Characterization of vascular leak syndrome induced by the toxin component of Pseudomonas exotoxin-based immunotoxins and its potential inhibition with nonsteroidal anti-inflammatory drugs.
Clinical trials of immunotoxins in cancer patients have been limited in many cases by vascular leak syndrome (VLS). Recently, rats were identified as a model for VLS induced by BR96 sFv-PE40, a carcinoma-reactive single-chain immunotoxin. In this study, the toxin component of this immunotoxin, PE40, was found to be responsible for inducing hydrothorax in rats, thereby demonstrating that direct binding to the BR96 antigen was not essential to the onset of VLS. Mutational analysis of PE40 determined that both ADP ribosylation and proteolytic processing functions innate to Pseudomonas exotoxin A (PE) were necessary for PE40 to induce hydrothorax in rats; however, neither function by itself was sufficient for VLS induction. Additionally, nonsteroidal anti-inflammatory agents were found to block VLS in rats receiving BR96 sFv-PE40. These results demonstrate that the toxin component of PE-based immunotoxins induce VLS and suggest agents for clinical management of the toxicity.
Siegall
C B
CB
Molecular Immunology Department, Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121, USA. Clay_B._Siegall@ccmail.bms.com
Liggitt
D
D
Chace
D
D
Mixan
B
B
Sugai
J
J
Davidson
T
T
Steinitz
M
M
D036002:ADP Ribose Transferases; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents / Q000633:toxicity*; D001427:Bacterial Toxins; D019559:Capillary Leak Syndrome / Q000139:chemically induced* / Q000517:prevention & control*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D003907:Dexamethasone / Q000627:therapeutic use*; D005098:Exotoxins / Q000633:toxicity*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006876:Hydrothorax / Q000139:chemically induced* / Q000517:prevention & control*; D000922:Immunotoxins / Q000633:toxicity*; D007375:Interleukin-1 / Q000235:genetics; D007527:Isoenzymes / Q000235:genetics; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000633:toxicity; D014158:Transcription, Genetic / Q000187:drug effects*; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D001427:Bacterial Toxins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D003907:Dexamethasone; D005098:Exotoxins; D000922:Immunotoxins; D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D011993:Recombinant Fusion Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C089583:BR96 sFv-PE40; C496513:Ptgs1 protein, rat