The development of biologics inhibiting IL-33signaling on the basis of the signal transduction mechanisms

IL-33 contributes to the pathogenesis of allergic diseases. Upon the binding ofIL-33 to a membrane receptor ST2, IL-1 receptor accessory protein (IL-1RAcP) isrecruited to form a heterodimeric receptor complex which transmits a signal. Onthe other hand, a soluble form of ST2 acts as an endogenous inhibitor of IL-33signaling. Here, we aimed to develop the biologics inhibiting IL-33 signaling.First, we generated IL-33 reporter cell lines, in which IL-33 stimulationinduced NFkB-driven expression of DsRed. We then generated IL-33trap-Fc which iscomposed of extracellular domains of IL-1RAcP and ST2 fused to the Fc portion ofhuman IgG. Notably, IL-33trap-Fc more strongly suppressed IL-33-stimulated DsRedexpression in the reporter cells than ST2-Fc which is composed of anextracellular domain of ST2 fused to human IgG Fc. Consistently, IL-33trap-Fcremarkably inhibited IL-33-stimulated IL-6 production of bone marrow-derivedmast cells as compared with ST2-Fc. Moreover, intraperitoneal administration ofIL-33trap-Fc efficiently inhibited IL-33-stimulated eosinophil accumulation invivo. Taken together, these results indicated that IL-33trap-Fc was effective ininhibiting IL-33 signaling. We also attempt to generate the biologics that bindto ST2 but fail to recruit IL-1RAcP, thereby blocking IL-33 signaling.