Keshtvarz Maryam, Salimian Jafar, Amani Jafar, Douraghi Masoumeh, Rezaie Ehsan
Division of Microbiology, Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
In Silico Pharmacol. 2021 Feb 10;9(1):19. doi: 10.1007/s40203-021-00079-w. eCollection 2021.
Today, the targeted therapies like the use of immunotoxins are increased which targeted specific antigens or receptors on the surface of tumor cells. Fibroblast growth factor-inducible 14 (Fn14) is a cytokine receptor which involves several intercellular signaling pathways and can be highly expressed in the surface of cancer cells. Since the cleavage of enzymatic domain of (PE) occurs in one step by furin protease, we fused enzymatic subunit of Shiga-like toxin type 2a (Stx2a) with domain II and a portion of Ib of PE to increase the toxicity of Stx. Then, we genetically fused the Fv fragment of an anti-Fn14 monoclonal antibody (P4A8) to STX2a-PE15 and evaluated the STX2a-PE15-P4A8 chimeric protein as a new immunotoxin candidate. In silico analysis showed that the STX2a-PE15-P4A8 is a stable chimeric protein with high affinity to the Fn14 receptor. Despite, the STX2a-PE15-P4A8 can be bind to the B cell receptor, but it has been weakly presented by major histocompatibility complex molecules II (MHC-II). So, it may have a little immunogenicity. On the basis of our in-silico studies we predict that STX2a-PE15-P4A8 can be a good candidate for cancer immunotherapy.
The online version contains supplementary material available at 10.1007/s40203-021-00079-w.
如今，诸如使用免疫毒素之类的靶向疗法有所增加，这些疗法靶向肿瘤细胞表面的特定抗原或受体。成纤维细胞生长因子诱导蛋白14（Fn14）是一种细胞因子受体，涉及多种细胞内信号通路，并且在癌细胞表面可高度表达。由于（PE）酶结构域的切割由弗林蛋白酶一步完成，我们将2a型志贺样毒素（Stx2a）的酶亚基与PE的结构域II和Ib的一部分融合，以增加Stx的毒性。然后，我们将抗Fn14单克隆抗体（P4A8）的Fv片段基因融合到STX2a-PE15上，并评估STX2a-PE15-P4A8嵌合蛋白作为一种新型免疫毒素候选物。计算机模拟分析表明，STX2a-PE15-P4A8是一种稳定的嵌合蛋白，对Fn14受体具有高亲和力。尽管STX2a-PE15-P4A8可以与B细胞受体结合，但它由主要组织相容性复合体分子II（MHC-II）呈递的能力较弱。因此，它可能具有较低的免疫原性。基于我们的计算机模拟研究，我们预测STX2a-PE15-P4A8可能是癌症免疫治疗的良好候选物。
在线版本包含可在10.1007/s40203-021-00079-w获取的补充材料。
