Pre-clinical toxicity and immunogenicity evaluation of a MUC1-MBP/BCG anti-tumor vaccine
Pre-clinical toxicity and immunogenicity evaluation of a MUC1-MBP/BCG anti-tumor vaccine
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DOI：
10.1016/j.intimp.2016.02.006
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发表时间：
2016-04-01
影响因子：
5.6
通讯作者：
Tai, Guixiang
中科院分区：
文献类型：
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作者：
Hu, Boqi;Wang, Juan;Tai, Guixiang
粘蛋白1（MUC 1）作为一种癌基因，在许多人类腺癌的发生发展中起着关键作用，是肿瘤免疫治疗的一个有吸引力的靶点。我们前期的研究表明，MUC 1-MBP/BCG抗肿瘤疫苗能诱导小鼠产生MUC 1特异性Th 1优势免疫应答，模拟MUC 1特异性细胞毒性T淋巴细胞杀伤活性，并能显著抑制MUC 1表达的B16细胞的生长。为了帮助疫苗进入I期临床试验，在本研究中，对疫苗进行了临床前毒性和免疫原性评价。评价包括小鼠单次给药急性毒性研究、大鼠重复给药慢性毒性和免疫原性研究以及食蟹猴初步毒性和免疫原性研究。结果显示，用MUC 1-MBP/BCG抗肿瘤疫苗治疗没有引起任何器官毒性，除了在几只大鼠中由BCG诱导的关节炎或局部结节。此外，疫苗显著增加了大鼠体内IFN-γ的水平，表明Th 1细胞被激活。此外，结果显示MUC 1-MBP/BCG抗肿瘤疫苗在大鼠和食蟹猴中均诱导MUC 1特异性IgG抗体应答。总的来说，这些数据有利于MUC 1-MBP/BCG抗肿瘤疫苗进入I期临床试验。(C)2016爱思唯尔B. V.保留所有权利。
Mucin 1 (MUC1), as an oncogene, plays a key role in the progression and tumorigenesis of many human adenocarcinomas and is an attractive target in tumor immunotherapy. Our previous study showed that the MUC1-MBP/BCG anti-tumor vaccine induced a MUC1-specific Th1-dominant immune response, simulated MUC1-specific cytotoxic T lymphocyte killing activity, and could significantly inhibit MUC1-expression B16 cells' growth in mice. To help move the vaccine into a Phase I clinical trial, in the current study, a pre-clinical toxicity and immunogenicity evaluation of the vaccine was conducted. The evaluation was comprised of a single-dose acute toxicity study in mice, repeat-dose chronic toxicity and immunogenicity studies in rats, and pilot toxicity and immunogenicity studies in cynomolgus monkeys. The results showed that treatment with the MUC1-MBP/BCG anti-tumor vaccine did not cause any organ toxicity, except for arthritis or local nodules induced by BCG in several rats. Furthermore, the vaccine significantly increased the levels of IFN-gamma in rats, indicating that Th1 cells were activated. In addition, the results showed that the MUC1-MBP/BCG anti-tumor vaccine induced a MUC1-specific IgG antibody response both in rats and cynomolgus monkeys. Collectively, these data are beneficial to move the MUC1-MBP/BCG anti-tumor vaccine into a Phase I clinical trial. (C) 2016 Elsevier B.V. All rights reserved.