Design of a genetic immunotoxin to eliminate toxin immunogenicity.
Host antibody response to toxin molecules is a major obstacle to the use of immunotoxins as efficacious agents in the treatment of human cancer and other diseases. In this study, a genetic form of immunotoxin has been designed which should eliminate toxin immunogenicity by replacing the toxin protein moiety with weakly immunogenic or nonimmunogenic plasmid DNA. A recombinant bifunctional fusion protein, which consists of a human antibody Fab targeting moiety [directed against gp120, the envelope glycoprotein of human immunodeficiency virus (HIV)-1] and a human DNA binding moiety (protamine), is used as a gene carrier. Toxin plasmid DNAs expressing the catalytic fragment of Pseudomonas exotoxin A (PEA) statically interact with the fusion proteins to form soluble protein-DNA complexes. The complexes are specifically transferred into HIV-1-infected cells by receptor-mediated endocytosis, resulting in selective killing of the target cells. These 'genetic immunotoxins' may have significant advantages over protein immunotoxins for the treatment of a variety of human diseases.
Chen
S Y
SY
Department of Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115.
Zani
C
C
Khouri
Y
Y
Marasco
W A
WA
D036002:ADP Ribose Transferases; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D001427:Bacterial Toxins; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000821:virology; D002461:Cell Line, Transformed; D002522:Chlorocebus aethiops; D003587:Cytomegalovirus / Q000235:genetics; D004247:DNA / Q000378:metabolism; D015195:Drug Design; D005098:Exotoxins / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics / Q000633:toxicity; D005822:Genetic Vectors; D015483:HIV Antibodies / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology*; D007143:Immunoglobulin Heavy Chains / Q000276:immunology* / Q000378:metabolism; D000922:Immunotoxins / Q000276:immunology* / Q000378:metabolism; D008969:Molecular Sequence Data; D011479:Protamines / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000911:Antibodies, Monoclonal; D001427:Bacterial Toxins; D004247:DNA; D005098:Exotoxins; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D007140:Immunoglobulin Fab Fragments; D007143:Immunoglobulin Heavy Chains; D000922:Immunotoxins; D011479:Protamines; D011993:Recombinant Fusion Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A