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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

Authors' Affiliations: Departments of ¹ Oncology, ² Tumor Immunology, and ³ Medical Radiation Physics, Lund University; ⁴ Mitra Medical AB, Lund, Sweden; ⁵ Seattle Genetics, Seattle, Washington; and ⁶ Shanxi Tumor Hospital and Shanxi Tumor Radiotherapy Center, P.R. China

Requests for reprints: Linda Mårtensson, Department of Oncology, Lund University Hospital, SE-221 85 Lund, Sweden. Phone: 46-46-709-54-25-54; Fax: 46-46-286-24-61; E-mail: Linda.Martensson{at}onk.lu.se.

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 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.

Experimental Design: 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 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.

Conclusions: 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.

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