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Multifunctional Antibody Agonists Targeting Glucagon‐like Peptide‐1, Glucagon, and Glucose‐Dependent Insulinotropic Polypeptide Receptors
Author(s) -
Wang Ying,
Du Jintang,
Zou Huafei,
Liu Yan,
Zhang Yuhan,
Gonzalez Jose,
Chao Elizabeth,
Lu Lucy,
Yang Pengyu,
Parker Holly,
NguyenTran Van,
Shen Weijun,
Wang Danling,
Schultz Peter G.,
Wang Feng
Publication year - 2016
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201606321
Subject(s) - receptor , agonist , glucagon , gastric inhibitory polypeptide , antibody , glucagon receptor , peptide , chemistry , endocrinology , medicine , glucagon like peptide 1 , peptide hormone , glucagon like peptide 1 receptor , biochemistry , biology , hormone , immunology , diabetes mellitus , type 2 diabetes
Glucagon‐like peptide‐1 (GLP‐1) receptor (GLP‐1R), glucagon (GCG) receptor (GCGR), and glucose‐dependent insulinotropic polypeptide (GIP, also known as gastric inhibitory polypeptide) receptor (GIPR), are three metabolically related peptide hormone receptors. A novel approach to the generation of multifunctional antibody agonists that activate these receptors has been developed. Native or engineered peptide agonists for GLP‐1R, GCGR, and GIPR were fused to the N‐terminus of the heavy chain or light chain of an antibody, either alone or in pairwise combinations. The fusion proteins have similar in vitro biological activities on the cognate receptors as the corresponding peptides, but circa 100‐fold longer plasma half‐lives. The GLP‐1R mono agonist and GLP‐1R/GCGR dual agonist antibodies both exhibit potent effects on glucose control and body weight reduction in mice, with the dual agonist antibody showing enhanced activity in the latter.