A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer.
A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer.
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DOI：
10.1126/scitranslmed.aad0293
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发表时间：
2016-01-06
影响因子：
17.1
通讯作者：
Brigman BE
中科院分区：
文献类型：
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作者：
Whitley MJ;Cardona DM;Lazarides AL;Spasojevic I;Ferrer JM;Cahill J;Lee CL;Snuderl M;Blazer DG 3rd;Hwang ES;Greenup RA;Mosca PJ;Mito JK;Cuneo KC;Larrier NA;O'Reilly EK;Riedel RF;Eward WC;Strasfeld DB;Fukumura D;Jain RK;Lee WD;Griffith LG;Bawendi MG;Kirsch DG;Brigman BE
局部复发是实体瘤患者治疗失败的常见原因。术中检测肿瘤床中显微镜下残留癌可用于降低手术切缘阳性的风险，降低再次切除率，并定制辅助治疗。我们使用蛋白酶激活的荧光成像探针LUM015在软组织肉瘤（STS）小鼠模型中体内检测癌症，并在首次人体1期临床试验中离体检测癌症。在小鼠中，静脉内注射LUM015标记的肿瘤细胞和肿瘤床内的残留荧光预测局部复发。在15名STS或乳腺癌患者中，术前静脉注射LUM015耐受性良好。切除的人体组织的成像显示，来自肿瘤的荧光显著高于来自正常组织的荧光。LUM015生物分布、药代动力学特征和代谢在小鼠和人受试者中相似。LUM015及其代谢物（包括荧光标记的赖氨酸）的组织浓度证明LUM015选择性地分布到肿瘤中，在肿瘤中LUM015被蛋白酶激活。用组成型活性聚乙二醇化荧光成像探针在小鼠中进行的实验支持肿瘤选择性探针分布是癌症中荧光增加的决定因素的模型。这些联合临床研究表明，蛋白酶激活成像探针（例如LUM 015）的肿瘤特异性取决于生物分布和酶活性。我们的首次人体试验数据支持LUM015和其他蛋白酶敏感探针的未来临床试验。
Local recurrence is a common cause of treatment failure for patients with solid tumors. Intraoperative detection of microscopic residual cancer in the tumor bed could be used to decrease the risk of a positive surgical margin, reduce rates of reexcision, and tailor adjuvant therapy. We used a protease-activated fluorescent imaging probe, LUM015, to detect cancer in vivo in a mouse model of soft tissue sarcoma (STS) and ex vivo in a first-in-human phase 1 clinical trial. In mice, intravenous injection of LUM015 labeled tumor cells, and residual fluorescence within the tumor bed predicted local recurrence. In 15 patients with STS or breast cancer, intravenous injection of LUM015 before surgery was well tolerated. Imaging of resected human tissues showed that fluorescence from tumor was significantly higher than fluorescence from normal tissues. LUM015 biodistribution, pharmacokinetic profiles, and metabolism were similar in mouse and human subjects. Tissue concentrations of LUM015 and its metabolites, including fluorescently labeled lysine, demonstrated that LUM015 is selectively distributed to tumors where it is activated by proteases. Experiments in mice with a constitutively active PEGylated fluorescent imaging probe support a model where tumor-selective probe distribution is a determinant of increased fluorescence in cancer. These co-clinical studies suggest that the tumor specificity of protease-activated imaging probes, such as LUM015, is dependent on both biodistribution and enzyme activity. Our first-in-human data support future clinical trials of LUM015 and other protease-sensitive probes.