Dapiglutide, a potential first-in-class therapy targeting obesity and low-grade inflammation, is designed for activating both GLP-1 and GLP-2 receptors. In a MAD trial, healthy participants receiving once-weekly s.c. injections of dapiglutide up to 6 mg for 4 weeks showed dose-dependent body weight loss up to a mean 4.3%, and dose-dependent reductions of plasma glucose and insulin. At the cellular level, GLP-1R activation by native GLP-1 induces formation of its major second messenger cAMP and recruitment of β-arrestin. Recent studies hypothesized that biased agonists displaying lack of β-arrestin recruitment at the GLP-1R are beneficial in controlling blood glucose and body weight loss in DIO rats. Here we investigated the in vitro profile of dapiglutide, emphasizing on GLP-1R signaling bias and functional consequences.
Binding assays using 125-iodinated radioligands were used to estimate binding affinities of dapiglutide for human GLP-1R and GLP-2R. The human GLP-1R in vitro signaling profile was investigated in a kinetic cAMP formation assay and for recruitment of β-arrestin in HEK293 cells.
Initial in vitro characterization indicated that dapiglutide is more potent for binding to GLP-1R over GLP-2R, with estimated binding affinities of 38 nM and 102 nM, respectively. At the GLP-1R, dapiglutide showed signaling bias, displaying full agonist activity in cAMP formation, whilst having significantly blunted response to β-arrestin recruitment. Further in vitro characterization showed that dapiglutide-induced cAMP formation kinetics persisted for up to 12 hours unlike native GLP-1, potentially reflecting signal bias, lack of receptor desensitization, and a promising efficacy profile in the MAD trial.
Dapiglutide, a dual GLP-1/GLP-2 agonist, has a unique GLP-1R biased agonism signaling profile that combined with additional GLP-2R activity may translate into an efficacious weight management therapy in individuals with obesity.
L. Gjelstrup: Employee; Zealand Pharma A/S. B. Lundholt: Employee; Zealand Pharma A/S. B.D. Larsen: None. N.J. Johansen: Employee; Zealand Pharma A/S. M.B. Olsen: None. J.M. Mathiesen: Employee; Zealand Pharma A/S.
