Determining Maximal Tolerable Dose of the Monoclonal Antibody BR96 Labeled with 90Y or 177Lu in Rats: Establishment of a Syngeneic Tumor Model to Evaluate Means to Improve Radioimmunotherapy

Abstract

To evaluate therapeutic strategies, it is essential to use biological models reflecting important aspects of the clinical situation. The aim of the present study was to compare the maximal tolerable dose of the monoclonal antibody BR96 labeled with 90Y or 177Lu in immunocompetent rats. Maximal tolerable dose was defined as the highest activity that allows 100% of the animals to survive without clinical signs, such as infections, bleeding, or diarrhea, and with <20% loss in body weight. Increasing activity levels of BR96 labeled with 90Y or 177Lu were administered to groups of rats. Blood parameters, body weight, and general performance were monitored for 8 weeks. Two days postinjection, all groups had decreased leukocyte counts down to 5% to 15% of initial values. Initiation of recovery (at 14-21 days) showed a dose-response relationship. All groups, except the group given the highest activity of 90Y, had complete resolution in their leukopenia. The decrease in platelets was delayed to days 7 to 14 postinjection with a dose-dependent response regarding both severity of the nadir (10-40% of initial value) and the start of recovery. Animals in the groups given the highest activities of both 90Y and 177Lu exhibited skin infections on day 21. The results showed good reproducibility and dose-dependent toxicity for both radionuclides, indicating that the maximal tolerable dose for 177Lu-BR96 (1,000 MBq/kg) is 1.7 times that for 90Y-BR96 (600 MBq/kg) in rats. This model makes it feasible to evaluate strategies to escalate therapeutic doses to tumors without increasing normal tissue toxicity.