Design of a modular immunotoxin connected by polyionic adapter peptides.
Immunotoxins are genetically engineered fusion proteins of an antibody Fv fragment and a toxin from bacteria or plants, which function as anti-cancer therapeutics. Here, we describe a new generation of immunotoxins in which both proteins do not form a single fusion protein but are coupled specifically via cysteine-containing polyionic fusion peptides. The engineered Pseudomonas exotoxin PE38 was N-terminally fused to the peptide E(8)C. In combination with the disulfide-stabilized Fv fragment of the tumor-specific antibody B3, which was extended by the peptide R(8)CP, the fusion peptides ensured a specific and covalent coupling of the Fv fragment and the toxin. The resulting immunotoxin was as active and as specific as an immunotoxin consisting of a fusion protein of the same antibody fragment connected to the toxin.
Kleinschmidt
Martin
M
Institut für Biotechnologie, Martin-Luther-Universitat, Universität Halle, Kurt-Mothes Strasse 3, Germany.
Rudolph
Rainer
R
Lilie
Hauke
H
D036002:ADP Ribose Transferases / Q000737:chemistry* / Q000235:genetics; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001427:Bacterial Toxins / Q000737:chemistry* / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D004220:Disulfides / Q000737:chemistry*; D015195:Drug Design; D005098:Exotoxins / Q000737:chemistry* / Q000235:genetics; D007128:Immunoglobulin Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000922:Immunotoxins / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology*; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D010957:Plasmids; D011550:Pseudomonas aeruginosa; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D037521:Virulence Factors / Q000737:chemistry* / Q000235:genetics; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000911:Antibodies, Monoclonal; D001427:Bacterial Toxins; D004220:Disulfides; D005098:Exotoxins; D007128:Immunoglobulin Fragments; D000922:Immunotoxins; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C055966:immunoglobulin Fv; C092978:immunotoxin LMB-7