By Jamshed Arslan, Pharm. D., PhD.
We live in a world where 39% of adults are overweight. Our meals trigger the secretion of various gut-derived metabolic hormones called incretins. Fats and carbohydrates in our diet stimulate the release of an incretin from the duodenum called glucose-dependent insulinotropic polypeptide or gastric inhibitory polypeptide (GIP). GIP acts on its receptor (GIPR) in adipocytes and pancreas to promote fatty acid uptake and insulin secretion, respectively. Obesity is positively correlated with after-meal secretion of GIP, and GIPR knockout mice resist diet-induced obesity. Overall, mouse and human studies encourage the development of GIPR antagonists to treat obesity. A team of scientists in Amgen Inc., USA, were finally able to do exactly that, by developing GIPR antagonist antibodies for which they report in vitro and in vivo anti-obesity effects. They also co-administered these GIPR antagonists with agonists of a satiety-inducing incretin called glucagon-like peptide-1 (GLP-1) and found that this combined treatment effected greater weight loss in mouse and monkey models than the individual treatments.
(Left) GIP detection in human stomach. Analysis of GIP expression in sections of human stomach tissue (immersion fixed paraffin-embedded sections) with Mouse Anti-Human GIP Monoclonal Antibody (MAB8864) at 5 µg/mL overnight at 4 °C, followed by staining with Anti-Mouse HRP-DAB Cell & Tissue Staining Kit-CTS002 (brown) and counterstaining with hematoxylin (blue). Specific GIP staining was localized to gastric glands. (Right) GIPR detection in human pancreas. Analysis of GIPR expression in sections of human pancreas (immersion fixed paraffin-embedded) with Mouse Anti-Human GIPR Monoclonal Antibody (MAB8210) at 15 µg/mL overnight at 4 °C. Tissue was subjected to heat-induced epitope retrieval using Antigen Retrieval Reagent-Basic (CTS013) prior to incubation with primary antibody. For staining, tissue was incubated with Anti-Mouse HRP-DAB Cell & Tissue Staining Kit (brown; CTS002) and counterstained with hematoxylin (blue). Specific GIPR staining was localized to Islet cells.
A newly developed antibody against GIPR has anti-obesity effects in mouse models
To study the anti-obesity effect of GIPR antagonism, the researchers developed a mouse monoclonal anti-GIPR antibody (muGIPR-Ab). When diet-induced obese (DIO) mice were injected with muGIPR-Ab, the insulin-inducing effect of synthetic GIP was abolished. Upon long-term treatment, muGIPR-Ab led to reduced 4-hour fasting glucose and insulin levels on day 35, and a 37% lower fat mass relative to a non-neutralizing (control) anti-GIPR antibody. The team found that the percent weight loss produced by the combination of muGIPR-Ab and liraglutide (a standard GLP 1 receptor agonist analog effective against obesity) was greater than the sum of the two alone. Other metabolic measurements, like blood glucose and insulin levels and adiposity, showed a similar trend.
This means that the newly developed muGIPR-Ab is efficacious in a mammalian (mouse) model of obesity. The next step was to determine the anti-obesity effects of a similar but fully human anti-GIPR antibody in non-human primates and human adipocytes, thereby paving the way for clinical trials.
GLP-1 receptor detection in mouse pancreas. Analysis of GLP-1 receptor expression in paraffin-embedded tissue section from mouse pancreas with GLP-1R Rabbit Polyclonal Antibody [NBP1-97308] at 1:200 dilution followed by staining with HRP labeled anti-rabbit IgG secondary antibody and DAB reagent. Cell nuclei were counter-stained with hematoxylin. Specific GLP-1R staining in pancreatic beta cells.
Anti-obesity effects of anti-human GIPR in human adipocytes and monkey models
Based on the success in mouse models, the team identified and assessed a monoclonal anti-human GIPR antibody (hGIPR-Ab) in human cells. As expected, hGIPR-Ab inhibited GIP-induced cAMP production in GIPR-expressing adipocytes and blocked insulin secretion in pancreatic microtissues.
The researchers wanted to evaluate the translational efficacy of these results in spontaneously obese monkeys. After monitoring monkeys for 76 days under different treatments, the team found results similar to those in mice: combination of GIPR antagonism (through hGIPR-Ab) and GLP-1 receptor agonism led to a greater loss in weight and reduced food intake than the individual therapies alone. Therefore, scientists at Amgen Inc. have developed novel incretin receptor (GIPR) antibodies against obesity that show efficacy in significant preclinical models.
Significance of targeting GIP-GIPR axis
This study presents GIP receptor as a potential therapeutic target to tackle excessive weight gain. These preclinical results need further evaluation in human trials. Although the crystallographic analysis in this study shows hGIPR-Ab-induced GIP displacement from GIPR as a potential mode of action, further research is warranted on the precise mechanism of action of anti-human GIPR antibodies.
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Jamshed Arslan, Pharm D, PhD
Dr. Arslan is an Assistant Professor at Dow University of Health Sciences, Pakistan,
where he teaches Pharmacology to future pharmacists.
Killion, E. A., Wang, J., Yie, J., Shi, S. D.-H., Bates, D., Min, X., … Lloyd, D. J. (2018). Anti-obesity effects of GIPR antagonists alone and in combination with GLP-1R agonists in preclinical models. Science Translational Medicine. https://doi.org/10.1126/scitranslmed.aat3392