Anti-obesity effects of GIPR antagonists alone and in combination with GLP-1R agonists in preclinical models

TLDR

GIPR is linked to obesity in GWAS and knockout mice are protected from diet‑induced obesity. The study developed anti‑GIPR antibodies as a therapeutic strategy for obesity, showing that a mouse anti‑GIPR antibody reduced weight gain, improved metabolic parameters, and lowered food intake and RER in DIO mice. Using a conditional β‑cell GIPR knockout mouse, the authors demonstrated that GIPR in pancreatic β‑cells does not regulate body weight or response to antagonism. In obese mice and nonhuman primates, anti‑GIPR antibodies produced significant weight loss, which was further enhanced when combined with GLP‑1R agonists; crystallographic data showed the antibody displaces GIP by binding the same hydrophobic residues, validating anti‑GIPR antibodies as a preclinical obesity therapy.

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) has been identified in multiple genome-wide association studies (GWAS) as a contributor to obesity, and GIPR knockout mice are protected against diet-induced obesity (DIO). On the basis of this genetic evidence, we developed anti-GIPR antagonistic antibodies as a potential therapeutic strategy for the treatment of obesity and observed that a mouse anti-murine GIPR antibody (muGIPR-Ab) protected against body weight gain, improved multiple metabolic parameters, and was associated with reduced food intake and resting respiratory exchange ratio (RER) in DIO mice. We replicated these results in obese nonhuman primates (NHPs) using an anti-human GIPR antibody (hGIPR-Ab) and found that weight loss was more pronounced than in mice. In addition, we observed enhanced weight loss in DIO mice and NHPs when anti-GIPR antibodies were codosed with glucagon-like peptide-1 receptor (GLP-1R) agonists. Mechanistic and crystallographic studies demonstrated that hGIPR-Ab displaced GIP and bound to GIPR using the same conserved hydrophobic residues as GIP. Further, using a conditional knockout mouse model, we excluded the role of GIPR in pancreatic β-cells in the regulation of body weight and response to GIPR antagonism. In conclusion, these data provide preclinical validation of a therapeutic approach to treat obesity with anti-GIPR antibodies.