Comparative toxicity studies of yttrium-90 MX-DTPA and 2-IT-BAD conjugated monoclonal antibody (BrE-3).
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).


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.
DeNardo
G L
GL
Department of Internal Medicine, University of California at Davis, Sacramento.
Kroger
L A
LA
DeNardo
S J
SJ
Miers
L A
LA
Salako
Q
Q
Kukis
D L
DL
Fand
I
I
Shen
S
S
Renn
O
O
Meares
C F
CF
D000818:Animals; D001772:Blood Cell Count / Q000528:radiation effects; D001792:Blood Platelets / Q000528:radiation effects; D001835:Body Weight / Q000528:radiation effects; D001853:Bone Marrow / Q000528:radiation effects*; D002614:Chelating Agents; D005260:Female; D006571:Heterocyclic Compounds / Q000633:toxicity*; D006573:Heterocyclic Compounds, 1-Ring; D051379:Mice; D008807:Mice, Inbred BALB C; D009077:Mucins / Q000276:immunology; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D016499:Radioimmunotherapy / Q000009:adverse effects*; D011879:Radiotherapy Dosage; D015021:Yttrium Radioisotopes / Q000009:adverse effects*
D002614:Chelating Agents; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D009077:Mucins; D015021:Yttrium Radioisotopes; C077295:2-(4-isothiocyanatobenzyl)-6-methyldiethylenetriaminepentaacetic acid; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D004369:Pentetic Acid