(90)YTTRIUM-LABELED COMPLEMENTARITY-DETERMINING-REGION-GRAFTED MONOCLONAL-ANTIBODIES FOR RADIOIMMUNOTHERAPY - RADIOLABELING AND ANIMAL BIODISTRIBUTION STUDIES

(90)Yttrium-labeled monoclonal antibodies (mAbs) are likely to be impo rtant to radioimmunotherapy (RAIT) of a variety of cancers. The goal o f this study was to select and evaluate a form of [Y-90]mAb suitable f or RAIT and determine conditions for high-yield, reproducible radiolab elings. Y-90-Labelings, at 2-40 mCi levels, of cdr-grafted versions of anti-B-cell lymphoma (hLL2) and anti-CEA (hIMMU-14) mAbs were optimiz ed to > 90% incorporations using the macrocyclic chelator DOTA as the metal carrier. In in vitro challenge assays, the stability of mAbs lab eled with [Y-90]DOTA was better than that of the corresponding [Y-90]b enzyl-DTPA conjugates. The retention of [Y-90]DOTA-hLL2 on Raji tumor cells in vitro was similar to that of the same mAb labeled with [Y-90] benzyl-DTPA and was about twice as much as with [I-125]hLL2, indicatin g residualization of metalated mAb. Both [Y-90]hLL2 conjugates, prepar ed using DOTA and Bz-DTPA, had similar maximum tolerated doses of 125 mu Ci in BALB/c mice and showed no discernible chelator-induced immune responses. Animal biodistribution studies in nude mice bearing Ramos human B-cell lymphoma xenografts revealed similar tumor and tissue upt ake over a 10 day period, with the exception of bone uptake which was up to 50% lower for [Y-88]DOTA-hLL2 compared to [Y-88]Bz-DTPA-hLL2 at time points beyond 24 h. With [SOY]DOTA-hLL2 fragments, in vivo animal tumor dosimetries were inferior to those for the IgG, and kidney upta ke was relatively high even with D-lysine administration. The ability of [In-111]-DOTA-hLL2 to accurately predict [Y-90]DOTA-hLL2 biodistrib ution was established. These preclinical findings demonstrate that [Y- 90]DOTA-(CDR-grafted) mAbs are suitable for examination in clinical RA IT.