Abstract 3: Developing a translational tool for GLP-1-based therapeutic agonists in humanized GLP1R mice

Abstract

Abstract Glucagon-like peptide-1 (GLP1) is a pleiotropic hormone released from gut enteroendocrine cells following nutrient ingestion. In addition to promoting insulin secretion and inhibiting glucagon secretion, GLP1 acts via the glucagon-like peptide-1 receptor (GLP1R) to reduce gastric emptying and food intake. Therefore, development of GLP1R agonists appears to be a promising therapeutic option for type 2 diabetes. To evaluate the efficacy of GLP1 analogs in preclinical studies, Biocytogen has successfully generated a novel humanized GLP1R (B-hGLP1R) knock-in mouse line to support related drug development studies. In this mouse model, the full coding sequence of the human GLP1R gene was inserted into the mouse Glp1r gene locus. Human GLP1R mRNA expression was detected by RT-PCR in B-hGLP1R mice but not in wild-type mice. Protein expression of human GLP1R in B-hGLP1R mice was confirmed by western blot analysis and immunohistochemistry using pancreatic tissues. Furthermore, flow cytometry analysis of leukocyte subpopulations showed that B-hGLP1R mice do not exhibit a change in the overall development, differentiation, or distribution of immune cell types in the spleen, blood, and lymph nodes. Additionally, our in vivo efficacy study confirmed Dulaglutide, a GLP1 receptor agonist, reduced the non-fasting blood glucose, fasting blood glucose, glucagon, and food intake levels in B-hGLP1R obese mice and increased plasma insulin and GLP1 secretion. In B-hGLP1R mice, glucose tolerance (GTT) was also improved by Dulaglutide treatment, similar GTT results were observed after treatment with PF-06882961, a phase II agent specifically recognizing human GLP1R. Altogether, B-hGLP1R mice provide an efficacious preclinical animal model to evaluate novel GLP1 based therapeutic drugs. Keywords: Humanized mice, GLP1R, agonist Citation Format: Yuelei Shen, Jiawei Yao, Mostafa Kokabee, Yanan Guo, Yang BaI, Chengzhang Shang. Developing a translational tool for GLP-1-based therapeutic agonists in humanized GLP1R mice [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 3.