A phase I toxicity, pharmacology, and dosimetry trial of monoclonal antibody OKB7 in patients with non-Hodgkin's lymphoma: effects of tumor burden and antigen expression.
A phase I toxicity, pharmacology, and dosimetry trial of monoclonal antibody OKB7 in patients with non-Hodgkin's lymphoma: effects of tumor burden and antigen expression.
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单克隆抗体 OKB7 在非霍奇金淋巴瘤患者中的 I 期毒性、药理学和剂量测定试验：肿瘤负荷和抗原表达的影响。
作者：
D. Scheinberg;D. Straus;S. Yeh;C. Divgi;P. Garin‐Chesa;M. Graham;K. Pentlow;D. Coit;H. Oettgen;L. Old
18例复发性非霍奇金淋巴瘤（NHL）患者输注递增剂量的单克隆抗体（mAb）OKB 7，示踪标记的碘-131（131I），以研究毒性，药理学，抗体定位和放射性碘剂量测定。OKB 7是一种非细胞毒性小鼠免疫球蛋白G2 B b（IgG2 B）mAb，可与B细胞和大多数B细胞NHL反应。各3例患者接受了0.1 mg至40 mg范围内的6个剂量水平治疗。所有患者每天进行放射性核素显像和计数，连续采血以研究药代动力学、人抗鼠抗体（HAMA）和循环抗原，并对可及淋巴瘤进行活检以确定向肿瘤递送同位素并评估肿瘤抗原表达对mAb递送的影响。大多数患者还进行了骨髓活检。没有毒性。血清清除率显示中位早期半衰期为1.9小时，晚期半衰期为21.7小时。中位全身清除半衰期为22小时。药代动力学与剂量无关。5例患者检测到HAMA。在4例患者的血清中检测到循环阻断抗原，但仅在1例患者中检测到具有药理学后果的水平。5例患者的活检肿瘤组织不表达OKB 7抗原。在这些肿瘤部位未观察到显著的抗体摄取。在活检中测量的淋巴瘤的平均同位素总摄取与注射mAb剂量增加400倍呈线性相关。然而，每克肿瘤的注射剂量百分比与剂量无关，但与肿瘤负荷呈负相关。在两名肿瘤负荷最小的患者中，1.0 mg和5.0 mg剂量的OKB 7导致肿瘤与身体放射性同位素剂量比为22和7，如果OKB 7与更高剂量的131 I缀合，理论上分别允许4，400和1，400拉德的可耐受递送到这些肿瘤。
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.
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--
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