Pharmacokinetics and Tumor Localization of 111 In-Labeled HuCC49ΔC H 2 in BALB/c Mice and Athymic Murine Colon Carcinoma Xenograft

Abstract

The primary limitation of IgG antibodies for radioimmunotherapy of solid tumors is their prolonged serum half-life, leading to dose-limiting bone marrow toxicity at doses providing inadequate radiation to the tumor. A humanized C_H2 domain-deleted variant of the anti-TAG-72 antibody CC49 (HuCC49ΔC_H2) has faster blood clearance, compared to the IgG, while retaining tumor targeting. We compared the pharmacokinetics and tumor uptake of ¹¹¹In-HuCC49ΔC_H2 in BALB/c mice and a colon carcinoma (LS-174T) mouse xenograft with that of ¹¹¹In-labeled chimeric CC49 (cCC49), an antibody with pharmacokinetics similar to the humanized CC49 parent. Immunoconjugates of HuCC49ΔC_H2 and cCC49 prepared with the ¹¹¹In chelator Mx-DTPA (1-isothiocyantobenzyl-3-methyldiethylenetriaminepentaacetic acid) retained low nM affinity and radiolabeling protocols provided greater than 95% radioincorporation with ¹¹¹In while retaining greater than 80% immunoreactivity. Blood clearance of ¹¹¹In-HuCC49ΔC_H2 in BALB/c mice was monoexponential (t_1/2 5.4 hours) and faster than ¹¹¹In-cCC49 (biexponential clearance; t1/2Δ 1.5 hours; t1/2β 162 hours). The ¹¹¹In-HuCC49ΔC_H2 also cleared more rapidly from the blood in the murine xenograft. At 1 hour postinjection, blood concentrations for ¹¹¹In-HuCC49ΔC_H2 and ¹¹¹In-cCC49 were comparable (25.5 injected dose per g [%ID/g] and 21.3 %ID/g, respectively); tumor uptake for ¹¹¹In- HuCC49ΔC_H2 was 7.9 %ID/g, compared to 7.5 %ID/g for ¹¹¹In-cCC49. However, at 24 hours, blood concentration for ¹¹¹In-HuCC49ΔC_H2 was less than ¹¹¹In-cCC49 (0.9 %ID/g versus 5.2 %ID/g, respectively) with comparable tumor retention (14.4 %ID/g versus 19.0 %ID/g, respectively). Faster blood clearance of ¹¹¹In-HuCC49ΔC_H2 and tumor localization comparable to that of ¹¹¹In-cCC49 provided a fourfold improved tumor-to-blood ratio for ¹¹¹In-HuCC49ΔC_H2 at 24 hours postinjection.