Abstract 2090: Humanized IL36R mice provide a preclinical tool for the evaluation of therapeutic drugs targeting IL36R

Abstract

Abstract The IL36 family of cytokines (IL36a, IL36b, and IL36g) is part of the IL-1 superfamily and triggers proinflammatory signaling through the IL36 receptor complex. This heterodimer complex is formed by the IL36 Receptor (IL1RL2) and IL-1R co-receptor accessory protein (IL-1RAcP). IL36R is present on a diverse variety of cell types, including the surface of dendritic cells, CD4+ T cells, and epithelial cells in various tissues. IL36 signaling can exert widespread inflammation, and its activity is implicated in several inflammatory diseases affecting epithelial tissues, including inflammatory bowel disease, rheumatoid arthritis, and psoriasis. Thus, identification of novel therapeutics targeting this pathway are of significant clinical interest. To provide a preclinical platform for efficacy assessments of novel anti-human IL36R drugs, we generated a humanized hIL36R knock-in mouse model. In this model, a chimeric IL1RL2 coding sequence, which is composed of the human IL1RL2 extracellular region and the mouse Il1rl2 cytoplasmic region, was inserted after the 5’UTR of mouse Il1rl2 gene using CRISPR-Cas9-based gene editing technology. The mouse cytoplasmic region was maintained to ensure intact downstream signaling. Polymerase chain reaction assessment of mRNA isolated from the lung tissue of edited homozygous humanized IL36R mice confirmed the absence of mouse Il1rl2 transcripts. Finally, to confirm the expression of human IL36R protein, immunohistochemistry was performed on the small intestine and skin tissue of humanized mice subjected to a chemical induction of psoriasis. Psoriasis-like symptoms were achieved by application of imiquimod cream on the back skin of the mice for 5 consecutive days. As expected, IL36R protein expression was detected in both tissues isolated from the homozygous humanized mice. These results indicate the successful generation of humanized IL36R mice, and suggest that this model will be an effective tool for future in vivo efficacy evaluation of immunomodulatory drugs targeting human IL36R. Citation Format: Xiaofei Zhou, Jiahui Chang, Jenna Frame, Chong Li, Zhifang Bai, Yuelei Shen. Humanized IL36R mice provide a preclinical tool for the evaluation of therapeutic drugs targeting IL36R [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2090.