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Inhibition of Antibody Response to Pseudomonas Exotoxin and an Immunotoxin Containing Pseudomonas Exotoxin by 15-Deoxyspergualin in Mice

Laboratory of Molecular Biology, National Cancer Institute, NIH, Bethesda, Maryland 20892 [L. H. P., D. J. F., I. P.], and Bristol-Myers Squibb Co., Wallingford, Connecticut 06942 [M. T., B. S., G. S.]

Immunotoxins are potent cell-killing agents that may be useful in the treatment of cancer. The early production of neutralizing antibodies to immunotoxins is one of the major limiting factors for their use in humans. 15-Deoxyspergualin (DSG), a derivative of spergualin, which is a metabolite of Bacillus laterosporus, has been found to have immunosuppressive activity in rodents, dogs, and primates. We examined the suppressive activity of DSG on the antibody response to Pseudomonas exotoxin in mice by enzyme-linked immunosorbent assay. Male BDF₁ mice were immunized with a single dose of a nontoxic mutant of Pseudomonas exotoxin (40 µg) and then treated with i.p. injections of DSG at a dose of 10 mg/kg for 3 days. Although antibodies to Pseudomonas exotoxin were observed within 7 days in the control group, there was complete suppression of antibody production in the DSG-treated group. Immunosuppression has also been observed in animals immunized with multiple doses (10 mg x 7 d) of Pseudomonas exotoxin and treated with DSG at a dose of 5 mg/kg for 21 days. Similar immunosuppression was observed in mice given multiple doses of the immunotoxin, anti-Tac-LysPE40. We conclude that the immunosuppressive activity of DSG may be useful in increasing the duration of immunotoxin treatment.

¹ To whom requests for reprints should be addressed, at National Cancer Institute, NIH, 9000 Rockville Pike, Building 37, Room 4E16, Bethesda, MD 20892.

Received 5/14/90. Accepted 9/17/90.

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