Pseudomonas exotoxin conjugated to monoclonal antibody MRK16 specifically kills multidrug resistant cells in cultured renal carcinomas and in MDR-transgenic mice.
Using renal carcinoma and prostate carcinoma cell lines, we investigated the concept of targeting and killing multidrug resistant cells in urogenital cancers. Renal carcinoma lines HTB44, 45, 46, and 47 expressed a relatively low, but detectable level of multidrug resistance (MDR)1 mRNA as indicated by Northern blot analysis, whereas prostate lines LNCaP and DU145 were found to be MDR1-negative. Anti-P-glycoprotein monoclonal antibody MRK16 was conjugated to Pseudomonas exotoxin (PE) by a stable thioether bond. Treatment with MRK16-PE resulted in a dose-dependent killing of multidrug resistant renal carcinoma cells, while non-MDR expressing prostate carcinoma cells were not affected. Addition of excess MRK16 blocked the effect of MRK16-PE. Furthermore, MOPC-PE, a non-MDR associated monoclonal antibody control conjugate, did not target and kill multidrug resistant renal carcinoma cells. Having established that MRK16-PE was active against and specific for multidrug resistant cells in culture, we also tested bioactivity in MDR-transgenic mice, whose bone marrow cells express the human MDR1 gene at a level approximately equal to that found in many human cancers. Again, MRK16-PE killed multidrug resistant bone marrow cells with high efficiency in an intact animal, and killing was blocked by unconjugated MRK16.
Mickisch
G H
GH
Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Pai
L H
LH
Siegsmund
M
M
Campain
J
J
Gottesman
M M
MM
Pastan
I
I
D036002:ADP Ribose Transferases; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001427:Bacterial Toxins / Q000494:pharmacology / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D004351:Drug Resistance; D005098:Exotoxins / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000911:Antibodies, Monoclonal; D001427:Bacterial Toxins; D005098:Exotoxins; D000922:Immunotoxins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A