Fc-binding Exendin-4 conjugate 7 achieves semaglutide-comparable long-acting glycemic control in db/db mice

Effective therapies for Type 2 diabetes mellitus require both efficacy and durability. While incretin mimetics like exendin-4 (Ex4) improve glycemic control, their short plasma half-life necessitates frequent dosing. Current half-life extension methods, such as Fc fusion, often introduce challenges like immunogenicity or complex manufacturing. This creates a need for novel, broadly applicable strategies to prolong peptide action without these drawbacks, specifically by utilizing the body's natural circulating proteins.

Researchers engineered a series of site-specific IgG Fc-binding motif-modified Exendin-4 analogues, using two conjugation methods to leverage Fc-III-4C-mediated IgG binding. They performed structure-activity relationship studies to identify conjugate 7 as the lead candidate, confirming robust GLP-1R activation. In human IgG-preconditioned db/db mice, they assessed acute glucose-lowering efficacy and hypoglycemic duration. Chronic once-daily dosing of conjugate 7 was compared against semaglutide for its impact on HbA1c and pancreatic islet protection, while also monitoring for toxicity.

Structure-activity relationship studies confirmed that conjugate 7 retained robust GLP-1R activation and acute glucose-lowering efficacy. The engineered motif demonstrated high affinity for human IgG, with a KD of 20.1 nM, indicating effective engagement with the endogenous antibody reservoir.

In human IgG-preconditioned db/db mice, conjugate 7 achieved a hypoglycemic duration comparable to that of semaglutide, a benchmark long-acting GLP-1 agonist. Furthermore, chronic once-daily dosing of conjugate 7 rivaled semaglutide in its ability to significantly reduce HbA1c levels and provide protection to pancreatic islets. Importantly, no toxicity was observed during the chronic treatment regimen. This novel strategy effectively leverages >80% of endogenous circulating IgG as a biological reservoir, overcoming the inherent short half-life limitations of peptide therapies.