Abstract 5339: Establishment of a humanized IL5/IL5RA mouse model to evaluate modulators of eosinophilic inflammation in vivo

Abstract

Abstract IL-5/IL-5R signaling plays a key role in the maturation, activation, survival, and recruitment of eosinophils to sites of inflammation. Targeting this pathway is an attractive therapeutic strategy for certain inflammatory diseases, such as asthma. Here, we generated a novel humanized IL5/IL5RA model (B-hIL5/hIL5RA) to examine the utility of human IL-5/IL5R-targeting therapeutic candidates. Specifically, the entire murine Il5 coding region was replaced by the corresponding human IL5 sequence, and the human IL5RA sequence coding the extracellular domain was inserted to replace the corresponding murine sequence. Successful generation of the model was confirmed by expression of human IL-5 by ELISA and IL5RA by flow cytometry. Furthermore, the proportion of eosinophils in the blood of B-hIL5/hIL5RA mice increased after stimulation with human IL5 recombinant protein, indicating that the humanized IL5RA protein is functional. Next, the ability of the humanized mice to establish asthma-like disease was tested using ovalbumin: following a 14 day sensitization period, mice were challenged with nebulized OVA daily from day 21 until the endpoint; treatment with mepolizumab or benralizumab analog was performed. Flow cytometric analysis of the bronchioalveolar fluid indicates that treatment with mepolizumab or benralizumab analog significantly lowered the number of eosinophils when compared to the isotype control in homozygous B-hIL5/hIL5RA mice. Blood counts and quantification of lung H&E sections also confirm that the treatments lowered the number of eosinophils in circulation and lung tissue, respectively. Taken together, these data indicate that B-hIL5/hIL5RA mice are a suitable preclinical model to test novel modulators of human IL-5/IL-5RA signaling. Citation Format: Suman Zhao, Shujin Zhang, Zhen Chen, Liya Yang, Mari Kuraguchi, Jiangfeng Yuan, Heiling Shen. Establishment of a humanized IL5/IL5RA mouse model to evaluate modulators of eosinophilic inflammation in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5339.