2014/06/26 by Jon Kenniston, Ryan Faucette, Diana Martik +18 · 2 citations
Medicine · Chemistry · #Coagulation, Bradykinin, Polyphosphates, and Angioedema #Blood Coagulation and Thrombosis Mechanisms #Peptidase Inhibition and Analysis #Kallikrein #High-molecular-weight kininogen #Kininogen #Bradykinin #Prekallikrein #Chemistry #Serine protease #Hereditary angioedema #Zymogen #Serpin #C1-inhibitor #Pharmacology #Molecular biology #Internal medicine #Biochemistry #Angioedema #Immunology #Protease #Medicine #Biology #Enzyme #Receptor
paper · doi:10.1074/jbc.m114.569061
openalex publication_date 2014/06/26 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/28
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 (Ki = 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 (t½ ∼ 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.