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

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

SUBMITTER: Hecht R

PROVIDER: S-EPMC3507880 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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

Hecht Randy R Li Yue-Sheng YS Sun Jeonghoon J Belouski Ed E Hall Michael M Hager Todd T Yie Junming J Wang Wei W Winters Dwight D Smith Stephen S Spahr Chris C Tam Lei-Ting LT Shen Zhongnan Z Stanislaus Shanaka S Chinookoswong Narumol N Lau Yvonne Y Sickmier Allen A Michaels Mark Leo ML Boone Thomas T Véniant Murielle M MM Xu Jing J

PloS one 20121127 11

Fibroblast growth factor 21 (FGF21) is a promising drug candidate for the treatment of type 2 diabetes. However, the use of wild type native FGF21 is challenging due to several limitations. Among these are its short half-life, its susceptibility to in vivo proteolytic degradation and its propensity to in vitro aggregation. We here describe a rationale-based protein engineering approach to generate a potent long-acting FGF21 analog with improved resistance to proteolysis and aggregation. A recomb ...[more]

PMID: 23209571

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Project description:BackgroundIncreasing availability of competing biosimilar alternatives makes it challenging to make treatment decisions. The purpose of this review is to evaluate the comparative efficacy and safety of ultra-long-/long-/intermediate-acting insulin products and biosimilar insulin compared to human/animal insulin in adults with type 1 diabetes mellitus (T1DM).MethodsMEDLINE, EMBASE, CENTRAL, and grey literature were searched from inception to March 27, 2019. Randomized controlled trials (RCTs), quasi-experimental studies, and cohort studies of adults with T1DM receiving ultra-long-/long-/intermediate-acting insulin, compared to each other, as well as biosimilar insulin compared to human/animal insulin were eligible for inclusion. Two reviewers independently screened studies, abstracted data, and appraised risk-of-bias. Pairwise meta-analyses and network meta-analyses (NMA) were conducted. Summary effect measures were mean differences (MD) and odds ratios (OR).ResultsWe included 65 unique studies examining 14,200 patients with T1DM. Both ultra-long-acting and long-acting insulin were superior to intermediate-acting insulin in reducing A1c, FPG, weight gain, and the incidence of major, serious, or nocturnal hypoglycemia. For fasting blood glucose, long-acting once a day (od) was superior to long-acting twice a day (bid) (MD - 0.44, 95% CI: - 0.81 to - 0.06) and ultra-long-acting od was superior to long-acting bid (MD - 0.73, 95% CI - 1.36 to - 0.11). For weight change, long-acting od was inferior to long-acting bid (MD 0.58, 95% CI: 0.05 to 1.10) and long-acting bid was superior to long-action biosimilar od (MD - 0.90, 95% CI: - 1.67 to - 0.12).ConclusionsOur results can be used to tailor insulin treatment according to the desired results of patients and clinicians and inform strategies to establish a competitive clinical market, address systemic barriers, expand the pool of potential suppliers, and favor insulin price reduction.Prospero registrationCRD42017077051.

Dataset Information

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

Publications

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

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