(Press-News.org) SAN DIEGO, March 23, 2025 — 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.”
The research was funded by Pentelute’s discretionary funds at MIT and the National Cancer Institute at the National Institutes of Health.
This technology is included in a pending provisional patent from MIT. Katsushi Kitahara, a study co-author, is employed by a pharmaceutical company. Pentelute is a co-founder and involved with several companies focusing on the development of protein and peptide therapeutics.
Visit the ACS Spring 2025 program to learn more about this presentation, “In vivo antibody painting for next generation of weight loss drugs” and other science presentations.
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Title
In vivo antibody painting for next generation of weight loss drugs
Abstract
Peptides are gaining tremendous interest as therapeutics over the last decades but suffer from short pharmacokinetic (PK) and pharmacodynamic (PD). Here, we developed Fc-binder electrophilic peptides for the delivery of therapeutic drugs to native immunoglobulins (IgG). More than just another tool to engineer antibody-drug-conjugates, we found that this technology can also “paint” the IgGs circulating in living animals, enabling the bioorthogonal addition of small molecules, radionuclides, or bioactive long peptide drugs. Applied to glucagon-like peptide-1 (GLP1) agonists, this technology showed an extended PK/PD with a sustained body weight loss and a prolonged blood glucose management. These results demonstrate the versatility and translational potential of the IgG painting technology for the next generation of long-acting medicines, with promising outcomes for the management of obesity and type II diabetes.
END
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