90Yttrium-labeled complementarity-determining-region-grafted monoclonal antibodies for radioimmunotherapy:: Radiolabeling and animal biodistribution studies

(90)Yttrium-labeled monoclonal antibodies (mAbs) are likely to be important to radioimmunotherapy (RAIT) of a variety of cancers. The goal of this study was to select and evaluate a form of [Y-90]mAb suitable for RAIT and determine conditions for high-yield, reproducible radiolabelings. 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 optimized to > 90% incorporations using the macrocyclic chelator DOTA as the metal carrier. In in vitro challenge assays, the stability of mAbs labeled with [Y-90]DOTA was better than that of the corresponding [Y-90]benzyl-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, indicating residualization of metalated mAb. Both [Y-90]hLL2 conjugates, prepared 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 uptake 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 uptake was relatively high even with D-lysine administration. The ability of [In-111]-DOTA-hLL2 to accurately predict [Y-90]DOTA-hLL2 biodistribution was established. These preclinical findings demonstrate that [Y-90]DOTA-(CDR-grafted) mAbs are suitable for examination in clinical RAIT.