Phase I evaluation of J591 as a vascular targeting agent in progressive solid tumors
Phase I evaluation of J591 as a vascular targeting agent in progressive solid tumors
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DOI：
10.1158/1078-0432.ccr-06-2935
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发表时间：
2007-05-01
影响因子：
11.5
通讯作者：
Scher, Howard I.
中科院分区：
文献类型：
--
作者：
Morris, Michael J.;Pandit-Taskar, Neeta;Scher, Howard I.
目的：抗体J591靶向前列腺特异性膜抗原的外部结构域，该抗原在非前列腺实体瘤的新血管中表达。本I期试验验证了J591可用作非前列腺实体瘤患者血管靶向平台的假设。实验设计：进行性实体瘤患者符合条件。将20名患者分成6个剂量组，每组3至6名患者，每3周使用5、10、20、40、60或100 mg J591抗体治疗最多4个剂量。用10 mCi的铟-111标记2 mg抗体。结果：检测了各种实体瘤患者;所有患者均具有良好的肿瘤定位。未观察到剂量限制性毒性。血清清除率随着抗体量的增加而降低，可能是早期肝脏摄取抗体的结果。每个连续队列的半衰期分别为0.71、0.84、1.86、1.83、3.32和3.56天。60 mg时似乎出现肝脏饱和。17 18（94%）的软组织疾病患者的标准扫描显示在软组织中的抗体扫描6例骨diseases.Conclusions：各种实体瘤的肿瘤新生血管吸收可以选择性和安全地有针对性地使用J591。在计划使用J591作为辐射输送平台的未来研究时，应考虑60 mg的抗体质量，因为它似乎可以最大限度地减少输送到肝脏的辐射，同时最大限度地减少骨的辐射剂量。
Purpose:The antibody J591 targets the external domain of prostate-specific membrane antigen, which is expressed in the neovasculature of nonprostate solid tumors. This phase I trial tested the hypothesis that J591 could be used as a vascular targeting platform for patients with nonprostate solid tumors.Experimental Design: Patients with progressive solid tumors were eligible. Twenty patients, divided into six dosage cohorts of 3 to 6 patients each, were treated every 3 weeks to a maximum of four doses using either 5,10, 20, 40, 60, or 100 mg of J591 antibody. Two milligrams of antibody were labeled with 10 mCi of indium-111.Results: Patients with a wide variety of solid tumors were tested; all had good tumor localization. No dose-limiting toxicities were observed. The serum clearance rate decreased with increasing antibody mass, likely a result of early hepatic uptake of antibody. Half-life for each successive cohort was 0.71, 0.84,1.86,1.83, 3.32, and 3.56 days. Hepatic saturation seemed to occur by 60 mg. Seventeen of 18 (94%) patients with soft tissue disease on standard scans showed uptake in the soft tissues on antibody scans as did 6 of 6 patients with bone disease.Conclusions: The tumoral neovasculature of a variety of solid tumors can be selectively and safely targeted using J591. In planning for future studies using J591 as a radiation delivery platform, an antibody mass of 60 mg should be considered, as it would seem to minimize the radiation delivered to the liver while minimizing the radiation dose to bone.