Pharmacokinetics and Tumor Localization of¹¹¹In-Labeled HuCC49ΔC_H2 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(H)2 domain-deleted variant of the anti-TAG-72 antibody CC49 (HuCC49DeltaC(H)2) has faster blood clearance, compared to the IgG, while retaining tumor targeting. We compared the pharmacokinetics and tumor uptake of (111)In-HuCC49DeltaC(H)2 in BALB/c mice and a colon carcinoma (LS-174T) mouse xenograft with that of (111)In-labeled chimeric CC49 (cCC49), an antibody with pharmacokinetics similar to the humanized CC49 parent. Immuno-conjugates of HuCC49DeltaC(H)2 and cCC49 prepared with the (111)In chelator Mx-DTPA (1-isothiocyantobenzyl-3-methyldiethylenetriaminepentaacetic acid) retained low nM affinity and radiolabeling protocols provided greater than 95% radio-incorporation with (111)In while retaining greater than 80% immunoreactivity. Blood clearance of (111)In-HuCC49DeltaC(H)2 in BALB/c mice was monoexponential (t(1/2) 5.4 hours) and faster than (111)In-cCC49 (biexponential clearance; t1/2Delta 1.5 hours; t1/2beta 162 hours). The (111)In-HuCC49DeltaC(H)2 also cleared more rapidly from the blood in the murine xenograft. At 1 hour postinjection, blood concentrations for (111)In-HuCC49DeltaC(H)2 and (111)In-cCC49 were comparable (25.5 injected dose per g [%ID/g] and 21.3 %ID/g, respectively); tumor uptake for (111)In- HuCC49DeltaC(H)2 was 7.9 %ID/g, compared to 7.5 %ID/g for (111)In-cCC49. However, at 24 hours, blood concentration for (111)In-HuCC49DeltaC(H)2 was less than (111)In-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 (111)In-HuCC49DeltaC(H)2 and tumor localization comparable to that of (111)In-cCC49 provided a fourfold improved tumor-to-blood ratio for (111)In-HuCC49DeltaC(H)2 at 24 hours postinjection.

Development of an imaging-guided CEA-pretargeted radionuclide treatment of advanced colorectal cancer: first clinical results

“…The interval of 5 days that was applied in the first cohort was selected based on blood clearance studies of TF2 in rabbits (Sharkey et al , 2010), but when it became clear that TF2 cleared relatively rapidly in humans, the interval was reduced to 1 day. The blood clearance of TF2 was much faster than that of similarly sized IgG molecules, which could be explained by the fact that TF2 lacks a C H2 domain (Chinn et al , 2006). In nude mouse-human tumour xenograft models, an interval of 16–24 h was optimal (Sharkey et al , 2003a; Schoffelen et al , 2010b).…”

A Novel Benzodiazepine Increases the Sensitivity of B Cells to Receptor Stimulation with Synergistic Effects on Calcium Signaling and Apoptosis

“…Considering that other receptors on B cells, which are effectively targeted by therapeutic antibodies presently in clinical use, are also coupled to calcium signals (for example the CD20 B cell-specific surface molecule targeted by Rituxan; Ref. 43), it may be possible to exploit Bz-423 for cancer chemotherapy. Our findings suggest how the properties of Bz-423 could provide therapeutic utility for autoimmunity, and current efforts are aimed at evaluating these possibilities.…”

Synthesis and biodistribution studies of iodine‐131 D‐amino acid YYK peptide as a potential therapeutic agent for labeling an anti‐CD20 antibody

“…4 The absence of antigen expression on stem cells allows for the recovery of normal B-cell following RIT, which leads to the destruction of both malignant and normal B-cells. 5 The first antibody to be approved in 1997 for treating NHL was Rituximab, a chimeric anti-CD20 immunoglobulin. 6 Rituximab acts via various mechanisms to kill tumor cells, including complement-dependent cytotoxicity, antibodydependent cell cytotoxicity and induction of apoptosis.…”

“…It has a long halflife of 8.1 days with beta emission of 0.69 MeV for therapy, and a gamma emission for imaging, which is useful for making dosimetry estimates. 5 The widespread use of iodine-131 for the labeling of tumor-associated antibodies has shown that this nuclide suffers substantially from undesirable physical and biological properties, principally the rapid and persistent in vivo dehalogenation of the radiolabeled antibody. 9 Such in vivo removal of radioiodine from target cells within the first 24-120 h postinjection of the labeled antibodies reduces tumor to nontumor ratio, which is important for radiodiagnosis.…”