Multifunctional antibodies by the dock-and-lock method for improved cancer Imaging and therapy by pretargeting
Multifunctional antibodies by the dock-and-lock method for improved cancer Imaging and therapy by pretargeting
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DOI：
10.2967/jnumed.107.046185
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发表时间：
2008-01-01
影响因子：
9.3
通讯作者：
Chang, Chien-Hsing
中科院分区：
文献类型：
--
作者：
Goldenberg, David M.;Rossi, Edmund A.;Chang, Chien-Hsing
Dock-and-Lock（DNL）方法，它使生物活性分子具有多价性和多功能性，是一种新的方法来开发靶向分子，以改善癌症成像和治疗。它涉及使用一对不同的蛋白质结构域，这些蛋白质结构域参与环磷酸腺苷（cAMP）依赖性蛋白激酶A（PKA）和A-激酶锚定蛋白（AKAP）之间的天然结合。PKA调节亚基中发现的二聚化和对接结构域和相互作用AKAP的锚定结构域（AD）各自连接到生物实体，所得衍生物在组合时容易形成具有确定组成的稳定束缚复合物，完全保留单个成分的功能。DNL方法已经产生了几种三价、双特异性结合蛋白，每种蛋白由2个相同的Fab片段组成，所述Fab片段与不同的Fab片段位点特异性连接。例如，与癌胚抗原（CEA）反应的2个相同Fab结合至与带有诊断性或治疗性放射性核素的半抗原肽反应的Fab。使用将靶向肿瘤的二价抗CEA抗体与由三Fab构建体的第二Fab捕获的放射性肽的递送分开的2步预靶向方法，已经开发了癌症成像和治疗的改进方法，并且对于诊断成像（例如用免疫SPECT和免疫PET）或放射免疫治疗显示出非常敏感和特异性的CEA表达肿瘤靶向。在给予胰腺癌MUC 1的tri-Fab和用Y-90标记的半抗原肽的胰腺癌异种移植模型中预靶向显示出改善的治疗功效。
The Dock-and-Lock (DNL) method, which makes bioactive molecules with multivalency and multifunctionality, is a new approach to develop targeting molecules for improved cancer imaging and therapy. It involves the use of a pair of distinct protein domains involved in the natural association between cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) and A-kinase anchoring proteins (AKAPs). The dimerization and docking domain found in the regulatory subunit of PKA and the anchoring domain (AD) of an interactive AKAP are each attached to a biologic entity, and the resulting derivatives, when combined, readily form a stably tethered complex of a defined composition that fully retains the functions of the individual constituents. The DNL method has generated several trivalent, bispecific, binding proteins, each consisting of 2 identical Fab fragments linked site-specifically to a different Fab fragment. For example, 2 identical Fabs reacting with carcinoembryonic antigen (CEA) are bound to a Fab reacting with a hapten peptide that bears a diagnostic or therapeutic radionuclide. Using a 2-step, pretargeting method that separates the bivalent anti-CEA antibody targeting of tumor from the delivery of the radioactive peptide that is captured by the second Fab of the tri-Fab construct, an improved method of cancer imaging and therapy has been developed and shows very sensitive and specific targeting of CEA-expressing tumors for either diagnostic imaging, such as with immunoSPECT and immunoPET, or radioimmunotherapy. Improved therapeutic efficacy is shown with pretargeting in a pancreatic cancer xenograft model given a tri-Fab to a pancreatic cancer MUC1 and the hapten peptide labeled with Y-90.