shock in humans.

Pharmacokinetics, safety and tolerability of the novel β‐hCG derived immunomodulatory compound, EA‐230

“…20 Recent studies in animal models of systemic inflammation have shown that these oligopeptides exert immunomodulatory effects and limit organ failure and mortality. [21][22][23][24][25][26][27][28][29] Of particular interest is the linear tetrapeptide alanine-glutamine-glycine-valine (AQGV), which has shown the most promising effects up till now. This peptide preserved kidney function and substantially reduced mortality in murine models of renal ischaemia and reperfusion.…”

“…22 Furthermore, it attenuated the release of inflammatory mediators during haemorrhagic and endotoxemiainduced shock in mice and monkeys. 23,24,28 AQGV is currently developed under the product name EA-230 as a potential novel immune modulatory compound. The present work describes three phase I studies in which the first-in-human pharmacokinetics, safety and tolerability of EA-230 are investigated, using escalating single and multiple dosages as well as escalating continuous dosages.…”

Immunomodulatory and Kidney-Protective Effects of the Human Chorionic Gonadotropin Derivate EA-230

“…EA-230 prevented mortality in endotoxemic mice both when administered early (2 h) and late (24 h) after endotoxin administration [10]. Furthermore, a cocktail of 3 oligopeptides including EA-230 reduced the severity of sepsis induced by infusion of live E. coli in rhesus monkeys [10]. EA-230 also mitigated the release of inflammatory mediators, preserved renal function and improved survival in murine models of renal ischaemiareperfusion and kidney transplantation [12,13].…”

“…Of particular interest is the linear tetrapeptide AlanineGlutamine-Glycine-Valine, later coined EA-230, which showed high efficacy in terms of beneficial effects [8,10,12]. EA-230 prevented mortality in endotoxemic mice both when administered early (2 h) and late (24 h) after endotoxin administration [10]. Furthermore, a cocktail of 3 oligopeptides including EA-230 reduced the severity of sepsis induced by infusion of live E. coli in rhesus monkeys [10].…”

“…Recent studies in animal models of systemic inflammation showed that these oligopeptides exert immunomodulatory properties and limit organ failure and mortality [8][9][10][11]. Of particular interest is the linear tetrapeptide AlanineGlutamine-Glycine-Valine, later coined EA-230, which showed high efficacy in terms of beneficial effects [8,10,12]. EA-230 prevented mortality in endotoxemic mice both when administered early (2 h) and late (24 h) after endotoxin administration [10].…”