90Yttrium-Labeled Complementarity-Determining-Region-Grafted Monoclonal Antibodies for Radioimmunotherapy: Radiolabeling and Animal Biodistribution Studies

Abstract

⁹⁰Yttrium-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 [⁹⁰Y]mAb suitable for RAIT and determine conditions for high-yield, reproducible radiolabelings. ⁹⁰Y-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 [⁹⁰Y]DOTA was better than that of the corresponding [⁹⁰Y]benzyl−DTPA conjugates. The retention of [⁹⁰Y]DOTA-hLL2 on Raji tumor cells in vitro was similar to that of the same mAb labeled with [⁹⁰Y]benzyl-DTPA and was about twice as much as with [¹²⁵I]hLL2, indicating residualization of metalated mAb. Both [⁹⁰Y]hLL2 conjugates, prepared using DOTA and Bz-DTPA, had similar maximum tolerated doses of 125 μCi 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 [⁸⁸Y]DOTA-hLL2 compared to [⁸⁸Y]Bz-DTPA-hLL2 at time points beyond 24 h. With [⁹⁰Y]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 [¹¹¹In]DOTA-hLL2 to accurately predict [⁹⁰Y]DOTA-hLL2 biodistribution was established. These preclinical findings demonstrate that [⁹⁰Y]DOTA-(CDR-grafted) mAbs are suitable for examination in clinical RAIT.