Uckun F M, Yanishevski Y, Tumer N, Waurzyniak B, Messinger Y, Chelstrom L M, Lisowski E A, Ek O, Zeren T, Wendorf H, Langlie M C, Irvin J D, Myers D E, Fuller G B, Evans W, Gunther R
Biotherapy Institute, University of Minnesota Academic Health Center, Roseville, Minnesota, USA.
Clin Cancer Res. 1997 Mar;3(3):325-37.
We studied the pharmacokinetic features, immunogenicity, and toxicity of B43-pokeweed antiviral protein (PAP) immunotoxin in 13 cynomolgus monkeys. The disposition of B43-PAP in two monkeys, when administered as a single i.v. bolus dose, was characterized by a slow clearance (1-2 ml/h/kg) with a very discrete peripheral distribution. B43-PAP was retained and distributed largely in the blood as the sole compartment with no significant equilibration with the extravascular compartment. The circulating B43-PAP immunotoxin detected in monkey plasma samples by ELISA and protein immunoblotting was both immunoreactive with, and active against, human leukemic cells in vitro. In systemic immunogenicity and toxicity studies, which involved 11 cynomolgus monkeys, each monkey received a total of seven i.v. doses of B43-PAP at a specific dose level of the dose escalation schedule. B43-PAP-treated monkeys mounted a dose-dependent humoral immune response against both the mouse IgG and PAP moieties of the immunotoxin. When administered i.v. either on an every-day or every-other-day schedule, B43-PAP was very well tolerated, with no significant clinical or laboratory signs of toxicity at total dose levels ranging from 0.007 to 0.7 mg/kg. A transient episode of a mild capillary leak with a grade 2 hypoalbuminemia and 2+ proteinuria was observed at total dose levels equal to or higher than 0.35 mg/kg. At total dose levels of 3.5 and 7.0 mg/kg, B43-PAP caused dose-limiting renal toxicity due to severe renal tubular necrosis. The present study completes the preclinical evaluation of B43-PAP and provides the basis for its clinical evaluation in children with therapy-refractory B-lineage acute lymphoblastic leukemia.
我们在13只食蟹猴中研究了B43-商陆抗病毒蛋白（PAP）免疫毒素的药代动力学特征、免疫原性和毒性。当以单次静脉推注剂量给药时，两只猴子体内B43-PAP的处置特点是清除缓慢（1-2毫升/小时/千克），外周分布非常离散。B43-PAP主要保留并分布在血液中，作为唯一的隔室，与血管外隔室没有明显的平衡。通过酶联免疫吸附测定（ELISA）和蛋白质免疫印迹在猴血浆样本中检测到的循环B43-PAP免疫毒素在体外对人白血病细胞具有免疫反应性且有活性。在涉及11只食蟹猴的全身免疫原性和毒性研究中，每只猴子在剂量递增方案的特定剂量水平下总共接受了7次静脉注射B43-PAP。经B43-PAP处理的猴子对免疫毒素的小鼠IgG和PAP部分产生了剂量依赖性的体液免疫反应。当按照每日或隔日方案静脉给药时，B43-PAP的耐受性非常好，在总剂量水平为0.007至0.7毫克/千克时，没有明显的临床或实验室毒性迹象。在总剂量水平等于或高于0.35毫克/千克时，观察到有轻度毛细血管渗漏的短暂发作，伴有2级低白蛋白血症和2+蛋白尿。在总剂量水平为3.5和7.0毫克/千克时，B43-PAP由于严重的肾小管坏死导致剂量限制性肾毒性。本研究完成了B43-PAP的临床前评估，并为其在治疗难治性B系急性淋巴细胞白血病儿童中的临床评估提供了依据。
