New research-Improving GLP-1 drug delivery by 'painting' it on antibodies

Glucagon-like peptide-1 (GLP-1) receptor agonists are peptide-based therapeutics for treating diabetes and for weight loss. Unfortunately, shortages and high costs have made it difficult for people to start and maintain treatment. Now, researchers report a drug delivery system that “paints” these peptides directly on the antibodies they target. In studies with mice, the system led to sustained weight loss and prolonged blood sugar management with a GLP-1 injection one fourth that of the standard dose.

Bradley Pentelute, professor of chemistry at the Massachusetts Institute of Technology (MIT), will present his team’s results at the spring meeting of the American Chemical Society (ACS). ACS Spring 2025 is being held March 23-27; it features about 12,000 presentations on a range of science topics.

Peptide-based therapies are highly effective. However, they are easily degraded by enzymes in a person’s body because peptides lack the structural stability that larger, more complex proteins have. One way that scientists have tried to work around this limitation for GLP-1 receptor agonists is fusing the peptide directly to a person’s immunoglobulin G (IgG) antibodies. These long-acting, drug-fused IgGs act as excellent peptide ferries, but they are costly because the antibodies must be extracted and modified in a laboratory before they can be effective inside that same person’s body.

Pentelute and his team have developed a technology to attach GLP-1 receptor agonists to IgGs within the body. The drug delivery system, which he calls in vivo antibody painting, is itself a peptide and is composed of a binder region that attaches to the IgG, a payload region that carries the GLP-1 receptor agonist, and a reactive region that attaches (i.e., paints) the GLP-1 drug onto the IgG with a covalent bond.

In laboratory tests of the antibody painting platform on mouse and human IgGs, the researchers found that nearly half of all antibodies successfully attached to GLP-1 receptor agonists at a body temperature of 98.6 degrees Fahrenheit (37 degrees Celsius).

Next, they tested the platform for delivering GLP-1 receptor agonists in a mouse model for Type 2 diabetes and metabolic-induced obesity. Pentelute and his colleagues found that the mice experienced sustained blood glucose management and weight loss for up to 15 days after a single treatment. In fact, mice that received antibody painting had better and longer lasting results at a GLP-1 drug dose much lower than the current traditionally administered dose.

The researchers have shared their findings in a preprint research article that is currently under peer review. Pentelute will expand upon this work during his ACS Spring 2025 presentation, including new results from demonstrations showing that the platform can effectively paint antibodies in the presence of extracellular debris such as cellular proteins.

“We’re also expanding the technology to make antibody drug conjugates for cancer,” shares Pentelute. “And we’re modifying this technology to be able to paint multiple drugs onto one antibody,” he adds. “With new technology like this, the future of peptide-based therapies could see reduced costs and enhanced effectiveness.”

Reference:

Improving GLP-1 drug delivery by ‘painting’ it on antibodies, American Chemical Society, Meeting: ACS Spring 2025.