Development of a humanized IL-17A/IL-17F mouse model for preclinical efficacy studies of IL-17-related diseases

Background: IL-17 cytokine family members exert diverse biological functions, promoting protective immunity against many pathogens while also driving inflammatory pathology in infection and autoimmunity. The IL-17 pathway has therefore become a major therapeutic target in autoimmune and chronic inflammatory disorders such as rheumatoid arthritis, multiple sclerosis, and psoriasis. Therapeutic monoclonal antibodies targeting IL-17A, IL-17A/IL-17F, the IL-17 receptor, or IL-23 have demonstrated substantial clinical efficacy in several of these conditions. In this study, we developed a novel humanized IL-17A/IL-17F mouse model and established an imiquimod (IMQ) -induced psoriasis model to evaluate the preclinical efficacy of bimekizumab and other test articles. Methods: The hIL-17A/hIL-17F dual knockin mice were generated by homologous recombination, replacing the entire coding sequences of mouse I l -17 a and I l -17 f with their human counterparts while preserving the endogenous murine signal peptides. Human IL-17A and IL-17F mRNA transcription was validated by qRT-PCR, and corresponding serum protein levels were quantified by ELISA. Finally, topical IMQ application was used to trigger psoriasiform dermatitis on the back and ear skin of the hIL-17A/hIL-17F dual knockin mice. Bimekizumab and additional test agents were administered, and in vivo efficacy was assessed by H&E staining, pathological scoring, and cytokine profiling. Results and Conclusion: IMQ treatment induced a psoriasis-like phenotype in hIL-17A/hIL-17F mice and resulted in high expression of human IL-17F. Bimekizumab and the test articles markedly improved histopathological features and reduced the levels of IL-17F in our mice. Overall, these findings demonstrate that the hIL-17A/hIL-17F dual humanized mouse provides an advanced tool for preclinical efficacy studies of IL-17-related therapeutics.