"Cytokine Storm" in the phase I trial of monoclonal antibody TGN1412: Better understanding the causes to improve preclinical testing of immunotherapeutics
"Cytokine Storm" in the phase I trial of monoclonal antibody TGN1412: Better understanding the causes to improve preclinical testing of immunotherapeutics
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DOI：
10.4049/jimmunol.179.5.3325
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发表时间：
2007-09-01
影响因子：
4.4
通讯作者：
Poole, Stephen
中科院分区：
文献类型：
--
作者：
Stebbings, Richard;Findlay, Lucy;Poole, Stephen
在该超级激动剂的I期临床试验中，CD28特异性mAb TGN 1412在所有6名健康志愿者中迅速引起危及生命的“细胞因子风暴”，标志着临床前安全性测试失败。我们报告了新的体外程序，其中TGN 1412，以各种方式固定，以刺激细胞因子的惊人释放和人类体内发生的淋巴细胞增殖的方式呈现给人类白色血细胞。新的程序将预测这种超级激动剂的毒性，现在正被应用于新兴的免疫治疗和其他有可能作用于免疫系统的治疗。来自这些新方法的数据，沿着来自非人灵长类动物的体外和体内研究的数据，表明给予人类志愿者的TGN 1412剂量接近最大免疫刺激剂量，并且TGN 1412不是非人灵长类动物的超激动素。
The CD28-specitic mAb TGN1412 rapidly caused a life-threatening "cytokine storm" in all six healthy volunteers in the Phase I clinical trial of this superagonist, signaling a failure of preclinical safety testing. We report novel in vitro procedures in which TGN1412, immobilized in various ways, is presented to human white blood cells in a manner that stimulates the striking release of cytokines and profound lymphocyte proliferation that occurred in vivo in humans. The novel procedures would have predicted the toxicity of this superagonist and are now being applied to emerging immunotherapeutics and to other therapeutics that have the potential to act upon the immune system. Data from these novel procedures, along with data from in vitro and in vivo studies in nonhuman primates, suggest that the dose of TGN1412 given to human volunteers was close to the maximum immunostimulatory dose and that TGN1412 is not a superagonistin nonhuman primates.