NDLI: An inhibitory antibody against dipeptidyl peptidase IV improves glucose tolerance in vivo.

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An inhibitory antibody against dipeptidyl peptidase IV improves glucose tolerance in vivo.

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An inhibitory antibody against dipeptidyl peptidase IV improves glucose tolerance in vivo.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Sudom, Athena Min, Xiaoshan Wang, Wei Sharkov, Nik Lu, Mei Wang, Zhulun Shao, Hui Liu, Qiang Zhang, Yi Xiong, Yumei Shen, Wenyan Wang, Yan Majeti, Jiangwen Tu, Hua Johnstone, Sheree Yang, Xiaoping Higbee, Jared Yu, Timothy Cao, Ping Xia, Zhen Walker, Nigel Tang, Jie
Description	Author Affiliation: Tang J ( Department of Biologics, Amgen Inc., South San Francisco, California 94080, USA. jiet@amgen.com)
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.
ISSN	00219258
e-ISSN	1083351X
Journal	Journal of Biological Chemistry
Issue Number	2
Volume Number	288
Language	English
Publisher	American Society for Biochemistry and Molecular Biology (United States)
Publisher Date	2013-01-11
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Antibodies, Monoclonal Immunology Dipeptidyl Peptidase 4 Glucose Tolerance Test Animals Chemistry Crystallography, X-Ray Enzyme-Linked Immunosorbent Assay Mice Mice, Inbred C57BL Models, Molecular Rats, Zucker Biochemistry Molecular Biology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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