Humanized B-hIL4/hIL4RA/hTSLP/hTSLPR plus mice Model for Efficacy and Toxicity Evaluation 2302190
The IL-4 receptor (IL4RA) is a key mediator of the signaling pathways for both IL-4 and IL-13, which play pivotal roles in the pathophysiology of type 2 inflammatory diseases. Thymic stromal lymphopoietin (TSLP) is an alarmin cytokine derived from epithelial cells that has the capacity to initiate both type 2 and non-type 2 inflammatory responses in asthma. TSLP is closely associated with the production of T helper (Th) 2 cytokines, such as IL-4, and is implicated in various inflammatory conditions, including asthma and atopic dermatitis. By simultaneously targeting IL4RA and TSLP, there is significant potential to concurrently suppress both type 2 and non-type 2 inflammation, potentially yielding synergistic effects that inhibit type 2 inflammation more effectively. This therapeutic strategy is anticipated to offer enhanced efficacy in the treatment of type 2 inflammatory diseases. However, TSLP and IL-4 do not cross-react with their receptors between humans and mice. To address this issue, we developed the humanized B-hIL4/hIL4RA/hTSLP/hTSLPR plus mice model for in vivo efficacy evaluation. The humanized mice exhibit characteristics that closely resemble those of wild-type mice, including body weight, blood biochemical indices, and routine blood parameters. The stability of these fundamental physiological indices provides a critical assurance for safety evaluations. In the asthma model developed in B-hIL4/hIL4RA/hTSLP/hTSLPR plus mice, we observed elevated levels of eosinophils, IgE production, and distinct lung pathological features. Notably, the combination of anti-IL4RA and anti-TSLP antibody therapies demonstrated enhanced therapeutic efficacy compared to administering a single antibody drug alone. In conclusion, the humanized B-hIL4/hIL4RA/hTSLP/hTSLPR plus mice model serves as an excellent platform for assessing the efficacy and safety of human IL-4RA and TSLP-related antibodies. N/A Cellular Adhesion, Migration, and Inflammation (CAM)