Conjugation Reaction with 8-Arm PEG Markedly Improves the Immunogenicity of Mycobacterium tuberculosis CFP10-TB10.4 Fusion Protein,Bioconjugate Chemistry

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Conjugation Reaction with 8-Arm PEG Markedly Improves the Immunogenicity of Mycobacterium tuberculosis CFP10-TB10.4 Fusion Protein
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2017-05-26 00:00:00 , DOI: 10.1021/acs.bioconjchem.7b00131
Xiaowei Sun _{1,

2} , Weili Yu ₂ , Quanhai Pang ₁ , Tao Hu ₂

Affiliation

Mycobacterium tuberculosis (Mtb) is a serious fatal pathogen responsible for tuberculosis (TB). Effective vaccination is highly desired for immunoprotection against Mtb infection. CFP10 and TB10.4 are two important immunodominant Mtb-secreted protein antigens, which suffer from poor immunogenicity. Thus, an antigen delivery system and adjuvants are needed to improve the immunogenicity of the two proteins. A CFP10-TB10.4 fusion protein (CT) was used as the antigen in the present study. Conjugation of 4–6 CT molecules in one entity with 8-arm polyethylene glycol (PEG) acted as an antigen delivery system. Aluminum-loxoribine mixture (A-L) and poly(I:C) functioned as the adjuvants. As compared with CT, the polymerized CT (CT-PEG) elicited significantly higher CT-specific IgG titers, higher Th1- and Th2-type cytokines and higher percentages of CD4⁺ IFN-γ⁺ and CD4⁺ IL-4⁺ cells in BALB/c mice. The presence of A-L and poly(I:C) could both increase the immune response to CT-PEG. Conjugation reaction with 8-arm PEG showed a predominant driving force to improve the immunogenicity of CT. Pharmacokinetic study in SD rats revealed that conjugation reaction with 8-arm PEG prolonged the systemic circulation of CT and exposure to the immune system. CT-PEG with A-L showed no apparent toxicity to organs, whereas CT-PEG with poly(I:C) displayed some toxicity to organs. Thus, an effective and safe vaccine against Mtb infection could be rationally designed by conjugation reaction of Mtb-secreted protein antigen with 8-arm PEG and subsequent addition of A-L.

中文翻译：

与8臂PEG的共轭反应显着提高了结核分枝杆菌CFP10-TB10.4融合蛋白的免疫原性

结核分枝杆菌（Mtb）是导致结核病（TB）的严重致命病原体。对于针对Mtb感染的免疫保护，非常需要有效的疫苗接种。CFP10和TB10.4是Mtb分泌的两种重要的免疫显性蛋白抗原，免疫原性较差。因此，需要抗原递送系统和佐剂来改善两种蛋白质的免疫原性。在本研究中，将CFP10-TB10.4融合蛋白（CT）用作抗原。一个实体中的4–6 CT分子与8臂聚乙二醇（PEG）的结合可作为抗原递送系统。铝氧氟比林混合物（AL）和聚（I：C）充当佐剂。与CT相比，聚合CT（CT-PEG）产生更高的CT特异性IgG滴度，更高的Th1-和Th2型细胞因子以及更高的CD4 ⁺百分比。BALB / c小鼠中的IFN-γ ⁺和CD4 ⁺ IL-4 ⁺细胞。AL和聚（I：C）的存在均可以增加对CT-PEG的免疫应答。与8臂PEG的缀合反应显示出主要的驱动力，以改善CT的免疫原性。在SD大鼠中进行的药代动力学研究表明，与8臂PEG的偶联反应延长了CT的全身循环并暴露于免疫系统。含AL的CT-PEG对器官无明显毒性，而含聚（I：C）的CT-PEG对器官无毒性。因此，可以通过将分泌Mtb的蛋白抗原与8臂PEG偶联反应并随后添加AL来合理设计抗Mtb感染的有效且安全的疫苗。

更新日期：2017-05-26

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