Imaging tumors with an albumin-binding Fab, a novel tumor-targeting agent

被引:197
作者
Dennis, Mark S.
Jin, Hongkui
Dugger, Debra
Yang, Renhui
McFarland, Leanne
Ogasawara, Annie
Williams, Simon
Cole, Mary J.
Ross, Sarajane
Schwall, Ralph
机构
[1] Genentech Inc, Antibody Engn Dept, San Francisco, CA 94080 USA
[2] Genentech Inc, Dept Translat Oncol, San Francisco, CA 94080 USA
[3] Genentech Inc, Dept Biomed Engn, San Francisco, CA 94080 USA
关键词
D O I
10.1158/0008-5472.CAN-06-2531
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Association with albumin as a means to improve biodistribution and tumor deposition of a Fab was investigated using AB.Fab4D5, a bifunctional molecule derived from trastuzumab (HERCEPTIN) capable of binding albumin and tumor antigen HER2 (erbB2) simultaneously. AB.Fab4D5 was compared with trastuzumab and a trastuzumab-derived Fab (Fab4D5) for the ability to target tumors overexpressing HER2 in mouse mammary tumor virus/HER2 allograft models. Biodistriution was monitored using intravital microscopy, histology, and integrated single-photon emission computed tomography/ computed tomography analysis. Fab4D5 tumor deposition was characterized by rapid but transient appearance in tumor at 2 h with little retention, followed by rapid accumulation in kidney by 6 h. Trastuzumab was slow to accumulate in tumors and slow to clear from normal tissues, although significant tumor deposition was achieved by 24 h. In contrast, AB.Fab4D5 was observed at 2 h in tumor and its presence was sustained beyond 24 h similar to trastuzumab. Intravital microscopy revealed that at peak tumor accumulation, tumor cell staining by AB.Fab4D5 was more uniform than for Fab4D5 or trastuzumab. Similar tumor deposition was achieved for both AB.Fab4D5 and trastuzumab at 48 h (35.9 +/- 1.8% and 38.2 +/- 3.1% injected dose/g); however, AB.Fab4D5 targeted tumors more rapidly and quickly cleared from blood, leading to a lower overall normal tissue exposure. Importantly, unlike Fab4D5, AB.Fab4D5 did not accumulate in kidney, suggesting that association with albumin leads to an altered route of clearance and metabolism. Rapid targeting, excellent tumor deposition and retention, coupled with high tumor to blood ratios may make AB.Fab an exceptional molecule for imaging and cancer therapy.
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页码:254 / 261
页数:8
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