Multifunctional Antibody Agonists Targeting Glucagon-like Peptide-1, Glucagon, and Glucose-Dependent Insulinotropic Polypeptide Receptors

Ying Wang; Jintang Du; Huafei Zou; Yan Liu; Yuhan Zhang; Jose Gonzalez; Elizabeth Chao; Lucy Lu; Pengyu Yang; Holly Parker; Van Nguyen-Tran; Weijun Shen; Danling Wang; Peter G Schultz; Feng Wang

doi:10.1002/anie.201606321

Multifunctional Antibody Agonists Targeting Glucagon-like Peptide-1, Glucagon, and Glucose-Dependent Insulinotropic Polypeptide Receptors

Angew Chem Int Ed Engl. 2016 Sep 26;55(40):12475-8. doi: 10.1002/anie.201606321. Epub 2016 Sep 6.

Authors

Affiliations

¹ California Institute for Biomedical Research (Calibr), 11119 N. Torrey Pines Road, La Jolla, CA, 92037, USA.
² California Institute for Biomedical Research (Calibr), 11119 N. Torrey Pines Road, La Jolla, CA, 92037, USA. [email protected].
³ California Institute for Biomedical Research (Calibr), 11119 N. Torrey Pines Road, La Jolla, CA, 92037, USA. [email protected].

PMID: 27595986
DOI: 10.1002/anie.201606321

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.

MeSH terms

Animals
Antibodies / genetics
Antibodies / immunology*
Antibodies / metabolism
Body Weight / drug effects
Female
Glucagon / agonists*
Glucagon / immunology
Glucagon-Like Peptide 1 / agonists*
Glucagon-Like Peptide 1 / immunology
HEK293 Cells
Half-Life
Humans
Immunoglobulin Heavy Chains / genetics
Immunoglobulin Heavy Chains / immunology
Immunoglobulin Heavy Chains / metabolism
Immunoglobulin Light Chains / genetics
Immunoglobulin Light Chains / immunology
Immunoglobulin Light Chains / metabolism
Mice
Mice, Obese
Peptides / chemistry
Peptides / genetics
Peptides / metabolism
Protein Engineering
Rats
Rats, Sprague-Dawley
Receptors, Gastrointestinal Hormone / agonists*
Receptors, Gastrointestinal Hormone / immunology
Recombinant Fusion Proteins / biosynthesis
Recombinant Fusion Proteins / pharmacokinetics
Recombinant Fusion Proteins / pharmacology

Substances

Antibodies
Immunoglobulin Heavy Chains
Immunoglobulin Light Chains
Peptides
Receptors, Gastrointestinal Hormone
Recombinant Fusion Proteins
Glucagon-Like Peptide 1
Glucagon
gastric inhibitory polypeptide receptor