Butyric Acid-Modified m-P14 Peptide Ameliorates Anti-Glomerular Basement Membrane Disease

The non-collagenous domain 1 of the α3 chain of type IV collagen (α3(IV)NC1) is the primary autoantigen in anti-glomerular basement membrane (anti-GBM) disease. We previously developed a modified antigen-specific peptide, m-P14, derived from the nephritogenic epitope α3_127-148, which ameliorated experimental anti-GBM nephritis. However, its short half-life limits clinical translation. This study evaluated a butyrate-conjugated derivative (m-P14-BA) to improve pharmacokinetic properties while preserving therapeutic efficacy. M-P14-BA and m-P14 were administered to α3_127-148 immunized Wistar Kyoto rats in early and late treatment settings. Renal injury parameters and intrarenal inflammation were assessed, and pharmacokinetic profiles were evaluated following intraperitoneal administration in beagle dogs. M-P14-BA reduced proteinuria, crescent formation, glomerular IgG deposition, complement activation, and inflammatory cell infiltration, with overall efficacy comparable to m-P14 in early treatment settings. In late treatment settings, m-P14-BA was associated with a significant improvement in blood urea nitrogen levels and modest reductions in proteinuria and histopathological injury. Butyrate conjugation markedly improved pharmacokinetics, prolonging plasma elimination half-life by approximately 2.8-fold and increasing systemic exposure nearly fourfold. These pharmacokinetic improvements were associated with maintained therapeutic efficacy at a reduced dose, with 10 mg/kg m-P14-BA achieving effects broadly similar to those observed with 30 mg/kg m-P14. In summary, butyrate conjugation improves the pharmacokinetic profile of an antigen-specific therapeutic peptide while preserving therapeutic activity, suggesting a potential strategy to enhance the translational feasibility of peptide-based immunotherapy in anti-GBM disease.