Toward once-monthly insulin therapy via synergy in two pharmacokinetic protractors: Fc-conjugation and fatty acid acylation

Pharmacokinetic properties and duration of therapeutic action of a pharmaceutical agent can be significantly extended through the combination of two distinct strategies aimed at increasing plasma half-life: fatty acid acylation and Fc-conjugation. Using insulin as a case study, we demonstrate that a...

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Bibliographic Details
Published in:RSC chemical biology 2024-07, Vol.5 (8), p.763-775
Main Authors: Zaykov, Alexander N, Gelfanov, Vasily M, Tagmose, Tina M, Demozay, Damien, Manfè, Valentina, Rohlfs, Rebecca, Rivir, Marita, Perez-Tilve, Diego, Finan, Brian, DiMarchi, Richard D
Format: Article
Language:English
Subjects:
Chemistry
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Summary:Pharmacokinetic properties and duration of therapeutic action of a pharmaceutical agent can be significantly extended through the combination of two distinct strategies aimed at increasing plasma half-life: fatty acid acylation and Fc-conjugation. Using insulin as a case study, we demonstrate that a doubly protracted insulin analog produces a substantial prolongation of pharmacodynamic effect to lower blood glucose in STZ-treated mice when compared to the Fc-only counterparts. This enhancement is further corroborated by direct pharmacokinetic measurements in rat and dog models, demonstrating the potential for once-monthly insulin therapy. The results suggest that this approach might have broad application across a diverse spectrum of peptide- and protein-based therapeutics.
ISSN:2633-0679
2633-0679
DOI:10.1039/d4cb00078a