Scientists at Amgen Inc., with colleagues at the Texas A & M Health Science Center, have developed an antibody that, when administered to obese cynomolgus monkeys, improved the animals' insulin sensitivity and lipid profiles, and led to significant weight loss.

The antibody's effects on metabolism have obvious clinical potential. But, senior author Yang Li told BioWorld Today, the antibody, which his team has called mimAb, also breaks new scientific ground. Beyond its specific effects, the experiments "expand the view of what the whole class of molecules can do," Li said. The team published its findings in the Nov. 29, 2012, issue of Science Translational Medicine.

MimAb mimics the effects of fibroblast growth factor 21, or FGF21. The antibody is unusual in that it activates, rather than blocks the complex it binds to – and that complex is, well, complex, consisting of the transmembrane protein beta-Klotho and one of several different FGF receptors.

The FGF family has, at last count, more than 20 members. But FGF21 is unusual in several ways.

For one, only a select few family members – FGF19, 21 and 23 – work as hormones, meaning that they are released into the bloodstream and work on targets that are distant from the release sites. "All the rest of them can only function locally," Li said.

FGF21 is further unusual because it affects metabolism. Most other fibroblast growth factors play roles in organ formation and development more generally.

Previous work had shown that FGF21 "seemed to have a lot of beneficial effects under pharmacological conditions," Li said, and so "there is quite a bit of interest in exploring the pathway" to see whether those metabolic benefits can be induced pharmacologically.

In principle, one possibility would be a recombinant protein. But if FGF21 has beneficial effects, it doesn't exactly have staying power. The protein itself is "not very stable in plasma," Li said, being degraded within a few hours of administration. And "to treat chronic indications, obviously it's not the most convenient thing if the patients have to inject themselves frequently."

To top it off, any attempt to activate the FGF21-dependent metabolic benefits has to be fairly specific in order to avoid pathways that are activated by other members of the FGF family – seeing as those pathways, with their importance in developmental processes, can lead to out-of-control cell proliferation.

In fact, part of the paper's scientific novelty is in identifying "the receptor complex that mediates the beneficial effects of FGF21," Li said. Though beta-Klotho interacts with several different FGF receptors, its beneficial effects on metabolism appear to be mediated only by one receptor, FGFR-1c.

In their experiments, Li and his colleagues first isolated an antibody that would interact only with the beta-Klotho /FGFR-1c complex. They then injected obese cynomolgus monkeys with such antibodies weekly for four weeks.

They found that the animals lost about 10 percent of their body weight, and that the weight loss lasted for more than two months after the last injection. The animals also had better blood sugar control, and lower levels of blood lipids.

The monkeys initially ate less than placebo-treated controls after treatment started, but their food intake went back up to baseline values about three weeks into the study, "suggesting," the authors wrote in their study, that the reduction in food intake was not solely responsible for the decrease in body weight." Instead, mimAb may be acting by increasing energy expenditure. Li and his team found that the antibody affected mainly fat cells.

Li was level-headed about possible practical applications of his team's research, saying that the results now published in Science Translational Medicine "are profound and encouraging. They are also preclinical."

When asked about development plans for the antibody, or any related ones, Li said, "We are still evaluating the results. But they do demonstrate the feasibility of the approach."