Scientific Reports (Apr 2021)

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

  • Ella Fung,
  • Liya Kang,
  • Diana Sapashnik,
  • Susan Benard,
  • Annette Sievers,
  • Yan Liu,
  • Guoying Yan,
  • Jing Zhou,
  • Linette Rodriguez,
  • Weijun Ma,
  • Wayne R. Stochaj,
  • Edward LaVallie,
  • Liliana Wroblewska,
  • Kerry Kelleher,
  • Amy Tam,
  • Olivier Bezy,
  • Danna Breen,
  • Jeffrey R. Chabot,
  • Tao He,
  • Laura Lin,
  • Zhidan Wu,
  • Lidia Mosyak

DOI
https://doi.org/10.1038/s41598-021-87959-5
Journal volume & issue
Vol. 11, no. 1
pp. 1 – 12

Abstract

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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 addition, we identified a set of mutations at the receptor binding site of GDF15 that show increased GFRAL binding affinity and led to significant half-life extension. We also identified a single point mutation that increases p-ERK signaling activity and results in improved weight loss efficacy in vivo. Taken together, our findings allowed us to develop GDF15 in a new therapeutic format that demonstrates better efficacy and potential for improved manufacturability.