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Background <p>Connexin (Cx) hemichannels (HCs) contribute to glioblastoma (GBM) progression by facilitating intercellular communication and releasing pro-tumorigenic molecules, including ATP and glutamate.</p> Methods <p>The efficacy of abEC1.1, a monoclonal antibody that inhibits Cx26, Cx30, and Cx32 HCs, was assessed in vitro by measuring invasion capability, dye and Ca<sup>2+</sup> uptake, glutamate and ATP release in patient-derived GBM cultures or organoids. Adeno-associated virus (AAV)-mediated antibody gene delivery, or convection-enhanced delivery (CED) of the purified antibody, was used in vivo to test the effect on tumor growth and animal survival, using a syngeneic GBM mouse model. The ability of the antibody to affect glioma-related hyperexcitability was evaluated by patch-clamp recordings in a 2D co-culture model comprising astrocytes and neurons isolated from mouse hippocampi, seeded with GL261 cells.</p> Results <p>abEC1.1 suppressed GBM cell invasion, reducing gliotransmitter release, and impairing tumor progression. In patient-derived GBM cultures, abEC1.1 significantly decreased cell migration and ATP/glutamate release. In vivo, AAV-mediated antibody gene delivery or CED of the purified antibody reduced tumor burden and prolonged survival in the GL261 syngeneic mouse model of GBM. Furthermore, abEC1.1 mitigated glioma-induced excitatory synaptic activity in the 2D co-culture model, suggesting a dual role in tumor control and hyperexcitability suppression.</p> Conclusions <p>Our findings establish Cx HC inhibition as a promising therapeutic avenue in GBM and highlight abEC1.1 as a potential candidate for clinical translation.</p>

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Connexin hemichannel blockade by abEC1.1 disrupts glioblastoma progression, suppresses invasiveness, and reduces hyperexcitability in preclinical models

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月2日

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  • Viola Donati,
  • Chiara Di Pietro,
  • Luca Persano,
  • Elena Rampazzo,
  • Mariateresa Panarelli,
  • Clara Cambria,
  • Anna Selimi,
  • Lorenzo Manfreda,
  • Ana Gabriela de Oliveira do Rêgo,
  • Gina La Sala,
  • Camilla Sprega,
  • Arianna Calistri,
  • Catalin Dacian Ciubotaru,
  • Guang Yang,
  • Francesco Zonta,
  • Flavia Antonucci,
  • Daniela Marazziti,
  • Fabio Mammano

摘要

Background

Connexin (Cx) hemichannels (HCs) contribute to glioblastoma (GBM) progression by facilitating intercellular communication and releasing pro-tumorigenic molecules, including ATP and glutamate.

Methods

The efficacy of abEC1.1, a monoclonal antibody that inhibits Cx26, Cx30, and Cx32 HCs, was assessed in vitro by measuring invasion capability, dye and Ca2+ uptake, glutamate and ATP release in patient-derived GBM cultures or organoids. Adeno-associated virus (AAV)-mediated antibody gene delivery, or convection-enhanced delivery (CED) of the purified antibody, was used in vivo to test the effect on tumor growth and animal survival, using a syngeneic GBM mouse model. The ability of the antibody to affect glioma-related hyperexcitability was evaluated by patch-clamp recordings in a 2D co-culture model comprising astrocytes and neurons isolated from mouse hippocampi, seeded with GL261 cells.

Results

abEC1.1 suppressed GBM cell invasion, reducing gliotransmitter release, and impairing tumor progression. In patient-derived GBM cultures, abEC1.1 significantly decreased cell migration and ATP/glutamate release. In vivo, AAV-mediated antibody gene delivery or CED of the purified antibody reduced tumor burden and prolonged survival in the GL261 syngeneic mouse model of GBM. Furthermore, abEC1.1 mitigated glioma-induced excitatory synaptic activity in the 2D co-culture model, suggesting a dual role in tumor control and hyperexcitability suppression.

Conclusions

Our findings establish Cx HC inhibition as a promising therapeutic avenue in GBM and highlight abEC1.1 as a potential candidate for clinical translation.