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双特异性T细胞接合剂(BiTE)具有很好的抗癌特性.然而,潜在的细胞因子释放综合征(CRS)对于所有BiTE而言都是危险的信号.尽管这种毒性被认为与细胞因子释放有关,CRS的作用机制仍然不完全清楚.为进一步深化BiTE临床应用研发,对BiTE进行CRS风险评估的非临床研究是降低药物研发风险的关键.本综述讨论了CRS的可能机制,特别是包括一些有助于CRS发展的主要因素,如T细胞的激活和白细胞介素的升高.T细胞活化可能只是CRS级联反应的开始,其他类型的细胞也可以极大促进CRS,包括由下游B细胞、单核细胞和内皮细胞触发的连锁反应.可基于CRS级联中的这些组件来设计非临床前风险规避程序.体外细胞因子释放测定与体内小鼠和非人类灵长类动物研究的结合可以预测和减轻临床中的CRS风险.此外,良好的风险规避程序能够为药物候选物的进一步研发提供一些CRS风险区域性排列,并提供足够的信心来选择临床试验首例剂量.“,”Bi-specific T-cell engagers (BiTEs) show great clinical outcomes for anti-cancer purposes. However, potential cytokine release syndrome (CRS) is notorious to all BiTEs. The mechanism underlying CRS is still not fully known, even though such toxicities are considered to be cytokine release related. Assessment of CRS is a key to non-clinical de-risk programs for BiTEs therapeutic development. In the present review, possible mechanisms are discussed, especially factors contributing to CRS develop?ment. T cell activation may be just an initiation of the CRS cascade, and other cell types can greatly contribute to CRS, such as a chain reaction triggered by downstream B-cells, monocytes, and endothe?lium cells. A non-clinical de-risk program can be designed based on these components in the CRS cascade. Combination of in vitro cytokine release assay, and in vivo mouse and non-human primates studies should be reliable enough to predict and mitigate CRS risk in the clinics. Further more, a good de-risk program should be able to provide ranking for candidates for further development and provide enough confidence to select a first-in-human dose.