Prolonged Benefit of Reltecimod Despite Short Plasma Half-Life

Reltecimod (previously AB103 or p2TA) is a short-peptide mimetic of the CD28 costimulatory receptor on T cells that attenuates CD28/B7-2 signaling, which are responsible for the hyperinflammatory response that is observed during severe infections. A single-dose of reltecimod provides sustained survival benefit in animal models of sepsis and clinical benefit in patients with necrotizing soft tissue infections. Here, the pharmacokinetic/pharmacodynamics profile of reltecimod was evaluated to determine the basis of its sustained single-dose effect. The half-life of reltecimod was assessed using bioanalytical methods in different animals, and the biodistribution was studied in male BALB/c mice that were administered a single intravenous dose of [¹⁴C]-reltecimod. Blood partitioning was performed, and the minimal time to observe efficacy of reltecimod was evaluated in vitro. The plasma half-life of reltecimod was short in humans and all tested animal models, ranging from 1 to 8 min. Upon leaving the blood vessels, reltecimod quickly redistributed to lymphatic tissues, where T cells are produced and exposed to antigens. Lymphatic concentration of reltecimod was 22 times higher than plasma concentration by 20 min post-administration, and reltecimod was enriched in the white blood cell fraction of blood (6.8% after 2 h). Reltecimod had a rapid onset of effect (5 min) that lasted for at least 12 h based on levels of IFN-γ that were secreted by antigen-activated human peripheral blood mononuclear cells. This suggests that reltecimod’s prolonged clinical benefits are based on fast distribution to target organs and rapid intervention with signaling pathways, irrespective of its short residence time in the plasma.