Engineered Antibody May Be the Key to New Therapies for Obesity and Diabetes
An antibody called mimAb1 has positive effects on the weight and body mass index of cynomolgus monkeys.
-- by Michael Harkin
Obesity and diabetes are major health concerns in the United States and much of the rest of the world. They are closely associated conditions; where obesity is prevalent, diabetes tends to be a major problem as well. Due to the omnipresence of these conditions in developed countries, scientists around the world are trying to find effective new therapies for these diseases.
A hormone called fibroblast growth factor 21, or FGF21, is a protein that prior studies have determined has significant positive effects on the body’s metabolism. For instance, mice given the FGF21 hormone have improved glucose metabolism and insulin sensitivity, in addition to being resistant to obesity resulting from their diets.
FGF21 does not function effectively as a drug, however, due to its short half-life. In order to circumvent this problem, Ian Foltz and his colleagues at Amgen engineered an antibody they called mimAb1, which functions in much the same way as FGF21. As the findings of their new Science Translational Medicine study reveal, treating a group of obese cynomolgus monkeys with mimAb1 led to positive effects on the monkeys’ metabolism, including decreases in body mass index (BMI) and body weight.
The researchers say this finding was unexpected. The fact that mimAb1 activated FGF21-type signaling to cell surface receptors points to the importance of further clinical research and its potential usefulness for future drug therapies.
The Expert Take
Yang Li, one of the study’s co-authors, gave an overview of the study’s significance in an interview with Healthline. FGF21 has, he said, attracted a great deal of interest as a potential therapeutic for diabetes and obesity, but problems with its applicability to drug development led to this study.
“FGF21 is a unique member of the fibroblast growth factor family and a novel hormone that demonstrated multiple benefits, including improving glucose metabolism, plasma lipid profiles, and reducing body weight in preclinical studies,” said Li. “However, challenges exist in developing native FGF21 as a therapeutic due to its short plasma half-life. To circumvent these challenges, we explored a novel approach to generate FGF21-like beneficial effects but with a monoclonal antibody modality.”
The metabolic effects of the use of mimAb1—namely, decreases in body weight, triglycerides, plasma insulin, and glucose—are promising. As far as how these findings could be applied to potential treatments, however, Li emphasizes that there is still a considerable amount of research to be done.
“The metabolic effects are encouraging, but we must be mindful that this is preclinical research and we’re still evaluating the results of the study,” said Li.
Source and Method
The scientists in the study identified beta-Kloth o/FGFR1c as the receptor complex that mediates FGF21’s metabolic effects, Li said. Identifying this complex allowed them to develop an antibody, mimAb1, that mimicked the function of FGF21.
MimAb1 activates the signaling pathway of beta-Kloth o, a protein that makes both animals and humans sensitive to insulin. This antibody also targets the FGF receptor in much the same way that FGF21 does.
In order to test mimAb1’s effectiveness, a group of obese cynomolgus monkeys were treated over the course of several weeks with the antibody. Over the course of the study, there was a progressive decrease in the monkeys' body weight and BMI, and the weight loss remained until the end of the study, which was nine weeks after the second injection of mimAb1. Abdominal circumference and skinfold thickness were also found to decrease during this time, even though the monkeys’ food intake was reduced only slightly over the course of the study.
Native FGF21 is difficult to apply directly as a therapeutic for treating diabetes and obesity, said the study’s authors. The difficulties arise from the short plasma half-life of the protein, as well as the likely necessity for reengineering the protein in order to give it drug-like properties. However, mimAb1 looks more promising.
“We have identified a very special antibody,” said Li. “Testing of this antibody in preclinical model generated FGF21-like beneficial effects. Our results provide validation for innovative therapeutic approaches targeting the FGF21 pathway for treating diabetes and obesity.”
A 2012 study in Nature Reviews Drug Discovery looked at an agonistic FGF receptor antibody that had long-lasting effects in terms of its antidiabetic and lipid-lowering properties.
An earlier study from 2011 published in Diabetes looked at the presence of FGF21 in human cerebrospinal fluid (CSF), and tried to determine whether or not there was a relationship between this CSF FGF21 and the regulation of metabolism and body fat in the human body.
The researchers found that there were higher CSF and plasma FGF21 levels when BMI and fat mass increased, but concluded that further research was necessary to determine whether FGF21 could help with managing obesity.