title: 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 muCi 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.
authors.affiliation: Immunomedics, Inc., 300 American Road, Morris Plains, New Jersey 07950, and Garden State Cancer Center, Belleville, New Jersey 07109, USA.
authors.forename: S V
authors.initials: SV
authors.lastname: Govindan
authors.forename: L B
authors.initials: LB
authors.lastname: Shih
authors.forename: D M
authors.initials: DM
authors.lastname: Goldenberg
authors.forename: R M
authors.initials: RM
authors.lastname: Sharkey
authors.forename: H
authors.initials: H
authors.lastname: Karacay
authors.forename: J E
authors.initials: JE
authors.lastname: Donnelly
authors.forename: M J
authors.initials: MJ
authors.lastname: Losman
authors.forename: H J
authors.initials: HJ
authors.lastname: Hansen
authors.forename: G L
authors.initials: GL
authors.lastname: Griffiths
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000493:pharmacokinetics*; D001667:Binding, Competitive / Q000187:drug effects; D004355:Drug Stability; D006801:Humans; D066298:In Vitro Techniques; D007205:Indium Radioisotopes; D007553:Isotope Labeling; D008223:Lymphoma / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016499:Radioimmunotherapy; D014018:Tissue Distribution; D015019:Yttrium / Q000737:chemistry* / Q000493:pharmacokinetics*; D015021:Yttrium Radioisotopes
chemical_list: D000911:Antibodies, Monoclonal; D007205:Indium Radioisotopes; D015021:Yttrium Radioisotopes; D015019:Yttrium