Antibody-Pseudomonas exotoxin A conjugates cytotoxic to human breast cancer cells in vitro.
Breast tumor selective antibodies (MAB) conjugated to Pseudomonas exotoxin A (PE) formed immunotoxins with potent cytotoxicities for human breast tumor cell lines. The most effective of the MAB-PE conjugates were about 500-fold more toxic to the breast tumor target cell lines than to the nontarget human fibroblast cell line. Specificity of cytotoxicity by MAB-PE conjugates was demonstrated by protection of target cells in the presence of excess unconjugated homologous antibody. A MAB-PE conjugate inhibited protein synthesis more rapidly than the corresponding MAB-ricin toxin A chain (RTA) conjugate. Generally, there was a direct correlation between the cytotoxicity of RTA and PE when conjugated to the same MAB: MABs that made highly cytotoxic RTA conjugates made effective PE conjugates and MABs that made poorly cytotoxic RTA conjugates made PE conjugates of low cytotoxicity; however, one MAB-PE immunotoxin was cytotoxic to the human breast tumor cell lines, whereas the corresponding MAB-RTA immunotoxin was noncytotoxic at the highest dose tested. In contrast to MAB-RTA conjugates, which require a cleavable (disulfide) linkage for maximal in vitro cytotoxicity, MAB-PE conjugates were about equally cytotoxic when linked by either a cleavable or noncleavable (thioether) bond.
D036002:ADP Ribose Transferases; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001427:Bacterial Toxins; D001943:Breast Neoplasms / Q000628:therapy*; D002478:Cells, Cultured; D004220:Disulfides; D005098:Exotoxins / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D007700:Kinetics; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009500:Neutralization Tests; D009713:Nucleotidyltransferases / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000911:Antibodies, Monoclonal; D001427:Bacterial Toxins; D004220:Disulfides; D005098:Exotoxins; D009363:Neoplasm Proteins; D009713:Nucleotidyltransferases; D011065:Poly(ADP-ribose) Polymerases; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A