Authors:
CJ Tape, SH Willems, SL Dombernowsky, PL Stanley, M Fogarasi, W Ouwehand, J McCafferty, G Murphy
Journal name: 
Proc Natl Acad Sci U S A
Citation info: 
108(14):5578-5583
Abstract: 
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.
DOI: 
http://doi.org/10.1073/pnas.1017067108
Research group: 
Murphy Group
E-pub date: 
05 Apr 2011