Novel IL4/IL4RA double humanized mouse models for in vivo efficacy evaluation of human IL4 and human IL4RA antibodies in asthma models
Pleiotropic cytokines (interleukin(IL)-4/13) and their pertinent receptors (such as IL-4 receptor) are promising therapeutic targets due to their pivotal roles in the physiopathology of asthma, atopic dermatitis (AD), and other auto-immune diseases. Dupilumab (Dupixent), a monoclonal antibody drug, has been developed to treat allergic conditions due to its ability to inhibit the biological effects of both IL-4 and IL-13 and prevent the interaction of IL4/IL13 with the α-subunit of the IL-4 receptor complex (IL4RA). However, human antibodies, such as Dupilumab, are specific to human IL-4RA and do not cross-react with mouse endogenous IL-4RA. The inability of mouse IL-4 to recognize human IL-4RA is a hurdle for the development of therapeutics using wildtype mouse models for efficacy screening. To tackle this problem, Biocytogen generated an IL4/IL4RA double humanized mouse model for the in vivo efficacy evaluation of IL-4 and IL4-RA antibodies. The double humanized mice are comparable to wildtype mice in terms of basal leukocyte subpopulations, including T/B cells, NK cells, DC, granulocytes and monocytes/macrophages. The asthma model established in IL4/IL4R humanized mice showed an increased level of eosinophils, neutrophils, IgE production and lung pathological phenotypes. Upon the treatment with Dupixent analog, the number of inflammatory cells in the lung and the serum IgE levels became lower than the PBS control group in homozygous B-hIL4/hIL4RA mice.
In conclusion, IL4/IL4R double humanized mice by Biocytogen is proven to be a suitable asthma model for in vivo efficacy evaluation of human IL4 and IL4RA antibodies.