Chiloscyllium plagiosum 抗人血管内皮生长因子受体 2 单域抗体的筛选和抗血管生成活性

IF 3.4 3区 医学 Q3 IMMUNOLOGY Clinical and experimental immunology Pub Date : 2024-10-16 DOI:10.1093/cei/uxae060
Yanwen Guo, Ruiqi Wang, Yun Wang, Feijian Zheng, Jianqing Chen, Zhengbing Lyu, Chen Yuan, Lili Liu, Xiaofeng Jiang
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引用次数: 0

摘要

近来,恶性肿瘤的发病率呈上升趋势,寻找新的治疗方法已成为研究的重点。阻断血管内皮生长因子(VEGF)及其受体(VEGFR)是开发特定抗血管生成药物的治疗策略之一。组织穿透性和亲和力成熟度方面的缺陷成为这些药物在抗肿瘤应用中的弱点。鹅掌楸中发现的单重链抗体分子量低,可变区(VNARs)的组织穿透性强,被认为具有较高的抗原结合活性和稳定性。这类抗体结构简单,可以原核表达,易于生产新型抗血管生成靶向药物。特异性抗 IgNAR 兔多抗已被用于评估鲨鱼体内的 VNAR 水平,结果显示三联免疫后 IgNAR 显著富集。使用抗血管内皮生长因子受体2噬菌体文库进行靶向VNARs筛选,随后通过噬菌体筛选获得了五个候选VNARs序列,再与转录组文库进行联合筛选,分析保守区域并建立三维模型,结果与VNAR概况相匹配。ELISA 和基于细胞的检测表明,其中两个 VNARs(VNAR-A6 和 VNAR-E3)具有卓越的抗原亲和力和抗血管生成活性,因此能够抑制人脐静脉内皮细胞的增殖和迁移。这些抗血管内皮生长因子受体2(anti-VEGFR2)VNARs来源于免疫接种的鹅掌楸,并通过噬菌体文库进行了筛选,为新药开发提供了新的研究思路和特异性方法。抗血管内皮生长因子受体2(VEGFR2)VNARs能够阻断血管内皮生长因子-血管内皮生长因子受体通路,有助于扩大抗血管生成药物的应用范围。
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Screening and anti-angiogenesis activity of Chiloscyllium plagiosum anti-human VEGFR2 single-domain antibody.

Recently, the incidence of malignant tumors is on the rise and searching for new treatments on it has become the research priority. Blocking the vascular endothelial growth factor (VEGF) and its receptor (VEGFR) is one of the treatment strategies that used in the development of specific anti-angiogenic drugs. The deficiencies in tissue penetration and affinity maturation become the weakness of these drugs in anti-tumors applications. The single heavy chain antibody found in Chiloscyllium plagiosum, which has a low molecular weight and superior tissue penetration of variable region (variable new antigen receptor, VNARs), was considered to have the high antigen-binding activity and stability. This type of antibody has a simple structure that can be prokaryoticaly expressed, which makes it easily to produce new antiangiogenic target drugs. Specific anti-IgNAR rabbit multiple antibodies have been used to assess the level of VNARs in sharks and have shown a significant enrichment of IgNAR after triple immunization. An anti-VEGFR2 phage library was used for the targeted VNARs screening, and five candidate VNARs sequences were subsequently obtained by phage screening, followed by combined screening with the transcriptome library, and analysis of conserved regions along with 3D modelling matched the VNAR profile. ELISA and cell-based assays showed that two of the VNARs, VNAR-A6, and VNAR-E3, had a superior antigen affinity and anti-angiogenic activity thereby being able to inhibit human Umbilical Vein Endothelial Cells proliferation and migration. The anti-VEGFR2 VNARs derived from the immunized C. plagiosum and screened by phage library, which provide the new research ideas and specific approaches for the development of new drugs. The anti-VEGFR2 VNARs are capable for blocking the VEGF-VEGFR pathway, which of these may contribute to expanding the use of anti-angiogenic drugs.

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来源期刊
CiteScore
8.40
自引率
2.20%
发文量
101
审稿时长
3-8 weeks
期刊介绍: Clinical & Experimental Immunology (established in 1966) is an authoritative international journal publishing high-quality research studies in translational and clinical immunology that have the potential to transform our understanding of the immunopathology of human disease and/or change clinical practice. The journal is focused on translational and clinical immunology and is among the foremost journals in this field, attracting high-quality papers from across the world. Translation is viewed as a process of applying ideas, insights and discoveries generated through scientific studies to the treatment, prevention or diagnosis of human disease. Clinical immunology has evolved as a field to encompass the application of state-of-the-art technologies such as next-generation sequencing, metagenomics and high-dimensional phenotyping to understand mechanisms that govern the outcomes of clinical trials.
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