TODAY’S PATENT – TISSUE PLASMINOGEN ACTIVATORS HAVING ZYMOGENIC OR FIBRIN-SPECIFIC PROPERTIES

This invention “Tissue plasminogen activators having zymogenic or fibrin-specific properties” was invented by Stephen Anderson, William F. Bennett, David Botstein, Deborah L. Higgins, Nicholas F. Paoni, and Mark J. Zoller assigned to Genentech Inc and was granted a patent on 11th April 1995 by USPTO bearing patent grant number US5405771A to the patentee.

Tissue plasminogen activator (t-PA) zymogens and variants are prepared, including a fibrinolytic ally active variant of t-PA that has an amino acid alteration at a site within the protease domain of t-PA as compared with the corresponding wild-type t-PA, which alteration renders the variant zymogenic in the presence of plasmin-degraded fibrinogen, and/or fibrin (or plasma clot) specific, as compared to the corresponding wild-type t-PA. DNA sequences can be prepared that encode the zymogens and variants, as well as expression vectors incorporating the DNA sequences, and host cells transformed with the expression vectors. The zymogens and variants may be used in a pharmaceutical preparation to treat a vascular disease or condition or to prevent fibrin deposition or adhesion formation or reformation in mammals.

The invention relates to a tissue plasminogen activator (t-PA) zymogen that can be activated by plasmin to treat vascular conditions or prevent fibrin deposition. The invention also provides a variant of t-PA that is zymogenic and has an amino acid alteration in the protease domain. The invention includes methods of introducing amino acid variations and screening for zymogenic character, as well as DNA sequences, replicable vectors, and host cells transformed with the variant. A composition for treating vascular conditions or preventing fibrin deposition is also provided, as well as methods of administering the composition to a mammal. The invention’s aim is to provide a more fibrin-specific t-PA that acts preferentially at the site of the clot.