Prevention of immunotoxin-mediated vascular leak syndrome in rats with retention of antitumor activity.
Immunotoxins are hybrid molecules composed of a cell-surface binding domain and a protein toxin moiety that together target specific cell populations for elimination. These agents represent a promising approach for the treatment of many human diseases, most notably cancer. However, it has recently become clear that many immunotoxins when used in human clinical trials induce vascular leak syndrome (VLS), restricting the administration of doses necessary to achieve good therapeutic responses. The lack of an appropriate animal model has hindered efforts to understand and prevent immunotoxin-induced VLS. We have found that in rats, intravenous administration of the single-chain immunotoxin BR96 sFv-PE40 results in symptoms that closely resemble VLS seen in human immunotoxin trials. A large fluid accumulation in the thoracic cavity was observed, along with an increase in hematocrit and body weight and a decrease in serum albumin. The VLS was apparent within 24 hr after administration of immunotoxin and was seen in both immunocompetent and athymic rats. Similar symptoms were not found in mice even at lethal doses. Prophylactic administration of the corticosteroid dexamethasone resulted in prevention of VLS and survival of rats injected with what would otherwise be lethal doses of BR96 sFv-PE40. Prophylactic treatment with dexamethasone in rats xenografted with human tumors either did not inhibit or minimally inhibited the antitumor activity of BR96 sFv-PE40. The use of prophylactic corticosteroids should be considered for immunotoxin clinical trials, since it may improve therapeutic efficacy by decreasing the dose-limiting toxicity of VLS.
Siegall
C B
CB
Molecular Immunology Department, Bristol-Myers Squibb, Pharmaceutical Research Institute, Seattle, WA 98121.
Liggitt
D
D
Chace
D
D
Tepper
M A
MA
Fell
H P
HP
D000818:Animals; D000911:Antibodies, Monoclonal; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology*; D016572:Cyclosporine / Q000494:pharmacology; D003907:Dexamethasone / Q000627:therapeutic use*; D004155:Diphenhydramine / Q000494:pharmacology; D005260:Female; D006146:Guanidines / Q000494:pharmacology; D006400:Hematocrit; D006801:Humans; D006876:Hydrothorax / Q000139:chemically induced* / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000494:pharmacology; D000922:Immunotoxins / Q000627:therapeutic use* / Q000633:toxicity*; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy*; D051381:Rats; D011920:Rats, Inbred WF; D011923:Rats, Nude; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use* / Q000633:toxicity*; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; C089583:BR96 sFv-PE40; D006146:Guanidines; D007166:Immunosuppressive Agents; D000922:Immunotoxins; D011993:Recombinant Fusion Proteins; D003907:Dexamethasone; D016572:Cyclosporine; D004155:Diphenhydramine; C037258:gusperimus