Pseudomonas exotoxin (PE) or genetically modified forms of PE have been attached to monoclonal antibodies (mAbs) or growth factors to create cell- specific cytotoxic agents. Mutant PE molecules in which domain I has been replaced by TGFalpha, IL2, IL4, IL6, CD4 or single chain antibody combining regions have been created by gene fusion, the chimeric proteins produced in E. coli, and purified to near homogeneity. Such molecules may be useful in the elimination of tumor cells or other cells responsible for several human diseases. Mutational analysis has been used to delineate the function of the various domains of PE. Mutations at positions 276 and 279 of PE block cytotoxicity probably by preventing proteolytic processing of PE. Mutations at the carboxyl end of PE abolish cytotoxicity by interfering with translocation of a processed form of PE. The activity of CD4-PE40 has been further evaluated and the chimeric toxin has been found to block the spread of HIV in vitro and to be active against several different strains of HIV as well as SIV.
