Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 14, Pages 5578-5583Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1017067108
Keywords
ADAM17; antibody phage display; cancer therapeutics
Categories
Funding
- Cancer Research UK
- British Heart Foundation [RG/09/012/28096] Funding Source: researchfish
Ask authors/readers for more resources
Proteolytic release from the cell surface is an essential activation event for many growth factors and cytokines. TNF-alpha 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available