PHARMACOKINETICS OF AN ANTIBODY-RICIN CONJUGATE ADMINISTERED INTRAPERITONEALLY TO MICE

Immunotoxins have been extensively studied for the treatment of neopla sias; their intracavitary administration could be useful for the thera py of tumors confined to the pleural or peritoneum spaces. To study th e feasibility of this ''locoregional'' treatment, a pharmacokinetic st udy of immunotoxins delivery is necessary. Ricin, a plant toxin extrac ted from the seeds of Ricinus communis, has often been used in immunoc onjugates for its high activity; nevertheless, appropriate strategies have been necessary to limit the aspecific toxicity. We previously pre pared a AR-3-ricin immunotoxin lacking the ability to bind galactosidi c cell surface residues, a so-called sterically blocked immunotoxin. T he monoclonal antibody AR-3, an ISG1 specific to the CAR-3 antigen, wa s able to recognize human colorectal adenocarcinomas. Preclinical tria ls in nude mice, intraperitoneally grafted with the target neoplasia, showed that this immunotoxin suppressed tumor growth without showing a ny undesirable ricin toxicity. In the present work we report the pharm acokinetic properties of this immunotoxin, showing the in vivo stabili ty and a relatively long blood survival. With a biodistribution study in tumor-bearing mice, we demonstrate that in tumor-invaded tissues, t he concentration of the specific AR-3-ricin immunotoxin was higher and progressively increased in a multiple-dose regimen. In contrast, an i rrelevant immunotoxin behaved differently because it did not show spec ific tumor uptake. Moreover the pharmacokinetic data reported in this work improve the potential for ''locoregional'' treatment of malignanc y with blocked immunotoxins.