BACKGROUND: BrE-3 is monoclonal antibody that has promise for imaging and therapy of human adenocarcinoma. Because of observations in therapeutic trials of yttrium-90 (90Y) escape from radioimmunoconjugates and uptake by the skeleton with resultant bone marrow toxicity, the authors attempted to evaluate the importance of this factor by a comparison of the LD50 in healthy mice treated with 90Y that had been chelated with either of two high affinity chelators, methylbenzyldiethylene-triaminepentaacetic acid (MX-DTPA) or bromoacetamidobenzyl-1,4,7,10-tetraazocyclododecane- N,N',N'',N'''-tetraacetic acid (BAD). METHODS AND RESULTS: Bone marrow hematopoietic toxicity was dose-limiting and the source of death for both chelators. The LD50 for 90Y-BrE-3-MX-DTPA was 220.9 microCi, and that for 90Y-BrE-3-2IT-BAD and was 307.8 microCi. Whole-body autoradiography revealed substantially greater uptake of 90Y in the skeleton when MX-DTPA was used as the chelator. CONCLUSIONS: These observations suggest that 90Y escape to bone is a significant factor in the maximum tolerated dose of radioimmunoconjugate that can be used in therapeutic trials. These results probably underestimate the importance of 90Y escape since 90Y in the skeleton of patients is likely to be more significant than in mice because more of the 90Y energy is absorbed in the marrow of larger species.
BACKGROUND: BrE-3 is monoclonal antibody that has promise for imaging and therapy of humanadenocarcinoma. Because of observations in therapeutic trials of yttrium-90 (90Y) escape from radioimmunoconjugates and uptake by the skeleton with resultant bone marrow toxicity, the authors attempted to evaluate the importance of this factor by a comparison of the LD50 in healthy mice treated with 90Y that had been chelated with either of two high affinity chelators, methylbenzyldiethylene-triaminepentaacetic acid (MX-DTPA) or bromoacetamidobenzyl-1,4,7,10-tetraazocyclododecane- N,N',N'',N'''-tetraacetic acid (BAD). METHODS AND RESULTS: Bone marrow hematopoietic toxicity was dose-limiting and the source of death for both chelators. The LD50 for 90Y-BrE-3-MX-DTPA was 220.9 microCi, and that for 90Y-BrE-3-2IT-BAD and was 307.8 microCi. Whole-body autoradiography revealed substantially greater uptake of 90Y in the skeleton when MX-DTPA was used as the chelator. CONCLUSIONS: These observations suggest that 90Y escape to bone is a significant factor in the maximum tolerated dose of radioimmunoconjugate that can be used in therapeutic trials. These results probably underestimate the importance of 90Y escape since 90Y in the skeleton of patients is likely to be more significant than in mice because more of the 90Y energy is absorbed in the marrow of larger species.
Authors: D B Axworthy; J M Reno; M D Hylarides; R W Mallett; L J Theodore; L M Gustavson; F Su; L J Hobson; P L Beaumier; A R Fritzberg Journal: Proc Natl Acad Sci U S A Date: 2000-02-15 Impact factor: 11.205
Authors: A Natarajan; C Gruettner; R Ivkov; G L DeNardo; G Mirick; A Yuan; A Foreman; S J DeNardo Journal: Bioconjug Chem Date: 2008-06-03 Impact factor: 4.774
Authors: P Antoniw; A P Farnsworth; A Turner; A M Haines; A Mountain; J Mackintosh; D Shochat; J Humm; S Welt; L J Old; G T Yarranton; D J King Journal: Br J Cancer Date: 1996-08 Impact factor: 7.640
Authors: D J King; P Antoniw; R J Owens; J R Adair; A M Haines; A P Farnsworth; H Finney; A D Lawson; A Lyons; T S Baker Journal: Br J Cancer Date: 1995-12 Impact factor: 7.640