Treatment with One Dose of Reltecimod is Superior to Two Doses in Mouse Models of Lethal Infection

Abstract

Soft-tissue bacterial infection can progress to severe sepsis and septic shock as a result of a disproportionate infammatory response, characterized by an excessive release of cytokines and infux of immune cells. Reltecimod (previously known as AB103 or p2TA), a peptide derived from the T-cell receptor CD28, modulates the host immune response by targeting the co-stimulatory pathway, which is essential for the induction of multiple pro-infammatory cytokines. Consequently, reltecimod has demonstrated benefcial efects against diferent bacterial infections, their exotoxins and endotoxins, and ionizing radiation. The dosing regimen of reltecimod was evaluated in three mouse models of infection. The efect of the number of reltecimod doses with respect to survival, cytokine/chemokine levels, and blood leukocyte profles was assessed. Overall, mice treated with a single intravenous dose of reltecimod (5 mg/kg) at 1–2 h after infection showed signifcantly greater survival as compared with saline-treated controls. Mice treated with a second doses demonstrated improved survival compared with saline-treated controls. However, in all models of infection, administration of a single therapeutic dose of reltecimod was superior to two or multiple doses. Further examination showed that the single therapeutic dose of reltecimod was associated with an early (within 24 h) decrease in cytokine/chemokine levels and most circulating leukocyte subpopulations. A second dose of reltecimod did not improve these early positive efects and appeared to attenuate further changes. These results provided insight into the mechanism of action of reltecimod and established a basis for the dosing regimen utilized in clinical trials, where reltecimod is administered as a single dose.