Potent and specific chemically-conjugated immunotoxins

摘要

The present invention involves a mutant Pseudomonas exotoxin having alterations in domain I. A first alteration includes an amino acid, dipeptide, tripeptide or tetrapeptide insertion in domain I of Pseudomonas exotoxin. This insertion attenuates eukaryotic cell binding while allowing substantial prokaryotic secretion, ADP ribosylation activity and eukaryotic membrane translocation. A second alteration involves a cysteine substitution in a surface residue of exotoxin domain I. This substitution is preferably on a side opposite to domains II and III of the exotoxin. The latter substitution allows attachment of a carrier molecule by a disulfide or thioether linkage. Attachment of carriers such as monoclonal antibodies results in immunotoxins having the binding specificity of the antibody rather than the native exotoxin.