Pharmacokinetic mAb-mAb Interaction: Anti-VEGF mAb Decreases the Distribution of Anti-CEA mAb into Colorectal Tumor Xenografts
Pharmacokinetic mAb-mAb Interaction: Anti-VEGF mAb Decreases the Distribution of Anti-CEA mAb into Colorectal Tumor Xenografts
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DOI：
10.1208/s12248-012-9357-2
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发表时间：
2012-09-01
期刊：
影响因子：
4.5
通讯作者：
Balthasar, Joseph P.
中科院分区：
文献类型：
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作者：
Abuqayyas, Lubna;Balthasar, Joseph P.
到目前为止，几乎没有关于涉及单抗的药物-药物相互作用风险的调查。本文研究了抗血管内皮生长因子(抗血管内皮生长因子)抗体对抗癌胚抗原(CEA)抗体T84.66在小鼠体内的血浆、组织和肿瘤处置的影响。将携带CEA表达的人结直肠癌(LS174T)移植瘤的SCID小鼠随机分为对照组和抗血管内皮生长因子治疗组。当肿瘤直径达到200~300 mm(3)时，I-125-T84.66以10 mg/kg(400亩Ci/kg)静脉注射。计数血浆和组织标本中的放射性，测定T84.66浓度。计算药物浓度-时间曲线下面积(AUC)。在不同的小鼠组中，伊文斯蓝染料被用来评估抗血管内皮生长因子对肿瘤血管通透性的影响。研究未发现抗血管内皮生长因子治疗对T84.66在血浆或非肿瘤组织中的药代动力学有显著影响。对照组和治疗组T84.66血浆AUC值分别为2.37x10(3)+/-1.54x10(2)和2.56x10(3)+/-1.01x10(2)nmxd(P=0.148)。相反，抗血管内皮生长因子治疗显著降低肿瘤血管对伊文斯蓝染料的渗透率45.0%(p=0.0012)，抗血管内皮生长因子治疗使T84.66肿瘤AUC值(0-10天)降低超过60%(7.27x10(2)+/-51.4vs.1.98x10(3)+/-90.1nMxday，p<；0.0001)。我们的研究结果表明，抗血管内皮生长因子疗法可能会导致向肿瘤组织输送单抗的大幅减少。值得注意的是，这种药代动力学相互作用发生在目标部位，仅根据血浆药代动力学评估，T84.66处置没有明显变化。
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 mm(3) in size, I-125-T84.66 was administered intravenously at 10 mg/kg (400 mu Ci/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 x 10(3) +/- 1.54 x 10(2) and 2.56 x 10(3) +/- 1.01 x 10(2) nM x 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 x 10(2) +/- 51.4 vs. 1.98 x 10(3) +/- 90.1 nM x 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.