Institute for Refractory Cancer Research, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Seoul, Korea.
Cancer Res Treat. 2018 Jul;50(3):1009-1022. doi: 10.4143/crt.2017.315. Epub 2017 Nov 10.
Glioblastoma (GBM) is classified as one of the most aggressive and lethal brain tumor. Great strides have been made in understanding the genomic and molecular underpinnings of GBM, which translated into development of new therapeutic approaches to combat such deadly disease. However, there are only few therapeutic agents that can effectively inhibit GBM invasion in a clinical framework. In an effort to address such challenges, we have generated anti-SEMA3A monoclonal antibody as a potential therapeutic antibody against GBM progression.
We employed public glioma datasets, Repository of Molecular Brain Neoplasia Data and The Cancer Genome Atlas, to analyze SEMA3AmRNA expression in human GBM specimens. We also evaluated for protein expression level of SEMA3A via tissue microarray (TMA) analysis. Cell migration and proliferation kinetics were assessed in various GBM patient-derived cells (PDCs) and U87-MG cell-line for SEMA3A antibody efficacy. GBM patient-derived xenograft (PDX) models were generated to evaluate tumor inhibitory effect of anti-SEMA3A antibody in vivo.
By combining bioinformatics and TMA analysis, we discovered that SEMA3A is highly expressed in human GBM specimens compared to non-neoplastic tissues. We developed three different anti-SEMA3A antibodies, in fully human IgG form, through screening phage-displayed synthetic antibody library using a classical panning method. Neutralization of SEMA3A significantly reduced migration and proliferation capabilities of PDCs and U87-MG cell line in vitro. In PDX models, treatment with anti-SEMA3A antibody exhibited notable tumor inhibitory effect through down-regulation of cellular proliferative kinetics and tumor-associated macrophages recruitment.
In present study, we demonstrated tumor inhibitory effect of SEMA3A antibody in GBM progression and present its potential relevance as a therapeutic agent in a clinical framework.
胶质母细胞瘤（GBM）被归类为最具侵袭性和致命性的脑肿瘤之一。在理解 GBM 的基因组和分子基础方面已经取得了重大进展，这转化为开发新的治疗方法来对抗这种致命疾病。然而，在临床框架内，只有少数治疗剂能够有效地抑制 GBM 的侵袭。为了应对这些挑战，我们生成了抗 SEMA3A 单克隆抗体，作为一种针对 GBM 进展的潜在治疗性抗体。
我们使用了公共的神经胶质瘤数据集、分子脑肿瘤数据库和癌症基因组图谱，来分析人类 GBM 标本中 SEMA3A mRNA 的表达。我们还通过组织微阵列（TMA）分析评估了 SEMA3A 的蛋白表达水平。我们评估了 SEMA3A 抗体在各种 GBM 患者来源细胞（PDCs）和 U87-MG 细胞系中的细胞迁移和增殖动力学。我们生成了 GBM 患者来源异种移植（PDX）模型，以评估抗 SEMA3A 抗体在体内的肿瘤抑制作用。
通过结合生物信息学和 TMA 分析，我们发现与非肿瘤组织相比，SEMA3A 在人类 GBM 标本中高度表达。我们通过使用经典的淘选方法筛选噬菌体展示的合成抗体文库，开发了三种不同的完全人源 IgG 形式的抗 SEMA3A 抗体。SEMA3A 的中和显著降低了 PDCs 和 U87-MG 细胞系的体外迁移和增殖能力。在 PDX 模型中，抗 SEMA3A 抗体的治疗表现出显著的肿瘤抑制作用，通过下调细胞增殖动力学和肿瘤相关巨噬细胞的募集。
在本研究中，我们证明了 SEMA3A 抗体在 GBM 进展中的肿瘤抑制作用，并提出了其作为临床框架中治疗剂的潜在相关性。
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