title: An inhibitory antibody against dipeptidyl peptidase IV improves glucose tolerance in vivo.
abstract: Dipeptidyl peptidase IV (DPP-IV) degrades the incretin hormone glucagon-like peptide 1 (GLP-1). Small molecule DPP-IV inhibitors have been used as treatments for type 2 diabetes to improve glucose tolerance. However, each of the marketed small molecule drugs has its own limitation in terms of efficacy and side effects. To search for an alternative strategy of inhibiting DPP-IV activity, we generated a panel of tight binding inhibitory mouse monoclonal antibodies (mAbs) against rat DPP-IV. When tested in vitro, these mAbs partially inhibited the GLP-1 cleavage activity of purified enzyme and rat plasma. To understand the partial inhibition, we solved the co-crystal structure of one of the mAb Fabs (Ab1) in complex with rat DPP-IV. Although Ab1 does not bind at the active site, it partially blocks the side opening, which prevents the large substrates such as GLP-1 from accessing the active site, but not small molecules such as sitagliptin. When Ab1 was tested in vivo, it reduced plasma glucose and increased plasma GLP-1 concentration during an oral glucose tolerance test in rats. Together, we demonstrated the feasibility of using mAbs to inhibit DPP-IV activity and to improve glucose tolerance in a diabetic rat model.
authors.affiliation: Department of Biologics, Amgen Inc., South San Francisco, California 94080, USA. jiet@amgen.com
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.forename: Jiangwen
authors.initials: J
authors.lastname: Majeti
authors.forename: Athena
authors.initials: A
authors.lastname: Sudom
authors.forename: Yumei
authors.initials: Y
authors.lastname: Xiong
authors.forename: Mei
authors.initials: M
authors.lastname: Lu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
authors.forename: Jared
authors.initials: J
authors.lastname: Higbee
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Ping
authors.initials: P
authors.lastname: Cao
authors.forename: Zhen
authors.initials: Z
authors.lastname: Xia
authors.forename: Sheree
authors.initials: S
authors.lastname: Johnstone
authors.forename: Xiaoshan
authors.initials: X
authors.lastname: Min
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Yang
authors.forename: Hui
authors.initials: H
authors.lastname: Shao
authors.forename: Timothy
authors.initials: T
authors.lastname: Yu
authors.forename: Nik
authors.initials: N
authors.lastname: Sharkov
authors.forename: Nigel
authors.initials: N
authors.lastname: Walker
authors.forename: Hua
authors.initials: H
authors.lastname: Tu
authors.forename: Wenyan
authors.initials: W
authors.lastname: Shen
authors.forename: Zhulun
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology*; D018360:Crystallography, X-Ray; D018819:Dipeptidyl Peptidase 4 / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005951:Glucose Tolerance Test; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D051381:Rats; D011924:Rats, Zucker
chemical_list: D000911:Antibodies, Monoclonal; D018819:Dipeptidyl Peptidase 4