GIPR antagonist antibodies conjugated to GLP-1 peptide are bispecific molecules that decrease weight in obese mice and monkeys

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) regulate glucose and energy homeostasis. Targeting both pathways with GIP receptor (GIPR) antagonist antibody (GIPR-Ab) and GLP-1 receptor (GLP-1R) agonist, by generating GIPR-Ab/GLP-1 bispecific molecules, is an approach for treating obesity and its comorbidities. In mice and monkeys, these molecules reduce body weight (BW) and improve many metabolic parameters. BW loss is greater with GIPR-Ab/GLP-1 than with GIPR-Ab or a control antibody conjugate, suggesting synergistic effects. GIPR-Ab/GLP-1 also reduces the respiratory exchange ratio in DIO mice. Simultaneous receptor binding and rapid receptor internalization by GIPR-Ab/GLP-1 amplify endosomal cAMP production in recombinant cells expressing both receptors. This may explain the efficacy of the bispecific molecules. Overall, our GIPR-Ab/GLP-1 molecules promote BW loss, and they may be used for treating obesity. [Display omitted] GIPR-Ab/GLP-1 is a bispecific molecule used for the treatment of obesityGIPR-Ab/GLP-1 antagonizes GIPR and agonizes GLP-1R in vitroGIPR-Ab/GLP-1 synergistically reduces body weight and metabolic values in animalsGreater receptor internalization with GIPR-Ab/GLP-1 amplifies endosomal cAMP levels Lu et al. show that tackling obesity with bispecific molecules that antagonize/agonize GIPR/GLP-1R pathways decreases body weight and metabolic parameters in obese mice and monkeys. Mechanistic studies suggest that such molecules bind to GIPR and GLP-1R simultaneously and trigger receptor internalization, amplifying endosomal cAMP signaling in cells expressing both receptors.