Stably tethered multifunctional structures of defined composition made by the dock and lock method for use in cancer targeting
Stably tethered multifunctional structures of defined composition made by the dock and lock method for use in cancer targeting
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DOI：
10.1073/pnas.0600982103
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发表时间：
2006-05-02
影响因子：
11.1
通讯作者：
Chang, CH
中科院分区：
文献类型：
--
作者：
Rossi, EA;Goldenberg, DM;Chang, CH
我们描述了一种平台技术，称为停靠和锁定方法，该技术利用camp依赖性蛋白激酶的调节亚基与a激酶锚定蛋白的锚定结构域之间的自然结合，用于根据需要从模块化亚基构建不同蛋白质和非蛋白质分子的生物活性偶联物。这种方法可以对许多不同的生物物质进行定量和位点特异性耦合，用于不同的医学应用。通过生产由三个稳定连接的Fab片段组成的双特异性、三价结合复合物，验证了dock和lock方法，该复合物能够选择性地向人类癌症异种移植物递送放射性示踪剂，从而快速、显著地改善癌症靶向和成像，提供肿瘤/血液比率从1小时的66 +/- 5到24小时的395 +/- 26。
We describe a platform technology, termed the dock and lock method, which uses a natural binding between the regulatory subunits of CAMP-dependent protein kinase and the anchoring domains of A kinase anchor proteins for general application in constructing bioactive conjugates of different protein and nonprotein molecules from modular subunits on demand. This approach could allow quantitative and site-specific coupling of many different biological substances for diverse medical applications. The dock and lock method is validated herein by producing bispecific, trivalent-binding complexes composed of three stably linked Fab fragments capable of selective delivery of radiotracers to human cancer xenografts, resulting in rapid, significantly improved cancer targeting and imaging, providing tumor/blood ratios from 66 +/- 5 at 1 h to 395 +/- 26 at 24 h.