1. Multifunctional Antibody Agonists Targeting Glucagon-like Peptide-1, Glucagon, and Glucose-Dependent Insulinotropic Polypeptide Receptors
- Author
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Van Nguyen-Tran, Huafei Zou, Elizabeth Chao, Jose Gonzalez, Danling Wang, Weijun Shen, Yuhan Zhang, Peter G. Schultz, Peng-Yu Yang, Feng Wang, Ying Wang, Jintang Du, Lucy Lu, Yan Liu, and Holly Parker
- Subjects
Agonist ,0301 basic medicine ,endocrine system ,medicine.drug_class ,Recombinant Fusion Proteins ,Mice, Obese ,Peptide ,Peptide hormone ,010402 general chemistry ,Immunoglobulin light chain ,Protein Engineering ,Glucagon ,01 natural sciences ,Catalysis ,Antibodies ,Receptors, Gastrointestinal Hormone ,Rats, Sprague-Dawley ,Mice ,03 medical and health sciences ,Gastric inhibitory polypeptide ,Glucagon-Like Peptide 1 ,medicine ,Animals ,Humans ,Receptor ,chemistry.chemical_classification ,Chemistry ,010405 organic chemistry ,digestive, oral, and skin physiology ,Body Weight ,General Chemistry ,General Medicine ,Fusion protein ,Rats ,0104 chemical sciences ,HEK293 Cells ,030104 developmental biology ,Biochemistry ,Female ,Immunoglobulin Light Chains ,Immunoglobulin Heavy Chains ,Peptides ,hormones, hormone substitutes, and hormone antagonists ,Half-Life - 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.
- Published
- 2016