The dawn of the dual-target era in respiratory disease: promise, pitfalls, and a roadmap for bispecific antibodies

Bispecific antibodies targeting two inflammatory pathways are entering respiratory medicine at an unprecedented pace. TSLP/IL-13 bispecifics have progressed into mid-to-late-stage clinical development, with two distinct molecules (lunsekimig and CM512) in Phase II/III and Phase II trials, respectively. Preclinical and early clinical signals indicate that alarmin blockade may extend beyond classical type 2 immunity, offering therapeutic potential in mixed and non-type 2 inflammatory phenotypes. Yet this molecular acceleration risks outpacing our capacity to deploy these agents rationally. No biomarker-guided framework currently exists to determine which patients require dual-pathway versus single-pathway blockade, or which target pair best matches a given patient’s inflammatory endotype. The central clinical tension is whether the incremental benefit of dual-pathway neutralization justifies any increase in immunosuppressive risk. In this Perspective, we argue that the bispecific antibody race may deliver more molecules than necessary unless the field simultaneously builds biomarker-guided matching frameworks. Limited clinical support, drawn mainly from single-target agents such as tezepelumab (efficacy across eosinophil strata) and itepekimab (benefit in former smokers with COPD independent of eosinophils), together with biological rationale, suggests that alarmin blockade may hold promise in mixed and non-type 2 phenotypes; dedicated dual-alarmin trials in these populations remain needed.