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: S V Govindan, L B Shih, D M Goldenberg, R M Sharkey, H Karacay, J E Donnelly, M J Losman, H J Hansen, G L Griffiths
• Journal: Bioconjugate chemistry (Bioconjug Chem) 1998 Nov-Dec Vol. 9 Issue 6 Pg. 773-82 ISSN: 1043-1802 [Print] United States
• PMID: 9815172 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Indium Radioisotopes
• Yttrium Radioisotopes
• Yttrium

Topics

• Animals
• Antibodies, Monoclonal (chemistry, pharmacokinetics)
• Binding, Competitive (drug effects)
• Drug Stability
• Humans
• In Vitro Techniques
• Indium Radioisotopes
• Isotope Labeling
• Lymphoma (metabolism)
• Mice
• Mice, Nude
• Radioimmunotherapy
• Tissue Distribution
• Yttrium (chemistry, pharmacokinetics)
• Yttrium Radioisotopes