Harnessing native corticosteroid-binding globulin to treat life-threatening septic shock

Septic shock urgently requires new treatments. We reported that low circulating concentrations of the native glucocorticoid carrier, corticosteroid-binding globulin (CBG), predict a three-fold increase in human septic shock mortality. To explore this, we used our murine model of high-grade polymicrobial sepsis (cecal ligation and puncture, CLP) to test CBG therapy. We pre-fitted adult male C57BL/6 mice (n=106) with wireless arterial telemetry, then induced high-grade CLP. Mice were randomised with or without intravenous CBG therapy at 6 hr (3.5 mg/kg) and 30 hr (2.5 mg/kg). Terminal bloods, collected on humane endpoints or at 96 hr, were assessed for inflammation and organ damage; PET imaging was used to assess [124I]I-CBG biodistribution. CLP mice developed septic shock leading to multi-organ failure and 58% mortality. CBG therapy reduced mortality to 17% (a relative decrease of 72%), reduced hypotension duration by 75%, and lowered organ damage markers. CBG transiently suppressed the pro-inflammatory cytokine peak at 12 hr (45-59%) and markedly augmented anti-inflammatory IL-10 and IFN-β1 (2-fold to 96 hr). The decrease in corticosterone alongside this profile suggests an intrinsic anti-inflammatory response. Combined with PET-confirmed [124I]I-CBG targeting to the injury site, these data suggest CBG survival benefits are due to targeted delivery or direct immunomodulation. While host responses involve a complex interplay of neuroendocrine and metabolic factors, our findings demonstrate marked improvements in disease progression and mortality with CBG therapy in murine modelled septic shock. These results provide a strong impetus for a study of CBG therapy in patients with septic shock.