Fully synthetic Tn-based three-component cancer vaccine using covalently linked TLR4 ligand MPLA and iNKT cell agonist KRN-7000 as built-in adjuvant effectively protects mice from tumor development.
Fully synthetic Tn-based three-component cancer vaccine using covalently linked TLR4 ligand MPLA and iNKT cell agonist KRN-7000 as built-in adjuvant effectively protects mice from tumor development.
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DOI：
10.1016/j.apsb.2022.05.028
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发表时间：
2022-12
影响因子：
14.5
通讯作者：
Liao, Guochao
中科院分区：
文献类型：
--
作者：
Yang, Deying;Luo, Xiang;Lian, Qinghai;Gao, Lingqiang;Wang, Chengxin;Qi, Xiaoxiao;Zhang, Rong;Liu, Zhongqiu;Liao, Guochao
我们提出了一种以不同类型的共价连锁免疫刺激剂作为载体分子的自佐剂疫苗开发新策略。以Tn抗原为模型，设计合成了含有TLR4配体MPLA和iNKT细胞激动剂KRN7000的三组分疫苗（MPLA-Tn-KRN7000）。这将使用单一载体的完全合成自佐剂疫苗研究扩展到使用两种不同类型载体的研究。同时合成相应的双组分结合疫苗Tn-MPLA、Tn-KRN7000和Tn-CRM197作为对照。免疫学评价发现，MPLA-Tn-KRN7000可引发强大的n特异性和T细胞依赖性免疫。抗体特异性识别，结合并表现出对n阳性癌细胞的补体依赖性细胞毒性。此外，MPLA-Tn-KRN7000增加了肿瘤攻击小鼠的存活率和生存时间，存活的小鼠在没有任何额外治疗的情况下拒绝进一步的肿瘤攻击。与糖蛋白疫苗Tn-CRM197、双组分结合疫苗Tn-MPLA和Tn-KRN7000以及Tn-MPLA和Tn-KRN7000的物理混合疫苗相比，MPLA-Tn-KRN7000在体外和体内均表现出最强的抗肿瘤效果。通过对野生型和TLR4敲除小鼠的免疫学研究比较，以及对CD1d蛋白的结合亲和性测试表明，共价连接的MPLA-KRN7000免疫刺激剂可诱导TLR4和iNKT细胞的协同活化，从而提高Tn的免疫原性。这一工作表明，MPLA-Tn-KRN7000具有成为候选疫苗的潜力，为全合成疫苗设计提供了新的方向。提出了一种构建自佐剂抗肿瘤疫苗的新策略。由此产生的三组分疫苗引发了强烈的体液和细胞免疫反应，并保护小鼠免受肿瘤的发展。
We present a new strategy for self-adjuvanting vaccine development that has different types of covalently-linked immunostimulants as the carrier molecule. Using Tn antigen as the model, a three-component vaccine (MPLA-Tn-KRN7000) containing the TLR4 ligand MPLA and the iNKT cell agonist KRN7000 was designed and synthesized. This expands fully synthetic self-adjuvanting vaccine studies that use a single carrier to one with two different types of carriers. The corresponding two-component conjugate vaccines Tn-MPLA, Tn-KRN7000 and Tn-CRM197 were also synthesized, as controls. The immunological evaluation found that MPLA-Tn-KRN7000 elicits robust Tn-specific and T cell-dependent immunity. The antibodies specifically recognized, bound to and exhibited complement-dependent cytotoxicity against Tn-positive cancer cells. In addition, MPLA-Tn-KRN7000 increased the survival rate and survival time of tumor-challenged mice, and surviving mice reject further tumor attacks without any additional treatment. Compared to the glycoprotein vaccine Tn-CRM197, the two-component conjugate vaccines, Tn-MPLA and Tn-KRN7000, and the physical mixture of Tn-MPLA and Tn-KRN7000, MPLA-Tn-KRN7000 showed the most effect at combating tumor cells both in vitro and in vivo. The comparison of immunological studies in wild-type and TLR4 knockout mice, along with the test of binding affinity to CD1d protein suggests that the covalently linked MPLA-KRN7000 immunostimulant induces a synergistic activation of TLR4 and iNKT cell that improves the immunogenicity of Tn. This work demonstrates that MPLA-Tn-KRN7000 has the potential to be a vaccine candidate and provides a new direction for fully synthetic vaccine design. A new strategy to construct self-adjuvanting antitumor vaccine was developed. The resulting three-component vaccine elicited strong humoral and cellular immune responses, and protected mice from tumor development.
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DOI：
10.1097/cji.0b013e3181b56af4
发表时间：
2010-01
期刊：
Journal of immunotherapy (Hagerstown, Md. : 1997)
影响因子：
--
作者：
Liu P;Jaffar J;Hellstrom I;Hellstrom KE
通讯作者：
Hellstrom KE
影响因子：
3.1
作者：
Chao, Chin-Sheng;Chen, Min-Chun;Mong, Kwok-Kong T.
通讯作者：
Mong, Kwok-Kong T.
影响因子：
4.3
作者：
Buskas, T;Li, YH;Boons, GJ
通讯作者：
Boons, GJ
影响因子：
7.3
作者：
Broecker, Felix;Goetze, Sebastian;Seeberger, Peter H.
通讯作者：
Seeberger, Peter H.
DOI：
10.3390/molecules23071583
发表时间：
2018-06-29
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Li Q;Guo Z
通讯作者：
Guo Z