Rationale-Based Engineering of a Potent Long-Acting FGF21 Analog for the Treatment of Type 2 Diabetes

摘要: Fibroblast growth factor 21 (FGF21) is a promising drug candidate for the treatment of type 2 diabetes. However, use wild native FGF21 challenging due to several limitations. Among these are its short half-life, susceptibility in vivo proteolytic degradation and propensity vitro aggregation. We here describe rationale-based protein engineering approach generate potent long-acting analog with improved resistance proteolysis A recombinant Fc-FGF21 fusion was constructed by fusing Fc domain human IgG1 N-terminus mature via linker peptide. The positioned at determined be superior C-terminus as N-terminal retained βKlotho binding affinity potency similar FGF21. Two specific point mutations were introduced into leucine arginine substitution position 98 (L98R) suppressed aggregation high concentrations elevated temperatures. proline glycine replacement 171 (P171G) eliminated site-specific cleavage identified mice cynomolgus monkeys. derived Fc-FGF21(RG) molecule demonstrated significantly circulating half-life while maintaining activity that protein. 11 h 30 monkeys compared 1-2 or type. single administration diabetic resulted sustained reduction blood glucose levels body weight gains up 5-7 days, whereas efficacy lasted only 1 day. In summary, we engineered efficacious favorable pharmaceutical property potential clinical development.