rationale-based engineering of a potent long-acting fgf21 analog for the treatment of type 2 diabetesrationale-based工程的长效fgf21模拟治疗2型糖尿病.pdfVIP

Rationale-Based Engineering of a Potent Long-Acting FGF21 Analog for the Treatment of Type 2 Diabetes 1 1 1 1 3 3 2 Randy Hecht , Yue-Sheng Li , Jeonghoon Sun , Ed Belouski , Michael Hall , Todd Hager , Junming Yie , 1 1 1 1 1 1 Wei Wang , Dwight Winters , Stephen Smith , Chris Spahr , Lei-Ting Tam , Zhongnan Shen , 2 2 3 1 1 Shanaka Stanislaus , Narumol Chinookoswong , Yvonne Lau , Allen Sickmier , Mark Leo Michaels , 1 ´ 2 2 Thomas Boone , Murielle M. Veniant , Jing Xu * 1 Department of Protein Sciences, Amgen Inc., Thousand Oaks, California, United States of America, 2 Departments of Metabolic Disorders, Amgen Inc., Thousand Oaks, California, United States of America, 3 Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Thousand Oaks, California, United States of America 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 h