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Self-adjuvanting cancer vaccines from conjugation-ready lipid A analogues and synthetic long peptides.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-09-22 , DOI: 10.1021/acs.jmedchem.0c00851 Niels R M Reintjens 1 , Elena Tondini 2 , Ana R de Jong 1 , Nico J Meeuwenoord 1 , Fabrizio Chiodo 1, 3 , Evert Peterse 1 , Herman S Overkleeft 1 , Dmitri V Filippov 1 , Gijsbert A van der Marel 1 , Ferry Ossendorp 2 , Jeroen D C Codée 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-09-22 , DOI: 10.1021/acs.jmedchem.0c00851 Niels R M Reintjens 1 , Elena Tondini 2 , Ana R de Jong 1 , Nico J Meeuwenoord 1 , Fabrizio Chiodo 1, 3 , Evert Peterse 1 , Herman S Overkleeft 1 , Dmitri V Filippov 1 , Gijsbert A van der Marel 1 , Ferry Ossendorp 2 , Jeroen D C Codée 1
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Self-adjuvanting vaccines, wherein an antigenic peptide is covalently bound to an immunostimulating agent, have been shown to be promising tools for immunotherapy. Synthetic Toll-like receptor (TLR) ligands are ideal adjuvants for covalent linking to peptides or proteins. We here introduce a conjugation-ready TLR4 ligand, CRX-527, a potent powerful lipid A analogue, in the generation of novel conjugate-vaccine modalities. Effective chemistry has been developed for the synthesis of the conjugation-ready ligand as well as the connection of it to the peptide antigen. Different linker systems and connection modes to a model peptide were explored, and in vitro evaluation of the conjugates showed them to be powerful immune-activating agents, significantly more effective than the separate components. Mounting the CRX-527 ligand at the N-terminus of the model peptide antigen delivered a vaccine modality that proved to be potent in activation of dendritic cells, in facilitating antigen presentation, and in initiating specific CD8+ T-cell-mediated killing of antigen-loaded target cells in vivo. Synthetic TLR4 ligands thus show great promise in potentiating the conjugate vaccine platform for application in cancer vaccination.
中文翻译：
自缀合脂质A类似物和合成长肽的自佐剂癌症疫苗。
抗原肽与免疫刺激剂共价结合的自佐剂疫苗已被证明是用于免疫疗法的有前途的工具。合成的Toll样受体（TLR）配体是与肽或蛋白质共价连接的理想佐剂。在此，我们在新型偶联物-疫苗形式的产生中，引入了偶联准备就绪的TLR4配体CRX-527，一种有效的强大脂质A类似物。已经开发了用于结合准备的配体的合成以及其与肽抗原的连接的有效化学。探索了不同的接头系统和模型肽的连接模式，并在体外对缀合物的评估显示它们是强大的免疫激活剂，比单独的成分更有效。将CRX-527配体安装在模型肽抗原的N末端可提供一种疫苗形式，该疫苗形式被证明可有效激活树突状细胞，促进抗原呈递以及启动特异性CD8 + T细胞介导的抗原杀伤体内加载的靶细胞。因此，合成的TLR4配体在增强缀合疫苗平台用于癌症疫苗接种中显示出巨大的希望。
更新日期：2020-10-22
中文翻译：
自缀合脂质A类似物和合成长肽的自佐剂癌症疫苗。
抗原肽与免疫刺激剂共价结合的自佐剂疫苗已被证明是用于免疫疗法的有前途的工具。合成的Toll样受体（TLR）配体是与肽或蛋白质共价连接的理想佐剂。在此，我们在新型偶联物-疫苗形式的产生中，引入了偶联准备就绪的TLR4配体CRX-527，一种有效的强大脂质A类似物。已经开发了用于结合准备的配体的合成以及其与肽抗原的连接的有效化学。探索了不同的接头系统和模型肽的连接模式，并在体外对缀合物的评估显示它们是强大的免疫激活剂，比单独的成分更有效。将CRX-527配体安装在模型肽抗原的N末端可提供一种疫苗形式，该疫苗形式被证明可有效激活树突状细胞，促进抗原呈递以及启动特异性CD8 + T细胞介导的抗原杀伤体内加载的靶细胞。因此，合成的TLR4配体在增强缀合疫苗平台用于癌症疫苗接种中显示出巨大的希望。
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