| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Martik, Diana Cosic, Janja Lindberg, Allison P. Tenhoor, Christopher Kenniston, Jon A. Kuzmic, Petr Comeau, Stephen R. Nixon, Andrew E. Ladner, Robert C. Chen, Jie Viswanathan, Malini Faucette, Ryan R. Edwards, Thomas E. Sexton, Daniel J. Adelman, Burt A. Kopacz, Kris J. Mason, Shauna Conley, Gregory P. Abendroth, Jan Kastrapeli, Niksa Dileo, Mike |
| Description |
Author Affiliation: Kenniston JA ( From the Dyax Corp., Burlington, Massachusetts 01803.); Faucette RR ( From the Dyax Corp., Burlington, Massachusetts 01803.); Martik D ( From the Dyax Corp., Burlington, Massachusetts 01803.); Comeau SR ( From the Dyax Corp., Burlington, Massachusetts 01803.); Lindberg AP ( From the Dyax Corp., Burlington, Massachusetts 01803.); Kopacz KJ ( From the Dyax Corp., Burlington, Massachusetts 01803.); Conley GP ( From the Dyax Corp., Burlington, Massachusetts 01803.); Chen J ( From the Dyax Corp., Burlington, Massachusetts 01803.); Viswanathan M ( From the Dyax Corp., Burlington, Massachusetts 01803.); Kastrapeli N ( From the Dyax Corp., Burlington, Massachusetts 01803.); Cosic J ( From the Dyax Corp., Burlington, Massachusetts 01803.); Mason S ( From the Dyax Corp., Burlington, Massachusetts 01803.); DiLeo M ( From the Dyax Corp., Burlington, Massachusetts 01803.); Abendroth J ( Beryllium, Bainbridge Island, Washington 98110, and.); Kuzmic P ( Biokin, Watertown, Massachusetts 02472.); Ladner RC ( From the Dyax Corp., Burlington, Massachusetts 01803.); Edwards TE ( Beryllium, Bainbridge Island, Washington 98110, and.); TenHoor C ( From the Dyax Corp., Burlington, Massachusetts 01803.); Adelman BA ( From the Dyax Corp., Burlington, Massachusetts 01803.); Nixon AE ( From the Dyax Corp., Burlington, Massachusetts 01803.); Sexton DJ ( From the Dyax Corp., Burlington, Massachusetts 01803, dsexton@dyax.com.) |
| Abstract |
Plasma kallikrein (pKal) proteolytically cleaves high molecular weight kininogen to generate the potent vasodilator and the pro-inflammatory peptide, bradykinin. pKal activity is tightly regulated in healthy individuals by the serpin C1-inhibitor, but individuals with hereditary angioedema (HAE) are deficient in C1-inhibitor and consequently exhibit excessive bradykinin generation that in turn causes debilitating and potentially fatal swelling attacks. To develop a potential therapeutic agent for HAE and other pKal-mediated disorders, we used phage display to discover a fully human IgG1 monoclonal antibody (DX-2930) against pKal. In vitro experiments demonstrated that DX-2930 potently inhibits active pKal $(K_{i}$ = 0.120 ± 0.005 nm) but does not target either the zymogen (prekallikrein) or any other serine protease tested. These findings are supported by a 2.1-Å resolution crystal structure of pKal complexed to a DX-2930 Fab construct, which establishes that the pKal active site is fully occluded by the antibody. DX-2930 injected subcutaneously into cynomolgus monkeys exhibited a long half-life $(t_{½}$ ∼12.5 days) and blocked high molecular weight kininogen proteolysis in activated plasma in a dose- and time-dependent manner. Furthermore, subcutaneous DX-2930 reduced carrageenan-induced paw edema in rats. A potent and long acting inhibitor of pKal activity could be an effective treatment option for pKal-mediated diseases, such as HAE. |
| ISSN |
00219258 |
| e-ISSN |
1083351X |
| Journal |
Journal of Biological Chemistry |
| Issue Number |
34 |
| Volume Number |
289 |
| Language |
English |
| Publisher |
American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date |
2014-08-22 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Antibodies Immunology Kallikreins Amino Acid Sequence Animals Catalytic Domain Crystallography, X-Ray Enzyme-Linked Immunosorbent Assay Blood Molecular Sequence Data Rats, Sprague-Dawley Surface Plasmon Resonance Biochemistry Molecular Biology |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Cell Biology Biochemistry Molecular Biology |
