DESIGN OF A GENETIC IMMUNOTOXIN TO ELIMINATE TOXIN IMMUNOGENICITY

Host antibody response to toxin molecules is a major obstacle to the u se of immunotoxins as efficacious agents in the treatment of human can cer and other diseases. In this study, a genetic form of immunotoxin h as been designed which should eliminate toxin immunogenicity by replac ing the toxin protein moitey with weakly immunogenic or nonimmunogenic plasmid DNA. A recombinant bifunctional fusion protein, which consist s of a human antibody Fab targeting moiety [directed against gp 120, t he envelope glycoprotein of human immunodeficiency virus (HIV)-1] and a human DNA binding moiety (protamine), is used as a gene carrier. Tox in plasmid DNAs expressing the catalytic fragment of Pseudomonas exoto xin A (PEA) statically interact with the fusion proteins to form solub le protein-DNA complexes. The complexes are specifically transferred i nto HIV-1-infected cells by receptor-mediated endocytosis, resulting i n selective killing of the target cells. These 'genetic immunotoxins' may have significant advantages over protein immunotoxins for the trea tment of a variety of human diseases.