ENGINEERED ANTHRAX LETHAL TOXIN FOR TARGETED DELIVERY

摘要

The present invention provides methods and systems for targeted delivery of a compound to a target cell that overexpresses two different proteinases. Specifically, two different modified protective antigen proteins, each comprising a cleavage site recognized by a distinct proteinase in place of the native proteinase cleavage site recognized by furin, are administered in combination with a compound that contains a protective antigen binding site. Upon cleavage by the two proteinases the two modified protective antigen proteins form a hetero-oligomer, allowing the compound to bind to the hetero-oligomer and subsequently to be translocated into the target cell.

主权项

1. A method of targeted delivery of a compound to a cell overexpressing a first proteinase and a second proteinase that are different from each other, the method comprising the steps of:
(a) administering to the cell (1) a first mutant protective antigen protein that comprises a cleavage site recognized by the first proteinase in place of the native protective antigen furin-recognized cleavage site and is cleavable by the first proteinase; and (2) a second mutant protective antigen protein that comprises a cleavage site recognized by the second proteinase in place of the native protective antigen furin-recognized cleavage site and is cleavable by the second proteinase, wherein the first and second mutant protective antigen proteins each comprises an additional mutation other than the cleavage sites recognized by the first and second proteinases, and wherein after cleavage by the first and second proteinases the first and second mutant protective antigen proteins form a hetero-oligomer but do not form a homo-oligomer; and (b) administering to the cell a compound comprising a protective antigen binding site, wherein the compound binds to the hetero-oligomer and is translocated into the cell.