IgG Fc-Binding Motif-Conjugated Exendin-4: A Long-Acting Hypoglycemic Agent via Broad-Spectrum Antibody Engagement for Type 2 Diabetes Therapy

Type 2 diabetes mellitus requires therapies that optimize both efficacy and durability. Although incretin mimetics such as exendin-4 (Ex4) enhance glycemic control, their short half-life restricts their clinical utility. Current extension strategies (e.g., Fc fusion) encounter challenges including immunogenicity and manufacturing complexity. Here, we engineered a series of site-specific IgG Fc-binding motif-modified Ex4 analogues using two orthogonal conjugation methods, leveraging Fc-III-4C-mediated IgG binding (human IgG: KD = 20.1 nM) to achieve a significantly extended plasma half-life. Structure–activity relationship studies revealed that the lead candidate, conjugate 7, retained robust GLP-1R activation and acute glucose-lowering efficacy. In human IgG-preconditioned db/db mice, conjugate 7 achieved a hypoglycemic duration comparable to that of semaglutide. Chronic once-daily dosing of the lead conjugate rivaled semaglutide in reducing HbA1c and protecting pancreatic islets, without toxicity. This strategy leverages >80% of endogenous circulating IgG as a biological reservoir to overcome peptide therapy limitations, offering a translatable platform for long-acting antidiabetic agents.