Human antibody-based chemically induced dimerizers for cell therapeutic applications
Human antibody-based chemically induced dimerizers for cell therapeutic applications
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DOI：
10.1038/nchembio.2529
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发表时间：
2018-02-01
影响因子：
14.8
通讯作者：
Wells, James A.
中科院分区：
文献类型：
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作者：
Hill, Zachary B.;Martinko, Alexander J.;Wells, James A.
化学诱导二聚体（cid）已成为人为调节细胞信号通路的最强大工具之一；然而，目前可用的CID系统缺乏用于调节细胞治疗所需的特性。在这里，我们报道了从已知的小分子-蛋白质复合物中，通过选择能够识别由结合的小分子产生的化学表位的合成抗体，开发出基于人类抗体的化学诱导二聚体（abcid）。我们通过生成三种抗体来证明这一概念，与单独的BCL-xL相比，它们对BCL-xL- abt -737复合物具有高度选择性。我们通过使用abcid诱导crispr介导的基因表达和调节CAR - t细胞活化，展示了abcid在调节人类细胞疗法中的应用潜力。我们相信，本研究产生的AbCID将在细胞治疗调控中得到应用，并且AbCID开发的一般方法可能导致许多新的和正交的cid的产生。
Chemically induced dimerizers (CIDs) have emerged as one of the most powerful tools for artificially regulating signaling pathways in cells; however, currently available CID systems lack the properties desired for use in regulating cellular therapies. Here, we report the development of human antibody-based chemically induced dimerizers (AbCIDs) from known small-molecule-protein complexes by selecting for synthetic antibodies that recognize the chemical epitope created by the bound small molecule. We demonstrate this concept by generating three antibodies that are highly selective for the BCL-xL-ABT-737 complex compared to BCL-xL alone. We show the potential of AbCIDs for application in regulating human cell therapies by using them to induce CRISPRa-mediated gene expression and to regulate CAR T-cell activation. We believe that the AbCIDs generated in this study will find application in regulating cell therapies and that the general method of AbCID development may lead to the creation of many new and orthogonal CIDs.