Comparative toxicity studies of yttrium-90 mx-dtpa and 2-it-bad conjugated monoclonal antibody (bre-3)

Abstract

Background. BrE‐3 is a 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 μCi, and that for 90Y‐BrE‐3‐2IT‐BAD was 307.8 μCi. 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. Cancer 1994 73:1012–22.

A Single Treatment of Yttrium-90-labeled CHX-A″–C6.5 Diabody Inhibits the Growth of Established Human Tumor Xenografts in Immunodeficient Mice

“…Two to three times per week, the mice were observed for signs of weight loss and toxicity, and tumor volumes were measured with calipers. The LD 10 was determined using the method described by DeNardo et al (17). Briefly, the percentage lethal dose (LD) at each 90 Y dose level was calculated by adding the number of mice that died at that dose level and all lower dose levels (accumulated deaths), adding the number of survivors at that dose level and all higher dose levels (accumulated survivors), and then dividing the accumulated deaths by the sum of the accumulated deaths and accumulated survivors.…”

Preparation and preclinical evaluation of humanised A33 immunoconjugates for radioimmunotherapy

“…Attempts to circumvent this problem by the co-administration of free EDTA to chelate free 9Y released have also been made but showed only a very limited improvement (Stewart et al, 1990). Stable macrocyclic chelators for 9'Y have now been developed based on the macrocycle 12N4 (also known as DOTA), which essentially completely prevents loss of the isotope from the conjugate under physiological conditions (Deshpande et al, 1990;Harrison et al, 1991;DeNardo et al, 1994).…”

Characteristics of dimeric (bis) bidentate selective high affinity ligands as HLA-DR10 beta antibody mimics targeting non-Hodgkin's lymphoma

“…WBAR studies were conducted as previously described (28,29); each mouse was anesthetized with 5 mg/100 μl aqueous solution of sodium pentobarbital i.p., flash frozen in a hexane-dry ice bath, and embedded in frozen 4% carboxymethylcellulose. Sagittal sections of 50 μm thickness taken to show tumors, spleen, kidney, liver and the midline of the vertebral column were taken at -20˚C with a cryomicrotome (Leica Polycut, Nussloch, Germany).…”