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含对硝基苯丙氨酸HER2疫苗的免疫原性研究

何羽, 田浤, 戴鑫, 姚文兵, 高向东

何羽, 田浤, 戴鑫, 姚文兵, 高向东. 含对硝基苯丙氨酸HER2疫苗的免疫原性研究[J]. 中国药科大学学报, 2018, 49(3): 369-375. DOI: 10.11665/j.issn.1000-5048.20180317
引用本文: 何羽, 田浤, 戴鑫, 姚文兵, 高向东. 含对硝基苯丙氨酸HER2疫苗的免疫原性研究[J]. 中国药科大学学报, 2018, 49(3): 369-375. DOI: 10.11665/j.issn.1000-5048.20180317
HE Yu, TIAN Hong, DAI Xin, YAO Wenbing, GAO Xiangdong. Immunogenicity of HER2 vaccine containing p-nitrophenylalanine[J]. Journal of China Pharmaceutical University, 2018, 49(3): 369-375. DOI: 10.11665/j.issn.1000-5048.20180317
Citation: HE Yu, TIAN Hong, DAI Xin, YAO Wenbing, GAO Xiangdong. Immunogenicity of HER2 vaccine containing p-nitrophenylalanine[J]. Journal of China Pharmaceutical University, 2018, 49(3): 369-375. DOI: 10.11665/j.issn.1000-5048.20180317

含对硝基苯丙氨酸HER2疫苗的免疫原性研究

基金项目: 国家自然科学基金资助项目(No.81673343,No.81573335,No.91753112)

Immunogenicity of HER2 vaccine containing p-nitrophenylalanine

  • 摘要: 为了打破HER2自身蛋白的免疫耐受,产生高效的免疫应答,利用遗传密码扩充技术,将免疫原性氨基酸对硝基苯丙氨酸定点引入到HER2片段的第5、26、79位,获得了含有对硝基苯丙氨酸的HER2突变体。通过镍亲和色谱柱,获得纯度达95%以上的原型和突变体HER2分子。对HER2疫苗的免疫原性进行分析,结果显示,pNO2Phe79HER2能够在C57BL/6小鼠体内产生高滴度的交叉性抗体。免疫小鼠的抗血清能够识别具有完整HER2受体胞外区的SKBR-3细胞,并通过ADCC效应裂解HER2高表达的HER2+B16F10细胞。这些研究结果提示,定点引入了对硝基苯丙氨酸的pNO2Phe79HER2可以作为靶向HER2的肿瘤疫苗候选分子。
    Abstract: In order to delete the immune tolerance of self-protein HER2 and produce an efficient immune response, the genetic code expansion technique was employed to introduce the immunogenic amino acid p-nitrophenylalanine into the position 5, 26 and 79 of the HER2 fragment and HER2 mutants containing p-nitrophenylalanine were obtained. Prototype and mutant HER2 molecules with a purity of more than 95% were obtained through a nickel affinity column. Immunogenicity analysis of the HER2 vaccine showed that pNO2Phe79HER2 was able to produce high titer cross-reactive antibodies in C57BL/6 mice and that the mouse antisera could recognize SKBR-3 cells with intact HER2 receptor extracellular domain and cleave HER2 highly expressed HER2+B16F10 cells through ADCC effect. These findings suggested that pNO2Phe79HER2 which incorporates p-nitrophenylalanine could be used as a tumor vaccine candidate targeting HER2.
  • [1] Liu Y,el-Ashry D,Chen D,et al.MCF-7 breast cancer cells ove-rexpressing transfected cerbB-2 have an in vitro growth advantage in estrogen-depleted conditions and reduced estrogen-dependence and tamoxifen-sensitivity in vivo[J].Breast Cancer Res Treat,1995,34(2):97-117.
    [2] Tsang R,Finn R.Beyond trastuzumab:novel therapeutic strategies in HER2-positive metastatic breast cancer [J].Br J Cancer,2012,106(1):6-13.
    [3] De Santes K,Slamon D,Anderson SK,et al.Radiolabeled antibody targeting of the HER-2/neu oncoprotein [J].Cancer Res,1992,52(7):1916-1923.
    [4] Spector NL,Xia W,Burris H,et al.Study of the biologic effects of lapatinib,a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases,on tumor growth and survival pathways in patients with advanced malignancies [J].J Clin Oncol,2005,23(11):2502-2512.
    [5] Earl HM,Vallier AL,Dunn J,et al.Trastuzumab-associated cardiac events in the Persephone trial [J].Br J Cancer,2016,115(12):1462-1470.
    [6] Eryilmaz A,Demirci B,Gunel C,et al.Evaluation of lapatinib and trastuzumab for ototoxic effects [J].J Int Adv Otol,2015,11(3):207-211.
    [7] Spector NL,Xia W,Burris H,et al.Study of the biologic effects of lapatinib,a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases,on tumor growth and survival pathways in patients with advanced malignancies [J].J Clin Oncol,2005,23(11):2502-2512.
    [8] Costa RLB,Soliman H,Czerniecki BJ.The clinical development of vaccines for HER2+ breast cancer:current landscape and future perspectives [J].Cancer Treat Rev,2017,61:107-115.
    [9] Tabi Z,Man S.Challenges for cancer vaccine development [J].Adv Drug Deliv Rev,2006,58(8):902-915.
    [10] Dalgleish AG.Therapeutic cancer vaccines:why so few randomised phase III studies reflect the initial optimism of phase II studies [J].Vaccine,2011,29(47):8501-8505.
    [11] Grunewald J,Hunt GS,Dong L,et al.Mechanistic studies of the immunochemical termination of self-tolerance with unnatural amino acids [J].Proc Natl Acad Sci U S A,2009,106(11):4337-4342.
    [12] Dai HT,Tian H,Huang J,et al.Protective effects of p-nitrophenylalanine-containing BAFF vaccine on lupus nephritis model mice [J].J China Pharm Univ(中国药科大学学报),2017,48(4):483-489.
    [13] Kessel C,Nandakumar KS,Peters FB,et al.A single functional group substitution in C5a breaks B cell and T cell tolerance and protects against experimental arthritis [J].Arthritis Rheumatol,2014,66(3):610-621.
    [14] Cai D,Tian H,Yao WB.Molecular dynamics simulation and analysis of BAFF which is incorporated with p-nitro-L-phenylalanine[J].J China Pharm Univ(中国药科大学学报),2017,48(2):227-232.
    [15] Gauba V, Grunewald J, Gorney V, et al. Loss of CD4 T-cell-dependent tolerance to proteins with modified amino acids [J].Proc Natl Acad Sci U S A,2011,108(31):12821-12826.
    [16] Kageyama S, Kitano S, Hirayama M, et al. Humoral immune responses in patients vaccinated with 1-146 HER2 protein complexed with cholesteryl pullulan nanogel [J].Cancer Sci,2008,99(3):601-607.
    [17] Hardy LL, Wick DA, Webb JR. Conversion of tyrosine to the inflammation-associated analog 3′-nitrotyrosine at either TCR- or MHC-contact positions can profoundly affect recognition of the MHC class I-restricted epitope of lymphocytic choriomeningitis virus glycoprotein 33 by CD8 T cells [J].J Immunol,2008,180(9):5956-5962.
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  • 刊出日期:  2018-06-24

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