Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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ADP Ribose Transferases*
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Animals
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Antibodies, Monoclonal / immunology*
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Bacterial Toxins*
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Base Sequence
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / virology
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Cell Line, Transformed
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Chlorocebus aethiops
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Cytomegalovirus / genetics
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DNA / metabolism
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Drug Design
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Exotoxins / administration & dosage*
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Exotoxins / chemistry
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Exotoxins / genetics
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Exotoxins / toxicity
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Genetic Vectors
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HIV Antibodies / immunology*
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HIV Envelope Protein gp120 / immunology*
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HIV Envelope Protein gp120 / metabolism
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HIV-1 / immunology*
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Humans
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Immunoglobulin Fab Fragments / immunology*
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Immunoglobulin Heavy Chains / immunology*
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Immunoglobulin Heavy Chains / metabolism
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Immunotoxins / immunology*
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Immunotoxins / metabolism
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Molecular Sequence Data
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Protamines / immunology*
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Pseudomonas aeruginosa Exotoxin A
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Recombinant Fusion Proteins / immunology*
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Recombinant Fusion Proteins / metabolism
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Tumor Cells, Cultured
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Virulence Factors*
Substances
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Antibodies, Monoclonal
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Bacterial Toxins
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Exotoxins
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HIV Antibodies
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HIV Envelope Protein gp120
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Immunoglobulin Fab Fragments
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Immunoglobulin Heavy Chains
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Immunotoxins
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Protamines
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Recombinant Fusion Proteins
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Virulence Factors
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DNA
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ADP Ribose Transferases