4PUB

Crystal structure of Fab DX-2930

Summary for 4PUB

• Entry DOI: 10.2210/pdb4pub/pdb
• Related: 4ogx 4ogy
• Descriptor: DX-2930 HEAVY CHAIN, DX-2930 LIGHT CHAIN, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: fab, antibody, kallikrein, blood, plasma, plasma kallikrein-mediated edema, acute hereditary angioedema, hae, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 47520.60

Authors

Abendroth, J.,Edwards, T.E.,Nixon, A.,Ladner, R. (deposition date: 2014-03-12, release date: 2014-07-09, Last modification date: 2024-10-16)

Primary citation

Kenniston, J.A.,Faucette, R.R.,Martik, D.,Comeau, S.R.,Lindberg, A.P.,Kopacz, K.J.,Conley, G.P.,Chen, J.,Viswanathan, M.,Kastrapeli, N.,Cosic, J.,Mason, S.,DiLeo, M.,Abendroth, J.,Kuzmic, P.,Ladner, R.C.,Edwards, T.E.,TenHoor, C.,Adelman, B.A.,Nixon, A.E.,Sexton, D.J.
Inhibition of plasma kallikrein by a highly specific active site blocking antibody.
J.Biol.Chem., 289:23596-23608, 2014

PubMed 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 (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.

PubMed: 24970892
DOI: 10.1074/jbc.M114.569061

Experimental method

X-RAY DIFFRACTION (1.75 Å)