In vivo evidence of effective complement modulation by TriFu in comparison to C5 inhibition and complement depletion.

The therapeutic landscape of complement inhibition has recently expanded considerably. However, most approved agents specifically target single complement components systemically, which can result in limited functional effects. In fact, stoichiometric inhibition has shown limitations both in vitro and in vivo. In this study, we evaluated, to our knowledge, for the first time the in vivo efficacy of "triple-fusion" (TriFu), an engineered fusion protein comprising key domains of 3 natural complement regulators, CD55, factor H, and CD35, including a host-recognition motif. In a rat xenotransfusion model, TriFu provided favorable protection of transfused human red blood cells compared to C5 inhibition by Ornithodoros moubata complement inhibitor, prolonging circulation time on par with cobra venom factor-mediated complement depletion and completely inhibiting C3 opsonization. Furthermore, TriFu treatment improved multiple clinical inflammatory parameters (eg, interleukin-6 and tumor necrosis factor α). These findings suggest that regulatory modulation of complement could offer advantages over C5 inhibition, providing a more balanced and adaptive therapeutic approach.