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靶向 IGF-1 受体的乳腺癌相关表位在嵌合人细小病毒 B19 病毒样颗粒中的表达。

Expression of Breast Cancer-Related Epitopes Targeting the IGF-1 Receptor in Chimeric Human Parvovirus B19 Virus-Like Particles.

机构信息

Laboratorio de Inmunidad en Mucosas, Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Avenida de los Barrios 1, Los Reyes Iztacala, 54090, Tlalnepantla, Mexico.

Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Av. Universidad 3000, C.U., 04510, Mexico City, Mexico.

出版信息

Mol Biotechnol. 2019 Oct;61(10):742-753. doi: 10.1007/s12033-019-00198-y.

Abstract

Breast cancer is a worldwide health problem, and the complexity of the disease, as well as the lack of treatment specificity, generates an urgent need for developing prophylactic and therapeutic measures. Searching for novel epitope-based approaches able to induce tumour immunity, we designed virus-like particles (VLPs) derived from Human parvovirus B19 assembled of chimeric VP2 proteins displaying two epitopes from the insulin-like growth factor-1 receptor (IGF-1R). Here, we present the generation of two chimeric VP2s that retain the stability, solubility and conditions of purification and assembly of the native VP2. We generated versatile chimeric multiepitope anti-cancer vaccine candidates, which prevented and delayed tumour growth when used in a prophylactic scheme of 4 weekly immunizations prior to 4T1 cell inoculation in female BALB/c mice. The presence of specific antibodies against the displayed epitopes suggests their participation in the protective effect; in contrast, no significant proliferative T-cell responses were recorded following stimulation by specific epitopes. The results comprise an approach whereby fusing desired epitopes from cancer to the N-terminus of B19 VP2 protein can generate a library of chimeric VP2-desired epitopes for further assembly in a designed and personalized epitope delivery system.

摘要

乳腺癌是一个全球性的健康问题,由于疾病的复杂性以及缺乏治疗的特异性,因此迫切需要开发预防和治疗措施。为了寻找能够诱导肿瘤免疫的新型基于表位的方法,我们设计了源自人细小病毒 B19 的病毒样颗粒(VLPs),这些颗粒由嵌合 VP2 蛋白组装而成,这些蛋白展示了来自胰岛素样生长因子-1 受体(IGF-1R)的两个表位。在这里,我们介绍了两种嵌合 VP2 的产生,它们保留了天然 VP2 的稳定性、可溶性以及纯化和组装条件。我们生成了多功能嵌合多表位抗癌疫苗候选物,当在雌性 BALB/c 小鼠中接种 4T1 细胞之前,以每周 4 次免疫的预防性方案使用时,它们可以预防和延迟肿瘤生长。针对所展示表位的特异性抗体的存在表明它们参与了保护作用;相比之下,在用特异性表位刺激时,未记录到明显的增殖性 T 细胞反应。这些结果构成了一种方法,通过将癌症的所需表位融合到 B19 VP2 蛋白的 N 末端,可以生成嵌合 VP2-所需表位的文库,以便在设计和个性化的表位递呈系统中进一步组装。

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