Hepatotoxicity in cancer patients receiving erb-38, a recombinant immunotoxin that targets the erbB2 receptor.
To exploit overexpression of erbB2 in human cancers, we constructed a single-chain immunotoxin (erb-38) that contains the Fv portion of monoclonal antibody e23 fused to a truncated form of Pseudomonas exotoxin A. In a Phase I study, five breast cancer patients and one esophageal cancer patient received three doses of erb-38 at 1.0 and 2.0 microg/kg. Hepatotoxicity was observed in all patients. Immunohistochemistry showed the presence of erbB2 on hepatocytes explaining the liver toxicity of erb-38. We suggest that targeting of tumors with antibodies to erbB2 armed with radioisotopes or other toxic agents may result in unexpected organ toxicities due to erbB2 on normal cells.
Pai-Scherf
L H
LH
Laboratory of Molecular Biology, Division of Basic Sciences, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Villa
J
J
Pearson
D
D
Watson
T
T
Liu
E
E
Willingham
M C
MC
Pastan
I
I
D036002:ADP Ribose Transferases; D000328:Adult; D000410:Alanine Transaminase / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use; D000912:Antibodies, Neoplasm / Q000096:biosynthesis; D001219:Aspartate Aminotransferases / Q000378:metabolism; D001427:Bacterial Toxins / Q000009:adverse effects* / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D005098:Exotoxins / Q000009:adverse effects* / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000009:adverse effects* / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008107:Liver Diseases / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000009:adverse effects* / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000410:Alanine Transaminase; D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D001219:Aspartate Aminotransferases; D001427:Bacterial Toxins; D005098:Exotoxins; D000922:Immunotoxins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A