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Pharmacokinetics in the Rat of a Panel of Immunotoxins Made with Abrin A Chain, Ricin A Chain, Gelonin, and Momordin¹

Drug Targeting Laboratory, Section of Medicine [E. J. W., A. J. C., R. V. H., J. M., G. D. P., N. R. W., J. A. F.], and Section of Drug Development [D. R. N.], Institute of Cancer Research, Cotswold Road, Sutton, Surrey, SM2 5NG, England

A panel of immunotoxins was constructed by chemically attaching the ribosome-inactivating proteins abrin A chain, ricin A chain, gelonin, and momordin to the monoclonal mouse IgG2a antibody Fib75 by means of a disulfide linkage. All the immunotoxins were toxic in tissue culture to the EJ human bladder carcinoma cell line expressing the antigen recognized by Fib75, inhibiting the incorporation of [³H]leucine by 50% at concentrations between 1 x 10^-10 M and 8 x 10^-10 M. The pharmacokinetics of the immunotoxins in the normal Wistar rat was determined following i.v. administration. The concentrations of intact immunotoxin in serum samples taken at various intervals after injection for up to 24 h were measured by solid-phase enzyme-linked immunosorbent assays specific for each of the four different ribosome-inactivating proteins. The Fib75 immunotoxins were cleared from the circulation with comparable, but not identical, biphasic kinetics best described by a two compartment open pharmacokinetic model. The -phase half-lives of the panel, between 0.35 and 0.71 h, were similar. The ß-phase half-life of Fib75-abrin A chain, 13.3 h, was significantly longer than the ß-phase half-lives of Fib75-ricin A chain, Fib75-gelonin, and Fib75-momordin, between 7.5 and 8.6 h. Fib75-abrin A chain was found to be about 3- to 4-fold more resistant than the other immunotoxins to breakdown by reduction of the disulfide linkage between the A chain and the antibody with glutathione in vitro. This suggests that the longer serum half-life of Fib75-abrin A chain may have been due to greater stability against reduction in vivo. Analysis of serum samples obtained up to 24 h after injection of Fib75-abrin A chain revealed that the chemically intact immunotoxin present in the circulation retained full cytotoxic activity. An abrin A chain immunotoxin made with a different monoclonal mouse IgG2a antibody was also found to be more stable against reduction by glutathione in vitro than an analogous ricin A chain immunotoxin. Thus, abrin A chain may possess unique molecular properties that endow immunotoxins made with this A chain with greater stability in vivo than immunotoxins made with ricin A chain or other ribosome-inactivating proteins.

¹ This work was supported by funds from the Medical Research Council and the Cancer Research Campaign, United Kingdom.

² To whom requests for reprints should be addressed.

³ Present address: University of Newcastle-upon-Tyne, Department of Clinical Oncology, Cancer Research Unit, Medical School, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, England.

Received 6/12/90. Accepted 8/30/90.

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