A Fusion Receptor as a Safety Switch, Detection, and Purification Biomarker for Adoptive Transferred T Cells

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作者：Wu, X., Shi, B., Zhang, J., Shi, Z., Di, S., Fan, M., Gao, H., Wang, H., Gu, J., Jiang, H. & Li, Z.
期刊：Molecular therapy : the journal of the American Society of Gene Therapy 25, 2270-2279 (2017)
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The incorporation of an endogenous safety switch represents a rational strategy for the control of toxicities following the administration of adoptive T?cell therapies. An ideal safety switch should be capable of depleting the transferred T?cells with minimal injury to normal tissues. We generated a fusion receptor by engineering a cryptic 806 epitope of human epidermal growth factor receptor (EGFR) into the N terminus of the full-length human folate receptor 1 (FOLR1), designated as FR806. The expression of FR806 allows transduced T?cells to be targeted with CH12, a monoclonal antibody recognizing the 806 epitope, but not wild-type EGFR in healthy tissues. FR806, therefore, constitutes a specific cell-surface marker for the elimination of transduced T?cells. We demonstrate that the antibody-drug conjugate (ADC) CH12-MMAF is efficiently internalized by FR806-expressing T?cells and has the potential to eliminate them. Transfected T?cells could, furthermore, be efficiently detected and purified using CH12 antibodies. In immuno-compromised mice, CH12-MMAF eliminated the majority of transferred T?cells expressing FR806 and anti-CD19 chimeric antigen receptor (CAR). The selectivity for the 806 epitope and internalization capacity of FOLR1 makes FR806 an efficient safety switch, which may additionally be used as a detection and purification biomarker for human T?cell immunotherapies.