Mohd Shuaib, Atul Kumar Singh, Sanjay Gupta, Abdullah F Alasmari, Flaeh Alqahtani, Shashank Kumar
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引用次数: 0
摘要
癌症的特点是基因不稳定,因为基因中的体细胞突变不断积累,从而产生新表位(突变表位),供细胞毒性 T 淋巴细胞(CTL)靶向。乳腺癌具有较高的转化率,其突变负荷和新表位的负荷构成独特,为设计基于新表位的疫苗提供了平台。由新抗原设计的基于新表位的治疗性癌症疫苗已被证明是可行的、无毒的,并且对癌症患者具有免疫原性。基于新表位的自身抗原蛋白疫苗对 CTL 的刺激在区分癌细胞和正常细胞方面起着关键作用,并且只选择性地针对恶性细胞。我们结合免疫学和生物信息学方法设计了一种基于新表位的乳腺癌疫苗。疫苗构建体由 CTL 新表位、辅助序列(用于更好地分离表位)和佐剂以及连接体融合而成。新表位是从 MUC16、TP53、RYR2、F5、DNAH17、ASPM 和 ABCA13 自身抗原蛋白的体细胞突变中鉴定出来的。对疫苗构建物进行了免疫模拟(IS)、理化特性(PP)、分子对接(MD)和模拟研究,并克隆到适当的载体中。这些参数共同确定了疫苗的安全性、稳定性以及与 I 类 MHC 分子的强结合亲和力,能够诱导针对乳腺癌细胞的完全免疫反应。
Designing of neoepitopes based vaccine against breast cancer using integrated immuno and bioinformatics approach.
Cancer is characterized by genetic instability due to accumulation of somatic mutations in the genes which generate neoepitopes (mutated epitopes) for targeting by Cytotoxic T lymphocytes (CTL). Breast cancer has a high transformation rate with unique composition of mutational burden and neoepitopes load that open a platform to designing a neoepitopes-based vaccine. Neoepitopes-based therapeutic cancer vaccines designed by neoantigens have shown to be feasible, nontoxic, and immunogenic in cancer patients. Stimulation of CTL by neoepitope-based vaccine of self-antigenic proteins plays a key role in distinguishing cancer cells from normal cells and selectively targets only malignant cells. A neoepitopes-based vaccine to combat breast cancer was designed by combining immunology and bioinformatics approaches. The vaccine construct was assembled by the fusion of CTL neoepitopes, helper sequences (used for better separation of the epitopes), and adjuvant together with linkers. The neoepitopes were identified from somatic mutations in the MUC16, TP53, RYR2, F5, DNAH17, ASPM, and ABCA13 self-antigenic proteins. The vaccine construct was undertaken to study the immune simulations (IS), physiochemical characteristics (PP), molecular docking (MD) and simulations, and cloning in appropriate vector. Together, these parameters establish safety, stability, and a strong binding affinity against class I MHC molecules capable of inducing a complete immune response against breast cancer cells.Communicated by Ramaswamy H. Sarma.
期刊介绍:
The Journal of Biomolecular Structure and Dynamics welcomes manuscripts on biological structure, dynamics, interactions and expression. The Journal is one of the leading publications in high end computational science, atomic structural biology, bioinformatics, virtual drug design, genomics and biological networks.