Improving GLP-1 drug delivery by fusing the peptide directly to immunoglobulin antibodies

Massachusetts Institute of Technology (MIT) researchers have revealed a drug delivery system that "paints" glucagon-like peptide-1 (GLP-1) directly onto 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.

General overview of the in vivo IgG ‘painting’ technology. In vivo reaction to native IgGs. Z33 peptide variant conjugated to electrophile-drug moieties is administered in vivo. The peptide recognizes lysine-317 of the IgG Fc-domain heavy chain A enabling the transfer of its payload to IgGs through proximity effect. The reaction is fast (a few hours), biocompatible and covalent. The binding of IgGs to the neonatal Fc receptor (FcRn) the half-life is expected to extend and enhance drug efficacy. This technology is versatile and can be accomplished with a variety of cargoes: small molecules, therapeutic peptides, or even radionuclides (Credit: bioRxiv)

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 by 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.

Dr Bradley Pentelute, professor of chemistry at MIT, who will present his team's results at the spring meeting of the American Chemical Society (ACS 2025) in San Diego, 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°F (37°C).

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.

Pentelute’s presentation will 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," said Pentelute. "And we're modifying this technology to be able to paint multiple drugs onto one antibody. With new technology like this, the future of peptide-based therapies could see reduced costs and enhanced effectiveness."

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.

The researchers have shared their findings in a preprint research article on bioRxiv that is currently under peer review. The findings were reported in the paper, ‘In vivo Antibody Painting for Next Generation Weight Loss Drugs’, published in bioRxiv. To access this paper, please click here