Preclinical immunological characterization of rademikibart (CBP-201), a next-generation human monoclonal antibody targeting IL-4Rα, for the treatment of Th2 inflammatory diseases

Rademikibart (CBP-201) is a next-generation human monoclonal antibody targeting IL-4Rα, undergoing evaluation in Phase 2 clinical trials for the treatment of moderate-to-severe Th2 inflammatory diseases. We report the immunological characterization of rademikibart. Rademikibart and dupilumab were associated with K_D of 20.7 pM and 45.8 pM, respectively, when binding to distinct human IL-4Rα epitopes. Rademikibart did not bind to IL-4Rα from other species. Rademikibart inhibited IL-4 and IL-13-mediated STAT6 signaling (mean ± SD IC₅₀: 7.0 ± 2.5 and 6.6 ± 1.5 ng/mL, respectively), TF-1 cell proliferation (IC₅₀: 8.0 ± 1.6 and 9.7 ± 0.8 ng/mL, respectively) and TARC production in PBMCs (IC₅₀: 59.2 ± 3.9 and 13.5 ± 0.2 ng/mL, respectively). Rademikibart versus dupilumab was more potent in the STAT6 assays (IL-4, p < 0.01; IL-13, p = 0.03), with non-significant trends towards greater potency in the TF-1 cell assays (IL-4, p = 0.09; IL-13, p = 0.20), and similar potency in the TARC assays. In experiments with mice expressing human IL-4Rα and IL-4, rademikibart and dupilumab demonstrated similar potency; both monoclonal Antibodies eliminated IL-4 (p < 0.0001) and IL-13 (p < 0.05) mediated B cell activation in vitro and ovalbumin-induced IgE (p < 0.01) and eosinophilic lung infiltration (p < 0.0001) in vivo. In Th2-stimulated human skin explants, rademikibart rapidly downregulated IL-4, IL-13, and TARC gene expression, with greater effectiveness than dupilumab for IL-4 (p < 0.01) and a non-significant trend towards superiority for IL-13. In summary, rademikibart bound to a distinct IL-4Rα epitope with high affinity and demonstrated reductions in Th2 inflammatory biomarkers with at least similar and potentially superior potency to dupilumab.