Multifunctional Antibody Agonists Targeting Glucagon-like Peptide-1, Glucagon, and Glucose-Dependent Insulinotropic Polypeptide Receptors.
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.
California Institute for Biomedical Research (Calibr), 11119 N. Torrey Pines Road, La Jolla, CA, 92037, USA.
Ying
Y
Wang
California Institute for Biomedical Research (Calibr), 11119 N. Torrey Pines Road, La Jolla, CA, 92037, USA.
Jintang
J
Du
California Institute for Biomedical Research (Calibr), 11119 N. Torrey Pines Road, La Jolla, CA, 92037, USA.
Huafei
H
Zou
California Institute for Biomedical Research (Calibr), 11119 N. Torrey Pines Road, La Jolla, CA, 92037, USA.
Yan
Y
Liu
California Institute for Biomedical Research (Calibr), 11119 N. Torrey Pines Road, La Jolla, CA, 92037, USA.
Yuhan
Y
Zhang
California Institute for Biomedical Research (Calibr), 11119 N. Torrey Pines Road, La Jolla, CA, 92037, USA.
Jose
J
Gonzalez
California Institute for Biomedical Research (Calibr), 11119 N. Torrey Pines Road, La Jolla, CA, 92037, USA.
Elizabeth
E
Chao
California Institute for Biomedical Research (Calibr), 11119 N. Torrey Pines Road, La Jolla, CA, 92037, USA.
Lucy
L
Lu
California Institute for Biomedical Research (Calibr), 11119 N. Torrey Pines Road, La Jolla, CA, 92037, USA.
Pengyu
P
Yang
California Institute for Biomedical Research (Calibr), 11119 N. Torrey Pines Road, La Jolla, CA, 92037, USA.
Holly
H
Parker
California Institute for Biomedical Research (Calibr), 11119 N. Torrey Pines Road, La Jolla, CA, 92037, USA.
Van
V
Nguyen-Tran
California Institute for Biomedical Research (Calibr), 11119 N. Torrey Pines Road, La Jolla, CA, 92037, USA.
Weijun
W
Shen
California Institute for Biomedical Research (Calibr), 11119 N. Torrey Pines Road, La Jolla, CA, 92037, USA.
Danling
D
Wang
California Institute for Biomedical Research (Calibr), 11119 N. Torrey Pines Road, La Jolla, CA, 92037, USA. schultz@calibr.org.
Peter G
PG
Schultz
California Institute for Biomedical Research (Calibr), 11119 N. Torrey Pines Road, La Jolla, CA, 92037, USA. fwang@calibr.org.
Feng
F
Wang
D000818:Animals; D000906:Antibodies / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D005260:Female; D005934:Glucagon / Q000819:agonists* / Q000276:immunology; D052216:Glucagon-Like Peptide 1 / Q000819:agonists* / Q000276:immunology; D057809:HEK293 Cells; D006207:Half-Life; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007147:Immunoglobulin Light Chains / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015202:Protein Engineering; D051381:Rats; D017207:Rats, Sprague-Dawley; D011964:Receptors, Gastrointestinal Hormone / Q000819:agonists* / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000493:pharmacokinetics / Q000494:pharmacology
D000906:Antibodies; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D010455:Peptides; D011964:Receptors, Gastrointestinal Hormone; D011993:Recombinant Fusion Proteins; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; C041086:gastric inhibitory polypeptide receptor
antibodies; dual agonists; obesity; peptides; protein engineering