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Evaluation of the Serum Stability and In Vivo Biodistribution of CHX-DTPA and Other Ligands for Yttrium Labeling of Monoclonal Antibodies

Department of Nuclear Medicine, Warren G. Magnuson Clinical Center
Chemistry Section, Radiation Oncology Branch and Laboratory of Molecular Biology, National Cancer Institute
National Institutes of Health, Bethesda, Maryland

Correspondence: For correspondence and reprints contact: Jorge A. Carrasquillo, MD, Dept. of Nuclear Medicine, National Institutes of Health, Bldg 10/Rm 1C-401, Bethesda, MD 20892.

ABSTRACT

Serum stability and in vivo biodistribution of both A and B isomers of the 2-(p-isothiocyanatobenzyl) (p-SCN-Bz)-cyclohexyldiethylenetriaminepentaacetic acid ligand (CHX-DTPA), a recently developed backbone-substituted derivative of DTPA, were evaluated and compared to those of 2-(p-SCN-Bz)-6-methyl-DTPA (1B4M-DTPA) and 2-(p-SCN-Bz)-1,4,7,10-tetraazacyclododecane tetra-acetic acid (2B-DOTA). Methods: Stability of ⁸⁸Y-labeled ligands (01 µM) was evaluated in serum for up to 17 days. For biodistribution, ligands were conjugated to monoclonal antibody (Mab) B3, a murine IgG1k, and labeled with ⁸⁸Y at 0.1–0.3 mCl/mg. Nontumor-bearing nude mice were injected intravenously with 1–2 µCi/4–10 µg of ⁸⁸Y-labeled B3-conjugates and killed at 6 hr and daily up to 168 hr postinjection. Indium-111-(1B4M)-B3 was co-injected in all mice as internal control. Results: Serum stability of ⁸⁸Y-DOTA failed to show any significant release of activity, whereas pseudo-first-order dissociation rate constants of 3.97 x 10^–3, 2.54 x 10^–3 and 1.46 x 10^–2 (day^–1) were calculated for ⁸⁸Y-1B4M, ⁸⁸Y-CHX-A and ⁸⁸Y-CHX-B, respectively. Accordingly, cortical bone uptake of ⁸⁸Y was significantly higher for all DTPA-derivative chelates than for DOTA. Conclusions: While none of the DTPA-derivative chelates could challenge DOTA in its ability to hold the radioyttrium, significant differences were observed in the kinetic inertness of the A and B isomers of CHX, indicating that the CHX-B ligand is not as suitable for ⁹⁰Y-labeling of Mabs.

Key Words: yttrium-88 • ligands • monoclonal antibodies • biodistribution • serum stability

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