COMPARATIVE TOXICITY STUDIES OF Y-90 MX-DTPA AND 2-IT-BAD CONJUGATED MONOCLONAL-ANTIBODY (BRE-3)

Background. BrE-3 is a monoclonal antibody that has promise for imagin g and therapy of human adenocarcinoma. Because of observations in ther apeutic trials of yttrium-90 (Y-90) escape from radioimmunoconjugates and uptake by the skeleton with resultant bone marrow toxicity, the au thors attempted to evaluate the importance of this factor by a compari son of the LD(50) in healthy mice treated with Y-90 that had been chel ated with either of two high affinity chelators, methylbenzyldiethylen e-triaminepentaacetic acid (MX-DTPA) or 10-tetraazocyclododecane-N,N', N'',N'''-tetraacetic acid (BAD). Methods and Results. Bone marrow hema topoietic toxicity was dose-limiting and the source of death for both chelators. The LD(50) for Y-90-BrE-3-MX-DTPA was 220.9 mu Ci, and that for Y-90-BrE-3-2IT-BAD was 307.8 mu Ci. Whole-body autoradiography re vealed substantially greater uptake of Y-90 in the skeleton when MX-DT PA was used as the chelator. Conclusions. These observations suggest t hat Y-90 escape to bone is a significant factor in the maximum tolerat ed dose of radioimmunoconjugate that can be used in therapeutic trials . These results probably underestimate the importance of Y-90 escape s ince Y-90 in the skeleton of patients is likely to be more significant than in mice because more of the Y-90 energy is absorbed in the marro w of larger species.