Paracrine-endocrine FGF chimeras as potent therapeutics for metabolic diseases.

Background: The development of a clinically useful fibroblast growth factor 21 (FGF21) hormone has been impeded by its inherent instability and weak FGF receptor (FGFR) binding affinity. There is an urgent need for innovative approaches to overcome these limitations.

Methods: We devised a structure-based chimerisation strategy in which we substituted the thermally labile and low receptor affinity core of FGF21 with an HS binding deficient endocrinised core derived from a stable and high receptor affinity paracrine FGF1 (FGF1). The thermal stability, receptor binding ability, heparan sulfate and βKlotho coreceptor dependency of the chimera were measured using a thermal shift assay, SPR, SEC-MALS and cell-based studies. The half-life, tissue distribution, glucose lowering activity and adipose tissue remodeling were analyzed in normal and diabetic mice and monkeys.

Findings: The melting temperature of the engineered chimera (FGF1-FGF21) increased by ∼22 °C relative to wild-type FGF21 (FGF21), and resulted in a ∼5-fold increase in half-life in vivo. The chimera also acquired an ability to bind the FGFR1c isoform - the principal receptor that mediates the metabolic actions of FGF21 - and consequently was dramatically more effective than FGF21 in correcting hyperglycemia and in ameliorating insulin resistance in db/db mice. Our chimeric FGF21 also exerted a significant beneficial effect on glycemic control in spontaneous diabetic cynomolgus monkeys.

Interpretation: Our study describes a structure-based chimerisation approach that effectively mitigates both the intrinsically weak receptor binding affinities and short half-lives of endocrine FGFs, and advance the development of the FGF21 hormone into a potentially useful drug for Type 2 diabetes.