title: A noncytolytic antibody-like extendin-4-IgG4 fusion protein as a long-acting potential anti-diabetic agent.
abstract: BACKGROUND
  GLP-1 and its analogs have a variety of anti-diabetic effects. However, short half-life and rapid degraded by DPP-IV limits the therapeutic potential of the native GLP-1. So, many DPP-IV-resistant and long-acting GLP-1 analogs were developed. In this study, an antibody-like extendin-4-IgG4 fusion protein was developed.
  
  
  METHODS
  The γ4 constant region contains two amino acid substitutions relative to native γ4 (S228P and L235E) lead to affinity for FcγRI to be low and stability of the IgG4 molecular. The fusion protein was expressed in CHO cells and assembled into an immunoglobulin-like structure with molecular weight of approximately 130 kDa.
  
  
  RESULTS
  The Exendin-4-IgG4 fusion protein was found to affinity bind GLP-1R in vitro. In vivo when compared the potency and duration of glucose-lowering effects in diabetic (db/db) mice at the same dose, exendin-4 resulted in a glucose-lowering effect that persisted only for 6 hours, but the extendin-4-IgG4 fusion protein for more than 168 hours. Injecting subcutaneously with a high dose of the fusion protein led normal BALB/c mice to the lower blood glucose level but did not cause serious hypoglycemia. Especially, the half-life time of the fusion protein in cynomolgus monkeys was about 180 hours, almost the longest half-life time among the developed GPL-1 analogues, which suggested a longer half-life time in human.
  
  
  CONCLUSIONS
  The intact antibody-like fusion protein has more advantages than the Fc fusion protein including the intent of prolonging the half-life. These results also suggested the fusion protein was a safe and long-acting potential anti-diabetic agent.
authors.affiliation: Department of Clinical Lab of Nanlou, Chinese PLA General Hospital Beijing 100853, China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
authors.affiliation: Genete Biopharmaceutical Co. Ltd Taizhou 225300, Jiangsu Province, China.
authors.forename: Pinliang
authors.initials: P
authors.lastname: Hu
authors.affiliation: Department of Orthopedics, First Affiliated Hospital, Chinese PLA General Hospital Beijing 100048, China.
authors.forename: Rungong
authors.initials: R
authors.lastname: Yang
authors.affiliation: Department of Clinical Lab of Nanlou, Chinese PLA General Hospital Beijing 100853, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Bai
authors.affiliation: Genete Biopharmaceutical Co. Ltd Taizhou 225300, Jiangsu Province, China.
authors.forename: Xingheng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Clinical Lab of Nanlou, Chinese PLA General Hospital Beijing 100853, China.
authors.forename: Shuhong
authors.initials: S
authors.lastname: Fu
authors.affiliation: Genete Biopharmaceutical Co. Ltd Taizhou 225300, Jiangsu Province, China.
authors.forename: Siyi
authors.initials: S
authors.lastname: Yang
authors.affiliation: Genete Biopharmaceutical Co. Ltd Taizhou 225300, Jiangsu Province, China.
authors.forename: Jinwei
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Clinical Lab of Nanlou, Chinese PLA General Hospital Beijing 100853, China.
authors.forename: Meiliang
authors.initials: M
authors.lastname: Gong
authors.affiliation: Genete Biopharmaceutical Co. Ltd Taizhou 225300, Jiangsu Province, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.affiliation: Genete Biopharmaceutical Co. Ltd Taizhou 225300, Jiangsu Province, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Genete Biopharmaceutical Co. Ltd Taizhou 225300, Jiangsu Province, China.
authors.forename: Yanbing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Genete Biopharmaceutical Co. Ltd Taizhou 225300, Jiangsu Province, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhou
keywords: Extendin-4-IgG4 fusion protein; GLP-1 analog; anti-diabetic agent; antibody-like; long-acting