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Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5578-83. doi: 10.1073/pnas.1017067108. Epub 2011 Mar 17.

Cross-domain inhibition of TACE ectodomain.

Author information

1
Department of Oncology, University of Cambridge, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, United Kingdom.

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.

PMID:
21415364
PMCID:
PMC3078358
DOI:
10.1073/pnas.1017067108
[Indexed for MEDLINE]
Free PMC Article

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