Scholarlink

<p>Ovarian cancer remains a highly lethal gynecologic malignancy with limited early detection and frequent relapse. Claudin-6 (CLDN6), minimally expressed in normal tissues but frequently upregulated in ovarian cancer, represents a promising tumor-specific target. Bispecific T-cell engagers (BiTEs) effectively redirect cytotoxic T cells toward tumor cells. However, previous studies have reported that protein-based BiTEs, particularly scFv-based constructs, may encounter challenges related to protein folding, aggregation, and in vivo stability. To address these limitations, CLDN6-nanobodies were developed through our screening platform, which display cross-species reactivity to human, murine and non-human primate CLDN6. Using this binder, we constructed CLDN6 nanobody-based BiTE (CLDN6-Nb-BiTE) encoded by self-amplifying mRNA (sa-mRNA) and delivered by lipid nanoparticles (LNPs), providing a functional alternative to protein administration. The LNP-sa-mRNA formulation was stable and uniform, enabling robust CLDN6-Nb-BiTE expression, antigen-dependent cytotoxicity, and cytokine release in vitro, while sustained CLDN6-Nb-BiTE production in vivo promoted T-cell recruitment and durable tumor control without systemic toxicity. Overall, our work introduces the first CLDN6-Nb-BiTE delivered by sa-mRNA, establishing a foundation for next-generation ovarian cancer immunotherapy.</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

A novel CLDN6 nanobody-based bispecific T-cell engager delivered by self-amplifying RNA platform exhibits potent antitumor efficacy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月25日

查看全文
  • Zhixiong Zhu,
  • Jia Li,
  • Qizhong Lu,
  • Wanqin Zeng,
  • Zhengyu Yu,
  • Nanxi Liu,
  • Zongliang Zhang,
  • Zeng Wang,
  • Nian Yang,
  • Yongdong Chen,
  • Huaqing Lu,
  • Long Xu,
  • Chunlai Nie,
  • Hexian Li,
  • Aiping Tong

摘要

Ovarian cancer remains a highly lethal gynecologic malignancy with limited early detection and frequent relapse. Claudin-6 (CLDN6), minimally expressed in normal tissues but frequently upregulated in ovarian cancer, represents a promising tumor-specific target. Bispecific T-cell engagers (BiTEs) effectively redirect cytotoxic T cells toward tumor cells. However, previous studies have reported that protein-based BiTEs, particularly scFv-based constructs, may encounter challenges related to protein folding, aggregation, and in vivo stability. To address these limitations, CLDN6-nanobodies were developed through our screening platform, which display cross-species reactivity to human, murine and non-human primate CLDN6. Using this binder, we constructed CLDN6 nanobody-based BiTE (CLDN6-Nb-BiTE) encoded by self-amplifying mRNA (sa-mRNA) and delivered by lipid nanoparticles (LNPs), providing a functional alternative to protein administration. The LNP-sa-mRNA formulation was stable and uniform, enabling robust CLDN6-Nb-BiTE expression, antigen-dependent cytotoxicity, and cytokine release in vitro, while sustained CLDN6-Nb-BiTE production in vivo promoted T-cell recruitment and durable tumor control without systemic toxicity. Overall, our work introduces the first CLDN6-Nb-BiTE delivered by sa-mRNA, establishing a foundation for next-generation ovarian cancer immunotherapy.

Graphical Abstract