Pharmacokinetic mAb–mAb Interaction: Anti-VEGF mAb Decreases the Distribution of Anti-CEA mAb into Colorectal Tumor Xenografts

Abstract

To date, there has been little investigation of the risk for drug–drug interactions involving monoclonal antibodies. The present work examined the effects of an anti-vascular endothelial growth factor (anti-VEGF) antibody on the plasma, tissue, and tumor disposition of T84.66, an anti-carcinoembryonic antigen (CEA) antibody, in mice. SCID mice bearing CEA-expressing human colorectal cancer (LS174T) xenografts were divided into control and anti-VEGF-treated groups. When tumors reached 200–300 mm³ in size, ¹²⁵I-T84.66 was administered intravenously at 10 mg/kg (400 μCi/kg). Radioactivity in plasma and tissue samples was counted, and T84.66 concentrations were determined. Areas under the concentration vs. time curves (AUC) were calculated. In separate groups of mice, Evans Blue Dye was administered to evaluate the effect of anti-VEGF on tumor vascular permeability. The investigations did not demonstrate significant effects of anti-VEGF therapy on T84.66 pharmacokinetics in plasma or in non-tumor tissues. T84.66 plasma AUC_{(0–10 days)} values were 2.37 × 10³ ± 1.54 × 10² and 2.56 × 10³ ± 1.01 × 10² nM × day, for the control and treated groups (p = 0.148). Conversely, anti-VEGF treatment significantly reduced tumor vascular permeability to Evans Blue Dye by 45.0 % (p = 0.0012), and anti-VEGF therapy decreased T84.66 tumor AUC_{(0–10 days)} by more than 60 % (7.27 × 10² ± 51.4 vs. 1.98 × 10³ ± 90.1 nM × day, p < 0.0001). Our findings suggest that anti-VEGF therapies may lead to a substantial reduction in the delivery of monoclonal antibodies to tumor tissues. It is interesting and important to note that this pharmacokinetic interaction occurs at the target site, and that no alterations in T84.66 disposition were visible based on assessment of plasma pharmacokinetics alone.