Davis Ian D, Wiseman Gregory A, Lee Fook-Thean, Gansen Denise N, Hopkins Wendie, Papenfuss Anthony T, Liu Zhanqi, Moynihan Timothy J, Croghan Gary A, Adjei Alex A, Hoffman Eric W, Ingle James N, Old Lloyd J, Scott Andrew M
Ludwig Institute for Cancer Research, Victoria, Australia.
Cancer Immun. 2007 Aug 17;7:13.
The chimeric monoclonal antibody cG250 recognises the G250/CAIX/MN antigen found on 95% of clear cell renal cell carcinomas (RCCs). We performed a phase I clinical trial to evaluate the safety, blood pharmacokinetics (PK), and biodistribution of repeated doses of cG250. The primary endpoint was toxicity. Secondary endpoints were cG250 biodistribution and PK; measurement of human anti-chimeric-antibodies (HACA); and tumour response rates. Eligible patients had unresectable or metastatic clear cell RCC. Doses of 5, 10, 25, or 50 mg/m(2) were given weekly by intravenous infusion for six weeks. Three patients were treated at each dose level. Trace (131)I-labelled cG250 was administered on weeks 1 and 5. Thirteen patients participated and were evaluable. One patient developed brain metastases and was replaced. No grade 3 or 4 toxicities and no dose-limiting toxicity occurred. One patient died due to progressive disease within 30 days of receiving the study drug. One patient developed HACA during the second six-week cycle. PK analysis showed mean whole body and blood alpha and beta half-lives of cG250 of 18.99 +/- 6.84 and 180.19 +/- 86.68 hours, respectively. All patients had cG250 tumour localization by gamma camera imaging in week 1 and 5. One patient had a complete response, nine patients had stable disease, and three had progressive disease. One patient received 11 six-week cycles of treatment with no toxicity or HACA. In conclusion, repeated intravenous doses of up to 50 mg/m(2) of cG250 are safe. Furthermore cG250 has a long half-life and targets clear cell RCC effectively.
嵌合单克隆抗体cG250可识别95%的透明细胞肾细胞癌（RCC）中存在的G250/碳酸酐酶IX/膜联蛋白抗原。我们开展了一项I期临床试验，以评估重复剂量的cG250的安全性、血液药代动力学（PK）及生物分布。主要终点为毒性。次要终点为cG250的生物分布和PK；人抗嵌合抗体（HACA）的检测；以及肿瘤缓解率。符合条件的患者患有不可切除或转移性透明细胞RCC。每周通过静脉输注给予5、10、25或50 mg/m²的剂量，共六周。每个剂量水平治疗3例患者。在第1周和第5周给予微量（131）I标记的cG250。13例患者参与并可进行评估。1例患者发生脑转移并被替换。未发生3级或4级毒性反应，也未出现剂量限制性毒性。1例患者在接受研究药物后30天内因疾病进展死亡。1例患者在第二个六周周期出现HACA。PK分析显示，cG250的全身平均α和β半衰期以及血液平均α和β半衰期分别为18.99±6.84小时和180.19±86.68小时。所有患者在第1周和第5周通过γ相机成像显示cG250在肿瘤部位定位。1例患者完全缓解，9例患者病情稳定，3例患者病情进展。1例患者接受了11个六周周期的治疗，未出现毒性反应或HACA。总之，重复静脉给予高达50 mg/m²的cG250是安全的。此外，cG250半衰期长，能有效靶向透明细胞RCC。
