Universud, Faculty of Pharmacy, INSERM UMR 996, Chatenay-Malabry, France.
Br J Pharmacol. 2010 Oct;161(3):509-11. doi: 10.1111/j.1476-5381.2010.00925.x.
The failure of toxicity studies in non-human primates to predict the cytokine release syndrome during a first-in-man study of the CD28-specific monoclonal antibody TGN1412 has remained unexplained so far. In this issue of the BJP, work from the NIBSC first identifies the effector memory subset of human T-lymphocytes as the most likely source of the pro-inflammatory cytokines released during the study, and goes on to show that in cynomolgus monkeys, this subset lacks CD28, the target molecule of TGN1412. We discuss the implications for the TGN1412 catastrophe and for preclinical evaluation of biologicals in animal models in general.
到目前为止,在人类首次研究 CD28 特异性单克隆抗体 TGN1412 时,非灵长类动物的毒性研究未能预测细胞因子释放综合征,其原因仍未得到解释。在本期 BJP 中,NIBSC 的工作首次确定了人类 T 淋巴细胞中的效应记忆亚群是研究中释放的促炎细胞因子的最可能来源,并进一步表明,在食蟹猴中,该亚群缺乏 TGN1412 的靶分子 CD28。我们讨论了这对 TGN1412 灾难以及对一般动物模型中生物制品的临床前评估的影响。