Anti-IL-4R-JAKi antibody-drug conjugate effectively reduces IgE levels and inflammatory cell infiltration in Atopic Dermatitis 9245

Description Background IL-4R blockade has demonstrated effectiveness and tolerability in atopic dermatitis (AD) and other type 2 autoimmune diseases. While Janus kinase inhibitors (JAKi) show strong efficacy, their use is limited by severe side effects. Combining anti-IL-4R antibodies with JAKi into an antibody-drug conjugate (ADC) offers a promising solution by targeting JAK inhibition selectively to IL-4R-expressing cells, potentially enhancing therapeutic synergy. Method and Results We developed an anti-IL-4R-JAKi ADC to address AD and associated IgE overproduction. In a humanized IL-4/IL-4R mouse model of AD, the ADC demonstrated significant efficacy by day 18 of sensitization, reducing IgE levels to 4.20 ± 1.02 ng/mL (vs. 8.18 ± 7.55 ng/mL for Dupilumab and 279.4 ± 7.55 ng/mL for untreated controls). By day 26, IgE levels were 3.25 ± 2.15 ng/mL with ADC treatment, compared to 41.72 ± 39.64 ng/mL for Dupilumab and 208.5 ± 35.81 ng/mL for controls. ADC treatment also significantly reduced inflammatory cell and eosinophil infiltration compared to anti-IL-4R (P < 0.05). Notably, RNA-seq analysis revealed that ADC treatment, while effective in suppressing IgE observed in AD mice, did not globally alter the transcriptome compared to anti-IL-4R alone. Conclusion The anti-IL-4R-JAKi ADC exhibits superior efficacy over anti-IL-4R therapy alone, offering a novel approach for treating type 2 autoimmune diseases like AD while minimizing systemic side effects associated with conventional JAKi use. Funding Sources Supported by Bioray Pharmaceutical.