Enhanced plasma half-life and efficacy of engineered human albumin-fused GLP-1 despite enzymatic cleavage of its C-terminal end.

ABSTRACT: Albumin has a long plasma half-life due to engagement of the neonatal Fc receptor (FcRn), which prevents intracellular degradation. However, its C-terminal end can be cleaved by carboxypeptidase A, and removal of the last leucine residue (L585) weakens receptor binding, reducing its half-life from 20 days to 3.5 days in humans. This biology has so far been overlooked when designing human albumin-fused biologics. Thus, there is a need for an engineering strategy to secure favorable FcRn binding and pharmacokinetic properties. Here, we show that a branched aliphatic amino acid or methionine at position 585 of albumin is required for optimal receptor binding, which cannot be replaced to prevent enzymatic cleavage without negatively affecting FcRn engagement. As a solution, we report that C-te

SUBMITTER: Nilsen J 

PROVIDER: S-EPMC12106674 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature