Giorgio Walter Canonica, José Antonio Ortega-Martell, Rosalaura V. Villarreal-González, Ignácio Ansotegui, Claus Bachert, Jonathan Bernstein, Eugene R. Bleecker, Benedetta Bondi, Marco Caminati, Tara Carr, Antonella Cianferoni, Ignacio Dávila González, Sandra González Díaz, René Maximiliano Gómez, Nicola Hanania, Enrico Heffler, Parameswaran Nair, Nida Öztop, Hae-Sim Park, Helena Pite, Phillip Rouadi, Hirohisa Saito, Massimo Triggiani, Gilda Varricchi, Christian Virchow, Yoshiyuki Yamada, Anahí Yáñez, Mário Morais-Almeida
Background: Advances in the understanding of type 2 inflammation have driven the development of novel biologics and small molecules for allergic diseases. New therapies targeting cytokines, receptors, and intracellular pathways offer opportunities to refine disease management and modify long-term outcomes. Methods: The World Allergy Organization (WAO) Biologics Therapies in Allergic Diseases Committee conducted this state-of-the-art review. We analyzed current literature on investigational monoclonal antibodies, nanobody-based agents, kinase inhibitors, and small molecules with potential applications in asthma, chronic rhinosinusitis with nasal polyposis, atopic dermatitis, and chronic spontaneous urticaria. Mechanistic considerations, therapeutic targets, and clinical trial outcomes were evaluated to highlight emerging trends in biologic and small-molecule therapy. Results: Biologics targeting IL-4, IL-5, IL-13, IL-31, TSLP, and IgE continue to expand therapeutic options across allergic disorders. Innovations such as Fc-engineered antibodies, bispecific antibodies, and nanobody platforms enhance efficacy, extend half-life, and improve tissue penetration. Novel intracellular inhibitors, including JAK, SYK, and STAT6 degraders, show promise as oral alternatives to injectable therapies. Clinical trials report high efficacy and favorable safety profiles, though variability remains across diseases and endotypes. Pediatric data are limited, and the long-term safety and cost-effectiveness of this approach require further evaluation. Conclusions: Emerging biologics and small molecules are transforming the therapeutic landscape of allergic diseases, providing targeted and personalized interventions. Advances in molecular engineering, particularly nanobody technology and intracellular inhibitors, hold promise for improving patient outcomes and reducing treatment burden. Future research should prioritize long-term safety and standardized approaches to optimize integration of these therapies into clinical practice.