LOCALIZATION OF I-131-LABELED P97-SPECIFIC FAB FRAGMENTS IN HUMAN-MELANOMA AS A BASIS FOR RADIOTHERAPY
LOCALIZATION OF I-131-LABELED P97-SPECIFIC FAB FRAGMENTS IN HUMAN-MELANOMA AS A BASIS FOR RADIOTHERAPY
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DOI：
10.1172/jci111175
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发表时间：
1983-01-01
影响因子：
15.9
通讯作者：
HELLSTROM, I
中科院分区：
文献类型：
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作者：
LARSON, SM;CARRASQUILLO, JA;HELLSTROM, I
对33例晚期恶性黑色素瘤患者进行了静脉注射治疗。给药131I标记的针对人黑色素瘤的癌胚糖蛋白p97的Fab片段。总共进行了47次伽马相机成像研究，目的是定位转移性沉积。除肿瘤外，肝脏和肾脏也可见131I-Fab摄取。其中20项研究包括同时给予p97特异性的131I标记的Fab和非p97特异性的125I标记的Fab。P97特异性Fab的血液清除速度明显快于非特异性Fab。这些患者中有8人有S.C.的活检。在注射后48小时和72小时观察结节，以评估放射性定位是否具有抗原特异性。特异性/非特异性摄取比值分别为3.7(48 H)和3.4(72 H)；摄取与肿瘤p97浓度密切相关(r=0.81，P<；0.01)。对~(131)I标记的抗p97 Fab在高p97肿瘤浓度患者体内的生物分布的成像研究表明，肿瘤摄取活跃，标记的Fab在肿瘤中的滞留时间比正常组织更长。根据这些研究，在观察到剂量限制性毒性之前，患者可以安全地给予总计500mCI的131I剂量。因此，在选定的7名患者中，开始了I期放射治疗试验。为了提高辐射安全性，开发了自动化方法来标记高达200mCI的131I的Fab片段。到目前为止，总共有12个单独的治疗剂量，从34-197mCi的131I标记到5-10 mg的Fab，已经获得了良好的肿瘤定位，并且没有主要的靶器官毒性。累积剂量范围为132-529mCI-131I。可归因于辐射的副作用很轻微，在接受累积剂量500 mCI的2名患者中，观察到血小板和中性粒细胞绝对计数略有下降50%。在47项诊断和12项治疗研究的联合系列中，观察到以下4种急性反应：一过性寒战和发热各1例，面色潮红和低血压，2例皮疹。所有这些反应对对症治疗都有迅速反应。在多次注射131I-(抗p97)Fab(IgG1)后，3例患者观察到同型特异性免疫。在这些患者中，有2例可能在用不同同型(IgG2a)的131I-(抗p97)Fab产生免疫后成功回输。根据131I-Fab在这些患者中的生物分布进行剂量估算。每100mCI的131I-Fab，肿瘤1040rad，肝脏325rad，骨髓30rad。如果给予~gt；500 mCI~(131)I-Fab剂量，骨髓有望成为关键器官。如果采取适当的预防措施，显然可以通过重复静脉注射大剂量(免疫特异性为人黑色素瘤相关抗原的131I标记的小鼠Fab片段)给人类。打针。
Thirty-three patients with advanced malignant melanoma were studied after i.v. administration of 131I-labeled Fab fragments specific for p97, an oncofetal glycoprotein of human melanoma. In all, 47 .gamma.-camera imaging studies were performed for the purpose of localization of metastatic deposits. In addition to tumor, 131I-Fab uptake was also seen in liver and kidney. Twenty of these studies included simultaneous administration of an 131I-labeled Fab specific for p97 and an 125I-labeled Fab not specific for p97. Blood clearance of p97-specific Fab was significantly more rapid than for nonspecific Fab. Eight of these patients had biopsies of s.c. nodules at 48 h and 72 h postinjection to assess whether localization of radioactivity was antigen specific. Antigen-specific localization was observed with average ratios of specific/nonspecific uptake of 3.7 (48 h) and 3.4 (72 h); uptake was strongly correlated with tumor p97 concentration (r = 0.81, P < 0.01). Imaging studies of the biodistribution of 131I-labeled anti-p97 Fab in patients selected for high p97 tumor concentration showed avid tumor uptake and more prolonged retention of labeled Fab in tumor than in normal tissues. Based on these studies, total 131I doses of 500 mCi could be safely given to patients before dose-limiting toxicity would be observed. Accordingly, in 7 selected patients, phase I radiotherapeutic trials were begun. For improved radiation safety, automated methods were developed to label Fab fragments with up to 200 mCi of 131I. So far, a total of 12 individual theapeutic doses, ranging from 34-197 mCi of 131I-labeled to 5-10 mg of Fab, have been administered with excellent tumor localization and without major target organ toxicity. Cumulative doses ranged from 132-529 mCi 131I. Side effects attributable to the radiation were mild, with a transient drop slightly > 50% in platelet and absolute neutrophil counts being observed in the 2 patients who received cumulative doses > 500 mCi. In the combined series of 47 diagnostic and 12 therapeutic studies, the following 4 acute reactions were observed: 1 episode each of transient chills and fever; flushing and hypotension; and 2 skin rashes. All of these reactions responded promptly to symptomatic therapy. After multiple administrations of 131I-(anti-p97) Fab (IgG1), isotype-specific immunity was observed in 3 patients. In 2 of these patients it was possible to successfully reinfuse afer immunity had developed with 131I-(anti-p97) Fab of a different isotype (IgG2a). Dosimetry estimates were performed based on the biodistribution of 131I-Fab in these patients. For every 100 mCi of 131I-Fab given, tumor received 1040 rad; liver, 325 rad; and bone marrow, 30 rad. Marrow would be expected to be the critical organ, if doses > 500 mCi 131I-Fab are given. With proper precautions, large doses (of an 131I-labeled murine Fab fragments immunologically specific for a human melanoma-associated antigen) could apparently be safely given to humans by using repetitive i.v. injections.