Multifunctional Antibody Agonists Targeting Glucagon‐like Peptide‐1, Glucagon,and Glucose‐Dependent Insulinotropic Polypeptide Receptors |
| |
Authors: | Dr. Ying Wang Dr. Jintang Du Dr. Huafei Zou Dr. Yan Liu Yuhan Zhang Jose Gonzalez Elizabeth Chao Lucy Lu Pengyu Yang Holly Parker Dr. Van Nguyen‐Tran Dr. Weijun Shen Dr. Danling Wang Dr. Peter G. Schultz Dr. Feng Wang |
| |
Affiliation: | California Institute for Biomedical Research (Calibr), La Jolla, CA, USA |
| |
Abstract: | 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. |
| |
Keywords: | antibodies dual agonists obesity peptides protein engineering |
|
|