Selective inhibition of tumor cell growth by a recombinant single-chain antibody-toxin specific for the erbB-2 receptor.
A high percentage of human breast and ovarian tumors display amplified c-erbB-2 gene copies, leading to overexpression of the growth factor receptor. Its membrane location and elevated expression make the erbB-2 protein an appropriate target for a directed tumor therapy. We have used recombinant DNA technology to produce a single-chain antibody-exotoxin A (scFv-ETA) fusion protein which specifically binds the human erbB-2 receptor. The scFv portion is composed of the heavy- and light-chain variable domains of a monoclonal antibody which recognizes the extracellular domain of the human erbB-2 receptor. The bacterially produced scFv-ETA protein was shown to bind specifically to cells expressing the human erbB-2 protein. The scFv-ETA inhibits protein synthesis in erbB-2-expressing tumor cells at doses ranging from 2 to 200 ng/ml and is cytotoxic for these cells at equivalent doses. In athymic nude mice, administration of the scFv-ETA inhibited the growth of erbB-2-overexpressing human ovarian carcinoma cells.
Wels
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Friedrich Miescher Institute, Pharmaceuticals Division, Ciba-Geigy, Basel, Switzerland.
Harwerth
I M
IM
Mueller
M
M
Groner
B
B
Hynes
N E
NE
D036002:ADP Ribose Transferases; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity; D001427:Bacterial Toxins; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002678:Chimera / Q000235:genetics; D004274:DNA, Recombinant / Q000235:genetics; D005098:Exotoxins / Q000235:genetics / Q000494:pharmacology*; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology*; D011994:Recombinant Proteins; D014183:Transplantation, Heterologous; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000911:Antibodies, Monoclonal; D001427:Bacterial Toxins; D002352:Carrier Proteins; D004274:DNA, Recombinant; D005098:Exotoxins; D000922:Immunotoxins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C064822:single-chain antigen-binding protein B6.2-212