Determining maximal tolerable dose of the MAb BR96 labeled with 90Y or 177Lu in rats-Establishment of a syngeneic tumor model

Abstract

Objective To compare the maximal tolerable dose (MTD) of MAb BR96 labeled with 90Y or 177Lu in immunocompetent rats. Methods 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. Results Two days post injection (p.i.) all groups had decreased leukocyte counts down to 5 %-15 % of initial values. Initiation of recovery (at 14-21 days) showed a dose-response relationship. All groups except the one given the highest activity of 90Y fully recovered in leukocyte number. The decrease in platelets was delayed to day 7-14 p.i. with a dose-dependent response regarding both severity of the nadir value (10 %-40 % of initial value) and the start of recovery. The animals in the groups given the highest activities of both 90Y and 177Lu exhibited skin infections on day 21. Conclusion The results showed good reproducibility and dose-dependent toxicity for both radionuclides indicating that the MTD for 177Lu-BR96 (1000 MBq/kg) is 1.7 times that for 90Y-BR96 (600 MBq/kg) in rats; therefore, the therapeutic gain-T/N could be improved in former group. This model makes it feasible to evaluate strategies to escalate therapeutic doses to tumors without increasing normal tissue toxicity, such as radioimmunotherapy. Key words: Rats; 90Y; 177Lu; Antibodies, monoclonal; Maximum tolerated dose; Radioimmunotherapy