This invention provides protease-activatable Pseudomonas exotoxin A-like (\"PE-like\") proproteins. The proproteins comprise (1) a cell recognition domain of between 10 and 1500 amino acids that binds to a cell surface receptor; (2) a modified PE translocation domain comprising an amino acid sequence sufficiently homologous to domain II of PE to effect translocation to a cell cytosol upon proteolytic cleavage, wherein the translocation domain comprises a cysteine-cysteine loop that comprises a protease activatable sequence cleavable by a protease and wherein the cysteine-cysteine loop is substantially un-activatable by furin; (3) optionally, a PE Ib-like domain comprising an amino acid sequence up to 1500 amino acids; (4) a cytotoxicity domain comprising an amino acid sequence substantially homologous to domain m of PE, the cytotoxicity domain having ADP-ribosylating activity; and (5) an endoplasmic reticulum (\"ER\") retention sequence. The invention also provides methods of using these proproteins for killing target cells.
Inventor(s):
Fitzgerald; David J. (Rockville, MD), Reiter; Yoram (Ness Ziona, IL), Pastan; Ira (Potomac, MD)
Assignee:
The United States of America as represented by the Department of Health and (N/A) (Washington, DC)
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