title: Rational Design of Dual Agonist-Antibody Fusions as Long-acting Therapeutic Hormones.
abstract: Recent studies have suggested that modulation of two or more signaling pathways can achieve substantial weight loss and glycemic stability. We have developed an approach to the generation of bifunctional antibody agonists that activate leptin receptor and GLP-1 receptor. Leptin was fused into the complementarity determining region 3 loop of the light chain alone, or in combination with exendin-4 (EX4) fused at the N-terminus of the heavy chain of Herceptin. The antibody fusions exhibit similar or increased in vitro activities on their cognate receptors, but 50-100-fold longer circulating half-lives in rodents compared to the corresponding native peptides/proteins. The efficacy of the leptin/EX4 dual antibody fusion on weight loss, especially fat mass loss, was enhanced in ob/ob mice and DIO mice compared to the antibody fusion of either EX4 or leptin alone. This work demonstrates the versatility of this combinatorial fusion strategy for generating dual antibody agonists with long half-lives.
authors.affiliation: California Institute for Biomedical Research , La Jolla, California 92037, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: California Institute for Biomedical Research , La Jolla, California 92037, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: California Institute for Biomedical Research , La Jolla, California 92037, United States.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, The Scripps Research Institute , La Jolla, California 92037, United States.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: California Institute for Biomedical Research , La Jolla, California 92037, United States.
authors.forename: Haiqun
authors.initials: H
authors.lastname: Jia
authors.affiliation: California Institute for Biomedical Research , La Jolla, California 92037, United States.
authors.forename: Huafei
authors.initials: H
authors.lastname: Zou
authors.affiliation: California Institute for Biomedical Research , La Jolla, California 92037, United States.
authors.forename: Qiangwei
authors.initials: Q
authors.lastname: Fu
authors.affiliation: California Institute for Biomedical Research , La Jolla, California 92037, United States.
authors.forename: Yuhan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: California Institute for Biomedical Research , La Jolla, California 92037, United States.
authors.forename: Lucy
authors.initials: L
authors.lastname: Lu
authors.affiliation: California Institute for Biomedical Research , La Jolla, California 92037, United States.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Chao
authors.affiliation: California Institute for Biomedical Research , La Jolla, California 92037, United States.
authors.forename: Holly
authors.initials: H
authors.lastname: Parker
authors.affiliation: California Institute for Biomedical Research , La Jolla, California 92037, United States.
authors.forename: Van
authors.initials: V
authors.lastname: Nguyen-Tran
authors.affiliation: California Institute for Biomedical Research , La Jolla, California 92037, United States.
authors.forename: Weijun
authors.initials: W
authors.lastname: Shen
authors.affiliation: California Institute for Biomedical Research , La Jolla, California 92037, United States.
authors.forename: Danling
authors.initials: D
authors.lastname: Wang
authors.affiliation: California Institute for Biomedical Research , La Jolla, California 92037, United States.|Department of Chemistry, The Scripps Research Institute , La Jolla, California 92037, United States.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
authors.affiliation: California Institute for Biomedical Research , La Jolla, California 92037, United States.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry*; D006207:Half-Life; D006728:Hormones / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice
chemical_list: D000906:Antibodies; D006728:Hormones