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 for the first time the in vivo efficacy of TriFu, an engineered fusion protein comprising key domains of three 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 OmCI, 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 (e.g., IL-6, TNF-α). These findings suggest that regulatory modulation of complement could offer advantages over C5 inhibition, providing a more balanced and adaptive therapeutic approach.