Scholarlink

Background <p>Glioblastoma is the most aggressive primary brain tumor, and, despite intensive studies, remains one of the most fatal malignancy in adult humans. Among multiple onco-promoters produced by glioblastoma cells, erythropoietin was found. However, the presence/function of Epo alternatively spliced variants in cancer remains unexplored. Here, we investigated the expression and role of Epo-variants in glioblastoma, and the therapeutic potential of their targeting through a novel monoclonal antibody (mAb).</p> Methods <p>Transcripts and protein levels of Epo-variants in a cohort of human brain tumors were evaluated by RT-PCR, ELISA, and immunohistochemistry. Monoclonal antibodies targeting Epo-Vs were prepared and functionally selected by assaying proliferation, migration, stemness, and angiogenesis in glioblastoma patient-derived cells. Antibody affinity for Epo/Epo-variant was determined by SPR. In vivo toxicity and therapeutic efficacy of the lead antibody were evaluated in GBM mouse models.</p> Results <p>We found a significant overexpression of Epo-variant transcripts in tissues and cells from GBM patients. After functional selection of newly-produced antibodies, we identified AND-C4 as the lead one for its potent anti-tumoral properties, absence of anti-erythropoietic effects and of toxicity on human brain cells. AND-C4 exhibited high affinity for the Epo-variant EV-3. We demonstrated that EV-3 was efficiently produced and secreted by glioblastoma cells, particularly by stem cells. EV-3 exerted tumorigenic, angiogenic and immunomodulatory properties, and AND-C4 was effective in antagonizing all these actions. In vivo studies in rodent glioblastoma models revealed that AND-C4 selectively bound to tumor tissue and exhibited significant efficacy on tumor growth and animal survival.</p> Conclusion <p>This study represents the first evidence on the presence, origin and pro-tumoral activity of EV-3 in human glioblastoma. Moreover, in vitro and in vivo results revealed AND-C4 as novel and promising anti-glioblastoma immunotherapeutic.</p> Graphical Abstract <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Revealing erythropoietin variant EV-3 as novel driving force and immunotherapeutic target in human glioblastoma

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月26日

查看全文
  • Stefania Elena Navone,
  • Giovanni Marfia,
  • Laura Guarnaccia,
  • Massimiliano Rizzaro,
  • Giorgio Fiore,
  • Rolando Campanella,
  • Chiara Gaudino,
  • Daniele Santini,
  • Giovanni Andrea Alotta,
  • Monica Rosa Miozzo,
  • Emanuela Barilla,
  • Marco Locatelli,
  • Laura Riboni

摘要

Background

Glioblastoma is the most aggressive primary brain tumor, and, despite intensive studies, remains one of the most fatal malignancy in adult humans. Among multiple onco-promoters produced by glioblastoma cells, erythropoietin was found. However, the presence/function of Epo alternatively spliced variants in cancer remains unexplored. Here, we investigated the expression and role of Epo-variants in glioblastoma, and the therapeutic potential of their targeting through a novel monoclonal antibody (mAb).

Methods

Transcripts and protein levels of Epo-variants in a cohort of human brain tumors were evaluated by RT-PCR, ELISA, and immunohistochemistry. Monoclonal antibodies targeting Epo-Vs were prepared and functionally selected by assaying proliferation, migration, stemness, and angiogenesis in glioblastoma patient-derived cells. Antibody affinity for Epo/Epo-variant was determined by SPR. In vivo toxicity and therapeutic efficacy of the lead antibody were evaluated in GBM mouse models.

Results

We found a significant overexpression of Epo-variant transcripts in tissues and cells from GBM patients. After functional selection of newly-produced antibodies, we identified AND-C4 as the lead one for its potent anti-tumoral properties, absence of anti-erythropoietic effects and of toxicity on human brain cells. AND-C4 exhibited high affinity for the Epo-variant EV-3. We demonstrated that EV-3 was efficiently produced and secreted by glioblastoma cells, particularly by stem cells. EV-3 exerted tumorigenic, angiogenic and immunomodulatory properties, and AND-C4 was effective in antagonizing all these actions. In vivo studies in rodent glioblastoma models revealed that AND-C4 selectively bound to tumor tissue and exhibited significant efficacy on tumor growth and animal survival.

Conclusion

This study represents the first evidence on the presence, origin and pro-tumoral activity of EV-3 in human glioblastoma. Moreover, in vitro and in vivo results revealed AND-C4 as novel and promising anti-glioblastoma immunotherapeutic.

Graphical Abstract