Rosenblum M G, Murray J L, Haynie T P, Glenn H J, Jahns M F, Benjamin R S, Frincke J M, Carlo D J, Hersh E M
Cancer Res. 1985 May;45(5):2382-6.
Twenty-eight patients with metastatic malignant melanoma received anti-p97 murine monoclonal antibody (96.5) infused over 2 h at doses between 1 and 20 mg coupled to either 2.5 or 5.0 mCi of 111In by the bifunctional chelating agent diethyltriaminepentaacetic acid. Clearance of 111In from plasma closely fit an open, one-compartment mathematical model (r2 greater than 0.90). The overall half-life of 111In plasma was approximately 31 h and did not appear to be dependent on the total dose of antibody administered. The apparent volume of distribution of the 111In label approximated the total blood volume (7.8 +/- 0.7 liters) at the 1-mg dose and decreased to 3.0 +/- 0.14 liters at the 20-mg dose, suggesting saturation of antigenic or other extravascular binding sites at higher antibody doses. The clearance of the murine monoclonal antibody itself from plasma was measured by an enzyme-linked immunosorbent assay. The pharmacokinetics for the murine antibody in plasma also fit an open, one-compartment mathematical model. All pharmacokinetic parameters for unlabeled antibody closely paralleled those found for 111In-labeled antibody pharmacokinetics. This suggests that the 111In radiolabel remains complexed to the monoclonal antibody after in vivo administration. The cumulative urinary excretion of the 111In label over 48 h was between 12 and 23% of the total administered dose and is assumed to represent 111In-labeled chelate complex unattached to antibody. Analysis of the 111In label in spleen, liver, heart, and kidney showed that the concentration of label in liver tissue was reduced with increasing antibody doses and coincided with changes in the apparent volume of distribution. These studies show that murine monoclonal antibodies are cleared slowly from the circulation in humans and that early, rapid distribution of labeled antibody to the liver can be reduced by increasing the dose of unlabeled antibody. This may be particularly important in limiting hepatic toxicity when administering antibody coupled to drugs, radionuclides, or toxins.
28例转移性恶性黑色素瘤患者接受了抗p97鼠单克隆抗体（96.5），通过双功能螯合剂二乙三胺五乙酸与2.5或5.0 mCi的111In偶联，以1至20 mg的剂量在2小时内输注。111In从血浆中的清除率与开放的一室数学模型拟合良好（r2大于0.90）。111In血浆的总体半衰期约为31小时，似乎不依赖于所给予抗体的总剂量。111In标记物的表观分布容积在1 mg剂量时接近总血容量（7.8±0.7升），在20 mg剂量时降至3.0±0.14升，表明在较高抗体剂量下抗原性或其他血管外结合位点饱和。通过酶联免疫吸附测定法测量鼠单克隆抗体本身从血浆中的清除率。血浆中鼠抗体的药代动力学也符合开放的一室数学模型。未标记抗体的所有药代动力学参数与111In标记抗体药代动力学的参数密切平行。这表明111In放射性标记物在体内给药后仍与单克隆抗体结合。48小时内111In标记物的累积尿排泄量为总给药剂量的12%至23%，假定代表未与抗体结合的111In标记螯合物。对脾脏、肝脏、心脏和肾脏中的111In标记物分析表明，肝脏组织中标记物的浓度随着抗体剂量的增加而降低，并且与表观分布容积的变化一致。这些研究表明，鼠单克隆抗体在人体内从循环中清除缓慢，并且通过增加未标记抗体的剂量可以减少标记抗体早期向肝脏的快速分布。这在给予与药物、放射性核素或毒素偶联的抗体时，对于限制肝脏毒性可能特别重要。
