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.

• Purpose: 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 Y-90 or Lu-177 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. Experimental Design: Increasing activity levels of BR96 labeled with Y-90 or Lu-177 were administered to groups of rats. Blood parameters, body weight, and general performance were monitored for 8 weeks. Results: 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 Y-90 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 Y-90 and Lu-177 exhibited skin infections on day 21. Conclusions: The results showed good reproducibility and dose-dependent toxicity for both radionuclides, indicating that the maximal tolerable dose for Lu-177 - BR96 (1,000 MBq/kg) is 1.7 times that for Y-90 - 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.

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MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

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