Format

Send to

Choose Destination
Sci Transl Med. 2018 Dec 19;10(472). pii: eaat3392. doi: 10.1126/scitranslmed.aat3392.

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

Author information

1
Amgen Research, Department of Cardiometabolic Disorders, Amgen Inc., One Amgen Center Dr., Thousand Oaks, CA 91320, USA.
2
Amgen Research, Department of Cardiometabolic Disorders, Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, USA.
3
Amgen Research, Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Dr., Thousand Oaks, CA 91320, USA.
4
Amgen Research, Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, USA.
5
Amgen Research, Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Dr., Thousand Oaks, CA 91320, USA.
6
Amgen Research, Department of Therapeutic Discovery, Amgen Inc., 7990 Enterprise Street, Burnaby, BC V5A 1V7, Canada.
7
Amgen Research, Comparative Biology and Safety Sciences, Amgen Inc., 360 Binney St., Cambridge, MA 02141, USA.
8
Amgen Research, Department of Cardiometabolic Disorders, Amgen Inc., One Amgen Center Dr., Thousand Oaks, CA 91320, USA. dlloyd@amgen.com.

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.

LinkOut - more resources

Full Text Sources

Molecular Biology Databases

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center