The dock and lock method: A novel platform technology for building multivalent, multifunctional structures of defined composition with retained bioactivity
The dock and lock method: A novel platform technology for building multivalent, multifunctional structures of defined composition with retained bioactivity
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DOI：
10.1158/1078-0432.ccr-07-1217
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发表时间：
2007-09-15
影响因子：
11.5
通讯作者：
Goldenberg, David M.
中科院分区：
文献类型：
--
作者：
Chang, Chien-Hsing;Rossi, Edmund A.;Goldenberg, David M.
本文综述了具有制备大量多价、多功能生物活性分子潜力的对接锁定法（DNL）的思想、方法和概念验证。DNL方法的关键似乎是明智地应用一对不同的蛋白质结构域，这些蛋白质结构域参与蛋白激酶A（PKA;环AMP依赖性蛋白激酶）和A-激酶锚定蛋白之间的天然结合。实质上，PKA的调节亚基中发现的二聚化和对接结构域和相互作用的A-激酶锚定蛋白的锚定结构域各自连接到生物实体，并且所得衍生物在组合时容易形成完全保留单个组分的功能的确定组成的稳定拴系的复合物。DNL方法的初始验证通过成功产生几种三价双特异性结合蛋白来提供，每种三价双特异性结合蛋白由位点特异性连接至不同Fab的两个相同Fab片段组成。用DNL方法实现的基因工程和缀合化学的整合不仅可以创造新的人类治疗剂，而且还可以为构建优于目前商业化的重组产品（包括细胞因子、疫苗和单克隆抗体）的改良重组产品提供希望和挑战。
The idea, approach, and proof-of-concept of the dock and lock (DNL) method, which has the potential for making a large number of bioactive molecules with multivalency and multifunctionality, are reviewed. The key to the DNL method seems to be the judicious application of a pair of distinct protein domains that are involved in the natural association between protein kinase A (PKA; cyclic AMP-dependent protein kinase) and A-kinase anchoring proteins. In essence, the dimerization and docking domain found in the regulatory subunit of PKA and the anchoring domain of an interactive A-kinase anchoring protein are each attached to a biological entity, and the resulting derivatives, when combined, readily form a stably tethered complex of a defined composition that fully retains the functions of individual constituents. Initial validation of the DNL method was provided by the successful generation of several trivalent bispecific binding proteins, each consisting of two identical Fab fragments linked site-specifically to a different Fab. The integration of genetic engineering and conjugation chemistry achieved with the DNL method may not only enable the creation of novel human therapeutics but could also provide the promise and challenge for the construction of improved recombinant products over those currently commercialized, including cytokines, vaccines, and monoclonal antibodies.