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Cross-domain inhibition of TACE ectodomain

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Christopher J Tape
  • Sofie H Willems
  • Sarah L Dombernowsky
  • Peter L Stanley
  • Marton Fogarasi
  • Willem Ouwehand
  • John McCafferty
  • Gillian Murphy
Proteolytic release from the cell surface is an essential activation event for many growth factors and cytokines. TNF-a 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.
OriginalsprogEngelsk
TidsskriftProceedings of the National Academy of Sciences USA (PNAS)
Vol/bind108
Udgave nummer14
Sider (fra-til)5578-83
Antal sider6
ISSN0027-8424
DOI
StatusUdgivet - 2011

ID: 38029041