Scheinberg D A, Straus D J, Yeh S D, Divgi C, Garin-Chesa P, Graham M, Pentlow K, Coit D, Oettgen H F, Old L J
Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
J Clin Oncol. 1990 May;8(5):792-803. doi: 10.1200/JCO.1990.8.5.792.
Eighteen patients with relapsed non-Hodgkin's lymphoma (NHL) were infused with escalating doses of monoclonal antibody (mAb) OKB7, trace-labeled with iodine-131 (131I), in order to study toxicity, pharmacology, antibody localization, and dosimetry of radioiodine. OKB7 is a noncytotoxic mouse immunoglobulin G2b (IgG2b) mAb reactive with B cells and most B-cell NHL. Three patients each were treated at six dose levels ranging from 0.1 mg to 40 mg. All patients had radionuclide imaging and counting daily, had serial blood sampling to study pharmacokinetics, human antimouse antibody (HAMA), and circulating antigen, and had a biopsy of accessible lymphoma to determine delivery of isotope to tumors and assess the effect of tumor antigen expression on mAb delivery. Bone marrow biopsies were also done in the majority of patients. There was no toxicity. Serum clearance showed a median early phase half-life of 1.9 hours and a later phase half-life of 21.7 hours. Median total body clearance half-life was 22 hours. Pharmacokinetics were not dose-related. HAMA was detected in five patients. Circulating blocking antigen was detected in the serum of four patients, but at levels that were of pharmacologic consequence only in one. Biopsied tumor tissue from five patients did not express OKB7 antigen. No significant uptake of antibody was seen in these tumor sites. Mean total uptake of isotope into lymphoma measured in biopsies correlated linearly over the 400-fold increase in injected mAb dose. However, the percent of injected dose found per gram of tumor was unrelated to dose, but correlated inversely with tumor burden. In two patients with minimal tumor burden, 1.0 mg and 5.0 mg doses of OKB7 resulted in tumor to body radioisotope dose ratios of 22 and 7, which would theoretically permit tolerable delivery of 4,400 and 1,400 rads to these tumors, respectively, if OKB7 were conjugated with higher doses of 131I.
为研究放射性碘的毒性、药理学、抗体定位及剂量测定，对18例复发性非霍奇金淋巴瘤（NHL）患者输注逐步递增剂量的用碘-131（¹³¹I）微量标记的单克隆抗体（mAb）OKB7。OKB7是一种无细胞毒性的小鼠免疫球蛋白G2b（IgG2b）单克隆抗体，可与B细胞及大多数B细胞NHL发生反应。分别以0.1mg至40mg的六个剂量水平对3例患者进行治疗。所有患者每日均进行放射性核素成像及计数，进行系列血样采集以研究药代动力学、人抗鼠抗体（HAMA）及循环抗原，并对可触及的淋巴瘤进行活检以确定同位素在肿瘤中的递送情况，并评估肿瘤抗原表达对单克隆抗体递送的影响。大多数患者还进行了骨髓活检。未观察到毒性反应。血清清除率显示早期半衰期的中位数为1.9小时，后期半衰期的中位数为21.7小时。全身清除半衰期的中位数为22小时。药代动力学与剂量无关。在5例患者中检测到HAMA。在4例患者的血清中检测到循环阻断抗原，但仅在1例患者中其水平具有药理学意义。5例患者的活检肿瘤组织未表达OKB7抗原。在这些肿瘤部位未观察到明显的抗体摄取。活检中测得的淋巴瘤对同位素的平均总摄取量与注射的单克隆抗体剂量增加400倍呈线性相关。然而，每克肿瘤中发现的注射剂量百分比与剂量无关，但与肿瘤负荷呈负相关。在2例肿瘤负荷极小的患者中，1.0mg和5.0mg剂量的OKB7导致肿瘤与身体放射性同位素剂量比分别为22和7，理论上如果OKB7与更高剂量的¹³¹I偶联，分别可允许向这些肿瘤耐受递送4400和1400拉德。
