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Medientyp:
E-Artikel
Titel:
Cross-domain inhibition of TACE ectodomain
Beteiligte:
Tape, Christopher J.;
Willems, Sofie H.;
Dombernowsky, Sarah L.;
Stanley, Peter L.;
Fogarasi, Marton;
Ouwehand, Willem;
McCafferty, John;
Murphy, Gillian
Erschienen:
Proceedings of the National Academy of Sciences, 2011
Erschienen in:
Proceedings of the National Academy of Sciences, 108 (2011) 14, Seite 5578-5583
Sprache:
Englisch
DOI:
10.1073/pnas.1017067108
ISSN:
0027-8424;
1091-6490
Entstehung:
Anmerkungen:
Beschreibung:
Proteolytic release from the cell surface is an essential activation event for many growth factors and cytokines. TNF-α converting enzyme (TACE) is a membrane-bound metalloprotease responsible for solubilizing many pathologically significant membrane substrates and is an attractive therapeutic target for the treatment of cancer and arthritis. Prior attempts to antagonize cell-surface TACE activity have focused on small-molecule inhibition of the metalloprotease active site. Given the highly conserved nature of metalloprotease active sites, this paradigm has failed to produce a truly specific TACE inhibitor and continues to obstruct the clinical investigation of TACE activity. We report the bespoke development of a specific TACE inhibitory human antibody using “two-step” phage display. This approach combines calculated selection conditions with antibody variable-domain exchange to direct individual antibody variable domains to desired epitopes. The resulting “cross-domain” human antibody is a previously undescribed selective TACE antagonist and provides a unique alternative to small-molecule metalloprotease inhibition.