Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
University of Basel, Faculty of Science, Basel, Switzerland.
Nat Chem Biol. 2018 Jul;14(7):723-729. doi: 10.1038/s41589-018-0046-z. Epub 2018 Apr 23.
Strategies for expanding the sensor space of designer receptors are urgently needed to tailor cell-based therapies to respond to any type of medically relevant molecules. Here, we describe a universal approach to designing receptor scaffolds that enables antibody-specific molecular input to activate JAK/STAT, MAPK, PLCG or PI3K/Akt signaling rewired to transgene expression driven by synthetic promoters. To demonstrate its scope, we equipped the GEMS (generalized extracellular molecule sensor) platform with antibody fragments targeting a synthetic azo dye, nicotine, a peptide tag and the PSA (prostate-specific antigen) biomarker, thereby covering inputs ranging from small molecules to proteins. These four GEMS devices provided robust signaling and transgene expression with high signal-to-noise ratios in response to their specific ligands. The sensitivity of the nicotine- and PSA-specific GEMS devices matched the clinically relevant concentration ranges, and PSA-specific GEMS were able to detect pathological PSA levels in the serum of patients diagnosed with prostate cancer.
为了使基于细胞的疗法能够针对任何类型的医学相关分子做出响应，迫切需要扩展设计受体的传感器空间的策略。在这里，我们描述了一种通用的受体支架设计方法，该方法能够使抗体特异性分子输入激活 JAK/STAT、MAPK、PLCγ 或 PI3K/Akt 信号通路，从而重新连接到由合成启动子驱动的转基因表达。为了展示其范围，我们在 GEMS（广义细胞外分子传感器）平台上配备了针对合成偶氮染料、尼古丁、肽标签和 PSA（前列腺特异性抗原）生物标志物的抗体片段，从而涵盖了从小分子到蛋白质的输入。这四个 GEMS 设备在响应其特定配体时提供了强大的信号和转基因表达，具有高信噪比。尼古丁和 PSA 特异性 GEMS 设备的灵敏度与临床相关浓度范围相匹配，并且 PSA 特异性 GEMS 能够检测到诊断为前列腺癌的患者血清中的病理性 PSA 水平。
