Synthesis and Evaluation of Liposomal Anti-GM3 Cancer Vaccine Candidates Covalently and Noncovalently Adjuvanted by αGalCer
Synthesis and Evaluation of Liposomal Anti-GM3 Cancer Vaccine Candidates Covalently and Noncovalently Adjuvanted by αGalCer
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α GalCer 共价和非共价佐剂脂质体抗 GM3 癌症疫苗候选物的合成和评价
DOI：
10.1021/acs.jmedchem.0c01186
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发表时间：
2021-02-04
影响因子：
7.3
通讯作者：
Guo, Jun
中科院分区：
文献类型：
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作者：
Yin, Xu-Guang;Lu, Jie;Guo, Jun
GM3是一种典型的肿瘤相关糖类抗原，被视为癌症疫苗研发的重要靶点，但其免疫原性低限制了其应用。α-半乳糖神经酰胺（α GalCer）是一种不变自然杀伤T细胞（iNKT）激动剂，通过一种独特的免疫模式被用作佐剂。在此，我们制备并研究了两种抗肿瘤疫苗候选物：（a）通过将GM3与α GalCer偶联得到的自佐剂疫苗GM3 - α GalCer；（b）非共价疫苗GM3 - 脂质/α GalCer，其中GM3与脂质锚连接并与α GalCer共组装。这表明β - 半乳糖神经酰胺（β GalCer）是一种特别优化的脂质锚，它使非共价疫苗候选物GM3 - β GalCer/α GalCer能够引发与GM3 - α GalCer相当的抗体水平。然而，由GM3 - α GalCer诱导的抗体在识别B16F10癌细胞方面表现更好，并且能更有效地激活补体系统。我们的研究强调了在α GalCer与糖类抗原之间利用共价或非共价组装构建疫苗以及为非共价疫苗配方选择合适脂质锚的重要性。
GM3, a typical tumor-associated carbohydrate antigen, is considered as an important target for cancer vaccine development, but its low immunogenicity limits its application. alpha GalCer, an iNKT cell agonist, has been employed as an adjuvant via a unique immune mode. Herein, we prepared and investigated two types of antitumor vaccine candidates: (a) self-adjuvanting vaccine GM3-alpha GalCer by conjugating GM3 with alpha GalCer and (b) noncovalent vaccine GM3-lipid/alpha GalCer, in which GM3 is linked with lipid anchor and coassembled with alpha GalCer. This demonstrated that beta GalCer is an exceptionally optimized lipid anchor, which enables the noncovalent vaccine candidate GM3-beta GalCer/alpha GalCer to evoke a comparable antibody level to GM3-alpha GalCer. However, the antibodies induced by GM3-alpha GalCer are better at recognition B16F10 cancer cells and more effectively activate the complement system. Our study highlights the importance of vaccine constructs utilizing covalent or noncovalent assembly between alpha GalCer with carbohydrate antigens and choosing an appropriate lipid anchor for use in noncovalent vaccine formulation.