Fc-GDF15 glyco-engineering and receptor binding affinity optimization for body weight regulation.

ABSTRACT: GDF15 is a distant TGF-β family member that induces anorexia and weight loss. Due to its function, GDF15 has attracted attention as a potential therapeutic for the treatment of obesity and its associated metabolic diseases. However, the pharmacokinetic and physicochemical properties of GDF15 present several challenges for its development as a therapeutic, including a short half-life, high aggregation propensity, and protease susceptibility in serum. Here, we report the design, characterization and optimization of GDF15 in an Fc-fusion protein format with improved therapeutic properties. Using a structure-based engineering approach, we combined knob-into-hole Fc technology and N-linked glycosylation site mutagenesis for half-life extension, improved solubility and protease resistance. In ad

SUBMITTER: Fung E 

PROVIDER: S-EPMC8076310 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature